Sean Mackey, M.D., Ph.D.

All Publications

• Stanford pragmatic effectiveness comparison (SPEC) protocol: Comparing long-term effectiveness of high-frequency and burst spinal cord stimulation in real-world application. Contemporary clinical trials Petrou, P. A., Leong, M. S., Mackey, S. C., Salmasi, V. 2021: 106324

  Abstract

  OBJECTIVES: High-frequency and burst stimulation are newer waveforms that have demonstrated promise compared to traditional tonic spinal cord stimulation (SCS), but more studies are needed to compare their effectiveness. We report the study methods for an ongoing, single center, pragmatic randomized clinical trial to compare the effectiveness of high-frequency and burst SCS in patients with chronic back and/or leg pain.MATERIALS AND METHODS: Participants who are candidates for spinal cord stimulation are enrolled and screened. Participants will be randomly assigned using point-of-care randomization to receive either high-frequency or burst SCS. Data collection will be through Stanford Pain Management Center's learning healthcare system: CHOIR. CHOIR surveys include National Institutes of Health Patient Reported Outcomes Measurement Information System item banks, a body map, questions about pain intensity, pain catastrophizing scale, and questions about patients' pain experience and healthcare utilization. Participants will complete online surveys at baseline and then 1, 3, 6, 12, 18, 24 and 36 months after their device implant. All participants will use our routine process of trial and implant. Reported adverse events are monitored throughout the study. Our primary outcome is change from baseline in pain intensity at 12 months.RESULTS: We hypothesize that high-frequency SCS is more effective than burst SCS in improving pain, physical function and pain interference in participants with chronic low back and/or leg pain.CONCLUSIONS: The pragmatic nature of our proposed trial enables us to recruit a larger participant cohort faster and to follow up these participants longer than currently published clinical trials.

  View details for DOI 10.1016/j.cct.2021.106324

  View details for PubMedID 33621631

• Development and validation of the Collaborative Health Outcomes Information Registry body map. Pain reports Scherrer, K. H., Ziadni, M. S., Kong, J., Sturgeon, J. A., Salmasi, V., Hong, J., Cramer, E., Chen, A. L., Pacht, T., Olson, G., Darnall, B. D., Kao, M., Mackey, S. 2021; 6 (1): e880

  Abstract

  Introduction: Critical for the diagnosis and treatment of chronic pain is the anatomical distribution of pain. Several body maps allow patients to indicate pain areas on paper; however, each has its limitations.Objectives: To provide a comprehensive body map that can be universally applied across pain conditions, we developed the electronic Collaborative Health Outcomes Information Registry (CHOIR) self-report body map by performing an environmental scan and assessing existing body maps.Methods: After initial validation using a Delphi technique, we compared (1) pain location questionnaire responses of 530 participants with chronic pain with (2) their pain endorsements on the CHOIR body map (CBM) graphic. A subset of participants (n = 278) repeated the survey 1 week later to assess test-retest reliability. Finally, we interviewed a patient cohort from a tertiary pain management clinic (n = 28) to identify reasons for endorsement discordances.Results: The intraclass correlation coefficient between the total number of body areas endorsed on the survey and those from the body map was 0.86 and improved to 0.93 at follow-up. The intraclass correlation coefficient of the 2 body map graphics separated by 1 week was 0.93. Further examination demonstrated high consistency between the questionnaire and CBM graphic (<10% discordance) in most body areas except for the back and shoulders (15-19% discordance). Participants attributed inconsistencies to misinterpretation of body regions and laterality, the latter of which was addressed by modifying the instructions.Conclusions: Our data suggest that the CBM is a valid and reliable instrument for assessing the distribution of pain.

  View details for DOI 10.1097/PR9.0000000000000880

  View details for PubMedID 33490848

• The problem of pain in lupus: an explication of the role of biopsychosocial mechanisms. The Journal of rheumatology Falasinnu, T., Drenkard, C., Bao, G., Mackey, S., Lim, S. S. 2020

  Abstract

  OBJECTIVE: To define biopsychosocial mechanisms of pain that go above and beyond disease activity and organ damage in systemic lupus erythematosus (SLE).METHODS: We conducted a cross-sectional analysis of patient-reported data in a population-based registry of 766 people with SLE. Predictors of pain intensity and interference were examined using hierarchical linear regression. We built two main hierarchical regression models: pain intensity regressed on disease activity and organ damage; and pain interference regressed on disease activity and organ damage. For each model, we sought to establish the relationship between pain outcomes and the primary exposures using sequential steps comprising the inclusion of each construct in six stages: demographic, socioeconomic, physical, psychological, behavioral and social factors. We also conducted sensivity analyses eliminating all overt aspects of pain in the disease activity measure and reestimated the models.RESULTS: Disease activity and organ damage explained 32-33% of the variance in pain intensity and interference. Sociodemographic factors accounted for an additional 4-9% of variance in pain outcomes, while psychosocial/behavioral factors accounted for the final 4% of variance. In the sensitivity analyses, we found that disease activity and organ damage explained 25% of the variance in pain outcomes.CONCLUSION: Disease activity only explained 33% of the variance of pain outcomes. However, there was an attenuation in these associations after accounting for psychosocial/behavioral factors, highlighting their roles in modifying the relationship between disease activity and pain. These findings suggest that multilevel interventions may be needed to tackle the negative impact of pain in SLE.

  View details for DOI 10.3899/jrheum.200595

  View details for PubMedID 33262298

• Efficacy of motivational-interviewing and guided opioid tapering support for patients undergoing orthopedic surgery (MI-Opioid Taper): A prospective, assessor-blind, randomized controlled pilot trial. EClinicalMedicine Hah, J. M., Trafton, J. A., Narasimhan, B., Krishnamurthy, P., Hilmoe, H., Sharifzadeh, Y., Huddleston, J. I., Amanatullah, D., Maloney, W. J., Goodman, S., Carroll, I., Mackey, S. C. 2020; 28: 100596

  Abstract

  Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia.Methods: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003.Findings: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06-2.46; p=003). No trial-related adverse events occurred.Interpretation: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation.Funding: National Institute on Drug Abuse.

  View details for DOI 10.1016/j.eclinm.2020.100596

  View details for PubMedID 33294812

• Brain Strength: Multi-Modal Brain MRI Predicts Grip Strength Weber, K. A., Wager, T. D., Upadhyayula, P. A., Law, C. S., Ashar, Y. K., Prabhakar, N. K., Zhu, S., Gilam, G., Banerjee, S., Delp, S. L., Glover, G. H., Hastie, T. J., Mackey, S. WILEY. 2020: S223–S224

  View details for Web of Science ID 000572509100411

• Assessing the Spatial Distribution of Cervical Spinal Cord Activity during Tactile Stimulation of the Upper Extremity in Humans with Functional Magnetic Resonance Imaging. NeuroImage Weber, K. A., Chen, Y., Paliwal, M., Law, C. S., Hopkins, B. S., Mackey, S., Dhaher, Y., Parrish, T. B., Smith, Z. A. 2020: 116905

  Abstract

  Dermatomal maps are a mainstay of clinical practice and provide information on the spatial distribution of the cutaneous innervation of spinal nerves. Dermatomal deficits can help isolate the level of spinal nerve root involvement in spinal conditions and guide clinicians in diagnosis and treatment. Dermatomal maps, however, have limitations, and the spatial distribution of spinal cord sensory activity in humans remains to be quantitatively assessed. Here we used spinal cord functional MRI to map and quantitatively compare the spatial distribution of sensory spinal cord activity during tactile stimulation of the left and right lateral shoulders (i.e. C5 dermatome) and dorsal third digits of the hands (i.e., C7 dermatome) in healthy humans (n = 24, age = 36.0 ± 11.8 years). Based on the central sites for processing of innocuous tactile sensory information, we hypothesized that the activity would be localized more to the ipsilateral dorsal spinal cord with the lateral shoulder stimulation activity being localized more superiorly than the dorsal third digit. The findings demonstrate lateralization of the activity with the left- and right-sided stimuli having more activation in the ipsilateral hemicord. Contradictory to our hypotheses, the activity for both stimulation sites was spread across the dorsal and ventral hemicords and did not demonstrate a clear superior-inferior localization. Instead, the activity for both stimuli had a broader than expected distribution, extending across the C5, C6, and C7 spinal cord segments. We highlight the complexity of the human spinal cord neuroanatomy and several sources of variability that may explain the observed patterns of activity. While the findings were not completely consistent with our a priori hypotheses, this study provides a foundation for continued work and is an important step towards developing normative quantitative spinal cord measures of sensory function, which may become useful objective MRI-based biomarkers of neurological injury and improve the management of spinal disorders.

  View details for DOI 10.1016/j.neuroimage.2020.116905

  View details for PubMedID 32387628

• PERCEIVED INJUSTICE MEDIATES THE RELATIONSHIP BETWEEN CHILDHOOD NEGLECT AND CURRENT FUNCTION IN PATIENTS WITH CHRONIC PAIN Ziadni, M., You, D. S., Mackey, S., Darnall, B. D. OXFORD UNIV PRESS INC. 2020: S92

  View details for Web of Science ID 000546262400190

• ASSOCIATION BETWEEN PAIN CATASTROPHIZING AND FREQUENT CRAVING FOR PRESCRIPTION OPIOIDS IN PATIENTS WITH CHRONIC PAIN You, D. S., Ziadni, M., Hah, J., Darnall, B. D., Mackey, S. OXFORD UNIV PRESS INC. 2020: S89

  View details for Web of Science ID 000546262400184

• Clinical Profiles of Concurrent Cannabis Use in Chronic Pain: A CHOIR Study. Pain medicine (Malden, Mass.) Sturgeon, J. A., Khan, J., Hah, J. M., Hilmoe, H., Hong, J., Ware, M. A., Mackey, S. C. 2020

  Abstract

  OBJECTIVE: Despite evidence of the analgesic benefits of cannabis, there remains a relative scarcity of research on the short- and long-term effects of cannabis use in individuals with chronic pain.DESIGN: The current study is a secondary analysis of clinical data from the Collaborative Health Outcomes Information Registry (CHOIR).SETTING: Data were drawn from a cohort of patients of a multidisciplinary tertiary care pain clinic.SUBJECTS: The study sample consisted of data from 7,026 new patient visits from CHOIR; of these, 1,668 patients with a follow-up time point within 180days were included in a longitudinal analysis.METHODS: Clinical data were analyzed to characterize cross-sectional differences in pain and indicators of psychological and physical function according to self-reported, concurrent cannabis use. Additionally, a propensity score-weighted longitudinal analysis was conducted, examining cannabis use as a predictor of changes in clinical variables across time.RESULTS: Cross-sectional analyses suggested significantly poorer sleep and significantly higher intensities of pain, emotional distress, and physical and social dysfunction in patients reporting ongoing cannabis use; however, these differences were relatively small in magnitude. However, no differences between cannabis users and nonusers in terms of longitudinal changes in clinical variables were noted.DISCUSSION: Our results are among the first to examine concurrent cannabis use as a prognostic variable regarding trajectories of pain-related variables in tertiary care. Future studies may benefit from examining the effect of cannabis initiation, concurrent medication use, and specific aspects of cannabis use (dose, duration of use, or cannabis type) on clinical outcomes.

  View details for DOI 10.1093/pm/pnaa060

  View details for PubMedID 32232476

• The Decline in Task Performance After Witnessing Rudeness Is Moderated by Emotional Empathy-A Pilot Study. Frontiers in psychology Gilam, G., Horing, B., Sivan, R., Weinman, N., Mackey, S. C. 2020; 11: 1584

  Abstract

  Rude behaviors engulf societies across the world on a daily basis. Witnessing rudeness toward others increases negative affect and decreases performance in various tasks requiring behavioral and cognitive efforts, such as solving word puzzles or creative and flexible thinking. In this pilot study, we examined whether different levels of emotional empathy that may influence susceptibility to others' distress, moderated the declined performance in several such tasks. The study was conducted online as a naturalistic setting for witnessing movie-clips portraying rudeness. We hypothesized that all participants will demonstrate decreased task performance following a rude compared to a neutral condition, but more so for those higher on emotional empathy. Results confirmed each of these hypotheses in one of two different cognitive tasks. Findings suggest that after witnessing rudeness, those higher on emotional empathy perform worse in cognitive tasks. While requiring replication in a larger sample size, empathic processing seems to be a potential moderator of the effect of rudeness on task performance.

  View details for DOI 10.3389/fpsyg.2020.01584

  View details for PubMedID 32733343

  View details for PubMedCentralID PMC7358519

• Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nature reviews. Neurology Davis, K. D., Aghaeepour, N., Ahn, A. H., Angst, M. S., Borsook, D., Brenton, A., Burczynski, M. E., Crean, C., Edwards, R., Gaudilliere, B., Hergenroeder, G. W., Iadarola, M. J., Iyengar, S., Jiang, Y., Kong, J. T., Mackey, S., Saab, C. Y., Sang, C. N., Scholz, J., Segerdahl, M., Tracey, I., Veasley, C., Wang, J., Wager, T. D., Wasan, A. D., Pelleymounter, M. A. 2020

  Abstract

  Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

  View details for DOI 10.1038/s41582-020-0362-2

  View details for PubMedID 32541893

• Efficacy and mechanisms of a single-session behavioral medicine class among patients with chronic pain taking prescription opioids: study protocol for a randomized controlled trial. Trials Ziadni, M. S., Chen, A. L., Winslow, T., Mackey, S. C., Darnall, B. D. 2020; 21 (1): 521

  Abstract

  Independent of pain intensity, pain-specific distress is highly predictive of pain treatment needs, including the need for prescription opioids. Given the inherently distressing nature of chronic pain, there is a need to equip individuals with pain education and self-regulatory skills that are shown to improve adaptation and improve their response to medical treatments. Brief, targeted behavioral medicine interventions may efficiently address the key individual factors, improve self-regulation in the context of pain, and reduce the need for opioid therapy. This highlights the critical need for targeted, cost-effective interventions that efficiently address the key psychological factors that can amplify the need for opioids and increased risk for misuse. In this trial, the primary goal is to test the comparative efficacy of a single-session skills-based pain management class to a health education active control group among patients with chronic pain who are taking opioids.Our study is a randomized, double-blind clinical trial testing the superiority of our 2-h, single-session skills-based pain management class against a 2-h health education class. We will enroll 136 adult patients with mixed-etiology chronic pain who are taking opioid prescription medication and randomize 1:1 to one of the two treatment arms. We hypothesize superiority for the skills-based pain class for pain control, self-regulation of pain-specific distress, and reduced opioid use measured by daily morphine equivalent. Team researchers masked to treatment assignment will assess outcomes up to 12 months post treatment.This study aims to test the utility of a single-session, 2-h skills-based pain management class to improve self-regulation of pain and reduce opioid use. Findings from our project have the potential to shift current research and clinical paradigms by testing a brief and scalable intervention that could reduce the need for opioids and prevent misuse effectively, efficiently, and economically. Further, elucidation of the mechanisms of opioid use can facilitate refinement of more targeted future treatments.ClinicalTrials.gov, ID: NCT03950791. Registered on 10 May 2019.

  View details for DOI 10.1186/s13063-020-04415-x

  View details for PubMedID 32532346

• Effect of Electroacupuncture vs Sham Treatment on Change in Pain Severity Among Adults With Chronic Low Back Pain: A Randomized Clinical Trial. JAMA network open Kong, J. T., Puetz, C., Tian, L., Haynes, I., Lee, E., Stafford, R. S., Manber, R., Mackey, S. 2020; 3 (10): e2022787

  Abstract

  Chronic low back pain has high societal and personal impact but remains challenging to treat. Electroacupuncture has demonstrated superior analgesia compared with placebo in animal studies but has not been extensively studied in human chronic pain conditions.To evaluate the treatment effect of real electroacupuncture vs placebo in pain and disability among adults with chronic low back pain and to explore psychophysical, affective, and demographic factors associated with response to electroacupuncture vs placebo in treating chronic low back pain.This double-blind randomized clinical trial was conducted between August 2, 2016, and December 18, 2018, at a single center in Stanford, California. Primary outcomes were collected at approximately 2 weeks before and after intervention. Participants included English-speaking adults with at least 6 months of chronic low back pain, pain intensity of at least 4 on a scale of 0 to 10, and no radiculopathy. Data analyses for this intent-to-treat study were conducted from June 2019 to June 2020.Twelve sessions of real or placebo (sham) electroacupuncture administered twice a week over 6 weeks.The main outcome was change in pain severity from baseline to 2 weeks after completion of treatment, measured by the National Institutes of Health PROMIS pain intensity scale. A secondary outcome was change in the Roland Morris Disability Questionnaire (RMDQ). Baseline factors potentially associated with these outcomes included psychophysical testing (ie, thermal temporal summation, conditioned pain modulation, pressure pain threshold), participant's self-report (ie, widespread pain, coping strategies, expectations, self-efficacy, and pain catastrophizing), and demographic characteristics (eg, age, sex, and race).A total of 121 adults were recruited to the study, among whom 59 participants (mean [SD] age, 46.8 [11.9] years; 36 [61.0%] women) were randomized to real electroacupuncture and 62 participants (mean [SD] age, 45.6 [12.8] years; 33 [53.2%] women) were randomized to sham electroacupuncture. At baseline, the mean (SD) PROMIS T-score was 50.49 (3.36) in the real electroacupuncture group and 51.71 (4.70) in the sham acupuncture group, and the mean (SD) RMDQ score was 10.16 (4.76) in the real electroacupuncture group and 10.03 (5.45) in the sham acupuncture group. After adjusting for baseline pain scores, there was no statistically significant difference between groups in change in T-scores 2 weeks after completion of treatment (real electroacupuncture: -4.33; 95% CI, -6.36 to -2.30; sham acupuncture: -2.90; 95% CI, -4.85 to -0.95; difference: -2.09; 95% CI, -4.27 to 0.09; P = .06). After adjusting for baseline RMDQ, there was a significantly greater reduction in RMDQ in the real electroacupuncture group (-2.77; 95% CI, -4.11 to -1.43) compared with the sham electroacupuncture group (-0.67; 95% CI, -1.88 to 0.55; difference: -2.11; 95% CI, -3.75 to -0.47; P = .01). Within the real electroacupuncture group, effective coping at baseline was associated with greater RMDQ reduction (r = -0.32; 95% CI, -0.54 to -0.05; P = .02), and White race was associated with worse outcomes in PROMIS score (β = 3.791; 95% CI, 0.616 to 6.965; P = .02) and RMDQ (β = 2.878; 95% CI, 0.506 to 5.250; P = .02).This randomized clinical trial found no statistically significant difference in change in PROMIS pain score in real electroacupuncture vs sham electroacupuncture. There was a statistically significant treatment effect for the secondary outcome of RMDQ compared with sham electroacupuncture. Effective coping skills and non-White race were associated with response to electroacupuncture.ClinicalTrials.gov Identifier: NCT02890810.

  View details for DOI 10.1001/jamanetworkopen.2020.22787

  View details for PubMedID 33107921

• AAAPT Diagnostic Criteria for Acute Low Back Pain with and Without Lower Extremity Pain. Pain medicine (Malden, Mass.) Nicol, A. L., Adams, M. C., Gordon, D. B., Mirza, S., Dickerson, D., Mackey, S., Edwards, D., Hurley, R. W. 2020

  Abstract

  Low back pain is one of the most common reasons for which people visit their doctor. Between 12% and 15% of the US population seek care for spine pain each year, with associated costs exceeding $200 billion. Up to 80% of adults will experience acute low back pain at some point in their lives. This staggering prevalence supports the need for increased research to support tailored clinical care of low back pain. This work proposes a multidimensional conceptual taxonomy.A multidisciplinary task force of the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) with clinical and research expertise performed a focused review and analysis, applying the AAAPT five-dimensional framework to acute low back pain.Application of the AAAPT framework yielded the following: 1) Core Criteria: location, timing, and severity of acute low back pain were defined; 2) Common Features: character and expected trajectories were established in relevant subgroups, and common pain assessment tools were identified; 3) Modulating Factors: biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: domains of impact were outlined and defined; 5) Neurobiological Mechanisms: putative mechanisms were specified including nerve injury, inflammation, peripheral and central sensitization, and affective and social processing of acute low back pain.The goal of applying the AAAPT taxonomy to acute low back pain is to improve its assessment through a defined evidence and consensus-driven structure. The criteria proposed will enable more rigorous meta-analyses and promote more generalizable studies of interindividual variation in acute low back pain and its potential underlying mechanisms.

  View details for DOI 10.1093/pm/pnaa239

  View details for PubMedID 32914195

• The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS). Neurourology and urodynamics Clemens, J. Q., Kutch, J. J., Mayer, E. A., Naliboff, B. D., Rodriguez, L. V., Klumpp, D. J., Schaeffer, A. J., Kreder, K. J., Clauw, D. J., Harte, S. E., Schrepf, A. D., Williams, D. A., Andriole, G. L., Lai, H. H., Buchwald, D., Lucia, M. S., van Bokhoven, A., Mackey, S., Moldwin, R. M., Pontari, M. A., Stephens-Shields, A. J., Mullins, C., Landis, J. R. 2020

  Abstract

  The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments.This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol.Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing.This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.

  View details for DOI 10.1002/nau.24423

  View details for PubMedID 32578257

• Self-reported traumatic etiology of pain and psychological function in tertiary care pain clinic patients: a collaborative health outcomes information registry (CHOIR) study. Scandinavian journal of pain Taub, C. J., Sturgeon, J. A., Chahal, M. K., Kao, M. C., Mackey, S. C., Darnall, B. D. 2020

  Abstract

  Background and aims A sizable body of research has elucidated the significant role of psychological reactions to trauma on pain coping and outcomes. In order to best inform intervention development and clinical care for patients with both trauma and pain at the tertiary care level, greater clarity is needed regarding the magnitude of these effects and the specific pathways through which they may or may not function at the time of first presentation to such a treatment setting. To achieve this, the current study examined the cross-sectional relationships between traumatic etiology of pain, psychological distress (anger, depressive symptoms, and PTSD symptoms), and pain outcomes (pain catastrophizing, physical function, disability status). Methods Using a structural path modeling approach, analyses were conducted using a large sample of individuals with chronic pain (n = 637) seeking new medical evaluation at a tertiary pain management center, using the Collaborative Health Outcomes Information Registry (CHOIR). We hypothesized that the relationships between traumatic etiology of pain and poorer pain outcomes would be mediated by higher levels of psychological distress. Results Our analyses revealed modest relationships between self-reported traumatic etiology of pain and pain catastrophizing, physical function, and disability status. In comparison, there were stronger relationships between indices of psychological distress and pain catastrophizing, but a weaker pattern of associations between psychological distress and physical function and disability measures. Conclusions To the relatively small extent that self-reported traumatic etiology of pain correlates with pain-related outcomes, these relationships appear to be due primarily to the presence of psychiatric symptoms and manifest most notably in the context of psychological responses to pain (i.e. catastrophizing about pain). Implications Findings from this study highlight the need for early intervention for patients with traumatic onset of pain and for clinicians at tertiary pain centers to include more detailed assessments of psychological distress and trauma as a component of comprehensive chronic pain treatment.

  View details for DOI 10.1515/sjpain-2019-0154

  View details for PubMedID 32191626

• Magnetization Transfer Ratio and Morphometrics Of the Spinal Cord Associates with Surgical Recovery in Patients with Degenerative Cervical Myelopathy. World neurosurgery Paliwal, M., Weber, K. A., Hopkins, B. S., Cantrell, D. R., Hoggarth, M. A., Elliott, J. M., Dahdaleh, N. S., Mackey, S., Parrish, T. D., Dhaher, Y., Smith, Z. A. 2020

  Abstract

  Longitudinal Cohort Study OBJECTIVES: To assess prognostic value of pre-surgical Magnetization Transfer Ratio (MTR) and morphometrics of the spinal cord in patients with Degenerative Cervical Myelopathy (DCM).Thirteen subjects with DCM underwent 3T magnetization transfer imaging. MTR was calculated for spinal cord regions and specific white matter tracts. Morphometric measures were extracted. Clinical (modified Japanese orthopedics Association (mJOA) and Nurick) and health related quality of life scores were assessed before and after cervical decompression surgery. Association between MRI metrics and post- surgical recovery was assessed (Spearman's correlation). Receiver operator characteristics (ROC) assessed the accuracy of MRI metrics in identifying at least 50% recovery in function.Preoperative anterior cord MTR were associated with recovery in mJOA scores (ρ =0.608, p=0.036 and AUC =0.66). Preoperative lateral cord MTR was correlated with neck disability index (ρ =0.699, p=0.011) and pain interference (ρ =0.732, p=0.007). Preoperative rubrospinal tract MTR was associated mJOA score recovery (ρ =0.573, p=0.041, AUC= 0.86). Preoperative corticospinal tract and reticulospinal MTR were related to recovery in pain interference scores (ρ =0.591, p=0.033 and ρ =0.583, p=0.035). Eccentricity of the cord was associated with Nurick scores (ρ = 0.606, p=0.028) and mJOA (ρ =0.651, p=0.025, AUC=0.92).Preoperative MTR and eccentricity measurements of the spinal cord have prognostic value in assessing response to surgery and recovery in patient with DCM. Advanced MRI and atlas-based post processing techniques can inform interventions and advance healthcare received by patients with DCM.

  View details for DOI 10.1016/j.wneu.2020.09.148

  View details for PubMedID 33010502

• Baseline Characteristics of a Dyadic Cohort of Mothers with Chronic Pain and Their Children. The Clinical journal of pain Wilson, A. C., Stone, A. L., Poppert Cordts, K. M., Holley, A. L., Mackey, S., Darnall, B. D., Palermo, T. M. 2020

  Abstract

  A growing body of research has demonstrated a robust link between parental chronic pain and child pain and psychological function. Although the association between parent and child pain is strong, there are limited data to understand environmental and behavioral processes that account for the association and how this develops over time. This longitudinal cohort study was designed to understand potential mechanisms that confer risk or resilience for chronic pain among child offspring of mothers with chronic pain.The current paper presents baseline data on the cohort to describe pain and psychosocial characteristics of mothers with chronic pain and their 8-12-year old children. 400 mothers with chronic pain and their children were enrolled into the longitudinal study and completed measures of pain, physical, and psychosocial functioning.Mothers reported a range of pain and pain-related disability, and were grouped into four pain grades representing different pain and disability levels. Mothers in these groups differed on rates of widespread pain and opioid use. Maternal pain grades also differed by physical function, fatigue, sleep disturbance, and psychological function. Most children in this sample reported pain and psychosocial symptoms in the non-clinical range, and child variables did not differ by maternal pain grade. Maternal disability and function were concurrently associated with child psychosocial function.While maternal pain grades map broadly onto several dimensions of maternal functioning, they were not significantly related to child pain or function. Results may help identify potential protective factors in the intergenerational transmission of risk for chronic pain.

  View details for DOI 10.1097/AJP.0000000000000864

  View details for PubMedID 32701524

• Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial. Journal of pain research Hah, J. M., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Hernandez Boussard, T., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2020; 13: 2959–70

  Abstract

  Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016).Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

  View details for DOI 10.2147/JPR.S269370

  View details for PubMedID 33239904

  View details for PubMedCentralID PMC7680674

• Perceived Injustice Mediates the Relationship Between Perceived Childhood Neglect and Current Function in Patients with Chronic Pain: A Preliminary Pilot Study. Journal of clinical psychology in medical settings Ziadni, M. S., You, D. S., Sturgeon, J. A., Mackey, S. C., Darnall, B. D. 2020

  Abstract

  Cumulative evidence supports the association between perceived childhood neglect and adulthood psychological and physical health. To date, pathways mediating this association remain largely unknown, though other evidence suggests that negative patterns of appraisal, including injustice perception related to pain, may be shaped by prior adverse social experiences. Consequently, the current study examined perceived injustice about chronic pain as a possible factor connecting childhood neglect and pain-related outcomes, given its relevance for both adaptation to chronic pain and to prior adverse life experiences. Patients (n = 742) visiting a tertiary pain clinic completed a survey administered via the Collaborative Health Outcomes Information Registry. Path modeling analyses were used to examine perceived injustice as a mediator of the relationships between childhood neglect and affective distress and physical function, after controlling for pain intensity and pain catastrophizing. Patients endorsing childhood neglect reported higher levels of perceived injustice and worse affective distress and physical function. Further, inclusion of perceived injustice as a mediator fully accounted for the relationship between neglect and current levels of physical function, and accounted for a significant proportion of the relationship between neglect and current levels of affective distress. These preliminary findings suggest that perceived injustice appears to be a more proximal factor by which prior experiences of neglect may adversely affect adaptation to chronic pain. Given the single-item assessment of childhood neglect and cross-sectional nature of the current findings, further research may focus on replicating these findings in longitudinal studies with validated measures and examining other adverse social experiences (e.g., abuse, social disparities) that may contribute to injustice perception and poor pain-related outcomes.

  View details for DOI 10.1007/s10880-020-09722-8

  View details for PubMedID 32382872

• What Is the Relationship between Pain and Emotion? Bridging Constructs and Communities. Neuron Gilam, G., Gross, J. J., Wager, T. D., Keefe, F. J., Mackey, S. C. 2020

  Abstract

  Although pain is defined as a sensory and emotional experience, it is traditionally researched and clinically treated separately from emotion. Conceptual and mechanistic relationships between these constructs highlight the need for better understanding of their bi-directional influences and the value of bridging the pain and emotion research and clinical communities.

  View details for DOI 10.1016/j.neuron.2020.05.024

  View details for PubMedID 32562660

• Resting State Functional Connectivity Machine Learning Classification of Chronic Back Pain Weber, K. A., Law, C. S., Asher, Y. K., Martucci, K. T., Gilam, G., Lewis, B., Narayan, S., Hastie, T., Wager, T. D., Mackey, S. WILEY. 2019: S266

  View details for Web of Science ID 000488891800418

• Evaluation of the Preliminary Validity of Misuse of Prescription Pain Medication Items from the Patient-Reported Outcomes Measurement Information System (PROMIS)(R) PAIN MEDICINE You, D., Hah, J. M., Collins, S., Ziadni, M. S., Domingue, B. W., Cook, K. F., Mackey, S. C. 2019; 20 (10): 1925–33

  View details for DOI 10.1093/pm/pnz001

  View details for Web of Science ID 000498052000007

• Implementation Challenges Using a Novel Method for Collecting Patient-Reported Outcomes After Injury JOURNAL OF SURGICAL RESEARCH Rosenberg, G. M., Shearer, E. J., Zion, S. R., Mackey, S. C., Morris, A. M., Spain, D. A., Weiser, T. G. 2019; 241: 277–84

  View details for DOI 10.1016/j.jss.2019.04.008

  View details for Web of Science ID 000471137000039

• Acyloxyacyl hydrolase modulates depressive-like behaviors through aryl hydrocarbon receptor AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Aguiniga, L. M., Yang, W., Yaggie, R. E., Schaeffer, A. J., Klumpp, D. J., Clemens, J., Hanno, P., Kirkali, Z., Kusek, J. W., Landis, J., Lucia, M., Moldwin, R. M., Mullins, C., Pontari, M. A., van Bokhoven, A., Osypuk, A. A., Dayton, R., Triolo, C. S., Jonscher, K. R., Sullivan, H. T., Wilson, R., Grasmick, Z. D., Bavendam, T. G., Barrell, T., Doe, R., Farrar, J. T., Fernando, M., Gallagher, L., Hou, X., Howard, T., Jemielita, T., Kuzla, N., Newcomb, C., Robinson-Garvin, N., Smith, S., Stephens-Shields, A., Wang, Y., Wang, X., (Vania) Apkarian, A., Arroyo, C., Bass, M., Cella, D., Farmer, M. A., Fitzgerald, C., Gershon, R., Griffith, J. W., Heckman, C. J., Jiang, M., Keefer, L., Lloyd, R., Marko, D. S., Michniewicz, J., Miller, R., Parrish, T., Tu, F., Yaggi, R., Mayer, E. A., Rodriguez, L., Alger, J., Ashe-McNalley, C. P., Ellingson, B., Heendeniya, N., Kilpatrick, L., Cara, K., Kutch, J., Labus, J. S., Naliboff, B. D., Randal, F., Smith, S. R., Kreder, K. J., Bradley, C. S., Eno, M., Greiner, K., Luo, Y., Lutgendorf, S. K., O'Donnell, M. A., Ziegler, B., Schrepf, A., Hardy, I., Magnotta, V., Erickson, B., Clauw, D. J., As-Sanie, S., Berry, S., Grayhack, C., Halvorson, M. E., Harris, R., Harte, S., Ichesco, E., Oldendorf, A., Scott, K. A., Williams, D. A., Buchwald, D., Afari, N., Bacus, T., Edwards, T., Krieger, J., Maravilla, K., Miller, J., Patrick, D., Qin, X., Richey, S., Risques, R., Robertson, K., Ross, S. O., Spiro, R., Strachan, E., Sundsvold, T. J., Sutherland, S., Yang, C. C., Andriole, G. L., Lai, H., Bristol, R. L., Gereau, R. W., Hong, B. A., Klim, A. P., Sutcliffe, S., Vetter, J., Song, D. G., Milbrandt, M., Haroutounian, S., Vijairania, P., Parker (Chaturvedi), K., Hung, T., Colditz, G., Gardner, V. C., Henderson, J. P., Spitznagle, T. M., Pakpahan, R., James, A., Yan, Y., Langston, M., Hong, B., Mueller, S., Crowley, J., Vogt, S., Hultgren, S., Nguyen, N., Blasche, G., Qiu, C., Cupps, L., Bok, S., Hooten, T. M., Grullon, L., Atis, N., Ness, T. J., Deutsch, G., Den Hollander, J., Corbitt, B. D., Bradley, L., North, C. S., Downs, D., Anger, J., Ackerman, J., Ackerman, A., Cha, J., Eilber, K., Freeman, M., Funari, V., Kim, J., Van Eyk, J., Yang, W., Moses, M. A., Briscoe, A. C., Briscoe, D., Curatolo, A., Froehlich, J., Lee, R. S., Sachdev, M., Solomon, K. R., Steen, H., Mackey, S., Bagarinao, E., Foster, L. C., Hubbard, E., Johnson, K. A., Martucci, K. T., McCue, R. L., Moericke, R. R., Nilakantan, A., Noor, N., Nickel, J., Ehrlich, G. D., MAPP Res Network Study Grp 2019; 317 (2): R289–R300

  Abstract

  Corticotropin-releasing factor (CRF) regulates stress responses, and aberrant CRF signals are associated with depressive disorders. Crf expression is responsive to arachidonic acid (AA), where CRF is released from the hypothalamic paraventricular nucleus (PVN) to initiate the hypothalamic-pituitary-adrenal axis, culminating in glucocorticoid stress hormone release. Despite this biological and clinical significance, Crf regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by Aoah, is expressed in the PVN, and Aoah regulates Crf through the aryl hydrocarbon receptor (AhR). We previously showed that AOAH-deficient mice mimicked interstitial cystitis/bladder pain syndrome, a condition frequently associated with comorbid anxiety and depression. With the use of novelty-suppressed feeding and sucrose preference assays to quantify rodent correlates of anxiety/depression, AOAH-deficient mice exhibited depressive behaviors. AOAH-deficient mice also had increased CNS AA, increased Crf expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human Crf promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPARγ). PPARγ did not affect AA-dependent Crf expression in vitro, and conditional Pparγ knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPARγ as a therapeutic target for depression. In contrast, Crf induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional Ahr knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that Aoah is a novel genetic regulator of Crf mediated through AhR, and AhR is a therapeutic target for depression.

  View details for DOI 10.1152/ajpregu.00029.2019

  View details for Web of Science ID 000481616900008

  View details for PubMedID 31017816

• Neuroimmune modulation of pain across the developmental spectrum CURRENT OPINION IN BEHAVIORAL SCIENCES Karshikoff, B., Tadros, M., Mackey, S., Zouikr, I. 2019; 28: 85–92

  View details for DOI 10.1016/j.cobeha.2019.01.010

  View details for Web of Science ID 000482197800015

• Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter, Factorial, Randomized, Controlled Pilot Trial JOURNAL OF PAIN Khan, J. S., Hodgson, N., Choi, S., Reid, S., Paul, J. E., Hong, N., Holloway, C., Busse, J. W., Gilron, I., Buckley, D., McGillion, M., Clarke, H., Katz, J., Mackey, S., Avram, R., Pohl, K., Rao-Melacini, P., Devereaux, P. J. 2019; 20 (8): 980–93

  View details for DOI 10.1016/j.jpain.2019.02.010

  View details for Web of Science ID 000482544600011

• Adult Cancer Pain, Version 3.2019 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Swarm, R. A., Paice, J. A., Anghelescu, D. L., Are, M., Bruce, J., Buga, S., Chwistek, M., Cleeland, C., Craig, D., Gafford, E., Greenlee, H., Hansen, E., Kamal, A. H., Kamdar, M. M., LeGrand, S., Mackey, S., McDowell, M., Moryl, N., Nabell, L. M., Nesbit, S., O'Connor, N., Rabow, M. W., Rickerson, E., Shatsky, R., Sindt, J., Urba, S. G., Youngwerth, J. M., Hammond, L. J., Gurski, L. A. 2019; 17 (8): 977–1007

  Abstract

  In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.

  View details for DOI 10.6004/jnccn.2019.0038

  View details for Web of Science ID 000487240600012

  View details for PubMedID 31390582

• Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine. Pain reports Mackey, S., Greely, H. T., Martucci, K. T. 2019; 4 (4): e762

  Abstract

  One of the key ambitions of neuroimaging-based pain biomarker research is to augment patient and clinician reporting of clinically relevant phenomena with neural measures for prediction, prognosis, and detection of pain. Despite years of productive research on the neuroimaging of pain, such applications have seen little advancement. However, recent developments in identifying brain-based biomarkers of pain through advances in technology and multivariate pattern analysis provide some optimism. Here, we (1) define and review the different types of potential neuroimaging-based biomarkers, their clinical and research applications, and their limitations and (2) describe frameworks for evaluation of pain biomarkers used in other fields (eg, genetics, cancer, cardiovascular disease, immune system disorders, and rare diseases) to achieve broad clinical and research utility and minimize the risks of misapplication of this emerging technology. To conclude, we discuss future directions for neuroimaging-based biomarker research to achieve the goal of personalized pain medicine.

  View details for DOI 10.1097/PR9.0000000000000762

  View details for PubMedID 31579854

• Response to BotulinumtoxinA in a migraine cohort with multiple comorbidities and widespread pain. Regional anesthesia and pain medicine Barad, M., Sturgeon, J. A., Fish, S., Dexter, F., Mackey, S., Flood, P. D. 2019; 44 (6): 660–68

  Abstract

  BACKGROUND: The phase III research evaluating migraine prophylaxis therapy (PREEMPT) protocol was developed in low-risk migraine patients. We studied longitudinal response to treatment in a sequential retrospective observational cohort to evaluate predictors of effectiveness in patients with multiple overlapping pain syndromes treated in a quaternary pain management clinic.METHODS: We evaluated indicators of individual response in 402 consecutive chronic migraine patients who provided demographic information and used the Collaborative Health Outcomes Information Registry.RESULTS: The patients were middle aged 47 (38-56) median (IQR) years old and 83% women. They reported multiple complex pain problems with 11 (6-18) regions represented on a pain body map. Evaluated with National Institutes of Health Patient-Reported Outcomes Measurement Information System measures, they reported higher scores for sleep impairment and disturbance, anxiety, depression, fatigue, pain behavior, pain interference and worse function and satisfaction with social roles compared with the general US population; p<0.001for all domains. Within 120days of treatment, 62% of patients reported reduced headache frequency. The best multivariable model developed for prediction of reduced headache frequency in response to treatment included lower treatment number, lower pain interference score, and less depression (p=0.001, 0.002, and 0.009). Depression may have been an obstacle to successful treatment; there was no association between depression score and number of treatments (p=0.54).CONCLUSIONS: Our findings point to the importance of identifying and addressing pain interference and depression early in chronic migraine management and, more broadly, highlights the importance of multidisciplinary evaluation and treatment in chronic migraine.

  View details for DOI 10.1136/rapm-2018-100196

  View details for PubMedID 31101743

• Optimization of DNA extraction from human urinary samples for mycobiome community profiling PLOS ONE Ackerman, A., Anger, J., Khalique, M., Ackerman, J. E., Tang, J., Kim, J., Underhill, D. M., Freeman, M. R., Clemens, J., Hanno, P., Kirkali, Z., Kusek, J. W., Landis, J., Lucia, M., Moldwin, R. M., Mullins, C., Pontari, M. A., Lucia, M., van Bokhoven, A., Osypuk, A. A., Dayton, R., Triolo, C. S., Jonscher, K. R., Sullivan, H. T., Wilson, R., Grasmick, Z. D., Mullins, C., Kusek, J. W., Kirkali, Z., Bavendam, T. G., Landis, J., Barrell, T., Doe, R., Farrar, J. T., Fernando, M., Gallagher, L., Hanno, P., Hou, X., Howard, T., Jemielita, T., Kuzla, N., Moldwin, R. M., Newcomb, C., Pontari, M. A., Robinson-Garvin, N., Smith, S., Stephens-Shields, A., Wang, Y., Wang, X., Klumpp, D. J., Schaeffer, A. J., Apkarian, A., Arroyo, C., Bass, M., Cella, D., Farmer, M. A., Fitzgerald, C., Gershon, R., Griffith, J. W., Heckman, C. J., Jiang, M., Keefer, L., Lloyd, R., Marko, D. S., Michniewicz, J., Miller, R., Parrish, T., Tu, F., Yaggi, R., Mayer, E. A., Rodriguez, L. V., Alger, J., Ashe-McNalley, C. P., Ellingson, B., Heendeniya, N., Kilpatrick, L., Cara, K., Kutch, J., Labus, J. S., Naliboff, B. D., Randal, F., Smith, S. R., Kreder, K. J., Bradley, C. S., Eno, M., Greiner, K., Luo, Y., Lutgendorf, S. K., O'Donnell, M. A., Ziegler, B., Schrepf, A., Hardy, I., Magnotta, V., Clauw, D. J., Clemens, J., As-Sanie, S., Berry, S., Grayhack, C., Halvorson, M. E., Harris, R., Harte, S., Ichesco, E., Oldendorf, A., Scott, K. A., Williams, D. A., Buchwald, D., Afari, N., Bacus, T., Edwards, T., Krieger, J., Maravilla, K., Miller, J., Patrick, D., Qin, X., Richey, S., Risques, R., Robertson, K., Ross, S. O., Spiro, R., Strachan, E., Sundsvold, T. J., Sutherland, S., Yang, C. C., Andriole, G. L., Lai, H., Bristol, R. L., Gereau, R. W., Hong, B. A., Klim, A. P., Sutcliffe, S., Vetter, J., Song, D. G., Milbrandt, M., Haroutounian, S., Vijairania, P., Parker (Chaturvedi), K., Tran Hung, Colditz, G., Gardner, V. C., Henderson, J. P., Spitznagle, T. M., Pakpahan, R., James, A., Yan, Y., Langston, M., Hong, B., Mueller, S., Crowley, J., Vogt, S., Hultgren, S., Nang Nguyen, Blasche, G., Qiu, C., Cupps, L., Bok, S., Hooten, T. M., Grullon, L., Atis, N., Ness, T. J., Deutsch, G., Den Hollander, J., Corbitt, B. D., Bradley, L., North, C. S., Downs, D., Anger, J., Ackerman, J., Ackerman, A., Cha, J., Eilber, K., Freeman, M., Funari, V., Kim, J., Van Eyk, J., Yang, W., Moses, M. A., Briscoe, A. C., Briscoe, D., Curatolo, A., Froehlich, J., Lee, R. S., Sachdev, M., Solomon, K. R., Steen, H., Mackey, S., Bagarinao, E., Foster, L. C., Hubbard, E., Johnson, K. A., Martucci, K. T., Mccue, R. L., Moericke, R. R., Nilakantan, A., Noor, N., Nickel, J., Ehrlich, G. D., NIH Multidisciplinary Approach Stu 2019; 14 (4): e0210306

  Abstract

  Recent data suggest the urinary tract hosts a microbial community of varying composition, even in the absence of infection. Culture-independent methodologies, such as next-generation sequencing of conserved ribosomal DNA sequences, provide an expansive look at these communities, identifying both common commensals and fastidious organisms. A fundamental challenge has been the isolation of DNA representative of the entire resident microbial community, including fungi.We evaluated multiple modifications of commonly-used DNA extraction procedures using standardized male and female urine samples, comparing resulting overall, fungal and bacterial DNA yields by quantitative PCR. After identifying protocol modifications that increased DNA yields (lyticase/lysozyme digestion, bead beating, boil/freeze cycles, proteinase K treatment, and carrier DNA use), all modifications were combined for systematic confirmation of optimal protocol conditions. This optimized protocol was tested against commercially available methodologies to compare overall and microbial DNA yields, community representation and diversity by next-generation sequencing (NGS).Overall and fungal-specific DNA yields from standardized urine samples demonstrated that microbial abundances differed significantly among the eight methods used. Methodologies that included multiple disruption steps, including enzymatic, mechanical, and thermal disruption and proteinase digestion, particularly in combination with small volume processing and pooling steps, provided more comprehensive representation of the range of bacterial and fungal species. Concentration of larger volume urine specimens at low speed centrifugation proved highly effective, increasing resulting DNA levels and providing greater microbial representation and diversity.Alterations in the methodology of urine storage, preparation, and DNA processing improve microbial community profiling using culture-independent sequencing methods. Our optimized protocol for DNA extraction from urine samples provided improved fungal community representation. Use of this technique resulted in equivalent representation of the bacterial populations as well, making this a useful technique for the concurrent evaluation of bacterial and fungal populations by NGS.

  View details for DOI 10.1371/journal.pone.0210306

  View details for Web of Science ID 000465519100004

  View details for PubMedID 31022216

  View details for PubMedCentralID PMC6483181

• Aberrant Functional Connectivity of the Dorsolateral Prefrontal Cortex and the Insula During Cognitive Control in Chronic Low Back Pain Patients on Opioids Jarrahi, B., Mackey, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965906177

• Multivariate Pattern Analysis of Emotion Regulation in Opioid-Dependent and Opioid-Naive Chronic Pain Patients Jarrahi, B., Mackey, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965902003

• Electronic Patient-Reported Outcomes: Semi-Automated Data Collection in the Interventional Radiology Clinic JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Hoang, N. S., Hwang, W., Katz, D. A., Mackey, S. C., Hofmann, L. 2019; 16 (4): 472–77

  View details for DOI 10.1016/j.jacr.2018.08.033

  View details for Web of Science ID 000464627700012

• A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network JOURNAL OF CLINICAL MEDICINE Nickel, J., Stephens-Shields, A. J., Landis, J., Mullins, C., van Bokhoven, A., Lucia, M., Henderson, J. P., Sen, B., Krol, J. E., Ehrlich, G. D., Clemens, J., Hanno, P., Kirkali, Z., Kusek, J. W., Pontari, M. A., Klumpp, D. J., Schaeffer, A. J., Apkarian, A., Cella, D., Farmer, M. A., Fitzgerald, C., Gershon, R., Griffith, J. W., Heckman, C. J., Jiang, M., Keefer, L., Marko, D. S., Michniewicz, J., Parrish, T., Tu, F., Mayer, E. A., Rodriguez, L., Alger, J., Ashe-McNalley, C. P., Ellingson, B., Heendeniya, N., Kilpatrick, L., Kutch, J., Labus, J. S., Naliboff, B. D., Randal, F., Smith, S. R., Kreder, K. J., Bradley, C. S., Eno, M., Greiner, K., Luo, Y., Lutgendorf, S. K., O'Donnell, M. A., Ziegler, B., Clauw, D. J., As-Sanie, S., Berry, S., Halvorson, M. E., Harris, R., Harte, S., Ichesco, E., Oldendorf, A., Scott, K. A., Williams, D. A., Buchwald, D., Afari, N., Krieger, J., Miller, J., Richey, S., Ross, S. O., Spiro, R., Sundsvold, T. J., Strachan, E., Yang, C. C., Andriole, G. L., Lai, H., Bristol, R. L., Colditz, G., Deutsch, G., Gardner, V. C., Gereau, R. W., Hong, B. A., Hooton, T. M., Ness, T. J., North, C. S., Spitznagle, T. M., Sutcliffe, S., Barrell, T., Creighton, T., Fluharty, L., Hou, X., Robinson, N., Stephens, A., Wang, Y., Osypuk, A. A., Dayton, R., Jonscher, K. R., Sullivan, H. T., Wilson, R., Moses, M. A., Briscoe, A. C., Briscoe, D., Curatolo, A., Froehlich, J., Lee, R. S., Sachdev, M., Solomon, K. R., Steen, H., Mackey, S., Bagarinao, E., Foster, L. C., Hubbard, E., Johnson, K. A., Martucci, K. T., McCue, R. L., Moericke, R. R., Nilakantan, A., Noor, N., Bavendam, T. G., MAPP Res Network 2019; 8 (3)

  Abstract

  We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level (p = 0.726 species level, p = 0.222 genus level). IC/BPS participants urine trended to an overabundance of Lactobacillus gasseri (p = 0.09) detected but had a lower prevalence of Corynebacterium compared with control participants (p = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than Lactobacillus gasseri and Corynebacterium (p = 0.08 and p = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.

  View details for DOI 10.3390/jcm8030415

  View details for Web of Science ID 000464435800001

  View details for PubMedID 30917614

  View details for PubMedCentralID PMC6462969

• Evaluation of the Preliminary Validity of Misuse of Prescription Pain Medication Items from the Patient-Reported Outcomes Measurement Information System (PROMIS). Pain medicine (Malden, Mass.) You, D. S., Hah, J. M., Collins, S., Ziadni, M. S., Domingue, B. W., Cook, K. F., Mackey, S. C. 2019

  Abstract

  OBJECTIVE: The National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) includes an item bank for measuring misuse of prescription pain medication (PROMIS-Rx Misuse). The bank was developed and its validity evaluated in samples of community-dwelling adults and patients in addiction treatment programs. The goal of the current study was to investigate the validity of the item bank among patients with mixed-etiology chronic pain conditions.METHOD: A consecutive sample of 288 patients who presented for initial medical evaluations at a tertiary pain clinic completed questionnaires using the open-source Collaborative Health Outcomes Information Registry. Participants were predominantly middle-aged (M [SD]=51.6 [15.5] years), female (62.2%), and white/non-Hispanic (51.7%). Validity was evaluated by estimating the association between PROMIS-Rx Misuse scores and scores on other measures and testing the ability of scores to distinguish among risk factor subgroups expected to have different levels of prescription pain medicine misuse (known groups analyses).RESULTS: Overall, score associations with other measures were as expected and scores effectively distinguished among patients with and without relevant risk factors.CONCLUSION: The study results supported the preliminary validity of PROMIS-Rx Misuse item bank scores for the assessment of prescription opioid misuse in patients visiting an outpatient pain clinic.

  View details for PubMedID 30856659

• Managing twin crises in chronic pain and prescription opioids. BMJ (Clinical research ed.) Mackey, S., Kao, M. 2019; 364: l917

  View details for PubMedID 30842099

• Managing twin crises in chronic pain and prescription opioids BMJ-BRITISH MEDICAL JOURNAL Mackey, S., Kao, M. 2019; 364

  View details for DOI 10.1136/bmj.l917

  View details for Web of Science ID 000461062400006

• Perioperative pregabalin and intraoperative lidocaine infusion to reduce persistent neuropathic pain after breast cancer surgery: a multicenter, factorial, randomized controlled pilot trial. The journal of pain : official journal of the American Pain Society Khan, J. S., Hodgson, N., Choi, S., Reid, S., Paul, J. E., Hong, N. J., Holloway, C., Busse, J. W., Gilron, I., Buckley, D. N., McGillion, M., Clarke, H., Katz, J., Mackey, S., Avram, R., Pohl, K., Rao-Melacini, P., Devereaux, P. J. 2019

  Abstract

  Persistent post-surgical pain is defined as pain localized to the area of surgery of at least 2-month duration and is unfortunately a common complication after breast cancer surgery. While there is insufficient evidence to support any preventative strategy, prior literature suggests possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2-by-2 factorial randomized placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/hr) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for nine days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients within 42-weeks, follow-up rate of 100%, and study-drug compliance of ≥80%. At 3-months, 53% of patients reported persistent neuropathic pain. While there was no interaction between lidocaine and pregabalin, lidocaine reduced the development of persistent neuropathic pain (43.1% vs 63.3%; RR 0.68, 95% CI 0.47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; RR 1.3, 95% CI 0.90 to 1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions in breast cancer surgeries. Clinical trial number: NCT02240199 Perspectives: This article reports the findings of a pilot randomized controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated feasibility of conducting a larger trial and provided promising data that these interventions may reduce the development of persistent pain.

  View details for PubMedID 30844507

• International Stakeholder Community of Pain Experts and Leaders Call for an Urgent Action on Forced Opioid Tapering PAIN MEDICINE Darnall, B. D., Juurlink, D., Kerns, R. D., Mackey, S., Van Dorsten, B., Humphreys, K., Gonzalez-Sotomayor, J. A., Furlan, A., Gordon, A. J., Gordon, D. B., Hoffman, D. E., Katz, J., Kertesz, S. G., Satel, S., Lawhern, R. A., Nicholson, K. M., Polomano, R. C., Williamson, O. D., McAnally, H., Kao, M., Schug, S., Twillman, R., Lewis, T. A., Stieg, R. L., Lorig, K., Mallick-Searle, T., West, R. W., Gray, S., Ariens, S. R., Potter, J., Cowan, P., Kollas, C. D., Laird, D., Ingle, B., Grove, J., Wilson, M., Lockman, K., Hodson, F., Palackdharry, C. S., Fillingim, R. B., Fudin, J., Barnhouse, J., Manhapra, A., Henson, S. R., Singer, B., Ljosenvoor, M., Griffith, M., Doctor, J. N., Hardin, K., London, C., Mankowski, J., Anderson, A., Ellsworth, L., Budzinski, L., Brandt, B., Hartley, G., Heck, D., Zobrosky, M. J., Cheek, C., Wilson, M., Laux, C. E., Datz, G., Dunaway, J., Schonfeld, E., Cady, M., LeDantec-Boswell, T., Craigie, M., Sturgeon, J., Flood, P., Giummarra, M., Whelan, J., Thorn, B. E., Martin, R. L., Schatman, M. E., Gregory, M. D., Kirz, J., Robinson, P., Marx, J. G., Stewart, J. R., Keck, P. S., Hadland, S. E., Murphy, J. L., Lumley, M. A., Brown, K. S., Leong, M. S., Fillman, M., Broatch, J. W., Perez, A., Watford, K., Kruska, K., You, D., Ogbeide, S., Kukucka, A., Lawson, S., Ray, J. B., Martin, T., Lakehomer, J. B., Burke, A., Cohen, R. I., Grinspoon, P., Rubenstein, M. S., Sutherland, S., Walters, K., Lovejoy, T. 2019; 20 (3): 429–33

  View details for DOI 10.1093/pm/pny228

  View details for Web of Science ID 000467966600003

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery: Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3): e190168

  Abstract

  Importance: Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.Objective: To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes.Design, Setting, and Participants: A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018.Interventions: Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours.Main Outcomes and Measures: A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery.Results: Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P<.001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P<.001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P=.89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P=.008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P<.001), a history of alcohol or drug abuse treatment (ARR,1.90; 95% CI, 1.42-2.53; P<.001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P=.03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P<.001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P<.001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P<.001).Conclusions and Relevance: This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings.Trial Registration: ClinicalTrials.gov Identifier: NCT01067144.

  View details for PubMedID 30821824

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery Secondary Analysis of a Randomized Clinical Trial JAMA NETWORK OPEN Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3)

  View details for DOI 10.1001/jamanetworkopen.2019.0168

  View details for Web of Science ID 000465424000048

• Use of Immersive Learning and Simulation Techniques to Teach and Research Opioid Prescribing Practices PAIN MEDICINE Heirich, M. S., Sinjary, L. S., Ziadni, M. S., Sacks, S., Buchanan, A. S., Mackey, S. C., Newmark, J. L. 2019; 20 (3): 456–63

  View details for DOI 10.1093/pm/pny171

  View details for Web of Science ID 000467966600006

• Altered Cervical Spinal Cord Resting-State Activity in Fibromyalgia ARTHRITIS & RHEUMATOLOGY Martucci, K. T., Weber, K. A., Mackey, S. C. 2019; 71 (3): 441–50

  View details for DOI 10.1002/art.40746

  View details for Web of Science ID 000459806500014

• Association of Overlapping Surgery With Perioperative Outcomes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Sun, E., Mello, M. M., Rishel, C. A., Vaughn, M. T., Kheterpal, S., Saager, L., Fleisher, L. A., Damrose, E. J., Kadry, B., Jena, A. B., Kooij, F., Wilczak, J., Soto, R., Berris, J., Price, Z., Urman, R. D., Lins, S., Harris, J. M., Cummings, K. C., Berman, M. F., Nanamori, M., Adelman, B. T., Wedeven, C., Bittner, E. A., LaGorio, J., McCormick, P. J., Tom, S., Aziz, M. F., Coffman, T., Ellis, T. A., Molina, S., Peterson, W., Mackey, S. C., van Klei, W. A., Mahajan, A., Geffen, D., Jameson, L. C., Biggs, D. A., Craft, R., Pace, N. L., Paganelli, W. C., Durieux, M. E., Nair, B. J., Wanderer, J. P., Miller, S. A., Helsten, D. L., Turnbull, Z. A., Schonberger, R. B., MPOG 2019; 321 (8): 762–72

  View details for DOI 10.1001/jama.2019.0711

  View details for Web of Science ID 000460191400017

• Dynamic per slice shimming for simultaneous brain and spinal cord fMRI MAGNETIC RESONANCE IN MEDICINE Islam, H., Law, C. W., Weber, K. A., Mackey, S. C., Glover, G. H. 2019; 81 (2): 825–38

  View details for DOI 10.1002/mrm.27388

  View details for Web of Science ID 000462086300010

• Negative Affect-Related Factors Have the Strongest Association with Prescription Opioid Misuse in a Cross-Sectional Cohort of Patients with Chronic Pain. Pain medicine (Malden, Mass.) Gilam, G., Sturgeon, J. A., You, D. S., Wasan, A. D., Darnall, B. D., Mackey, S. C. 2019

  Abstract

  Increased opioid prescription to relieve pain among patients with chronic pain is associated with increased risk for misuse, potentially leading to substance use disorders and overdose death. We aimed to characterize the relative importance and identify the most significant of several potential risk factors for the severity of self-reported prescribed opioid misuse behaviors.A sample of 1,193 patients (mean age ± SD = 50.72 ± 14.97 years, 64.04% female) with various chronic pain conditions completed a multidimensional registry assessing four pain severity measures and 14 physical, mental, and social health status factors using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS). A validated PROMIS measure of medication misuse was completed by 692 patients who endorsed currently taking opioid medication. Patients taking opioid medications were compared across all measures with those who do not take opioid medications. Subsequently, a data-driven regression analysis was used to determine which measures best explained variability in severity of misuse. We hypothesized that negative affect-related factors, namely anxiety, anger, and/or depression, would be key predictors of misuse severity due to their crucial role in chronic pain and substance use disorders.Patients taking opioid medications had significantly greater impairment across most measures. Above and beyond demographic variables, the only and most significant predictors of prescribed opioid misuse severity were as follows: anxiety (β = 0.15, P = 0.01), anger (β = 0.13, P = 0.02), Pain Intensity-worst (β = 0.09, P = 0.02), and depression (β = 0.13, P = 0.04).Findings suggest that anxiety, anger, and depression are key factors associated with prescribed opioid misuse tendencies in patients with chronic pain and that they are potential targets for therapeutic intervention.

  View details for DOI 10.1093/pm/pnz249

  View details for PubMedID 31617916

• The Impact of Social Isolation on Pain Interference: A Longitudinal Study ANNALS OF BEHAVIORAL MEDICINE Karayannis, N. V., Baumann, I., Sturgeon, J. A., Melloh, M., Mackey, S. C. 2019; 53 (1): 65–74

  View details for DOI 10.1093/abm/kay017

  View details for Web of Science ID 000480798700006

• Comparative Effectiveness of Cognitive Behavioral Therapy for Chronic Pain and Chronic Pain Self-Management within the Context of Voluntary Patient-Centered Prescription Opioid Tapering: The EMPOWER Study Protocol. Pain medicine (Malden, Mass.) Darnall, B. D., Mackey, S. C., Lorig, K., Kao, M. C., Mardian, A., Stieg, R., Porter, J., DeBruyne, K., Murphy, J., Perez, L., Okvat, H., Tian, L., Flood, P., McGovern, M., Colloca, L., King, H., Van Dorsten, B., Pun, T., Cheung, M. 2019

  Abstract

  Evidence to date, while sparse, suggests that patients taking long-term opioids require special considerations and protections to prevent potential iatrogenic harms from opioid de-prescribing, such as increased pain or suffering. Following this study protocol, the EMPOWER study seeks to address multiple unmet needs of patients with chronic pain who desire to reduce long-term opioid therapy, and provide the clinical evidence on effective methodology.EMPOWER applies patient-centered methods for voluntary prescription opioid reduction conducted within a comprehensive, multi-state, 3-arm randomized controlled comparative effectiveness study of three study arms (1) group cognitive behavioral therapy for chronic pain; (2) group chronic pain self-management; and (3) usual care (taper only). Specialized electronic data capture systems collect patient reported symptoms and satisfaction data weekly and monthly during the taper, with real-time clinical alerts and electronic feedback loops informing, documenting, and steering needed care actions.The EMPOWER study seeks to provide granular evidence on patient response to voluntary opioid tapering, and will provide evidence to inform clinical systems changes, clinical care, patient satisfaction, and patient outcomes for opioid reduction.

  View details for DOI 10.1093/pm/pnz285

  View details for PubMedID 31876947

• Evidence for decreased Neurologic Pain Signature activation following thoracic spinal manipulation in healthy volunteers and participants with neck pain. NeuroImage. Clinical Weber Ii, K. A., Wager, T. D., Mackey, S., Elliott, J. M., Liu, W. C., Sparks, C. L. 2019; 24: 102042

  Abstract

  Spinal manipulation (SM) is a common treatment for neck and back pain, theorized to mechanically affect the spine leading to therapeutic mechanical changes. The link between specific mechanical effects and clinical improvement is not well supported. SM's therapeutic action may instead be partially mediated within the central nervous system.To introduce brain-based models of pain for spinal pain and manual therapy research, characterize the distributed central mechanisms of SM, and advance the preliminary validation of brain-based models as potential clinical biomarkers of pain.Secondary analysis of two functional magnetic resonance imaging studies investigating the effect of thoracic SM on pain-related brain activity: A non-controlled, non-blinded study in healthy volunteers (Study 1, n = 10, 5 females, and mean age = 31.2 ± 10.0 years) and a randomized controlled study in participants with acute to subacute neck pain (Study 2, n = 24, 16 females, mean age = 38.0 ± 15.1 years).Functional magnetic resonance imaging was performed during noxious mechanical stimulation of the right index finger cuticle pre- and post-intervention. The effect of SM on pain-related activity was studied within brain regions defined by the Neurologic Pain Signature (NPS) that are predictive of physical pain.In Study 1, evoked mechanical pain (p < 0.001) and NPS activation (p = 0.010) decreased following SM, and the changes in evoked pain and NPS activation were correlated (rRM2 = 0.418, p = 0.016). Activation within the NPS subregions of the dorsal anterior cingulate cortex (dACC, p = 0.012) and right secondary somatosensory cortex/operculum (rS2_Op, p = 0.045) also decreased following SM, and evoked pain was correlated with dACC activity (rRM2 = 0.477, p = 0.019). In Study 2, neck pain (p = 0.046) and NPS (p = 0.033) activation decreased following verum but not sham SM. Associations between evoked pain, neck pain, and NPS activation, were not significant and less clear, possibly due to inadequate power, methodological limitations, or other confounding factors.The findings provide preliminary evidence that SM may alter the processing of pain-related brain activity within specific pain-related brain regions and support the use of brain-based models as clinical biomarkers of pain.

  View details for DOI 10.1016/j.nicl.2019.102042

  View details for PubMedID 31670070

• Novel Characterization Of Thermal Temporal Summation Response By Analysis Of Continuous Pain Vs Time Curves And Exploratory Modeling. Journal of pain research Kong, J., Bagarinao, E., Olshen, R. A., Mackey, S. 2019; 12: 3231–44

  Abstract

  Background: Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. While thermal TS is generally considered a behavioral correlate of spinal windup, noxious heat pulses also trigger additional sensory processes which were modeled in this study.Methods: Nineteen healthy volunteers (9 females, mean age 29.2, SD 10.5) underwent two identical TS experiments, spaced a week apart. The TS paradigm consisted of 10 identical heat pulses with individualized temperatures at the thenar eminence (0.5Hz). We extracted 3 features from continuous TS response curves: Lag, time to first feel pain; Slope, the rate of pain increase between the first and most painful heat pulse; and Delta, the maximum drop in pain after peak pain is reached. We then examined the within-individual stability of these features, followed by the Pearson's correlations among these features and between the features and negative affect.Results: All 3 features were stable over 1 week. Lag and Delta were negatively correlated (r = -0.5, p = 0.042). Slope did not correlate with Lag or Delta, but strongly correlated with a traditional TS measure, first pulse pain and peak pain difference (r = 0.91, p < 0.0001). Negative affects such as trait and state anxiety were negatively correlated with baseline (r = -0.49, p = 0.031) and peak stimulating temperature (r = -0.48, p = 0.039), respectively, suggesting an association between anxiety and greater pain sensitivity.Conclusion: We were able to decouple spinal windup from other perceptual processes generated by phasic thermal TS paradigms and demonstrate temporal stability of these curve features. These curve features may help better characterize the complex sensory response to noxious heat pulses and serve as biomarkers to profile patients with chronic pain.

  View details for DOI 10.2147/JPR.S212137

  View details for PubMedID 31819607

• Neuroimmune modulation of pain across the developmental spectrum. Current opinion in behavioral sciences Karshikoff, B., Tadros, M. A., Mackey, S., Zouikr, I. 2019; 28: 85–92

  Abstract

  Today's treatment for chronic pain is inadequate, and novel targets need to be identified. This requires a better understanding of the mechanisms involved in pain sensitization and chronification. In this review, we discuss how peripheral inflammation, as occurs during an infection, modulates the central pain system. In rodents, neonatal inflammation leads to increased pain sensitivity in adulthood by priming immune components both peripherally and centrally. The excitability of neurons in the spinal cord is also altered by neonatal inflammation and may add to pain sensitization later in life. In adult humans, inflammation modulates pain sensitivity as well, partly by affecting the activity in brain areas that process and regulate pain signals. Low-grade inflammation is common in clinical populations both peripherally and centrally, and priming of the immune system has also been suggested in some pain populations. The nociceptive and immune systems are primed by infections and inflammation. The early life programming of nociceptive responses following exposure to infections or inflammation will define individual differences in adult pain perception. Immune-to-brain mechanisms and neuroimmune pathway need further investigation as they may serve both as predictors and therapeutic targets in chronic pain.

  View details for DOI 10.1016/j.cobeha.2019.01.010

  View details for PubMedID 32190717

  View details for PubMedCentralID PMC7079707

• Implementation Challenges Using a Novel Method for Collecting Patient-Reported Outcomes After Injury. The Journal of surgical research Rosenberg, G. M., Shearer, E. J., Zion, S. R., Mackey, S. C., Morris, A. M., Spain, D. A., Weiser, T. G. 2019; 241: 277–84

  Abstract

  Monitoring longitudinal patient-reported outcomes after injury is important for comprehensive trauma care. Current methodologies are resource-intensive and struggle to engage patients.Patients ≥18 y old admitted to the trauma service were prospectively enrolled. The following inclusion criteria were used: emergency operation, ICU length of stay ≥2 midnights, or hospital length of stay ≥4 d. Validated and customized questionnaires were administered using a novel internet-based survey platform. Three-month follow-up surveys were administered. Contextual field notes regarding barriers to enrollment/completion of surveys and challenges faced by participants were recorded.Forty-seven patients were eligible; 26 of 47 (55%) enrolled and 19 of 26 (73%) completed initial surveys. The final sample included 14 (74%) men and 5 (26%) women. Primary barriers to enrollment included technological constraints and declined participation. Contextual field notes revealed three major issues: competing hospital tasks, problems with technology, and poor engagement. The average survey completion time was 43 ± 27 min-21% found this too long. Seventy-four percent reported the system "easy to use" and 95% reported they would "very likely" or "definitely" respond to future surveys. However, 10 of 26 (38%) patients completed 3-mo follow-up.Despite a well-rated internet-based survey platform, study participation remained challenging. Lack of email access and technological issues decreased enrollment and the busy hospitalization posed barriers to completion. Despite a thoughtful operational design and implementation plan, the trauma population presented a challenging group to engage. Next steps will focus on optimizing engagement, broadening access to survey reminders, and enhancing integration into clinical workflows.

  View details for PubMedID 31042606

• Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review. Anesthesiology Larach, M. G., Klumpner, T. T., Brandom, B. W., Vaughn, M. T., Belani, K. G., Herlich, A., Kim, T. W., Limoncelli, J., Riazi, S., Sivak, E. L., Capacchione, J., Mashman, D., Kheterpal, S., Kooij, F., Wilczak, J., Soto, R., Berris, J., Price, Z., Lins, S., Coles, P., Harris, J. M., Cummings, K. C., Berman, M. F., Nanamori, M., Adelman, B. T., Wedeven, C., LaGorio, J., McCormick, P. J., Tom, S., Aziz, M. F., Coffman, T., Ellis, T. A., Molina, S., Peterson, W., Mackey, S. C., van Klei, W. A., Ginde, A. A., Biggs, D. A., Neuman, M. D., Craft, R. M., Pace, N. L., Paganelli, W. C., Durieux, M. E., Nair, B. J., Wanderer, J. P., Miller, S. A., Helsten, D. L., Turnbull, Z. A., Schonberger, R. B., Multicenter Perioperative Outcomes Group 2019; 130 (1): 41–54

  Abstract

  WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.METHODS: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.RESULTS: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100mg, 1.2mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.CONCLUSIONS: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

  View details for PubMedID 30550426

• Deep Learning Convolutional Neural Networks for the Automatic Quantification of Muscle Fat Infiltration Following Whiplash Injury. Scientific reports Weber, K. A., Smith, A. C., Wasielewski, M., Eghtesad, K., Upadhyayula, P. A., Wintermark, M., Hastie, T. J., Parrish, T. B., Mackey, S., Elliott, J. M. 2019; 9 (1): 7973

  Abstract

  Muscle fat infiltration (MFI) of the deep cervical spine extensors has been observed in cervical spine conditions using time-consuming and rater-dependent manual techniques. Deep learning convolutional neural network (CNN) models have demonstrated state-of-the-art performance in segmentation tasks. Here, we train and test a CNN for muscle segmentation and automatic MFI calculation using high-resolution fat-water images from 39 participants (26 female, average = 31.7 ± 9.3 years) 3 months post whiplash injury. First, we demonstrate high test reliability and accuracy of the CNN compared to manual segmentation. Then we explore the relationships between CNN muscle volume, CNN MFI, and clinical measures of pain and neck-related disability. Across all participants, we demonstrate that CNN muscle volume was negatively correlated to pain (R = -0.415, p = 0.006) and disability (R = -0.286, p = 0.045), while CNN MFI tended to be positively correlated to disability (R = 0.214, p = 0.105). Additionally, CNN MFI was higher in participants with persisting pain and disability (p = 0.049). Overall, CNN's may improve the efficiency and objectivity of muscle measures allowing for the quantitative monitoring of muscle properties in disorders of and beyond the cervical spine.

  View details for DOI 10.1038/s41598-019-44416-8

  View details for PubMedID 31138878

• Effects of smoking on patients with chronic pain: a propensity-weighted analysis on the Collaborative Health Outcomes Information Registry. Pain Khan, J. S., Hah, J. M., Mackey, S. C. 2019

  Abstract

  Tobacco smoking is associated with adverse health effects and its relationship to pain is complex. The longitudinal effect of smoking on patients attending a tertiary pain management center is not wellestablished. Using the Collaborative Health Outcomes Information Registry (CHOIR) of patients attending the Stanford Pain Management Center from 2013-2017, we conducted a propensity-weighted analysis to determine independent effects of smoking on chronic pain patients. We adjusted for covariates including age, gender, body mass index, depression and anxiety history, ethnicity, alcohol use, marital status, disability, and education. We compared smokers and non-smokers on pain intensity, physical function, sleep, and psychological and mood variables using self-reported NIH PROMIS outcomes. We also conducted a linear mixed-model analysis to determine effect of smoking over time. 12,368 patients completed the CHOIR questionnaire of which 8,584 patients had complete data for propensity analysis. Smokers at time of pain consultation reported significantly worse pain intensities, pain interference, pain behaviors, physical functioning, fatigue, sleep-related impairment, sleep disturbance, anger, emotional support, depression, and anxiety symptoms than non-smokers (all p<0.001). In mixed model analysis, smokers tended to have worse pain interference, fatigue, sleeprelated impairment, anger, emotional support, and depression over time compared to non-smokers. Patients with chronic pain who smoke have worse pain, functional, sleep, and psychological and mood outcomes compared to non-smokers. Smoking also has prognostic importance for poor recovery and improvement over time. Further research is needed on tailored therapies to assist people with chronic pain who smoke and to determine an optimal strategy to facilitate smoking cessation.

  View details for DOI 10.1097/j.pain.0000000000001631

  View details for PubMedID 31149975

• Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment Database Analyses and Systematic Review ANESTHESIOLOGY Larach, M., Klumpner, T. T., Brandom, B. W., Vaughn, M. T., Belani, K. G., Herlich, A., Kim, T. W., Limoncelli, J., Riazi, S., Sivak, E. L., Capacchione, J., Mashman, D., Kheterpal, S., Kooij, F., Wilczak, J., Soto, R., Berris, J., Price, Z., Lins, S., Coles, P., Harris, J. M., Cummings, K. C., Berman, M. F., Nanamori, M., Adelman, B. T., Wedeven, C., LaGorio, J., McCormick, P. J., Tom, S., Aziz, M. F., Coffman, T., Ellis, T. A., Molina, S., Peterson, W., Mackey, S. C., van Klei, W. A., Ginde, A. A., Biggs, D. A., Neuman, M. D., Craft, R. M., Pace, N. L., Paganelli, W. C., Durieux, M. E., Nair, B. J., Wanderer, J. P., Miller, S. A., Helsten, D. L., Turnbull, Z. A., Schonberger, R. B., Multictr Perioperative Outcomes G 2019; 130 (1): 41–54

  View details for DOI 10.1097/ALN.0000000000002490

  View details for Web of Science ID 000466746000008

• Evaluation of Candidate Items for Severe PTSD Screening for Patients with Chronic Pain: Pilot Data Analysis with IRT Approach. Pain practice : the official journal of World Institute of Pain You, D. S., Ziadni, M. S., Gilam, G., Darnall, B. D., Mackey, S. C. 2019

  Abstract

  Post-traumatic Stress Disorder (PTSD) commonly co-occurs with chronic pain. Although PTSD symptoms are associated with negative health outcomes in patients with chronic pain, PTSD is typically under-detected and under-treated in outpatient pain settings. There is a need for rapid, brief screening tools to identify those at greatest risk for severe PTSD symptoms. To achieve that goal, our aim was to use item response theory (IRT) to identify the most informative PTSD symptoms characterizing severe PTSD in patients with chronic pain.Fifty-six patients (71% female, 61% White) with mixed etiology chronic pain completed the PTSD Checklist Civilian Version (PCL-C) as part of their appointment with a pain psychologist at a tertiary outpatient pain clinic. We used an IRT approach to evaluate each item's discriminant (a) and severity (b) parameters.Findings revealed that 'feeling upset at reminders' (a = 3.67, b = 2.44) and 'avoid thinking or talking about it' (a = 3.61, b = 2.17) as being highly discriminant for severe PTSD.We identified two candidate items for a brief PTSD screener as they were associated with severe PTSD symptoms. These two items may provide clinical utility in outpatient pain treatment settings to identify those suffering from severe PTSD enabling physicians to refer them to trauma-specific evaluation or therapy. Future research is needed to further validate and confirm these candidate PTSD items in a larger clinic sample.

  View details for DOI 10.1111/papr.12848

  View details for PubMedID 31646748

• Apparent Effects of Opioid Use on Neural Responses to Reward in Chronic Pain. Scientific reports Martucci, K. T., MacNiven, K. H., Borg, N., Knutson, B., Mackey, S. C. 2019; 9 (1): 9633

  Abstract

  Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively "normalized" neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.

  View details for DOI 10.1038/s41598-019-45961-y

  View details for PubMedID 31270360

• Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial. Trials Kong, J., MacIsaac, B., Cogan, R., Ng, A., Law, C. S., Helms, J., Schnyer, R., Karayannis, N. V., Kao, M., Tian, L., Darnall, B. D., Gross, J. J., Mackey, S., Manber, R. 2018; 19 (1): 685

  Abstract

  BACKGROUND: Chronic low back pain (CLBP) is the most common chronic pain condition and is often resistant to conventional treatments. Acupuncture is a popular alternative for treating CLBP but its mechanisms of action remain poorly understood. Evidence suggests that pain regulatory mechanisms (particularly the ascending and secondarily the descending pain modulatory pathways) and psychological mechanisms (e.g., expectations, pain catastrophizing and self-efficacy) may be involved in the pathogenesis of CLBP and its response to treatments. We will examine these mechanisms in the treatment of CLBP by electroacupuncture (EA).METHODS: We present the aims and methods of a placebo-controlled, participant-blinded and assessor-blinded mechanistic study. Adult patients with CLBP will be randomized to receiving 16 sessions of real (active) or sham (placebo) EA over the course of 8weeks. The primary pain regulatory measure for which the study was powered is temporal summation (TS), which approximates ascending pain facilitation. Conditioned pain modulation (CPM), representing a descending pain modulatory pathway, will be our secondary pain regulatory measure. The primary psychological measure is expectations of benefit, and the secondary psychological measures are pain catastrophizing and self-efficacy in managing pain. Main clinical outcomes are back pain bothersomeness on a 0-100 visual analog scale (primary), Roland Morris Disability Questionnaire (secondary), and relevant items from the National Institutes of Health (NIH) Patient-Reported Outcome Measures Information System (secondary). We hypothesize that compared to sham, real EA will lead to greater reduction in TS after 8 treatment sessions (4weeks); and that reduction in TS (and secondarily, increase in CPM) after 8 treatment sessions will mediate reduction in back pain bothersomeness from baseline to week 10 (clinical response) to EA. We also hypothesize that the three psychological factors are moderators of clinical response. With 100 treatment completers, the study is designed to have 80% power to detect a medium-sized between-group effect (d=0.5) on temporal summation.DISCUSSION: To the best of our knowledge, this is the first appropriately powered, placebo-controlled clinical trial evaluating mechanisms of EA in the treatment of CLBP.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02503475 . Registered on 15 July 15 2015. Retrospectively registered.

  View details for PubMedID 30541586

• Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial TRIALS Kong, J., MacIsaac, B., Cogan, R., Ng, A., Law, C., Helms, J., Schnyer, R., Karayannis, N., Kao, M., Tian, L., Darnall, B. D., Gross, J. J., Mackey, S., Manber, R. 2018; 19

  View details for DOI 10.1186/s13063-018-3044-2

  View details for Web of Science ID 000453069900001

• Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent 11C-raclopride positron emission tomography and functional magnetic resonance imaging investigation. Translational psychiatry Hamilton, J. P., Sacchet, M. D., Hjornevik, T., Chin, F. T., Shen, B., Kampe, R., Park, J. H., Knutson, B. D., Williams, L. M., Borg, N., Zaharchuk, G., Camacho, M. C., Mackey, S., Heilig, M., Drevets, W. C., Glover, G. H., Gambhir, S. S., Gotlib, I. H. 2018; 8 (1): 264

  Abstract

  Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

  View details for PubMedID 30504860

• Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent C-11-raclopride positron emission tomography and functional magnetic resonance imaging investigation TRANSLATIONAL PSYCHIATRY Hamilton, J., Sacchet, M. D., Hjornevik, T., Chin, F. T., Shen, B., Kampe, R., Park, J., Knutson, B. D., Williams, L. M., Borg, N., Zaharchuk, G., Camacho, M., Mackey, S., Heilig, M., Drevets, W. C., Glover, G. H., Gambhir, S. S., Gotlib, I. H. 2018; 8

  View details for DOI 10.1038/s41398-018-0316-2

  View details for Web of Science ID 000452318900002

• International Stakeholder Community of Pain Experts and Leaders Call for an Urgent Action on Forced Opioid Tapering. Pain medicine (Malden, Mass.) Darnall, B. D., Juurlink, D., Kerns, R. D., Mackey, S., Van Dorsten, B., Humphreys, K., Gonzalez-Sotomayor, J. A., Furlan, A., Gordon, A. J., Gordon, D. B., Hoffman, D. E., Katz, J., Kertesz, S. G., Satel, S., Lawhern, R. A., Nicholson, K. M., Polomano, R. C., Williamson, O. D., McAnally, H., Kao, M., Schug, S., Twillman, R., Lewis, T. A., Stieg, R. L., Lorig, K., Mallick-Searle, T., West, R. W., Gray, S., Ariens, S. R., Sharpe Potter, J., Cowan, P., Kollas, C. D., Laird, D., Ingle, B., Julian Grove, J., Wilson, M., Lockman, K., Hodson, F., Palackdharry, C. S., Fillingim, R. B., Fudin, J., Barnhouse, J., Manhapra, A., Henson, S. R., Singer, B., Ljosenvoor, M., Griffith, M., Doctor, J. N., Hardin, K., London, C., Mankowski, J., Anderson, A., Ellsworth, L., Davis Budzinski, L., Brandt, B., Harkootley, G., Nickels Heck, D., Zobrosky, M. J., Cheek, C., Wilson, M., Laux, C. E., Datz, G., Dunaway, J., Schonfeld, E., Cady, M., LeDantec-Boswell, T., Craigie, M., Sturgeon, J., Flood, P., Giummarra, M., Whelan, J., Thorn, B. E., Martin, R. L., Schatman, M. E., Gregory, M. D., Kirz, J., Robinson, P., Marx, J. G., Stewart, J. R., Keck, P. S., Hadland, S. E., Murphy, J. L., Lumley, M. A., Brown, K. S., Leong, M. S., Fillman, M., Broatch, J. W., Perez, A., Watford, K., Kruska, K., Sophia You, D., Ogbeide, S., Kukucka, A., Lawson, S., Ray, J. B., Wade Martin, T., Lakehomer, J. B., Burke, A., Cohen, R. I., Grinspoon, P., Rubenstein, M. S., Sutherland, S., Walters, K. R., Lovejoy, T. 2018

  View details for PubMedID 30496540

• Electronic Patient-Reported Outcomes: Semi-Automated Data Collection in the Interventional Radiology Clinic. Journal of the American College of Radiology : JACR Hoang, N. S., Hwang, W., Katz, D. A., Mackey, S. C., Hofmann, L. V. 2018

  Abstract

  INTRODUCTION: Patient-reported outcomes are important for clinical research and will likely be used in the near future as a metric for physician reimbursement. This study aims to evaluate the implementation of an electronic data collection system for deep vein thrombosis and lymphedema quality-of-life (QOL) questionnaires in a tertiary care interventional radiology practice.METHODS: A single provider's clinic patients were automatically e-mailed validated questionnaires 1 week before their appointments. If not completed via e-mail, the questionnaire was administered on an electronic tablet in clinic by a research coordinator. Patients were also sent postprocedure questionnaires.RESULTS: In all, 106 patients visited the clinic for a pre-intervention venous consultation. Of them, 96% (n= 102 of 106) completed the pre-intervention questionnaire: 48% (n= 47 of 98) via e-mail and 52% (n= 51 of 98) via tablet. Of the patients who had procedures and were sent questionnaires, 49% (n= 26 of 53) were seen in person. Of the postprocedure in-person clinic patients, 76% (n= 20 of 26) completed the questionnaire via e-mail, and the remainder with the tablet in clinic. Twenty-seven of the 53 (51%) patients did not return for follow-up and instead were sent an electronic questionnaire as their only source of follow-up, of which 74% (n= 20 of 27) complied.CONCLUSION: After an initial introduction to electronic QOL reporting, patients were more likely to complete the questionnaires remotely for their follow-up appointment. A semi-automated electronic QOL system allows physicians to collect patient outcome data even in the absence of a clinic visit.

  View details for PubMedID 30297246

• Dynamic per slice Shimming for Simultaneous Brain and Spinal Cord fMRI. Magnetic resonance in medicine Islam, H., Law, C. S., Weber, K. A., Mackey, S. C., Glover, G. H. 2018

  Abstract

  PURPOSE: Simultaneous brain and spinal cord functional MRI is emerging as a new tool to study the central nervous system but is challenging. Poor B0 homogeneity and small size of the spinal cord are principal obstacles to this nascent technology. Here we extend a dynamic shimming approach, first posed by Finsterbusch, by shimming per slice for both the brain and spinal cord.METHODS: We shim dynamically by a simple and fast optimization of linear field gradients and frequency offset separately for each slice in order to minimize off-resonance for both the brain and spinal cord. Simultaneous acquisition of brain and spinal cord fMRI is achieved with high spatial resolution in the spinal cord by means of an echo-planar RF pulse for reduced FOV. Brain slice acquisition is full FOV.RESULTS: T2*-weighted images of brain and spinal cord are acquired with high clarity and minimal observable image artifacts. Fist-clenching fMRI experiments reveal task-consistent activation in motor cortices, cerebellum, and C6-T1 spinal segments.CONCLUSIONS: High quality functional results are obtained for a sensory-motor task. Consistent activation in both the brain and spinal cord is observed at individual levels, not only at group level. Because reduced FOV excitation is applicable to any spinal cord section, future continuation of these methods holds great potential.

  View details for PubMedID 30284730

• Altered Cervical Spinal Cord Resting State Activity in Fibromyalgia. Arthritis & rheumatology (Hoboken, N.J.) Martucci, K. T., Weber, K. A., Mackey, S. C. 2018

  Abstract

  OBJECTIVE: Altered afferent input and central neural modulation are thought to contribute to fibromyalgia symptoms, and these processes converge within the spinal cord. We hypothesized that, using resting state functional magnetic resonance imaging (rs-fMRI) of the cervical spinal cord, we would observe altered frequency dependent activity in fibromyalgia.METHODS: Cervical spinal cord rs-fMRI was performed in fibromyalgia patients and healthy controls. We analyzed a measure of low frequency oscillatory power, the amplitude of low frequency fluctuations (ALFF), for frequencies 0.01 - 0.198 Hz and frequency sub-bands, to determine regional and frequency-specific alterations in fibromyalgia. Functional connectivity and graph metrics were also analyzed.RESULTS: As compared to controls, greater ventral and lesser dorsal Mean ALFF of the cervical spinal cord was observed in fibromyalgia (p < 0.05, uncorrected) for frequencies 0.01 - 0.198 Hz and all sub-bands. Additionally, lesser Mean ALFF within the right dorsal quadrant (p < 0.05, corrected) for frequencies 0.01 - 0.198 Hz and sub-band frequencies 0.073 - 0.198 Hz was observed in fibromyalgia. Regional Mean ALFF was not correlated with pain, however, regional lesser Mean ALFF was correlated with fatigue in patients (r = 0.763, p = 0.001). Functional connectivity and graph metrics were similar between groups.CONCLUSION: Our results indicate unbalanced activity between the ventral and dorsal cervical spinal cord in fibromyalgia. Increased ventral neural processes and decreased dorsal neural processes may reflect the presence of central sensitization and contribute to fatigue and other bodily symptoms in fibromyalgia. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30281205

• The factor structure and subscale properties of the pain catastrophizing scale: are there differences in the distinctions? Cook, K., Darnall, B., Mackey, S. SPRINGER. 2018: S38

  View details for Web of Science ID 000445248500093

• Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Dahlhamer, J., Lucas, J., Zelaya, C., Nahin, R., Mackey, S., DeBar, L., Kerns, R., Von Korff, M., Porter, L., Helmick, C. 2018; 67 (36): 1001–6

  Abstract

  Chronic pain, one of the most common reasons adults seek medical care (1), has been linked to restrictions in mobility and daily activities (2,3), dependence on opioids (4), anxiety and depression (2), and poor perceived health or reduced quality of life (2,3). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% (5), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions (5). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.

  View details for Web of Science ID 000444728500001

  View details for PubMedID 30212442

• Use of Immersive Learning and Simulation Techniques to Teach and Research Opioid Prescribing Practices. Pain medicine (Malden, Mass.) Heirich, M. S., Sinjary, L. S., Ziadni, M. S., Sacks, S., Buchanan, A. S., Mackey, S. C., Newmark, J. L. 2018

  Abstract

  Introduction: Unsafe opioid prescribing practices to treat acute and chronic pain continue to contribute to the opioid overdose crisis in the United States, a growing public health emergency that harms patients and their communities. Poor opioid prescribing practices stem in part from a lack of education and skills training surrounding pain and opioid management.Methods: As part of the Clinical Pain Medicine Fellowship at Stanford University, physicians were given the opportunity to participate in a pilot program to practice opioid management in a live, simulated interaction. Twenty-seven physician trainees participated in the simulation with a live, standardized patient actor. Before beginning the simulation, participants were given a detailed patient history that included the patient's risk for opioid abuse. They were also provided with relevant risk evaluation and mitigation (REM) tools. All simulation interactions were video-recorded and coded by two independent reviewers. A detailed coding scheme was developed before video analysis, and an inter-rater reliability score showed substantial agreement between reviewers.Results: Contrary to expectations, many of the observed performances by trainees contained aspects of unsafe opioid prescribing, given the patient history. Many trainees did not discuss their patient's aberrant behaviors related to opioids or the patient's risk for opioid abuse. Marked disparities were also observed between the trainees' active patient interactions and their written progress notes.Discussion: This simulation addresses a pressing need to further educate, train, and provide point-of-care tools for providers prescribing opioids. We present our experience and preliminary findings.

  View details for PubMedID 30215778

• Altered prefrontal correlates of monetary anticipation and outcome in chronic pain PAIN Martucci, K. T., Borg, N., MacNiven, K. H., Knutson, B., Mackey, S. C. 2018; 159 (8): 1494–1507

  View details for DOI 10.1097/j.pain.0000000000001232

  View details for Web of Science ID 000451223700009

• Cold Water Pressor Test Differentially Modulates Functional Network Connectivity in Fibromyalgia Patients Compared with Healthy Controls. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Jarrahi, B., Martucci, K. T., Nilakantan, A. S., Mackey, S. 2018; 2018: 578–82

  Abstract

  Fibromyalgia is a multifaceted chronic pain condition of unknown etiology. Conditioned pain modulation (CPM) such as cold water pressor test of the foot, is widely documented as being disrupted in patients with fibromyalgia. To date, the mechanisms underlying such dysregulation of the descending control of pain in fibromyalgia remain poorly understood. In this study, we used ICA-based network analysis to comprehensively compare differences in functional network connectivity among relevant (nonartifactual) intrinsic connectivity brain networks during the resting state before and after cold pressor test in patients with fibromyalgia and healthy controls. The results revealed significant differences in functional connectivity between the two groups that included the networks that integrate cognitive control and attention systems with memory, emotion and brainstem regions. Specifically, functional connectivity involving central executive network was absent in patients with fibromyalgia compared with controls. Patients showed significant functional connectivity changes involving subcortical and brainstem networks with the sensorimotor and dorsal attention networks. Accordingly, aberrant CPM in patients with fibromyalgia may be due to the differences in functional connectivity involving the subcortical/brainstem regions, and is facilitated by the recruitment of the dorsal attention network in lieu of the central executive network. Future research replicating the present findings with larger sample size can shed more light on neurobiology of endogenous pain modulation in fibromyalgia.

  View details for DOI 10.1109/EMBC.2018.8512350

  View details for PubMedID 30440463

• Characterizing the Effects of MR Image Quality Metrics on Intrinsic Connectivity Brain Networks: A Multivariate Approach. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Jarrahi, B., Mackey, S. 2018; 2018: 1041–45

  Abstract

  Motion-induced artifact detection has become a fixture in the assessment of functional magnetic resonance imaging (fMRI) quality control. However, the effects of other MR image quality (IQ) metrics on intrinsic connectivity brain networks are largely unexplored. Accordingly, we report herein the initial assessment of the effects of a comprehensive list of IQ metrics on resting state networks using a multivariate analysis of covariance (MANCOVA) approach based on high-order spatial independent component analysis (ICA). Three categories of MR IQ metrics were considered: (1) metrics for artifacts including the AFNI outlier ratio and quality index, framewise displacement, and ghost to signal ratio, (2) metrics for the temporal quality of MRI data including the temporal framewise change in global BOLD signals (DVARS), global correlation of time-series, and temporal signal to noise ratio, (3) metrics for the structural quality of MRI data including the entropy focus criterion, foreground-background energy ratio, full-width half maximum smoothness, and static signal to noise ratio. After FDR-correction for multiple comparisons, results showed significant effects of the static and temporal signal to noise ratios on the spatial map intensities of the basal ganglia, default-mode and cerebellar networks. AFNI outlier ratio, framewise displacement and DVARS exhibited significant effects on the BOLD power spectra of sensorimotor networks. The global correlation of time-series displayed wide-spread modulation of the spectral power in most networks. Further investigations of the effect of IQ metrics on the characteristics of intrinsic connectivity brain networks allow more accurate interpretation of the fMRI results.

  View details for DOI 10.1109/EMBC.2018.8512478

  View details for PubMedID 30440569

• Measuring the Influence of Physiological Noise Corrections on ICA Derived Intrinsic Connectivity Brain Networks in Rest and Task fMRI. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Jarrahi, B., Mackey, S. 2018; 2018: 1046–49

  Abstract

  Physiological noise corrections using RETROICOR algorithm has been shown to increase signal sensitivity in resting state networks such as the default-mode network. However, independent component analysis (ICA)-based network approach may suffer from such corrections especially if there is any overlap between two sources in the decomposition domain. To address the extent the physiological noise corrections may impact ICA derived intrinsic connectivity brain networks, we measured network features including functional network connectivity (FNC), power spectra, and network spatial maps in the resting state and task functional magnetic resonance imaging (fMRI) data that were acquired in the same visit from a group of healthy volunteers. Statistical analysis showed functional connectivity between several networks were significantly changed after RETROICOR corrections in both rest and task fMRI. Significant FNC alterations were found in the subcortical, basal ganglia, salience, and default-mode networks. Power spectra analysis showed a trend toward lower power spectra in the subcortical and salience networks at [0.20 and 0.24] Hz after RETROICOR corrections in both rest and task fMRI. Furthermore, physiological noise corrections led to volumetric decrease in the resting state networks that included the subcortical, basal ganglia, salience, and default-mode networks, and volumetric enlargement in the sensorimotor and cerebellar networks. In task fMRI data, physiological noise corrections generally resulted in the expansion of networks except for task-activated networks including the anterior salience, central executive, dorsal attention, and cerebellar networks. If confirmed with larger sample sizes, these results suggest that physiological noise corrections alter some network features, and that such alterations are different between resting state and task fMRI data.

  View details for DOI 10.1109/EMBC.2018.8512391

  View details for PubMedID 30440570

• Neuroimaging of Pain: Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation. Anesthesiology Martucci, K. T., Mackey, S. C. 2018; 128 (6): 1241–54

  Abstract

  Neuroimaging research has demonstrated definitive involvement of the central nervous system in the development, maintenance, and experience of chronic pain. Structural and functional neuroimaging has helped elucidate central nervous system contributors to chronic pain in humans. Neuroimaging of pain has provided a tool for increasing our understanding of how pharmacologic and psychologic therapies improve chronic pain. To date, findings from neuroimaging pain research have benefitted clinical practice by providing clinicians with an educational framework to discuss the biopsychosocial nature of pain with patients. Future advances in neuroimaging-based therapeutics (e.g., transcranial magnetic stimulation, real-time functional magnetic resonance imaging neurofeedback) may provide additional benefits for clinical practice. In the future, with standardization and validation, brain imaging could provide objective biomarkers of chronic pain, and guide treatment for personalized pain management. Similarly, brain-based biomarkers may provide an additional predictor of perioperative prognoses.

  View details for PubMedID 29494401

• Neuroimaging of Pain Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation ANESTHESIOLOGY Martucci, K. T., Mackey, S. C. 2018; 128 (6): 1241–54

  View details for DOI 10.1097/ALN.0000000000002137

  View details for Web of Science ID 000441172900026

• A Case-Crossover Study of Urological Chronic Pelvic Pain Syndrome Flare Triggers in the MAPP Research Network JOURNAL OF UROLOGY Sutcliffe, S., Jemielita, T., Lai, H., Andriole, G. L., Bradley, C. S., Clemens, J., Gallop, R., Hooton, T. M., Kreder, K. J., Krieger, J. N., Kusek, J. W., Labus, J., Lucia, M., Mackey, S., Naliboff, B. D., Robinson, N. A., Rodriguez, L. V., Stephens-Shields, A., van Bokhoven, A., Wolin, K. Y., Yan, Y., Yang, C. C., Landis, J., Colditz, G. A., MAPP Res Network 2018; 199 (5): 1245–51

  Abstract

  Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers.We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression.In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress).Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.

  View details for PubMedID 29288643

  View details for PubMedCentralID PMC5911194

• The Impact of Social Isolation on Pain Interference: A Longitudinal Study. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine Karayannis, N. V., Baumann, I., Sturgeon, J. A., Melloh, M., Mackey, S. C. 2018

  Abstract

  Background: Evidence suggests social interactions play an important role in pain perception.Purpose: The aim of this study was to determine whether social isolation (SI) in people with persistent pain determines pain interference (PI) and physical function over time.Methods: Patients seeking care at a tertiary pain management referral center were administered the Patient Reported Outcome Measurement Information System (PROMIS) SI, PI, physical function, depression, and average pain intensity item banks at their initial consultation and subsequent visits as part of their routine clinical care. We used a post hoc simulation of an experiment using propensity score matching (n = 4,950) and carried out a cross-lagged longitudinal analysis (n = 312) of retrospective observational data.Results: Cross-lagged longitudinal analysis showed that SI predicted PI at the next time point, above and beyond the effects of pain intensity and covariates, but not vice versa.Conclusions: These data support the importance of SI as a factor in pain-related appraisal and coping and demonstrate that a comprehensive assessment of the individuals' social context can provide a better understanding of the differential trajectories for a person living with pain. Our study provides evidence that the impact of pain is reduced in individuals who perceive a greater sense of inclusion from and engagement with others. This study enhances the understanding of how social factors affect pain and have implications for how the effectiveness of therapeutic interventions may be improved. Therapeutic interventions aimed at increasing social connection hold merit in reducing the impact of pain on engagement with activities.

  View details for PubMedID 29668841

• Effects of Opioids on Causal Relationships Between Intrinsic Connectivity Brain Networks in Patients with Chronic Low Back Pain - A Resting-State fMRI Study Jarrahi, B., Mackey, S. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090806080

• Altered prefrontal correlates of monetary anticipation and outcome in chronic pain. Pain Martucci, K. T., Borg, N., MacNiven, K. H., Knutson, B., Mackey, S. C. 2018

  Abstract

  Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

  View details for PubMedID 29790868

• Predictors of Daily Pain Medication Use in Individuals with Recurrent Back Pain INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE Sturgeon, J. A., Hah, J. M., Sharifzadeh, Y., Middleton, S. K., Rico, T., Johnson, K. A., Mackey, S. C. 2018; 25 (2): 252–58

  Abstract

  A key component to chronic pain management regimens is the use of analgesic medications. Psychological factors, such as mood states, may also affect the use of pain medications for individuals with chronic pain, but few observational studies have examined how these factors may predict pain medication use at the daily level.Daily assessments from 104 individuals with back pain were used to examine fluctuations in daily pain intensity, mood, sleep quality, and physical activity as predictors of the likelihood of pain medication (opioid and non-opioid) use and levels of medication use on the same day.Pain intensity and mood ratings significantly predicted whether participants used pain medication on the same day, while only pain intensity predicted whether participants used more medication than usual. Further, current opioid users were more likely to increase the amount of their medication use on days of higher pain.This article identifies fluctuations in daily pain intensity and mood as salient predictors of daily pain medication use in individuals with recurrent back pain. The current study is among the first to highlight both pain and mood states as predictors of daily pain medication use in individuals with back pain, though future studies may expand on these findings through the use of higher-resolution daily medication use variables.

  View details for PubMedID 28875436

  View details for PubMedCentralID PMC5837935

• The impact of perceived injustice on pain-related outcomes: A combined model examining the mediating roles of pain acceptance and anger in a chronic pain sample Clin J Pain Carrier, J., Sturgeon, J., Yakabov, E., Kao, M., Mackey, S., Darnall, B. 2018: 739–47

  Abstract

  Perceived injustice (PI) has been identified as an important risk factor for pain-related outcomes. To date, research has shown that pain acceptance and anger are mediators of the association between PI and pain-related outcomes. However, a combined conceptual model that addresses the interrelationships between these variables is currently lacking. Therefore, the current study aimed to examine the potential mediating roles of pain acceptance and anger on the association between PI and adverse pain-related outcomes (physical function, pain intensity, opioid use status).This cross-sectional study used a sample of 354 patients with chronic pain being treated at a tertiary pain treatment center. Participants completed measures of PI, pain acceptance, anger, physical function, pain intensity, and opioid use status. Mediation analyses were used to examine the impact of pain acceptance and anger on the association between PI and pain-related outcomes.Examination of the specific indirect effects revealed that pain acceptance fully mediated the relationship between PI and physical function, as well as the relationship between PI and opioid use status. Pain acceptance emerged as a partial mediator of the relationship between PI and pain intensity.This is the first study to provide a combined conceptual model investigating the mediating roles of pain acceptance and anger on the relationship between PI and pain outcomes. On the basis of our findings, low levels of pain acceptance associated with PI may help explain the association between PI and adverse pain outcomes. Clinical and theoretical implications are discussed.

  View details for DOI 10.1097/AJP.0000000000000602

• The Impact of Perceived Injustice on Pain-related Outcomes: A Combined Model Examining the Mediating Roles of Pain Acceptance and Anger in a Chronic Pain Sample. The Clinical journal of pain Carriere, J. S., Sturgeon, J. A., Yakobov, E., Kao, M. C., Mackey, S. C., Darnall, B. D. 2018; 34 (8): 739–47

  Abstract

  Perceived injustice (PI) has been identified as an important risk factor for pain-related outcomes. To date, research has shown that pain acceptance and anger are mediators of the association between PI and pain-related outcomes. However, a combined conceptual model that addresses the interrelationships between these variables is currently lacking. Therefore, the current study aimed to examine the potential mediating roles of pain acceptance and anger on the association between PI and adverse pain-related outcomes (physical function, pain intensity, opioid use status).This cross-sectional study used a sample of 354 patients with chronic pain being treated at a tertiary pain treatment center. Participants completed measures of PI, pain acceptance, anger, physical function, pain intensity, and opioid use status. Mediation analyses were used to examine the impact of pain acceptance and anger on the association between PI and pain-related outcomes.Examination of the specific indirect effects revealed that pain acceptance fully mediated the relationship between PI and physical function, as well as the relationship between PI and opioid use status. Pain acceptance emerged as a partial mediator of the relationship between PI and pain intensity.This is the first study to provide a combined conceptual model investigating the mediating roles of pain acceptance and anger on the relationship between PI and pain outcomes. On the basis of our findings, low levels of pain acceptance associated with PI may help explain the association between PI and adverse pain outcomes. Clinical and theoretical implications are discussed.

  View details for PubMedID 29485535

• Advancing Transcranial Magnetic Stimulation Methods for Complex Regional Pain Syndrome: An Open-Label Study of Paired Theta Burst and High-Frequency Stimulation. Neuromodulation : journal of the International Neuromodulation Society Gaertner, M., Kong, J. T., Scherrer, K. H., Foote, A., Mackey, S., Johnson, K. A. 2018; 21 (4): 409–16

  Abstract

  Complex Regional Pain Syndrome (CRPS), a rare and severe chronic pain condition, often responds poorly to existing treatments. Previous studies demonstrated Transcranial Magnetic Stimulation (TMS) provided short-term pain relief for upper extremity CRPS.Building on previous methodologies, we employed a TMS protocol that may lead to significant pain relief for upper and lower extremity CRPS in a nonrandomized open label pilot trial involving 21 participants. We individualized TMS coil positioning over motor cortex of somatic pain location, and administered intermittent theta-burst stimulation followed by 10 Hz high-frequency stimulation using a deeper targeting coil. We assessed response (≥30% pain reduction) from a single session (n = 5) and five consecutive daily sessions (n = 12) and compared change in pain from baseline, after one treatment and one-week posttreatment between groups using a mixed ANVOA.Both groups demonstrated significant pain reduction after one session and one-week posttreatment; however, no group differences were present. From a single session, 60% of participants responded at Week 1. From five sessions, 58% and 50% of participants responded at Weeks 1 and 2, respectively. Two from each group achieved >50% pain reduction beyond six to eight weeks. No serious adverse events occurred. Though headache and nausea were the most common side-effects, we urge careful monitoring to prevent seizures with this protocol.We used a TMS protocol that, for the first time, led to significant pain relief in upper and lower extremity CRPS, and will soon examine our protocol in a larger, controlled trial.

  View details for PubMedID 29504190

• Comparative Efficacy and Mechanisms of a Single-Session Pain Psychology Class in Chronic Low Back Pain: Study Protocol for a Randomized Controlled Trial. Trials Darnall, B. D., Ziadni, M. S., Roy, A., Kao, M. C., Sturgeon, J. A., Cook, K. F., Lorig, K., Burns, J. W., Mackey, S. C. 2018; 19 (1): 165

  Abstract

  The Institute of Medicine (IOM) reported that chronic pain affects about 100 million U.S. adults, with chronic low back pain (CLBP) cited as the most prevalent type. Pain catastrophizing is a psychological construct shown to predict the development and trajectory of chronic pain and patient response to pain treatments. While effective treatment for pain catastrophizing typically includes eight-session groups of cognitive behavioral therapy (CBT), a single-session targeted treatment class yielded promising results which, if replicated and extended, could prove to efficiently and cost-effectively reduce pain catastrophizing. In this trial, we seek to determine the comparative efficacy of this novel single-session pain catastrophizing class to an eight-session course of pain CBT and a single-session back pain health education class. We will also explore the psychosocial mechanisms and outcomes of pain catastrophizing treatment.In this trial we will randomize 231 individuals with CLBP to one of three treatment arms: (1) pain-CBT (eight weekly 2-h group sessions with home exercises and readings); (2) a single 2-h pain catastrophizing class; or (3) a single 2-h back pain health education class (active control). For the primary outcome of pain catastrophizing, the trial is designed as a non-inferiority test between pain-CBT and the single-session pain catastrophizing class, and as a superiority test between the single-session pain catastrophizing class and the health education class. Team researchers masked to treatment assignment will assess outcomes up to six months post treatment.If the single-session targeted pain catastrophizing class is found to be an effective treatment for patients with CLBP, this low cost and low burden treatment could dismantle many of the current barriers and burdens of effective pain care. Further, elucidation of the mechanisms of pain catastrophizing treatments will facilitate future research on the topic as well as further development and refinement of treatments.ClinicalTrials.gov, NCT03167086 . Registered on 22 May 2017.

  View details for PubMedID 29510735

• Scope and Nature of Pain and Analgesia-Related Content of the United States Medical Licensing Examination (USMLE) Pain Medicine Fishman, S., Carr, D., Hogans, B., Cheatle, M., Gallagher, R., Katzman, J., Mackey, S., Young, H. 2018: 449–59

  Abstract

  "The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE).An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance.Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain.This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

  View details for DOI 10.1093/pm/pnx336

• The impact of perceived injustice on pain-related outcomes: A combined model examining the mediating roles of pain acceptance and anger in a chronic pain sample Clin J Pain Carriere, J., Sturgeon, J., Yakobov, E., Kao, M., Mackey, S., Darnall, B. 2018
• Advancing Transcranial Magnetic Stimulation Methods for Complex Regional Pain Syndrome: An Open-Label Study of Paired Theta Burst and High-Frequency Stimulation Neuromodulation Gaertner, M., Kong, J., Scherrer, K., Foote, A., Mackey, S., Johnson, K. 2018

  View details for DOI 10.1111/ner.12760

• Comparative Efficacy and Mechanisms of a Single-Session Pain Psychology Class in Chronic Low Back Pain: Study Protocol for a Randomized Controlled Trial Trials Darnall, B., Siadni, M., Roy, A., Kao, M., Sturgeon, J., Cook, K., Lorig, K., Burns, J., Mackey, S. 2018: 165

  Abstract

  The Institute of Medicine (IOM) reported that chronic pain affects about 100 million U.S. adults, with chronic low back pain (CLBP) cited as the most prevalent type. Pain catastrophizing is a psychological construct shown to predict the development and trajectory of chronic pain and patient response to pain treatments. While effective treatment for pain catastrophizing typically includes eight-session groups of cognitive behavioral therapy (CBT), a single-session targeted treatment class yielded promising results which, if replicated and extended, could prove to efficiently and cost-effectively reduce pain catastrophizing. In this trial, we seek to determine the comparative efficacy of this novel single-session pain catastrophizing class to an eight-session course of pain CBT and a single-session back pain health education class. We will also explore the psychosocial mechanisms and outcomes of pain catastrophizing treatment.In this trial we will randomize 231 individuals with CLBP to one of three treatment arms: (1) pain-CBT (eight weekly 2-h group sessions with home exercises and readings); (2) a single 2-h pain catastrophizing class; or (3) a single 2-h back pain health education class (active control). For the primary outcome of pain catastrophizing, the trial is designed as a non-inferiority test between pain-CBT and the single-session pain catastrophizing class, and as a superiority test between the single-session pain catastrophizing class and the health education class. Team researchers masked to treatment assignment will assess outcomes up to six months post treatment.If the single-session targeted pain catastrophizing class is found to be an effective treatment for patients with CLBP, this low cost and low burden treatment could dismantle many of the current barriers and burdens of effective pain care. Further, elucidation of the mechanisms of pain catastrophizing treatments will facilitate future research on the topic as well as further development and refinement of treatments.ClinicalTrials.gov, NCT03167086 . Registered on 22 May 2017.

  View details for DOI 10.1186/s13063-018-2537-3

  View details for PubMedCentralID PMC5838852

• Neuroimaging of Pain: Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation Anesthesiology Martucci, K., Mackey, S. 2018
• Automatic Segmentation of Cervical Spinal Cord Damage in Incomplete Spinal Cord Injury using Three-Dimensional T₂-Weighted Magnetic Resonance Imaging and Convolutional Neural Networks: An Application of V-Net on the NiftyNet Platform Radiology Weber, K., Mackey, S. 2018
• Scope and Nature of Pain- and Analgesia-Related Content of the United States Medical Licensing Examination (USMLE). Pain medicine (Malden, Mass.) Fishman, S. M., Carr, D. B., Hogans, B., Cheatle, M., Gallagher, R. M., Katzman, J., Mackey, S., Polomano, R., Popescu, A., Rathmell, J. P., Rosenquist, R. W., Tauben, D., Beckett, L., Li, Y., Mongoven, J. M., Young, H. M. 2018; 19 (3): 449–59

  Abstract

  "The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE).An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance.Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain.This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

  View details for PubMedID 29365160

• Radiofrequency Denervation for Chronic Low Back Pain JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kao, M., Leong, M. S., Mackey, S. 2017; 318 (22): 2256

  View details for DOI 10.1001/jama.2017.16382

  View details for Web of Science ID 000417822700026

• Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations NATURE REVIEWS NEUROLOGY Davis, K. D., Flor, H., Greely, H. T., Iannetti, G., Mackey, S., Ploner, M., Pustilnik, A., Tracey, I., Treede, R., Wager, T. D. 2017; 13 (10): 624–38

  Abstract

  Chronic pain is the greatest source of disability globally and claims related to chronic pain feature in many insurance and medico-legal cases. Brain imaging (for example, functional MRI, PET, EEG and magnetoencephalography) is widely considered to have potential for diagnosis, prognostication, and prediction of treatment outcome in patients with chronic pain. In this Consensus Statement, a presidential task force of the International Association for the Study of Pain examines the capabilities of brain imaging in the diagnosis of chronic pain, and the ethical and legal implications of its use in this way. The task force emphasizes that the use of brain imaging in this context is in a discovery phase, but has the potential to increase our understanding of the neural underpinnings of chronic pain, inform the development of therapeutic agents, and predict treatment outcomes for use in personalized pain management. The task force proposes standards of evidence that must be satisfied before any brain imaging measure can be considered suitable for clinical or legal purposes. The admissibility of such evidence in legal cases also strongly depends on laws that vary between jurisdictions. For these reasons, the task force concludes that the use of brain imaging findings to support or dispute a claim of chronic pain - effectively as a pain lie detector - is not warranted, but that imaging should be used to further our understanding of the mechanisms underlying pain.

  View details for PubMedID 28884750

• Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study PAIN Kutch, J. J., Ichesco, E., Hampson, J. P., Labus, J. S., Farmer, M. A., Martucci, K. T., Ness, T. J., Deutsch, G., Apkarian, A., Mackey, S. C., Klumpp, D. J., Schaeffer, A. J., Rodriguez, L. V., Kreder, K. J., Buchwald, D., Andriole, G. L., Lai, H., Mullins, C., Kusek, J. W., Landis, J., Mayer, E. A., Clemens, J., Clauw, D. J., Harris, R. E., MAPP Res Network 2017; 158 (10): 1979–91

  Abstract

  Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

  View details for PubMedID 28692006

  View details for PubMedCentralID PMC5964335

• A prospective, multisite, international validation of the Complex Regional Pain Syndrome Severity Score PAIN Harden, R., Maihofner, C., Abousaad, E., Vatine, J., Kirsling, A., Perez, R. M., Kuroda, M., Brunner, F., Stanton-Hicks, M., Marinus, J., van Hilten, J. J., Mackey, S., Birklein, F., Schlereth, T., Mailis-Gagnon, A., Graciosa, J., Connoly, S. B., Dayanim, D., Massey, M., Frank, H., Livshitz, A., Bruehl, S. 2017; 158 (8): 1430–36

  Abstract

  Clinical diagnosis of complex regional pain syndrome (CRPS) is a dichotomous (yes/no) categorization, a format necessary for clinical decision making. Such dichotomous diagnostic categories do not convey an individual's subtle gradations in the severity of the condition over time and have poor statistical power when used as an outcome measure in research. This prospective, international, multicenter study slightly modified and further evaluated the validity of the CRPS Severity Score (CSS), a continuous index of CRPS severity. Using a prospective design, medical evaluations were conducted in 156 patients with CRPS to compare changes over time in CSS scores between patients initiating a new treatment program and patients on stable treatment regimens. New vs stable categorizations were supported by greater changes in pain and function in the former. Results indicated that CSS values in the stable CRPS treatment group exhibited much less change over time relative to the new treatment group, with intraclass correlations nearly twice as large in the former. A calculated smallest real difference value revealed that a change in the CSS of ≥4.9 scale points would indicate real differences in CRPS symptomatology (with 95% confidence). Across groups, larger changes in CRPS features on the CSS over time were associated in the expected direction with greater changes in pain intensity, fatigue, social functioning, ability to engage in physical roles, and general well-being. The overall pattern of findings further supports the validity of the CSS as a measure of CRPS severity and suggests it may prove useful in clinical monitoring and outcomes research.

  View details for DOI 10.1097/j.pain.0000000000000927

  View details for Web of Science ID 000406932300006

  View details for PubMedID 28715350

• Resting-state functional connectivity predicts longitudinal pain symptom change in urologic chronic pelvic pain syndrome: a MAPP network study. Pain Kutch, J. J., Labus, J. S., Harris, R. E., Martucci, K. T., Farmer, M. A., Fenske, S., Fling, C., Ichesco, E., Peltier, S., Petre, B., Guo, W., Hou, X., Stephens, A. J., Mullins, C., Clauw, D. J., Mackey, S. C., Apkarian, A. V., Landis, J. R., Mayer, E. A. 2017; 158 (6): 1069-1082

  Abstract

  Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.

  View details for DOI 10.1097/j.pain.0000000000000886

  View details for PubMedID 28328579

• Development and Validation of a Daily Pain Catastrophizing Scale. journal of pain Darnall, B. D., Sturgeon, J. A., Cook, K. F., Taub, C. J., Roy, A., Burns, J. W., Sullivan, M., Mackey, S. C. 2017

  Abstract

  To date, there is no validated measure for pain catastrophizing at the daily level. The Pain Catastrophizing Scale (PCS) is widely used to measure trait pain catastrophizing. We sought to develop and validate a brief, daily version of the PCS for use in daily diary studies to facilitate research on mechanisms of catastrophizing treatment, individual differences in self-regulation, and to reveal the nuanced relationships between catastrophizing, correlates, and pain outcomes. After adapting the PCS for daily use, we evaluated the resulting 14 items using 3 rounds of cognitive interviews with 30 adults with chronic pain. We refined and tested the final daily PCS in 3 independent, prospective, cross-sectional, observational validation studies conducted in a combined total of 519 adults with chronic pain who completed online measures daily for 14 consecutive days. For study 1 (N = 131), exploratory factor analysis revealed adequate fit and-unexpectedly-unidimensionality for item responses to the daily PCS. Study 2 (N = 177) correlations indicated adequate association with related constructs (anger, anxiety, pain intensity, depression). Similarly, results for study 3 (N = 211) revealed expected correlations for daily PCS and measures of daily constructs including physical activity, sleep, energy level, and positive affect. Results from complex/multilevel confirmatory factor analysis confirmed good fit to a unidimensional model. Scores on the daily PCS were statistically comparable with and more parsimonious than the full 14-item version. Next steps include evaluation of score validity in populations with medical diagnoses, greater demographic diversity, and in patients with acute pain.This article describes the development and validation of a daily PCS. This daily measure may facilitate research that aims to characterize pain mechanisms, individual differences in self-regulation, adaptation, and nuanced relationships between catastrophizing, correlates, and pain outcomes.

  View details for DOI 10.1016/j.jpain.2017.05.003

  View details for PubMedID 28528981

• The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions JOURNAL OF PAIN Kent, M. L., Tighe, P. J., Belfer, I., Brennan, T. J., Bruehl, S., Brummett, C. M., Buckenmaier, C. C., Buvanendran, A., Cohen, R. I., Desjardins, P., Edwards, D., Fillingim, R., Gewandter, J., Gordon, D. B., Hurler, R. W., Kehlet, H., Loeser, J. D., Mackey, S., McLean, S. A., Polomano, R., Rahman, S., Raja, S., Rowbotham, M., Suresh, S., Schachte, B., Schreiber, K., Schumacher, M., Staceyi, B., Stanos, S., Todd, K., Turk, D. C., Weisman, S. J., Wu, C., Carr, D. B., Dworkin, R. H., Terman, G. 2017; 18 (5): 479-489

  Abstract

  With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain.Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM).As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions.The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms.Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

  View details for DOI 10.1016/j.jpain.2017.02.421

  View details for Web of Science ID 000401219500001

  View details for PubMedID 28495013

• A Randomized Trial of Perioperative Gabapentin to Promote Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort Hah, J., Mackey, S., Efron, B., Mccue, R., Goodman, S., Curtin, C., Carroll, I. LIPPINCOTT WILLIAMS & WILKINS. 2017: 813–17

  View details for Web of Science ID 000412683000420

• Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis BMJ-BRITISH MEDICAL JOURNAL Sun, E. C., Dixit, A., Humphreys, K., Darnall, B. D., Baker, L. C., Mackey, S. 2017; 356

  Abstract

  Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose.Design Retrospective analysis of claims data, 2001-13.Setting Administrative health claims database.Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid.Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose.Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16).Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.

  View details for DOI 10.1136/bmj.j760

  View details for Web of Science ID 000397014900002

  View details for PubMedID 28292769

• A Double-Blind Placebo Randomized Controlled Trial of Minocycline to Reduce Pain After Carpal Tunnel and Trigger Finger Release. journal of hand surgery Curtin, C. M., Kenney, D., Suarez, P., Hentz, V. R., Hernandez-Boussard, T., Mackey, S., Carroll, I. R. 2017; 42 (3): 166-174

  Abstract

  Minocycline is a microglial cell inhibitor and decreases pain behaviors in animal models. Minocycline might represent an intervention for reducing postoperative pain. This trial tested whether perioperative administration of minocycline reduced time to pain resolution (TPR) after standardized hand surgeries with known prolonged pain profiles: carpal tunnel release (CTR) and trigger finger release (TFR).This double-blinded randomized controlled trial included patients undergoing CTR or TFR under local anesthesia. Before surgery, participants recorded psychological and pain measures. Participants received oral minocycline, 200 mg, or placebo 2 hours prior to procedure, and then 100 mg of minocycline or placebo 2 times a day for 5 days. After surgery, participants were called daily assessing their pain. The primary end point of TPR was when participants had 3 consecutive days of 0 postsurgical pain. Futility analysis and Kaplan-Meier analyses were performed.A total of 131 participants were randomized and 56 placebo and 58 controls were analyzed. Median TPR for CTR was 3 weeks, with 15% having pain more than 6 weeks. Median TPR for TFR was 2 weeks with 18% having pain more than 6 weeks. The overall median TPR for the placebo group was 2 weeks (10% pain > 6 weeks) versus 2.5 weeks (17% pain > 6 weeks) for the minocycline group. Futility analysis found that the likelihood of a true underlying clinically meaningful reduction in TPR owing to minocycline was only 3.5%. Survival analysis found minocycline did not reduce TPR. However, subgroup analysis of those with elevated posttraumatic distress scores found the minocycline group had longer TPR.Oral administration of minocycline did not reduce TPR after minor hand surgery. There was evidence that minocycline might increase length of pain in those with increased posttraumatic stress disorder symptoms.Therapeutic I.

  View details for DOI 10.1016/j.jhsa.2016.12.011

  View details for PubMedID 28259273

• SIMULATION FOR CHRONIC PAIN OPIOID MANAGEMENT: SYMPATHY AFFECTS PHYSICIAN PRESCRIBING DECISIONS Heirich, M., Mackey, S., Newmark, J. SPRINGER. 2017: S534–S535

  View details for Web of Science ID 000398947200344

• Pain interference and physical function demonstrate poor longitudinal association in people living with pain: A PROMIS investigation. Pain Karayannis, N. V., Sturgeon, J. A., Chih-Kao, M., Cooley, C., Mackey, S. C. 2017

  Abstract

  A primary goal in managing pain is to reduce pain and increase physical function (PF). This goal is also tied to continuing payment for treatment services in many practice guidelines. Pain interference (PI) is often used as a proxy for measurement and reporting of PF in these guidelines. A common assumption is that reductions in PI will translate into improvement in PF over time. This assumption needs to be tested in a clinical environment. Consequently, we used the patient reported outcomes measurement information system (PROMIS) to describe the topology of the longitudinal relationship between PI in relation to PF.Longitudinal data of 389 people with chronic pain seeking healthcare demonstrated that PI partially explained the variance in PF at baseline (r = -0.50) and over 90 days of care(r = -0.65). The relationship between pain intensity and PF was not significant when PI was included as a mediator. A parallel process latent growth curve model analysis showed a weak, unidirectional relationship (β = 0.18) between average PF scores and changes in PI over the course of 90 days of care, and no relationship between average PI scores and changes in PF across time.Although PI and PF appear moderately related when measured concurrently, they do not cluster closely together across time. The differential pathways between these two domains suggest that therapies which target both the consequences of pain on relevant aspects of persons' lives, and capability to perform physical activities are likely required for restoration of a vital life.

  View details for DOI 10.1097/j.pain.0000000000000881

  View details for PubMedID 28221284

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA surgery Hah, J., Mackey, S. C., Schmidt, P., McCue, R., Humphreys, K., Trafton, J., Efron, B., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J., Curtin, C., Carroll, I. 2017

  Abstract

  Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research.clinicaltrials.gov Identifier: NCT01067144.

  View details for PubMedID 29238824

• Pain Catastrophizing Moderates Relationships between Pain Intensity and Opioid Prescription: Nonlinear Sex Differences Revealed Using a Learning Health System. Anesthesiology Sharifzadeh, Y., Kao, M. C., Sturgeon, J. A., Rico, T. J., Mackey, S., Darnall, B. D. 2017; 127 (1): 136–46

  Abstract

  Pain catastrophizing is a maladaptive response to pain that amplifies chronic pain intensity and distress. Few studies have examined how pain catastrophizing relates to opioid prescription in outpatients with chronic pain.The authors conducted a retrospective observational study of the relationships between opioid prescription, pain intensity, and pain catastrophizing in 1,794 adults (1,129 women; 63%) presenting for new evaluation at a large tertiary care pain treatment center. Data were sourced primarily from an open-source, learning health system and pain registry and secondarily from manual review of electronic medical records. A binary opioid prescription variable (yes/no) constituted the dependent variable; independent variables were age, sex, pain intensity, pain catastrophizing, depression, and anxiety.Most patients were prescribed at least one opioid medication (57%; n = 1,020). A significant interaction and main effects of pain intensity and pain catastrophizing on opioid prescription were noted (P < 0.04). Additive modeling revealed sex differences in the relationship between pain catastrophizing, pain intensity, and opioid prescription, such that opioid prescription became more common at lower levels of pain catastrophizing for women than for men.Results supported the conclusion that pain catastrophizing and sex moderate the relationship between pain intensity and opioid prescription. Although men and women patients had similar Pain Catastrophizing Scale scores, historically "subthreshold" levels of pain catastrophizing were significantly associated with opioid prescription only for women patients. These findings suggest that pain intensity and catastrophizing contribute to different patterns of opioid prescription for men and women patients, highlighting a potential need for examination and intervention in future studies.

  View details for PubMedID 28614083

• Pain catastrophizing, perceived injustice, and pain intensity impair life satisfaction through differential patterns of physical and psychological disruption. Scandinavian journal of pain Sturgeon, J. A., Ziadni, M. S., Trost, Z., Darnall, B. D., Mackey, S. C. 2017; 17: 390–96

  Abstract

  Previous research has highlighted the importance of cognitive appraisal processes in determining the nature and effectiveness of coping with chronic pain. Two of the key variables implicated in appraisal of pain are catastrophizing and perceived injustice, which exacerbate the severity of pain-related distress and increase the risk of long-term disability through maladaptive behavioural responses. However, to date, the influences of these phenomena have not been examined concurrently, nor have they been related specifically to quality of life measures, such as life satisfaction.Using data from an online survey of 330 individuals with chronic pain, structural path modelling techniques were used to examine the independent effects of pain catastrophizing, perceived injustice, and average pain intensity on life satisfaction. Two potential mediators of these relationships were examined: depressive symptoms and pain-related interference.Results indicated that depressive symptoms fully mediated the relationship between pain catastrophizing and life satisfaction, and pain interference fully mediated the relationship between pain intensity and life satisfaction. Both depressive symptoms and pain interference were found to significantly mediate the relationship between perceived injustice and life satisfaction, but perceived injustice continued to demonstrate a significant and negative relationship with life satisfaction, above and beyond the other study variables.The current findings highlight the distinct affective and behavioural mediators of pain and maladaptive cognitive appraisal processes in chronic pain, and highlight their importance in both perceptions of pain-related interference and longer-term quality of life.

  View details for PubMedID 29074199

• Pain catastrophizing mediates the relationship between trait happiness and depressive symptoms in individuals with current pain. Journal of applied biobehavioral research Tran, P., Sturgeon, J. A., Nilakantan, A., Foote, A., Mackey, S., Johnson, K. 2017; 22 (4)

  Abstract

  There is an extensive relationship between chronic pain and depression; however, there is less research examining whether pain-specific factors, such as pain intensity, predict depression, above and beyond the role of normative factors, such as positive emotions. The current study characterized the independent contributions of pain intensity, pain catastrophizing, and a trait measure of happiness to self-rated depressive symptoms.We recruited and enrolled 70 volunteers across 3 groups of participants: two groups of patients with current low back pain (one group on opioids and one group opioid-naïve), and individuals in a methadone maintenance treatment program.Of note, participants reporting concurrent opioid use reported significantly higher levels of depressive symptomatology, although study groups did not differ on any other clinical variables. In our path model, we failed to find direct relationships between pain (intensity or duration) and either trait happiness or depressive symptoms (p > .05). However, our analysis did reveal that individuals with chronic back pain who reported higher levels of trait happiness reported lower levels of depressive symptomatology; this effect was significantly mediated by lower levels of pain catastrophizing (standardized ab = -.144, p = .002).Our analysis suggests that trait happiness, while unrelated to ongoing pain, may predict a decreased vulnerability to depressive symptoms in individuals with chronic pain, which may operate via lower levels of pain catastrophizing.

  View details for PubMedID 29456448

• Pain interference and physical function follow distinct trajectories for people with chronic pain PAIN Karayannis, N. V., Sturgeon, J. A., Kao, M. J., Cooley, C., Mackey, S. C. 2017

  Abstract

  A primary goal in managing pain is to reduce pain and increase physical function (PF). This goal is also tied to continuing payment for treatment services in many practice guidelines. Pain interference (PI) is often used as a proxy for measurement and reporting of PF in these guidelines. A common assumption is that reductions in PI will translate into improvement in PF over time. This assumption needs to be tested in a clinical environment. Consequently, we used the patient reported outcomes measurement information system (PROMIS) to describe the topology of the longitudinal relationship between PI in relation to PF.Longitudinal data of 389 people with chronic pain seeking healthcare demonstrated that PI partially explained the variance in PF at baseline (r = -0.50) and over 90 days of care(r = -0.65). The relationship between pain intensity and PF was not significant when PI was included as a mediator. A parallel process latent growth curve model analysis showed a weak, unidirectional relationship (β = 0.18) between average PF scores and changes in PI over the course of 90 days of care, and no relationship between average PI scores and changes in PF across time.Although PI and PF appear moderately related when measured concurrently, they do not cluster closely together across time. The differential pathways between these two domains suggest that therapies which target both the consequences of pain on relevant aspects of persons' lives, and capability to perform physical activities are likely required for restoration of a vital life.

  View details for DOI 10.1097/j.pain.0000000000000881

• Pain catastrophizing moderates the relationship between pain intensity and opioid prescription: Non-linear gender differences revealed using a learning health system Anesthesiology Sharifzadeh, Y., Kao, M., Sturgeon, J., Mackey, S., Darnall, B. 2017: 136–46

  Abstract

  Pain catastrophizing is a maladaptive response to pain that amplifies chronic pain intensity and distress. Few studies have examined how pain catastrophizing relates to opioid prescription in outpatients with chronic pain.The authors conducted a retrospective observational study of the relationships between opioid prescription, pain intensity, and pain catastrophizing in 1,794 adults (1,129 women; 63%) presenting for new evaluation at a large tertiary care pain treatment center. Data were sourced primarily from an open-source, learning health system and pain registry and secondarily from manual review of electronic medical records. A binary opioid prescription variable (yes/no) constituted the dependent variable; independent variables were age, sex, pain intensity, pain catastrophizing, depression, and anxiety.Most patients were prescribed at least one opioid medication (57%; n = 1,020). A significant interaction and main effects of pain intensity and pain catastrophizing on opioid prescription were noted (P < 0.04). Additive modeling revealed sex differences in the relationship between pain catastrophizing, pain intensity, and opioid prescription, such that opioid prescription became more common at lower levels of pain catastrophizing for women than for men.Results supported the conclusion that pain catastrophizing and sex moderate the relationship between pain intensity and opioid prescription. Although men and women patients had similar Pain Catastrophizing Scale scores, historically "subthreshold" levels of pain catastrophizing were significantly associated with opioid prescription only for women patients. These findings suggest that pain intensity and catastrophizing contribute to different patterns of opioid prescription for men and women patients, highlighting a potential need for examination and intervention in future studies.

  View details for DOI 10.1097/ALN.0000000000001656

  View details for PubMedCentralID PMC5478434

• Investigating the BOLD Spectral Power of the Intrinsic Connectivity Networks in Fibromyalgia Patients: A Resting-state fMRI Study Jarrahi, B., Martucci, K. T., Nilakantan, A. S., Mackey, S., IEEE IEEE. 2017: 497–500

  Abstract

  Recent advances in multivariate statistical analysis of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) have provided novel insights into the network organization of the human brain. Here, we applied group independent component analysis, a well-established approach for detecting brain intrinsic connectivity networks, to examine the spontaneous BOLD fluctuations in patients with fibromyalgia and healthy controls before and after exposure to a stressor. The BOLD spectral power characteristics of component time courses were calculated using the fast Fourier transform (FFT) algorithm, and group comparison was performed at six frequency bins between 0 and 0.24 Hz at 0.04 Hz intervals. Relative to controls, patients with fibromyalgia displayed significant BOLD spectral power differences in the default-mode, salience, and subcortical networks at the baseline level (PBon ferroni-corrected <; 0.05). Multivariate analysis of covariance (MANCOVA) further revealed significant effects of the cold water temperature, and pain rating on the spectral power of the sensorimotor, salience, and prefrontal networks, while the diagnosis of fibromyalgia influenced the BOLD spectral power of the salience and subcortical networks (PFDR-corrected <; 0.05). Since the BOLD spectral power reflects the degree of fluctuations within a network, future studies of the correlation between BOLD spectral power and pain processing can cast additional light on the nature of the central nervous system dysfunction in patients with chronic pain syndromes.

  View details for Web of Science ID 000427085300123

  View details for PubMedID 29059918

  View details for PubMedCentralID PMC5966014

• Pain catastrophizing, perceived injustice, and pain intensity impair life satisfaction through differential patterns of physical and psychological disruption Scand J Pain Sturgeon, J., Ziadni, M., Zina, T., Darnall, B., Mackey, S. 2017: 390–96

  Abstract

  Previous research has highlighted the importance of cognitive appraisal processes in determining the nature and effectiveness of coping with chronic pain. Two of the key variables implicated in appraisal of pain are catastrophizing and perceived injustice, which exacerbate the severity of pain-related distress and increase the risk of long-term disability through maladaptive behavioural responses. However, to date, the influences of these phenomena have not been examined concurrently, nor have they been related specifically to quality of life measures, such as life satisfaction.Using data from an online survey of 330 individuals with chronic pain, structural path modelling techniques were used to examine the independent effects of pain catastrophizing, perceived injustice, and average pain intensity on life satisfaction. Two potential mediators of these relationships were examined: depressive symptoms and pain-related interference.Results indicated that depressive symptoms fully mediated the relationship between pain catastrophizing and life satisfaction, and pain interference fully mediated the relationship between pain intensity and life satisfaction. Both depressive symptoms and pain interference were found to significantly mediate the relationship between perceived injustice and life satisfaction, but perceived injustice continued to demonstrate a significant and negative relationship with life satisfaction, above and beyond the other study variables.The current findings highlight the distinct affective and behavioural mediators of pain and maladaptive cognitive appraisal processes in chronic pain, and highlight their importance in both perceptions of pain-related interference and longer-term quality of life.

  View details for DOI 10.1016/j.sjpain.2017.09.020

  View details for PubMedCentralID PMC5726907

• Thermal Stimulation Alters Cervical Spinal Cord Functional Connectivity in Humans. Neuroscience Weber, K. A., Sentis, A. I., Bernadel-Huey, O. N., Chen, Y., Wang, X., Parrish, T. B., Mackey, S. 2017

  Abstract

  The spinal cord has an active role in the modulation and transmission of the neural signals traveling between the body and the brain. Recent advancements in functional magnetic resonance imaging (fMRI) have made the in vivo examination of spinal cord function in humans now possible. This technology has been recently extended to the investigation of resting state functional networks in the spinal cord, leading to the identification of distinct patterns of spinal cord functional connectivity. In this study, we expand on the previous work and further investigate resting state cervical spinal cord functional connectivity in healthy participants (n = 15) using high resolution imaging coupled with both seed-based functional connectivity analyses and graph theory-based metrics. Within spinal cord segment functional connectivity was present between the left and right ventral horns (bilateral motor network), left and right dorsal horns (bilateral sensory network), and the ipsilateral ventral and dorsal horns (unilateral sensory-motor network). Functional connectivity between the spinal cord segments was less apparent with the connectivity centered at the region of interest and spanning < 20 mm along the superior-inferior axis. In a subset of participants (n = 10), the cervical spinal cord functional network was demonstrated to be state-dependent as thermal stimulation of the right ventrolateral forearm resulted in significant disruption of the bilateral sensory network, increased network global efficiency, and decreased network modularity.

  View details for PubMedID 29101078

• First, Do No Harm - Marshaling clinician leadership to counter the opioid epidemic National Academy of Medicine - Special Publication Adams, S., Blanco, C., Chaudhry, H., Chen, H., Chou, R., Christopher, M., Harris, P., Levin, S., Mackey, S., McCance-Katz, E., Moore, P., Rathmell, J., Rieder, T., Twillman, B. 2017
• Psychological features and their relationship to movement based subgroups in people with low back pain. Archives of Physical Medicine and Rehabilitation Karayannis, N., Mackey, S. 2017
• Pain Catastrophizing Mediates the Relationship Between Trait Happiness and Depressive Symptoms in Individuals with Current Pain. J Appl Behav Res Tran, P., Sturgeon, J., Nilakantan, A., Foote, A., Mackey, S., Johnson, K. 2017

  View details for DOI 10.1111/jabr.12069

• Predictors of Daily Pain Medication Use in Individuals with Recurrent Back Pain. International Journal of Behavioral Medicine Sturgeon, J., Hah, J., Sharifzadeh, Y., Middleton, S. K., Rico, T., Johnson, K., Mackey, S. 2017
• Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study. Pain, October 2017, 158 (2017) 1979-1991. Pain Kutch, J., Ichesco, E., Hampson, J., Labus, J., Farmer, M., Martucci, K., Ness, T., Deutsch, G., Apkarian, A., Mackey, S., Klumpp, D., Schaeffer, A., Rodriguez, L., Kreder, K., Buchwald, D., Andriole, G., Lai, H., Mullins, C., Kusek, J., Landis, R., Mayer, E., Clemens, J., Clauw, D., Harris, R. 2017
• Thermal Stimulation alters Cervical Spinal Cord Functional Connectivity in Humans. Neuroscience Weber, K., Parrish, T., Bernadel-Huey, O., Sentis, A., Wang, X., Mackey, S. 2017
• A case-crossover study of urologic chronic pelvic pain syndrome flare triggers in the MAPP Research Network. J Urology Sutcliffe, S., Jemielita, T., Lai, H. H., Andriole, G. L., Bradley, C. S., Clemens, J. Q., Gallop, R., Hooton, T. M., Kreder, K. J., Krieger, J. N., Kusek, J. W., Labus, J., Lucia, M. S., Mackey, S., Naliboff, B. D., Robinson, N. A., Rodriguez, L. V., Stephens-Shields, A., van Bokhoven, A., Wolin, K. Y., Yan, Y., Yang, C. C., Landis, J. R., Colditz, G. A., MAPP Research Group 2017
• Factors associated with prescription opioid misuse in a cross-sectional cohort of patients with chronic non-cancer pain JOURNAL OF PAIN RESEARCH Hah, J. M., Sturgeon, J. A., Zocca, J., Sharifzadeh, Y., Mackey, S. C. 2017; 10: 979-987

  Abstract

  To examine demographic features, psychosocial characteristics, pain-specific behavioral factors, substance abuse history, sleep, and indicators of overall physical function as predictors of opioid misuse in patients presenting for new patient evaluation at a tertiary pain clinic.Overall, 625 patients with chronic non-cancer pain prospectively completed the Collaborative Health Outcomes Information Registry, assessing pain catastrophizing, National Institutes of Health Patient-Reported Outcomes Measurement Information System standardized measures (pain intensity, pain behavior, pain interference, physical function, sleep disturbance, sleep-related impairment, anger, depression, anxiety, and fatigue), and substance use history. Additional information regarding current opioid prescriptions and opioid misuse was examined through retrospective chart review.In all, 41 (6.6%) patients presented with some indication of prescription opioid misuse. In the final multivariable logistic regression model, those with a history of illicit drug use (odds ratio [OR] 5.45, 95% confidence interval [CI] 2.48-11.98, p<0.0001) and a current opioid prescription (OR 4.06, 95% CI 1.62-10.18, p=0.003) were at elevated risk for opioid misuse. Conversely, every 1-h increase in average hours of nightly sleep decreased the risk of opioid misuse by 20% (OR 0.80, 95% CI 0.66-0.97, p=0.02).These findings indicate the importance of considering substance use history, current opioid prescriptions, and sleep in universal screening of patients with chronic non-cancer pain for opioid misuse. Future work should target longitudinal studies to verify the causal relationships between these variables and subsequent opioid misuse.

  View details for DOI 10.2147/JPR.S131979

  View details for Web of Science ID 000400675500001

  View details for PubMedID 28496354

• Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study PAIN RESEARCH & MANAGEMENT Taub, C. J., Sturgeon, J. A., Johnson, K. A., Mackey, S. C., Darnall, B. D. 2017

  Abstract

  Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

  View details for DOI 10.1155/2017/7892494

  View details for Web of Science ID 000395018300001

  View details for PubMedID 28348505

• Lack of Association Between the Use of Nerve Blockade and the Risk of Persistent Opioid Use Among Patients Undergoing Shoulder Arthroplasty: Evidence From the Marketscan Database. Anesthesia and analgesia Mueller, K. G., Memtsoudis, S. G., Mariano, E. R., Baker, L. C., Mackey, S., Sun, E. C. 2017

  Abstract

  Persistent opioid use following surgery has received increasing attention from policymakers, researchers, and clinicians. Perioperative nerve blockade has been hypothesized to decrease the risk of persistent opioid use. We examined whether nerve blockade was associated with a decreased risk of persistent opioid use among patients undergoing shoulder arthroplasty, a procedure with high rates of persistent postoperative pain.Using health care claims data, we constructed a sample of 6695 patients undergoing shoulder arthroplasty between 2002 and 2012 and used billing data to identify the utilization of nerve blockade. We then used a multivariable logistic regression to estimate the association between nerve blockade and 2 measures of opioid use: having filled at least 1 prescription for an opioid between postoperative days (PODs) 0 and 90, and between POD 91 and 365. This regression adjusted for a variety of potential confounders, such as preoperative opioid use and medical history.There was no association between nerve blockade and our 2 measures of persistent opioid use: adjusted odds ratio, 1.12 (97.5% confidence interval, 0.939-1.34; P = .15) for opioid use between POD 0 and 90, and adjusted odds ratio, 0.997 (97.5% confidence interval, 0.875-1.14; P = .95) for opioid use between POD 91 and 365.Although the use of perioperative nerve blockade may offer short-term benefits, in this study, it was not associated with a reduction in the risk of persistent opioid use for patients undergoing shoulder arthroplasty.

  View details for PubMedID 28742777

• Radiofrequency Denervation for Chronic Low Back Pain. JAMA Kao, M. C., Leong, M. S., Mackey, S. 2017; 318 (22): 2256

  View details for PubMedID 29234799

• Brain white matter changes associated with urological chronic pelvic pain syndrome: multisite neuroimaging from a MAPP case-control study PAIN Huang, L., Kutch, J. J., Ellingson, B. M., Martucci, K. T., Harris, R. E., Clauw, D. J., Mackey, S., Mayer, E. A., Schaeffer, A. J., Apkarian, A. V., Farmer, M. A. 2016; 157 (12): 2782-2791

  Abstract

  Clinical phenotyping of urological chronic pelvic pain syndromes (UCPPSs) in men and women have focused on end organ abnormalities to identify putative clinical subtypes. Initial evidence of abnormal brain function and structure in male pelvic pain has necessitated large-scale, multisite investigations into potential UCPPS brain biomarkers. We present the first evidence of regional white matter (axonal) abnormalities in men and women with UCPPS, compared with positive (irritable bowel syndrome, IBS) and healthy controls. Epidemiological and neuroimaging data were collected from participants with UCPPS (n = 52), IBS (n = 39), and healthy sex- and age-matched controls (n = 61). White matter microstructure, measured as fractional anisotropy (FA), was examined by diffusion tensor imaging. Group differences in regional FA positively correlated with pain severity, including segments of the right corticospinal tract and right anterior thalamic radiation. Increased corticospinal FA was specific and sensitive to UCPPS, positively correlated with pain severity, and reflected sensory (not affective) features of pain. Reduced anterior thalamic radiation FA distinguished patients with IBS from those with UCPPS and controls, suggesting greater microstructural divergence from normal tract organization. Findings confirm that regional white matter abnormalities characterize UCPPS and can distinguish between visceral diagnoses, suggesting that regional axonal microstructure is either altered with ongoing pain or predisposes its development.

  View details for DOI 10.1097/j.pain.0000000000000703

  View details for Web of Science ID 000388501400019

  View details for PubMedID 27842046

  View details for PubMedCentralID PMC5117992

• Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans. Cell systems Shen-Orr, S. S., Furman, D., Kidd, B. A., Hadad, F., Lovelace, P., Huang, Y., Rosenberg-Hasson, Y., Mackey, S., Grisar, F. A., Pickman, Y., Maecker, H. T., Chien, Y., Dekker, C. L., Wu, J. C., Butte, A. J., Davis, M. M. 2016; 3 (4): 374-384 e4

  Abstract

  Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function.

  View details for DOI 10.1016/j.cels.2016.09.009

  View details for PubMedID 27746093

• United States National Pain Strategy for Population Research: Concepts, Definitions, and Pilot Data JOURNAL OF PAIN Von Korff, M., Scher, A. I., Helmick, C., Carter-Pokras, O., Dodick, D. W., Goulet, J., Hamill-Ruth, R., LeResche, L., Porter, L., Tait, R., Terman, G., Veasley, C., Mackey, S. 2016; 17 (10): 1068-1080

  Abstract

  National Pain Strategy population research objectives include: estimating chronic pain prevalence, studying pain treatment with electronic health care data, and developing metrics to assess progress in reducing chronic pain impact. In this article, the National Pain Strategy Population Research Workgroup reviews concepts relevant to achieving these aims. High-impact chronic pain was defined as persistent pain with substantial restriction of life activities lasting 6 months or more. In pilot work, we tested a brief assessment of high-impact chronic pain, and used electronic health records data to describe pain-related health care. A mail survey of adult health plan enrollees (N = 770) reported that 14% had high-impact chronic pain. Relative to persons with lower-impact chronic pain, those with high-impact chronic pain were more often frequent users of health care for pain, reported lower quality of life, greater pain-related interference with activities, and more often reported pain at multiple anatomic locations. Analyses of health care data (N = 289,464) reported that pain patients had higher health care costs compared with others and that pain services were typically delivered in primary care. These results support the feasibility of developing data on chronic pain through national health interview surveys and large electronic health care databases.Pilot analyses supported the feasibility of brief chronic pain assessments suitable for national health surveys and use of electronic health care databases to develop data regarding trends in the delivery of pain treatments, costs, and effectiveness. These methods are relevant to achieving the aims of the US National Pain Strategy.

  View details for DOI 10.1016/j.jpain.2016.06.009

  View details for Web of Science ID 000384874000003

  View details for PubMedID 27377620

• Incidence of and Risk Factors for Chronic Opioid Use Among Opioid-Naive Patients in the Postoperative Period. JAMA internal medicine Sun, E. C., Darnall, B. D., Baker, L. C., Mackey, S. 2016; 176 (9): 1286-1293

  Abstract

  Chronic opioid use imposes a substantial burden in terms of morbidity and economic costs. Whether opioid-naive patients undergoing surgery are at increased risk for chronic opioid use is unknown, as are the potential risk factors for chronic opioid use following surgery.To characterize the risk of chronic opioid use among opioid-naive patients following 1 of 11 surgical procedures compared with nonsurgical patients.Retrospective analysis of administrative health claims to determine the association between chronic opioid use and surgery among privately insured patients between January 1, 2001, and December 31, 2013. The data concluded 11 surgical procedures (total knee arthroplasty [TKA], total hip arthroplasty, laparoscopic cholecystectomy, open cholecystectomy, laparoscopic appendectomy, open appendectomy, cesarean delivery, functional endoscopic sinus surgery [FESS], cataract surgery, transurethral prostate resection [TURP], and simple mastectomy). Multivariable logistic regression analysis was performed to control for possible confounders, including sex, age, preoperative history of depression, psychosis, drug or alcohol abuse, and preoperatice use of benzodiazepines, antipsychotics, and antidepressants.One of the 11 study surgical procedures.Chronic opioid use, defined as having filled 10 or more prescriptions or more than 120 days' supply of an opioid in the first year after surgery, excluding the first 90 postoperative days. For nonsurgical patients, chronic opioid use was defined as having filled 10 or more prescriptions or more than 120 days' supply following a randomly assigned "surgery date."The study included 641 941 opioid-naive surgical patients (169 666 men; mean [SD] age, 44.0 [12.8] years), and 18 011 137 opioid-naive nonsurgical patients (8 849 107 men; mean [SD] age, 42.4 [12.6] years). Among the surgical patients, the incidence of chronic opioid in the first preoperative year ranged from 0.119% for Cesarean delivery (95% CI, 0.104%-0.134%) to 1.41% for TKA (95% CI, 1.29%-1.53%) The baseline incidence of chronic opioid use among the nonsurgical patients was 0.136% (95% CI, 0.134%-0.137%). Except for cataract surgery, laparoscopic appendectomy, FESS, and TURP, all of the surgical procedures were associated with an increased risk of chronic opioid use, with odds ratios ranging from 1.28 (95% CI, 1.12-1.46) for cesarean delivery to 5.10 (95% CI, 4.67-5.58) for TKA. Male sex, age older than 50 years, and preoperative history of drug abuse, alcohol abuse, depression, benzodiazepine use, or antidepressant use were associated with chronic opioid use among surgical patients.In opioid-naive patients, many surgical procedures are associated with an increased risk of chronic opioid use in the postoperative period. A certain subset of patients (eg, men, elderly patients) may be particularly vulnerable.

  View details for DOI 10.1001/jamainternmed.2016.3298

  View details for PubMedID 27400458

• Pediatric-Collaborative Health Outcomes Information Registry (Peds-CHOIR): a learning health system to guide pediatric pain research and treatment. Pain Bhandari, R. P., Feinstein, A. B., Huestis, S. E., Krane, E. J., Dunn, A. L., Cohen, L. L., Kao, M. C., Darnall, B. D., Mackey, S. C. 2016; 157 (9): 2033-2044

  Abstract

  The pediatric adaptation of the Collaborative Health Outcomes Information Registry (Peds-CHOIR) is a free, open-source, flexible learning health care system (LHS) that meets the call by the Institute of Medicine for the development of national registries to guide research and precision pain medicine. This report is a technical account of the first application of Peds-CHOIR with 3 aims: (1) to describe the design and implementation process of the LHS; (2) to highlight how the clinical system concurrently cultivates a research platform rich in breadth (eg, clinic characteristics) and depth (eg, unique patient- and caregiver-reporting patterns); and (3) to demonstrate the utility of capturing patient-caregiver dyad data in real time, with dynamic outcomes tracking that informs clinical decisions and delivery of treatments. Technical, financial, and systems-based considerations of Peds-CHOIR are discussed. Cross-sectional retrospective data from patients with chronic pain (N = 352; range, 8-17 years; mean, 13.9 years) and their caregivers are reported, including National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) domains (mobility, pain interference, fatigue, peer relations, anxiety, and depression) and the Pain Catastrophizing Scale. Consistent with the literature, analyses of initial visits revealed impairments across physical, psychological, and social domains. Patients and caregivers evidenced agreement in observable variables (mobility); however, caregivers consistently endorsed greater impairment regarding internal experiences (pain interference, fatigue, peer relations, anxiety, and depression) than patients' self-report. A platform like Peds-CHOIR highlights predictors of chronic pain outcomes on a group level and facilitates individually tailored treatment(s). Challenges of implementation and future directions are discussed.

  View details for DOI 10.1097/j.pain.0000000000000609

  View details for PubMedID 27280328

• Perturbed connectivity of the amygdala and its subregions with the central executive and default mode networks in chronic pain. Pain Jiang, Y., Oathes, D., Hush, J., Darnall, B., Charvat, M., Mackey, S., Etkin, A. 2016; 157 (9): 1970-1978

  Abstract

  Maladaptive responses to pain-related distress, such as pain catastrophizing, amplify the impairments associated with chronic pain. Many of these aspects of chronic pain are similar to affective distress in clinical anxiety disorders. In light of the role of the amygdala in pain and affective distress, disruption of amygdalar functional connectivity in anxiety states, and its implication in the response to noxious stimuli, we investigated amygdala functional connectivity in 17 patients with chronic low back pain and 17 healthy comparison subjects, with respect to normal targets of amygdala subregions (basolateral vs centromedial nuclei), and connectivity to large-scale cognitive-emotional networks, including the default mode network, central executive network, and salience network. We found that patients with chronic pain had exaggerated and abnormal amygdala connectivity with central executive network, which was most exaggerated in patients with the greatest pain catastrophizing. We also found that the normally basolateral-predominant amygdala connectivity to the default mode network was blunted in patients with chronic pain. Our results therefore highlight the importance of the amygdala and its network-level interaction with large-scale cognitive/affective cortical networks in chronic pain, and help link the neurobiological mechanisms of cognitive theories for pain with other clinical states of affective distress.

  View details for DOI 10.1097/j.pain.0000000000000606

  View details for PubMedID 27168362

• Complex regional pain syndrome: evidence for warm and cold subtypes in a large prospective clinical sample. Pain Bruehl, S., Maihöfner, C., Stanton-Hicks, M., Perez, R. S., Vatine, J., Brunner, F., Birklein, F., Schlereth, T., Mackey, S., Mailis-Gagnon, A., Livshitz, A., Harden, R. N. 2016; 157 (8): 1674-1681

  Abstract

  Limited research suggests that there may be Warm complex regional pain syndrome (CRPS) and Cold CRPS subtypes, with inflammatory mechanisms contributing most strongly to the former. This study for the first time used an unbiased statistical pattern recognition technique to evaluate whether distinct Warm vs Cold CRPS subtypes can be discerned in the clinical population. An international, multisite study was conducted using standardized procedures to evaluate signs and symptoms in 152 patients with clinical CRPS at baseline, with 3-month follow-up evaluations in 112 of these patients. Two-step cluster analysis using automated cluster selection identified a 2-cluster solution as optimal. Results revealed a Warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity and a Cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity. Median pain duration was significantly (P < 0.001) shorter in the Warm CRPS (4.7 months) than in the Cold CRPS subtype (20 months), with pain intensity comparable. A derived total inflammatory score was significantly (P < 0.001) elevated in the Warm CRPS group (compared with Cold CRPS) at baseline but diminished significantly (P < 0.001) over the follow-up period, whereas this score did not diminish in the Cold CRPS group (time × subtype interaction: P < 0.001). Results support the existence of a Warm CRPS subtype common in patients with acute (<6 months) CRPS and a relatively distinct Cold CRPS subtype most common in chronic CRPS. The pattern of clinical features suggests that inflammatory mechanisms contribute most prominently to the Warm CRPS subtype but that these mechanisms diminish substantially during the first year postinjury.

  View details for DOI 10.1097/j.pain.0000000000000569

  View details for PubMedID 27023422

• Social Disruption Mediates the Relationship Between Perceived Injustice and Anger in Chronic Pain: a Collaborative Health Outcomes Information Registry Study. Annals of behavioral medicine Sturgeon, J. A., Carriere, J. S., Kao, M. J., Rico, T., Darnall, B. D., Mackey, S. C. 2016: -?

  Abstract

  Perceptions of pain as unfair are a significant risk factor for poorer physical and psychological outcomes in acute injury and chronic pain. Chief among the negative emotions associated with perceived injustice is anger, arising through frustration of personal goals and unmet expectations regarding others' behavior. However, despite a theoretical connection with anger, the social mediators of perceived injustice have not been demonstrated in chronic pain.The current study examined two socially based variables and a broader measure of pain interference as mediators of the relationships between perceived injustice and both anger and pain intensity in a sample of 302 patients in a tertiary care pain clinic setting.Data from the Collaborative Health Outcomes Information Registry (CHOIR) were analyzed using cross-sectional path modeling analyses to examine social isolation, satisfaction with social roles and activities, and pain-related interference as potential mediators of the relationships between perceived injustice and both anger and pain intensity.When modeled simultaneously, ratings of social isolation mediated the relationship between perceived injustice and anger, while pain-related interference and social satisfaction did not. Neither social variable was found to mediate the relationship between perceived injustice and pain intensity, however.The current findings highlight the strongly interpersonal nature of perceived injustice and anger in chronic pain, though these effects do not appear to extend to the intensity of pain itself. Nevertheless, the results highlight the need for interventions that ameliorate both maladaptive cognitive appraisal of pain and pain-related disruptions in social relationships.

  View details for PubMedID 27325314

• Development of the Sensory Hypersensitivity Scale (SHS): a self-report tool for assessing sensitivity to sensory stimuli JOURNAL OF BEHAVIORAL MEDICINE Dixon, E. A., Benham, G., Sturgeon, J. A., Mackey, S., Johnson, K. A., Younger, J. 2016; 39 (3): 537-550

  Abstract

  Sensory hypersensitivity is one manifestation of the central sensitization that may underlie conditions such as fibromyalgia and chronic fatigue syndrome. We conducted five studies designed to develop and validate the Sensory Hypersensitive Scale (SHS); a 25-item self-report measure of sensory hypersensitivity. The SHS assesses both general sensitivity and modality-specific sensitivity (e.g. touch, taste, and hearing). 1202 participants (157 individuals with chronic pain) completed the SHS, which demonstrated an adequate overall internal reliability (Cronbach's alpha) of 0.81, suggesting the tool can be used as a cross-modality assessment of sensitivity. SHS scores demonstrated only modest correlations (Pearson's r) with depressive symptoms (0.19) and anxiety (0.28), suggesting a low level of overlap with psychiatric complaints. Overall SHS scores showed significant but relatively modest correlations (Pearson's r) with three measures of sensory testing: cold pain tolerance (-0.34); heat pain tolerance (-0.285); heat pain threshold (-0.271). Women reported significantly higher scores on the SHS than did men, although gender-based differences were small. In a chronic pain sample, individuals with fibromyalgia syndrome demonstrated significantly higher SHS scores than did individuals with osteoarthritis or back pain. The SHS appears suitable as a screening measure for sensory hypersensitivity, though additional research is warranted to determine its suitability as a proxy for central sensitization.

  View details for DOI 10.1007/s10865-016-9720-3

  View details for Web of Science ID 000375570700017

  View details for PubMedID 26873609

• Imaging Pain. Anesthesiology clinics Martucci, K. T., Mackey, S. C. 2016; 34 (2): 255-269

  Abstract

  The challenges and understanding of acute and chronic pain have been illuminated through the advancement of central neuroimaging. Through neuroimaging research, new technology and findings have allowed us to identify and understand the neural mechanisms contributing to chronic pain. Several regions of the brain are known to be of particular importance for the maintenance and amplification of chronic pain, and this knowledge provides novel targets for future research and treatment. This article reviews neuroimaging for the study of chronic pain, and in particular, the rapidly advancing and popular research tools of structural and functional MRI.

  View details for DOI 10.1016/j.anclin.2016.01.001

  View details for PubMedID 27208709

• Survalytics: An Open-Source Cloud-Integrated Experience Sampling, Survey, and Analytics and Metadata Collection Module for Android Operating System Apps JMIR MHEALTH AND UHEALTH O'Reilly-Shah, V., Mackey, S. 2016; 4 (2): 17-26

  Abstract

  We describe here Survalytics, a software module designed to address two broad areas of need. The first area is in the domain of surveys and app analytics: developers of mobile apps in both academic and commercial environments require information about their users, as well as how the apps are being used, to understand who their users are and how to optimally approach app development. The second area of need is in the field of ecological momentary assessment, also referred to as experience sampling: researchers in a wide variety of fields, spanning from the social sciences to psychology to clinical medicine, would like to be able to capture daily or even more frequent data from research subjects while in their natural environment.Survalytics is an open-source solution for the collection of survey responses as well as arbitrary analytic metadata from users of Android operating system apps.Surveys may be administered in any combination of one-time questions and ongoing questions. The module may be deployed as a stand-alone app for experience sampling purposes or as an add-on to existing apps. The module takes advantage of free-tier NoSQL cloud database management offered by the Amazon Web Services DynamoDB platform to package a secure, flexible, extensible data collection module. DynamoDB is capable of Health Insurance Portability and Accountability Act compliant storage of personal health information.The provided example app may be used without modification for a basic experience sampling project, and we provide example questions for daily collection of blood glucose data from study subjects.The module will help researchers in a wide variety of fields rapidly develop tailor-made Android apps for a variety of data collection purposes.

  View details for DOI 10.2196/mhealth.5397

  View details for Web of Science ID 000381182400002

  View details for PubMedID 27261155

  View details for PubMedCentralID PMC4912681

• (325) Pain catastrophizing correlates with neural activation in a maladaptive pain belief induction. journal of pain Sentis, A., Law, C., Sturgeon, J., Mackey, S. 2016; 17 (4S): S57-?

  View details for DOI 10.1016/j.jpain.2016.01.232

  View details for PubMedID 28162566

• (418) A novel glial cell inhibitor, low dose naltrexone, reduces pain and depression, and improves function in chronic pain: A CHOIR study. journal of pain Noon, K., Sturgeon, J., Kao, M., Darnall, B., Mackey, S. 2016; 17 (4S): S79-?

  View details for DOI 10.1016/j.jpain.2016.01.395

  View details for PubMedID 28162662

• (489) An examination of the roles of perceived injustice and pain acceptance on pain interference and pain intensity in patients with chronic pain: A Collaborative Health Outcomes Information Registry (CHOIR) Study. journal of pain Carriere, J., Darnall, B., Kao, M., Mackey, S. 2016; 17 (4S): S97-?

  View details for DOI 10.1016/j.jpain.2016.01.296

  View details for PubMedID 28162741

• (160) Body mass index is unrelated to concurrent clinical variables in a tertiary care pain clinic sample: a Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain Sharifzadeh, Y., Sturgeon, J., MACKEY, I., Mackey, S. 2016; 17 (4S): S15-S16

  View details for DOI 10.1016/j.jpain.2016.01.063

  View details for PubMedID 28162380

• (179) Depression mediates the relationship between pain intensity and effort in minor, but not major, decision making. journal of pain Middleton, S., Sturgeon, J., RICO, T., Mackey, S., Johnson, K. 2016; 17 (4S): S20-?

  View details for DOI 10.1016/j.jpain.2016.01.082

  View details for PubMedID 28162405

• (448) Perceived injustice, pain behavior and opioid prescriptions: a vicious circle? A Collaborative Health Outcomes Information Registry (CHOIR) Study. journal of pain Carriere, J., Darnall, B., Sullivan, M., Kao, M., Mackey, S. 2016; 17 (4S): S86-?

  View details for DOI 10.1016/j.jpain.2016.01.425

  View details for PubMedID 28162695

• (158) Cigarette smoking is a predictor of opioid use in a tertiary care pain clinic sample: a Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain MACKEY, I., Sharifzadeh, Y., Sturgeon, J., Mackey, S. 2016; 17 (4S): S15-?

  View details for DOI 10.1016/j.jpain.2016.01.061

  View details for PubMedID 28162381

• (139) Risk factors for long-term prescription opioid therapy for chronic non-cancer pain. journal of pain Hah, J., Zocca, J., Sharifzadeh, Y., Mackey, S. 2016; 17 (4S): S10-S11

  View details for DOI 10.1016/j.jpain.2016.01.042

  View details for PubMedID 28162301

• (218) Characterization of patients with complex regional pain syndrome (CRPS) in a tertiary care pain management setting: A Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain Adelus, M., Sturgeon, J., RICO, T., Tawfik, V., Mackey, S. 2016; 17 (4S): S30-?

  View details for DOI 10.1016/j.jpain.2016.01.122

  View details for PubMedID 28162448

• (321) Enhanced secondary hyperalgesia following a pain catastrophizing induction in women with chronic low back pain. journal of pain Taub, C., Darnall, B., Johnson, K., Mackey, S. 2016; 17 (4S): S56-?

  View details for DOI 10.1016/j.jpain.2016.01.228

  View details for PubMedID 28162559

• (162) Social disruption, but not pain interference, mediates the relationship between perceived injustice and anger in chronic pain: A Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain Sturgeon, J., Carriere, J., Darnall, B., Mackey, S. 2016; 17 (4S): S16-?

  View details for DOI 10.1016/j.jpain.2016.01.065

  View details for PubMedID 28162384

• (118) Physical and psychological predictors of dysfunction in complex regional pain syndrome (CRPS): a Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain Adelus, M., Sturgeon, J., RICO, T., Tawfik, V., Mackey, S. 2016; 17 (4S): S5-?

  View details for DOI 10.1016/j.jpain.2016.01.021

  View details for PubMedID 28162531

• (180) Development and validation of a Daily Pain Catastrophizing Scale (Daily PCS) measure. journal of pain Darnall, B., Sturgeon, J., Cook, K., Taub, C., Kao, M., RICO, T., Mackey, S. 2016; 17 (4S): S20-S21

  View details for DOI 10.1016/j.jpain.2016.01.083

  View details for PubMedID 28162404

• (161) Differential daily effects of pain intensity, sleep, and mood on physical activity in chronic back pain. journal of pain Sturgeon, J., Middleton, S., RICO, T., Mackey, S., Johnson, K. 2016; 17 (4S): S16-?

  View details for DOI 10.1016/j.jpain.2016.01.064

  View details for PubMedID 28162387

• (163) Pain catastrophizing, perceived injustice, and pain intensity impair life satisfaction through differential patterns of physical and psychological disruption. journal of pain Sturgeon, J., Dixon, E., Darnall, B., Mackey, S. 2016; 17 (4S): S16-?

  View details for DOI 10.1016/j.jpain.2016.01.066

  View details for PubMedID 28162385

• (167) Predicting disability status in chronic pain: the role of psychosocial and demographic factors. journal of pain Dixon, E., Sturgeon, J., Mackey, S. 2016; 17 (4S): S17-?

  View details for DOI 10.1016/j.jpain.2016.01.070

  View details for PubMedID 28162389

• Effects of salience-network-node neurofeedback training on affective biases in major depressive disorder. Psychiatry research Hamilton, J. P., Glover, G. H., Bagarinao, E., Chang, C., Mackey, S., Sacchet, M. D., Gotlib, I. H. 2016; 249: 91-96

  Abstract

  Neural models of major depressive disorder (MDD) posit that over-response of components of the brain's salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the real-neurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD.

  View details for DOI 10.1016/j.pscychresns.2016.01.016

  View details for PubMedID 26862057

  View details for PubMedCentralID PMC4803612

• Effects of salience-network-node neurofeedback training on affective biases in major depressive disorder PSYCHIATRY RESEARCH-NEUROIMAGING Hamilton, J. P., Glover, G. H., Bagarinao, E., Chang, C., Mackey, S., Sacchet, M. D., Gotlib, I. H. 2016; 249: 91-96

  Abstract

  Neural models of major depressive disorder (MDD) posit that over-response of components of the brain's salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the real-neurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD.

  View details for DOI 10.1016/j.pscychresns.2016.01.016

  View details for Web of Science ID 000372526600012

  View details for PubMedCentralID PMC4803612

• Future Directions for Pain Management: Lessons from the Institute of Medicine Pain Report and the National Pain Strategy HAND CLINICS Mackey, S. 2016; 32 (1): 91-?

  Abstract

  According to the Institute of Medicine Relieving Pain in America Report and the soon to be released National Pain Strategy, pain affects over 100 million Americans and costs our country in over $500 billion per year. We have a greater appreciation for the complex nature of pain and that it can develop into a disease in itself. As such, we need more efforts on prevention of chronic pain and for interdisciplinary approaches. For precision pain medicine to be successful, we need to link learning health systems with pain biomarkers (eg, genomics, proteomics, patient reported outcomes, brain markers) and its treatment.

  View details for DOI 10.1016/j.hc1.2015.08.012

  View details for Web of Science ID 000366955600012

  View details for PubMedID 26611393

  View details for PubMedCentralID PMC4818647

• Pain Psychology: A Global Needs Assessment and National Call to Action PAIN MEDICINE Darnall, B. D., Scheman, J., Davin, S., Burns, J. W., Murphy, J. L., Wilson, A. C., Kerns, R. D., Mackey, S. C. 2016; 17 (2): 250-263

  Abstract

  The Institute of Medicine and the draft National Pain Strategy recently called for better training for health care clinicians. This was the first high-level needs assessment for pain psychology services and resources in the United States.Prospective, observational, cross-sectional.Brief surveys were administered online to six stakeholder groups (psychologists/therapists, individuals with chronic pain, pain physicians, primary care physicians/physician assistants, nurse practitioners, and the directors of graduate and postgraduate psychology training programs).1,991 responses were received. Results revealed low confidence and low perceived competency to address physical pain among psychologists/therapists, and high levels of interest and need for pain education. We found broad support for pain psychology across stakeholder groups, and global support for a national initiative to increase pain training and competency in U.S. therapists. Among directors of graduate and postgraduate psychology training programs, we found unanimous interest for a no-cost pain psychology curriculum that could be integrated into existing programs. Primary barriers to pain psychology include lack of a system to identify qualified therapists, paucity of therapists with pain training, limited awareness of the psychological treatment modality, and poor insurance coverage.This report calls for transformation within psychology predoctoral and postdoctoral education and training and psychology continuing education to include and emphasize pain and pain management. A system for certification is needed to facilitate quality control and appropriate reimbursement. There is a need for systems to facilitate identification and access to practicing psychologists and therapists skilled in the treatment of pain.

  View details for DOI 10.1093/pm/pnv095

  View details for PubMedID 26803844

• Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network. NeuroImage. Clinical Alger, J. R., Ellingson, B. M., Ashe-McNalley, C., Woodworth, D. C., Labus, J. S., Farmer, M., Huang, L., Apkarian, A. V., Johnson, K. A., Mackey, S. C., Ness, T. J., Deutsch, G., Harris, R. E., Clauw, D. J., Glover, G. H., Parrish, T. B., Hollander, J. d., Kusek, J. W., Mullins, C., Mayer, E. A. 2016; 12: 65-77

  Abstract

  The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

  View details for DOI 10.1016/j.nicl.2015.12.009

  View details for PubMedID 27408791

  View details for PubMedCentralID PMC4925887

• Social Disruption Mediates the Relationship Between Perceived Injustice and Anger in Chronic Pain: a Collaborative Health Outcomes Information Registry Study Annals of Behavioral Medicine Sturgeon, J. A., Carriere, J. S., Kao, M. J., Rico, T. J., Darnall, B. D., Mackey, S. C. 2016: 802–12

  Abstract

  Perceptions of pain as unfair are a significant risk factor for poorer physical and psychological outcomes in acute injury and chronic pain. Chief among the negative emotions associated with perceived injustice is anger, arising through frustration of personal goals and unmet expectations regarding others' behavior. However, despite a theoretical connection with anger, the social mediators of perceived injustice have not been demonstrated in chronic pain.The current study examined two socially based variables and a broader measure of pain interference as mediators of the relationships between perceived injustice and both anger and pain intensity in a sample of 302 patients in a tertiary care pain clinic setting.Data from the Collaborative Health Outcomes Information Registry (CHOIR) were analyzed using cross-sectional path modeling analyses to examine social isolation, satisfaction with social roles and activities, and pain-related interference as potential mediators of the relationships between perceived injustice and both anger and pain intensity.When modeled simultaneously, ratings of social isolation mediated the relationship between perceived injustice and anger, while pain-related interference and social satisfaction did not. Neither social variable was found to mediate the relationship between perceived injustice and pain intensity, however.The current findings highlight the strongly interpersonal nature of perceived injustice and anger in chronic pain, though these effects do not appear to extend to the intensity of pain itself. Nevertheless, the results highlight the need for interventions that ameliorate both maladaptive cognitive appraisal of pain and pain-related disruptions in social relationships.

  View details for DOI 10.1007/s12160-016-9808-6

  View details for PubMedCentralID PMC5127748

• Overcoming barriers to implementing patient-reported outcomes in an electronic health record: a case report JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Harle, C. A., Listhaus, A., Covarrubias, C. M., Schmidt, S. O., Mackey, S., Carek, P. J., Fillingim, R. B., Hurley, R. W. 2016; 23 (1): 74-79

  Abstract

  In this case report, the authors describe the implementation of a system for collecting patient-reported outcomes and integrating results in an electronic health record. The objective was to identify lessons learned in overcoming barriers to collecting and integrating patient-reported outcomes in an electronic health record. The authors analyzed qualitative data in 42 documents collected from system development meetings, written feedback from users, and clinical observations with practice staff, providers, and patients. Guided by the Unified Theory on the Adoption and Use of Information Technology, 5 emergent themes were identified. Two barriers emerged: (i) uncertain clinical benefit and (ii) time, work flow, and effort constraints. Three facilitators emerged: (iii) process automation, (iv) usable system interfaces, and (v) collecting patient-reported outcomes for the right patient at the right time. For electronic health record-integrated patient-reported outcomes to succeed as useful clinical tools, system designers must ensure the clinical relevance of the information being collected while minimizing provider, staff, and patient burden.

  View details for DOI 10.1093/jamia/ocv085

  View details for Web of Science ID 000374179500010

  View details for PubMedID 26159464

  View details for PubMedCentralID PMC5009936

• Pain Duration and Resolution following Surgery: An Inception Cohort Study PAIN MEDICINE Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for Web of Science ID 000368297000020

  View details for PubMedCentralID PMC4706803

• Pain Duration and Resolution following Surgery: An Inception Cohort Study. Pain medicine Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for PubMedID 26179223

• Contributions of physical function and satisfaction with social roles to emotional distress in chronic pain: a Collaborative Health Outcomes Information Registry (CHOIR) study PAIN Sturgeon, J. A., Dixon, E. A., Darnall, B. D., Mackey, S. C. 2015; 156 (12): 2627-2633

  Abstract

  Individuals with chronic pain show a greater vulnerability to depression or anger than those without chronic pain, and also show greater interpersonal difficulties and physical disability. The current study examined data from 675 individuals with chronic pain during their initial visits to a tertiary care pain clinic using assessments from Stanford University's Collaborative Health Outcomes Information Registry (CHOIR). Using a path modeling analysis, the mediating roles of PROMIS Physical Function and PROMIS Satisfaction with Social Roles and Activities were tested between pain intensity and PROMIS Depression and Anger. Pain intensity significantly predicted both depression and anger, and both physical function and satisfaction with social roles mediated these relationships when modeled in separate 1-mediator models. Notably, however, when modeled together, ratings of satisfaction with social roles mediated the relationship between physical function and both anger and depression. Our results suggest that the process by which chronic pain disrupts emotional well-being involves both physical function and disrupted social functioning. However, the more salient factor in determining pain-related emotional distress appears to be disruption of social relationships, rather than global physical impairment. These results highlight the particular importance of social factors to pain-related distress, and highlight social functioning as an important target for clinical intervention in chronic pain.

  View details for DOI 10.1097/j.pain.0000000000000313

  View details for Web of Science ID 000365598300028

  View details for PubMedID 26230739

• Unique Microstructural Changes in the Brain Associated with Urological Chronic Pelvic Pain Syndrome (UCPPS) Revealed by Diffusion Tensor MRI, Super-Resolution Track Density Imaging, and Statistical Parameter Mapping: A MAPP Network Neuroimaging Study PLOS ONE Woodworth, D., Mayer, E., Leu, K., Ashe-McNalley, C., Naliboff, B. D., Labus, J. S., Tillisch, K., Kutch, J. J., Farmer, M. A., Apkarian, A. V., Johnson, K. A., Mackey, S. C., Ness, T. J., Landis, J. R., Deutsch, G., Harris, R. E., Clauw, D. J., Mullins, C., Ellingson, B. M. 2015; 10 (10)

  Abstract

  Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

  View details for DOI 10.1371/journal.pone.0140250

  View details for Web of Science ID 000362962300073

  View details for PubMedID 26460744

  View details for PubMedCentralID PMC4604194

• The posterior medial cortex in urologic chronic pelvic pain syndrome: detachment from default mode network-a resting-state study from the MAPP Research Network PAIN Martucci, K. T., Shirer, W. R., Bagarinao, E., Johnson, K. A., Farmer, M. A., Labus, J. S., Apkarian, A. V., Deutsch, G., Harris, R. E., Mayer, E. A., Clauw, D. J., Greicius, M. D., Mackey, S. C. 2015; 156 (9): 1755-1764

  Abstract

  Altered resting-state (RS) brain activity, as a measure of functional connectivity (FC), is commonly observed in chronic pain. Identifying a reliable signature pattern of altered RS activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed RS functional magnetic resonance imaging data from female patients with urologic chronic pelvic pain syndrome (N = 45) and matched healthy participants (N = 45) as part of an NIDDK-funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased FC of the default mode network to 2 regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and the left precuneus (threshold-free cluster enhancement, family-wise error corrected P < 0.05). Further investigation revealed that patients demonstrated increased FC between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (eg, insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased FC to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships, and self-esteem levels in patients. Collectively, these findings indicate that in patients with urologic chronic pelvic pain syndrome, regions of the PMC are detached from the default mode network, whereas neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes.

  View details for DOI 10.1097/j.pain.0000000000000238

  View details for Web of Science ID 000360579400021

  View details for PubMedCentralID PMC4545714

• Acute Pain Medicine in the United States: A Status Report PAIN MEDICINE Tighe, P., Buckenmaier, C. C., Boezaart, A. P., Carr, D. B., Clark, L. L., Herring, A. A., Kent, M., Mackey, S., Mariano, E. R., Polomano, R. C., Reisfield, G. M. 2015; 16 (9): 1806-1826

  Abstract

  Consensus indicates that a comprehensive,multimodal, holistic approach is foundational to the practice of acute pain medicine (APM),but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service,which is often unavailable or inconsistently applied.This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs.A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education.The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers,hospital administrators, and other key stake holders to convey the importance of APM.This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain.

  View details for DOI 10.1111/pme.12760

  View details for Web of Science ID 000362887700016

  View details for PubMedID 26535424

  View details for PubMedCentralID PMC4634553

• Report of the NIH Task Force on Research Standards for Chronic Low Back Pain. International journal of therapeutic massage & bodywork Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2015; 8 (3): 16-33

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. The NIH Pain Consortium therefore charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect the RTF recommendations will become a dynamic document, and undergo continual improvement.A Task Force was convened by the NIH Pain Consortium, with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimal dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for PubMedID 26388962

• The posterior medial cortex in urologic chronic pelvic pain syndrome: detachment from default mode network-a resting-state study from the MAPP Research Network. Pain Martucci, K. T., Shirer, W. R., Bagarinao, E., Johnson, K. A., Farmer, M. A., Labus, J. S., Apkarian, A. V., Deutsch, G., Harris, R. E., Mayer, E. A., Clauw, D. J., Greicius, M. D., Mackey, S. C. 2015; 156 (9): 1755-1764

  Abstract

  Altered resting-state (RS) brain activity, as a measure of functional connectivity (FC), is commonly observed in chronic pain. Identifying a reliable signature pattern of altered RS activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed RS functional magnetic resonance imaging data from female patients with urologic chronic pelvic pain syndrome (N = 45) and matched healthy participants (N = 45) as part of an NIDDK-funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased FC of the default mode network to 2 regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and the left precuneus (threshold-free cluster enhancement, family-wise error corrected P < 0.05). Further investigation revealed that patients demonstrated increased FC between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (eg, insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased FC to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships, and self-esteem levels in patients. Collectively, these findings indicate that in patients with urologic chronic pelvic pain syndrome, regions of the PMC are detached from the default mode network, whereas neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes.

  View details for DOI 10.1097/j.pain.0000000000000238

  View details for PubMedID 26010458

  View details for PubMedCentralID PMC4545714

• Nonlinear Effects of Noxious Thermal Stimulation and Working Memory Demands on Subjective Pain Perception PAIN MEDICINE Sturgeon, J. A., Tieu, M. M., Jastrzab, L. E., McCue, R., Gandhi, V., Mackey, S. C. 2015; 16 (7): 1301-1310

  Abstract

  A bidirectional relationship between working memory (WM) and acute pain has long been assumed, but equivocal evidence exists regarding this relationship. This study characterized the relationship between WM and acute pain processing in healthy individuals using an adapted Sternberg WM task.Participants completed a Sternberg task while receiving noxious thermal stimulation. Participants received a pseudorandom presentation of four different temperatures (baseline temperatures and individually determined low-, medium-, and high-temperature stimuli) and four levels of Sternberg task difficulty (0-, 3-, 6-, and 9-letter strings).Twenty-eight healthy participants were recruited from Stanford University and the surrounding community to complete this study.A nonlinear interaction between intensity of thermal stimulation and difficulty of the Sternberg task was noted. Increased cognitive load from the Sternberg task resulted in increased perception of pain in low-intensity thermal stimulation but suppressed pain perception in high-intensity thermal stimulation. Thermal stimulation had no significant effect on participants' response time or accuracy on the Sternberg task regardless of intensity level.Pain perception appears to decrease as a function of WM load only for sufficiently noxious stimuli. However, increasing noxious stimuli did not affect cognitive performance. These complex relationships may reflect a shared cognitive space that can become "overloaded" with input of multiple stimuli of sufficient intensity.

  View details for DOI 10.1111/pme.12774

  View details for Web of Science ID 000358017000013

• Urological chronic pelvic pain syndrome flares and their impact: qualitative analysis in the MAPP network INTERNATIONAL UROGYNECOLOGY JOURNAL Sutcliffe, S., Bradley, C. S., Clemens, J. Q., James, A. S., Konkle, K. S., Kreder, K. J., Lai, H. H., Mackey, S. C., Ashe-McNalley, C. P., Rodriguez, L. V., Barrell, E., Hou, X., Robinson, N. A., Mullins, C., Berry, S. H. 2015; 26 (7): 1047-1060

  Abstract

  Although in-depth qualitative information is critical to understanding patients' symptom experiences and to developing patient-centered outcome measures, only one previous qualitative study has assessed urological chronic pelvic pain syndrome (UCPPS) symptom exacerbations ("flares").We conducted eight focus groups of female UCPPS (interstitial cystitis/bladder pain syndrome) patients at four sites from the MAPP Research Network (n = 57, mean = 7/group) to explore the full spectrum of flares and their impact on patients' lives.Flare experiences were common and varied widely in terms of UCPPS symptoms involved, concurrent nonpelvic symptoms (e.g., diarrhea), symptom intensity (mild to severe), duration (minutes to years), and frequency (daily to < once/year), although the most commonly described flares were painful flares lasting days. These latter flares were also most disruptive to participants' lives, causing some to cancel social events, miss work or school, and in the worst cases, go to the emergency room or on disability leave. Participants also reported a longer-term impact of flares, including negative effects on their sexual functioning and marital, family, and social relationships; and the loss of employment or limited career or educational advancement. Emerging themes included the need for a sense of control over unpredictable symptoms and reduced social engagement.Given their negative impact, future research should focus on approaches to prevent flares, and to reduce their frequency, severity, and/or duration. Patients' quality of life may also be improved by providing them with a sense of control over their symptoms through ready access to flare medications/therapy, and by engaging them socially.

  View details for DOI 10.1007/s00192-015-2652-6

  View details for Web of Science ID 000357039700017

  View details for PubMedID 25792349

  View details for PubMedCentralID PMC4489981

• Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study JOURNAL OF UROLOGY Farmer, M. A., Huang, L., Martucci, K., Yang, C. C., Maravilla, K. R., Harris, R. E., Clauw, D. J., Mackey, S., Ellingson, B. M., Mayer, E. A., Schaeffer, A. J., Apkarian, A. V. 2015; 194 (1): 118-126

  Abstract

  Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network.We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence.Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi.To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.

  View details for DOI 10.1016/j.juro.2015.02.082

  View details for Web of Science ID 000356012100034

  View details for PubMedID 25711200

  View details for PubMedCentralID PMC4475466

• Utility of FDG PET/CT in patients with Myofascial Pain Syndrome Mittra, E., Marx, E., Biswal, S., Mackey, S. SOC NUCLEAR MEDICINE INC. 2015

  View details for Web of Science ID 000358738803314

• Relationship between Chronic Nonurological Associated Somatic Syndromes and Symptom Severity in Urological Chronic Pelvic Pain Syndromes: Baseline Evaluation of the MAPP Study JOURNAL OF UROLOGY Krieger, J. N., Stephens, A. J., Landis, J. R., Clemens, J. Q., Kreder, K., Lai, H. H., Afari, N., Rodriguez, L., Schaeffer, A., Mackey, S., Andriole, G. L., Williams, D. A. 2015; 193 (4): 1254-1262

  Abstract

  We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria.Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors.Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001).Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes.

  View details for DOI 10.1016/j.juro.2014.10.086

  View details for PubMedID 25444992

• Physical and psychological correlates of fatigue and physical function: a Collaborative Health Outcomes Information Registry (CHOIR) study. journal of pain Sturgeon, J. A., Darnall, B. D., Kao, M. J., Mackey, S. C. 2015; 16 (3): 291-8 e1

  Abstract

  Fatigue is a multidimensional construct that has significant implications for physical function in chronic non-cancer pain populations but remains relatively understudied. The current study characterized the independent contributions of self-reported ratings of pain intensity, sleep disturbance, depression, and fatigue to ratings of physical function and pain-related interference in a diverse sample of treatment-seeking individuals with chronic pain. Methods: These relationships were examined as a path modeling analysis of self-report scores obtained from 2,487 individuals with chronic pain from a tertiary care outpatient pain clinic.Our analyses revealed unique relationships of pain intensity, sleep disturbance, and depression with self-reported fatigue. Further, fatigue scores accounted for significant proportions of the relationships of both pain intensity and depression with physical function and pain-related interference, and accounted for the entirety of the unique statistical relationship between sleep disturbance and both physical function and pain-related interference.Fatigue is a complex construct with relationships to both physical and psychological factors that has significant implications for physical functioning in chronic non-cancer pain. The current results identify potential targets for future treatment of fatigue in chronic pain, and may provide directions for future clinical and theoretical research in the area of chronic non-cancer pain.Fatigue is an important physical and psychological variable that factors prominently in the deleterious consequences of pain intensity, sleep disturbance, and depression for physical function in chronic non-cancer pain.

  View details for DOI 10.1016/j.jpain.2014.12.004

  View details for PubMedID 25536536

• Perspective: Peripheral Nerve Stimulation and Peripheral Nerve Field Stimulation Birds of a Different Feather PAIN MEDICINE Deer, T. R., Levy, R. M., Verrills, P., Mackey, S., Abejon, D. 2015; 16 (3): 411–12

  View details for DOI 10.1111/pme.12662

  View details for Web of Science ID 000351538900002

  View details for PubMedID 25599816

• Physical and Psychological Correlates of Fatigue and Physical Function: A Collaborative Health Outcomes Information Registry (CHOIR) Study. journal of pain Sturgeon, J. A., Darnall, B. D., Kao, M. J., Mackey, S. C. 2015; 16 (3): 291-298 e1

  Abstract

  Fatigue is a multidimensional construct that has significant implications for physical function in chronic non-cancer pain populations but remains relatively understudied. The current study characterized the independent contributions of self-reported ratings of pain intensity, sleep disturbance, depression, and fatigue to ratings of physical function and pain-related interference in a diverse sample of treatment-seeking individuals with chronic pain. Methods: These relationships were examined as a path modeling analysis of self-report scores obtained from 2,487 individuals with chronic pain from a tertiary care outpatient pain clinic.Our analyses revealed unique relationships of pain intensity, sleep disturbance, and depression with self-reported fatigue. Further, fatigue scores accounted for significant proportions of the relationships of both pain intensity and depression with physical function and pain-related interference, and accounted for the entirety of the unique statistical relationship between sleep disturbance and both physical function and pain-related interference.Fatigue is a complex construct with relationships to both physical and psychological factors that has significant implications for physical functioning in chronic non-cancer pain. The current results identify potential targets for future treatment of fatigue in chronic pain, and may provide directions for future clinical and theoretical research in the area of chronic non-cancer pain.Fatigue is an important physical and psychological variable that factors prominently in the deleterious consequences of pain intensity, sleep disturbance, and depression for physical function in chronic non-cancer pain.

  View details for DOI 10.1016/j.jpain.2014.12.004

  View details for PubMedID 25536536

• Report of the NIH Task Force on research standards for chronic low back pain. Physical therapy Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2015; 95 (2): e1-e18

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.2522/ptj.2015.95.2.e1

  View details for PubMedID 25639530

• Increased Brain Gray Matter in the Primary Somatosensory Cortex is Associated with Increased Pain and Mood Disturbance in Patients with Interstitial Cystitis/Painful Bladder Syndrome JOURNAL OF UROLOGY Kairys, A. E., Schmidt-Wilcke, T., Puiu, T., Ichesco, E., Labus, J. S., Martucci, K., Farmer, M. A., Ness, T. J., Deutsch, G., Mayer, E. A., Mackey, S., Apkarian, A. V., Maravilla, K., Clauw, D. J., Harris, R. E. 2015; 193 (1): 131-137

  Abstract

  Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants.We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States.Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS).These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.

  View details for DOI 10.1016/j.juro.2014.08.042

  View details for Web of Science ID 000346171500033

  View details for PubMedID 25132239

• Nonlinear Effects of Noxious Thermal Stimulation and Working Memory Demands on Subjective Pain Perception. Pain medicine (Malden, Mass.) Sturgeon, J. A., Tieu, M. M., Jastrzab, L. E., McCue, R., Gandhi, V., Mackey, S. C. 2015

  Abstract

  A bidirectional relationship between working memory (WM) and acute pain has long been assumed, but equivocal evidence exists regarding this relationship. This study characterized the relationship between WM and acute pain processing in healthy individuals using an adapted Sternberg WM task.Participants completed a Sternberg task while receiving noxious thermal stimulation. Participants received a pseudorandom presentation of four different temperatures (baseline temperatures and individually determined low-, medium-, and high-temperature stimuli) and four levels of Sternberg task difficulty (0-, 3-, 6-, and 9-letter strings).Twenty-eight healthy participants were recruited from Stanford University and the surrounding community to complete this study.A nonlinear interaction between intensity of thermal stimulation and difficulty of the Sternberg task was noted. Increased cognitive load from the Sternberg task resulted in increased perception of pain in low-intensity thermal stimulation but suppressed pain perception in high-intensity thermal stimulation. Thermal stimulation had no significant effect on participants' response time or accuracy on the Sternberg task regardless of intensity level.Pain perception appears to decrease as a function of WM load only for sufficiently noxious stimuli. However, increasing noxious stimuli did not affect cognitive performance. These complex relationships may reflect a shared cognitive space that can become "overloaded" with input of multiple stimuli of sufficient intensity.

  View details for PubMedID 25929747

• Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study. NeuroImage. Clinical Kutch, J. J., Yani, M. S., Asavasopon, S., Kirages, D. J., Rana, M., Cosand, L., Labus, J. S., Kilpatrick, L. A., Ashe-McNalley, C., Farmer, M. A., Johnson, K. A., Ness, T. J., Deutsch, G., Harris, R. E., Apkarian, A. V., Clauw, D. J., Mackey, S. C., Mullins, C., Mayer, E. A. 2015; 8: 493–502

  Abstract

  Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.

  View details for PubMedID 26106574

• Factors Associated with Opioid Use in a Cohort of Patients Presenting for Surgery. Pain research and treatment Hah, J. M., Sharifzadeh, Y., Wang, B. M., Gillespie, M. J., Goodman, S. B., Mackey, S. C., Carroll, I. R. 2015; 2015: 829696-?

  Abstract

  Objectives. Patients taking opioids prior to surgery experience prolonged postoperative opioid use, worse clinical outcomes, increased pain, and more postoperative complications. We aimed to compare preoperative opioid users to their opioid naïve counterparts to identify differences in baseline characteristics. Methods. 107 patients presenting for thoracotomy, total knee replacement, total hip replacement, radical mastectomy, and lumpectomy were investigated in a cross-sectional study to characterize the associations between measures of pain, substance use, abuse, addiction, sleep, and psychological measures (depressive symptoms, Posttraumatic Stress Disorder symptoms, somatic fear and anxiety, and fear of pain) with opioid use. Results. Every 9-point increase in the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) score was associated with 2.37 (95% CI 1.29-4.32) increased odds of preoperative opioid use (p = 0.0005). The SOAPP-R score was also associated with 3.02 (95% CI 1.36-6.70) increased odds of illicit preoperative opioid use (p = 0.007). Also, every 4-point increase in baseline pain at the future surgical site was associated with 2.85 (95% CI 1.12-7.27) increased odds of legitimate preoperative opioid use (p = 0.03). Discussion. Patients presenting with preoperative opioid use have higher SOAPP-R scores potentially indicating an increased risk for opioid misuse after surgery. In addition, legitimate preoperative opioid use is associated with preexisting pain.

  View details for DOI 10.1155/2015/829696

  View details for PubMedID 26881072

• Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP Research Network Neuroimaging Study NEUROIMAGE-CLINICAL Kutch, J. J., Yani, M. S., Asavasopon, S., Kirages, D. J., Rana, M., Cosand, L., Labus, J. S., Kilpatrick, L. A., Ashe-McNalley, C., Farmer, M. A., Johnson, K. A., Ness, T. J., Deutsch, G., Harris, R. E., Apkarian, A. V., Clauw, D. J., Mackey, S. C., Mullins, C., Mayer, E. A. 2015; 8: 493-502

  Abstract

  Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.

  View details for DOI 10.1016/j.nicl.2015.05.013

  View details for Web of Science ID 000373187100053

  View details for PubMedCentralID PMC4474411

• Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study PAIN Bagarinao, E., Johnson, K. A., Martucci, K. T., Ichesco, E., Farmer, M. A., Labus, J., Ness, T. J., Harris, R., Deutsch, G., Apkarian, A. V., Mayer, E. A., Clauw, D. J., Mackey, S. 2014; 155 (12): 2502-2509

  Abstract

  Neuroimaging studies have shown that changes in brain morphology often accompany chronic pain conditions. However, brain biomarkers that are sensitive and specific to chronic pelvic pain (CPP) have not yet been adequately identified. Using data from the Trans-MAPP Research Network, we examined the changes in brain morphology associated with CPP. We used a multivariate pattern classification approach to detect these changes and to identify patterns that could be used to distinguish participants with CPP from age-matched healthy controls. In particular, we used a linear support vector machine (SVM) algorithm to differentiate gray matter images from the 2 groups. Regions of positive SVM weight included several regions within the primary somatosensory cortex, pre-supplementary motor area, hippocampus, and amygdala were identified as important drivers of the classification with 73% overall accuracy. Thus, we have identified a preliminary classifier based on brain structure that is able to predict the presence of CPP with a good degree of predictive power. Our regional findings suggest that in individuals with CPP, greater gray matter density may be found in the identified distributed brain regions, which are consistent with some previous investigations in visceral pain syndromes. Future studies are needed to improve upon our identified preliminary classifier with integration of additional variables and to assess whether the observed differences in brain structure are unique to CPP or generalizable to other chronic pain conditions.

  View details for DOI 10.1016/j.pain.2014.09.002

  View details for Web of Science ID 000345414700011

  View details for PubMedCentralID PMC4504202

• A Message from AAPM's President PAIN MEDICINE Mackey, S. 2014; 15 (12): 1991

  View details for DOI 10.1111/pme.12622

  View details for Web of Science ID 000347237200001

• Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study. Pain Bagarinao, E., Johnson, K. A., Martucci, K. T., Ichesco, E., Farmer, M. A., Labus, J., Ness, T. J., Harris, R., Deutsch, G., Apkarian, A. V., Mayer, E. A., Clauw, D. J., Mackey, S. 2014; 155 (12): 2502-2509

  Abstract

  Neuroimaging studies have shown that changes in brain morphology often accompany chronic pain conditions. However, brain biomarkers that are sensitive and specific to chronic pelvic pain (CPP) have not yet been adequately identified. Using data from the Trans-MAPP Research Network, we examined the changes in brain morphology associated with CPP. We used a multivariate pattern classification approach to detect these changes and to identify patterns that could be used to distinguish participants with CPP from age-matched healthy controls. In particular, we used a linear support vector machine (SVM) algorithm to differentiate gray matter images from the 2 groups. Regions of positive SVM weight included several regions within the primary somatosensory cortex, pre-supplementary motor area, hippocampus, and amygdala were identified as important drivers of the classification with 73% overall accuracy. Thus, we have identified a preliminary classifier based on brain structure that is able to predict the presence of CPP with a good degree of predictive power. Our regional findings suggest that in individuals with CPP, greater gray matter density may be found in the identified distributed brain regions, which are consistent with some previous investigations in visceral pain syndromes. Future studies are needed to improve upon our identified preliminary classifier with integration of additional variables and to assess whether the observed differences in brain structure are unique to CPP or generalizable to other chronic pain conditions.

  View details for DOI 10.1016/j.pain.2014.09.002

  View details for PubMedID 25242566

• Neuroimaging chronic pain: what have we learned and where are we going? Future neurology Martucci, K. T., Ng, P., Mackey, S. 2014; 9 (6): 615-626

  Abstract

  Advances in neuroimaging have helped illuminate our understanding of how the brain works in the presence of chronic pain, which often persists with unknown etiology or after the painful stimulus has been removed and any wounds have healed. Neuroimaging has enabled us to make great progress in identifying many of the neural mechanisms that contribute to chronic pain, and to pinpoint the specific regions of the brain that are activated in the presence of chronic pain. It has provided us with a new perception of the nature of chronic pain in general, leading researchers to move toward a whole-brain approach to the study and treatment of chronic pain, and to develop novel technologies and analysis techniques, with real potential for developing new diagnostics and more effective therapies. We review the use of neuroimaging in the study of chronic pain, with particular emphasis on magnetic resonance imaging.

  View details for DOI 10.2217/FNL.14.57

  View details for PubMedID 28163658

  View details for PubMedCentralID PMC5289824

• Focus article: report of the NIH task force on research standards for chronic low back pain EUROPEAN SPINE JOURNAL Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 23 (10): 2028-2045

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.1007/s00586-014-3540-3

  View details for PubMedID 25212440

• Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome. journal of urology Kilpatrick, L. A., Kutch, J. J., Tillisch, K., Naliboff, B. D., Labus, J. S., Jiang, Z., Farmer, M. A., Apkarian, A. V., Mackey, S., Martucci, K. T., Clauw, D. J., Harris, R. E., Deutsch, G., Ness, T. J., Yang, C. C., Maravilla, K., Mullins, C., Mayer, E. A. 2014; 192 (3): 947-955

  Abstract

  The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance in the processing of pain and viscerosensory signals. We identified differences in brain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome.We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands.Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest in patients who reported pain during bladder filling.Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations and connectivity in a cortico-cerebellar network previously associated with bladder function.

  View details for DOI 10.1016/j.juro.2014.03.093

  View details for PubMedID 24681331

• REPORT OF THE NATIONAL INSTITUTES OF HEALTH TASK FORCE ON RESEARCH STANDARDS FOR CHRONIC LOW BACK PAIN JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 37 (7): 449-467

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. The purpose of this article is to disseminate the report of the National Institutes of Health (NIH) task force on research standards for cLBP.The NIH Pain Consortium charged a research task force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved these recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of cLBP. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will become a dynamic document and undergo continual improvement.

  View details for DOI 10.1016/j.jmpt.2014.07.006

  View details for PubMedID 25127996

• In reply. Anesthesiology Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2014; 121 (2): 424-426

  View details for DOI 10.1097/ALN.0000000000000299

  View details for PubMedID 25050501

• Focus Article Report of the NIH Task Force on Research Standards for Chronic Low Back Pain CLINICAL JOURNAL OF PAIN Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 30 (8): 701-712

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus.The NIH Pain Consortium therefore charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.

  View details for PubMedID 24988192

• Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SPINE JOURNAL Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 14 (8): 1375-1391

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.1016/j.spinee.2014.05.002

  View details for PubMedID 24950669

• The MAPP research network: design, patient characterization and operations BMC UROLOGY Landis, J. R., Williams, D. A., Lucia, M. S., Clauw, D. J., Naliboff, B. D., Robinson, N. A., van Bokhoven, A., Sutcliffe, S., Schaeffer, A. J., Rodriguez, L. V., Mayer, E. A., Lai, H. H., Krieger, J. N., Kreder, K. J., Afari, N., Andriole, G. L., Bradley, C. S., Griffith, J. W., Klumpp, D. J., Hong, B. A., Lutgendorf, S. K., Buchwald, D., Yang, C. C., Mackey, S., Pontari, M. A., Hanno, P., Kusek, J. W., Mullins, C., Clemens, J. Q. 2014; 14

  Abstract

  The "Multidisciplinary Approach to the Study of Chronic Pelvic Pain" (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network's central study and common data elements are described.The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as "positive" controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.ClinicalTrials.gov identifier: NCT01098279 "Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)". http://clinicaltrials.gov/show/NCT01098279.

  View details for DOI 10.1186/1471-2490-14-58

  View details for Web of Science ID 000340005200001

  View details for PubMedID 25085119

  View details for PubMedCentralID PMC4126395

• Report of the NIH Task Force on Research Standards for Chronic Low Back Pain PAIN MEDICINE Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 15 (8): 1249-1267

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus.Expert panel and preliminary evaluation of key recommendations.The NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting.The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals.The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will become a dynamic document, and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.1111/pme.12538

  View details for PubMedID 25132307

• The Appropriate Use of Neurostimulation of the Spinal Cord and Peripheral Nervous System for the Treatment of Chronic Pain and Ischemic Diseases: The Neuromodulation Appropriateness Consensus Committee NEUROMODULATION Deer, T. R., Mekhail, N., Provenzano, D., Pope, J., Krames, E., Leong, M., Levy, R. M., Abejon, D., Buchser, E., Burton, A., Buvanendran, A., Candido, K., Caraway, D., Cousins, M., DeJongste, M., Diwan, S., Eldabe, S., Gatzinsky, K., Foreman, R. D., Hayek, S., Kim, P., Kinfe, T., Kloth, D., Kumar, K., Rizvi, S., Lad, S. P., Liem, L., Linderoth, B., Mackey, S., McDowell, G., McRoberts, P., Poree, L., Prager, J., Raso, L., Rauck, R., Russo, M., Simpson, B., Slavin, K., Staats, P., Stanton-Hicks, M., Verrills, P., Wellington, J., Williams, K., North, R. 2014; 17 (6): 515-550

  Abstract

  The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications.The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar.Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated.Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

  View details for DOI 10.1111/ner.12208

  View details for Web of Science ID 000340500200002

  View details for PubMedID 25112889

• National Pain Strategy Task Force: The Strategic Plan for the IOM Pain Report PAIN MEDICINE Mackey, S. 2014; 15 (7): 1070–71

  View details for PubMedID 25059928

• Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SPINE Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weiner, D. K. 2014; 39 (14): 1128-1143

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a research task force to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum data set to describe research participants (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The research task force believes that these recommendations will advance the field, help resolve controversies, and facilitate future research addressing the genomic, neurological, and other mechanistic substrates of cLBP. We expect that the research task force recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for cLBP. The results included recommendations for definitions, a minimum data set, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.1097/BRS.0000000000000434

  View details for PubMedID 24887571

• Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

  View details for PubMedCentralID PMC4083472

• The IOM Pain Report Revisited: Setting the Stage for What's Next in Transforming Pain Care, Education and Research PAIN MEDICINE Mackey, S. 2014; 15 (6): 885-886

  View details for DOI 10.1111/pme.12471

  View details for Web of Science ID 000338025900001

  View details for PubMedID 24964915

• Report of the NIH Task Force on Research Standards for Chronic Low Back Pain JOURNAL OF PAIN Deyo, R. A., Dworkin, S. F., Amtmann, D., Andersson, G., Borenstein, D., Carragee, E., Carrino, J., Chou, R., Cook, K., Delitto, A., Goertz, C., Khalsa, P., Loeser, J., Mackey, S., Panagis, J., Rainville, J., Tosteson, T., Turk, D., von Korff, M., Weinertt, D. K. 2014; 15 (6): 569-585

  Abstract

  Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement.A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

  View details for DOI 10.1016/j.jpain.2014.03.005

  View details for PubMedID 24787228

• Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain medicine Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for PubMedID 24964916

• Preoccupation in an Early-Romantic Relationship Predicts Experimental Pain Relief PAIN MEDICINE Nilakantan, A., Younger, J., Aron, A., Mackey, S. 2014; 15 (6): 947-953

  Abstract

  Individuals involved in the early stages of a passionate romantic relationship can be consumed by the experience and report emotional dependence and constant focus on their romantic partner. A few studies have shown that viewing pictures of a romantic partner can significantly reduce experimental pain. The strength of the effect, however, varies substantially between individuals. To study why some individuals experience significant pain reduction when looking at a picture of their partner, we examined partner preoccupation. We hypothesized that a greater degree of preoccupation in the early stages of a romantic relationship would be associated with greater analgesia during a pain induction task.Participants were shown pictures of their romantic partner or an equally attractive and familiar acquaintance while exposed to low, moderate, or high levels of thermal pain. Participants were also asked to rate how much time they spent thinking about their romantic partner during an average day. Degree of preoccupation was defined as the percentage of time participants spent thinking about their partner on an average day.In two separate experiments, viewing pictures of a romantic partner produced an analgesic effect. The degree of pain relief was positively correlated with partner preoccupation. The results suggest that preoccupation with a romantic partner during early stage romantic love is a predictor of pain relief when viewing pictures of the beloved.

  View details for DOI 10.1111/pme.12422

  View details for Web of Science ID 000338025900008

  View details for PubMedID 24716721

  View details for PubMedCentralID PMC4074230

• Response to letter to the editor. Pain Dworkin, R. H., O'Connor, A. B., Kent, J., Mackey, S. C., Raja, S. N., Stacey, B. R., Levy, R. M., Backonja, M., Baron, R., Harke, H., Loeser, J. D., Treede, R., Turk, D. C., Wells, C. D. 2014; 155 (5): 1045-1046

  View details for DOI 10.1016/j.pain.2014.01.029

  View details for PubMedID 24513276

• Multivariate Classification of Structural MRI Data Detects Chronic Low Back Pain CEREBRAL CORTEX Ung, H., Brown, J. E., Johnson, K. A., Younger, J., Hush, J., Mackey, S. 2014; 24 (4): 1037-1044

  Abstract

  Chronic low back pain (cLBP) has a tremendous personal and socioeconomic impact, yet the underlying pathology remains a mystery in the majority of cases. An objective measure of this condition, that augments self-report of pain, could have profound implications for diagnostic characterization and therapeutic development. Contemporary research indicates that cLBP is associated with abnormal brain structure and function. Multivariate analyses have shown potential to detect a number of neurological diseases based on structural neuroimaging. Therefore, we aimed to empirically evaluate such an approach in the detection of cLBP, with a goal to also explore the relevant neuroanatomy. We extracted brain gray matter (GM) density from magnetic resonance imaging scans of 47 patients with cLBP and 47 healthy controls. cLBP was classified with an accuracy of 76% by support vector machine analysis. Primary drivers of the classification included areas of the somatosensory, motor, and prefrontal cortices--all areas implicated in the pain experience. Differences in areas of the temporal lobe, including bordering the amygdala, medial orbital gyrus, cerebellum, and visual cortex, were also useful for the classification. Our findings suggest that cLBP is characterized by a pattern of GM changes that can have discriminative power and reflect relevant pathological brain morphology.

  View details for DOI 10.1093/cercor/bhs378

  View details for Web of Science ID 000333048200018

  View details for PubMedID 23246778

  View details for PubMedCentralID PMC3948494

• Identifying Erythema Migrans Rash in Patients with Lyme Disease REPLY AMERICAN FAMILY PHYSICIAN Juckett, G. 2014; 89 (6): 424

  View details for DOI 10.1097/ALN.0000000000000299

  View details for Web of Science ID 000333443400003

  View details for PubMedID 24620365

• Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain. journal of pain Barad, M. J., Ueno, T., Younger, J., Chatterjee, N., Mackey, S. 2014; 15 (2): 197-203

  Abstract

  Complex regional pain syndrome (CRPS) is a chronic condition that involves significant hyperalgesia of the affected limb, typically accompanied by localized autonomic abnormalities and frequently by motor dysfunction. Although central brain systems are thought to play a role in the development and maintenance of CRPS, these systems have not been well characterized. In this study, we used structural magnetic resonance imaging to characterize differences in gray matter volume between patients with right upper extremity CRPS and matched controls. Analyses were carried out using a whole brain voxel-based morphometry approach. The CRPS group showed decreased gray matter volume in several pain-affect regions, including the dorsal insula, left orbitofrontal cortex, and several aspects of the cingulate cortex. Greater gray matter volume in CRPS patients was seen in the bilateral dorsal putamen and right hypothalamus. Correlation analyses with self-reported pain were then performed on the CRPS group. Pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex. Pain intensity was positively correlated with volume in the left posterior hippocampus and left amygdala, and negatively correlated with the bilateral dorsolateral prefrontal cortex. Our findings demonstrate that CRPS is associated with abnormal brain system morphology, particularly pain-related sensory, affect, motor, and autonomic systems.This paper presents structural changes in the brains of patients with CRPS, helping us differentiate CRPS from other chronic pain syndromes and furthering our understanding of this challenging disease.

  View details for DOI 10.1016/j.jpain.2013.10.011

  View details for PubMedID 24212070

• Conditioned pain modulation is minimally influenced by cognitive evaluation or imagery of the conditioning stimulus JOURNAL OF PAIN RESEARCH Bernaba, M., Johnson, K. A., Kong, J., Mackey, S. 2014; 7: 689-697

  Abstract

  Conditioned pain modulation (CPM) is an experimental approach for probing endogenous analgesia by which one painful stimulus (the conditioning stimulus) may inhibit the perceived pain of a subsequent stimulus (the test stimulus). Animal studies suggest that CPM is mediated by a spino-bulbo-spinal loop using objective measures such as neuronal firing. In humans, pain ratings are often used as the end point. Because pain self-reports are subject to cognitive influences, we tested whether cognitive factors would impact on CPM results in healthy humans.We conducted a within-subject, crossover study of healthy adults to determine the extent to which CPM is affected by 1) threatening and reassuring evaluation and 2) imagery alone of a cold conditioning stimulus. We used a heat stimulus individualized to 5/10 on a visual analog scale as the testing stimulus and computed the magnitude of CPM by subtracting the postconditioning rating from the baseline pain rating of the heat stimulus.We found that although evaluation can increase the pain rating of the conditioning stimulus, it did not significantly alter the magnitude of CPM. We also found that imagery of cold pain alone did not result in statistically significant CPM effect.Our results suggest that CPM is primarily dependent on sensory input, and that the cortical processes of evaluation and imagery have little impact on CPM. These findings lend support for CPM as a useful tool for probing endogenous analgesia through subcortical mechanisms.

  View details for DOI 10.2147/JPR.S65607

  View details for Web of Science ID 000364591200001

  View details for PubMedID 25473310

  View details for PubMedCentralID PMC4251756

• Pilot study of a compassion meditation intervention in chronic pain. Journal of compassionate health care Chapin, H. L., Darnall, B. D., Seppala, E. M., Doty, J. R., Hah, J. M., Mackey, S. C. 2014; 1

  Abstract

  The emergence of anger as an important predictor of chronic pain outcomes suggests that treatments that target anger may be particularly useful within the context of chronic pain. Eastern traditions prescribe compassion cultivation to treat persistent anger. Compassion cultivation has been shown to influence emotional processing and reduce negativity bias in the contexts of emotional and physical discomfort, thus suggesting it may be beneficial as a dual treatment for pain and anger. Our objective was to conduct a pilot study of a 9-week group compassion cultivation intervention in chronic pain to examine its effect on pain severity, anger, pain acceptance and pain-related interference. We also aimed to describe observer ratings provided by patients' significant others and secondary effects of the intervention.Pilot clinical trial with repeated measures design that included a within-subjects wait-list control period. Twelve chronic pain patients completed the intervention (F= 10). Data were collected from patients at enrollment, treatment baseline and post-treatment; participant significant others contributed data at the enrollment and post-treatment time points.In this predominantly female sample, patients had significantly reduced pain severity and anger and increased pain acceptance at post-treatment compared to treatment baseline. Significant other qualitative data corroborated patient reports for reductions in pain severity and anger.Compassion meditation may be a useful adjunctive treatment for reducing pain severity and anger, and for increasing chronic pain acceptance. Patient reported reductions in anger were corroborated by their significant others. The significant other corroborations offer a novel contribution to the literature and highlight the observable emotional and behavioral changes in the patient participants that occurred following the compassion intervention. Future studies may further examine how anger reductions impact relationships with self and others within the context of chronic pain.

  View details for PubMedID 27499883

• From Catastrophizing to Recovery: a pilot study of a single-session treatment for pain catastrophizing JOURNAL OF PAIN RESEARCH Darnall, B. D., Sturgeon, J. A., Kao, M., Hah, J. M., Mackey, S. C. 2014; 7: 219-226

  Abstract

  Pain catastrophizing (PC) - a pattern of negative cognitive-emotional responses to real or anticipated pain - maintains chronic pain and undermines medical treatments. Standard PC treatment involves multiple sessions of cognitive behavioral therapy. To provide efficient treatment, we developed a single-session, 2-hour class that solely treats PC entitled "From Catastrophizing to Recovery" [FCR].To determine 1) feasibility of FCR; 2) participant ratings for acceptability, understandability, satisfaction, and likelihood to use the information learned; and 3) preliminary efficacy of FCR for reducing PC.Uncontrolled prospective pilot trial with a retrospective chart and database review component. Seventy-six patients receiving care at an outpatient pain clinic (the Stanford Pain Management Center) attended the class as free treatment and 70 attendees completed and returned an anonymous survey immediately post-class. The Pain Catastrophizing Scale (PCS) was administered at class check-in (baseline) and at 2, and 4 weeks post-treatment. Within subjects repeated measures analysis of variance (ANOVA) with Student's t-test contrasts were used to compare scores across time points.All attendees who completed a baseline PCS were included as study participants (N=57; F=82%; mean age =50.2 years); PCS was completed by 46 participants at week 2 and 35 participants at week 4. Participants had significantly reduced PC at both time points (P<0001) and large effect sizes were found (Cohen's d=0.85 and d=1.15).Preliminary data suggest that FCR is an acceptable and effective treatment for PC. Larger, controlled studies of longer duration are needed to determine durability of response, factors contributing to response, and the impact on pain, function and quality of life.

  View details for DOI 10.2147/JPR.S62329

  View details for Web of Science ID 000364587600005

  View details for PubMedID 24851056

  View details for PubMedCentralID PMC4008292

• Proinflammatory cytokines and DHEA-S in women with fibromyalgia: impact of psychological distress and menopausal status JOURNAL OF PAIN RESEARCH Sturgeon, J. A., Darnall, B. D., Zwickey, H. L., Wood, L. J., Hanes, D. A., Zava, D. T., Mackey, S. C. 2014; 7: 707-716

  Abstract

  Though fibromyalgia is not traditionally considered an inflammatory disorder, evidence for elevated inflammatory processes has been noted in this disorder in multiple studies. Support for inflammatory markers in fibromyalgia has been somewhat equivocal to date, potentially due to inattention to salient patient characteristics that may affect inflammation, such as psychiatric distress and aging milestones like menopause. The current study examined the relationships between proinflammatory cytokines and hormone levels, pain intensity, and psychological distress in a sample of 34 premenopausal and postmenopausal women with fibromyalgia. Our results indicated significant relationships between interleukin-8 and ratings of pain catastrophizing (r=0.555, P<0.05), pain anxiety (r=0.559, P<0.05), and depression (r=0.551, P<0.05) for postmenopausal women but not premenopausal women (r,0.20 in all cases). Consistent with previous studies, ratios of interleukin-6 to interleukin-10 were significantly lower in individuals with greater levels of depressive symptoms (r=-0.239, P<0.05). Contrary to previous research, however, dehydroepiandrosterone sulfate did not correlate with pain intensity or psychological or biological variables. The results of the current study highlight the importance of psychological functioning and milestones of aging in the examination of inflammatory processes in fibromyalgia.

  View details for DOI 10.2147/JPR.S71344

  View details for Web of Science ID 000364591400001

  View details for PubMedID 25506243

• Optimizing real time fMRI neurofeedback for therapeutic discovery and development. NeuroImage. Clinical Stoeckel, L. E., Garrison, K. A., Ghosh, S., Wighton, P., Hanlon, C. A., Gilman, J. M., Greer, S., Turk-Browne, N. B., deBettencourt, M. T., Scheinost, D., Craddock, C., Thompson, T., Calderon, V., Bauer, C. C., George, M., Breiter, H. C., Whitfield-Gabrieli, S., Gabrieli, J. D., LaConte, S. M., Hirshberg, L., Brewer, J. A., Hampson, M., van der Kouwe, A., Mackey, S., Evins, A. E. 2014; 5: 245-255

  Abstract

  While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

  View details for DOI 10.1016/j.nicl.2014.07.002

  View details for PubMedID 25161891

• Response to: Letter from Paul Eugene Summers, Federico Giove, and Carlo Adolfo Porro. Pain Nash, P., Glover, G., Mackey, S. 2013; 154 (11): 2574-2575

  View details for DOI 10.1016/j.pain.2013.08.014

  View details for PubMedID 23973361

• Interventional management of neuropathic pain: NeuPSIG recommendations PAIN Dworkin, R. H., O'Connor, A. B., Kent, J., Mackey, S. C., Raja, S. N., Stacey, B. R., Levy, R. M., Backonja, M., Baron, R., Harke, H., Loeser, J. D., Treede, R., Turk, D. C., Wells, C. D. 2013; 154 (11): 2249-2261

  Abstract

  Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

  View details for DOI 10.1016/j.pain.2013.06.004

  View details for Web of Science ID 000325927500006

  View details for PubMedID 23748119

  View details for PubMedCentralID PMC4484720

• Perioperative Gabapentinoids Choice of Agent, Dose, Timing, and Effects on Chronic Postsurgical Pain ANESTHESIOLOGY Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2013; 119 (5): 1215-1221

  View details for DOI 10.1097/ALN.0b013e3182a9a896

  View details for Web of Science ID 000329797900029

  View details for PubMedID 24051389

• Functional magnetic resonance imaging identifies somatotopic organization of nociception in the human spinal cord. Pain Nash, P., Wiley, K., Brown, J., Shinaman, R., Ludlow, D., Sawyer, A., Glover, G., Mackey, S. 2013; 154 (6): 776-781

  Abstract

  Functional magnetic resonance imaging (fMRI) is a technique that uses blood oxygen-level-dependent (BOLD) signals to elucidate discrete areas of neuronal activity. Despite the significant number of fMRI human brain studies, few researchers have applied fMRI technology to investigating neuronal activity within the human spinal cord. Our study goals were to demonstrate that fMRI could reveal the following: (i) appropriate somatotopic activations in response to noxious stimuli in the deep and superficial dorsal horn of the human cervical spinal cord, and (ii) lateralization of fMRI activations in response to noxious stimulation in the right and left upper extremity. We subjected healthy participants to noxious stimulation during fMRI scans. Using a spiral in-out image sequence and retrospective correction for physiologic noise, we demonstrated that fMRI can create high-resolution, neuronal activation maps of the human cervical spinal cord. During nociceptive stimulation of all 4 sites (left deltoid, right deltoid, left thenar eminence and right thenar eminence), we found ipsilateral dorsal horn activation. Stimulation of the deltoid activated C5, whereas stimulation of the thenar eminence activated C6. Our study contributes to creating an objective analysis of pain transmission; other investigators can use these results to further study central nervous system changes that occur in patients with acute and chronic pain.

  View details for DOI 10.1016/j.pain.2012.11.008

  View details for PubMedID 23618495

• Perioperative interventions to reduce chronic postsurgical pain. Journal of reconstructive microsurgery Carroll, I., Hah, J., Mackey, S., Ottestad, E., Kong, J. T., Lahidji, S., Tawfik, V., Younger, J., Curtin, C. 2013; 29 (4): 213-222

  Abstract

  Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

  View details for DOI 10.1055/s-0032-1329921

  View details for PubMedID 23463498

• Perioperative Interventions to Reduce Chronic Postsurgical Pain JOURNAL OF RECONSTRUCTIVE MICROSURGERY Carroll, I., Hah, J., Mackey, S., Ottestad, E., Kong, J. T., Lahidji, S., Tawfik, V., Younger, J., Curtin, C. 2013; 29 (4): 213-222

  Abstract

  Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

  View details for DOI 10.1055/s-0032-1329921

  View details for Web of Science ID 000317597000001

  View details for PubMedID 23463498

• Central Neuroimaging of Pain JOURNAL OF PAIN Mackey, S. C. 2013; 14 (4): 328-331

  View details for Web of Science ID 000317639200003

  View details for PubMedID 23548485

• Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis and rheumatism Younger, J., Noor, N., McCue, R., Mackey, S. 2013; 65 (2): 529-538

  Abstract

  To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

  View details for DOI 10.1002/art.37734

  View details for PubMedID 23359310

• Low-Dose Naltrexone for the Treatment of Fibromyalgia ARTHRITIS AND RHEUMATISM Younger, J., Noor, N., McCue, R., Mackey, S. 2013; 65 (2): 529-538

  Abstract

  To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

  View details for DOI 10.1002/art.37734

  View details for Web of Science ID 000314169400030

• Personalized Medicine and Opioid Analgesic Prescribing for Chronic Pain: Opportunities and Challenges JOURNAL OF PAIN Bruehl, S., Apkarian, A. V., Ballantyne, J. C., Berger, A., Borsook, D., Chen, W. G., Farrar, J. T., Haythornthwaite, J. A., Horn, S. D., Iadarola, M. J., Inturrisi, C. E., Lao, L., Mackey, S., Mao, J., Sawczuk, A., Uhl, G. R., Witter, J., Woolf, C. J., Zubieta, J., Lin, Y. 2013; 14 (2): 103-113

  Abstract

  Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms.Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality.

  View details for DOI 10.1016/j.jpain.2012.10.016

  View details for Web of Science ID 000314856600001

  View details for PubMedID 23374939

  View details for PubMedCentralID PMC3564046

• Understanding Central Mechanisms of Acupuncture Analgesia Using Dynamic Quantitative Sensory Testing: A Review EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE Kong, J., Schnyer, R. N., Johnson, K. A., Mackey, S. 2013

  Abstract

  We discuss the emerging translational tools for the study of acupuncture analgesia with a focus on psychophysical methods. The gap between animal mechanistic studies and human clinical trials of acupuncture analgesia calls for effective translational tools that bridge neurophysiological data with meaningful clinical outcomes. Temporal summation (TS) and conditioned pain modulation (CPM) are two promising tools yet to be widely utilized. These psychophysical measures capture the state of the ascending facilitation and the descending inhibition of nociceptive transmission, respectively. We review the basic concepts and current methodologies underlying these measures in clinical pain research, and illustrate their application to research on acupuncture analgesia. Finally, we highlight the strengths and limitations of these research methods and make recommendations on future directions. The appropriate addition of TS and CPM to our current research armamentarium will facilitate our efforts to elucidate the central analgesic mechanisms of acupuncture in clinical populations.

  View details for DOI 10.1155/2013/187182

  View details for Web of Science ID 000319569800001

  View details for PubMedID 23762107

  View details for PubMedCentralID PMC3666367

• Test-Retest Reliability of Thermal Temporal Summation Using an Individualized Protocol JOURNAL OF PAIN Kong, J., Johnson, K. A., Balise, R. R., Mackey, S. 2013; 14 (1): 79-88

  Abstract

  Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. It is a behavioral correlate of wind-up, the spinal facilitation of recurring C-fiber stimulation. In order to utilize TS in clinical pain research, it is important to characterize TS in a wide range of individuals and to establish its test-retest reliability. Building on a fixed-parameter protocol, we developed an individually adjusted protocol to broadly capture thermally generated TS. We then examined the test-retest reliability of TS within-day (intertrial intervals ranging from 2 to 30 minutes) and between-days (intersession interval of 7 days). We generated TS-like effects in 19 of the 21 participants. Strong correlations were observed across all trials over both days (intraclass correlation [ICC] [A, 10] = .97, 95% confidence level [CL] = .94-.99) and across the initial trials between days (ICC [A, 1] = .83, 95% CL = .58-.93). Repeated measures mixed-effects modeling demonstrated no significant within-day variation and only a small (5 out of 100 points) between-day variation. Finally, a Bland-Altman analysis suggested that TS is reliable across the range of observed scores. Without intervention, thermally-generated TS is generally stable within day and between days.Our study introduces a new strategy to generate thermal TS in a high proportion of individuals. This study confirms the test-retest reliability of thermal TS, supporting its use as a consistent behavioral correlate of central nociceptive facilitation.

  View details for DOI 10.1016/j.jpain.2012.10.010

  View details for Web of Science ID 000314081100009

  View details for PubMedID 23273835

  View details for PubMedCentralID PMC3541942

• Development of the Stanford Expectations of Treatment Scale (SETS): A tool for measuring patient outcome expectancy in clinical trials CLINICAL TRIALS Younger, J., Gandhi, V., Hubbard, E., Mackey, S. 2012; 9 (6): 767-776

  Abstract

  A patient's response to treatment may be influenced by the expectations that the patient has before initiating treatment. In the context of clinical trials, the influence of participant expectancy may blur the distinction between real and sham treatments, reducing statistical power to detect specific treatment effects. There is therefore a need for a tool that prospectively predicts expectancy effects on treatment outcomes across a wide range of treatment modalities.To help assess expectancy effects, we created the Stanford Expectations of Treatment Scale (SETS): an instrument for measuring positive and negative treatment expectancies. Internal reliability of the instrument was tested in Study 1. Criterion validity of the instrument (convergent, discriminant, and predictive) was assessed in Studies 2 and 3.The instrument was developed using 200 participants in Study 1. Reliability and validity assessments were made with an additional 423 participants in Studies 2 and 3.The final six-item SETS contains two subscales: positive expectancy (α = 0.81-0.88) and negative expectancy (α = 0.81-0.86). The subscales predict a significant amount of outcome variance (between 12% and 18%) in patients receiving surgical and pain interventions. The SETS is simple to administer, score, and interpret.The SETS may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.

  View details for DOI 10.1177/1740774512465064

  View details for Web of Science ID 000312452600015

  View details for PubMedID 23169874

• Outcomes in Pain Medicine: A Brief Review PAIN AND THERAPY Malhotra, A., Mackey, S. 2012; 1 (1): 5

  Abstract

  Pain, and particularly chronic pain, is a difficult outcome to measure due to its subjective and multidimensional nature. The Institute of Medicine estimates that 100 million Americans have chronic pain with a cost exceeding half a trillion dollars per year. There is a pressing need to identify appropriate outcome measures to better select and evaluate treatment modalities for these patients. It is also important that we demonstrate an evidence basis for these decisions given the current practice standard. Appropriate selection and implementation of these outcome measures can help accomplish both goals. The purpose of this review is to explore the difficulties and opportunities unique to pain outcome measures. The scope of the problem and impetus for implementation of appropriate measures is initially discussed, followed by requisite evaluation criteria for any measurement instrument. The authors then review frequently employed tools for measuring pain outcomes ranging from univariable and single domain scales to multidimensional instruments. A discussion of possible behavioral and objective measures is pursued, as well as measures of statistical and treatment efficacy. The article closes with a review of recent and ongoing efforts to validate and standardize pain outcome measures and suggests directions for future clinical and research assessment.

  View details for DOI 10.1007/s40122-012-0005-4

  View details for Web of Science ID 000218791200002

  View details for PubMedID 25134934

  View details for PubMedCentralID PMC4107859

• A Pilot Cohort Study of the Determinants of Longitudinal Opioid Use After Surgery ANESTHESIA AND ANALGESIA Carroll, I., Barelka, P., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F., Whyte, R. I., Donington, J. S., Cannon, W. B., Mackey, S. C. 2012; 115 (3): 694-702

  Abstract

  Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

  View details for DOI 10.1213/ANE.0b013e31825c049f

  View details for PubMedID 22729963

• Real-time fMRI applied to pain management NEUROSCIENCE LETTERS Chapin, H., Bagarinao, E., Mackey, S. 2012; 520 (2): 174-181

  Abstract

  Current views recognize the brain as playing a pivotal role in the arising and maintenance of pain experience. Real-time fMRI (rtfMRI) feedback is a potential tool for pain modulation that directly targets the brain with the goal of restoring regulatory function. Though still relatively new, rtfMRI is a rapidly developing technology that has evolved in the last 15 years from simple proof of concept experiments to demonstrations of learned control of single and multiple brain areas. Numerous studies indicate rtfMRI feedback assisted control over specific brain areas may have applications including mood regulation, language processing, neurorehabilitation in stroke, enhancement of perception and learning, and pain management. We discuss in detail earlier work from our lab in which rtfMRI feedback was used to train both healthy controls and chronic pain patients to modulate anterior cingulate cortex (ACC) activation for the purposes of altering pain experience. Both groups improved in their ability to control ACC activation and modulate their pain with rtfMRI feedback training. Furthermore, the degree to which participants were able to modulate their pain correlated with the degree of control over ACC activation. We additionally review current advances in rtfMRI feedback, such as real-time pattern classification, that bring the technology closer to more comprehensive control over neural function. Finally, remaining methodological questions concerning the further development of rtfMRI feedback and its implications for the future of pain research are also discussed.

  View details for DOI 10.1016/j.neulet.2012.02.076

  View details for Web of Science ID 000306162800007

  View details for PubMedID 22414861

  View details for PubMedCentralID PMC3377818

• Sensory Pain Qualities in Neuropathic Pain JOURNAL OF PAIN Mackey, S., Carroll, I., Emir, B., Murphy, T. K., Whalen, E., Dumenci, L. 2012; 13 (1): 58-63

  Abstract

  The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model.This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.

  View details for DOI 10.1016/j.jpain.2011.10.002

  View details for Web of Science ID 000299198300007

  View details for PubMedID 22172451

  View details for PubMedCentralID PMC3249485

• Strategy-dependent Dissociation of the Neural Correlates Involved in Pain Modulation ANESTHESIOLOGY Lawrence, J. M., Hoeft, F., Sheau, K. E., Mackey, S. C. 2011; 115 (4): 844-851

  Abstract

  Cognitive strategies are a set of psychologic behaviors used to modulate one's perception or interpretation of a sensation or situation. Although the effectiveness of each cognitive strategy seems to differ between individuals, they are commonly used clinically to help patients with chronic pain cope with their condition. The neural basis of commonly used cognitive strategies is not well understood. Understanding the neural correlates that underlie these strategies will enhance understanding of the analgesic network of the brain and the cognitive modulation of pain.The current study examines patterns of brain activation during two common cognitive strategies, external focus of attention and reappraisal, in patients with chronic pain using functional magnetic resonance imaging.Behavioral results revealed interindividual variability in the effectiveness of one strategy versus another in the patients. Functional magnetic resonance imaging revealed distinct patterns of activity when the two strategies were used. During external focus of attention, activity was observed mainly in cortical areas including the postcentral gyrus, inferior parietal lobule, middle occipital gyrus, and precentral gyrus. The use of reappraisal evoked activity in the thalamus and amygdala in addition to cortical regions. Only one area, the postcentral gyrus, was observed to be active during both strategies.The results of this study suggest that different cognitive behavioral strategies recruit different brain regions to perform the same task: pain modulation.

  View details for DOI 10.1097/ALN.0b013e31822b79ea

  View details for Web of Science ID 000295079500026

  View details for PubMedID 21934411

  View details for PubMedCentralID PMC3186353

• Towards a Physiology-Based Measure of Pain: Patterns of Human Brain Activity Distinguish Painful from Non-Painful Thermal Stimulation PLOS ONE Brown, J. E., Chatterjee, N., Younger, J., Mackey, S. 2011; 6 (9)

  Abstract

  Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p<0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings.

  View details for DOI 10.1371/journal.pone.0024124

  View details for Web of Science ID 000295321800020

  View details for PubMedID 21931652

  View details for PubMedCentralID PMC3172232

• Prescription opioid analgesics rapidly change the human brain PAIN Younger, J. W., Chu, L. F., D'Arcy, N. T., Trott, K. E., Jastrzab, L. E., Mackey, S. C. 2011; 152 (8): 1803-1810

  Abstract

  Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.

  View details for DOI 10.1016/j.pain.2011.03.028

  View details for PubMedID 21531077

• Morphine and its metabolites after patient-controlled analgesia: considerations for respiratory depression JOURNAL OF CLINICAL ANESTHESIA Sam, W. J., Mackey, S. C., Loetsch, J., Drover, D. R. 2011; 23 (2): 102-106

  Abstract

  To assess concentrations of morphine and its metabolites after patient-controlled analgesia (PCA).Pilot pharmacokinetic study of morphine and pharmacokinetic simulation.Post-anesthesia care room and ward of an academic teaching hospital.10 ASA physical status I, II, and III postoperative surgical patients.Patients received morphine via PCA by routine hospital protocols.The population mean plasma and effect-site concentrations of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) was simulated in 4 patient group scenarios: morphine PCA used alone, morphine PCA used with continuous background morphine infusion of 0.5 mg/hr, morphine PCA used with continuous background morphine infusion of 1.0 mg/hr, and morphine PCA used with continuous background morphine infusion of 2.0 mg/hr.The 4 groups exhibited simulated peak morphine, M6G, and M3G effect-site concentrations at 8 to 24 hours post-infusion. The highest peak morphine, M6G, and M3G effect-site concentrations decreased in the following order by group: 2.0 mg/hr morphine infusion + PCA group, 1.0 mg/hr morphine infusion + PCA group, and 0.5. mg/hr morphine infusion + PCA group.Patients receiving morphine PCA should be monitored closely from 8 to 24 hours postoperatively. Morphine PCA given with background infusion rates up to 1.0 mg/hr does not offer distinct pharmacokinetic advantages over morphine PCA alone. Morphine PCA with background infusion rate of 2.0 mg/hr is associated with the greatest risk of respiratory depression.

  View details for DOI 10.1016/j.jclinane.2010.08.002

  View details for PubMedID 21377072

• Human Response to Unintended Intrathecal Injection of Botulinum Toxin PAIN MEDICINE Carroll, I., Fischbein, N., Barad, M., Mackey, S. 2011; 12 (7): 1094-1097

  Abstract

  Describe the first reported human intrathecal (IT) botulinum toxin injection.Case report.We report here the sequelae to an unintended IT injection of botulinum toxin type B (BTB) in a 60-year-old woman with chronic back pain.Following the IT administration of BTB, the patient experienced the onset of symmetric ascending stocking distribution painful dysesthesias, which persisted for approximately 6 months before receding. Objective neurologic deficits were not appreciated, and analgesic effects were prominently absent.Analgesic actions of botulinum toxins in animals and in humans have led to speculation that IT botulinum toxin might exert significant analgesic effects. The unusual and unexpected subsequent clinical course, neurologic sequelae, dysesthesias, and absence of analgesia suggest that botulinum toxin will not be a therapeutic modality to treat pain as proposed by those studying botulinum toxin in animal models.

  View details for DOI 10.1111/j.1526-4637.2011.01135.x

  View details for Web of Science ID 000292697100016

  View details for PubMedID 21627762

• Development of a severity score for CRPS PAIN Harden, R. N., Bruehl, S., Perez, R. S., Birklein, F., Marinus, J., Maihofner, C., Lubenow, T., Buvanendran, A., Mackey, S., Graciosa, J., Mogilevski, M., Ramsden, C., Schlereth, T., Chont, M., Vatine, J. 2010; 151 (3): 870-876

  Abstract

  The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision-making. However, such dichotomous diagnostic categories do not convey an individual's subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non-CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically-assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non-CRPS patients (p<.001), and displayed strong associations with dichotomous CRPS diagnoses using both IASP diagnostic criteria (Eta=0.69) and proposed revised criteria (Eta=0.77-0.88). Higher CSS was associated with significantly higher clinical pain intensity, distress, and functional impairments, as well as greater bilateral temperature asymmetry and thermal perception abnormalities (p's<.05). In an archival prospective dataset, increases in anxiety and depression from pre-surgical baseline to 4 weeks post-knee arthroplasty were found to predict significantly higher CSS at 6- and 12-month follow-up (p's<.05). Results indicate the CSS corresponds with and complements currently accepted dichotomous diagnostic criteria for CRPS, and support its validity as an index of CRPS severity. Its utility as an outcome measure in research studies is also suggested, with potential statistical advantages over dichotomous diagnostic criteria.

  View details for DOI 10.1016/j.pain.2010.09.031

  View details for Web of Science ID 000283657300042

  View details for PubMedID 20965657

• Viewing Pictures of a Romantic Partner Reduces Experimental Pain: Involvement of Neural Reward Systems PLOS ONE Younger, J., Aron, A., Parke, S., Chatterjee, N., Mackey, S. 2010; 5 (10)

  Abstract

  The early stages of a new romantic relationship are characterized by intense feelings of euphoria, well-being, and preoccupation with the romantic partner. Neuroimaging research has linked those feelings to activation of reward systems in the human brain. The results of those studies may be relevant to pain management in humans, as basic animal research has shown that pharmacologic activation of reward systems can substantially reduce pain. Indeed, viewing pictures of a romantic partner was recently demonstrated to reduce experimental thermal pain. We hypothesized that pain relief evoked by viewing pictures of a romantic partner would be associated with neural activations in reward-processing centers. In this functional magnetic resonance imaging (fMRI) study, we examined fifteen individuals in the first nine months of a new, romantic relationship. Participants completed three tasks under periods of moderate and high thermal pain: 1) viewing pictures of their romantic partner, 2) viewing pictures of an equally attractive and familiar acquaintance, and 3) a word-association distraction task previously demonstrated to reduce pain. The partner and distraction tasks both significantly reduced self-reported pain, although only the partner task was associated with activation of reward systems. Greater analgesia while viewing pictures of a romantic partner was associated with increased activity in several reward-processing regions, including the caudate head, nucleus accumbens, lateral orbitofrontal cortex, amygdala, and dorsolateral prefrontal cortex--regions not associated with distraction-induced analgesia. The results suggest that the activation of neural reward systems via non-pharmacologic means can reduce the experience of pain.

  View details for DOI 10.1371/journal.pone.0013309

  View details for Web of Science ID 000282869800015

  View details for PubMedID 20967200

  View details for PubMedCentralID PMC2954158

• Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome PAIN Harden, R. N., Bruehl, S., Perez, R. S., Birklein, F., Marinus, J., Maihofner, C., Lubenow, T., Buvanendran, A., Mackey, S., Graciosa, J., Mogilevski, M., Ramsden, C., Chont, M., Vatine, J. 2010; 150 (2): 268-274

  Abstract

  Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the "Budapest Criteria") regarding diagnostic accuracy. Structured evaluations of CRPS-related signs and symptoms were conducted in 113 CRPS-I and 47 non-CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.

  View details for DOI 10.1016/j.pain.2010.04.030

  View details for Web of Science ID 000280611000014

  View details for PubMedID 20493633

  View details for PubMedCentralID PMC2914601

• Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems PAIN Younger, J. W., Shen, Y. F., Goddard, G., Mackey, S. C. 2010; 149 (2): 222-228

  Abstract

  Myofascial pain of the temporomandibular region (M-TMD) is a common, but poorly understood chronic disorder. It is unknown whether the condition is a peripheral problem, or a disorder of the central nervous system (CNS). To investigate possible CNS substrates of M-TMD, we compared the brain morphology of 15 women with M-TMD to that of 15 age- and gender-matched healthy controls. High-resolution structural brain and brainstem scans were carried out using magnetic resonance imaging (MRI), and data were analyzed using a voxel-based morphometry approach. The M-TMD group evidenced decreased or increased gray matter volume compared to controls in several areas of the trigeminothalamocortical pathway, including brainstem trigeminal sensory nuclei, the thalamus, and the primary somatosensory cortex. In addition, M-TMD individuals showed increased gray matter volume compared to controls in limbic regions such as the posterior putamen, globus pallidus, and anterior insula. Within the M-TMD group, jaw pain, pain tolerance, and pain duration were differentially associated with brain and brainstem gray matter volume. Self-reported pain severity was associated with increased gray matter in the rostral anterior cingulate cortex and posterior cingulate. Sensitivity to pressure algometry was associated with decreased gray matter in the pons, corresponding to the trigeminal sensory nuclei. Longer pain duration was associated with greater gray matter in the posterior cingulate, hippocampus, midbrain, and cerebellum. The pattern of gray matter abnormality found in M-TMD individuals suggests the involvement of trigeminal and limbic system dysregulation, as well as potential somatotopic reorganization in the putamen, thalamus, and somatosensory cortex.

  View details for DOI 10.1016/j.pain.2010.01.006

  View details for Web of Science ID 000276980900012

  View details for PubMedID 20236763

  View details for PubMedCentralID PMC2860657

• Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions BRAIN BEHAVIOR AND IMMUNITY Fredericks, C. A., Drabant, E. M., Edge, M. D., Tillie, J. M., Hallmayer, J., Ramel, W., Kuo, J. R., Mackey, S., Gross, J. J., Dhabhar, F. S. 2010; 24 (3): 350-357

  Abstract

  The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

  View details for DOI 10.1016/j.bbi.2009.10.014

  View details for Web of Science ID 000275217300004

  View details for PubMedID 19883751

  View details for PubMedCentralID PMC2826575

• Assessment and Treatment of Psychosocial Comorbidities in Patients With Neuropathic Pain MAYO CLINIC PROCEEDINGS Turk, D. C., Audette, J., Levy, R. M., Mackey, S. C., Stanos, S. 2010; 85 (3): S42-S50

  Abstract

  Chronic neuropathic pain is a prevalent problem that eludes cure and adequate treatment. The persistence of intense and aversive symptoms, inadequacy of available treatments, and impact of such pain on all aspects of functioning underscore the important role of several psychosocial factors in causing, maintaining, and amplifying the perception of pain severity, coping adequacy, adaptation, impaired physical function, and emotional distress responses. Moreover, these factors have an influential role in response to treatment recommendations. In this article, we (1) review the prevalence and nature of emotional distress, (2) describe and propose methods for screening and comprehensive psychosocial assessment, and (3) review evidence supporting the potential complementary role of psychosocial treatments of patients with chronic pain. The cognitive-behavioral perspective and treatment approach are emphasized because the greatest amount of evidence supports their benefits. Published results of psychological treatments are modest; however, the same indictment can be placed on currently available pharmacological, medical, and interventional treatments for patients with chronic pain. We note the limited research on the effectiveness of psychological treatment specifically applied to patients with chronic neuropathic pain but suggest that it is reasonable to extrapolate from successful trials in other types of chronic pain. Furthermore, psychological approaches should not be viewed as alternatives but rather should be integrated as part of a comprehensive approach to the treatment of patients with chronic neuropathic pain.

  View details for DOI 10.4065/mcp.2009.0648

  View details for Web of Science ID 000275807700005

  View details for PubMedID 20194148

  View details for PubMedCentralID PMC2844010

• Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update MAYO CLINIC PROCEEDINGS Dworkin, R. H., O'Connor, A. B., Audette, J., Baron, R., Gourlay, G. K., Haanpaa, M. L., Kent, J. L., Krane, E. J., LeBel, A. A., Levy, R. M., Mackey, S. C., Mayer, J., Miaskowski, C., Raja, S. N., Rice, A. S., Schmader, K. E., Stacey, B., Stanos, S., Treede, R., Turk, D. C., Walco, G. A., Wells, C. D. 2010; 85 (3): S3-S14

  Abstract

  The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

  View details for DOI 10.4065/mcp.2009.0649

  View details for Web of Science ID 000275807700001

  View details for PubMedID 20194146

  View details for PubMedCentralID PMC2844007

• A Novel CT-Guided Transpsoas Approach to Diagnostic Genitofemoral Nerve Block and Ablation PAIN MEDICINE Parris, D., Fischbein, N., Mackey, S., Carroll, I. 2010; 11 (5): 785-789

  Abstract

  Inguinal hernia repair is associated with a high incidence of chronic postsurgical pain. This pain may be caused by injury to the iliohypogastric, ilioinguinal, or genitofemoral nerves. It is often difficult to identify the specific source of the pain, in part, because these nerves are derived from overlapping nerve roots and closely colocalize in the area of surgery. It is therefore technically difficult to selectively block these nerves individually proximal to the site of surgical injury. In particular, the genitofemoral nerve is retroperitoneal before entering the inguinal canal, a position that puts anterior approaches to the proximal nerve at risk of transgressing into the peritoneum. We report a computed tomography (CT)-guided transpsoas technique to selectively block the genitofemoral nerve for both diagnostic and therapeutic purposes while avoiding injury to the nearby ureter and intestines.A 39-year-old woman with chronic lancinating right groin pain after inguinal hernia repair underwent multiple pharmacologic interventions and invasive procedures without relief. Using CT and Stimuplex nerve stimulator guidance, the genitofemoral nerve was localized on the anterior surface of the psoas muscle and a diagnostic block with local anesthetic block was performed. The patient had immediate relief of her symptoms for 36 hours, confirming the diagnosis of genitofemoral neuralgia. She subsequently underwent CT-guided radiofrequency and phenol ablation of the genitofemoral nerve but has not achieved long-term analgesia.CT-guided transpsoas genitofemoral nerve block is a viable option for safely and selectively blocking the genitofemoral nerve for diagnostic or therapeutic purposes proximal to injury caused by inguinal surgery.

  View details for Web of Science ID 000277206200018

  View details for PubMedID 20546515

• Subcutaneous Injection of Botulinum Toxin A Is Beneficial in Postherpetic Neuralgia PAIN MEDICINE Xiao, L., Mackey, S., Hui, H., Xong, D., Zhang, Q., Zhang, D. 2010; 11 (12): 1827-1833

  Abstract

  To assess the benefits of subcutaneous injection of botulinum toxin A (BTX-A) for the treatment of postherpetic neuralgia (PHN).We investigated the therapeutic benefits of BTX-A in subjects with PHN in a randomized, double-blind, placebo-controlled study. Sixty subjects with PHN were randomly and evenly distributed into BTX-A, lidocaine, and placebo groups.After randomization, one of the following solutions was injected subcutaneously in the affected dermatome: 5u/mL BTX-A, 0.5% lidocaine, or 0.9% saline (placebo). Visual analog scale (VAS) pain and sleeping time (hours) were evaluated at the time of pretreatment, day 1, day 7, and 3 months posttreatment. Opioid usage was calculated at day 7 and 3 months posttreatment.  Compared with pretreatment, VAS pain scores decreased at day 7 and 3 months posttreatment in all three groups (P<0.01). However, the VAS pain scores of the BTX-A group decreased more significantly compared with lidocaine and placebo groups at day 7 and 3 months posttreatment (P<0.01). Sleep time (hours) had improved at day 7 and at 3 months compared with pretreatment in all three groups, but the BTX-A group improved more significantly compared with lidocaine and placebo groups (P<0.01). The percent of subjects using opioids posttreatment in the BTX-A group was the lowest (21.1%) compared with the lidocaine (52.6%) and placebo (66.7%) groups (P<0.01).Subcutaneous administration of BTX-A significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased subjects' sleep times.

  View details for DOI 10.1111/j.1526-4637.2010.01003.x

  View details for Web of Science ID 000285066100014

  View details for PubMedID 21134121

• Pain Quality Predicts Lidocaine Analgesia among Patients with Suspected Neuropathic Pain PAIN MEDICINE Carroll, I. R., Younger, J. W., Mackey, S. C. 2010; 11 (4): 617-621

  Abstract

  Oral sodium channel blockers have shown mixed results in randomized controlled trials despite the known importance of sodium channels in generating pain. We hypothesized that differing baseline pain qualities (e.g. "stabbing" vs "dull") might define specific subgroups responsive to intravenous (IV) lidocaine-a potent sodium channel blocker.A prospective cohort study of 71 patient with chronic pain suspected of being neuropathic were recruited between January 2003 and July 2007 and underwent lidocaine infusions at Stanford University Hospital in a single-blind nonrandomized fashion. Baseline sensory pain qualities were measured with the Short-Form McGill Pain Questionnaire (SF-MPQ). Pain intensity was measured with a visual analog scale (VAS).Factor analysis demonstrated two underlying pain quality factors among SF-MPQ sensory items: a heavy pain and a stabbing pain. Baseline heavy pain quality, but not stabbing quality predicted subsequent relief of pain intensity in response to lidocaine. In contrast, these factors did not predict divergent analgesic responses to placebo infusions. In response to each 1 mcg/mL increase in lidocaine plasma level, patients with high heavy pain quality drop their VAS 0.24 (95% CI 0.05-0.43) more points than those with low heavy pain quality (P < 0.013)."Heavy" pain quality may indentify patients with enhanced lidocaine responsiveness. Pain quality may identify subgroups among patients with suspected neuropathic pain responsive to IV lidocaine. Further investigation is warranted to validate and extend these findings.

  View details for Web of Science ID 000276223500020

  View details for PubMedID 20210867

• Randomized Clinical Trial of Acupuncture for Myofascial Pain of the Jaw Muscles JOURNAL OF OROFACIAL PAIN Shen, Y. F., Younger, J., Goddard, G., Mackey, S. 2009; 23 (4): 353-359

  Abstract

  To evaluate the effectiveness of acupuncture in treating symptoms associated with myofascial pain of the jaw muscles.Twenty-eight subjects over the age of 18 and diagnosed with chronic myofascial pain of the jaw muscles were randomized to receive real (n = 16) or sham (n = 12) acupuncture. Prior to treatment, each subject clenched his or her teeth for 2 minutes. Acupuncture or sham acupuncture was then administered at the Hegu large intestine 4 (LI4) acupoint for 15 minutes. Real acupuncture was given by penetrating the needle through a sticky foam pad at the acupoint. Sham acupuncture was conducted by pricking the skin, without penetration, with a shortened, blunted acupuncture needle through a foam pad placed away from the acupoint. General head and neck pain ratings were obtained before and after treatment on a numerical rating scale. A mechanical pain stimulus on the masseter muscle was given before and after treatment and rated on a visual analog scale to measure pain tolerance level. Paired t tests were performed to detect significant changes in pain levels.Subjects receiving real acupuncture experienced a significant reduction in jaw pain (P = .04), jaw/face tightness (P = .04), and neck pain (P = .04), and a significant increase in pain tolerance of the masseter muscle (P = .001). Subjects were not able to determine whether they received real or sham acupuncture (P = .69). No significant pain reductions were observed in the sham acupuncture group.A single acupuncture session using one acupoint at Hegu large intestine 4 significantly reduced most myofascial pain endpoints when compared to sham acupuncture.

  View details for Web of Science ID 000271823900014

  View details for PubMedID 19888488

  View details for PubMedCentralID PMC2894813

• Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study PAIN MEDICINE Younger, J., Mackey, S. 2009; 10 (4): 663-672

  Abstract

  Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia.Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks).Ten women meeting criteria for fibromyalgia and not taking an opioid medication.Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation.Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity.Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

  View details for DOI 10.1111/j.1526-4637.2009.00613.x

  View details for Web of Science ID 000266678600010

  View details for PubMedID 19453963

  View details for PubMedCentralID PMC2891387

• Forebrain pain mechanisms BRAIN RESEARCH REVIEWS Neugebauer, V., Galhardo, V., Maione, S., Mackey, S. C. 2009; 60 (1): 226-242

  Abstract

  Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.

  View details for DOI 10.1016/j.brainresrev.2008.12.014

  View details for Web of Science ID 000265769600018

  View details for PubMedID 19162070

  View details for PubMedCentralID PMC2700838

• Sympathetic Block with Botulinum Toxin to Treat Complex Regional Pain Syndrome ANNALS OF NEUROLOGY Carroll, I., Clark, J. D., Mackey, S. 2009; 65 (3): 348-351

  Abstract

  Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12-253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0-12) after standard LSB (log-rank, p < 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study.

  View details for DOI 10.1002/ana.21601

  View details for PubMedID 19334078

• Pain outcomes: A brief review of instruments and techniques CURRENT PAIN AND HEADACHE REPORTS Younger, J., McCue, R., Mackey, S. 2009; 13 (1): 39-43

  Abstract

  Pain is a difficult outcome to measure due to its multifaceted and subjective nature. The need for selecting proper outcome measures is high because of the increasing demand for scientifically valid demonstrations of treatment efficacy. This article discusses some basic topics in the measurement of pain outcomes and addresses issues such as statistical versus clinical significance, daily home data collection, appropriate length of outcome measurement packets, and the possibility of objective pain measurements. This article also reviews some of the more commonly used tools for measuring pain and pain-related disability. By selecting the proper tools and employing them correctly, we can obtain highly reliable and valid measures of pain outcomes in research and clinical care.

  View details for DOI 10.1007/s11916-009-0009-x

  View details for Web of Science ID 000263064900009

  View details for PubMedID 19126370

  View details for PubMedCentralID PMC2891384

• Spinal cord stimulation compared with medical management for failed back surgery syndrome CURRENT PAIN AND HEADACHE REPORTS Coleman, S. D., Mackey, S. 2009; 13 (1): 1-2

  View details for DOI 10.1007/s11916-009-0001-5

  View details for PubMedID 19126362

• Serratus muscle stimulation effectively treats notalgia paresthetica caused by long thoracic nerve dysfunction: a case series. Journal of brachial plexus and peripheral nerve injury Wang, C. K., Gowda, A., Barad, M., Mackey, S. C., Carroll, I. R. 2009; 4: 17-?

  Abstract

  Currently, notalgia paresthetica (NP) is a poorly-understood condition diagnosed on the basis of pruritus, pain, or both, in the area medial to the scapula and lateral to the thoracic spine. It has been proposed that NP is caused by degenerative changes to the T2-T6 vertebrae, genetic disposition, or nerve entrapment of the posterior rami of spinal nerves arising at T2-T6. Despite considerable research, the etiology of NP remains unclear, and a multitude of different treatment modalities have correspondingly met with varying degrees of success. Here we demonstrate that NP can be caused by long thoracic nerve injury leading to serratus anterior dysfunction, and that electrical muscle stimulation (EMS) of the serratus anterior can successfully and conservatively treat NP. In four cases of NP with known injury to the long thoracic nerve we performed transcutaneous EMS to the serratus anterior in an area far lateral to the site of pain and pruritus, resulting in significant and rapid pain relief. These findings are the first to identify long thoracic nerve injury as a cause for notalgia paresthetica and electrical muscle stimulation of the serratus anterior as a possible treatment, and we discuss the implications of these findings on better diagnosing and treating notalgia paresthetica.

  View details for DOI 10.1186/1749-7221-4-17

  View details for PubMedID 19772656

  View details for PubMedCentralID PMC2758879

• Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification PAIN MEDICINE Younger, J., Barelka, P., Carroll, I., Kaplan, K., Chu, L., Prasad, R., Gaeta, R., Mackey, S. 2008; 9 (8): 1158-1163

  Abstract

  One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients.Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay.We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task.A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain.These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity.

  View details for DOI 10.1111/j.1526-4637.2008.00475.x

  View details for PubMedID 18564998

• Toward optimal health: A discussion on sex, gender, and pain JOURNAL OF WOMENS HEALTH Godfrey, J. R., Mackey, S. 2008; 17 (6): 917-920

  View details for DOI 10.1089/jwh.2008.0957

  View details for Web of Science ID 000258897000001

  View details for PubMedID 18582170

• Your pain or mine? Common and distinct neural systems supporting the perception of pain in self and other SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE Ochsner, K. N., Zaki, J., Hanelin, J., Ludlow, D. H., Knierim, K., Ramachandran, T., Glover, G. H., Mackey, S. C. 2008; 3 (2): 144-160

  Abstract

  Humans possess a remarkable capacity to understand the suffering of others. Cognitive neuroscience theories of empathy suggest that this capacity is supported by 'shared representations' of self and other. Consistent with this notion, a number of studies have found that perceiving others in pain and experiencing pain oneself recruit overlapping neural systems. Perception of pain in each of these conditions, however, may also cause unique patterns of activation, that may reveal more about the processing steps involved in each type of pain. To address this issue, we examined neural activity while participants experienced heat pain and watched videos of other individuals experiencing injuries. Results demonstrated (i) that both tasks activated anterior cingulate cortex and anterior insula, consistent with prior work; (ii) whereas self-pain activated anterior and mid insula regions implicated in interoception and nociception, other pain activated frontal, premotor, parietal and amygdala regions implicated in emotional learning and processing social cues; and (iii) that levels of trait anxiety correlated with activity in rostral lateral prefrontal cortex during perception of other pain but not during self-pain. Taken together, these data support the hypothesis that perception of pain in self and other, while sharing some neural commonalities, differ in their recruitment of systems specifically associated with decoding and learning about internal or external cues.

  View details for DOI 10.1093/scan/nsn006

  View details for Web of Science ID 000256525000008

  View details for PubMedID 19015105

  View details for PubMedCentralID PMC2555461

• Pulsed radiofrequency for chronic pain CURRENT PAIN AND HEADACHE REPORTS Byrd, D., Mackey, S. 2008; 12 (1): 37-41

  Abstract

  Pulsed radiofrequency (PRF), a technology related to continuous radiofrequency, is unique in that it provides pain relief without causing significant damage to nervous tissue. The mechanism by which PRF controls pain is unclear, but it may involve a temperature-independent pathway mediated by a rapidly changing electrical field. Although much anecdotal evidence exists in favor of PRF, there are few quality studies substantiating its utility.

  View details for Web of Science ID 000254517700006

  View details for PubMedID 18417022

• Role of neuroimaging in analgesic drug development DRUGS IN R&D Lawrence, J., Mackey, S. C. 2008; 9 (5): 323-334

  Abstract

  Rapidly developing, non-invasive, neuroimaging methods provide increasingly detailed structural and functional information about the nervous system, helping advance our understanding of pain processing, chronic pain conditions and the mechanisms of analgesia. However, effective treatment for many chronic pain conditions remains a large, unmet medical need. Neuroimaging techniques may enhance our understanding of why currently available analgesics are ineffective for so many patients and aid in identifying new neural targets for pharmacological interventions of pain. This review examines how neuroimaging has enhanced our understanding of the mechanisms of chronic pain, the neural correlates of pharmacological modulation of pain, and the role of neuroimaging in analgesic development. Rather than focusing on one method, we discuss the advantages and limitations of several techniques that may each serve a unique role in aiding drug development, and we discuss current issues that exist in the design and implementation of pharmacological neuroimaging studies. Particularly, experimental design must be carefully considered as there are limitations in terms of the pharmacokinetics of the drug of interest as well as in respect to the capabilities of the neuroimaging method in use. Finally, we identify future directions including novel approaches that may also play a role in furthering our knowledge of the neural basis of analgesia. In the future, neuroimaging will certainly impact the methodology of analgesic drug development as it may lead to quicker and more efficient methods of evaluating the neural modulation of chronic pain.

  View details for Web of Science ID 000259358800003

  View details for PubMedID 18721001

• Mexiletine Therapy for Chronic Pain: Survival Analysis Identifies Factors Predicting Clinical Success. Journal of Pain and Symptom Management Carroll, Kaplan, Mackey 2008; 35 (3): 321-6
• Multivariate analysis of chronic pain patients undergoing lidocaine infusions: Increasing pain severity and advancing age predict likelihood of clinically meaningful analgesia CLINICAL JOURNAL OF PAIN Carroll, I., Gaeta, R., Mackey, S. 2007; 23 (8): 702-706

  Abstract

  The proportion of chronic pain patients with suspected neuropathic pain who will have clinically meaningful pain relief with intravenous (IV) lidocaine and the clinical characteristics that identify these patients have not been described previously.We conducted a cohort study of 99 patients who underwent IV lidocaine infusions for suspected neuropathic pain. An 11-point Numerical Rating Score (NRS) of pain intensity was recorded at the beginning and end of each infusion. A predefined literature-based criteria for "clinically meaningful" reductions in pain score was used to classify patients as responders or nonresponders. Multivariate logistic regression was used to determine clinical variables that predicted an increased likelihood of being a lidocaine responder.The mean reduction in NRS during lidocaine infusions was 2.34 (95% confidence interval 2.83-1.85, P<0.001). Forty-two percent of patients (95% confidence interval 32.5%-52.8%) had NRS reductions of 30% or greater and met the predefined criteria as lidocaine responders. Univariate and multivariate analyses indicated that advancing age and pain severity significantly increased the odds of being a lidocaine responder. Controlled for all other factors, each decade of advancing age increased the odds of being a lidocaine responder by 36%. Each 1-point increase, on an 11-point scale of baseline pain severity, increased the odds of being a lidocaine responder by 29%.IV lidocaine effectively reduces pain in a minority of patients suspected of having neuropathic pain. Pain severity and patient age can be used to target therapy to those most likely to respond.

  View details for Web of Science ID 000249743000009

  View details for PubMedID 17885349

• Different circuits for different pain: Patterns of functional connectivity reveal distinct networks for processing pain in self and others SOCIAL NEUROSCIENCE Zaki, J., Ochsner, K. N., Hanellin, J., Wager, T. D., Mackey, S. C. 2007; 2 (3-4): 276-291

  Abstract

  The ability to empathize with the suffering of others is critical for maintaining relationships and engaging in prosocial behavior. Recently, a series of studies have demonstrated that while watching other people experience pain (other pain), participants engage the anterior insula (AI) and anterior cingulate cortex (ACC), brain regions involved in the direct experience of pain (self pain). Here we test the hypothesis that common activity in ACC and AI may reflect the operation of distinct but overlapping networks of regions that support perception of self or other pain. To address this possibility, we scanned participants using fMRI while they received noxious thermal stimulation (self pain) or watched short videos of other people sustaining painful injuries (other pain). We isolated overlapping regions for self and other pain in the ACC and AI and then used them as seed regions for two kinds of functional connectivity analyses. These analyses identified areas whose activity co-varied with ACC and AI activity during self or other pain either across time (intra-individual connectivity) or across participants (inter-individual connectivity). Both connectivity analyses identified clusters in the midbrain and periaqueductal gray with greater connectivity to the AI during self pain as opposed to other pain. The opposite pattern was found in the dorsal medial prefrontal cortex, that showed greater connectivity to the ACC and AI during other pain than during self pain using both types of analysis. Intra-individual connectivity analyses also revealed regions in the superior temporal sulcus, posterior cingulate, and precuneus that became more connected to ACC during other pain as compared to self pain. Together, these data demonstrated that regions showing similar activity during self and other pain may nonetheless be part of distinct functional networks. These networks could not have been detected in prior work that examined overlap between self and other pain in terms of average activity, but not connectivity.

  View details for DOI 10.1080/17470910701401973

  View details for Web of Science ID 000252245400008

  View details for PubMedID 18633819

  View details for PubMedCentralID PMC2913618

• Pulsed radiofrequency for the treatment of chronic ilioinguinal neuropathy. Hernia Mitra, R., Zeighami, A., Mackey, S. 2007; 11 (4): 369-371

  Abstract

  Ilioinguinal neuropathy is a rare but disabling condition. The condition may arise spontaneously or in the setting of pelvic surgery. To date, most therapeutic options have been limited to neuropathic pain medications, anti-inflammatory medications, nerve blocks with local anesthetics, or neurectomy. Long-term results of non-surgical interventions are fair at best. We present a case of chronic ilioinguinal neuropathy treated with pulsed radiofrequency.To examine the efficacy of pulsed radiofrequency (PRF) lesioning on pain in ilioinguinal neuropathy.A 58-year old man with chronic ilioinguinal neuropathy was treated with PRF and was followed for 3 months.The patient had significant pain relief at 3 months follow up.Pulsed radiofrequency lesioning may be a good treatment for chronic ilioinguinal neuropathy in cases refractory to conservative management.

  View details for PubMedID 17273814

• Potential clinical applications for spinal functional MRI. Current pain and headache reports Kornelsen, J., Mackey, S. 2007; 11 (3): 165-170

  Abstract

  Functional MRI (fMRI) of the spinal cord is a noninvasive technique for obtaining information regarding spinal cord neuronal function. This article provides a brief overview of recent developments in spinal cord fMRI and outlines potential applications, as well as the limitations that must be overcome, for using spinal fMRI in the clinic. This technique is currently used for research purposes, but significant potential exists for spinal fMRI to become an important clinical tool.

  View details for PubMedID 17504642

• Pharmacologic therapies for complex regional pain syndrome. Current pain and headache reports Mackey, S., Feinberg, S. 2007; 11 (1): 38-43

  Abstract

  Complex regional pain syndrome (CRPS) remains a challenging condition to diagnose and treat. There are few large-scale, randomized trials of pharmacologic agents, and most published studies are small, uncontrolled, or presented only in abstract form at meetings. The most commonly used agents, such as anticonvulsants, antidepressants, and opiates, have been found to be useful for other neuropathic pain conditions in large-scale trials but have not been adequately studied in CRPS. Systemic steroids delivered by multiple routes continue to be used, with some good evidence for short-term administration. N-methyl-D-aspartate antagonists have recently gained in popularity, without evidence from well-controlled trials. Bisphosphonates have been well studied and offer promise. In addition, there has been interest in thalidomide; however, we are still awaiting well-controlled trials. This article presents an overview of the available data regarding pharmacologic therapies for CRPS. These agents should be used in conjunction with a comprehensive interdisciplinary approach aimed at functional restoration and improved quality of life.

  View details for PubMedID 17214920

• The role of adrenergic receptors and pain: The good, the bad, and the unknown. Seminars in Anesthesia and Perioperative Pain Carroll I, Mackey S, Gaeta R 2007; 26 (1): 17-21
• Imaging the Spinal Cord Current Pain and Headache Reports (accepted) Mackey S 2007
• Neural correlates of individual differences in pain-related fear and anxiety PAIN Ochsner, K. N., Ludlow, D. H., Knierim, K., Hanelin, J., Ramachandran, T., Glover, G. C., Mackey, S. C. 2006; 120 (1-2): 69-77

  Abstract

  Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus, little is known about the neural systems mediating this relationship. The present study provided the first examination of the neural correlates of individual differences in the tendency to (1) feel anxious about the potentially negative implications of physical sensations, as measured by the anxiety sensitivity index (ASI), and (2) fear various types of physical pain, as indexed by the fear of pain questionnaire (FPQ). In separate sessions, participants completed these questionnaires and experienced alternating blocks of noxious thermal stimulation (45-50 degrees C) and neutral thermal stimulation (38 degrees C) during the collection of whole-brain fMRI data. Regression analyses demonstrated that during the experience of pain, ASI scores predicted activation of a medial prefrontal region associated with self-focused attention, whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses. These functional relationships cannot be wholly explained by generalized anxiety (indexed by STAI-T scores), which did not significantly correlate with activation of any regions. The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain, and the roles in anxiety, fear, and pain processing played by medial and orbitofrontal systems.

  View details for DOI 10.1016/j.pain.2005.10.014

  View details for Web of Science ID 000235111100009

  View details for PubMedID 16364548

  View details for PubMedCentralID PMC2914607

• Control over brain activation and pain learned by using real-time functional MRI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA deCharms, R. C., Maeda, F., Glover, G. H., Ludlow, D., Pauly, J. M., Soneji, D., Gabrieli, J. D., Mackey, S. C. 2005; 102 (51): 18626-18631

  Abstract

  If an individual can learn to directly control activation of localized regions within the brain, this approach might provide control over the neurophysiological mechanisms that mediate behavior and cognition and could potentially provide a different route for treating disease. Control over the endogenous pain modulatory system is a particularly important target because it could enable a unique mechanism for clinical control over pain. Here, we found that by using real-time functional MRI (rtfMRI) to guide training, subjects were able to learn to control activation in the rostral anterior cingulate cortex (rACC), a region putatively involved in pain perception and regulation. When subjects deliberately induced increases or decreases in rACC fMRI activation, there was a corresponding change in the perception of pain caused by an applied noxious thermal stimulus. Control experiments demonstrated that this effect was not observed after similar training conducted without rtfMRI information, or using rtfMRI information derived from a different brain region, or sham rtfMRI information derived previously from a different subject. Chronic pain patients were also trained to control activation in rACC and reported decreases in the ongoing level of chronic pain after training. These findings show that individuals can gain voluntary control over activation in a specific brain region given appropriate training, that voluntary control over activation in rACC leads to control over pain perception, and that these effects were powerful enough to impact severe, chronic clinical pain.

  View details for DOI 10.1073/pnas.0505210102

  View details for Web of Science ID 000234174300068

  View details for PubMedID 16352728

  View details for PubMedCentralID PMC1311906

• A vaccine to prevent herpes zoster NEW ENGLAND JOURNAL OF MEDICINE Carroll, I., Gaeta, R., Mackey, S. 2005; 353 (13): 1414-1415

  View details for Web of Science ID 000232146200022

  View details for PubMedID 16196123

• Continuous peripheral nerve blocks. Current pain and headache reports Shinaman, R. C., Mackey, S. 2005; 9 (1): 24-29

  Abstract

  Sophisticated regional anesthesia techniques have experienced substantial growth throughout the past 5 years for acute and chronic pain management. The recognition that regional anesthesia leads to superior postoperative outcomes in acute pain management and to an increased understanding of the pathogenesis of chronic pain has led to increased use of continuous peripheral nerve catheters. Furthermore, the availability of new equipment and techniques specifically designed to facilitate effective catheter placement has increased interest and adoption of peripheral nerve catheters to manage painful conditions. This has become particularly relevant as the scope of ambulatory surgery continues to grow. To maximize success rates with continuous peripheral nerve catheters, clinicians must be intimately aware of the pertinent regional anatomy and technical issues surrounding placement and maintenance of continuous nerve blockade. The recent development of outpatient infusion systems and novel anesthetics has been exciting and is likely to lead to an increase in the use of continuous peripheral catheter techniques. The consistent recognition that these techniques dramatically increase patient satisfaction should dictate an increasing presence in the field of pain management throughout the next several years.

  View details for PubMedID 15625022

• Reflecting upon feelings: an fMRI study of neural systems supporting the attribution of emotion to self and other JOURNAL OF COGNITIVE NEUROSCIENCE Ochsner, K. N., Knierim, K., Ludlow, D. H., Hanelin, J., Ramachandran, T., Glover, G., Mackey, S. C. 2004; 16 (10): 1746-1772

  Abstract

  Understanding one's own and other individual's emotional states is essential for maintaining emotional equilibrium and strong social bonds. Although the neural substrates supporting ref lection upon one's own feelings have been investigated, no studies have directly examined attributions about the internal emotional states of others to determine whether common or distinct neural systems support these abilities. The present study sought to directly compare brain regions involved in judging one's own, as compared to another individual's, emotional state. Thirteen participants viewed mixed valence blocks of photos drawn from the International Affective Picture System while whole-brain fMRI data were collected. Preblock cues instructed participants to evaluate either their emotional response to each photo, the emotional state of the central figure in each photo, or (in a baseline condition) whether the photo was taken indoors or outdoors. Contrasts indicated (1) that both self and other judgments activated the medial prefrontal cortex (MPFC), the superior temporal gyrus, and the posterior cingulate/precuneus, (2) that self judgments selectively activated subregions of the MPFC and the left temporal cortex, whereas (3) other judgments selectively activated the left lateral prefrontal cortex (including Broca's area) and the medial occipital cortex. These results suggest (1) that self and other evaluation of emotion rely on a network of common mechanisms centered on the MPFC, which has been hypothesized to support mental state attributions in general, and (2) that medial and lateral PFC regions selectively recruited by self or other judgments may be involved in attention to, and elaboration of, internally as opposed to externally generated information.

  View details for Web of Science ID 000226002800007

  View details for PubMedID 15701226

• Functional imaging and the neural systems of chronic pain NEUROSURGERY CLINICS OF NORTH AMERICA Mackey, S. C., Maeda, F. 2004; 15 (3): 269-?

  Abstract

  Pain remains a serious health care problem affecting millions of individuals, costing billions of dollars, and causing an immeasurable amount of human suffering. In designing improved therapies, there is still much to learn about peripheral nociceptor, nerves, and the spinal cord, and brain stem modulatory systems. Nevertheless, it is the brain that presents us with an incredible opportunity to understand the experience we call pain. Functional neuroimaging is helping to unlock the secrets of the sensory and emotional components of pain and its autonomic responses. These techniques are helping us to understand that pain is not a static disease with the pathologic findings localized to the periphery but is instead a highly plastic condition affecting multiple central neural systems. Functional neuroimaging is transforming our understanding of the neurobiology of pain and will be instrumental in helping us to design more rational treatments ultimately aimed at reducing the impact of pain on our patients. It is opening windows into the function of the brain that were previously closed.

  View details for DOI 10.1016/j.nec.2004.03.001

  View details for Web of Science ID 000222809500003

  View details for PubMedID 15246336

• Mechanisms of inflammatory pain - Therapeutic implications 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Mackey, S. LIPPINCOTT WILLIAMS & WILKINS. 2004: S5–S11

  Abstract

  The study and treatment of clinical pain has historically identified particular pain syndromes and linked their etiology with disease factors. Missing in this approach is consideration of the mechanisms accounting for the pain that is experienced by the patient. The recent increase in our understanding of how peripheral and central mechanisms contribute to the perception of pain, including the identified role of prostaglandins, has led to a shift in treatment strategy to directly target these mechanisms. This article provides a brief overview of pain mechanisms, focusing on inflammatory pain, and discusses the role of cyclooxygenase (COX)-2 inhibitors as analgesic agents.

  View details for DOI 10.1097/01.rhu.0000130684.35729.55

  View details for Web of Science ID 000222352500002

  View details for PubMedID 17043503

• Low Back Pain: Management Across a Spectrum of Presentations (book chapter) Current Issues in Pain Management for the Primary Care Physician Mackey S 2004
• Mechanisms of inflammatory pain: therapeutic implications Journal of Clinical Rheumatology Mackey S 2004; 10 (3S): S5-11
• Perioperative Pain Management (book chapter) Anesthesiologist's Manual of Surgical Procedures Mackey S, Gaeta R 2003; 3rd ed.
• MR guidance of sympathetic nerve blockade: Measurement of vasomotor response-initial experience in seven patients RADIOLOGY Sze, D. Y., Mackey, S. C. 2002; 223 (2): 574-580

  Abstract

  The authors performed sympathetic nerve blockades in seven patients with peripheral ischemia and possible autonomic dysfunction. Magnetic resonance (MR) imaging was used to guide needle placement, to monitor distribution of injected agents, and to measure increases in blood flow, which were as much as 10-fold. MR imaging can provide both procedural imaging guidance and measurement of efficacy for sympathetic nerve blocks.

  View details for DOI 10.1148/radiol.2231010751

  View details for Web of Science ID 000175270000043

  View details for PubMedID 11997570

• Delayed subdural block after a stellate ganglion block ANESTHESIOLOGY Leong, M. S., Mackey, S. 2001; 94 (2): 358-359

  View details for Web of Science ID 000166694900026

  View details for PubMedID 11176103

• Selection and placement of the double-lumen tube in the Asian patient Asian Cardiovascular & Thoracic Annals Mackey S, Brodsky JB 1998; 6 (3): 199-202
• Selecting the correct size left double-lumen tube JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Brodsky, J. B., Cannon, W. B. 1997; 11 (7): 924-925

  View details for Web of Science ID A1997YK55600028

  View details for PubMedID 9412902

• Bilateral vocal cord paralysis after radical cystectomy in a patient with a history of bulbar polio ANESTHESIA AND ANALGESIA Macario, A., Mackey, S., Terris, D. 1997; 85 (5): 1171-1172

  View details for Web of Science ID A1997YD31300040

  View details for PubMedID 9356120

• Reduction of propofol injection pain with a double lumen IV set JOURNAL OF CLINICAL ANESTHESIA Angst, M. S., Mackey, S. C., Zupfer, G. H., Tataru, C. D., BROCKUTNE, J. G. 1997; 9 (6): 462-466

  Abstract

  To investigate if the use of a new double lumen i.v. set (DLIS) decreases the incidence of propofol injection pain compared with single lumen i.v. set (SLIS) administration.Prospective, randomized, double-blinded study.Operating rooms in a university hospital.50 adult ASA physical status I and II patients of both genders undergoing general anesthesia for elective surgery.Patients were injected with propofol either through a DLIS or a SLIS.Three different pain indices were recorded to be present or absent: (1) verbal report of pain during propofol injection (2) grimacing during propofol injection, and (3) recall of injection pain in the recovery room. When the DLIS was used, the incidence of verbal pain, grimacing during propofol injection, and recall of pain during recovery were lowered significantly by 53%, 46%, and 52%, respectively (chi square analysis of contingency table with Yates correction, p < 0.05).The DLIS significantly reduced the incidence of propofol injection pain compared with SLIS. Further studies are indicated to evaluate the cost-effectiveness of this device.

  View details for PubMedID 9278832

• Isolation techniques - adances in thoracic anesthesia and postoperative care Seminars in Cardiothoracic and Vascular Anesthesia Brodsky JB, Mackey S 1997; 1 (3): 225-35
• Simultaneous multipolar radiofrequency ablation in the monopolar mode increases lesion size PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Mackey, S., Thornton, L., He, D. S., Marcus, F. I., LAMPE, L. F. 1996; 19 (7): 1042-1048

  Abstract

  Delivery of radiofrequency (RF) energy from the distal tip of electrophysiology catheters produces lesions that may be too small to ablate arrhythmogenic sites during a single application of RF energy. To produce larger lesions, we delivered RF energy via a quadripolar catheter in which all four electrodes were connected in unipolar fashion. The catheter (Webster Labs) had a 4-mm tip, 2-mm ring electrodes, and 2-mm interelectrode distance. Lesion size was compared using RF energy delivered in a multipolar configuration with that delivered only to the distal tip using fresh bovine ventricular tissue. In vivo, RF lesions were made in dogs using the distal tip as well as all four poles of the same catheter inserted percutaneously. RF energy was delivered using a constant voltage at a frequency of 400 kHz. Preliminary experiments were conducted to determine the maximum power deliverable without coagulation using each electrode configuration. The use of simultaneous multipolar RF ablation produced significantly larger lesions both in vitro and in vivo. The length of the lesion was increased by a factor of approximately 2 in both the in vitro and in vivo experiments. There was a trend toward an increasing depth of the lesion by simultaneously applying RF energy to all four electrodes. Lesion width was significantly increased in the in vivo studies. We concluded that simultaneous multipolar delivery of RF energy produces larger lesions than can be obtained with delivery of RF energy to the distal tip alone. This technique may offer a means of increasing lesion size, leading to a decrease in the number of applications of RF energy necessary for ablation of arrhythmias.

  View details for Web of Science ID A1996UW43600006

  View details for PubMedID 8823830

• Comparison of gold versus platinum electrodes on myocardial lesion size using radiofrequency energy PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Simmons, W. N., Mackey, S., He, D. S., Marcus, F. I. 1996; 19 (4): 398-402

  Abstract

  During radiofrequency (RF) catheter ablation of arrhythmias, temperatures that approach 100 degrees C cause a coagulum to form on the ablation electrode that results in an increase in electrical impedance and prevents further energy delivery. Since gold has nearly four times the thermal conductivity as platinum, the metal commonly used, it was postulated that gold tip electrodes could deliver more power and produce deeper lesions because of its greater heat dissipation from the electrode-tissue interface to the circulating blood. To test this hypothesis, RF energy was applied to fresh bovine ventricular myocardium using 6 French catheters with 2-mm long distal electrodes made from gold or platinum. Similar studies were also conducted using 7 French catheters with 4-mm long distal electrodes. Maximum lesion depth was defined as that produced with the level of energy just below that causing an impedance rise. A maximum lesion depth of 6.2 +/- 0.7 mm (mean +/- SD) was obtained with the gold 2-mm electrode and 4.7 +/- 0.5 mm with the platinum electrode (P = 0.003). The 4-mm gold electrode produced a maximum lesion depth of 7.2 +/- 1.4 mm, while a catheter with a 4-mm platinum electrode caused a maximum lesion depth of 5.8 +/- 0.7 mm (P = 0.05). We conclude that deeper lesions should be able to be made when RF energy is delivered to a gold rather than platinum tip electrode.

  View details for Web of Science ID A1996UD73300003

  View details for PubMedID 8848386