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

Journal Articles

• 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

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

• 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 Web of Science ID 000331593000009

  View details for PubMedID 24212070

• 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

• 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

  View details for DOI 10.1055/s-0032-1329921

  View details for Web of Science ID 000317597000001

• 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

• 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

• 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

• 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

• 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 (? = 0.81-0.88) and negative expectancy (? = 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

• 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 Web of Science ID 000307942900028

  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

• 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

• 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

• 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

• 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 Web of Science ID 000292862400020

  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 Web of Science ID 000288723100004

  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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Web of Science ID 000264779600016

  View details for PubMedID 19334078

• 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 Web of Science ID 000263064900001

  View details for PubMedID 19126362

• 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

• 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

• 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 Web of Science ID 000261106100026

  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

• 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

• 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

• 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

• 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 JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Mackey, S. 2004; 10 (3): 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 Web of Science ID A1997XT09600007

  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