Clinical Science



Larry Chu, MD, MS

My research focuses on the study opiate-induced hyperalgesia in patients suffering from chronic pain.

I am currently conducting an NIH-funded five year double-blinded randomized controlled clinical study that prospectively examines the following hypotheses: 1) pain patients on chronic opioid therapy develop dose-dependent tolerance and/or hyperalgesia to these medications over time, 2) opiate-induced tolerance and hyperalgesia develop differently with respect to various types of pain, 3) opioid-induced hyperalgesia occurs independently of withdrawal phenomena, and 4) opiate-induced tolerance and hyperalgesia develop differently based on gender and/or ethnicity.

The study is the first quantitative and prospective examination of tolerance and hyperalgesia in pain patients and may have important implications for the rational use of opioids in the treatment of chronic pain.


David Clark, MD, PhD

Current projects being pursued in the Clark lab can generally be placed in one of to categories. One group of projects involves the investigation of the roles of heme oxygenase in nociceptive mechanisms. To this point we have demonstrated a role for this enzyme in many rodent pain models including models of inflammatory, incisional and neuropathic pain. We are currently addressing issues related to specific spinal neurotransmitter systems which may be modulated by heme oxygenase, examining the role of heme oxygenase in modifying analgesic responses to opioids, and determining the extent and nature of the interactions between heme oxygenase and nitric oxide.

The second group of projects involves the mechanistic exploration of opioid-induced hyperalgesia. Experiments from our lab have to this point demonstrated thermal hyperalgesia and mechanical allodynia in mice and rats after the cessation of opioid administration. This hyperalgesia has been partially characterized pharmacologically. Ongoing studies seek to further elucidate the mechanism of this form of hyperalgesia as well as test methods for preventing or limiting its manifestation. We are currently using behavioral, immunohistochemical and biochemical methods.

E-mail Dr. Clark


David Drover, MD

My research interest is in clinical research on the pharmacokinetics and pharmacodynamics of drugs. Medications studied are those commonly used for anesthesia and analgesia. Additionally, other drugs are studied if they have unique characteristics that require intensive or specialized monitoring. Particular effort is used to obtain quality real-time data from intensive pharmacokinetic - pharmacodynamic studies to enable mathematical modeling of drug effect on the human body. Mathematical modeling of data is mainly performed with NONMEMâ. Where possible, research projects use the electroencephalogram to quantitate pharmacodynamic effect and develop mathematical models to relate pharmacokinetics to pharmacodynamic response. The main interest of my research projects is to develop novel ways to model and describe clinical pharmacology relationships.

E-mail Dr. Drover


David Gaba, MD

The Patient Safety Center of Inquiry (PSCI) at VA Palo Alto incorporates the research conducted by Drs. Gaba, Howard, K. Fish, and Bushell, and Dr. Sowb (Ph.D.). It is a major research unit associated with the Department of Anesthesia (although we cover many aspects of health care, not just anesthesia).

E-mail Dr. Gaba   |   VA Simulation Center


Alvin Hackel, MD

Real-Time Data Connectivity and Information Integration for the Transport of Critically Ill Infants and Children with the Stanford Digital Library Project, Computer Sciences, Stanford, and the Northern California Perinatal Dispatch Center. Anesthesiologist and patient care facility requirements for pediatric anesthesia: Their impact on the demography and cost of pediatric anesthesia in California with Alex Macario, Mark Singleton, George Gregory and the California Childrens Hospital Association.

E-mail Dr. Hackel


Gregory Hammer, MD

My current clinical studies are: Determination of remifentanil pharmacokinetics and pharmacodynamics in infants and a comparison of remifentanil with or without spinal anesthesia for children undergoing open heart surgery.

E-mail Dr. Hammer

Alex Macario, MD

Dr. Macario is interested in the economics of health care, in particular the tradeoffs between costs and outcomes for patients having surgery and anesthesia. He has completed internationally recognized studies on the management of the operating room suite, as well as pioneering work on the cost-effectiveness of drugs and devices. He is Founder and Director of a Postgraduate Fellowship for physicians interested in applying quantitative tools to solve health services research questions. More recently, as Program Director for the anesthesia residency he is interested in education, core competencies of physicians in training, and innovations for clinical training.


Sean Mackey, MD, PhD

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Pain is the primary complaint resulting in physician visits and health care resource utilization. The importance of pain as a major worldwide health care problem has been recognized by the World Health Organization, and the need for further research into its mechanisms and control was recognized by the U.S. Congress in its declaration of the years 2001-2010 as the Decade of Pain Control and Research.

The presence of pain and its inadequate treatment in a variety of clinical settings has significant societal impact.  Pain contributes to the overall economic burden of disease through increased direct medical costs caused by additional health care resource utilization.  It has been estimated that in the United States the cost of health care, compensation, and litigation resulting from pain is more than $200 billion annually.

Historically, pain has been considered in relation to its etiologic or disease factors, such as the relationship between surgery and postoperative pain, herpes zoster and postherpetic neuralgia, and arthritis and painful joints.  This has had the effect of addressing pain as a symptom of disease, and although much progress has been made in understanding the molecular and cellular mechanisms of disease, the resulting pain has not necessarily been alleviated.  What is required, and has been missing from the evaluation, is an understanding of the underlying mechanisms responsible for the pain itself.

Dr. Mackey has focused his efforts on elucidating and characterizing these underlying mechanisms of pain.  In particular, he has focused his efforts on characterizing the mechanisms of pain from the level of the network to behavior (see figure).  He uses a systems neuroscience approach which includes the integration of advanced neurobehavioral, psychophysical and neuroimaging techniques.



Learned control of ACC activity and pain. A) Change in fMRI activity B) Control over BOLD activity increased significantly through training. C) Control over pain increased significantly throuhg training. *p<0.05, linear regression.Some current research projects and themes:

1. Real-Time Brain Control for Pain
Attaining control over specific neural processes is the primary goal of neuropharmacology and neurostimulation; it is also a critical objective of biological psychiatry and psychology. Training people to be able to modulate specific neural processes has the potential to enable them to have greater control over the resulting behavior, cognition, or associated disease. Recently we have demonstrated that patients with chronic pain can learn to control a specific region of their brain – the rostral anterior cingulate cortex (rACC) – that is associated with pain processing and perception (PNAS, December 2005, 102:51; 18626-31). Importantly, we found in that study that the increased control in localized brain activity was associated with improvement in pain control. We are expanding this work to: (1) investigate learned control of specific brain networks, (2) determine the optimal brain regions for learned control, (3) characterize the long term effects of this unique methodology and (4) apply it to other neuroscience fields such as depression, addiction and cognitive development. This exciting and unique multidisciplinary collaboration brings together expertise from the fields of Pain, Radiology, Psychology, and Electrical Engineering.  Stanford is currently the only institution in the world where this work is occurring.

2. Neuroimaging of the human spinal cord, brainstem and brain and characterization of reward systems, affective dimensions of pain and neural plasticity of pain.

3. Personalized Pain Medicine
The last decade has seen a significant increase in the number and type of pharmacologic therapies for the treatment of chronic pain. Frustratingly, each medication produces pain relief for only a minority (typically 30%) of patients.  Not surprisingly, few physicians have the patience required to persist in a strategy involving months of frustrating side-effect laden medication trials until the correct one is found. What we need is a method to identify which individual patient with a particular chronic pain problem will respond to a specific drug. We have put together a multidisciplinary team of researchers and clinicians  to achieve this goal.  We have been developing and using techniques such as: (1) pharmacologic fMRI to elucidate central neural correlates of drug response and side effects, (2) sophisticated pharmacokinetic/pharmacodynamic drug models to characterize individual drug concentrations and effects, (4) novel neurobehavioral and psychophysical measurements to precisely characterize the perceptual aspects of the pain experience, (5) genomics to characterize candidate gene polymorphisms responsible for individual differences in pain perception and analgesic efficacy and (6) novel epidemiologic and statistical methods to develop multivariate models which ultimately predict individual drug responsiveness.

For further information see: Systems Neuroscience and Pain Lab and Paincenter Web Site

E-mail Dr. Mackey   |   http://paincenter.stanford.edu/fmrilab/


Ronald Pearl, MD, PhD

My research examines mechanisms and therapy of experimental pulmonary hypertension. We use the combination of pneumonectomy and monocrotaline administration to produce proliferative pulmonary hypertension in rats. We are currently examining the changes at a transcriptional and cellular level which result in pulmonary hypertension and the ability of vasodilator, immunosuppresive, and antiproliferative therapies to prevent and/or reverse the pulmonary hypertension. Ongoing research will develop a model of pulmonary hypertension in genetically altered mice and the ability of gene therapy to cure pulmonary hypertension.

E-mail Dr. Pearl


Edward Riley, MD

The primary focus of my research is on spinal opioids used for labor and post-operative pain. I have extensive research experience with spinal opioids in the labor and delivery suite, the general operating room, and in the laboratory with human volunteers. I also do a significant amount of research on spinal and combined spinal/epidural anesthesia and analgesia for cesarean and vaginal delivery.

E-mail Dr. Riley


Audrey Shafer, MD

My interests include medical humanities, literature and medicine, communication in the operating room, ethics and anesthesia, and creative writing. I direct the Art & Humanities Medical Scholars Program and contribute to the online medical humanities database.

E-mail Dr. Shafer


Jumbo Williams, MB, ChB

My research has been entirely clinical and focused primarily on (1) anesthesia and pediatric congenital heart disease, (2) perioperative management of coagulation in children and (3) aspects of general pediatric anesthesia. I hope to establish coagulation and open-heart surgery in children as an area of research interest at Stanford. The challenges of pediatric open-heart surgery for congenital heart disease are unique and offer good research opportunities. Stanford's pediatric cardiac anesthesiologists plan to collaborate in research in order to efficiently utilize the relatively small numbers of patients potentially available for clinical study.

E-mail Dr. Williams


Anthony G. Doufas, MD, PhD

My research focuses on the pharmacokinetic and pharmacodynamic (PKPD) evaluation of commonly used sedatives and anesthetics, as well as in the PKPD and mathematical foundations of closed-loop control of anesthesia using EEG-derivative indices as the controlled variables. In particular, I am interested in identifying disease-related or other patient phenotypes, which are associated with alterations in the clinical pharmacology of anesthetics and could affect perioperative outcomes. Currently, I study the effect of sleep-disordered (SDB) breathing on pain processing before and after the administration of opioids in patients suffering from SDB and in healthy volunteers. Also, in the same area of research we investigate the effect of obstructive sleep apnea on postoperative neurobehavioral and medical outcomes in patients undergoing bariatric surgery. In particular, we are interested in identifying metabolic and genetic markers for suboptimum neurobehavioral outcomes and correlate those with the severity of nocturnal hypoxia in this patient population. In collaboration with the Department of Computer Science in Texas Tech University we develop a new system to control anesthesia using the bispectrum of the EEG (BIS) as the controlled variable. This control strategy is based on a method of unsupervised learning called reinforcement learning (RL) and has already demonstrated an excellent performance in simulation studies. The application of RL-based anesthetic control in human subjects is upcoming.

E-mail Dr. Doufas