Systems Neuroscience and Pain Lab–

Current Pain Research Studies

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.  Furthermore, pain has been reported to be the primary reason for absenteeism and on-the-job loss of productivity, resulting in high indirect costs.  It has been estimated that in the United States the cost of health care, compensation, and litigation resulting from pain is more than $100 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.
           
The Stanford Pain Management Center and Dr. Mackey's Stanford Systems Neuroscience and Pain Lab (SNAPL) has focused their efforts on elucidating and characterizing these underlying mechanisms of pain.  In particular, their efforts are focused on characterizing the mechanisms of pain from the level of the network to behavior (see figure).  There are important mechanisms of nociception that exist at the level of the gene through the neuron.  However, pain is ultimately a subjective experience that does not commonly correspond to the level of tissue injury or nociception that a person experiences. 

While much has been learned from animal models of pain, it is ultimately the human patient that needs to be studied to best understand and treat this terrible condition. SNAPL is using advanced neuroimaging techniques, and psyshophysical and neurobehavioral assessments combined with genomic analysis to characterize the individual
experience of pain and individual differences in analgesic responsiveness. 

Our ultimate goal is the development of personalized pain management. We want to integrate a person’s unique neurophysiology and pain condition into models in which we can predict which therapy will be most effective for that patient. Additionally, we want to use these same modeling techniques to better understand the factors which lead a patient to develop chronic pain after an acute injury and how to prevent it from occurring.

Our current ongoing research studies offer patients access to new medications and procedures which may not be generally available.

If you are interested in participating in any of our research studies, please call the Stanford Systems Neuroscience and Pain Lab at 650-724-0522. All phone calls are confidential.

Details on individual studies, including which studies are currently recruiting subjects, can be found below.

Funding for Research Studies

Neuroimaging Studies

Cymbalta: Functional MRI and Correlates of Efficacy
       in Patients with Chronic Low Back Pain
Intravenous Lidocaine in Neuropathic Pain
Brainstem Mechanisms of Analgesia in Patients with
        Post-Surgical Nerve Pain:  An fMRI Study
fMRI of the Human Cervical Spine
Cognitive Load and Perceived Pain Intensity
Cortical Restructuring in Patients with Chronic Pain
Applications of real-time fMRI Phase II
Neural Correlates of Fear in Patients with Chronic Low Back Pain:
        A Functional MRI Investigation

Clinical Studies

T3 for the Treatment of Fibromyalgia
Low-Dose Naltrexone for the Treatment of Fibromyalgia
Post-operative Pain Study (POPS)
Neurotoxin Based Therapies in Chronic Pain
Opiate Induced Hyperalgesia
Effect of Ondansetron for Withdrawal Symptoms


Neuroimaging Studies  

Cymbalta: Functional MRI and Correlates of Efficacy in Patients with Chronic Low Back Pain (IRB #97150)

We are beginning a research study to better understand how duloxetine (Cymbalta) acts in the brain to decrease pain. This study uses functional neural imaging (MRI) to assess brain activation during a pain experience. The aim of this study is to elucidate the brain structures involved in duloxetine’s effects on pain perception. In doing so, we hope to advance our understanding of central processing of pain, which may lead to improvements in drug design and a more objective method for identifying characteristics associated with treatment responders from nonresponders. We are currently recruiting males with low back pain to participate in this study.
Details here.

PI: Dr. Sean Mackey

Intravenous Lidocaine in Neuropathic Pain (IRB #73980)

Purpose: Intravenous (IV) lidocaine has been used for years in certain neuropathic pain medications. However, its peripheral and central pain relieving effects have not been characterized. Only a proportion of patients with neuropathic pain respond to conventional anti-neuropathic pain medications--most of which are sodium channel blockers.  The mechanisms responsible for analgesia in response to a sodium channel blocker remain unknown.  In this translational research at Stanford Hospital we are using functional MRI to define supraspinal changes in neuropathic pain patients specifically associated with analgesic responses to systemic lidocaine--a prototypical sodium channel blocker.

 We aim to elucidate the inter-individual differences that underlie the frequently  differing responses to medications used for neuropathic pain.  By further  identifying neuroimaging, psyshophysical and neurobahvioral factors that predict responsiveness and unresponsiveness to intravenous  lidocine we hope to gain insight into the mechanism underlying the heterogeneity seen in clinical response to more commonly used drugs for neuropathic pain.

PIs: Drs. Ian Carroll & Sean Mackey

fMRI of the Human Cervical Spine (IRB #77831)

Purpose: The way in which the brain processes pain is becoming better understood with the use of functional MRI. However, significant processing of pain occurs in the spinal cord and neuroplastic changes in the spinal cord associated with chronic pain warrant further investigation. We have developed novel techniques that allow us to, for the first time, image pain processing within the human spinal cord. This is a group of several experiments that serve to characterize the processing of pain in the human spinal cord that range from elucidating basic somatotopic organization to nociceptive intensity encoding to the effects of chronic pain induced neuroplasticity. Ultimately, we believe that a better understanding of the spinal-brain system will lead to the development of more effective targets for therapy.

PI: Dr. Sean Mackey

Cognitive Load and Perceived Pain Intensity (IRB #78011)

Purpose: The aim of this study is to examine the role of attention in the experience of pain using a cognitive load task. We use various cognitive loads and thermal heat temperatures in order to determine how cognitive load can influence the experience of pain in both healthy and pain patients. Does an attention-demanding task modulate the perceived intensity of pain? This is just one of few questions we are posing in this study. This investigation also has clinical implications in that chronic pain has been shown to impact the ability to modulate attention between certain tasks and the experience of pain. By better understanding and characterizing this phenomenon, we can design more effective therapies to help those with chronic pain.

PI: Dr. Sean Mackey

Cortical Restructuring in Patients with Chronic Pain (IRB #78011)

Purpose: Recent research has demonstrated that chronic pain can induce changes in the brain that can amplify and maintain the pain experience. We are characterizing this phenomenon in patients with a variety of chronic pain conditions (neuropathic pain, low back pain, fibromyalgia, interstitial cystitis, etc.) using a variety of neuroimaging techniques. We are following these preliminary studies with further investigations into the effects of treatment on reversing the brain changes induced by chronic pain. Recruitment is currently closed. 

PI: Dr. Sean Mackey

Applications of real-time fMRI (IRB #95194)

Detailed information available at our rtfMRI page.
Purpose: The goal of this study is to use real time imaging of the functions of the human brain to train patients and healthy volunteers to change activations in brain regions that control the experience of pain. Using functional imaging, we are able to visualize activity taking place in brain areas involved in the perception and control of pain. By visually feeding back the subjects’ own brain signal we are training them to learn how to control and change their pain experience. If successful, this allows patients to have greater control over their own pain. Currently there are several studies underway utilizing this technology including experiments to identify specific brain regions and cognitive strategies that are the most effective for controlling chronic pain. 

Recruitment is currently on hold for this study.

PIs: Dr. Sean Mackey

Neural Correlates of Fear in Patients with Chronic Low Back Pain: a Functional MRI Investigation (IRB #78011)
Purpose: In this study, we will investigate how fear is processed in the brain in patients with chronic low back pain. It is known that pain-related fear plays an important role in the development of pain-related disability in back pain patients, but the neural correlates of this process are unknown.  This study will use functional magnetic resonance imaging (fMRI) to investigate which regions of the brain are activated during exposure to faces that display fearful expressions. We will examine neurological, psychophysical and behavioral responses to these stimuli as well as to an evoked noxious thermal stimulus.  We hope that by better understanding the neural mechanisms underlying responses to threatening cues, we can design more effective therapeutic approaches for patients suffering from chronic low back pain.
PIs: Dr. Sean Mackey, Dr Amit Etkin and Dr Julia Hush

Clinical Studies

T3 for the Treatment of Fibromyalgia (IRB Protocl #16295)

Purpose: We are investigating whether the thyroid hormone T3 is one such treatment that may alleviate the symptoms of Fibromyalgia. There is significant overlap between the symptoms ofhypothyroidism (low thyroid hormone production), depression, chronic fatigue, and Fibromyalgia. Patients with low thyroid hormone production who have been treated with T3 for depression have had some improvement in symptoms. In this double-blind, placebo controlled, cross-over trial, we hope to learn whether T3 can improve the symptoms of Fibromyalgia.  This study is ongoing and we are currently recruiting participants.  More information can be found here.

PIs: Drs. Ian Carroll, Jarred Younger, and Sean Mackey

Low-Dose Naltrexone for the Treatment of Fibromyalgia (IRB Protocol #98032)

Purpose: Fibromyalgia is a costly and sometimes debilitating chronic multisymptom illness that is characterized by widespread sensitivity to pain, muscle weakness, and fatigue. We are testing low-dose naltrexone (LDN) for this disorder in a double-blind randomized, controlled trial. LDN (<5mg) may work by antagonizing opioid receptors on hyperexcitable glial cells, preventing the production of proinflammatory cytokines. As opposed to regular doses of naltrexone (>50mg), LDN does not appear to adversely affect analgesia-related opioid receptors on neurons. LDN is an inexpensive drug with a low incidence of side-effects. This trial is ongoing and recruitment is currently complete. More information can be found here.

PIs: Drs. Jarred Younger and Sean Mackey

Post-operative Pain Study (POPS) (IRB #97496)

Purpose: Every year thousands of individuals are chronically affected by persistent pain after surgery. Our study, The Natural History of Pain Resolution and Opioid Cessation Following Surgery seeks to answer fundamental questions regarding chronic pain using surgery as a model of injury.  We aim to study the duration of pain and identify factors contributing to delayed pain resolution.  In addition we are beginning studies  to try to reduce the duration of pain  following surgery.  Furthermore we are identifying factors contributing to delayed opioid cessation among patients with pain of similar duration.  We hope to gain an improved understanding of the factors contributing to chronic opioid use and discontinuation among patients with ongoing pain. Recruitment is curently on hold.

PIs: Drs. Ian Carroll,  and Sean Mackey

Neurotoxin Based Therapies in Chronic Pain (IRB #79622)

Purpose: We are conducting a placebo controlled randomized study of patients with pain following the injury of a peripheral nerve during surgery using neurotoxins in novel ways to investigate their effectiveness in treating  neuropathic pain. In this randomized, blinded cross-over study in  each patient will receive both a placebo and the neurotoxin at two different points in time. Measurements of pain, quality of life, function, are collected throughout the study period. We hope to introduce a novel therapy for patients with persistent neuropathic pain following surgery and trauma.  This trial is ongoing and we are currently recruiting participants. More information can be found here.

PIs: Drs. Ian Carroll, and Sean Mackey

Effect of Ondansetron for Withdrawal Symptoms (IRB # e-14228)

We hope to determine whether Ondansetron, an anti-nausea medication, works to help relieve withdrawal symptoms experienced while the patient is being weaned off opioid medications. This medication has shown anecdotal evidence of being affective for the treatment of withdrawal symptoms and we hope to determine whether this is affective. Patients undergoing an opioid taper in the Stanford Comprehensive Interdisciplinary Pain Program are offered enrollment in this pilot trial. 

PI: Dr. Sean Mackey

Sources of Support

Support for research is provided by the following sponsors:

For information on making a tax deductible donation or to set up a fund for research and education on pain disorders, please call Sean Mackey, M.D.,Ph.D. at (650) 725-9636, or e-mail via his assistant at

 

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