Anesthesiology, Perioperative and Pain Medicine

Pain Research at Stanford: Engaging the Nervous System

By Patricia Rohrs and Joanne Rugen, MD

If you could be granted one wish to make your life easier as an anesthesiologist, what would it be?

• A magical anesthetic agent that gave a smooth induction, perfect operating conditions, and a quick wake-up, without any cardiovascular effects?
• An enchanted laryngoscope that would give you a grade 1 view every time?
• Or, a crystal ball that revealed patients whose pain will be difficult to control post-operatively and a way to predict an individualized treatment plan?

Many of us wish most especially for answers to the third question—better acute and chronic pain control through individualized treatment. Now imagine examining each patient’s genetic makeup, history, and planned procedure and being able to predict the analgesia mode and target that will alleviate that patient’s pain with minimal systemic effects. In other words, imagine a patient-specific, receptor-specific regimen. Imagination may translate into reality sooner than you think in the rapidly expanding world of pain research.

“How can we intelligently engage with a patient’s complex, multi-layered nervous system to treat pain successfully?”

Stanford’s Martin Angst, MD, identifies this question as the single most important one to answer in the pain research world. Indeed, several internationally recognized pain investigators in the Stanford Department of Anesthesia, in conjunction with their collaborators worldwide, are intelligently engaging the nervous system. By studying such fundamental, interrelated topics as pain-related biomarkers, nociceptive gene expression in opioid-induced hyperalgesia, the natural course of post-surgical pain, gene therapy to treat pain, and the neuroimaging of the brain and spinal cord during pain, they are advancing ever closer to answering basic science questions and translating their answers into more effective, individualized pain therapy in patients.


Clearly fascinated with pain, Martin Angst believes the subject compellingly reflects the central and peripheral nervous systems’ multi-level, bidirectional processing and interaction—from peripheral nerve terminals to consciousness. “Body, mind, and soul— all happen within one system, the nervous system.” The Angst lab projects reflect that comprehensive view.

How can we use biomarkers to more precisely diagnose and better treat discogenic back pain, osteoarthritic pain, and pain associated with acute tissue injury and inflammation?
In Angst’s lab researchers and their collaborators, including spine surgeons, succeeded at detecting a biomarker indicative of discogenic radicular back pain—commonly called sciatica. In animals, they found that blocking this biomarker with an antagonist drastically reduced the animals’ pain. They devised novel techniques for identifying and characterizing biomarkers. For example, they employ micro-catheters to collect fluids and cells from inflamed and injured tissue in volunteers and patients. They also use modern assay techniques to reveal protein-release profiles, cellular responses, gene-expression patterns and genomic make-ups that underlie individuals’ pain. They hope their work may apply to osteoarthritic as well as discogenic radicular back pain and pain related to tissue injury and inflammation.

Current projects include further exploration and classification of pain states on the basis of their underlying mechanisms: genes, proteins, and biomarkers. Researchers will continue to devise novel techniques for gathering and analyzing these microscopic structures.
How can we help soldiers wounded on the battlefield to control their own pain?
Researchers in the Angst lab hope to address this question by developing a biomarker-based, feedback-controlled, automated opioid-delivery system to control pain in soldiers wounded in the battlefield

Can patients in chronic pain learn to control their pain the way people with phobias have learned to change their behavior?

Researchers are pursuing yet another approach to engaging the nervous system—investigating whether a patient in chronic pain can learn how to control pain by being in a virtual-reality (simulation) situation, then applying their learning to real life.


After cesarean section, how can we use our study of a wound’s cytokines, genes, and proteins, combined with reported pain states, to predict the best anesthesia for a patient?
Dr. Brendan Carvalho and his colleagues pursue pain mechanisms and treatments, particularly in the obstetrics arena: labor and cesarean delivery. They collect and profile cytokines, pain-signaling compounds that are released from surgical wounds. Correlating these cytokines to post-surgical pain states, they investigate how specific analgesia affects those states. To further understand these complex interactions, they also examine proteomic and genomic changes that occur after wound incisions. They study extended-release epidural morphine for post-cesarean delivery analgesia and the pharmacogenomics of variable responses to intravenous and intrathecal fentanyl in labor.


Do patients paradoxically become more sensitive to pain after chronic exposure to opioid medications?

Dr. Larry Chu and his collaborators are interested in an intruiging phenomenon: opioid-induced hyperalgesia (OIH). Most broadly defined as a paradoxical state of increased sensitivity to pain caused by exposure to opioids, its precise mechanism and clinical relevance remains unclear. As Dr. Chu notes, “Despite multiple lines of evidence showing that OIH exists in animals, the translational work in humans has only just begun.”

“We are funded by the National Institutes of Health (NIH) to ask a very simple question: Does a patient’s sensitivity to pain change after chronic opioid exposure? Suprisingly, there was no high quality prospective evidence to answer this question in humans. We thought there should be.”

Chu’s lab aims to show, for the first time, whether OIH develops in humans after chronic opioid exposure. Their work is difficult since it involves quantitative sensory testing using painful stimuli in patients who already suffer from chronic pain. “There are unique challenges to clinical research that basic scientists working with animal volunteers rarely face. For instance, if patients develop side effects or find pain testing unpleasant they will drop out of our study. Placebo-controlled studies are also harder to conduct in patients who suffer from chronic pain because they are often unwilling forgo receiving some type of pain medication. Ultimately, the reward of translational discovery is substantial because of the direct impact it can have to improve patient outcomes,” says Dr. Chu.
How can we choose the best analgesic medications for patients with chronic pain?
If Chu can predict which patients will develop OIH after chronic opioid exposure, he could guide clinicians to choose the best types of analgesics for these patients, avoiding ones that may actually worsen their patients’ pain. By understanding the underlying mechanism of OIH, Dr. Chu hopes to one day be able to prevent troublesome side-effects of opioids to make them more effective and tolerable drugs.

Is there a future in translational pain research?

Another priority for Dr. Chu is nurturing the next generation of clinical scientists. “Translational research is critically important to move discoveries from the bench top to the bedside. Yet, many of our brightest students and residents choose not to pursue research careers,” notes Dr. Chu. He chooses the time-consuming route of hand-picking and training students to perform clinical research studies. “Engaging students in clinical research early in their careers is essential to nurturing the next generation of clinician scientists.” Dr. Chu currently has four students in his laboratory: Stanford undergraduate Ben Kenigsberg, Kim Boynton from San Jose State University, Nicole D’Arcy who is spending a year in Dr. Chu’s lab before starting medical school at Stanford in 2008 and Caitlin Brady, who will begin medical school at Georgetown University this Fall.


How can we distinguish patients who will benefit from opioids from those who will instead experience opioid-induced hyperalgesia (OIH)?

Having observed OIH in his patients, using modern in silico techniques, Dr. David Clark and his extended group of collaborators identified two OIH-related genes, whose variants help explain OIH in mice after their extended exposure to morphine. Researchers hope to translate their studies into humans, so that they can better predict which patients will or will not benefit from opioids, a step in formulating individualized therapy for each patient.
In post-surgical patients, how can we better alleviate their pain and inflammation?
The Clark lab also seeks pain mediators in surgical wounds, focusing on the immune system’s complement system and on cytokines. The complement system’s C5a fragment likely causes swelling and immunocyte infiltration around surgical wounds, especially in the four day period after surgery. Researchers hope to develop C5a antagonists to fight inflammatory disease and pain. In addition, they learned that many cytokines probably help control incisional sensitization, swelling, and other aspects of inflammation after surgery.


What are the underlying electrophysiological and biochemical responses in and around pain receptors?

Pain in humans is primarily transmitted by two nociceptor types: myelinated A-delta fibers and unmyelinated C fibers. The former create sharp, pricking pain, whereas the latter produce a burning or aching sensation. Researchers in David Yeomans’ lab, in collaboration with the Neurosciences Institute at Stanford, laser-stimulate these nociceptors in rodents and record electrophysiological and biochemical responses from single-unit nociceptors and nociceptive neurons in the
spinal cord.

What can brain maps of patients responding to pain stimuli tell us?

In humans, researchers visualize and map brains’ responses to pain stimuli, hoping to learn the pain physiology of unknown nociceptor dominance, so that they can better diagnose and treat different types of pain. Using equipment similar to that used to measure EEGs (brainwaves), David Yeomans’ lab measures volunteers’ brain responses to pain stimuli that selectively activate different nociceptors. They use this information to examine brain responses of patients in pain to better predict what treatments will help.
How can we treat chronic pain with gene therapy?

Investigators in the Yeomans lab also pursue gene therapy—an exciting, novel approach to treating chronic pain. They created viral vectors, based on herpes simplex I, that carry analgesic genes into nociceptors. In rodents and monkeys, a “safe” virus vector containing the transgene for human preproenkephalin is transported to cell bodies in the dorsal root ganglia’s nerve fibers. When expressed, this special transgene produces enkephalins—endorphin-like endogenous opioid peptides— that selectively inhibit the nociceptors (reducing pain) for up to 20 weeks. If translated to humans, gene-therapy technology may help treat long-term, intense, localized pain that does not respond, even to high-dose opioids. For example, we may be able to deliver analgesic viral vectors directly to cancer patients’ painful, metastatic sites. Pending FDA approval of safety and toxicology studies, Yeomans plans to perform clinical trials, in conjunction with Dr. David Clark, Director of the Veterans Administration Pain Service and the VA hospice.
How can we apply biomarker methodology to development of novel analgesic and anti-inflammatory drugs?

Finally, the Yeomans lab and its collaborators measure biomarker changes (changes in expression and release) that occur during different pain and inflammatory states in various parts of the body: skin, nerve tissue, spinal epidural space, and surgical wounds. Biomarkers, some of which can act as surrogates for pain sensations, allow for a completely objective and quantitative measurement of what is going on in the body in different pain states. Pharmaceutical companies are excited by their biomarker methodology, as it may result in developing novel analgesic and anti-inflammatory drugs.


In Sean Mackey’s Systems Neuroscience and Pain Lab (SNAPL), researchers and their collaborators engage the nervous system in a variety of ways, as evidenced by the diverse questions they pursue.

Why, after identical injuries in patients, does pain last a short time for most, but longer—even indefinitely— for others?

Patients who undergo similar surgical procedures vary greatly in their response to analgesics and the length of their recovery. A surprisingly large number develop chronic, post-surgical pain. Dr. Ian Carroll and collaborators in surgery study the “natural history” of post-surgical pain in patients, hoping to gain insight into factors that affect its resolution, so that high-risk patients can be targeted for early intervention and treatment.
How do medications used to treat pain actually work in the brain? How do individuals differ in their perception of pain and response to analgesics?

No pain medication is a silver bullet for all patients. However, researchers are making headway investigating how sodium channel-blockers and antidepressants—both used to treat neuropathic pain—actually affect the brain, spinal cord, and patients’ perceptions of pain and responses to analgesics. It is hoped that this kind of data, combined with a patient’s genomic information, will ultimately result in personalized medicine for a patient experiencing pain.

How does chronic pain affect the brain and spinal cord?

Investigators approach this question from several angles: neurobehavioral, neuroimaging, and psychophysical. Pursuing a systems neuroscience approach, researchers in the Mackey Lab study neural circuit functions as a way to understand the mechanisms of acute and chronic pain. They and their collaborators have developed sophisticated tools and methods: fMRI to measure changes in brain, brainstem and spinal cord activity; structural imaging to measure changes in gray and white matter; and network analysis to characterize information flow within the brain. With these tools, they are at work fully characterizing both a patient’s experience of pain and the brain and spinal cord responses that generate it.

Paradoxically, the patient’s experience of pain and the degree of nociception do not always agree. In fact, many people suffer from chronic pain syndromes, yet do not evidence ongoing nociception. Enter the brain. It has now been appreciated that pain can be generated in the brain and maintained with minimal or no nociceptive input. Through neuroimaging, investigators have discovered that the brains of patients with neuropathic pain atrophy and the cortex reorganizes in selected regions. Amazingly, they have applied specific therapies that have reversed the atrophy and reorganization, thus demonstrating that pain does indeed change the brain.

The spinal cord is more difficult to image, owing to its extensive movement artifacts and small size, but the Mackey researchers have been the first to investigate and characterize nociceptive processing in the spinal cord. Further NIH-sponsored work is planned to characterize the role of spinal systems in descending modulation and neuropathic pain.
Mackey himself is also fascinated by the cognitive and emotional aspects of chronic pain— How do fear and anxiety affect our experience of pain? What brain systems are responsible for these effects? Additionally, he has learned the startling fact that the neural systems of a person who empathizes with someone in pain respond the same as those of the person actually experiencing the pain. An empathic person truly feels the other’s pain.
Can patients learn to control their own brain activity and thereby reduce their pain?
Imagine yourself in a state of persistent pain, then stepping outside of your body, and looking inside your brain to see how it responds at the neural-network level. Then imagine consciously changing your brain activity, so that your pain attenuates. Although this notion sounds far-fetched, over the last five years researchers in the Mackey lab have used real-time fMRI (rt-fMRI) to enact this seemingly fantastic scenario. This astonishing feat demonstrates not only the nervous system’s plasticity, but also one’s ability to direct it. Mackey lab investigators believe their work has profound implications not only for pain, but also for many brain-related illnesses such as depression, addiction, phobias, and impaired cognitive development.


Expect radical change in the practice of anesthesia.

We have learned the nervous system is dynamic and plastic; it swiftly adapts and responds to external signals, on many levels, often resulting in the unexpected. Consequently, our talented pain researchers now envision novel strategies and modes to help understand, predict, diagnose, and relieve pain—new analgesic and CNS compounds, electro-stimulation devices, viral vectors to administer gene therapy, stem cells to repair deficiencies in the nervous system, and both virtual reality and rt-fMRI to change behavior. It is hoped that if we know a patient’s pain signature—his genetic make-up, profile of tissue or plasma biomarkers, and psychological and epidemiological factors, we can target our responses to that particular signature and relieve the patient’s pain.

Expect intensified collaboration.

The synergistic effects of intra-departmental, inter-departmental, and inter-institutional collaboration in pain research are astonishing! Members of the labs whose work we discussed here constantly confer with each other, but they also converse with colleagues all over the world. Together, they concentrate on solving the complex mysteries of pain, but they also advance many other fields— epidemiology, psychology, and neuro-imaging, to name a few. Expect Stanford pain researchers to continue their efforts to address this seminal question:

“How can we intelligently engage with a patient’s complex, multi-layered nervous system to treat pain successfully?”

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