Publications
APS Bulletin • Volume 15, Number 3, Summer 2005
Translational Research in Pain
Christine Sang, MD MPH, Department Editor
The Emergence of Translational Research and its Significance
Ronald Dubner, DDS PhD
Preface
I am delighted to inaugurate this new department of the APS Bulletin, Translational Research in Pain. Our mission is to promote regular dialogue among the clinicians and scientists within the APS membership. This section will allow basic scientists to communicate to clinicians their new tools for use with patients. In turn, it will allow clinicians to communicate to basic scientists their novel clinical observations, which will stimulate basic research ideas. I hope this exchange will promote a direct and open approach to discovering new treatments. We are honored to have Ronald Dubner, DDS PhD, and Roger Fillingim, PhD, launch this new department. Dr. Dubner places translational research in the proper context. Dr. Fillingim reflects on the infusion of translational research in pain in the content of the program at the APS annual meeting this spring.
Introduction
The new emphasis in biomedical research is on interdisciplinary and translational research. The major focus on basic science research during the tenure of Harold Varmus, MD, as Director of the National Institutes of Health (NIH) led to increased interest in how this new information, generated by a doubling of the NIH budget, could be translated into clinical research. The present director of NIH, Elias Zerhouni, MD, initiated an interdisciplinary and translational road map for NIH research that focuses on collaborative research among scientists in many different disciplines. It emphasizes the need to move basic research from the bench to research approaches that can rapidly translate into clinical research and improvements in the management of disease. Thus, it is quite appropriate for the APS Bulletin to inaugurate a department that focuses on translational research, in the study of pain. My purpose in this introductory presentation on the subject is to provide background information on how pain scientists took the lead in translational research and to give examples of how it has been used.
Background
Most of my research on pain has focused on the basic mechanisms of acute and chronic pain. I am very comfortable, however, with the concept of interdisciplinary and translational research, which embodied the research program I directed at the NIH for over 30 years. The translational concept—bringing basic scientists and clinical scientists together to study diverse aspects of chronic or persistent pain and moving research in the laboratory to the clinic—has been a major aspect of the pain field for the last quarter of a century. Two visionaries in the pain field, John Bonica, MD DSc FRCAneas, and Patrick Wall, DM FRS, recognized the importance of this idea. In the 1950s, Dr. Bonica, an anesthesiologist, wrote about the importance of multidisciplinary approaches to the study of pain. Dr. Wall, a neuroscientist and a clinical neurologist, used the multidisciplinary approach to help unravel some of the major mysteries of persistent or chronic pain and to offer ideas and approaches on how this knowledge could be used in the clinical arena.
Pain emerged as an important field of research in the 1960s and early 1970s. Ronald Melzack, PhD, and Dr. Wall published their gate-control theory in 1965. Their theory led to a renewed interest in mechanisms of nociception in peripheral tissues, the spinal cord, and the brain. In response to the initial findings of John Liebeskind, PhD, and his colleagues, a number of laboratories elucidated the physiology and pharmacology of the brain’s pain-suppressing systems and the role of naturally occurring opioids.
These studies generated excitement and renewed interest in clinical pain problems. Dr. Bonica, whose innovative abilities and motivational drive spearheaded the movement, organized an interdisciplinary meeting in Issaquah (Seattle) in 1973 to bring together leading scientists and clinicians with an interest in pain. This meeting led to the development of the International Association for the Study of Pain (IASP), which ultimately spawned the American Pain Society (APS) and national chapters throughout the world.
One of the most important outcomes of the proliferation of national and international pain societies is the recognition of the importance of communication among basic and clinical scientists. I have had the opportunity to work with many scientists who went on to develop successful independent research programs on the study of pain. A major characteristic of these research programs is their multidisciplinary nature.
The field of pain is a model for multidisciplinary and interdisciplinary research. There is an interaction among scientists in the fields of neuroscience; specialties of medicine (e.g., neurology, neurosurgery, anesthesiology, and psychiatry); experimental and clinical psychology; psycho-physics; dentistry; and nursing. And today, there is also considerable interaction with people in the physical sciences and engineering.
This merging of ideas and approaches is seen in the organization of the major pain societies—the IASP and the APS—which are truly multidisciplinary organizations. Pain, the journal of the IASP, publishes articles across all of these disciplines and has a remarkable reputation. Its impact is higher than some of the most reputable journals in neuroscience. Such a level of recognition is most unusual for a multidisciplinary journal that spans the basic and clinical sciences. The pain program at the NIH was also multidisciplinary. It included physicians, dentists, nurses, psychologists, and neuroscientists. Neuroscience is one of the first truly interdisciplinary fields today. I consider myself a neuroscientist studying pain mechanisms in the nervous system. Interdisciplinary approaches are not new to me; they have been part of my whole career in neuroscience and pain research.
Bench to Bedside, Bedside to Bench
Pain research is a model of translational research. I would define translational research as research that takes laboratory findings and applies them to clinical problems to study underlying mechanisms of disease and illness. This research generates opportunities for better diagnosis and the development of new technical approaches that can lead to better treatment. It is followed closely by the application of this knowledge in clinical trial studies to test the efficacy and the adverse effects of new drugs and other treatment approaches. Thus, translational research links the bench and the bedside approaches and also provides the link to the reverse approach, the bedside to bench approach: the ability to examine clinical evidence and use that knowledge to study underlying mechanisms. Let me give you an example of each of these approaches.
How has bedside knowledge led to basic research findings? Increases in noxious stimulation normally lead to increases in pain sensation in the range of tissue damage. Such sensations characterize our behavioral response to transient pain. After persistent injury, however, this relationship changes. Stimuli that are normally nonpainful produce pain. This is called allodynia. Also, noxious stimuli produce greater levels of pain than they do when applied to uninjured tissues. This is called hyperalgesia. For decades, clinicians have recognized these characteristics, but it is only through basic research in the past 20 years that we have begun to unravel the mechanisms that underlie these clinical signs of amplification and persistence of pain. This is an example of how the need for knowledge, based on the bedside experience, leads to new laboratory discoveries.
What scientists have learned in the laboratory in the last decade has helped further the understanding of hyperalgesia and allodynia. For example, tissue damage results in an increased sensitivity of specialized nociceptors at the site of injury. This is called peripheral sensitization. Molecular approaches have cloned many of these receptors. The increase in nociceptor activity ultimately leads to an increased neuronal barrage into the central nervous system (CNS) and hyperalgesia and allodynia. The neural barrage also produces functional changes in the spinal cord and brain that contribute to allodynia, hyperalgesia, and spontaneous pain. This is referred to as central sensitization. Central sensitization is a form of activity-dependent plasticity in the CNS. Activity-dependent plasticity is associated with neural pathways involved in learning and memory and, in general, is a neural response to environmental events relevant to the survival of the organism.
Major advances in understanding these mechanisms have come from the development of animal models of hyperalgesia and allodynia after tissue and nerve injuries. Often in these models, an inflammatory agent is injected into an animal’s paw. Paw withdrawal latency is used as an indirect measure of hyperalgesia or allodynia, depending on the effect of the stimulus on normal tissue. Inflammation results in dramatic reductions in forces required to produce paw withdrawal, indicating nocifensive behavior in response to innocuous stimuli that are normally considered nonpainful (i.e., mechanical allodynia).
The development of allodynia and hyperalgesia after inflammation is dependent upon the persistence of peripheral nociceptive activation. By blocking peripheral input with an injection of lidocaine into a rat’s hind paw, the early development of allodynia or hyperalgesia can be blocked or delayed. These findings suggest that peripheral nociceptor activation evoked by inflammation is necessary for the initiation of the allodynia and hyperalgesia that is maintained by central sensitization.
A Clinical Example
How does this new information help us diagnose clinical conditions? Gracely, Lynch, and Bennett (1992) provide us with a good example. A 52-year-old woman developed severe shooting pains in the elbow following ulnar nerve transposition surgery. After 18 months of various treatments that resulted in partial relief, she experienced severe pain in the forearm and hand. Clinical exam revealed spontaneous pain in the forearm. Light touch from a cotton wisp on the elbow, forearm, and hand evoked pain. This response indicated mechanical allodynia. The injection of 1.5% lidocaine took only 2 minutes to completely anesthetize the injected site and eliminate the allodynia from all areas. The authors proposed that the A beta-mediated allodynia was due to input from a nociceptive focus at the original site of injury, which dynamically maintained altered central processing and resulted in touch being perceived as pain. They proposed that the peripheral input potentially came from several sources: neuromas, sympathetic stimulation, or soft issue injury. Blocking this input caused the central processing to revert to normal, eliminating the allodynia.
The above example shows that peripheral nerve injury can lead to activation of peripheral nerve fibers by multiple mechanisms. It appears that CNS plasticity leading to amplification of pain can be maintained even after most of the peripheral injury has healed. Such changes, in the past, were mistakenly identified as cases of functional pain related to psychological disorders. These findings point the way to new treatment approaches for neuropathic pain.
These clinical examples illustrate the importance of peripheral sensitization and central sensitization in mechanisms of ongoing pain (Ren & Dubner, 1999). Peripheral sensitization and central sensitization should not be considered as pathological changes in the nervous system but rather as part of the normal function of nociceptive systems in response to persistent injury. This normal function is protective: to guard the injured site and also recuperate and heal the injury. Under some circumstances, however, the changes in the CNS may persist, even after much of the peripheral tissue injury response has healed. Future research is needed to better understand the factors that contribute to such nonprotective disturbances of the nervous system, leading to the abnormal persistence of pain.
The Future of Pain Management
In spite of these major advances, unfortunately, basic research findings have not been readily translated into new approaches. Pain management still relies mainly on drugs, such as local anesthetics, aspirin-like drugs, and opioid- or morphine-like compounds, that have been available in one form or another since the early 20th century.
The NIH roadmap (see introduction) provides increased funding opportunities for new interdisciplinary approaches to the study of disease and the translation of basic science findings into the clinical arena. The roadmap should help in the development of research methodologies that will lead to new treatment approaches in pain and other fields.
In the pain field, how can we take advantage of new research findings and translate them into appropriate clinical management targeted to the individual patient? We need to realize that there will be no silver bullet for the treatment of persistent pain. Persistent pain conditions are too diverse, each with multiple mechanisms that contribute to the diseases.
New advances in interdisciplinary research will be particularly important in the pain field in view of new research in genetics and brain imaging. We can now develop a susceptibility profile—or signature—of individual patients to different persistent pain conditions and to new analgesic drugs. A multiparametric analysis of the psychological profile and sensitivity to pain can be determined, along with an analysis of changes in neural function using brain imaging techniques and genomics/ proteomics to determine an individual’s genetic profile to pain sensitivity and analgesic agents.
The genetic profile will establish a hypothesis of disease susceptibility for each individual and a clustering of patients based on similar signatures or patterns. These hypotheses then need to be tested with various manipulations, such as old drugs, new drugs, and behavioral outcomes. Clusters should predict similar responses to a manipulation, and the higher the correlation of the changes with a particular cluster, the more likely the effectiveness of the manipulation. I am hopeful that the NIH roadmap can provide the merging of innovative ideas, along with the necessary funding, to achieve our goal of new translational methodology and clinical research leading to a 21st century approach to the treatment of persistent pain.
References
Gracely, R. H., Lynch, S. A., & Bennett, G. J. (1992). Painful neuropathy: Altered central processing maintained dynamically by peripheral input. Pain, 51, 175–194.
Ren, K., & Dubner, R. (1999). Central nervous system plasticity and persistent pain. Orofacial Pain, 13, 155–163.
Ronald Dubner, DDS PhD, is Professor and Chair of the Department of Biomedical Sciences, University of Maryland, Baltimore.
Please direct your comments or suggestions about these articles or this department to Christine Sang, MD MPH, Department Editor, at csang@partners.org