INtERVIEW: Reflections on Pain Research and Management: Past, Present and Future

Abstract

C Richard Chapman is Professor and Director of the Pain Research Center in the department of Anesthesiology at the University of Utah, Salt Lake City (UT, USA). A psychologist and psychophysiologist, he has worked in the pain research field since 1970. He spent 29 years at the University of Washington before coming to the University of Utah. His interests span acute pain, chronic pain, cancer pain and pain measurement.

Q How did you initially become interested in the field of pain research?

It all began when I was a postdoctoral fellow at Duke University Medical Center (NC, USA) in 1970, working within a multidisciplinary program called Aging and Human Development. My mentor was Ben Feather, a psychiatrist with a PhD in experimental psychology, and he had a psychophysiology laboratory. Ben came across a paper by Crawford Clark that applied signal detection theory to the study of pain and asked me if I knew how to carry out a signal detection theory analysis. I did, and we generated some papers on pain along these lines. John Bonica at the University of Washington (WA, USA) noticed this work and recruited me for his new program in pain research. Today, 40 years later, I am still in the same field.

Q In recent years, you have attempted to bridge stress research with pain research & you have emphasized the importance of stress concepts for acute & chronic pain management. Why do you feel this is important?

Acute and chronic pain pose formidable management challenges in today‘s medicine. Individual patients vary greatly in the severity and duration of acute pain that they experience in response to an identical injury, such as specific surgical procedures, and some undergo the transition to chronic pain despite wound healing. Many chronic pain syndromes defy conventional diagnosis and pain is embedded in a constellation of other disabling symptoms. These symptoms comprise abnormal chronobiology, including sleep disturbance, various digestive system dysfunctions, sexual dysfunction, fatigue and mood problems. John Bonica often referred to chronic pain as a “malefic force.” I have come to understand this as a disorder of the whole person and believe that in many cases chronic pain is rooted in stress.

The concept of stress requires an evolutionary framework. A human is a complex adaptive system equipped by evolution to rise to the occasion when threatened. Adaptation and survival require that we meet threats to our well being, termed stressors, with psychophysiological arousal responses, termed stress responses. These responses involve heightened sympathetic nervous system activity, catecholamine release and pro-inflammatory cytokines. When the threat passes, the stress response should resolve, fully restoring the system to approximate equilibrium. Unfortunately, a severe stressor, a relentless stressor or a series of stressors in rapid succession can prevent the normal cycle of stress response and resolution, leaving the system partly aroused for an indefinite time period and subsequently dysregulated. Dysregulation can manifest as abnormal biorhythms, failed negative feedback mechanisms in hormonal regulation, excessive inflammatory conditions and central hyperalgesia. Stress-induced dysregulation can exacerbate and extend the duration of acute pain. It can generate myriad symptoms and dysfunctions in chronic pain patients, including hyperalgesia and mood disorders. Ultimately, diagnosing and treating dysregulation needs to be a part of acute and chronic pain management.

Q The mission of the Pain Research Center (UT, USA), where you are currently Professor & Director, is to “develop and sustain multidisciplinary research programs related to pain & suffering”. Why do you feel such an approach is important?

The domain of pain research extends from gene expression to policy studies. A well-known ancient Indian tale describes a group of blind men who went to investigate an elephant. Each felt a different part of the animal, and a quarrel broke out because each was certain that he was right and the others were wrong. Although each was right, all were wrong because they failed to appreciate the limitations of their individual viewpoints. Like the elephant in the story of the blind men, pain has many facets and we can only delude ourselves by thinking that we are on the right track while others are doing less important work. Very little in the pain domain reduces to a single mechanism, and everyone‘s progress is necessary if we are to complete the big picture. Collaboration across disciplines has a high potential for payoff.

Q Could you explain the focus of your current research & what you hope to achieve through it?

My emphasis is on the measurement of acute pain. Current methods for assessing acute pain have poor precision and they fail to take time into account. The precision problem means that, although conventional pain rating measures work if we calculate the means of groups, they fail when we try to track the pain of the individual patient. In addition, the rate at which a patient resolves his or her pain is at least as important as the severity of the initial pain. Therefore, the goals of our work are to generate tools that produce more precise measures and to measure acute pain, not as a static point in time, but as a dynamic process characterized by both intensity and rate of resolution.

Q Your homepage states that you “hope to help bridge research on consciousness with the study of pain” [1]. What do you feel this will involve?

Consciousness is a product of evolution that promotes adaptation to a changing environment. The brain produces a constantly changing, or dynamic, model of the external world and the body‘s internal environment. In this context, pain is an aspect of somatic awareness that informs the brain of tissue trauma. Consciousness is an emergent property of brain activity. By this I mean that consciousness is greater than the sum of its brain mechanisms, we cannot reduce it to lower level properties, and somatic awareness does not tend to be predictable from underlying physiological processes. Functional brain imaging studies of pain inform us greatly about dynamic patterns of brain activity associated with pain [2,3], but these processes are prepain rather than pain itself. Pain is emergent, dynamic awareness and, therefore, consciousness.

At present, we study pain as though we should be able to account for the whole of the experience by assembling the sum of its mechanisms, but this premise is untenable in consciousness studies. Although we have much to gain from reductionistic science, we need to realize its limitations. The alternative, or better yet, complementary, strategy is a complex systems approach. This is why I have emphasized the concept that humans are complex adaptive systems.

Q From the viewpoint of pain management, what are the major achievements in the field of pain research to date & what are the most pressing challenges that remain?

I have watched the development of this field from its inception. Gate control theory, put forward 46 years ago, initiated interdisciplinary pain research. Psychologist Ronald Melzack and neurophysiologist Patrick Wall teamed up to provide an account of injury-specific neurotransmission and its modulation [4]. This theory did little to advance patient care directly, but it was a key catalyst for interdisciplinary collaboration.

From 1970 to roughly the end of the century, the sensory neurophysiology paradigm dominated pain research. The implicit assumption at the root of this paradigm is that pain is a sensory message generated by an injury-sensitive receptor, a nociceptor in the periphery. Specific spinal cord pathways transmit this message to the thalamus, and from the thalamus it goes to the somatosensory cortex where the brain ‘realizes‘ the injury. Emotional and cognitive processes, in this paradigm, are secondary to the sensory processes. They are reactions to the pain signal. The job of scientists in this paradigm is to find the various lines of transmission and label them. The line-labeling task of identifying the descending pathways and mechanisms involved in modulating the noxious signals is paired with this.

Psychologists, such as myself and some others, maintain that noxious signaling directly activates central structures involved in emotion and cognition as well as the somatosensory cortex. Functional brain imaging studies have now provided extensive, incontrovertible evidence that this is the case [5]. Emotion and cognition are a part of pain and not consequences of the ‘realized‘ message. For me, this paradigm shift is the greatest accomplishment of the field to date. From the clinical perspective, it means that the clinician must see the patient living with pain in a different and more holistic way. Chronic pain is not a sensory disorder with emotional, mood and cognitive consequences. It is a condition of the whole person with sensory, emotional, mood and cognitive features. To manage pain is to assess and manage all of these aspects of the patient.

Many challenges remain. Our major interventions are still variations of willow bark, secretions from poppies, animal toxins and the properties of electrical fish. A disquieting gap exists between the knowledge we gain in science and the management of patients with acute and chronic pain. If drug development is to close this gap, investigators need to relinquish their narrow concept of pain as a property of the nervous system. Pain has emotional and cognitive as well as sensory dimensions, and its underlying physiology extends to the endocrine and immune systems. For example, microglia clearly play a role in sensitization, even though they are not a part of the nervous system. They are organs of the immune system that resemble macrophages, and they respond to different drugs than nervous structures do. Similarly, adrenoceptors play a key role in some neuropathic pain states, and they are part of the interface that links the endocrine system to the nervous system. Adrenoceptors also influence immune function and pro-inflammatory cytokines. If the endocrine system becomes dysregulated as a result of stress, adrenoceptors will function in a dysregulated manner. We have drugs that act on adrenoceptors, but we lack the theoretical framework to target the underlying problem of dysregulation, and are at risk of increasing dysregulation rather than resolving it. Understanding chronic pain states as conditions involving systemic dysregulation that transcend the conventional boundaries of the nervous, endocrine and immune systems could be an important step to opening new interventions that can help close the gap between scientific knowledge and clinical practice. To achieve this kind of progress, we need to go beyond the confines of randomized controlled trials and meta-analyses. Progress at a systems level will require multivariate statistical modeling.

Q How do you see the field of pain research & management evolving over the next 5 years?

Three incipient trends are likely to develop substantially in the next 5 years. The first is inquiry into the fundamental question of how acute pain becomes chronic. The second is the pursuit of individualized medicine in the domain of pain. The third is a shift away from reliance on randomized controlled trials of interventions to alternative, more advanced statistical methods for evaluating treatment effects.

Although how acute pain becomes chronic is unlikely to be reduced to a single mechanism, this is a frontier for investigators at every level of inquiry. New interventions for prevention and treatment are likely to emerge, as are algorithms for risk prediction in postoperative settings and emergency departments. This field is substantially more advanced in Europe than in the USA. European investigators have realized that the question is not confined to neuropathic pain. Psychosocial factors and pre-existing pain conditions are formidable predictors of chronic pain following acute tissue trauma.

Clinical pain management today involves a great deal of trial and error intervention, just as it did half a century ago. Advances in pharmacogenetics, pharmacogenomics and epigenetics now offer hope for developing truly individualized patient care. To my delight, we are beginning to realize that past history, immediate psychosocial factors and various stressors do more than influence the psyche, they determine gene expression. Of course, gene expression is a mechanism of the dysregulation that I have repeatedly mentioned. I expect to see more research in these areas along with related advances in drug development.

Finally, rigid adherence to the principles of evaluating interventions with randomized controlled trials and meta-analyses has costs as well as benefits. In the field of opioid pharmacotherapy for chronic pain, prescribing practices have run ahead of the evidence base, creating a crisis in the USA. Randomized controlled trials are the current state of the art, but they are costly and inefficient. We urgently need alternative sources of evidence, and I expect to see some of these emerge in the next 5 years. Advanced multivariate statistical modeling methods, Bayesian adaptive design approaches, and the development of pain registries are among the alternatives on the horizon.

Financial & competing interests disclosure

CR Chapman has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.