Wednesday, July 27, 2011

The Pain Project |

Anyone who has been given painkillers for a sore back, or a morphine drip after surgery, should consider themselves lucky.  While morphine is the standard treatment is most Western hospitals, more than half the countries in the world have little to no access to these drugs.  Millions of patients around the globe suffer long-term illnesses in excruciating pain.

Unlike so many global health problems, pain treatment is not about money or a lack of drugs, since morphine costs pennies per dose. The culprits are bureaucratic hurdles and the chilling effect of the global war on drugs.

The International Reporting Program traveled to Ukraine, India and Uganda, to uncover this hidden human rights crisis.  The resulting report is "Freedom from Pain," a half hour documentary produced in partnership with Al Jazeera English.

Monday, July 25, 2011

NIH grant program on Pharmacological Management of Chronic Pain in Older Adults

Section I. Funding Opportunity Description

The number of Americans age 65 or older currently exceeds 40 million, or about 13% of the US population. Over the next 20 years, this number is expected to reach approximately 70 million, or 20% of the population. The oldest old, those individuals age 85 or older, are the fastest growing segment of the US population, and the proportion of these individuals is expected to more than triple by 2050. 

As the age of the population increases, so too will the diseases and conditions that accompany advancing age. Chronic pain is highly prevalent among older adults. Primary causes of chronic pain in this population include musculoskeletal diseases (e.g., osteoarthritis and degenerative disk disease), cancer, and neuropathic conditions (e.g., diabetic neuropathy, post-herpetic neuralgia, and chemotherapy-induced neuralgia). Chronic pain is also associated with a variety of adverse health outcomes such as disability, cognitive deficits, mood disturbance, and impaired sleep.

Current management of chronic pain involves a stepwise approach that frequently includes non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioids for moderate-to-severe pain. A variety of adjuvant drugs, devices, and non-pharmacologic therapies may also be used, often in combination with NSAIDs and/or opioids. Despite this panoply of therapeutic options, however, older adults continue to be undertreated disproportionately, due in large part to lack of evidence, under-recognition of pain, and safety concerns among prescribers, patients, and caregivers.

In 2009, an American Geriatrics Society (AGS) special panel published updated guidelines for pharmacologic management of chronic pain in older adults [1]. Specifically, these guidelines recommended that "[n]onselective NSAIDs and COX-2 selective inhibitors may be considered rarely, and with extreme caution, in highly selected individuals." At the same time, the AGS guidelines also recommended that "[a]ll patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy." While there is a fair amount of evidence supporting contraindications to treatment, there is a much smaller evidentiary base to identify those older adults with chronic pain who may safely benefit from NSAIDs or opioids over months or years of treatment. The evidence base for other classes of drugs, such as adjuvant analgesics, also requires further development.

Consequently, there is a need to generate evidence guiding safe and effective treatment for chronic pain in older persons. In 2010, an "Expert Panel Discussion on Pharmacological Management of Chronic Pain in Older Adults" was convened under the aegis of the NIH Pain Consortium to identify research gaps and suggest approaches to address them. A summary of the research gaps and methods to address them are in press at Pain Medicine with publication expected in the September, 2011 issue. Among many recommendations, panelists noted that a variety of factors may influence the selection and outcomes of treatment, including patient-, medication-, provider-, and system-level factors. A cost-effective approach to investigating these myriad factors may be to examine available datasets or add new measures to existing studies to identify variables associated with successful or adverse outcomes of treatment.

The purpose of this FOA is to support small, self-contained research projects that aim to leverage existing data or longitudinal studies in order to evaluate the safety and/or effectiveness of pharmacological management for chronic pain in older adults. Applicants are invited to submit innovative proposals using administrative databases, health care records, clinical trial datasets, patient registries, cohort studies, or other resources to further our understanding of treatment outcomes from pharmacologic or combination pharmacologic/non-pharmacologic interventions, particularly involving NSAIDs or opioids, in older individuals with chronic pain. Proposed approaches may include, but are not limited to 1) secondary analyses of existing datasets; 2) adding new measures to existing observational or interventional studies; or 3) developing methodologies to facilitate the preceding two approaches.

Examples of aging-related studies that this FOA may support include, but are not restricted to:

  • Identification of patient-level factors (e.g., cormorbidities, pharmacogenomic profiles, renal function, cognitive function, vulnerabilities), medication-level factors (e.g., initiating dose, titration method, specific pattern of analgesic use, mode of delivery, interactions with alcohol, benzodiazepines, anti-depressants, or other sedatives), provider-level factors (e.g., communication patterns with patients, attitudes and beliefs), and/or system-level factors (e.g., guideline recommendations, care models) associated with outcomes from specific treatment strategies (e.g., pharmacotherapy or combination pharmacotherapy/ non-pharmacologic therapy) in older adults with chronic pain.
  • Comparative safety and/or effectiveness studies of different treatment approaches in older adults or in specific sub-populations (e.g., individuals with dementia), such as comparisons between primary treatments to reduce pain, co-administered treatments to reduce side effects, or additive treatments to enhance therapeutic effects.
  • Development of a methodology to link datasets with complementary data elements in order to enable valid evaluations of pain treatment outcomes that would not be possible using datasets individually.
  • Evaluation of the utility of pain-related measures or indices in guiding treatment initiation, titration, or discontinuation in specific older populations (e.g., individuals with dementia).

Investigators hypothesizing mediatory roles for specific characteristics on treatment outcomes are encouraged to provide an empirical or theoretical rationale for selecting such characteristics. In addition, investigators are encouraged to provide adequate analytic plans to address potential methodological pitfalls of analyzing observational data, especially those collected in non-randomized studies or during clinical care.

Applicants are encouraged to study older subjects with a range of ages. Studies in older subjects with multiple morbidities, vulnerabilities, and those from ethnically diverse backgrounds are particularly encouraged, as these populations are among the most commonly undertreated and understudied patients with chronic pain.

The NIA Database of Longitudinal Studies contains an extensive listing of NIH-supported cohort studies involving older subjects and/or aging research questions. The database can be found at

The National Institute on Drug Abuse (NIDA) is also interested in applications responsive to this FOA that fall within its scientific mission. NIDA may support such meritorious applications contingent on availability of funds.


1. American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons: American Geriatrics Society. Journal of the American Geriatrics Society. 2009; 57:1331-1346

Sunday, July 24, 2011

Gut memories: Towards a cognitive neurobiology of irritable bowel syndrome [Neurosci Biobehav Rev. 2011]

Neurosci Biobehav Rev. 2011 Jul 13. [Epub ahead of print]

Gut memories: Towards a cognitive neurobiology of irritable bowel syndrome.


Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.


The brain and the gut are engaged in continual crosstalk along a number of pathways collectively termed the 'brain-gut axis'. Over recent years it has been becoming increasingly clear that dysregulation of the axis at a number of levels can result in disorders such as irritable bowel syndrome (IBS). With recent advances in neuroimaging technologies, insights into the neurobiology of IBS are beginning to emerge. However the cognitive neurobiology of IBS has remained relatively unexplored to date. In this review we summarise the available data on cognitive function in IBS. Moreover, we specifically address three key pathophysiological factors, namely; stress, immune activation and chronic pain, together with other factors involved in the manifestation of IBS, and explore how each of these components may impact centrally, what neurobiological mechanisms might be involved, and consider the implications for cognitive functioning in IBS. We conclude that each factor addressed could significantly impinge on central nervous system function, supporting the view that future research efforts must be directed towards a detailed assessment of cognitive function in IBS.

Thursday, July 21, 2011

Behavioral Treatment For Migraines A Cost-Effective Alternative To Meds - Medical News Today

Treating chronic migraines with behavioral approaches - such as relaxation training, hypnosis and biofeedback - can make financial sense compared to prescription-drug treatment, especially after a year or more, a new study found. 

Longtime behavioral therapy researcher and practitioner Dr. Donald Penzien, University of Mississippi Medical Center professor of psychiatry, coauthored the study. He said the costs of prescription prophylactic drugs - the kind chronic migraine sufferers take every day to prevent onset - may not seem much even at several dollars a day. 

"But those costs keep adding up with additional doctor visits and more prescriptions," Penzien said. "The cost of behavioral treatment is front-loaded. You go to a number of treatment sessions but then that's it. And the benefits last for years." 

Published in the June issue of the journal Headache, the study compared the costs over time of several types of behavioral treatments with prescription-drug treatments. The research team included investigators from Wake Forest University, UMMC and the University of Mississippi. 

The researchers found that after six months, the cost of minimal-contact behavioral treatment was competitive with pharmacologic treatments using drugs costing 50 cents or less a day. Minimal-contact treatment is when a patient sees a therapist a few times but largely practices the behavioral techniques at home, aided by literature or audio recordings. 

After one year, the minimal-contact method was nearly $500 cheaper than pharmacologic treatment.

"We have a whole armamentarium of behavioral treatments and their efficacy has been proven. But headache sufferers are only getting a tip of these options," said Dr. Timothy Houle, associate professor of anesthesiology and neurology at Wake Forest University, and the study's principal investigator. 

"One reason is people think behavioral treatment costs a lot. Now with this study, we know that the costs are actually comparable, if not cheaper, in the long run." 

At a time when health-care costs are under national scrutiny, the study offers a framework for comparing costs that researchers can update and use for years to come. 

"We thought, 'Wouldn't it be fun to model this and see how it comes out over time?'" Penzien said. "All the figures are there so if someone disagrees with it, they can plug in their own numbers." 

The researchers didn't compare the effectiveness of methods, nor did they calculate the costs over time of individual drugs, since dosages and prices vary widely. Rather, they figured the per-day costs of each method based on fees of physicians and psychologists. For the physician group, they added in the cost of prescription beta-blocker drugs at various prices. 

For instance, among the psychologists surveyed, one-on-one behavioral sessions cost between $70 and $250 for the intake visit and $65 and $200 for follow-up visits. That put the median intake cost at $175 and median follow-up cost at $125 for a median 10 visits. 

The researchers calculated the median cost of pharmacologic approaches at $250 for the intake session and a professional fee of $140 per session. Median time to the first follow-up was 52.2 days, rising to 60 for the second with a median five visits per year. 

To get information on behavioral treatments, the researchers surveyed members of the Behavioral Issues Group of the American Headache Society. For figures on pharmacologic treatments, the researchers surveyed a group of Headache Society-member physicians they knew treated substantial numbers of headache sufferers. 

The most expensive behavioral treatment method - individual sessions with a psychologist in clinic - cost more than pharmacologic treatment with $6-a-day drugs in the first months. But at about five months, individual sessions become competitive. After a year, they are cheaper than all methods except treatment with drugs costing 50 cents or less a day. 

Overall, group therapy and minimal-contact behavioral treatment were cost-competitive with even the cheapest medication treatment in the initial months. At one year, they become the least-expensive headache treatment choice.

CRC Press Online - Maldynia - James Giordano, Ed.


• Provides an overview of the history of pain and its treatment since Hippocrates

• Addresses the neurobiology and experience of chronic pain

• Discusses possible relationships of chronic pain to spirituality

• Details the role and value of narrative and expression, as well as technology in assessing maldynic pain

• Posits the basis for an ethic of pain care

• Explores the problematic nature and implications of pediatric maldynia

• Examines the importance of goal-directed health care


Whether initiated by injury or disease, induced and sustained by changes in the nervous system, or manifested by society and culture, chronic pain can change one's first-person experience of the body and the world, and ultimately impacts cognitions, emotions, and behavior. Many fine medical books address the causes and management of chronic intractable pain, but rarely do they focus on the ways that such pain creates illness and is experienced and expressed by persons in pain.

Maldynia: Multidisciplinary Perspectives on the Illness of Chronic Pain is about chronic pain that has progressed to a multidimensional illness state in and of itself. Although often dismissed as such, this pain is not imaginary, but rather represents an interaction of neurobiological processes, emotional and behavioral responses, and socio-cultural effects and reactions that become enduring elements in the life and world of the pain patient, and often remain enigmatic for those who provide care.

Taking a comprehensive approach that covers science, humanities, and culture, this volume emphasizes the need for researchers, clinicians, and caregivers to regard the ways in which chronic intractable pain becomes illness and affects a patient's biological, social, and psychological states, as well as his or her sense of self. Edited by neuroscientist and neuroethicist James Giordano, this book contains 17 insightful chapters representing medicine, neuroscience, psychology, philosophy, ethics, history, art, and the ministry, this volume:

• Provides an overview of the history of pain and its treatment since Hippocrates
• Addresses the neurobiology and experience of chronic pain
• Discusses possible relationships of chronic pain to spirituality
• Details the role and value of narrative and expression, as well as technology in assessing maldynic pain
• Posits the basis for an ethic of pain care
• Explores the problematic nature and implications of pediatric maldynia
• Examines the importance of goal-directed health care

This exceptional volume also looks at representations of pain in and through the arts, addresses the assignation of values and meaning in pain assessment and treatment, and considers ways to conjoin the sciences and humanities so as to inform the practice of pain medicine and improve the care of those suffering the illness of chronic pain. Magnet&utm_medium=Email

What Doctors Don't Know About Pain -

Most doctors view pain as a symptom of an underlying problem — treat the disease or the injury, and the pain goes away.

But for large numbers of patients, the pain never goes away. In a sweeping review issued last month, the Institute of Medicine — the medical branch of the National Academy of Sciences — estimated that chronic pain afflicts 116 million Americans, far more than previously believed.

The toll documented in the report is staggering. Childbirth, for example, is a common source of chronic pain: The institute found that 18 percent of women who have Caesarean deliveries and 10 percent who have vaginal deliveries report still being in pain a year later.

Ten percent to 50 percent of surgical patients who have pain after surgery go on to develop chronic pain, depending on the procedure, and for as many as 10 percent of those patients, the chronic postoperative pain is severe. (About 1 in 4 Americans suffer from frequent lower back pain.)

The risk of suicide is high among chronic pain patients. Two studies found that about 5 percent of those with musculoskeletal pain had tried to kill themselves; among patients with chronic abdominal pain, the number was 14 percent.

"Before, we didn't have good data on what is the burden of pain in our society," said Dr. Sean Mackey, chief of pain management at the Stanford School of Medicine and a member of the committee that produced the report. "The number of people is more than diabetes, heart disease and cancercombined."

For patients, acknowledgment of the problem from the prestigious Institute of Medicine is a seminal event. Chronic pain often goes untreated because most doctors haven't been trained to understand it. And it is isolating: Family members and friends may lose patience with the constant complaints of pain sufferers. Doctors tend to throw up their hands, referring patients for psychotherapy or dismissing them as drug seekers trying to get opioids.

"Most people with chronic pain are still being treated as if pain is a symptom of an underlying problem," said Melanie Thernstrom, a chronic pain sufferer from Vancouver, Wash., who wrote "The Pain Chronicles: Cures, Myths, Mysteries, Prayers, Diaries, Brain Scans, Healing and the Science of Suffering" (Farrar, Straus & Giroux, 2010) and was a patient representative on the committee.

"If the doctor can't figure out what the underlying problem is," she went on, "then the pain is not treated, it's dismissed and the patient falls down the rabbit hole."

Among the important findings in the Institute of Medicine report is that chronic pain often outlasts the original illness or injury, causing changes in the nervous system that worsen over time. Doctors often cannot find an underlying cause because there isn't one. Chronic pain becomes its own disease.

"When pain becomes chronic, when it becomes persistent even after the tissue and injury have healed, then people are suffering from chronic pain," Dr. Mackey said. "We're finding that there are significant changes in the central nervous system and spinal cord that cause pain to become amplified and persistent even after the injury has gone away."

The institute emphasized the importance of prevention and early treatment, a novel concept for many doctors who try to diagnose the source of pain before treating it or advise patients to wait it out in the hope it will go away on its own.

"Having pain that is not treated is like having diabetes that's not treated," said Ms. Thernstrom, who suffers from spinal stenosis and a form of arthritis in the neck. "It gets worse over time."

Ms. Thernstrom compared the effect of chronic pain on the body to the rushing waters of a river carving out a new tributary. Pain, she says, also changes the body's landscape.

"My pain is at the level where it's manageable," she said. "I do wish I had gotten aggressive treatment in the first year. There is a window of time to intervene, because pain changes your nervous system and pain pathways develop."

The report also acknowledged the "conundrum of opioids," noting that doctors are conflicted about how to treat pain because of worries about drug addiction. But the group noted that proper use of the drugs early in a pain cycle can resolve pain problems sooner, and stated that opioids are also particularly useful for pain management near the end of life.

The pain report is only a first step for the community of medical professionals who treat pain. It will be up to medical schools to begin better education of doctors in the treatment of pain, and the National Institutes of Health to decide whether to promote research into chronic pain. Patients, too, need to be educated about the importance of early treatment of pain rather than gutting it out or waiting until it has become severe and chronic.

"Some people were expecting a cure within the report," Dr. Mackey said. "There's no immediate cure. But I've seen a lot of patients who have said, 'Finally they are putting out a report that helps others understand what I'm going through.' "

The Genetics of Pain: Science, Medicine, and Drug Development - Miami Beach, February 7-9, 2012

With this IASP symposium we will:
  • Discuss key issues in pain research, including promising ongoing research, unanswered questions, emerging concepts
  • Emphasize translational research as the key to understanding mechanisms of susceptibility to chronic pain, and developing preventative approaches and novel treatment strategies
  • Explore the latest findings of genetic and genomic mediation of nociception from various models, emphasizing the conservation of pain-related genes, their functions and their advantages
  • Discuss the role of gene polymorphisms in normal and pathological modulation of pain in models, humans, and as future drug targets
  • Explore the latest findings from human genome-wide investigation of genomic variability and gene expression on pain and nociception
  • Review and discuss "gold standard" tools for comprehensive pain phenotyping in humans
  • Review and discuss current and future genetic and genomic techniques to study genetic contribution to human pain
  • Summarize the progress of cutting-edge clinical trials and those steps required to translate present research findings to clinical practice
  • Create a forum for the exchange of ideas on the impact of modern genetics on pain research

Michelle Bachmann's headaches: Why are migraines more common in women? - By Brian Palmer - Slate Magazine

Aides to Republican presidential candidate Michele Bachmann say she suffers from severe migraine headaches that can incapacitate her for days at a time. After Bachmann's campaign denied the claims, a secondary debate was sparked about whether reporting on the issue is sexist, since migraines are more common in women than men. Why do migraines disproportionately afflict women?
Hormones, probably. About 18 percent of women suffer from migraines, compared with just 6 percent of men. Doctors have proposed several explanations for the disparity, including different levels of external stress and gender-related differences in the psychological response to pain. The best research, however, now suggests that sex hormones are to blame, and loads of circumstantial evidence support this theory. In women, the headaches typically begin after puberty and tend to decrease in both frequency and intensity after menopause. (Migraines are one of the few neurological disorders to subside with age.) They are also more common during menstruation and less common during pregnancy. Intriguingly, doctors treating male-to-female transgendered people have noticed that after their patients begin hormone therapy, they start to experience migraines with the same frequency as genetic females.
Although the research is still unsettled, there is growing scientific evidence that estrogen is the primary culprit. Migraines occur when inflammation around the brain triggers trigeminal nociceptors—cells responsible for pain sensations around the face—to transmit chemical signals. Nancy Berman and Kenneth McCarson, neurology researchers at the University of Kansas Medical Center, have shown that in mice these cells have estrogen receptors. Also, rats exposed to estrogen exhibit significantly worse migraine symptoms—except for nausea, since rats don't vomit—than their estrogen-starved counterparts at the same level of inflammation. At a biochemical level, they've documented changes indicating that pain signals are stronger when estrogen receptors are activated. Such evidence suggests the possibility that men might experience the inflammation associated with migraine just as often as women but their pain receptors have a less forceful response to it.
Charges of sexism have hovered around migraines for years. Advocates point out that the National Institutes of Health will spend $15 million on migraine research in 2011, less than 0.05 percent of its annual research budget. That's peanuts compared with what we spend on some other debilitating but usually nonfatal diseases like arthritis ($253 million) and sleep disorders ($230 million).

Wednesday, July 20, 2011

Body in Mind — Research into the role of the brain in chronic pain (The Body in Mind Research Group, Australia)

The Body in Mind Research Group is based at The Sansom Institute for Health Research at the University of South Australia in Adelaide and Neuroscience Research Australia in Sydney. We have active collaborations with researchers scattered around the world. Together we are seeking a better understanding of the interaction between the body, brain and mind in chronic and complex pain disorders.

rTMS and chronic pain: Our two penny’s worth - O’Connell NE, & Wand BM

Some of you might have heard of repetitive transcranial magnetic stimulation (rTMS) and its use in chronic pain. Basically rTMS uses magnetic fields to generate electrical currents within the brain. This is a direct way of altering neuronal firing or excitability in the brain and a number of research groups have been investigating whether it might be used to treat chronic pain by altering pain processing in the brain. To get an idea of what it's all about check out this section of the BBC's Horizon programme "The Secret World of Pain".

While that video is emotionally compelling and at face value looks really promising, I lost count of the number of ways in which the placebo effect might be being ramped up in that interaction. In fact I personally felt that the programme did not really offer the viewer enough balance or caveats there. So what does the best evidence tell us about the efficacy of this technique? For a change we get to talk about our own research because after carrying out a Cochrane review on this very topic we have just written a commentary in the journal PAIN® that discusses the current state of the evidence for rTMS in chronic pain management.

Our review found a bunch (19) of small studies of rTMS. Overall the data was quite varied but when pooled it suggested a small effect. When we broke the data into pre-planned subgroups we found a small short-term effect on pain of single doses of high frequency rTMS applied to the motor cortex. Great news - it seemed to work better than sham (placebo) stimulation. But as usual there were reasons to be a tad less cheerful. The effect was small and while it tickled the feet of clinical importance it didn't clearly hit that target. There were also problems with risk of bias, particularly the tricky challenge of effectively blinding the studies, and we know that these issues tend to exaggerate effect sizes.

In fairness to rTMS these were single-dose one-off treatment studies. Maybe more doses would be more effective. Also they almost all recruited patients with severe neuropathic pain that didn't respond to anything else either, so not the easiest pain to influence. When we looked the few studies that delivered multiple doses the results were conflicting and inconsistent and there really aren't enough of them to make a confident judgement.

The point that we make in our commentary is that the evidence does suggest that rTMS might modulate pain, but this data has its problems, the studies are small and the evidence is a mixed bag of quality. There are more small, exploratory studies being published regularly, all justified by and based upon the initial promise of the earlier work but what is really needed is for researchers to take a nice big sample, deliver a good robust course of rTMS treatment using the parameters that look most promising right now (high frequency stimulation to the motor cortex), measure their outcomes over a decent time span, and all of this with good tight methods and better blinding. Sounds easy (but of course it never is)! But without this effort the next time we update our Cochrane review we might still only be able to say "maybe, maybe not".

O'Connell NE, & Wand BM (2011). Repetitive transcranial magnetic stimulation for chronic pain: Time to evolve from exploration to confirmation? Pain PMID: 21703764

‪Princess on the Pea - Mechanisms of Chronic Pain‬‏ - YouTube

Today we have a pretty good knowledge of the mechanisms behind chronic pain. This is a presentation of the basic understanding of how chronic pain starts, what causes it and why we most often are not able to see it on x-ray, MRI or other diagnostic procedures despite the fact that the patient are experiencing pain. We comes around allodynia, hyperalgesia, sensitization regulatory pathways and influence of sleep, depression and much more.

Friday, July 15, 2011

Specificity Versus Patterning Theory: Continuing the Debate - Allan Basbaum | Pain Research Forum

Does the brain process and interpret innocuous and noxious stimuli by "reading" a pattern of activity across multimodal lines of activity, or are there specific, labeled lines that carry functionally distinct modalities from the periphery to the spinal cord and then rostrally in the neuraxis?


The specificity camp has its origins in the nineteenth-century studies of German neurophysiologists who concluded that there are modality-specific spots on the skin (e.g., touch, cold, etc.), and that a percept is generated by activation of specific neuronal pathways in the periphery and CNS (for reviews, see Craig, 2003Ma, 2010; and Perl, 2007). This concept was originally articulated by Müller (Müller, 1840), who proposed that the stimulus did not even determine the perception, but rather that connectivity of the afferent and its ultimate projection site in the brain were critical.


The pattern theory, by contrast, proposed that afferent fibers respond to a host of stimulus modalities, and that the ultimate perception depends on the brain's deciphering and interpretation of the patterns of activity across the different nerve fibers. The late Patrick Wall, almost 30 years after coauthoring the Gate Control Theory of Pain in 1965 with Ronald Melzack (Melzack and Wall, 1965), wrote that "…specificity theory has failed to generate any explanation for clinical pains. Worse yet…it has encouraged ineffective, often counterproductive, surgical attempts to destroy the cells or their axons" (Wall, 1996). The poster boy/dartboard for the specificity camp, of course, is Descartes' little boy whose "pain pathway" runs from his foot to a pain center in his brain.


It is of interest that the focus of Melzack and Wall's seminal 1962 article "On the nature of cutaneous sensory mechanisms," which preceded the Gate Control Theory paper by three years, was on the processing of non-noxious thermal and mechanical stimuli, as compared to pain-producing stimuli. The paper dealt much less so, if at all, with the question of the processing of different modalities of noxious/painful stimuli (i.e., heat, cold, mechanical, and chemical pain) (Melzack and Wall, 1962). Pat Wall was, of course, strongly influenced by his discovery, with Lorne Mendell, of the wide dynamic range (WDR) dorsal horn neuron (Mendell and Wall, 1965). The WDR neuron clearly responds to both innocuous and noxious stimulation, which argued against a specific Cartesian "pain" pathway. However, subsequent demonstrations by Ed Perl and colleagues of primary afferents (nociceptors) and lamina I dorsal horn neurons that respond only to noxious stimulation, at least in uninjured animals (Bessou et al., 1971Christensen and Perl, 1970) provided fodder for the labeled line advocates.


So where are we today? As a student of both Melzack and Wall, I grew up with a firm belief in pattern theory. However, results from our recent studies have encouraged me to reexamine this basic tenet. Just as the ability to record from single fibers made possible the identification of afferents that respond rather exclusively to noxious stimulation, so the molecular revolution has revealed a detailed subclassification of the nociceptors. In fact, nociceptors are remarkably heterogeneous; different subsets express channels that are responsive to different noxious stimulus modalities (e.g., heat [TRPV1], cold [TRPM8], mustard oil [TRPA1], etc.) (Basbaum et al., 2009Julius and Basbaum, 2001). Of course, there is some overlap of these channels, and there is no question that many of the nociceptors are polymodal, responding to thermal as well as mechanical stimulation. Nevertheless, our studies argue strongly for a modality-specific contribution of subsets of primary afferents to the presumptive pain-generated behaviors evoked by the particular modality, (e.g., heat, cold, mechanical) (Cavanaugh et al., 2009Scherrer et al., 2009).


Although I have written (in a syllabus for an IASP Refresher course) that "there are no labeled lines….", I now believe that there is behaviorally relevant specificity, at least at the level of the primary afferent. To what extent the behaviorally relevant (pain, and likely itch) information generated by primary afferents is also manifest at the level of circuits in the spinal cord and at higher levels of neuraxis is the critical unanswered question. Yes, there are nociceptive-specific neurons in the dorsal horn, but the WDR neuron cannot be ignored (Price et al., 2003). Indeed, the relative contribution of these two neurons is worthy of continued discussion in this forum.


In their 1962 article, Melzack and Wall proposed that, "A satisfactory theory of somesthesis must be able to provide answers to two essential problems: 1) What is the nature of the information that is sent to the central nervous system when the skin is stimulated, and 2) How do the central cells select or abstract from this information to provide the many different qualities of our sensory experience?" We have come a long way to answering the first question, butclearly, we need more information as to the specificity versus patterning question at the level of CNS circuitry, so that answers to the second question can be generated.


These questions are not merely of interest to the basic scientist, but are relevant to the development of approaches to the clinical management of pain. Are there clinical pain conditions that arise from activity in subsets of nociceptors, and if so, can drugs be developed to block selectively the contribution of those afferents? For example, TRPV1 is generally associated with noxious heat transduction and heat hypersensitivity, but clearly that is not its function in a visceral afferent that innervates the pancreas. Thus, a drug that blocks TRPV1-expressing afferents selectively may have great utility, beyond regulating heat-pain sensibility (which is clearly not a major clinical concern).


The question of specificity is also relevant to ablative procedures. Because attempts in animals are now made to ablate chemically subsets of spinal cord neurons (e.g., with substance P-conjugated to saporin; Nichols et al., 1999), the controversy, unquestionably, has significant clinical implications. Does the preclinical development of these techniques mean that we are poised to go beyond what Pat Wall, as noted above, referred to as "ineffective, often counterproductive, surgical attempts to destroy the cells or their axons" (epitomized by anterolateral cordotomy), or are the new approaches built upon a misunderstanding of the way pain is generated? Should we be concerned that reducing information flow in a specificity-based "pain transmission network" can contribute to the development of central pain syndromes (as can occur post-stroke)?


Finally, and very importantly, this author certainly appreciates that this contemporary perspective on the question of specificity versus patterning relates more to the processing of nociceptive messages, and much less so to the sensory experience/perception of pain. The latter is clearly influenced and in some cases dominated by emotional and cognitive factors. To what extent specificity or patterning or some hybrid model integrates with these factors is not at all clear, and will not be determined by studies directed only at the primary afferent or spinal cord circuits. Studies that integrate an analysis of the pathways through which inputs are transmitted from the cord to the brain, with others directed at identifying where and how emotional/affective and cognitive factors are processed, will require combining psychophysical studies with novel imaging methods that can monitor the process of information transfer from the spinal cord to the brain.


Remember that the original discussion of specificity versus patterning was not a neurophysiological one. Rather, it was a perceptual one: How does the brain generate a pain percept? It is certainly possible that convergence of "specific" inputs at the level of the spinal cord or higher in the neuraxis generates an integrated pattern of activity that is read by the brain, the product of which is the ultimate percept.

References ...


Clifford Woolf , Children's Hospital Boston

Although many philosophical questions may ultimately be answered by neurobiology—the nature of self-knowledge and free will, for example—generally the two disciplines live in parallel separate universes. My first exposure in the late 1970s to the Specificity versus Pattern Theory debate, repeated endlessly over too many pints of ale at the Jeremy Bentham pub near University College London, was from Pat Wall. He was passionate in his hostility to Specificity, based I think on his philosophical certainty that the Pattern theory was much more intellectually challenging and interesting than "mere fixed telephone lines," and therefore it just had to be correct, a question of neuroaesthetics. However, in the end, facts are our currency and the accumulated data from the last 30 years demonstrate quite conclusively that at the primary afferent level, there is clear specificity. Sensory neuron subtypes display exquisite selectivity in deconvoluting the external work into defined neural representations by virtue of their specialized transduction processes, extracting information about particular aspects of the sensory environment, its intensity, nature, place, and time. Individual afferents capture enough information from defined stimuli to tempt us to conflate their firing patterns with the sensation generated, leading us into calling them warm, tickle, itch, or pain fibers. However, as Basbaum points out in describing his conversion from the Pattern Theory to the Specificity School, the way in which the CNS represents the sensory information at a systems level and the way in which it is read from neural circuitry as a sensation remains almost a closed book. Is the exquisite specificity engineered in the periphery maintained in the CNS, or is perception the consequence of an interrogation of complex multidimensional information across space and time, the translation of a pattern? Here, due to our lack of data, we can remain, for the moment, philosophical. However, the capacity to silence or activate designated subsets of central neurons, to record activity simultaneously from many neurons in vivo, and the new field of connectomics that will reveal the synaptic wiring diagram of the brain, means that it is only a matter of time before the answer will be revealed. Take your bets. I know mine.