Advancing Pain Therapies
Welcome and Opening Remarks
Nora D. Volkow, M.D., Pain Consortium Executive Committee Member and Director,
National Institute on Drug Abuse (NIDA)
Dr. Volkow described the goals of the National Institutes of Health (NIH) Pain Consortium, NIH pain research activities, and gaps in pain management research and education. The NIH Pain Consortium develops the NIH pain research agenda, pursues the research agenda through public–private partnerships, and increases the visibility of NIH pain research. NIH’s investment in chronic pain research grew by more than 50% between 2006 and 2011.
The Institute of Medicine (IOM) recently published a report, Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. In the report, the IOM offers a comprehensive plan to increase awareness about pain and its health consequences, improve pain assessment and management, and inform patients how to manage their pain. According to the report, 100 million Americans have chronic pain, with associated annual costs of $560–635 billion for medical care and decreased productivity. Up to 70% of patients with pain are not properly treated, and pain is becoming more common in the United States as a result of increased longevity, rising prevalence of obesity, and improved survival after trauma.
The number opioid prescriptions dispensed by U.S. retail pharmacies increased threefold in the last two decades. At the same time, the number of deaths from opioid overdoses has increased. According to the IOM report, improving pain treatment and minimizing opioid diversion requires improved education for primary care providers. The Pain Consortium has established the Centers of Excellence in Pain Education to help address this need.
Pain at a Crossroads: Challenges and Opportunities for Translating Knowledge into Practice
Roger B. Fillingim, Ph.D., President, American Pain Society
Dr. Fillingim discussed the current status of pain research and provided an update on some of the research, education, clinical, and advocacy activities of the American Pain Society (APS). At a time when record numbers of people are suffering from pain and current pain treatments provide adequate outcomes in only a minority of patients, pain research is at a crossroads. Experts know a great deal about nociception and are learning more about pain, but translating this knowledge into practice is still challenging. Advancing this translational process will require basic and clinical research as well as new approaches to education, clinical service, and public policy.
APS offers research grants for junior investigators and travel awards for the society’s annual meeting, and the society is analyzing NIH pain research funding. APS education and clinical practice activities include a pain management course for residents and fellows, a “Clinical Centers of Excellence” program, and the development of clinical practice guidelines. APS’s advocacy activities focus on increasing and improving pain research to identify best practices, disseminating these practices, and ensuring that all patients have access to the best pain care.
Novel Approaches in Opioid Analgesic Development and Use
Moderator: David Thomas, Ph.D., NIDA
Progress and Hurdles in Development and Use of Emerging Opioid Therapies and Therapeutic Strategies
Lynn R. Webster, M.D., Lifetree Clinical Research
Dr. Webster reviewed the evidence on opioid efficacy and effectiveness, progress in emerging opioid therapies, and challenges in the field.
Few long-term studies have examined opioid efficacy or effectiveness, and the existing evidence of long-term efficacy is weak. Growing evidence suggests that people with different genetic makeups respond differently to different opioids. This variation might explain why some, but not all, patients who develop tolerance to a given opioid respond well to a different opioid.
Concerns about opioids include opioid-related sleep apnea, the declining difference between the intoxicating dose and the lethal dose over time, and the increasing number of opioid-related suicide attempts. Opioids lead to the release of dopamine, which is one reason why many people abuse these medications. New analgesics should bypass the dopamine release system. Several studies have been designed to develop drugs that are more difficult to abuse, but different approaches are needed for medical and non-medical opioid users. The ideal opioid would be more effective than current opioids without causing respiratory depression, euphoria, abstinence syndrome, craving, tolerance, hyperalgesia, or endocrine effects.
Development of New Approaches to Pain
Victor J. Hruby, Ph.D., University of Arizona
Extensive research has shown that chronic pain and repeated use of opiates cause abnormal neural adaptations, but most analgesics are designed to modulate normal physiological states. Drugs designed for chronic pain states therefore should take advantage of these neural changes to provide better pain relief. His group is using the approach of drug design for disease that accounts for this altered neural function. Dr. Hruby discussed the therapeutic potential of multivalent ligands with combined mu-delta opioid agonist activity and neurokinin (NK)-1 antagonist activity for pain treatment. The combination would target the amplification of pain signaling in the nervous system and the changes caused by prolonged analgesic administration.
One such novel combination drug that his group is developing is called TY027, which would avoid some of the problems with current opioids. It has a bi-functional peptide ligand with mu and delta opioid agonist activity and an NK-1 receptor antagonist. TY027 produces similar analgesia to morphine in rat and mouse models of acute pain, is effective in neuropathic pain states, and maintains efficacy following its administration for up to 2 weeks. Unlike morphine, TY027 does not cause motor impairment, place preference, ie development of addiction, tolerance, or undesirable gastrointestinal effects. Multivalent ligands like TY027 with potent mu-delta agonist activity and NK-1 antagonist activity are potential analgesics in neuropathic and other prolonged pain states that are refractory to current pain relievers without the serious toxicities, tolerance, or addiction associated with opioids. TY027 shows great promise for treating prolonged and neuropathic pain states for which no good treatments exist.
Targeted Drug Delivery by Gene Transfer for the Treatment of Intractable Pain
David J. Fink, M.D., University of Michigan
Dr. Fink presented human and animal data on the use of a herpes simplex virus (HSV) to deliver genes into spinal dorsal root ganglion (DRG) neurons, which are cells in the pain signaling pathways, as a means to increase production of inhibitory neurotransmitters and reduce pain.
His group has developed a strategy to treat focal pain by delivering the gene for preproenkephalin into DRG neurons. The gene’s effect is to enhance the production and release of enkephalin, a naturally produced inhibitory neurotransmitter, in axon terminals in the spinal cord. The gene transfer vector, HSV, is naturally neurotropic, but the danger of infection is eliminated because selective deletion of an essential early gene from the parental virus destroys its ability to replicate. The delivery of the enkephalin-expressing HSV vector enhances production of enkephalin in DRG neurons. Enkephalin is then released from transfected DRG neurons and produces an analgesic effect by inhibiting pain signaling. Its efficacy was first shown in animal models of inflammatory pain. More recently, a Phase 1 clinical trial in which NP2, an HSV vector coding for preproenkephalin, was delivered to 10 patients with intractable cancer pain found that pain in the highest and middle dose groups dropped dramatically. This reduction persisted for 28 days after one injection. None of the patients had agent-related serious adverse events. A Phase 2 study of NP2 is currently ongoing.
To treat neuropathic pain, Dr. Fink constructed an HSV vector to express glutamic acid decarboxylase (GAD), the enzyme responsible for converting glutamate to GABA, also an inhibitory neurotransmitter involved in pain signaling. An injection of this vector into an animal’s foot leads to the transport of GAD to the afferent terminals in the spinal cord, GABA release, and GAD production in the DRG. GABA release by the vector reduces pain-related behavior in the spinal nerve ligation model of neuropathic pain and reverses pain-related behaviors in the STZ-diabetic rodent model of painful diabetic neuropathy.
Behavioral Therapies as Adjuncts to Treatment for Pain and Opioid Dependence
Richard Schottenfeld, M.D., Yale University
Dr. Schottenfeld described the use of cognitive-behavioral therapy (CBT) in patients with co-occurring chronic pain and opioid dependence that was being addressed with methadone or buprenorphine maintenance treatment. Patients with pain and opioid dependence are difficult to treat in physician offices because of lack of resources and physician training. Dr. Schottenfeld is looking into feasibility, acceptance, and efficacy of modules of CBT as a way to offer patients programs that can be delivered to help manage their pain in office settings.
He assessed several components of CBT including education, catastrophizing and coping skills training, activity-directed goal setting, relaxation training, and engaging in a pleasurable activity- singing -amongst groups of patients with chronic pain and who were enrolled in a methadone maintenance treatment (MMT) program for opioid dependence. Those in the CBT group noted a decrease in pain intensity, but not pain-related disability, after the first and second CBT sessions. The sessions’ patient acceptability levels were good. Those in the relaxation training group noted a decline in state-related anxiety and an increase in engaging in relaxing activities outside of the group after the first and second relaxation sessions. Acceptability ratings also were good for these sessions. In the singing groups, negative mood states decreased and positive mood states were reported immediately after the sessions. This provided encouragement for patients to engage in pleasurable activities. Dr. Schottenfeld plans to evaluate the efficacy and acceptability of these and other group treatments including yoga and walking meditation for patients with chronic pain and opioid dependence. They will also assess the feasibility of developing such group programs in a physician office setting.
In a pilot randomized controlled trial, patients with chronic pain and opioid dependence who were enrolled in buprenorphine maintenance office treatment programs were randomly assigned to 10 sessions of standard physician management (PM) only, PM and educational counseling for pain and opioid dependence, or PM and CBT. The 23 patients in the CBT or educational counseling arms attended 7 sessions, on average, and gave high satisfaction ratings for the program. The preliminary data suggest that retention rate and acceptance levels are high and that these programs are feasible for an office setting with a nurse provider. Further evaluation is ongoing to determine comparative efficacy of the programs.
Questions and Answers
A participant requested clarification on the HSV vector that Dr. Fink constructed to deliver gene therapy. Dr. Fink explained that this viral vector is non-replicating. Furthermore, in preproenkephalin studies, the vector was blocked by intrathecal administration of naltrexone, providing pharmacologic evidence that the gene product delivered by the vector is transported to the nerve terminal and released. The gene used to express enkephalin is a precursor gene that is probably packaged and cleaved by naturally occurring mechanisms present in all neurons, and the release of enkephalin is likely to be vesicular. Furthermore, in vitro and in vivo studies show that the GAD-expressing vector releases GABA inside the cytoplasm by reversing the direction of the GABA transporter that normally brings GABA into the cell.
A participant asked whether HSV vector injections release the vector into one or several DRGs. Dr. Fink explained the vector targets only the DRGs whose axons innervate the area in which the vector is injected. In response to a question about the use of the HSV vector in patients with a prior HSV infection. Dr. Fink replied that the vector can be used in patients with a previous HSV infection because the virus in the vector is non-replicating and therefore cannot re-infect the recipient.
A participant asked about the extent to which the efficacy of the hybrid molecules that Dr. Hruby described depends on the co-expression and dimerization of the two target receptors. Dr. Hruby replied that every treatment that affects the central nervous system probably leads to changes in the expressed genome. Research needs to evaluate these changes and their impact on treatments.
A participant commented that many provider settings might not have enough patients with opioid dependence and chronic pain to offer regular group treatments. Dr. Schottenfeld explained that group CBT programs are appropriate for MMT programs, which typically offer group programs and have many patients with both pain and chronic opioid dependence. These treatments might be feasible in other settings with many patients with co-occurring conditions. Dr. Schottenfeld is developing a CBT model for physician offices, using a nurse educator to counsel and follow patients.
Moderator: Patricia A. Grady, Ph.D., R.N., FAAN, Director, National Institute of Nursing Research
Dr. Grady introduced the junior investigators whose posters presented at the symposium were selected as the top three.
Amygdala‐Mediated Mechanisms Underlying Stress‐Induced Visceral Pain
Anthony C. Johnson, The University of Oklahoma Health Sciences Center
Mr. Johnson described an animal model of stress-induced pain to study potential brain mechanisms responsible for the symptoms of irritable bowel syndrome (IBS). His hypothesis was that stress induces visceral pain through glucocorticoid receptor regulation of cortico-trophin releasing factor in the central nucleus of the amygdala. Male Fischer rats exposed to 7 days of water avoidance stress had a significantly higher anxiety index score (based on several behaviors in the open field) than rats exposed to sham stress. Repeated stress also significantly decreased hind paw withdrawal threshold to Von Frey filament and increased hypersensitivity to bowel distension. Quantitative RT-PCR data on tissue samples from the central nucleus of the amygdala showed significant decreases in glucocorticoid receptor expression and increases in corticotropin-releasing factor expression 24 hours after the stress protocol. These animal studies demonstrated that abnormal activity in the central nucleus of the amygdala is modulated by repeated stress decreases glucocorticoid receptor expression, causing an increase in corticotropin-releasing factor and the associated development of key IBS sequelae; anxiety-like behavior, somatic sensitivity, and visceral pain.
Development of Novel Positive Allosteric Modulators of TRPV1 as Potential Analgesic Agents
Krisztian Kaszas, Ph.D., National Institute for Dental and Craniofacial Research (NIDCR)
The transient receptor potential cation channel subfamily V member 1 (TRPV1), is a multimodal, non-selective cation channel that initiates or modulates neuropathic and inflammatory nociceptive signals. Full-scale blockade of TRPV1 function suppresses the ability to sense noxious heat. Inhibition of TRPV1 therefore, should be a potent method to induce analgesia, but systemic delivery of orthosteric antagonists have problematic side effects that limit their use. Dr. Kaszas described efforts to develop a positive allosteric modulator (PAM) of TRPV1, which could avoid these side effects by blocking pain signals in a state-dependent fashion at only TRPV1 activated sites.
MRS1477, a TRPV1 PAM, enhances capsaicin and proton activation of TRPV1. Co-injection of capsaicin to activate the TRPV1 sites and MRS1477 to subsequently block nociceptive transmission, into rat hind paws resulted in a marked increase in withdrawal latency in response to a ramp-style heat stimulation, activating TRPV1-positive fibers. These combined injections can induce analgesia to painful heat for several days. These results, combined with RT-PCR findings from studies with NPT-32, a compound with even more PAM activity than MRS1477, showed that combining a TRPV1 PAM and a TRPV1 agonist results in local ablation of TRPV1-positive nerve endings and therefore, may be a viable approach to inducing local analgesia.
Dissociable Effects of the Cannabinoid Receptor Agonists Δ9‐tetrahydrocannabinol and CP55940 on Pain‐stimulated and Pain‐depressed Behavior in Rats
Andrew J. Kwilasz, Virginia Commonwealth University
Mr. Kwilasz reported on an assay of pain-depressed behavior that might be useful for developing candidate cannabinoid analgesics. In a preclinical study, ketoprofen (used as a positive control), Δ9‐tetrahydrocannabinol (THC), and CP55940 (a synthetic THC) produced dose-dependent antinociceptive effects on visceral pain from acid-stimulated stretching induced by peritoneal administration of lactic acid. However, clinical research has found only limited evidence of cannabinoid efficacy for acute pain.
Preclinical assays of pain-depressed behavior do not yield false-positive results with motor depressants and are used in clinical and veterinary medicine to diagnose pain. The rate, frequency, or intensity of ongoing behaviors, such as intracranial self-stimulation (ICSS), decreases in the presence of noxious stimuli. In a rat study, ketoprofen blocked lactic acid-stimulated ICSS and lactic acid-depressed ICSS. Low doses of THC or CP55940 had no effect on acid-induced ICSS depression, but high doses exacerbated this effect.
Questions and Answers
A participant commented that mechanical hypersensitivity is a more common clinical problem than thermal hypersensitivity. Dr. Kaszas explained that the selective activation of TRPV1-positive neurons does not affect mechanical hypersensitivity. His studies focus on thermal hypersensitivity to enable the examination of selective A-delta and C-fiber responses.
A participant asked for clarification on plans to develop PAMs as analgesic treatments. Dr. Kaszas explained that because PAMs have activity only at sites with TRPV1 activity, they could be delivered orally. Based on evidence showing that TRPV1 activity is low after PAM administration, PAMs are unlikely to have major central effects.
A participant asked Mr. Kwilasz about the implications of his data showing that cannabinoids do not reverse pain-suppressive behaviors, given the substantial data suggesting that these compounds are effective analgesics. Mr. Kwilasz explained that in the clinical literature, cannabinoids are not very effective for acute pain. Furthermore, all of the clinically effective analgesics that he has tested are effective in his preclinical assay and all of the agents known to be clinically ineffective are ineffective in his assay.
A participant wondered why rats did not modulate their pain states by increasing lever pressing. Mr. Kwilasz replied that noxious stimuli seem to depress mesolimbic dopamine, and the ability to restore mesolimbic dopamine might explain some of the therapeutic benefit of cannabinoids.
Novel Approaches in Nonopioid Analgesic Development and Use
Moderator: John Kusiak, Ph.D., NIDCR
Progress and Hurdles in Development and Use of Emerging Therapies and Therapeutic Strategies
Frank Porreca, Ph.D., University of Arizona
Dr. Porreca discussed some of the reasons why progress in developing effective analgesics has been limited and described some promising approaches to pain treatment. Translation of basic research into the clinic faces many hurdles. For example, we don’t fully understand the mechanisms of pain, nor do we know the mechanisms or sites of action for many current or new drugs, and we don’t know the best clinical trial designs for analgesics, including how to identify patients that may respond to a particular drug for the clinical studies. It is difficult therefore, to develop and validate assays and design trials that accurately test efficacy of new analgesics.
Furthermore, drugs that work in animal models, often are ineffective in relieving pain in humans. We are not very good at measuring spontaneous or ongoing pain in preclinical studies, which typically measure the effects of a drug using a behavioral response to a painful evoked stimulus. However, clinical studies do not evoke pain in humans, but rather measure spontaneous pain using different assessment tools (such as self- reports to questions about pain intensity) than in preclinical studies. Dr. Porreca has shown that measuring motivational drive to seek relief from the adversive stimulus of pain may provide a good means to identify and study spontaneous pain mechanisms and drug efficacy in animals. They measured negative reinforcement behavior with a conditioned place preference paradigm. They let animals move through each of three chambers for three days. They paired one chamber with administration of a test drug. Sham animals and animals with spinal nerve ligation injury were given a pain-alleviating drug in that chamber. The sham animals spent equal amounts of time in all three chambers. The injured animals however, spent more time in the chamber where they received the pain-relieving drug, because they associated the chamber with pain relief, an easy behavior to quantify. This study showed that peripheral nerve injury elicits a tonic aversive stimulus (i.e., spontaneous pain), and that measuring the behavior provided a simple way to quantify the analgesic/rewarding effects of the drugs.
Many drugs have multiple mechanisms of action and our screening assays for novel analgesics focus on single sites of actions. Drugs that might be effective therefore because they are multipurpose, often do not make it past the early screening assays. Drug development research has focused on antagonists, which typically require high doses that yield unwanted effects. A better approach might be to combine several selective but additive actions in one or more molecules, such as Tapentadol (Nucynta®), a mu opioid agonist and norepinephrine reuptake inhibitor. To develop new and effective drugs, we have to understand mechanisms, develop better screening and behavioral assays and bring clinical findings on effective drugs back to the research bench.
Novel Therapeutic Targets: Endonucleotidases and Adenosine Agonists
Mark J. Zylka, Ph.D., University of North Carolina at Chapel Hill
Dr. Zylka described his preclinical research on two enzymes, prostatic acid phosphatase (PAP) and ecto-5'-nucleotidase (NT5E), as novel therapeutics for pain treatment.
A transmembrane isoform of PAP is expressed in pain-sensing neurons. To determine PAP’s physiological function in nociception, Dr. Zylka examined withdrawal sensitivity in animals subjected to a noxious thermal stimulus following one intrathecal injection of PAP. Withdrawal latency increased, indicating an analgesic effect, after a single injection and stayed high for 3 days. He then explored the mechanism by which PAP induces its anti-nociceptive effects. In vivo and in vitrostudies showed that PAP dephosphorylates adenosine 5'-monophosphate, leading to the formation of the inhibitory molecule adenosine, which is known to inhibit pain signaling.
Inserting acupuncture needles into rodents is relieves pain, but these effects do not last long. If the adenosine receptor is A1inactivated, then the nociceptive effects of acupuncture are lost, indicating that the effect is mediated by engaging the receptor. Zylka hypothesized that because PAP forms adenosine, it might be an effective analgesic when delivered peripherally. Injecting PAP into an acupuncture point in the back of the knee (popliteal fossa, where two main branches of the sciatic nerve are located) in animals produces does dependent analgesia. The antinociceptive effects of a single high-dose injection last at least 100 times longer than standard acupuncture. PAP injections also had antinociceptive effects in chronic pain neuropathic pain models.
Both PAP and NT5E are extensively co-localized in small-diameter DRG neurons, suggesting that these pain-sensing neurons express high concentrations of at least two enzymes that make adenosine. Injections of NT5E, like PAP, have long-lasting antinociceptive effects. Knocking out PAP or NT5E reduces but does not eliminate the ability to make adenosine, but knocking out both enzymes does eliminate this ability. It seemed that these two enzymes were responsible for the production of adenosine. Further studies however, revealed that at least one other enzyme makes adenosine. They are continuing studies to explore the analgesic potential of these enzymes.
A One‐Time Permanent Elimination of Cancer Pain?
Douglas A. Lappi, Ph.D., Advanced Targeting Systems, Inc.
Dr. Lappi discussed the results of preclinical studies of a conjugate of substance P and saporin (SAP) to treat cancer pain and plans for clinical trials to test this compound in humans. Saporin is a protein that inactivates ribosomes and subsequent protein synthesis and thereby, destroys cells. It must enter cells to induce this process, but cannot enter cells on its own. Substance P however, can deliver saporin into cells. When saporin is attached to substance P, which is internalized when it binds to its receptor, the combined molecule is carried into the cell. The SAP component then destroys the neuron. The substance-SAP molecule can act therefore, only on cells that have substance P receptors. Few neurons in the spinal cord express this receptor and those that do are involved in pain signaling. Targeting neurons with these receptors provides a mean to selectively eliminate pain sensing neurons without harming others. Substance P-SAP, administered intrathecally, has long-lasting analgesic effects in several chronic pain models. It acts by preventing central sensitization, and has no effect on acute pain perception. Even after 200 days, Substance P-SAP continues to have anti-hyperalgesic effects. Toxicology studies have now been completed in rats and dogs, and veterinary use on companion animals appears to show efficacy. A clinical trial is being planned to evaluate Substance P-SAP use for cancer pain.
AV-101 (L-5-Clorokynurenine): A Prodrug for Treating Pain
Ralph Snodgrass, Ph.D., VistaGen Therapeutics, Inc.
Dr. Snodgrass described research on AV-101, a prodrug, for the treatment of neuropathic pain.
N-methyl-D-aspartate (NMDA) receptors play an essential role in inducing the synaptic plasticity in sensory pathways, which is associated with neuropathic pain. Conventional drugs that block NMDA receptor activation are effective in models of neuropathic pain. However, many NMDA antagonists such as kinerinic acid, which is produced primarily in astrocytes and activates glycineB and nicotinic receptors, have severe side effects and may not be permeable to the blood brain barrier. A screening project revealed a molecule produced by adding chlorine to kinerinin, named AV-101which targets the same molecular pathway as kinerinic acid, has fewer side effects, and is permeable to the blood brain barrier. It has greater promise therefore, as an effective drug. In astrocytes, the inactive prodrug AV-101 is converted into an active metabolite, 7-chlorokynurenic acid that is a very potent NMDA glycineB-site antagonist and its by-products inhibit overproduction of quinolinic acid production.
AV-101 blocks thermal hyperalgesia in a carrageenan model and blocks Phases I and II in the formalin model of pain. AV-101 has similar effectiveness to gabapentin for blocking pain in these inflammatory pain models as well as in neuropathic pain. 14-day full safety pharmacology studies safety studies have shown that AV-101 is safe in rats and dogs and has excellent bioavailability. A Phase Ia randomized, double-blind, placebo-controlled, single-dose study in humans found that AV-101 was well tolerated, had excellent bioavailability, and did not cause any serious adverse events. A Phase Ib study is ongoing to assess safety and tolerability, determine the minimal intolerable dose, and evaluate efficacy in capsaicin-induced hyperalgesia of repeated oral doses of AV-101 for up to 14 days. Phase II studies are currently being planned of AV-101 in neuropathic pain and depression.
Questions and Answers
A participant asked whether animals trained to prefer a low dose of morphine before experiencing pain would seek the chamber where they received the morphine after experiencing pain. Dr. Porreca said that in his studies, place preference only occurs when pain is present.
A participant wondered whether chronic pain models exist in which pain can be easily turned on and off to train the animals to indicate whether they are in pain or not. Dr. Porreca said that an animal model has been developed in which animals with strong, ongoing pain work for spinal administration of pain-relieving drugs. However, developing a self-administration model is difficult.
A participant asked how long a drug must provide an analgesic effect for an animal to learn to prefer the chamber in which it receives the drug. Dr. Porreca said that animals learn to prefer a chamber after a single administration of a drug. The animals need to form an association between the context and pain relief, so systematic administration does not lead to place preference.
A participant emphasized the importance of reflexive models and the need to study both evoked and spontaneous pain. Dr. Porreca said that reflexive models have been useful for determining whether compounds block the transmission of pain signals. However, the information from these models must be linked to the outcomes that need to be measured in an appropriate patient group.
A participant asked whether Dr. Porreca’s model reflects the experience of spontaneous pain and suggested that animals might prefer the chamber where they receive a drug because the drug relieves evoked pain. Dr. Porreca said that if animals’ hind paws are denervated, the animals no longer experience evoked pain but they still have a strong motivation to seek the place where they experienced pain relief. When the cingulate cortex is lesioned, animals do not have the motivation to seek the context paired with pain relief. Thus, Dr. Porreca’s model captures pain that is not related to evoked responses.
A participant suggested that Substance P-SAP might affect more than just a few neurons, and the compound might alter important spinal networks. Dr. Lappi agreed, adding that clinical trials will confirm the effects of SP-SAP on neurons. A participant asked whether the Substance P-SAP proteins remain where they were infused after 200 days of treatment. Dr. Lappi replied that macrophages digest all of the dead cells, eliminating the metabolites. A participant commented that interspecies differences in the molecular components of nociceptive processing circuits might limit the relevance of animal studies of Substance P-SAP to humans. Dr. Lappi replied that this is why the Food and Drug Administration wants studies to be conducted in two species.
In response to a question about the effects of PAP and NT5E on neurons, Dr. Zylka explained that PAP is expressed in pain-sensing neurons and in the prostate and some other tissue types, whereas NT5E is broadly expressed. When used as drugs and injected locally, these enzymes can activate adenosine receptors locally for extended periods.
A participant wondered about the implications of caffeine’s surprising lack of effects on pain pathways. Dr. Zylka said that researchers do not know why drinking coffee does not block pain receptors. In animal studies, low doses of caffeine have no effect, and perhaps coffee does not have enough caffeine to affect pain.
Dr. Zylka responded to a question about the acidity of NT5E and PAP by explaining that these enzymes are known as acid phosphatases because of their biochemical properties, but both of these enzymes function well at a neutral or basal pH.
A participant asked whether double-knockout animals exhibit the hyperalgesic phenotype. Dr. Zylka replied affirmatively but added that nerve impulses can take time to evoke a withdrawal response.
2012 Mitchell Max Best Poster Award
Martha J. Somerman, D.D.S., Ph.D., Director, NIDCR
Dr. Somerman presented the 2012 Mitchell Max Best Poster Award to Anthony Johnson, a doctoral candidate at the University of Oklahoma Health Science Center.
Development and Use of Nonpharmacological Strategies: Important Adjuncts to Pain Management
Moderator: Partap Khalsa, Ph.D., National Center for Complementary and Alternative Medicine (NCCAM)
CAM Therapies for Pain: Background and Hurdles
M. Catherine Bushnell, Ph.D., McGill University
Dr. Bushnell described research on the activation of descending modulatory pathways to modulate pain by complementary and alternative medicine (CAM) treatments that alter psychological states.
Distraction modulates perceived pain intensity but has little or no effect on the unpleasantness of pain, whereas changes in emotional state affect pain unpleasantness but not intensity. Evoked pain during attention or distraction modulates the primary somatosensory cortex, whereas mood alters pain-evoked activity in limbic brain regions, especially the anterior cingulate cortex. Thus, the psychological modulation of pain has a physiological basis.
Different types of hypnotic suggestions increase or decrease reported pain intensity and unpleasantness, and these effects are reflected in the brain. Meditation consistently alters pain perception by decoupling pain processing with executive control. Similarly, people who practice yoga have much higher pain tolerance than matched controls, and cognitive behavioral therapy (CBT) alters the pain experience, pain behaviors, and physical and emotional functioning.
Deep brain stimulation and acupuncture can have a strong placebo effect. Although acupuncture has a profound effect on pain perception, sham acupuncture or the insertion of acupuncture needles at non-acupuncture sites has a similar effect. Patient expectations can also influence the effects of acupuncture. Imaging shows that placebo analgesia affects pain circuitry in the brain. This placebo phenomenon must be considered in studies of all types of pain treatments.
CAM Therapies for Chronic Nonspecific Back Pain
Daniel Cherkin, Ph.D., Group Health Research Institute
Dr. Cherkin summarized studies of acupuncture, massage, and yoga to treat chronic nonspecific back pain. These studies contributed to the 2007 guidelines of the American College of Physicians and American Pain Society, which recommend several nonpharmacological therapies.
A randomized trial compared 10 treatments of acupuncture, simulated acupuncture, and usual care over 7 weeks for chronic low back pain found that individualized acupuncture (based on a customized prescription for acupuncture points), standardized acupuncture (regarded as effective by experts in chronic low back pain), and sham acupuncture. Individualized and standardized acupuncture had virtually identical results at all time points and were substantially more effective than usual care.
In a another study, relaxation massage and structural massage (which focuses on tissues related to pain) had virtually identical effects on back pain and both types of massage has better results than usual care. A comparison of 12 weeks of yoga, stretching, and a self-care book found that yoga and stretching had similar outcomes, and both were more effective than usual care.
Challenges in Implementing Mind‐Body Interventions for Pain Management in Older Adults with Chronic Low-Back Pain
Natalia E. Morone, M.D., M.S., University of Pittsburgh
Dr. Morone described a pilot study of mindfulness meditation to treat back pain in older adults and her plans for a randomized controlled clinical trial of this treatment. In mindfulness meditation, patients bring nonjudgmental moment-to-moment awareness to thoughts, sensations, and emotions as they arise.
A pilot study randomly assigned community-dwelling older adults with chronic low back pain to a weeklong mindfulness meditation program or a wait-list control group. People in the control group received the intervention after the intervention group. The mindfulness meditation included walking and sitting meditation, as well as body scans in which patients focus sequentially on feelings in different parts of the body. The mindfulness meditation group had better disability and chronic pain acceptance outcomes than the control group, and these effects were still evident after 3 months. A qualitative analysis of diaries kept by patients in the pilot study found that the intervention distracted patients from their pain, led to behavior change by heightening awareness of pain sensations, helped patients understand maladaptive coping strategies for pain, and directly eliminated pain.
Dr. Morone is recruiting patients for a randomized, controlled trial of mindfulness meditation in older adults with chronic back pain. A placebo group is not possible for a group mind-body meditation intervention, so Dr. Morone is controlling for as many characteristics as possible, including time and attention, group setting, and contacts with teachers or instructors. Adults assigned to the comparison group will participate in a healthy aging education program that does not provide education on managing pain. In addition to using standardized measures of pain and physical and psychological function, Dr. Morone plans to use focus groups to capture nonspecific and unanticipated effects.
Tailored Cognitive Behavioral and Massage Therapies for Chronic Pain
Diana J. Wilkie, Ph.D., R.N., FAAN, University of Illinois at Chicago
Dr. Wilkie summarized findings from randomized clinical trials of tailored patient education programs and massage therapy for pain in patients with cancer.
A randomized clinical trial compared the effects of PAINRelieveIt, a computerized patient education program, to usual care in 168 patients with cancer. Patients used a touch-screen device to report the characteristics of their pain, use of pain medications, and barriers to pain management. Based on patient responses, patients received tailored, multimedia education focused on pain management barriers (such as misconceptions about pain medications) and providers received computer-generated decision support, including suggestions for analgesics tailored to the patient’s pain. PAINRelieveIt significantly decreased average pain intensity compared to usual care. Further analyses will address the mechanisms underlying this effect.
A second randomized controlled trial compared the effects of five daily massages for 1 week to usual care in 161 patients with cancer undergoing hospice or palliative care. A licensed massage therapist delivered 60-minute full-body massages using a standardized protocol. ANCOVA analysis results controlling for pretest values, age, gender, and education found that worst pain was significantly lower in the massage group than the usual care group at post-test, but other variables (pain now, symptom distress, and mood state) did not differ significantly between groups.
Questions and Answers
A participant asked about distinguishing specific from nonspecific effects in clinical trials of pain therapies that rely on endogenous pain-regulatory systems. Dr. Bushnell said that identifying the most important effects of pain therapies is useful. Many experts believe that the effects of treatments that alter psychological states extend beyond their changes in mood, expectation, and the other factors that studies typically measure. For example, although Dr. Bushnell’s study showed that stretching was as effective as yoga for pain, this study might not have captured the effects of yoga’s meditative component. Sensitive measures are needed to identify all of these effects, including brain-imaging studies to determine which circuits are engaged. Clinical evidence shows that yoga, acupuncture, and other CAM treatments are effective for pain, but the mechanisms of these treatments still need to be understood.
A participant commented that the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM V) will include a category of complex somatic symptom disorder that appears to be catchall for chronic pain disorders. This category could imply that pain is due to mental illness if no physical explanation can be found and might result in stigmatization of chronic pain. Dr. Bushnell said that she hoped that in its pain categorizations, DSM V would reflect the brain changes that have been shown to occur with many pain conditions. Dr. Wilkie added that emotions have effects not only in the brain but also in the peripheral nervous system.
A participant commented that many of the CAM therapies discussed at this meeting lead to reductions in sympathetic nervous system activity. Perhaps different CAM therapies share a physiological mechanism involving the autonomic nervous system. Dr. Bushnell said that the autonomic nervous system creates a peripheral environment that alters pain processes, and more research needs to focus on autonomic responses to pain.
A participant said that many patients with complex persistent pain conditions have more than one type of pain and wondered whether brain imaging studies show different patterns for different chronic pain states. Dr. Bushnell replied that Vania Apkarian of Northwestern University has shown that back pain and other pain syndromes have unique brain patterns. Another useful approach is to identify anatomical changes associated with symptoms, regardless of diagnosis.
A participant asked whether CAM therapies affect the same sites on descending pathways and whether naloxone can block their effects. Dr. Bushnell said that the limited brain imaging data indicate that different CAM therapies engage different mechanisms. She does not believe that any research has examined the ability of naloxone to block the effects of yoga or meditation.
A patient advocate commented on the importance of determining the mechanisms that underlie CAM treatments for pain. Because many CAM treatments are not covered by health insurance, knowing which pain treatment is most likely to be helpful is critical. Dr. Cherkin agreed, noting basic and clinical scientific research results will strengthen efforts to improve pain care and help millions of people who are currently confused about how to address their problems.
A participant wondered whether differences in pain intensity at baseline and compliance with analgesics in the massage and control groups might explain the differences between the two groups in Dr. Wilkie’s clinical trial. Dr. Wilkie explained that pain intensity was higher in the massage group at baseline, and ANCOVA makes it possible to control these types of differences in baseline characteristics.
In response to a question about the duration of effects from massage, Dr. Wilkie explained that these effects lasted less than 24 hours after the last massage. Patients loved the massages and the study might not have measured the right variables.
Update on the Patient Protection and Affordable Care Act and Closing Remarks
Josephine P. Briggs, M.D., Director, NCCAM
Dr. Briggs provided updates on NIH activities resulting from the Patient Protection and Affordable Care Act of 2010 and a summary of the presentations and discussions at this symposium.
The Affordable Care Act tasked the Department of Health and Human Services with establishing the Interagency Pain Research Coordinating Committee to coordinate pain-related activities at all federal agencies. It also called on the Department to convene an IOM conference on pain. In response to the IOM’s recommendations in the report that resulted from this conference, Relieving Pain in America, the NIH designated the National Institute of Neurological Disorders and Stroke to serve as the lead NIH institute for the agency’s pain research efforts. NIH is coordinating efforts to improve regulatory science and drug development through the NIH-FDA Leadership Council, supporting interdisciplinary pain research and longitudinal studies of chronic pain conditions, encouraging health professional schools to develop Centers of Excellence in Pain Education, and sponsoring many training opportunities. NCCAM is leading the Research Task Force on Research Standards for Chronic Low Back pain and is establishing an intramural basic and clinical research program on pain mechanisms and management.
Many presenters at this symposium acknowledged the large gap between the goals of pain management and the current reality. Wonderful advances have been made in understanding the pathways of nociception and the downward modulation of pain. However, progress in pain management and care has been modest and many problems associated with pain management, such as misuse of opioids and high costs, persist. Experts at the symposium had discussed the ways in which new knowledge about pain pathways is being exploited to develop some exciting new therapeutic agents. The final presentations had shown the importance of CAM strategies to modulate the suffering, disability, and perhaps even nociception associated with pain. Many of the effects of CAM therapies are modest and researchers have not identified the best ways to study these treatments or to determine which treatments work best for which patients.
Dr. Briggs thanked the Pain Consortium members and program officers who organized the symposium. She also thanked participants for their time and participation in the discussions.