This is the first of a two-part report on selected talks from the NIH Pain Consortium’s 7th Annual Symposium on Advances in Pain Research, and from an FDA CDER public scientific workshop held in conjunction with the symposium. See also Part 2.
More than 100 million people in the United States alone suffer from chronic pain, yet physicians often have little to offer their patients in the way of treatment. New pharmacological approaches—both opioid and non-opioid—as well as non-drug strategies to satisfy the unmet need for better pain therapies were the focus of the US National Institutes of Health (NIH) Pain Consortium’s 7th Annual Symposium on Advances in Pain Research, which took place 29-30 May 2012 at the NIH campus in Bethesda, Maryland.
The Pain Consortium was established in 1996 to help advance a long-term pain research agenda across the NIH, and organizes an annual symposium on chronic pain. This year, the symposium was followed on 30-31 May by Assessment of Analgesic Treatment of Chronic Pain, a public scientific workshop sponsored by the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER).
NIH Pain Consortium: New Paths to Better Opioid Analgesics...
Opioids relieve pain in only about one-quarter of chronic pain patients, and often cause adverse effects including respiratory depression, tolerance, and addiction. Victor Hruby, University of Arizona, Tucson, US, described his efforts to develop bifunctional peptides that act at two biological targets to produce potent opioid analgesia. The rationale behind such ligands is that, compared to co-administration of two drugs, single molecules may be easier to administer; reach higher local concentrations near the synaptic cleft; and have strong biological activity at lower doses, hopefully avoiding some of the unwelcome consequences of current opioids. Hruby focused on peptides with both mu (μ)/delta (δ) opioid receptor agonist and neurokinin-1 (NK-1) receptor antagonist activity (Yamamoto et al., 2007). In particular, he reviewed his unpublished data on one such bifunctional peptide, called TYO27, which showed an analgesic effect on a par with morphine, but without the latter’s impairment of motor function, in rodent models of acute pain. Designed to cross the blood-brain barrier, TYO27 also alleviated tactile and thermal allodynia in animal models of neuropathic pain following either central or systemic administration. In addition, TYO27 did not produce tolerance following central administration after two weeks, nor did it result in addiction, as indicated by a conditioned place preference model, in studies up to 10 days long. Hruby is testing whether the encouraging findings on addiction will apply to longer periods, and hopes to receive funding to move this preclinical work into humans.
While Hruby is working to create new ligands, David Fink, University of Michigan, Ann Arbor, US, is employing a gene therapy approach for delivering endogenous opioid peptides to treat cancer and focal neuropathic pain using the cold sore-causing herpes simplex virus (HSV) as a vector. The strategy takes advantage of HSV’s natural affinity for sensory neurons in the dorsal root ganglia (DRG), where it persists throughout life in a latent state. After injection into skin, the vector is taken up by sensory neurons and transported to the DRG. Fink’s group has already published promising results from a Phase 1 study testing an HSV vector bearing the gene for preproenkephalin, a precursor protein that is cleaved to generate the endogenous opioid peptides met- and leu-enkephalin, in patients with localized cancer pain (Fink et al., 2011), and they expect results this summer from a randomized, double-blind, placebo-controlled Phase 2 trial in 32 patients with cancer pain. Meanwhile, an HSV vector carrying the gene for glutamic acid decarboxylase (GAD), the enzyme that converts glutamate into the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and one carrying the gene for neurotrophin-3, are in preclinical development for neuropathic pain and chemotherapy-induced peripheral neuropathy, respectively. HSV vectors expressing neurotrophin genes are also in the prototype design or discovery phase, targeting diabetic neuropathy.
Richard Schottenfeld, Yale University, New Haven, Connecticut, US, also wants to improve the efficacy of opioids, but rather than tinkering with drug molecules, he aims to combine existing opioids with behavioral interventions. Specifically, his work integrates psychosocial pain management interventions with opioid agonist maintenance strategies including methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT), in patients with co-occurring chronic pain and opioid dependence (POD). Schottenfeld presented results from his own studies demonstrating the feasibility and acceptability of group cognitive behavioral therapy in POD patients receiving MMT, with patients reporting decreases in pain intensity from one therapy session to the next. Group treatments involving relaxation training or singing appear similarly promising, and Schottenfeld is exploring the potential of other group interventions, such as yoga and walking meditation. Schottenfeld also presented his results from a pilot randomized controlled trial (RCT) in POD patients receiving office-based BMT. Patients were randomized to receive physician management alone, physician management and 10 sessions of educational counseling about pain and addiction, or physician management and 10 sessions of cognitive behavioral therapy, all in office-based practice settings. Patients receiving cognitive behavioral therapy and educational counseling exhibited high session attendance and satisfaction levels, and Schottenfeld is looking forward to results from a larger RCT he is finishing up to assess the potential efficacy of these approaches for pain relief.
…and non-opioid drugs
During a session on new avenues for non-opioid drug development, Mark Zylka, University of North Carolina, Chapel Hill, US, discussed the promise of ectonucleotidases and adenosine receptor agonists to treat pain. In 2008, Zylka reported that prostatic acid phosphatase (PAP), an enzyme expressed in pain-sensing neurons that increases adenosine levels by dephosphorylating adenosine monophosphate (AMP), decreased pain in chronic inflammatory and neuropathic pain models when injected into the mouse spinal cord (Zylka et al., 2008). More recently, he found that injecting PAP at a peripheral acupuncture point—dubbed “PAPupuncture”—in mice produced a long-lasting, adenosine receptor-dependent analgesic effect (Hurt et al., 2012; see PRF related news story). The PAPupuncture work suggests a way to treat pain that could avoid the adverse effects of opioids, because PAP works through a different, adenosine receptor-dependent mechanism.
NT5E is another ectonucleotidase that generates adenosine and is expressed in pain-sensing neurons. Zylka has shown that NT5E knockout mice exhibit enhanced pain sensitivity in inflammatory and neuropathic pain models, and last year other investigators reported inactivating mutations in the gene encoding NT5E in patients with a painful form of arterial and joint calcification in the lower extremities (St Hilaire et al., 2011). Zylka concluded his talk with the exciting prospect that pain phenotyping patients who harbor the mutations could help to illuminate the role of NT5E in pain.
In the next talk, Douglas Lappi, Advanced Targeting Systems, San Diego, California, US, described efforts to turn an old molecule, substance P-saporin (SP-SAP), into a new drug for pain. SP-SAP is a conjugate of substance P, a neurotransmitter in the dorsal horn of the spinal cord with a well-known role in pain, and saporin, a ribosome-inactivating protein from plants. Saporin itself is unable to gain entry to cells, but attaching it to substance P overcomes this hurdle; when the latter enters neurons after binding to its receptor, the former enters, too, and kills the cells. Lappi and colleagues’ studies from the late 1990s in rats revealed that SP-SAP ablated only superficial dorsal horn neurons expressing the substance P receptor (Mantyh et al., 1997), and that the conjugate reduced thermal hyperalgesia and mechanical allodynia in models of persistent neuropathic and inflammatory pain, even up to 200 days after intrathecal injection (Nichols et al., 1999). Lappi also described another group’s more recent studies showing that SP-SAP prevented central sensitization in pretreated rats (Choi et al., 2012). Transforming a substance that kills neurons in animals into a drug for people seemed too risky to the venture capital and pharmaceutical companies to which Lappi first turned for funding; they refused him outright. Subsequently, the NIH agreed to fund the studies, and Lappi expects SP-SAP to enter clinical trials in 2013 in terminal cancer patients with pain that is refractory to opioid treatment.
Finally, Ralph Snodgrass, VistaGen Therapeutics, Inc., South San Francisco, California, US, highlighted the potential of a pro-drug targeting the N-methyl-D-aspartate (NMDA)-type glutamate receptor for neuropathic pain. NMDA receptors have a key role in synaptic plasticity, and drugs that block them are effective in animal and human models of neuropathic pain. However, severe, dose-limiting side effects circumscribe the use of NMDA antagonists in people. Snodgrass seeks to overcome these hurdles with AV-101, a pro-drug and synthetic analogue of a tryptophan breakdown product, kynurenic acid. The latter is a naturally occurring neuroregulatory molecule that blocks both the regulatory glycineB site of the NMDA receptor, as well as the α-7 nicotinic acetylcholine receptor that plays a role in memory and cognition. Upon oral administration, AV-101 is converted to an active metabolite by astrocytes at sites of injury in the brain and spinal cord. The active metabolite mimics the actions of kynurenic acid at the glycineB site but leaves the α-7 nicotinic acetylcholine receptor relatively untouched. Snodgrass said that VistaGen’s Phase 1 safety studies of AV-101 are complete, while Phase 1 efficacy investigations are ongoing using capsaicin-induced hyperalgesia as a model of neuropathic pain. Snodgrass said the company is seeking financial support for planned Phase 2 studies in 120 patients with pain from diabetic neuropathy, post-herpetic neuralgia, post-traumatic nerve injury, or small fiber neuropathy. Interestingly, AV-101 also inhibits the production of quinolinic acid, an excitotoxic molecule implicated in neurodegenerative diseases, potentially extending the value of the pro-drug beyond pain to afflictions such as Huntington’s disease.
Future pain management approaches will not all be drug-based. In fact, evidence from brain imaging studies has already revealed a convincing physiological basis for effects of complementary and alternative (CAM) treatments on pain pathways, said Catherine Bushnell, McGill University, Montreal, Canada, during an overview talk in a session devoted specifically to CAM. For instance, Bushnell’s work and that of others has shown that hypnosis and meditation in healthy subjects can modulate pain perception, with accompanying altered activity in specific brain regions implicated in pain (Hofbauer et al., 2001; Grant and Rainville, 2009; Grant et al., 2011; Bushnell presented similar data on yoga, which she recently submitted for publication. CAM therapies have effects on pain pathways not only in healthy subjects, but in patients with pain, too. For example, recent work from another group found that cognitive behavioral therapy in people with fibromyalgia syndrome increased the activation of the ventrolateral prefrontal and lateral orbitofrontal cortex during pain processing after 12 weeks of treatment (Jensen et al., 2012).
In the next presentation, Daniel Cherkin, Group Health Research Institute, Seattle, Washington, US, provided further evidence of CAM’s scientific underpinnings: RCT data from patients with chronic low back pain (CLBP), he said, support the efficacy of CAM for improving function and relieving pain. Cherkin described results from three National Center for Complementary and Alternative Medicine (NCCAM)-funded studies for which he has been an investigator. In an RCT involving more than 600 adult CLBP patients, standardized acupuncture resulted in clinically meaningful improvements in back-related dysfunction and, to a lesser extent, in pain, compared to usual care, over a seven-week period (Cherkin et al., 2009). Needle insertion, however, did not seem necessary to elicit this effect, as simulated acupuncture that did not involve skin penetration provided equally strong effects; the mechanism by which acupuncture improves function and pain thus remains uncertain. Tailoring acupuncture to individual patients also did not appear vital, since an individualized and a standardized version were similarly beneficial. Another RCT in 400 adult CLBP patients revealed that both relaxation and structural massage therapy produced equally strong improvements in function and, once again, to a lesser degree, in pain, compared to usual care at 10 weeks (Cherkin et al., 2011). Finally, a third RCT in more than 200 adults with CLBP showed that 12 weekly yoga classes were more effective than self-care to improve function and ease pain, but were equally effective as stretching (Sherman et al., 2011). While the effects of these CAM practices diminish over time, Cherkin concluded that they provide meaningful improvement for 15-25 percent of CLBP patients compared to usual care. That makes them a good first option before trying costlier and riskier treatments, although future research is necessary to clarify the mechanisms involved. Finally, based on encouraging results from two small pilot RCTs showing improvements in function and pain in CLBP patients participating in a mindfulness meditation program (Morone et al., 2008; Morone et al., 2009), Natalia Morone, University of Pittsburgh, Pennsylvania, US, described plans for a larger RCT, currently recruiting patients, to test the effects of that CAM therapy in 300 elderly CLBP patients (Morone et al., 2012).
See also Part 2.