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The American Pain Society (APS) 26th Annual Scientific Meeting was held in Washington, DC, from May 2 to 5, 2007. The conference is a great venue for multiple disciplines, including physicians in many specialties, psychologists, basic science researchers, and nurses who share interest in clinical pain medicine as well as the neurobiology of pain and its control. Numerous posters and oral papers were presented and discussed, covering molecular and cellular biology, physiology, anatomy, animal models, specific disease entities, diverse treatments, and methods for diagnosis and assessment. Education as well as the legal and ethical aspects of pain were also discussed. This review highlights selected topics related to neuropathic pain.

Oxidative Stress

The role of reactive oxygen species in animal models of neuropathic pain was discussed in multiple papers. Yowtak and colleagues,^[1] from the University Texas Medical Branch in Galveston, Texas, reported in a poster that oxidative stress due to overproduction of reactive oxygen species may impair normal cellular processes and ultimately result in cellular death. They previously found that reactive oxygen species is significantly involved in neuropathic pain in the spinal nerve ligation model in the rat, a method that was used in mice for this study. They found that a scavenger of reactive oxygen species given intraperitoneally or intrathecally significantly reduced mechanical allodynia, assessed by response to von Frey stimuli, that lasted up to 3 weeks.

Schwartz and colleagues,^[2] also from the University Texas Medical Branch in Galveston, presented a poster on the role of free radicals in capsaicin-induced hyperalgesia. They examined the effects of 2 reactive oxygen species after intradermal capsaicin injection into the hind paw of mice, which leads to primary and secondary hyperalgesia. Systemic or intrathecal administration of a scavenger alleviated capsaicin-induced secondary hyperalgesia but had no effect on primary hyperalgesia. The intrathecal antihyperalgesic effect of scavengers suggests a spinal cord target. It is suggested that capsaicin-induced secondary hyperalgesia is due to central sensitization with an important role attributed to free radicals.

Opioid-Induced Hyperalgesia

Holtman and colleagues,^[3] from the University of Kentucky, Lexington, presented a poster on opioid-induced abnormal pain sensitivity. This presents a serious problem for long-term use of opioids in noncancer patients. The study authors indicated that opioid-induced hyperalgesia is an important consequence of opioid treatments. A pilot, double-blind, randomized, crossover study was performed on 24 volunteers given intravenous morphine at 3 doses vs placebo. The cold pressor test was employed to assess pain threshold, pain tolerance, and pain intensity (Visual Analog Scale [VAS]) at several time points (0-120 minutes). Morphine-induced hyperalgesia was evident as a decrease in threshold or tolerance, whereas morphine analgesia was demonstrated by an increase in both parameters. Opioid-induced hyperalgesia (OIH) was not evident in patient-reported VAS despite changes in threshold or tolerance of pain. The data demonstrated that OIH does occur after administration of even low-dose morphine (0.3 microgram [mcg]/kg). These findings suggest that more definitive, longer term studies are needed to identify individuals at risk for OIH and to investigate the potential contribution of OIH to clinical problems, such as tolerance, drug abuse, and addiction disorder, when managing neuropathic pain in patients chronically treated with opioids.

Pregabalin

This potent agent, which continues to provide significant interest in its applications for different types of neuropathic pain, was discussed in multiple posters. A study on pregabalin in painful diabetic neuropathy was presented by Rosenstock and colleagues,^[4] from Pfizer Global R&D in Ann Arbor, Michigan. They conducted a 12-week, double-blind, randomized evaluation of the safety and efficacy of high-dose pregabalin 600 mg/day in 82 patients receiving 600 mg/day pregabalin compared with 85 patients receiving placebo. Nerve conduction studies were performed on motor and sensory nerves to assess amplitude and conduction velocity. The primary efficacy measure was mean pain score derived from daily pain diaries. Nerve conduction studies showed no statistically significant differences. The pregabalin patients' mean pain score was significantly lower than that for the placebo patients. Significant pain improvement among the pregabalin patients was evident at 1 week and was sustained at every weekly time point. Sleep interference scores were also significantly improved in the pregabalin group. Pregabalin was generally well tolerated. The most common adverse effects included peripheral edema, dizziness, and somnolence, which led to withdrawal of only 14% of patients from an open-label extension of this study. The study authors concluded that high-dose pregabalin has robust and sustained efficacy, is well tolerated at the top end of its dosing range, but has no meaningful effect on nerve conduction.

Gore and colleagues,^[5] from Avalon Health Solutions in Philadelphia, Pennsylvania, studied achieving the minimally effective dose of pregabalin or gabapentin in patients with diabetic neuropathy or postherpetic neuralgia (PHN). They noted that pregabalin has linear pharmacokinetics related to its nonsaturable absorption at clinical doses, which leads to more predictable exposure compared with gabapentin. They analyzed the attainment of minimally effective doses among patients with diabetic peripheral neuropathy (DPN) or PHN who were started on pregabalin at 150 mg/day or higher (1237 patients) vs the patients (2816) who received gabapentin at 1800 mg/day or higher. The results suggest that patients on pregabalin received a clinically effective dose earlier in their treatment titration compared with gabapentin. Even in patients prescribed less than minimally effective doses, a considerably larger proportion of pregabalin patients achieved therapeutic dose levels within the time frame of the study.

Lacosamide

Three posters on this new agent were presented from Schwarz BioSciences in Monheim, Germany. Lacosamide is a novel N-methyl-D-aspartate (NMDA) receptor antagonist in development for the treatment of both epilepsy and neuropathic pain. In the poster presented by Stoehr and colleagues,^[6] lacosamide was shown to have a dual mode of action on sodium channels leading to selective enhancement and slow inactivation, as was evident in detailed electrophysiologic studies performed on neuroblastoma cells. Lacosamide inhibited Na current by 30%, an effect that was not abolished by hyperpolarizing prepulse, which is capable of abolishing inhibition seen by other anticonvulsive agents -- such as carbamazepine and lamotrigine -- confirming a distinct mechanism of action for this agent. Lacosamide did not influence the steady-state fast inactivation curve, but it increased the number of slow inactivated Na channels and enhanced entry of Na channels into slow inactivation. Lacosamide showed clear antinociceptive effects under conditions in which lamotrigine was without effect. Lamotrigine influences the fast inactivation of Na channels. Slow inactivation of Na channels is an endogenous mechanism for neurons to reduce hyperactivity. Thus, slow inactivation of Na channels by lacosamide represents a molecular mechanism underlining its pharmacologic activity.

Another poster from Schwarz BioSciences, presented by Freitag and colleagues,^[7] indicated that the site of action of lacosamide is not known but that it did not bind with significant affinity to numerous receptors and enzymes tested previously. In this study, they aimed to use proteomic affinity labeling to identify binding partners of lacosamide to define the molecular mechanisms of its action. A protein referred to as collapsin-response mediator protein (CRMP)-2, which is involved in neuronal differentiation and axonal growth, was studied with radioligand binding. Binding of lacosamide to CRMP-2 was confirmed with an affinity of about 5 mcM, which resulted in inhibition of certain molecular mechanisms, including the effect of neurotrophins on axonal growth. Given the important role of neurotrophic factors in the pathophysiology of chronic pain, the interaction of lacosamide with CRMP-2 may potentially have disease-modifying effects.

A third poster by Thomas and colleagues,^[8] from Schwarz BioSciences, investigated the pharmacokinetic drug-drug interaction of lacosamide as part of establishing its safety profile. It has been shown that lacosamide is not substantially metabolized. It has low potential to inhibit cytochrome P (CYP)450 isoforms. Drug displacement in plasma is not likely secondary to low plasma protein binding. Drugs that are known to induce or inhibit CYP450, such as carbamazepine or valproic acid, respectively, were not affected by lacosamide or vice versa, nor were plasma levels of phenytoin and other antiepileptics affected by lacosamide. No interactions were noted with digoxin, metformin, or an oral contraceptive. Gastrointestinal absorption of lacosamide was not influenced by food. Therefore, it appears that lacosamide has a low potential for drug-drug interaction in clinical use.

Spinal Cord Stimulation

DPN is a common and severe complication of diabetes mellitus. A need for advanced therapy for DPN is driven by potential lack of efficacy of oral and topical medications. Use of spinal cord stimulation (SCS) to manage the severe neuropathic pain associated with DPN was addressed in multiple posters at the meeting. McDonnell and colleagues,^[9] from Deaconess Pain Management Center in Evansville, Indiana, presented a chart review of 5 patients in whom previous treatments provided only temporary relief who were treated by the Precision SCS system (Advanced Bionics Corporation, Sylmar, California). All patients reported immediate and significant pain relief during the trial that was maintained after implantation for several months. Other outcomes included decreased numbness, improved circulation with warmer feet, a decreased use of opioids, and better sleep. Other posters also presented successful use of this modality for treatment of complex regional pain syndrome and phantom limb pain. Prospective, controlled studies on the use of SCS for these indications are needed.

Spinal Cord Injury Pain Symposium

This symposium included papers on the clinical presentation of spinal cord injury (SCI) pain and pathophysiologic mechanisms that suggest potential targets for new treatments.^[10] Dr. Eva Widerstrom-Noga reviewed the classification and epidemiology of chronic pain after SCI. Nociceptive pains include urinary tract infections, constipation, and various overuse musculoskeletal syndromes of the shoulders and arms. Neuropathic pains include peripheral nerve compression syndromes and complex regional pain syndromes that clinically often present with allodynia and hyperalgesia. Dr. Susan Carlton, from the University of Texas, Galveston, presented a series of studies examining pain after SCI in rats, suggesting that both central and peripheral sensitization contribute to neuropathic pain following SCI. Dorsal reflexes through presynaptic GABAA interneurons can lead to antidromic activation of peripheral nerves and neurogenic inflammation in areas distant from the initial injury (eg, forepaw in a T-10 SCI preparation), which may precede central sensitization. This suggests a mechanism for pain distant from the actual site of injury in other chronic pain states. Dr. Bryan Hains, from Yale University, New Haven, Connecticut, presented experiments suggesting that after SCI in rats, microglial activation causes an increase in pain and lowered nociceptive thresholds. Blocking cysteine-cysteine chemokine ligand 21, a gene associated with immunoregulatory and inflammatory processes, reduces microglial activation and evoked hyperexcitability and restores normal nociceptive thresholds in these preparations.

Immune-glial and Pain Interactions Symposium

Three papers examined laboratory evidence for the role of glial cells in mediating the relationship of inflammation and neuropathic pain and the analgesic response to opioids. Dr. Joyce DeLeo, from Dartmouth College, Hanover, New Hampshire, presented studies demonstrating the role that activation of spinal and supraspinal glial cells plays in the development of neuronal hypersensitivity.^[11] Astrocytes activate neuronal sensitization not only through inflammatory cytokines, but also more directly by release of glutamate, suggesting this target for new pain therapies. Dr. Fletcher White, from Loyola University, Chicago, Illinois, presented evidence that glial-released chemokines and inflammatory cytokines act as chemical mediators causing neuronal excitability.^[12]

Chemokine receptor block may be a target for the development of new antineuropathic pain agents. Dr. Mark Hutchinson, from the University of Colorado, presented evidence that neuronal-glial signals, including neuronal chemokines, neurotransmitters, and substances released by damaged and dead neurons, increase glial excitability in a chronic pain state.^[13] In addition, glial cells are activated by repeated administration of opioids contributing to OIH, opioid dependence, and tolerance. These interactions suggest glial activation as a target for new therapies for neuropathic pain and for improving the clinical utility of opioid analgesic drugs.

Conclusions

Neuropathic pain continued to be a major focus of interest at the annual APS meeting. Research is active in multiple areas related to the underlying mechanisms of this horrible entity, including particularly the impact of glial-neuronal interactions on the development and maintenance of pain and effects on opioid analgesia, suggesting opportunities to develop new targets for preventing and treating neuropathic pain. In addition, established medications are finding new uses, and promising medications are in the pipeline, which should encourage scientists, clinicians, and the public that the field is busily developing better treatment options. The preceding paragraphs contain highlights of just some of the posters and papers that were presented at the meeting. It is not intended to be a comprehensive summary.

Supported by an independent educational grant from Cephalon

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