Pharmacotherapy for Neuropathic Pain: The Old and the New

Dr McCarberg is Assistant Clinical Professor (voluntary), University of California School of Medicine, Boarded in Family Medicine, Geriatrics, and Pain Medicine, Family Medicine Kaiser Permanente, San Diego, California. Conflict of Interest: The author reports serving on the speaker’s bureau for Eli Lilly, Endo, Forest, Janssen, Ligand, Organon, Ortho-McNeil, Pfizer Inc, PriCara, and Purdue. Off-Label Product Discussion: All medications discussed will be off-label, except the following medications with the US Food and Drug Administration indication listed alphabetically: carbamazepine—trigeminal neuralgia; duloxetine—diabetic peripheral neuropathy; gabapentin—postherpetic neuralgia; opioids—pain; pregabalin—diabetic peripheral neuropathy and postherpetic neuralgia; and transdermal 5% lidocaine—postherpetic neuralgia. Address correspondence to: Bill McCarberg, MD, 732 North Broadway, Escondido, CA 92025. E-mail: [email protected]. PURPOSE: To review the use of pharmacotherapy for the treatment of neuropathic pain, with a special emphasis on anticonvulsant medications. EPIDEMIOLOGY: By conservative estimates, between 0.6% and 1.5% of the US population suffers from conditions leading to neuropathic pain. Most commonly, nearly 6 million individuals seek treatment for pain related to diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN), although the list of underlying etiologies for this type of pain includes a myriad of conditions ranging from infectious diseases to musculoskeletal causes. REVIEW SUMMARY: The pathophysiology of neuropathic pain and select mechanisms of action and pharmacologic targets for analgesia are discussed. At present, a complete understanding of the precise pathophysiology for this type of pain and the mechanisms of actions for many of these therapeutic agents is lacking; however, several research-based theories are presented. US Food and Drug Administration (FDA)-approved, first-line and second-line medication regimens, including several classes of medications, are reviewed, focusing on anticonvulsant medications and new related agents, such as pregabalin. Specifically, recommendations issued by the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain are discussed. Recommendations are based on the results of multiple, randomized clinical trials, published studies, and the clinical experience of the conference faculty. The 2 types of neuropathic pain emphasized in this article are PHN and DPN. Our understanding of pain mechanisms relate primarily to animal nerve injury models rather than these 2 conditions. The fact that PHN and DPN are primarily used for pharmacologic studies is related to: lack of other better uniform clinical models, and confounding psychosocial factors often seen in other lessdefined clinical problems as complex regional pain syndrome or low-back pain. TYPE OF AVAILABLE EVIDENCE: In all examples of recommendations below, randomized, placebo-controlled trials are used. Much of the information comes from the Annals of Neurology 2003, which is the result of an international expert panel using all available evidence for their conclusions on neuropathic pain. All trial data are cited whenever recommendations are made. GRADE OF AVAILABLE EVIDENCE: Fair CONCLUSION: A variety of pharmacologic agents from classes including anticonvulsants, antidepressants, and opioids, among others, are available for the management of neuropathic pain—a condition for which our understanding is still in its infancy despite the fact that it afflicts millions of individuals who suffer from diabetes and other chronic illnesses. Decisions regarding which medication to use for management of neuropathic pain may come down to a number of practical considerations. These may include which drugs have US FDA approval; evidence of efficacy and safety from randomized, controlled trials; cost or formulary limitations; and personal experience. In the end, rational polypharmacy—using combinations of multiple medications with different mechanisms of action—may be the most effective means of gaining relief for particularly challenging patients. In the future, research may focus on developing a more complete understanding of neuropathic pain, with the goal of targeting therapies to modulate pain at its source within the nervous system. (Adv Stud Med. 2006;6(9):399-408) ABSTRACT N E U R O LO G Y