Opioids for Neuropathic Pain Nathaniel Katz, MD, MS and Christine Benoit, BA Address Inflexxion, Inc., 320 Needham Street, Suite 100, Newton, MA 02464, USA. E-mail: NatPaulKatz@aol.com Current Pain and Headache Reports 2005, 9:153–160 Current Science Inc. ISSN 1531-3433 Copyright © 2005 by Current Science Inc. Introduction John Kent Spender once said “The greatest hindrance to our successful treatment of neuralgia has been our obsti- nate theorizing about its etiology. While we are busy in classifying…and are applying our chemical and dynamical drugs accordingly, we are apt to forget the simple clinical fact that a human being lies in agony by our side, and supplicates relief for that one symptom: pain.” Opioids have been used for millennia for the treat- ment of pain [1]. Because there is little reason to believe that neuropathic pain is a recent development, opioids likely have been used for neuropathic pain for a long time. Silas Weir Mitchell [2], considered by many to be the father of American neurology, provided a dramatic exposition of the use of opioids for neuropathic pain in the mid-19th century. Mitchell treated injured Civil War veterans in the era just after the crystallization of morphine and the invention of the hypodermic needle and described in great detail the indispensable use in his hands of morphine for the treatment of causalgia (a term he coined) and other neuropathic pain states. Opioids fell into relative disuse in the United States after the passage of the Harrison Act in 1920 and did not re-emerge in any force until the 1980s, in the wake of the hospice and patient rights movements [3]. Questions regarding the usefulness of opioids for neuropathic pain were fueled by anecdotal reports of “opioid resistance”; in addition, scientific findings had emerged, from preclinical and in vitro studies, proving that after nerve injury, spinal cord opioid receptors are lost [4••], appearing to explain the clinical stories of lack of efficacy. Several studies then emerged that purported to confirm that opioids were ineffective for neuropathic pain. One was a study of intravenous infusions of opioids in eight patients with neuropathic pain and pain that did not appear to have an “organic basis” [5]. Based on the lack of efficacy demonstrated in their study, the authors concluded that the existence of chronic pain as an entity required re-examination, that opioids were not effective for neuropathic pain, but that the intravenous morphine test was clinically useful. A second study [6] of single doses of intravenous opioids in cancer patients with neuropathic and non-neuropathic pain appeared to indi- cate that opioids were less effective in neuropathic pain. The controversy was discussed in scholarly journals [7] and despite calls for more scientific evidence on the issue [8], the impression became entrenched in the medical community that opioids and neuropathic pain were not a useful match. In 1999, an article summarizing the uncer- tainties in this area appeared entitled “Are Opioids Effec- tive in Relieving Neuropathic Pain?” [9•]. However, in the few short years since the late 1990s, enough evidence accumulated to allow the author of an editorial in the New England Journal of Medicine in 2003 [10••] to comment rather matter-of-factly that sufficient evidence had accumulated such that there is little doubt regarding the efficacy of opioids for neuropathic pain. This evidence will be reviewed in the following sections. Randomized, Controlled Trials A literature review for randomized, placebo-controlled clinical trials (RPCTs) of opioids for neuropathic pain, with at least 1 week of treatment, yielded eight studies (Table 1), all of which were published between 1998 and 2003. These studies created a seemingly instant database supporting the efficacy of opioids for neuropathic pain. Multiple opioids have been shown to be efficacious in these trials, including oxycodone, tramadol, morphine, levorphanol, and methadone. Multiple conditions have been studied, including postherpetic neuralgia, painful Whether opioids are effective for neuropathic pain has been a matter of controversy for decades. Within limits, it is clear that opioids in general are effective for neuropathic pain. Furthermore, there is no evidence that opioids are any less effective for neuropathic pain than for non-neuropathic pain, no evidence that opioids are less effective for neuropathic pain than are other medications, and no evidence that one opioid is any more effective than another for neuropathic pain. It remains uncertain whether opioids are effective for central pain, although they may have a role. Although some patients appear to enjoy long-term benefits, most studies have been short-term. Opioids have an important role in the treatment of neuropathic pain; however, skillful opioid use balances the benefits with management of side effects and prevention and treatment of abuse and addiction.