NEUROLOGIC PAIN IS UNLIKELY TO YIELD TO A "SINGLE MAGIC BULLET"

VIENNA—Recent years have seen a progressive unraveling of the mechanisms underlying the induction of neuropathic pain syndromes—such as diabetic neuropathy, postherpetic neuralgia, and chronic musculoskeletal disorders. Over the same interval, medications initially indicated for other uses have serendipitously been found effective in pain relief. Researchers at the 9th World Congress on Pain gave a brief overview of relevant pharmacologic agents and discussed the growing support for combination therapy based on underlying pain mechanisms.

Numerous new compounds that specifically target mechanisms mediating neuropathic pain—such as sodium channel mediated ectopic impulse generation in primary afferents and the N-methyl-D-aspartate (NMDA) receptor complex—are currently in clinical trials. So far, even the most effective compounds produce satisfactory pain relief in only 50% to 60% of research subjects. In clinical practice, response rates are likely to be even lower because general patient populations often fail to meet strict entry criteria on medical, psychological, or diagnostic grounds, noted Michael Rowbotham, MD, Associate Professor and Director of the Pain Clinical Research Center, University of California, San Francisco. "Overall, a goal of 'complete' relief from monotherapy is probably achieved in only 10% to 20% of patients with neuropathic pain," he said. As more drugs are found effective, especially new compounds with highly selective receptor binding profiles, combination therapy spanning the relevant underlying pain mechanisms will be needed, he believes.

For many years, tricyclic antidepressants have been used to manage neuropathic pain, beginning with studies of amitriptyline in postherpetic neuralgia. However, anticholinergic side effects and the risks of overdose have been sources of concern. The newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and nontricyclic mixed norepinephrine-serotonin reuptake inhibitors are safer in cases of intentional overdose, noted Dr. Rowbotham.

However, the newer classes of antidepressants are not necessarily better at reducing pain. "Although an SSRI or a mixed reuptake inhibitor may be as good as a tricyclic antidepressant, the chances are very low that it would be superior," Dr. Rowbotham said, describing recent data comparing imipramine and paroxetine. Whether to begin with a tricyclic, an SSRI, or a mixed reuptake inhibitor should be decided on a case-by-case basis. "We could try a patient on one of the SSRI antidepressants or the newer mixed reuptake inhibitors. If the response is suboptimal, try a tricyclic antidepressant," Dr. Rowbotham suggested. An alternative approach, he continued, "would be to start with the tried-and-true tricyclic and if side effects prove to be a problem, switch to one of these newer medications."

Soon after gabapentin was introduced as adjunctive therapy for partial seizures, evidence of its efficacy in neuropathic pain began to emerge. "There have now been two large multicenter trials [of gabapentin] for postherpetic neuralgia and painful diabetic neuropathy including nearly 400 subjects," Dr. Rowbotham said. The efficacy of gabapentin is apparently comparable to that of the tricyclic antidepressants. Minor side effects have included dizziness and somnolence, but the safety record has been very good and no significant drug-drug interactions have been reported. "In many pain clinics including our own," Dr. Rowbotham said, "if patients come in with neuropathic pain, they would be placed on gabapentin before they would be tried on a tricyclic antidepressant."

The NMDA receptor antagonists, including ketamine and dextromethorphan, are also currently being investigated. Interest in these drugs has stemmed primarily from animal model studies that found reductions in allodynia and temporal summation. The NMDA antagonists also reduce opioid tolerance and enhance opioid analgesia. However, side effects are the biggest problem with this drug class, Dr. Rowbotham noted.

The two most studied topical agents are capsaicin and lidocaine. They are particularly effective for allodynia, which can be markedly disabling in some patients, Dr. Rowbotham pointed out. Some patients, he said, "couldn't wear clothing, and as a result they had difficulty participating in any kind of social functions and preferred to remain at home partially undressed to keep the area uncovered."

Dr. Rowbotham and colleagues found that simple skin infiltration with a dilute solution of lidocaine would eliminate the pain and the large surrounding areas of allodynia. And in an interesting sidelight, he mentioned that one of his first experiences with topical lidocaine involved a preparation developed by a patient's husband. "Unbeknownst to us, the husband of one of our patients owned a pharmaceutical company. When I was away on vacation . . . his wife's pain returned and she couldn't get an injection. He became very frustrated, went to his laboratory, and concocted a 10% solution of lidocaine base." This worked so well, Dr. Rowbotham continued, that he and his colleagues eventually began testing topical lidocaine under controlled conditions. Their studies showed that lidocaine must be applied directly to the painful skin in order to produce an analgesic effect and is thus acting as a topical treatment, not as a transdermal therapy. A lidocaine patch is now available and is the only agent other than carbamazepine with a specific neuropathic pain indication, according to Dr. Rowbotham.

Opioids are often considered a last resort for neuropathic pain. Under controlled conditions, Dr. Rowbotham and his colleagues have demonstrated relief of postherpetic neuralgia with intravenous morphine. "We were able to show that not only was pain relieved, but allodynia was reduced, and the surface area of skin displaying allodynia was significantly reduced," Dr. Rowbotham reported.

Three trials of oral opioids for neuropathic pain have been reported. The first compared placebo with controlled-release oxycodone in postherpetic neuralgia. The second compared placebo with tramadol in diabetic neuropathy. Both drugs were significantly better than placebo at relieving pain and reducing disability. In the third study, Dr. Rowbotham and colleagues compared two dosage forms of levorphanol. Participating patients had either peripheral neuropathic pain or central neuropathic pain, such as poststroke pain, spinal cord injury pain, or clinically definite multiple sclerosis. Patients were randomized to either 0.15-mg capsules or 0.75-mg capsules of levorphanol, and were permitted to titrate their own doses over eight weeks of treatment to a maximum of 21 capsules per day. Subjects could remain in the study taking as little as one capsule per day.

"We were primarily interested in how well this treatment worked and weren't trying to force them into any particular dosing schedule," Dr. Rowbotham observed. Subjects randomized to the 0.15-mg dose averaged 18.3 capsules per day, about 2.8 mg of levorphanol. In this group, the subjects reported a 23% reduction in pain intensity on a visual analog scale and categorized pain relief as "slight." This was still a significant reduction compared with baseline, Dr. Rowbotham pointed out, and the pain relief was lost when patients were tapered off treatment at the end of the trial. Patients randomized to the 0.75-mg dose averaged 11.9 capsules per day. They reported a 35% pain reduction and categorized their relief as "slight to moderate."

As opposed to searching for a single "magic bullet" for each specific disorder, another promising approach is to orchestrate additive or synergistic effects targeting different mechanisms of neuropathic pain, suggested Dr. Rowbotham. "Currently we use disease-based classification to look at how different drugs perform in specific diseases. We might be better served by following a mechanism-based classification of pain and studying how specific drugs work on specific pain mechanisms."

Switching to a mechanism-based approach offers the potential for applying clinical trial results in one pain syndrome to other syndromes that share common mechanisms. "To make such an approach viable, more information from clinical studies of pain mechanisms underlying all the neuropathic pain syndromes is needed," Dr. Rowbotham said. Differentiating primary afferent-based mechanisms and central nervous system—based pain mechanisms, for example, can potentially be inferred through clinical examination and provocative tests. Development of better human experimental pain models to bridge the gap between animal models and the clinic would be useful, he added. He also suggested using intravenous infusions with highly selective drugs to predict long-term therapeutic response. Paralleling the growing understanding of neuropathic pain, he concluded, is a growing urgency to develop good clinical guidelines for polypharmacy.

—Janis Kelly
Contributing Writer

Suggested Reading
Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80:533-538.
Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998; 280:1837-1842.