Combination Therapy for Painful Neuropathy
December 1, 2009 3 minutes read
Combination Therapy for Painful Neuropathy
By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Combination therapies may be better than single agents for neuropathic pain relief, but side effects are a limiting factor.
Source: Gilron I, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomized controlled crossover trial. Lancet 2009;374; 1252-1261.
Numerous drugs are available for the long-term control of neuropathic pain. Regrettably, this is not entirely good news. If one choice is poorly tolerated or ineffective, another may be offered. However, the sheer number of drugs advertised underscores the fact that none works superbly in most patients. Hence the pursuit for alternatives, and combination therapy is one such avenue. In this double-blind, controlled, crossover trial undertaken through the Department of Anesthesiology at Queen's University, Kingston, Ontario, between November 2004 and December 2007, 56 patients with diabetic neuropathy or post-herpetic neuralgia were randomized to receive one of three sequences consisting of six weeks each of oral gabapentin, nortriptyline, and both. Each drug was titrated up to a maximum tolerated dose. Diagnostic criteria for diabetic neuropathy included a stocking sensory deficit on examination with decreased or absent ankle reflexes in a confirmed diabetic. Patients with post-herpetic neuralgia had a history of a zoster rash six months prior to trial enrolment. Inclusion criteria for both diagnoses required six months or more of a daily pain score measuring at least 4/10, serum liver function tests within 120% of normal, serum creatinine within 150% of normal, and HgbA1C < 13 %. Exclusion criteria comprised significant major organ system disease, psychiatric illness, substance abuse, hypersensitivity to study drug, a co-existing painful condition, and neuropathy due to other causes including hereditary conditions, thyroid disease, vitamin deficiency, collagen vascular disease, toxins, or amyloid. Outcome measures included measures of global pain relief, mood, quality of life, functional ability, and, the primary outcome measure, daily pain rated thrice daily for seven days on maximum tolerated dose of study drug. Secondary outcome measures included maximum study drug dosage and serum concentration, brief pain inventory, nocturnal pain as reported by patient, short McGill pain questionnaire, Beck depression inventory, global pain relief, and SF-36 general health survey. Analysis was by intention to treat, and data was analyzed by Fisher's exact method.
Of 73 patients screened, 56 were eligible and enrolled but, due to patient withdrawal, only 47 (84%) completed two treatment periods, with 45 (80%) completing all three. Compared to either drug alone, combination therapy resulted in significantly improved mean daily pain intensity, brief pain inventory score, and sleep interference. Dry mouth was the most common side effect, more so with nortriptyline (56%) than gabapentin (20%). Other adverse events included somnolence, fatigue, dizziness, headache, and inability to concentrate. No patient experienced any serious adverse event. Either gabapentin or nortriptyline alone may be used to control pain in diabetic neuropathy or post-herpetic neuralgia but, when necessary, their combination is safe and will provide even further significant pain relief.
Commentary
Along with transcutaneous electrical nerve stimulation (TENS), acupuncture, and spinal cord stimulation, peripheral nerve fields stimulation (PNFS) is emerging as an alternative treatment for pain refractory to pharmacologic management. A 55-year-old man with post-herpetic neuralgia was unresponsive to combined pregabalin, amitriptyline, and fentanyl patches (American Journal of Hospice & Palliative Medicine doi:10.1177/1049909109342089). Following an excellent response to a diagnostic left supraorbital nerve block given on three consecutive days, he underwent a PNFS trial with a subcutaneous electrode placed under the left temporal region into the left supraorbital region. Complete relief was obtained and a permanent stimulator was implanted with continued pain relief. PNFS likely has a mechanism of action similar to TENS and should be considered in post-herpetic neuralgia when other options have run out.
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