title: Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage 'enriched enrollment' design.
abstract: Because a variety of mechanisms may generate pain in neuropathic pain syndromes, conventional clinical trial methods may fail to identify some potentially useful drugs; a drug affecting just a single mechanism may work in too few patients to yield a statistically significant result for the trial. To test a previous clinical observation that approximately one-quarter of patients with painful diabetic neuropathy appear responsive to clonidine, we conducted a formal clinical trial of transdermal clonidine in painful diabetic neuropathy patients using a 2-stage enriched enrollment design. In the first stage (study 1), 41 patients with painful diabetic neuropathy completed a randomized, 3-period crossover comparison of transdermal clonidine (titrated from 0.1 to 0.3 mg/day) to placebo patches. Twelve apparent responders from study I were entered into the 'enriched enrollment' second stage (study II), consisting of an additional 4 double-blind, randomized, 1-week treatment periods with transdermal clonidine and placebo. Study I showed that in the overall group of 41 patients, pain intensity differed little during clonidine and placebo treatment. In study II, however, the 12 apparent responders from study I had 20% less pain with clonidine than placebo (95% confidence interval (CI): 4-35% pain reduction; P = 0.015), confirming that their pain was responsive to clonidine. None of the 3 consistent clonidine responders who were tested with the alpha-adrenergic blocker phentolamine had relief of pain, suggesting that clonidine's pain relief is not mediated by a decrease in sympathetic outflow. A post-hoc analysis of many variables suggested that patients who described their pain as sharp and shooting may have a greater likelihood of responding to clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Neurobiology and Anesthesiology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Byas-Smith
authors.forename: M B
authors.initials: MB
authors.lastname: Max
authors.forename: J
authors.initials: J
authors.lastname: Muir
authors.forename: A
authors.initials: A
authors.lastname: Kingman
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003000:Clonidine / Q000008:administration & dosage*; D018592:Cross-Over Studies; D003929:Diabetic Neuropathies / Q000150:complications*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010919:Placebos; D012107:Research Design
chemical_list: D010919:Placebos; D003000:Clonidine