TRANSDERMAL CLONIDINE COMPARED TO PLACEBO IN PAINFUL DIABETIC NEUROPATHY USING A 2-STAGE ENRICHED ENROLLMENT DESIGN

Because a variety of mechanisms may generate pain in neuropathic pain syndromes, conventional clinical trial methods may fail to identify so me potentially useful drugs; a drug affecting just a single mechanism may work in too few patients to yield a statistically significant resu lt for the trial. To test a previous clinical observation that approxi mately one-quarter of patients with painful diabetic neuropathy appear responsive to clonidine, we conducted a formal clinical trial of tran sdermal clonidine in painful diabetic neuropathy patients using a 2-st age enriched enrollment design. In the first stage (study I), 41 patie nts 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), c onsisting of an additional 4 double-blind, randomized, 1-week treatmen t periods with transdermal clonidine and placebo. Study I showed that in the overall group of 41 patients, pain intensity differed little du ring clonidine and placebo treatment. In study II, however, the 12 app arent responders from study I had 20% less pain with clonidine than pl acebo (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 cr-adrenergi c blocker phentolamine had relief of pain, suggesting that clonidine's pain relief is not mediated by a decrease in sympathetic outflow. A p ost-hoc analysis of many variables suggested that patients who describ ed their pain as sharp and shooting may have a greater likelihood of r esponding to clonidine. The results of this study support the hypothes is that there is a subset of patients with painful diabetic neuropathy who benefit from systemic clonidine administration and illustrate the value of an enriched enrollment technique in analgesic trials.