Efficacy of Tramadol Extended-Release for Opioid Withdrawal A Randomized Clinical Trial

IMPORTANCE Opioid use disorder (OUD) is a significant public health problem. Supervised withdrawal (ie, detoxification) from opioids using clonidine or buprenorphine hydrochloride is a widely used treatment. OBJECTIVE To evaluate whether tramadol hydrochloride extended-release (ER), an approved analgesic with opioid and nonopioid mechanisms of action and low abuse potential, is effective for use in supervised withdrawal settings. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trialwas conducted in a residential research setting with 103 participants with OUD. Participants' treatment was stabilized with morphine, 30mg, administered subcutaneously 4 times daily. A 7-day taper using clonidine (n = 36), tramadol ER (n = 36), or buprenorphine (n = 31) was then instituted, and patients were crossed-over to double-blind placebo during a post-taper period. The study was conducted from October 25, 2010, to June 23, 2015. MAIN OUTCOMES AND MEASURES Retention, withdrawal symptom management, concomitant medication utilization, and naltrexone induction. Results were analyzed over time and using area under the curve for the intention-to-treat and completer groups. RESULTS Of the 103 participants, 88 (85.4%) were men and 43 (41.7%) were white; mean (SD) age was 28.9 (10.4) years. Buprenorphine participants (28 [90.3%]) were significantly more likely to be retained at the end of the taper compared with clonidine participants (22 [61.16%]); tramadol ER retention was intermediate and did not differ significantly from that of the other groups (26 [72.2%]; chi(2) = 8.5, P = .01). Time-course analyses of withdrawal revealed significant effects of phase (taper, post taper) for the Clinical Opiate Withdrawal Scale (COWS) score (taper mean, 5.19 [SE,.26]; post-taper mean, 3.97 [SE,.23]; F-2,F-170 = 3.6, P=.03) and Subjective Opiate Withdrawal Scale (SOWS) score (taper mean, 8.81 [SE,.40]; post-taper mean, 4.14 [SE,.30]; F-2,F-170 = 15.7, P<.001), but no group effects or group x phase interactions. Analyses of area under the curve of SOWS total scores showed significant reductions (F-2,F-159 = 17.7, P<.001) in withdrawal severity between the taper and post-taper periods for clonidine (taper mean, 13.1; post-taper mean, 3.2; P<.001) and tramadol ER (taper mean, 7.4; post-taper mean, 2.8; P=.03), but not buprenorphine (taper mean, 6.4; post-taper mean, 7.4). Use of concomitant medication increased significantly (F-2,F-159 = 30.7, P<.001) from stabilization to taper in the clonidine (stabilization mean, 0.64 [SE,.05]; taper mean, 1.54 [SE,.10]; P<.001) and tramadol ER (stabilization mean, 0.53 [SE,.05]; taper mean, 1.19 [SE,.09]; P=.003) groups and from stabilization to post taper in the buprenorphine group (stabilization mean, 0.46 [SE,.05] post-taper mean, 1.17 [SE,.09]; P=.006), suggesting higher withdrawal for those groups during those periods. Naltrexone initiation was voluntary and the percentage of participants choosing naltrexone therapy within the clonidine (8 [22.2%]), tramadol ER (7 [19.4%]), or buprenorphine (3 [9.7%]) groups did not differ significantly (chi(2) = 2.5, P=.29). CONCLUSIONS AND RELEVANCE The results of this trial suggest that tramadol ER is more effective than clonidine and comparable to buprenorphine in reducing opioid withdrawal symptoms during a residential tapering program. Data support further examination of tramadol ER as amethod to manage opioid withdrawal symptoms.