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Efficacy of Tramadol Extended-Release for Opioid WithdrawalA Randomized Clinical Trial

Educational Objective To evaluate whether tramadol hydrochloride extended-release, an approved analgesic with opioid and nonopioid mechanisms of action and low abuse potential, is effective for use in supervised withdrawal settings.
1 Credit CME
Key Points

Question  What is the relative efficacy of tramadol hydrochloride extended-release vs clonidine or buprenorphine hydrochloride in supervised opioid withdrawal settings?

Findings  This randomized clinical trial shows that tramadol extended-release suppressed withdrawal more than clonidine and comparably to buprenorphine during a double-blind taper and did not produce a delayed onset of opioid withdrawal after the taper.

Meaning  Tramadol extended-release is a Schedule IV medication that is available generically and can suppress withdrawal comparably to buprenorphine and superior to clonidine, suggesting that tramadol extended-release may have clinical value for the indication of opioid withdrawal suppression.


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 trial was conducted in a residential research setting with 103 participants with OUD. Participants’ treatment was stabilized with morphine, 30 mg, 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 [61.1%]); tramadol ER retention was intermediate and did not differ significantly from that of the other groups (26 [72.2%]; χ2 = 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]; F2,170 = 3.6, P = .03) and Subjective Opiate Withdrawal Scale (SOWS) score (taper mean,8.81 [SE, .40]; post-taper mean, 4.14 [SE, .30]; F2,170 = 15.7, P < .001), but no group effects or group × phase interactions. Analyses of area under the curve of SOWS total scores showed significant reductions (F2,159 = 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 (F2,159 = 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 (χ2 = 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 a method to manage opioid withdrawal symptoms.

Trial Registration  Clinicaltrials.gov Identifier: NCT01188421

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Article Information

Accepted for Publication: May 16, 2017.

Corresponding Author: Kelly E. Dunn, PhD, Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Dr, Baltimore, MD 21224 (kdunn9@jhmi.edu).

Correction: This article was corrected on September 6, 2017, for errors in the abstract and an error in the discussion section; this article was corrected on February 14, 2018, to fix an error in the Key Points and the Conclusions of the article.

Published Online: July 12, 2017. doi:10.1001/jamapsychiatry.2017.1838

Author Contributions: Dr Dunn had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Strain.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Dunn, Strain.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Dunn, Strain.

Obtained funding: Strain.

Administrative, technical, or material support: All authors.

Supervision: Tompkins, Strain.

Conflict of Interest Disclosures: Dr Strain has been a paid consultant for Indivior Pharmaceuticals and is a paid advisory board member for the Egalet Corporation, The Oak Group, and Pinney Associates. Dr Tompkins has received medication supplies from Indivior Inc for an investigator-initiated research protocol; has been a paid consultant with Astra-Zeneca and Theravance; and is site principal investigator for a multisite clinical trial funded by Alkermes. No other disclosures are reported.

Funding/Support: This study was funded by National Institute on Drug Abuse grant R01DA-018125 (Dr Strain), with additional salary support provided by grants R01DA035246, R01DA040644 (Dr Dunn), K23DA029609 (Dr Tompkins), and T32DA007209 (Dr Bigelow). Buprenorphine sublingual tablets and placebo tablets were provided by an unrestricted, unsolicited investigator-initiated grant from Reckitt Benckiser Pharmaceuticals.

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Reckitt Benckiser Pharmaceuticals had no role in the study design, collection, analysis, and interpretation of data or in the writing of the manuscript, but reviewed the report for scientific accuracy.

Additional Contributions: Paul Nuzzo, MS (University of Kentucky), helped with data analyses and Jessica Sides, BA, and Hye Jeong Han, BA (conducted at The Johns Hopkins University), managed daily study activities; they received financial compensation for these contributions. The Behavioral Pharmacology Research Unit and Bayview Clinical Research Unit staff provided many varied and valuable contributions.

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