The extended-release (ER) formulation of tramadol was shown to be as effective as buprenorphine and more effective than clonidine for treating symptoms of opioid withdrawal, in a study published in JAMA Psychiatry.1
The use of clonidine and buprenorphine in supervised withdrawal treatment of patients with opioid use disorder (OUD) is complicated by several factors. Clonidine may cause sedation and hypotension, requires multiple doses per day, and is not as effective as opioid agonists in reducing withdrawal symptoms.2 In contrast, buprenorphine requires only once-daily dosing and is more effective than clonidine.3 Due to its abuse potential, however, in the United States, buprenorphine can only be used for OUD treatment with a specialized waiver.
Tramadol is a mild to moderate opioid agonist with low abuse potential, and the ER formulation can be administered once per day. Limited data suggest that tramadol may be as efficacious as buprenorphine and methadone in alleviating withdrawal symptoms.1
In the current study, researchers, led by Kelly E. Dunn, PhD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, compared the safety and efficacy of tramadol ER vs clonidine vs buprenorphine for managing opioid withdrawal symptoms in patients with OUD undergoing withdrawal treatment.
The study population included 103 patients, of which the majority (85.4%) were men and more than half (58.3%) were non-white. Patients were randomly assigned in a 1:1:1 ratio to clonidine, tramadol ER, or buprenorphine.
During the taper phase, Clinical Opiate Withdrawal Scale (COWS) scores initially increased from baseline, then decreased by the end of the phase (main effect of study phase on COWS, P =.03). In the area under the curve (AUC) analysis of the taper phase, the total COWS scores were 6.0, 4.6, and 4.9 for clonidine, tramadol ER, and buprenorphine, respectively. A significant group by phase interaction was observed (P <.001).
Similar patterns were found for Subjective Opiate Withdrawal Scale (SOWS) scores. In addition, AUC analyses of SOWS total scores indicated that withdrawal severity was significantly lower in the post-taper phase than in the taper phase for tramadol ER (taper mean, 7.4; post-taper mean, 2.8; P =.03) and clonidine (taper mean, 13.1; post-taper mean, 3.2; P <.001). However, a significant reduction in SOWS scores between the phases was not observed for buprenorphine.
Patients treated with clonidine and tramadol ER required more concomitant medications during the taper phase (P <.001 and P =.003) than in the initial stabilization phase. In contrast, patients treated with buprenorphine required more concomitant medications during the post-taper phase (P =.006) than in the stabilization phase.
Study retention rates at the end of the taper were higher with buprenorphine than with clonidine (90.3% vs 66.1%; P =.01). The rate of retention with tramadol ER (72.2%) was comparable to that of the other groups. The percentage of patients who voluntarily started naltrexone therapy was similar in all treatment groups. The most frequent adverse events were consistent with symptoms of opioid withdrawal, such as muscle aches and pains, diarrhea, and rhinorrhea. No serious adverse events were reported.
Summary and Clinical Applicability
Opioid withdrawal therapy involves the use of agents such as clonidine and buprenorphine, but their use is limited by adverse events and the potential for abuse. Researchers found that tramadol ER may reduce opioid withdrawal symptoms to a greater extent than clonidine and to a similar degree as buprenorphine.
“The fact that tramadol ER was not significantly different from buprenorphine suggests it may have particular value in settings where buprenorphine is not available for withdrawal management, such as places that are currently using clonidine to help patients manage withdrawal,” Dr Dunn told Clinical Pain Advisor. “However, these results are not definitive and more research is needed to support widespread use of tramadol ER for opioid withdrawal management.”
“This study was conducted in a highly controlled research setting, so it will be important to evaluate whether tramadol ER can produce the same outcomes when it is administered for opioid withdrawal management in real-world settings. It will also be important to determine whether tramadol ER can help patients bridge to other treatments, such as methadone or buprenorphine maintenance for ongoing agonist treatment or to naltrexone maintenance to prevent relapse,” she added.
Limitations and Disclosures
This study was underpowered, limiting its ability to detect significant differences in rates of voluntary naltrexone induction and taper completion between the study groups.
Dr Dunn reports no relevant disclosures. Buprenorphine tablets were provided by a grant from Reckitt Benckiser Pharmaceuticals.
- Dunn KE, Tompkins DA, Bigelow GE, Strain EC. Efficacy of tramadol extended-release for opioid withdrawal: a randomized clinical trial. [published online July 12, 2017] JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.1838
- Gowing L, Farrell M, Ali R, White JM. Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016;(5):CD002024. doi:10.1002/14651858.CD002024.pub5
- Dunn KE, Sigmon SC, Strain EC, Heil SH, Higgins ST. The association between outpatient buprenorphine detoxification duration and clinical treatment outcomes: a review. Drug Alcohol Depend. 2011;119(1-2):1-9. doi:10.1016/j.drugalcdep.2011.05.033