For patients with opioid use disorders, a 7-day taper with up to 600 mg of extended-release tramadol per day suppressed withdrawal symptoms as well as buprenorphine and significantly better than clonidine, in a randomized, double-blind, double-dummy placebo-controlled trial of 103 patients.

Tramadol ER also produced less severe withdrawal symptoms after taper than did buprenorphine, reported Kelly E. Dunn, PhD , of Johns Hopkins University in Baltimore, and her associates. The study was published online July 12 in JAMA Psychiatry.

“Tramadol ER is a schedule V medication that can be administered once a day and has lower abuse liability than other opioid agonists,” the researchers wrote. “These data suggest that tramadol ER is a promising and valuable medication for the management of opioid withdrawal in patients undergoing treatment for opioid use disorder.”

Successful opioid detoxification hinges on managing withdrawal symptoms, often with clonidine, which is an unscheduled adrenergic agonist, or buprenorphine HCl, which is a partial mu and opioid receptor like–1 receptor agonist and kappa antagonist. Clonidine has low abuse potential, but must be given several times daily, can cause sedation and hypotension, and is less effective than buprenorphine, which is a schedule III drug that requires a specialized waiver to prescribe. In contrast, tramadol ER has lower abuse potential (schedule V), a low affinity for mu, kappa, and delta opioid receptors, and an elimination half-life compatible with once-daily dosing, the investigators reported (JAMA Psychiatry. 2017 Jul 12. doi: 10.1001/jamapsychiatry.2017.1838 ).

Their study included three phases. First, participants were stabilized with subcutaneous morphine injections four times daily for 7-10 days. Next, they started a 7-day taper with buprenorphine (31 individuals), clonidine (36 individuals), or tramadol ER (36 individuals). Then they crossed over to a 7-day double-blind placebo period. The researchers measured withdrawal symptoms on the 11-item Clinical Opiate Withdrawal Scale (COWS) and the 16-item, 5-point Subjective Opiate Withdrawal Scale (SOWS).

For all three medications, average COWS and SOWS scores rose at the start of taper and subsequently dropped. For example, buprenorphine patients averaged higher SOWS scores after taper (7.2) than did clonidine (3.2) or tramadol ER patients (2.8), but the differences were not statistically significant. Post hoc analyses of SOWS scores linked clonidine with significantly worse withdrawal symptoms than tramadol ER (P = .02) or buprenorphine (P less than .001) during taper.

Patients also reported significant lessening of withdrawal symptoms after tapering off clonidine (P less than .001) and tramadol ER (P = .03), but not buprenorphine. Average pupil diameters increased only after stopping buprenorphine but rose slightly while tapering off the other medications. Patients also used significantly more concomitant medication after stopping buprenorphine. “Together, these findings suggest that buprenorphine participants experienced continued withdrawal following the removal of buprenorphine,” the researchers wrote. “Although a delayed onset of withdrawal has been previously reported following buprenorphine withdrawal, it is notable that this pattern was not observed in the other groups.”

In all, 85% of study participants were male, 42% were white, and the average age was 29 years. Retention rates were 66% for clonidine, 72% for tramadol ER, and 90% for buprenorphine. About half of patients reported adverse effects, and those rates were similar among the groups. Most of the adverse effects were related to opioid withdrawal, and no severe adverse events were reported.

The study “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,” the researchers wrote. However, the findings “are tempered by the high rates of relapse generally associated with supervised withdrawal relative to maintenance treatments, and epidemiologic evidence that tramadol is abusable.” Tramadol ER was previously unscheduled but now is a schedule V medication, which “adds complexity in its use for opioid withdrawal suppression,” they noted. They recommended more studies in patients with worse withdrawal symptoms, outpatient settings, and extended care to prevent overdose.

The National Institute on Drug Abuse funded the work. Reckitt Benckiser Pharmaceuticals provided buprenorphine and placebo tablets and reviewed the report for scientific accuracy. Dr. Dunn and one coinvestigator had no disclosures. The senior author, Eric C. Strain, MD, and another coinvestigator disclosed ties to Indivior Pharmaceuticals, Egalet, and several other pharmaceutical companies.