Efficacy of Tramadol ER for Opioid Withdrawal

Efficacy of Tramadol ER for Opioid Withdrawal
Brittany Bailey, Pharm.D., Avera Marshall Regional Medical Center

Background: Current first-line treatment of opioid use disorder (OUD) is medically supervised withdrawal. Medications used to manage withdrawal symptoms include clonidine and buprenorphine. Buprenorphine, has shown in past studies to be more effective than clonidine at suppressing withdrawal symptoms; however it also has the potential for abuse. Tramadol ER is an opioid agonist dosed once-daily, with less abuse potential.

Objective: Evaluate the efficacy of tramadol ER as an option to treat opioid withdrawal symptoms during supervised opioid withdrawal.

Study Design: This trial was a randomized 1:1:1, double-blind, double-dummy, placebo-controlled opioid withdrawal procedure. Patients recruited met DSM-IV criteria for opioid dependence and had a urine sample positive for opiates. Exclusion criteria included pregnancy, hypotension, physical dependence on alcohol and/or benzodiazepines requiring treatment, history of seizures, allergies to study medications, or current enrollment in opioid agonist treatment. Subjects were followed through three study phases. In phase one (stabilization phase), all subjects were given morphine 30 mg subcutaneous four times daily for seven to ten days followed by a naloxone challenge to determine level of physical dependence. Level of physical dependence was scored using the Clinical Opiate Withdrawal Scale (COWS) scores, completed by professional staff, and the Subjective Opiate Withdrawal Scale (SOWS) completed by participants. Subjects were stratified by sex, race, CYP2D6 (extensive, intermediate, and ultra-extensive poor metabolizer genotypes) and peak COWS score. In phase two (taper phase), stratified patients were randomized to receive starting doses of clonidine 0.4 mg/day, tramadol ER 300 mg/day, or buprenorphine/naloxone 4/1 mg/day. After day two of the taper phase, doses of each medication were reduced until day seven. Phase three was the post-taper period, occurring from day eight through day fourteen, during which all subjects received placebo. At least one dose of study drug was received by 103 subjects which was not enough to meet 80% power. Chi-square test was used for dichotomous variables and one-way ANOVA was used for continuous data results between the three groups. The primary endpoint was a comparison of opioid withdrawal symptoms (COWS and SOWS scores) during taper versus post-taper, using the modified intention to treat population (at least one dose of study drug). The secondary endpoint of retention was measured as enrollment on the final day of taper. Adverse effects and withdrawal symptoms were not differentiated.

Results: No statistically significant differences between treatment groups was found. Of the total participants, 85.4% were men and 41.7% were white. Regarding the primary outcome, initial mean peak COWS score was 8-9 on day one of taper for all three treatment arms. The time-course analyses of taper and post-taper showed significant reduction in COWS mean peak rating per day with taper mean of 5.19 and post-taper mean of 3.97 (F2170=3.6; P=0.03). The area under the curve (AUC) of the COWS total scores, showed statistically significant reductions (F2,159 = 14.6, p<0.001) in mean score from taper to post-taper periods for clonidine (taper: 6; post-taper: 3.4) and tramadol ER (taper: 4.6; post-taper: 3.2), but not buprenorphine (taper: 4.6; post-taper: 5.6). The AUC of the mean Subjective Opiate Withdrawal Scale (SOWS) total scores also resulted in significant reductions (F2,159 = 17.7, p<0.001) in withdrawal severity between taper and post-taper periods for clonidine (taper: 13.1; post-taper: 3.2; p<0.001) and tramadol ER (taper: 7.4; post-taper: 2.8; P=0.03), but not buprenorphine (taper: 6.4; post-taper: 7.4). Regarding the secondary endpoint of retention to the last taper day, tramadol ER (26 [72.2%]) showed no statistical difference compared to buprenorphine (28 [90.3%]) or clonidine (22 [66.1%]) (X2=8.5, P=0.1]). Most common adverse effects, seen in all treatment arms, included abdominal pain, agitation, anxiety, chills, headache, insomnia, muscle aches, restlessness, rhinorrhea, and tremor. The percent range of patient experiencing an adverse effect was approximately 0-50% for each treatment arm.

Conclusions: Results of this trial show potential of tramadol ER as an effective treatment option for opioid withdrawal symptoms with statistically significant reduction in COWS and SOWS scores. While buprenorphine showed lower taper COWS and SOWS scores, both tramadol ER and clonidine had lower post-taper scores compared to buprenorphine. Tramadol ER shows similar risk of adverse effects compared with clonidine and buprenorphine. Future research should be completed to include a larger sample size to meet 80% power and a study design focused on inferiority or superiority of tramadol ER compared to buprenorphine and clonidine for treatment of withdrawal symptoms.

Key Point: In treatment of OUD with medically supervised withdrawal, tramadol ER may be an effective option to reduce withdrawal symptoms when comparing taper and post-taper opiate withdrawal scale scores.


Dunn KE, Tompkins A, 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.