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Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial.

ABSTRACT: Tramadol is an atypical analgesic with monoamine and modest mu opioid agonist activity. The purpose of this study was to evaluate: (1) the efficacy of extended-release (ER) tramadol in treating prescription opioid withdrawal and (2) whether cessation of ER tramadol produces opioid withdrawal.Prescription opioid users with current opioid dependence and observed withdrawal participated in this inpatient, two-phase double blind, randomized placebo-controlled trial. In Phase 1 (days 1-7), participants were randomly assigned to matched oral placebo or ER tramadol (200 or 600 mg daily). In Phase 2 (days 8-13), all participants underwent double blind crossover to placebo. Breakthrough withdrawal medications were available for all subjects. Enrollment continued until 12 completers/group was achieved.Use of breakthrough withdrawal medication differed significantly (p<0.05) among groups in both phases; the 200mg group received the least amount in Phase 1, and the 600 mg group received the most in both phases. In Phase 1, tramadol 200mg produced significantly lower peak ratings than placebo on ratings of insomnia, lacrimation, muscular tension, and sneezing. Only tramadol 600 mg produced miosis in Phase 1. In Phase 2, tramadol 600 mg produced higher peak ratings of rhinorrhea, irritable, depressed, heavy/sluggish, and hot/cold flashes than placebo. There were no serious adverse events and no signal of abuse liability for tramadol.ER tramadol 200mg modestly attenuated opioid withdrawal. Mild opioid withdrawal occurred after cessation of treatment with 600 mg tramadol. These data support the continued investigation of tramadol as a treatment for opioid withdrawal.

SUBMITTER: Lofwall MR

PROVIDER: S-EPMC3786049 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial.

Lofwall Michelle R MR Babalonis Shanna S Nuzzo Paul A PA Siegel Anthony A Campbell Charles C Walsh Sharon L SL

Drug and alcohol dependence 20130604 1

<h4>Background</h4>Tramadol is an atypical analgesic with monoamine and modest mu opioid agonist activity. The purpose of this study was to evaluate: (1) the efficacy of extended-release (ER) tramadol in treating prescription opioid withdrawal and (2) whether cessation of ER tramadol produces opioid withdrawal.<h4>Methods</h4>Prescription opioid users with current opioid dependence and observed withdrawal participated in this inpatient, two-phase double blind, randomized placebo-controlled trial ...[more]

PMID: 23755929

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Project description:ImportanceOpioid 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.ObjectiveTo 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 participantsA 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 measuresRetention, 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.ResultsOf 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 relevanceThe 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 registrationClinicaltrials.gov Identifier: NCT01188421.

Project description:ContextNo randomized trials have examined treatments for prescription opioid dependence, despite its increasing prevalence.ObjectiveTo evaluate the efficacy of brief and extended buprenorphine hydrochloride-naloxone hydrochloride treatment, with different counseling intensities, for patients dependent on prescription opioids.DesignMultisite, randomized clinical trial using a 2-phase adaptive treatment research design. Brief treatment (phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week postmedication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week postmedication follow-up.SettingTen US sites. Patients A total of 653 treatment-seeking outpatients dependent on prescription opioids.InterventionsIn both phases, patients were randomized to standard medical management (SMM) or SMM plus opioid dependence counseling; all received buprenorphine-naloxone.Main outcome measuresPredefined "successful outcome" in each phase: composite measures indicating minimal or no opioid use based on urine test-confirmed self-reports.ResultsDuring phase 1, only 6.6% (43 of 653) of patients had successful outcomes, with no difference between SMM and SMM plus opioid dependence counseling. In contrast, 49.2% (177 of 360) attained successful outcomes in phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (phase 2, week 24) dropped to 8.6% (31 of 360), again with no counseling difference. In secondary analyses, successful phase 2 outcomes were more common while taking buprenorphine-naloxone than 8 weeks after taper (49.2% [177 of 360] vs 8.6% [31 of 360], P < .001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower phase 2 success rates while taking buprenorphine-naloxone.ConclusionsPrescription opioid-dependent patients are most likely to reduce opioid use during buprenorphine-naloxone treatment; if tapered off buprenorphine-naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome is high, even in patients receiving counseling in addition to SMM.

Project description:BACKGROUND:Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate???30 and?<?60 ml/min). METHODS:This was an exploratory, 3-month, phase II, multicenter, placebo-controlled, double-blind proof-of-concept study. Patients (n?=?189) were randomized 1:1:1:1:1 to receive placebo or febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg once daily. Endpoints included: proportion of patients with serum uric acid (sUA) <?5.0 mg/dl at month 3 (primary endpoint), proportion of patients with sUA <?6.0 mg/dl at month 3, and proportion of patients with ??1 gout flare requiring treatment over 3 months. RESULTS:At month 3, all febuxostat treatment groups were associated with greater proportions of patients achieving sUA <?5.0 mg/dl (p?<?0.05 vs placebo). A greater proportion of patients receiving XR 40 mg achieved sUA <?5.0 mg/dl versus those receiving IR 40 mg (p?=?0.034); proportions were similar in the IR 80 mg and XR 80 mg groups. Higher proportions of febuxostat-treated patients achieved sUA <?6.0 mg/dl at month 3 (p?<?0.05 vs placebo) and experienced ??1 gout flare (significant for all comparisons, except XR 40 mg). Incidences of treatment-related adverse events were low across all treatment groups; the majority were mild or moderate with no apparent trends correlating with IR or XR doses. The most common treatment-emergent adverse event was hypertension. One death (unrelated to the study drug) was reported. CONCLUSIONS:These exploratory data demonstrate that febuxostat (XR and IR) formulations were effective and well tolerated in patients with gout and moderate renal impairment. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02128490 Registered on 29 April 2014.

Project description:ObjectivesTo investigate the safety and efficacy of lofexidine for treating opioid withdrawal syndrome (OWS) and facilitating completion of opioid withdrawal.MethodsA multicenter, double-blind, placebo-controlled study was conducted at 18 US centers from June 2013 to December 2014. Participants (n = 603) aged ≥18 years, dependent on short-acting opioids, and seeking withdrawal treatment, randomized 3:3:2 to receive lofexidine 2.88 mg/d (n = 222), lofexidine 2.16 mg/d (n = 230), or placebo (n = 151) for 7 days. Primary outcome was the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) scores rating withdrawal symptoms over days 1 to 7.ResultsParticipants were of mean age, 35 years; 71% male. Pairwise differences in overall SOWS-Gossop log-transformed least squares means were statistically significant for lofexidine 2.16 mg (difference, -0.21; 95% CI, -0.37 to -0.04; P = 0.02) and 2.88 mg (-0.26; 95% CI, -0.44 to -0.09; P = 0.003) compared with placebo. Fewer than half of participants in both groups completed the study. Completion rates for lofexidine 2.16 mg (41.5%; odds ratio [OR], 1.85; P = 0.007) and 2.88 mg (39.6%; OR, 1.71; P = 0.02) were significantly better compared with placebo (27.8%). Overall adverse event (AE) rates were similar across groups. Common AEs for lofexidine included orthostatic hypotension, hypotension, and bradycardia, but resulted in few study discontinuations.ConclusionsLofexidine 2.16 mg and 2.88 mg significantly reduced symptoms of OWS versus placebo, and increased absolute rates of completing the 7-day study by 14% and 12%, respectively (a relative increase of 85% and 71%). Data suggest that lofexidine is a generally safe and effective nonopioid treatment for opioid withdrawal. Lofexidine could serve as a withdrawal treatment option when a nonopioid agent is preferred or required, when agonist-assisted withdrawal is unavailable, when agonist discontinuation caused OWS, and during induction into maintenance treatment with opioid agonists or antagonists.Trial registrationClinicalTrials.gov identifier: NCT01863186.

Dataset Information

Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial.

Publications

Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial.

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