Dataset Information

Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial.

ABSTRACT:

Objectives

To investigate the safety and efficacy of lofexidine for treating opioid withdrawal syndrome (OWS) and facilitating completion of opioid withdrawal.

Methods

A 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.

Results

Participants 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.

Conclusions

Lofexidine 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 registration

ClinicalTrials.gov identifier: NCT01863186.

SUBMITTER: Fishman M

PROVIDER: S-EPMC6541556 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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:Background and aimMedically managed opioid withdrawal (detox) can increase the risk of subsequent opioid overdose. We assessed the association between mortality following detox and receipt of medications for opioid use disorder (MOUD) and residential treatment after detox.DesignCohort study generated from individually linked public health data sets.SettingMassachusetts, USA.ParticipantsA total of 30 681 opioid detox patients with 61 819 detox episodes between 2012 and 2014.MeasurementsTreatment categories included no post-detox treatment, MOUD, residential treatment or both MOUD and residential treatment identified at monthly intervals. We classified treatment exposures in two ways: (a) 'on-treatment' included any month where a treatment was received and (b) 'with-discontinuation' individuals were considered exposed through the month following treatment discontinuation. We conducted multivariable Cox proportional hazards analyses and extended Kaplan-Meier estimator cumulative incidence for all-cause and opioid-related mortality for the treatment categories as monthly time-varying exposure variables.FindingsTwelve months after detox, 41% received MOUD for a median of 3 months, 35% received residential treatment for a median of 2 months and 13% received both for a median of 5 months. In on-treatment analyses for all-cause mortality compared with no treatment, adjusted hazard ratios (AHR) were 0.34 [95% confidence interval (CI) = 0.27-0.43] for MOUD, 0.63 (95% CI = 0.47-0.84) for residential treatment and 0.11 (95% CI = 0.03-0.43) for both. In with-discontinuation analyses for all-cause mortality, compared with no treatment, AHRs were 0.52 (95% CI = 0.42-0.63) for MOUD, 0.76 (95% CI = 0.59-0.96) for residential treatment and 0.21 (95% CI = 0.08-0.55) for both. Results were similar for opioid-related overdose mortality.ConclusionsAmong people who have undergone medically managed opioid withdrawal, receipt of medications for opioid use disorder, residential treatment or the combination of medications for opioid use disorder and residential treatment were associated with substantially reduced mortality compared with no treatment.

Project description:OBJECTIVES: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μ g oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration ’ s (FDA ’ s) primary end point for IBS-C (responder: improvement of ≥ 30 % in average daily worst abdominal pain score and increase by ≥ 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50 % of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9 / 12 weeks. Adverse events (AEs) were monitored. RESULTS: The trial evaluated 800 patients (mean age = 43.5 years, female = 90.5 % , white = 76.9 % ). The FDA end point was met by 136 / 405 linaclotide-treated patients (33.6 % ), compared with 83 / 395 placebo-treated patients (21.0 % ) ( P < 0.0001) (number needed to treat: 8.0, 95 % confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6 / 12 treatment period weeks, a reduction of ≥ 30 % in abdominal pain (50.1 vs. 37.5 % , P = 0.0003) and an increase of ≥ 1 CSBM from baseline (48.6 vs. 29.6 % , P < 0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points ( P < 0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points ( P < 0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7 % of linaclotide and 0.3 % of placebo patients. CONCLUSIONS: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.