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.

Conflict of interest statement

Conflicts of interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Fishman is a consultant for US WorldMeds, LLC, and for Alkermes, and reported receiving study funding from NIDA, Arnold Foundation, and Media Rez. Dr Tirado reported serving on speaker panels for Indivior and Alkermes plc. Dr Alam is a consultant for US WorldMeds, LLC, and for Alkermes, and reported receiving research support from Allergan, Otsuka, Janssen, and Alkermes. Ms Gullo is an employee and shareholder of US WorldMeds, LLC. Mr Clinch is an employee and shareholder of US WorldMeds, LLC. Dr Gorodetzky is a consultant to US WorldMeds, LLC. This work was supported by US WorldMeds, LLC, and the National Institute on Drug Abuse (grant U01DA033276).

Figures

FIGURE 1

Participant flow diagram. aOne participant was randomly assigned into the study, but not dosed. bIncludes nonrelated adverse events, lack of adherence, evidence of contraband drug use, therapy with exclusionary drug, intensive cravings, did not want to continue inpatient, left against medical advice, completed detoxification, and protocol nonadherence. AE, adverse event; DB, double-blind; LFX, lofexidine; mITT, modified intent-to-treat.

FIGURE 2

Geometric means (95% confidence interval) for Short Opiate Withdrawal Scale of Gossop score from days 1 to 7 (modified intent-to-treat population). In this pattern-mixture model analysis, the geometric mean SOWS-Gossop score on each study day is the back-transformed least squares mean estimate based on log-transformed data. Lower scores indicate less severe withdrawal symptoms. SOWS-Gossop, Short Opiate Withdrawal Scale of Gossop.

FIGURE 3

Least square means (95% confidence interval) for COWS score from days 1 to 7 (modified intent-to-treat population). LS means from mixed model repeat measures analysis. Lower scores indicate less severe withdrawal symptoms. COWS, Clinical Opiate Withdrawal Scale; LS, least squares.