FORWARDS-2; study protocol for a double-blind randomised placebo-controlled trial to evaluate baclofen as an adjunct to support methadone detoxification

IntroductionDetoxification from opioid substitution therapy (OST), particularly methadone, is challenging. Although many individuals on OST seek abstinence, withdrawal symptoms such as anxiety and insomnia often undermine these efforts. Baclofen, a GABA-B receptor agonist licensed for spasticity and used off-label in alcohol dependence, has shown promise in alleviating opioid withdrawal symptoms. The FORWARDS-1 trial established that baclofen can be safely co-administered with methadone. FORWARDS-2 now aims to investigate whether baclofen can facilitate methadone dose reduction and thus could be repurposed as a novel adjunct to support opioid detoxification. The protocol for this feasibility and proof-of-concept trial is described.MethodsFORWARDS-2 is a multi-centre, double-blind, randomised placebo-controlled trial, conducted in UK community addiction services. Participants are adults with DSM-5 severe opioid use disorder (OUD) receiving methadone and seeking dose reduction or detoxification. Participants will be randomised 1:1 to receive either baclofen or placebo (target dose: 10 mg tds; max: 20 mg tds) for up to 12 weeks. Methadone dose reductions will be managed by the addiction service team. The primary outcome measure to assess proof of concept is methadone dose (mg/d) at 12 weeks, or time of abstinence if sooner. The trial’s feasibility outcomes will be assessed after an initial internal 6 month feasibility phase and at the end of the study. These include recruitment rate, retention rate, and implementation across NHS and non-NHS (third sector) services. A parallel qualitative substudy will assess barriers and facilitators to detoxification and conduct a process evaluation.DiscussionThis pragmatic trial will represent the first such community-based UK opioid detoxification trial in decades and the first clinical trial of an ‘investigational medicinal product (CTIMP) to be delivered within non-NHS community addiction services. If the primary outcome demonstrates that baclofen provides clinically meaningful benefits over placebo, this could offer a new pharmacological tool to support opioid detoxification, marking a significant step forward for OUD treatment. Moreover, the trial will establish new infrastructure for OUD research in UK addiction services, supporting future studies on detox pathways, withdrawal management, and relapse prevention.Introduction