FORWARDS-1: Evaluating the safety of baclofen in methadone-maintained opiate dependence
Research type
Research Study
Full title
FORWARDS-1; Evaluating the safety of acute baclofen in methadone-maintained individuals with opiate dependence. An adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment; a pharmacokinetic-pharmacodynamic study.
IRAS ID
1003802
Contact name
Anne Lingford-Hughes
Contact email
Sponsor organisation
Imperial College London
Eudract number
2021-002556-36
Clinicaltrials.gov Identifier
Research summary
Research Summary
Opiate addiction is a major health challenge. The mainstay of treatment is opiate substitution therapy (OST), typically methadone, but many desire to be opiate-free. Abstinence in older opiate addicts with increasingly complex health needs may also be advantageous. Detoxification generally involves tapering of OST with adjunct medication to treat emerging symptoms, but these are often ineffective or inappropriate for longer-term prescribing. New treatments are therefore needed. We propose that baclofen has the desired properties to facilitate OST detoxification. It is licensed for spasticity, is currently used to treat alcoholism and there is promising pre-clinical and clinical evidence of potential efficacy in opiate dependence. Common symptoms of withdrawal are likely to be improved by baclofen. Whilst our clinical experience and other studies suggest baclofen can be taken safely with methadone, they could potentially interact causing adverse effects such as respiratory depression. Also, the possibility of abuse liability remains unexplored and is an important consideration in this indication. We will therefore determine the safe dose combinations of baclofen and methadone and to assess if baclofen is 'liked'. Patients engaged in treatment for opiate dependence from community addiction services and receiving stable doses of OST with methadone will be invited to undergo screening at the Imperial Clinical Research Facility (ICRF) at Hammersmith hospital, or at their local addiction clinic. Up to 64 eligible patients will attend the ICRF for an experimental visit. Acute baclofen or placebo will be orally administered (randomised, single-blind, 3:1 ratio respectively) with the dose determined by a Bayesian adaptive trial algorithm. Measures will comprise respiratory, sedation, self-report and cardiovascular monitoring, and blood sampling for 5 hours post-dose. The study duration will be ~2-3 weeks from pre-screening phone call to the post visit follow up phone call.
Summary of Results
People with opiate dependence who are receiving long-term opioid substitution treatments such as methadone may desire abstinence, or may benefit from detoxification or dose reduction. However disturbed sleep, anxiety and craving during withdrawal make detoxification challenging. There are very few treatments available to support methadone dose reduction or facilitate opiate detoxification. Baclofen is a promising medication that is licensed to treat spasticity and is also prescribed to treat alcohol addiction. Baclofen also has sleep promoting properties and can reduce anxiety and may therefore reduce withdrawal symptoms. This indicates that it could be a potential treatment to manage opiate withdrawal symptoms that emerge during detoxification. Methadone and baclofen are both sedative medications with central nervous system depressant effects, therefore it is important to make sure that combining these medications is safe.
FORWARDS-1 investigated the safety of baclofen when prescribed together with methadone. The aim was to determine whether a minimum of 30mg baclofen can be safely prescribed to individuals on methadone without evidence of changes in central nervous system function.
Methods: Sixteen opiate-dependent individuals (14 male) maintained on methadone were recruited and randomly allocated to receive a single dose of baclofen or placebo (3:1 ratio) in a dose finding trial design. Participants were unaware of which treatment they received. A statistical model decided the baclofen dose to give to participants, according to the participant’s prescribed methadone dose and the incidence of ‘Dose-Limiting Toxicity’ (DLT) events. DLT events were defined as respiratory, cardiovascular, or sedative measures that met a certain severity threshold in response to baclofen. On the study day, participants took their usual methadone dose and were then given baclofen (10, 30 or 60mg) or matched placebo to take 1h later. Vital signs including respiratory and cardiovascular measures, drug effects (e.g. craving, sedation, liking) and blood levels were monitored for 5h.
Results: Participants’ methadone doses ranged from 8 to 70mg/day. No DLT events occurred in response to the baclofen doses tested, and there were no serious adverse events. Baclofen was well tolerated with the most common side effects being sedation/sleepiness and stomach upset. The statistical model confirmed that at the highest doses tested (i.e. 60mg baclofen with up to 70mg/day methadone) the probability of dose limiting toxicity was low. In summary, baclofen doses of up to 60mg can be given safely with up to 70mg/d methadone.
Conclusions: We established that it is safe to prescribe up to 70mg methadone per day together with up to 60mg baclofen, i.e. doses of methadone that are consistent with current prescribing and doses of baclofen likely to be effective and well tolerated. However, due to the small sample size and the high proportion of males in the study, caution should be exercised when generalising the findings to female participants. FORWARDS-2 will now seek to investigate the effectiveness of baclofen in supporting methadone dose reduction and detoxification in a UK multi-site feasibility and proof-of-concept trial.
REC name
West of Scotland REC 1
REC reference
21/WS/0080
Date of REC Opinion
5 Aug 2021
REC opinion
Further Information Favourable Opinion