FORWARDS; Facilitating Opiate Recovery: Withdrawal and Abstinence through Detoxification Support.

Opiate addiction is a major health challenge. Treatment with opiate substitution treatment (OST; eg methadone or buprenorphine) and psychosocial support has been highly effective in improving health and social functioning. However there is now a growing focus on abstinence, particularly for older opiate addicts with increasingly complex physical and mental health needs; death rates are now the highest in those aged 40-49 years old. Detoxification generally involves tapering of OST with supportive medication including sleeping tablets or lofexidine to treat emerging symptoms, but their efficacy is limited and/or can only be used short-term. Currently lofexidine has been unavailable for over a year and it is unclear when it will become available again. There have been no new medications in decades. We need to develop treatments suitable for community settings since availability of inpatient or residential treatment is limited. Based on evidence, we propose that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse to meet this unmet need. Baclofen is generic, licensed for spasticity, and is currently used off-label to treat alcoholism. Despite desiring abstinence, few opiate addicts successfully complete detoxification due to presence or fear of withdrawal symptoms including anxiety, insomnia, muscle aches, restless legs and craving. Such symptoms 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. In addition, there is a possibility of addicts taking higher than recommended doses, so our first study will therefore determine what are safe dose combinations of baclofen and methadone and to assess if baclofen is 'liked'. We will only study methadone as it is the most common OST and due to its full agonist effects in the brain, more likely than buprenorphine (a partial agonist) to cause adverse effects. We will recruit stable opiate addicts (DSM-5) on stable doses of methadone. The study will be a placebo controlled, single ascending dose pharmacokinetic-pharmacodynamic study that involves measuring baclofen plasma levels alongside its objective (respiration, heart rate, growth hormone) and subjective effects (anxiety, sedation, 'liking'). Participants will attend our clinical research facility where they will complete assessments at baseline and for the next 6hrs including physical (cardiovascular, respiratory), mood (anxiety), and opiate-related measures (craving, withdrawal). An hour after taking their usual methadone medication, they will take baclofen or placebo. We will give increasing doses of baclofen (10mg, 30mg, 60mg, 90mg) to compare with placebo to patients on a range of methadone doses; if a combination results in no adverse effects, we will increase the baclofen dose level. Evidence from studies in alcoholism suggests that baclofen >90mg is unlikely to be efficacious so we do not intend to go higher than this. Assuming we can safely combine baclofen and methadone at clinically relevant doses, we will then conduct a placebo-controlled, randomized proof-of-concept trial to determine if baclofen is useful for facilitating detoxification from methadone in opiate addicts. We will recruit only those who are committed to our community opiate detoxification pathway so that 56 complete this trial. Our aim is to see whether baclofen produces a clinically meaningful reduction in methadone dose and increases abstinence rates. Data will be collected during the trial using validated measures eg opiate withdrawal, anxiety, sleep, restless legs. We will also collect information about adverse events and feasibility of recruitment and retention. We will obtain data to design the definitive trial for which the primary outcome will be the proportion of participants successfully achieving abstinence