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

This proposal targets improving the current poor outcomes for opiate detoxification. Based on supportive preclinical and preliminary clinical evidence, we will assess whether the GABA-B agonist, baclofen, can facilitate detoxification from methadone, the most commonly used opiate substitution therapy (OST) in opiate addiction. First, optimal combined doses of baclofen and methadone will be identified that show no safety concerns (study 1). Opiate addicts (DSM-5) on methadone maintenance for over 4 weeks will complete a placebo controlled, single (subject) blind, single ascending dose pharmacokinetic-pharmacodynamic study in a parallel group sequential design. Our planned escalation of baclofen is 10mg-30mg-60mg-90mg, with at least n=8 at each baclofen or placebo dose level in a 3:1 ratio respectively, at a range of methadone doses (<60mg, =/>60mg). Assessments of safety and tolerability include: cardiovascular, respiration, anxiety, sedation, opiate withdrawal, craving, plasma baclofen and growth hormone levels. To proceed with Study 2, at least 30mg baclofen must be safe with a minimum of 60mg/d methadone ie clinically relevant doses. Assuming safety is evident, Study 2 will be a proof-of-concept double-blind randomised placebo-controlled trial to determine if baclofen shows potential efficacy in facilitating detoxification from methadone in community-based opiate addicts. We will include an internal feasibility phase and recruit sufficient opiate addicts (DSM-5) so that 56 complete the trial. The primary outcome is the reduction in methadone dose in baclofen vs placebo within 12 weeks. Secondary outcomes of abstinence, time to abstinence, anxiety, sleep, restless legs, adverse events and feasibility regarding recruitment and retention will be collected. If a clinically meaningful reduction in methadone dose is observed and other measures are positive, we will design a full trial to determine if baclofen can successfully facilitate detoxification from OST.

Individuals with opiate addiction, their families and wider society.
There have been very limited advances in the treatment of opiate detoxification and relapse prevention. Currently available treatments are insufficient and outcomes are relatively poor. Further, the only licensed adjunctive medication for opiate detoxification, lofexidine, has been unavailable for over a year and is unclear when it will return. By supporting more people to achieve abstinence successfully, the individuals' physical and mental health will improve along with their quality of life and well-being. It is estimated that the annual cost to the family members and carers of heroin and/or crack cocaine users is £2bn (An evidence review of the outcomes that can be expected of drug misuse treatment in England, Public Health England, 2017). This included costs of being a victim of crime, lost employment opportunities, health service use, and financial support given to relatives. Further, every £1 invested in drug treatment results in a £2.50 benefit to society. Thus supporting individuals to achieve abstinence successfully will in turn lead to wider societal and economic benefits.

NHS, 3rd sector organisations and practitioners.
The health costs of opiate addiction to the UK are immense. The majority of individuals misusing illicit drugs in contact with services are receiving treatment for opiate dependence. The cost of illicit drug use in the UK is estimated at £11.4bn which includes drug-related crime, enforcement, health service use and deaths (An evidence review of the outcomes that can be expected of drug misuse treatment in England, Public Health England, 2017). Of which, 8% is incurred by drug treatment services and the NHS. By improving treatment, broader NHS services will therefore benefit by reduction in financial costs, resources and time taken to treat opiate related morbidity. Our research also gives an opportunity to clinicians gain experience in the addiction field (training posts for Drs in addictions have reduced by ~50% in a decade). This proposal also provides a valuable opportunity to improve knowledge and skills in those working in the 3rd sector since they may not have received training or experience in research or in the neurobiology of addiction. This is vital to optimise research and development since currently many of UK addiction treatment services are led by 3rd sector organisations.

Clinical guidelines, policy makers.
Providing further evidence about potential treatments and underlying neurobiology of opiate addiction is key to optimising clinical guidelines and informing policy makers about the best approach to managing and treating opiate addiction. Improved treatment strategies will in turn benefit patients, their families, the NHS and wider society. Treatment for opiate addiction should include 'appropriate psychosocial and pharmacological treatments' in line with NICE guidance. However currently in the UK, very few individuals undergo detoxification. This study will provide invaluable information about how to optimise opiate detoxification pathways so that abstinence can be achieved in those that desire it.

Academic beneficiaries.
The range of preclinical and clinical academic disciplines who will benefit is broad such as those interested in neuropharmacology and neuroscience in general and specifically neurobiology of addiction and fully detailed in the academic beneficiaries section. Industry: Within addictions, opiate addiction is an area of great interest for Pharma given the rising death rates for people abusing opiates - including prescription drugs. They appear more focussed on opiate substitute medications with and without opiate antagonists for opiate addiction with less visible interest in alternative approaches. Nevertheless GABA-B modulators are being actively pursued in alcohol and cocaine addiction so our study will be of interest to those academics and Pharma involved.