Characterizing the neurobiology of detoxification and early abstinence in opiate addiction: is there a role for NK1 antagonism to improve outcomes?

Opiate addiction is one of the major health challenges facing the UK today, with the numbers of opiate-related deaths rising to record levels. The harm minimisation approach to treatment with opiate substitution medication (e.g. methadone) and psychosocial support has been highly effective in improving health and social functioning, but there is now an increasing focus on achieving abstinence. Indeed abstinence is likely to be better for overall health, particularly in the aging opiate addict population who have increasingly complex health and social care needs. Many addicts desire abstinence but find it hard to achieve and maintain. The effectiveness of the only licensed medication to prevent relapse, naltrexone, is limited and take-up is low, so we are in need of new treatments. We believe that understanding brain processes better, such as reward, emotional processing and responses to drug-related cues, will inform how best to improve treatment of opiate detoxification and relapse prevention.

To do this we have established an experimental platform using lab-based tasks and functional magnetic resonance imaging (fMRI) to measure changes in brain responses during tasks that are relevant to relapse. In long-term abstinent addicts, we have shoen reduced responses in the striatum, a brain region that mediates reward and increased responses to negative images (e.g. of a car crash) in the amygdala, a part of the brain involved in emotional processing. This pattern of responses is consistent with addicts describing difficulty in experiencing pleasure, feeling anxious and 'stressed'. In addition, the blunted response to reward was associated with higher risk of relapse. We also showed that aprepitant, a medication that blocks a target in the brain (NK1 receptor) reduces the amygdalar hyper-reactivity to negative images seen in opiate addicts. Along with preclinical evidence, this suggests that aprepitant has therapeutic potential to treat opiate addiction.

We will now use this experimental approach to conduct a randomised, placebo-controlled study of a single dose of aprepitant in opiate dependent individuals towards the end of their community based detoxification from methadone and again within a few weeks of abstinence. Each participant will attend our clinical research unit for study days that will include fMRI scans to assess brain responses to reward anticipation, processing of negative images and also opiate-related cues given their involvement in relapse. We will assess the subjective (how they feel) and objective (how they perform) impact of lab-based tasks that involve processing of reward and of positive and negative emotional stimuli.

At the start of a study day, participants will take their daily methadone and then be randomly allocated to take either placebo or aprepitant before completing the MR protocol and cognitive tasks. On their 2nd visit at least a week later, they will take the other medication and complete the same study tasks. We will also measure whether aprepitant moderates any subjective (e.g. liking) or objective (e.g. breathing) effects of their dose of methadone. In their first few weeks of abstinence, they will return to complete the two study days again, though without taking methadone; the order of taking placebo and aprepitant will be randomly allocated.

Our proposal will provide evidence about whether the NK1 antagonist, aprepitant, is a credible target for a clinical trial to improve the current poor outcomes in either or both detoxification and early abstinence in opiate addiction. We already know that aprepitant is a safe and well tolerated medication as it is already licensed for another indication. In addition we will have characterised brain processes during opiate detoxification from methadone and early abstinence by characterizing task performance and brain responses to processes involved in relapse: reward, emotional processing and cue-reactivity.

We are one of the few groups in the world to characterize the neurobiology of opiate addiction to improve treatment outcomes. We established the largest multi-centre imaging study of its kind in addiction, the MRC-funded ICCAM platform study which assesses anticipation of monetary reward with the monetary incentive delay task and emotional processing networks with an evocative images task in abstinent substance addiction. We have identified the potential of the following as brain biomarkers for addiction: blunted striatal response during anticipation of reward and amygdalar hyper-reactivity in response to adverse images. We have shown that NK1 antagonism shows therapeutic potential as it normalised the amygdalar hyper-reactivity in polydrug (mostly opiate dependent) addicts. We now need to apply this ICCAM platform to provide evidence whether the NK1 antagonist, aprepitant, is a credible treatment to take forward to a clinical trial in opiate detoxification and early abstinence.

We will conduct a double-blind randomised, placebo-controlled crossover study of a single dose of aprepitant in opiate dependent individuals towards the end of their detoxification and again within a few weeks of abstinence. The MR scan protocol will be completed on a 3T Siemens Tim Trio: structural T1 weighted image, diffusion tensor imaging sequence, resting state, ASL, monetary incentive delay task, evocative images task and cue-reactivity task. We will assess neurocognitive correlates to provide behavioural measures of probabilistic reward learning and of emotional processing. A neuropsychological biomarker would be a clinically feasible and cost-effective approach to stratifying patient treatment. Our imaging and neurocognitive datasets provide a uniquely rich dataset to correlate functional brain responses with neuropsychological, clinical and outcome variables.

Individuals with opiate addiction, their families and wider society.
Without understanding the underlying neurobiology, there will be limited advances in the treatment of opiate detoxification and relapse prevention. Currently available treatments are insufficient and outcomes are relatively poor. 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). Our research 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 on the 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 receive naltrexone, a medication for relapse prevention. A major contributing factor to this low level of prescribing is limited evidence for its effectiveness.

Academic beneficiaries. Established academic individuals and groups will benefit through increased knowledge about the neurobiology of not only opiate addiction but also brain processes such as reward and emotional processing whose dysregulation is involved in many neuropsychiatric disorders. Thus the range of preclinical and clinical academic disciplines who will benefit is broad and detailed in the academic beneficiaries section.

Industry. Whilst Pharma is currently investing less in addiction and psychiatry, opiate addiction is an area of interest given the rising death rates for people abusing opiates - including prescription drugs. In addition the processes we study are involved in many aspects of health and illness and so are likely to be of interest to those working in other neuropsychiatry disorders. Understanding these processes is likely to inform management of other challenging global issues such as obesity where behavioural changes are also required.