Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Opioid use disorder is a chronic, debilitating, and costly disorder that has increased in prevalence in many countries, with an associated sharp rise in mortality. Maintenance opioid agonist therapy is the first-line treatment, but many patients do not stop using illicit or non-prescribed drugs concomitantly. We aimed to test the efficacy and cost-effectiveness of a personalised psychosocial intervention implemented with a toolkit of behaviour-change techniques as an adjunct to opioid agonist therapy. METHODS: We did a pragmatic, open-label, randomised controlled trial at a specialist UK National Health Service community addictions clinic in London, UK. Eligible patients were aged 18 years or older, met criteria for opioid or cocaine dependence, or both, in the past 12 months, and voluntarily sought continued oral maintenance opioid agonist therapy, which they had been prescribed for at least 6 weeks. All participants were treatment resistant (ie, had used illicit or non-prescribed opioids or cocaine on one or more days in the past 28 days at study screening, which was verified by positive urine drug screen). Participants were allocated (1:1) by a web-accessed randomisation sequence (stratified by opioid agonist medication, current cocaine use, and current rug use) to receive a personalised psychosocial intervention (comprising a flexible toolkit of psychological-change methods, including contingency management to reinforce abstinence, recovery activities, and clinic attendance) in addition to treatment as usual, or treatment as usual only (control group). The primary outcome was treatment response at 18 weeks, which was defined as abstinence from illicit and non-prescribed opioids and cocaine in the past 28 days, as measured with treatment outcomes profiles and urine drug screening. Taking a societal cost perspective, we did an evaluation of cost-effectiveness with a wide range of willingness-to-pay values for a unit improvement in the probability of treatment response. We also calculated quality-adjusted life-years (QALYs). Efficacy was analysed in a modified-intention-to-treat population, including all participants who were randomly allocated but excluding those who had previously completed the intervention. This trial is registered with ISRCTN, number ISRCTN69313751. The trial is completed. FINDINGS: Between June 7, 2013, and Dec 21, 2015, we randomly allocated 136 participants to the psychosocial intervention group and 137 to the control group. The trial database was locked on April 19, 2017. Three patients (one in the psychosocial intervention group and two in the control group) who were re-randomised in error were excluded from the analysis. 22 (16%) of 135 patients in the psychosocial intervention group had a treatment response, compared with nine (7%) of 135 in the control group (adjusted log odds 1·20 [95% CI 0·01-2·37]; p=0·048). The psychosocial intervention had a higher probability of being cost-effective than treatment as usual. There was a probability range of 47-87% for willingness-to-pay thresholds of £0-1000 for a unit improvement in the probability of treatment response. QALYs were higher in the psychosocial intervention group than in the control group (mean difference 0·048 [95% CI 0·016-0·080]; p=0·004) in adjusted analyses, with 60% and 67% probabilities of cost-effectiveness at the UK National Institute for Health and Care Excellence's willingness-to-pay thresholds of £20 000 and £30 000 per QALY, respectively. The number of adverse events was similar between groups, and no severe adverse events in either group were judged to be treatment related. One participant in the control group was hospitalised with drug-injection-related sepsis and died. INTERPRETATION: In maintenance opioid agonist therapy, an adjunctive personalised psychosocial intervention in addition to standard therapy was efficacious and cost-effective compared with standard therapy alone at helping treatment-resistant patients abstain from using illicit and non-prescribed opioids and cocaine. FUNDING: Indivior.

Memory-Focused Cognitive Therapy for Cocaine Use Disorder: Theory, Procedures and Preliminary Evidence From an External Pilot Randomised Controlled Trial.

BACKGROUND: Cocaine use disorder (CUD) is a debilitating condition with no NICE-recommended medication or specific psychosocial interventions. In the United Kingdom (UK), general counselling (treatment-as-usual; TAU) is widely delivered, but has limited effectiveness. We tested the feasibility, safety and preliminary efficacy of a novel, adjunctive psychosocial intervention for CUD, called 'memory-focused cognitive therapy' (MFCT). METHODS: We did a two-arm, external pilot randomised controlled trial at a specialist community National Health Service addictions clinic in London, UK. 30 adults (≥18years), voluntarily seeking treatment for CUD (enrolled ≥14days; all with moderate-to-severe DSM5 CUD), were individually randomised (1:1) to a control group (ongoing TAU; 3×90min CUD cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; and 3×30min research follow-ups); or to an intervention group (ongoing TAU; 3×90min cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; 5×120min, one-to-one, MFCT sessions [in 1week]; and 3×60min research follow-ups and MFCT-relapse prevention). The primary outcome was the total percentage score on the frequency version of the Craving Experiences Questionnaire (CEQ-F) at 1-month follow-up after the intensive intervention week (clinical endpoint; recall period past 2weeks; higher score indicating greater craving). Secondary outcomes at the 1-month follow-up were percentage days abstinent (PDA) from cocaine, and longest period (days) of continuous abstinence (LPA) in the prior 28days. Outcomes were analysed as an unadjusted group mean difference (with Hedge's g effect size [ES]) and a 95% Confidence Interval [CI] for the primary outcome and a 90% CI for the secondary outcomes. Exploratory, multivariable linear (primary outcome) and Poisson regression models (secondary outcomes), with sex, age, months of regular cocaine use, baseline outcome score, and group estimated the effectiveness of the intervention. The trial is registered with the ISCRTN (ISRCTN16462783). FINDINGS: Between July 15, 2015, and November 27, 2016, 58 patients were assessed for eligibility and 30 participants were randomised (14 to the control group and 16 to the intervention). With outcome data collected for all participants at the endpoint, the intervention group mean CEQ-F score (14·77; SD 21·47) was lower than the control group mean (51·75; SD 22·72); ES -1·62; 95% CI -2·45 to -0·80. MFCT was associated with more cocaine abstinence in the intervention group (PDA 85·94; SD 18·96) than the control group (PDA 54·59; SD 30·29); ES 1·19; 90% CI 0·54 to 1·84. There was also greater maximum abstinence in the intervention group (LPA 15·69; SD 10·10) than the control group (6·00; SD 7·36); ES 1·06; 90% CI 0·41 to 1·70. Exploratory, confounder-adjusted regression models for this preliminary effect supported the treatment association for reduced craving experiences (CEQ-F Coef. -28·25; 95% CI -45·15 to -11·35); more abstinence (PDA Incidence Rate Ratio [IRR] 1·56; 95% CI 1·31 to 1·88); and greater maximum abstinence (LPA IRR 2·56; 95% CI 1·96 to 3·35), although relative weak unmeasured confounding could overturn these model-adjusted exposure-outcome associations. There were four serious adverse events (among three participants). None were judged related to study procedures or interventions. INTERPRETATION: In this first external pilot randomised controlled trial of MFCT for CUD, we have shown that the intervention and control procedures and acceptable feasible and safe, and report preliminary evidence that MFCT is associated with reduced craving and increased abstinence. These findings support progression to a substantive trial. FUNDING SOURCE: UK National Institute for Health Research, Biomedical Research Centre.

Does exposure to opioid substitution treatment in prison reduce the risk of death after release? A national prospective observational study in England.

BACKGROUND AND AIMS: People with opioid use disorder (OUD) in prison face an acute risk of death after release. We estimated whether prison-based opioid substitution treatment (OST) reduces this risk. DESIGN: Prospective observational cohort study using prison health care, national community drug misuse treatment and deaths registers. SETTING: Recruitment at 39 adult prisons in England (32 male; seven female) accounting for 95% of OST treatment in England during study planning. PARTICIPANTS: Adult prisoners diagnosed with OUD (recruited: September 2010-August 2013; first release: September 2010; last release: October 2014; follow-up to February 2016; n = 15 141 in the risk set). INTERVENTION AND COMPARATOR: At release, participants were classified as OST exposed (n = 8645) or OST unexposed (n = 6496). The OST unexposed group did not receive OST, or had been withdrawn, or had a low dose. MEASUREMENTS: Primary outcome: all-cause mortality (ACM) in the first 4 weeks. SECONDARY OUTCOMES: drug-related poisoning (DRP) deaths in the first 4 weeks; ACM and DRP mortality after 4 weeks to 1 year; admission to community drug misuse treatment in the first 4 weeks. Unadjusted and adjusted Cox regression models (covariates: sex, age, drug injecting, problem alcohol use, use of benzodiazepines, cocaine, prison transfer and admission to community treatment), tested difference in mortality rates and community treatment uptake. FINDINGS: During the first 4 weeks after prison release there were 24 ACM deaths: six in the OST exposed group and 18 in the OST unexposed group [mortality rate 0.93 per 100 person-years (py) versus 3.67 per 100 py; hazard ratio (HR) = 0.25; 95% confidence interval (CI) = 0.10-0.64]. There were 18 DRP deaths: OST exposed group mortality rate 0.47 per 100 py versus 3.06 per 100 py in the OST unexposed group (HR = 0.15; 95% CI = 0.04-0.53). There was no group difference in mortality risk after the first month. The OST exposed group was more likely to enter drug misuse treatment in the first month post-release (odds ratio 2.47, 95% CI = 2.31-2.65). The OST mortality protective effect on ACM and DRP mortality risk was not attenuated by demographic, overdose risk factors, prison transfer or community treatment (fully adjusted HR = 0.25; 95% CI = 0.09-0.64 and HR = 0.15; 95% CI = 0.04-0.52, respectively). CONCLUSIONS: In an English national study, prison-based opioid substitution therapy was associated with a 75% reduction in all-cause mortality and an 85% reduction in fatal drug-related poisoning in the first month after release.

Memory-focused cognitive therapy for cocaine use disorder: Rationale, design and protocol for an external pilot randomised controlled trial.

INTRODUCTION: Cocaine use disorder (CUD) is a debilitating condition characterised by maladaptive cocaine-related memories and impaired cognitive and behavioural control. There are no evidence-supported pharmacotherapies and only weakly effective psychological interventions specific for CUD. Our novel Memory-focused Cognitive Therapy (MFCT) aims to modify cocaine-related memories to reduce craving and drug use. METHODS: This is a single-centre (outpatient), 15-week, two-arm, pilot randomised controlled trial (RCT) to address feasibility, safety, quality and preliminary efficacy. Thirty participants (adults ≥18 years; current CUD) will receive ongoing standard care (treatment-as-usual [TAU]) during the study and will be randomised (1:1) to a control or intervention group. The control group will receive 3 × 90min CUD cognitive case conceptualisation assessments and 2 × 30min cocaine-related cue-induction procedures (in vivo presentation of images and objects). Experimental group participants will receive 3 × 90min CUD cognitive case conceptualisation assessments; 2 × 30min cue-induction procedures; and individual MFCT (5 × 120min; daily for 1 week; with 3 relapse prevention follow-ups over 3-months). All study participants will complete research follow-ups at 1-week, 1-month and 3-months. The experimental and control groups will be compared on the mean score on the frequency version of the Craving Experience Questionnaire at 1-month (primary outcome measure). Secondary outcomes include: percentage of days abstinent and longest period of continuous abstinence from cocaine (past 28-days at 1-month follow-up); urine drug screen and CUD diagnosis (DSM-5). CONCLUSIONS: We will conduct a full external pilot RCT of a novel, MFCT for CUD. The findings will inform the case, and necessary modifications, for a substantive study.

Effectiveness of adjunctive, personalised psychosocial intervention for non-response to opioid agonist treatment: Study protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Opioid use disorder (OUD) is a debilitating and relapsing psychiatric disorder; opioid agonist therapy (OAT) is the front-line, evidence-supported treatment. A substantial number of patients relapse or continue to use heroin or other illicit drugs during OAT. There is considerable heterogeneity in the OAT-resistant sub-population, with many behavioural moderators of treatment response. We have developed a personalised psychosocial intervention (PSI) targeting these individuals. A formulation-guided assessment is linked to a toolkit of motivational, cognitive/behavioural and social support techniques. Change methods have been adapted from evidence-supported psychological therapies and are idiosyncratically tailored to the need and response. METHODS: In this single-centre, 18-week, parallel group, pragmatic randomised clinical trial, we will determine the clinical and cost-effectiveness of the PSI as an adjunctive intervention during OAT, in comparison to opioid agonist treatment-as-usual. We plan to recruit 368 adults. The primary outcome measure is the proportion of participants categorised as 'responders' at the end of the intervention (defined as self-reported abstinence from heroin and cocaine with no positive biological drug tests during the 28days prior to the endpoint). Secondary outcomes include: percentage of days abstinent from heroin and cocaine in the 28days before follow-up; treatment retention; therapy compliance; health and social functioning; exploratory genetic biomarkers; and analyses of treatment moderation and mediation. CONCLUSIONS: This pragmatic controlled trial determines the effectiveness and cost-effectiveness of a personalised PSI for non-responding patients during OAT. Our intervention applies motivational, cognitive/behavioural and social support techniques adapted from evidence-based therapies. Findings will inform stratified delivery of OAT.

An evaluation of a brief motivational intervention among young ecstasy and cocaine users: no effect on substance and alcohol use outcomes.

AIMS: To investigate whether a stimulant- and alcohol-focused brief motivational intervention induces positive behaviour change among young, regular users of MDMA ('ecstasy'), cocaine powder and crack cocaine. DESIGN AND MEASUREMENTS: A randomized trial of the intervention versus a control group who received written health risk information materials only. All participants completed a baseline self-assessment questionnaire before randomization. Outcome measures were self-reported period prevalence abstinence from ecstasy, cocaine powder and crack cocaine and the frequency and amount of stimulant and alcohol use in the previous 90 days, recorded at 6-month follow-up via self-completion questionnaire and personal interview. PARTICIPANTS AND SETTING: A total of 342 adolescent and young adult stimulant users (aged 16-22 years) were recruited and 87% were followed-up. The intervention was delivered by a team of 12 agency youth drug workers and two researchers at five locations in Greater London and south-east England. FINDINGS: There were no significant differences in abstinence for ecstasy, cocaine powder or crack cocaine use between the experimental and control groups. Contrasting follow-up with baseline self-reports, there were no between-group effects for changes in the frequency or amount of stimulant or alcohol use. Participant follow-up data suggested that the baseline assessment was a contributing factor in within-group behaviour change among experimental and control condition participants. CONCLUSIONS: Our brief motivational intervention was no more effective at inducing behaviour change than the provision of information alone. We hypothesize that research recruitment, baseline self-assessment and contact with study personnel are influences that induce positive reactive effects on stimulant use.

Alcohol use by young people from different ethnic groups: consumption, intoxication and negative consequences.

OBJECTIVE: To investigate alcohol consumption among mid-adolescents from different ethnic groups and explore overall and gender variations in drinking behaviours. METHODS: A survey of alcohol use by 609 14-16 year olds recruited from three schools in an ethnically diverse area of London. Approximately 70% of the sample was of white English, white Irish, black Caribbean or black African ethnic origin. Self-report information was collected via a researcher-administered structured interview. RESULTS: There was a significantly lower prevalence of lifetime alcohol use among black African respondents than among the other three ethnic groups. Black African males and males and females from the two white ethnic groups reported drinking above levels recommended by the English Department of Health. Among the recent drinkers, over half of the white Irish and white English groups and over a quarter of black Caribbean and black African groups had been intoxicated in the 90 days before interview. Approximately three quarters of the white English and white Irish recent drinkers, but only a half of black Caribbean and black African recent drinkers had experienced a negative drinking-related consequence during the last year. CONCLUSIONS: The survey findings suggest that while young people of white English or white Irish ethnic origin from the populations studied are more likely to drink excessively and experience negative consequences from their drinking than black African and black Caribbean youth, a substantial minority of black African and black Caribbean youth also experience alcohol-related problems.

Relationship between prescribing and risk of opiate overdose among drug users in and out of maintenance treatment.

Opiate users (n = 135) from southern England, Glasgow and Edinburgh were interviewed about opiate overdose (lifetime). Fifty-six percent had overdosed. The majority (66%) reported mixing opiates with at least one other drug (mainly alcohol and/or benzodiazepines) at their last overdose. Patients identified misjudgements of purity, mixing drugs and misjudgements of tolerance as causes of overdose. The sample was divided into groups: (1) 'no prescription', (2) prescribed 'diazepam only', (3) prescribed 'methadone only' and (4) prescribed 'methadone + diazepam'. The 'methadone + diazepam' group reported more lifetime and deliberate overdoses, the 'methadone only' group were more likely to have used several drugs at the time of their last overdose and the 'no prescription' group to have used only heroin. Drug users' overdose risk may vary as a result of their prescribed and non-prescribed drug use. Interventions should be developed and tailored according to clients' needs and current use patterns.

Minimizing respondent attrition in longitudinal research: practical implications from a cohort study of adolescent drinking.

The methods used to maximize retention in a longitudinal study of adolescent drinking are discussed. Data were collected at three time points: at recruitment to the study, after nine months and at 18 months. Strategies to minimize attrition included the collection of detailed contact information, incentives for participation, postcard and telephone reminders and telephone interviews. Ninety-six percent of the original sample completed the first follow-up questionnaire, 92% completed the second and the study lost contact with just 3% of participants. The success of the current project is notable as this type of population is notoriously difficult to retain in longitudinal studies.

Peer overdose resuscitation: multiple intervention strategies and time to response by drug users who witness overdose.

One hundred and thirty-five drug users in contact with treatment services in Scotland and England were interviewed about their experiences of witnessing overdoses - both overdoses resolved successfully and those leading to death - and actions taken to effect resuscitation. One hundred and four (77%) had witnessed a mean of 11.5 overdoses, of whom 41 (30.4% of the study sample) had witnessed an average of 4.2 fatal overdoses. A wide range of actions was reported at the most recent witnessed overdose, the most common being slapping or shaking the victim (an average of 2.5 minutes after overdose was first recognised) or walking the person around the room (3.2 minutes after recognizing overdose). There was no consistent relationship between the time taken to acting and the number of actions taken. Successful resolution of last witnessed overdose was associated more strongly with immediate onset of overdose, while those that led to death were more often those that involved slow onset of overdose. There is clear evidence of the opportunity and willingness of witnesses to intervene, particularly when overdose onset is immediate, with a wide range of strategies adopted to encourage recovery, although these may often be inappropriate and wrongly prioritized.

Prison based detoxification for opioid dependence: a randomised double blind controlled trial of lofexidine and methadone.

This paper reports results from the first controlled trial of opioid withdrawal treatment in the UK using lofexidine in a prison setting. Seventy-four opioid dependent male inmates at a Southern England prison were randomised to receive either methadone (the standard prison treatment) or lofexidine using a randomised double-blind design. No significant statistical difference between the treatment groups was found in relation to the primary variable of severity of withdrawal symptoms (effect size=0.12). No discernible difference was found in the sitting blood pressure or heart rate of the two groups during the trial. These results provide support for the use of lofexidine for the management of opioid detoxification in the prison setting.