Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60-120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8-24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8-168 (i.e., weeks 2-24; range: 0-161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0-161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24-161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05-1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively-most commonly rapidly-resolving (mild-moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group-none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] -1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00-0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone.

BACKGROUND: Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness - monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated. METHODS: This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2-24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards. DISCUSSION: This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere. TRIAL REGISTRATION: EU Clinical Trials register 2018-004460-63.

Improving access to treatment for patients with chronic hepatitis C through outreach.

BACKGROUND: Chronic hepatitis C infection (HCV) is common in injecting drug users and is a major cause of liver disease. Antiviral treatment can 'cure' HCV, but is frequently associated with side effects and requires regular monitoring. Non-attendance at hospital appointments is frequent. To try and improve attendance and increase the number of current and previous injecting drug users treated we developed three outreach clinics. OBJECTIVE: To review the outcome of patients referred to the outreach clinics. METHODS: Retrospective service review of three clinics at drug treatment centres in Newcastle and Northumberland. Data was collected on attendance rates, patient demographics, treatment rates and outcomes. RESULTS: 141 referrals were received across the three sites with an overall attendance rate of 75% (106 patients, 79% men and median age 36), which compared favourably with that at our hospital (50%). All patients were on methadone/subutex. 45% were infected with Genotype 1 HCV. 10% were cirrhotic. To date, 30% have started treatment and 21% are waiting to start or are still in workup. 13% elected to delay treatment due to early stage disease and 11% were not ready for treatment on psychological or social grounds. Only 12% failed to attend follow up after initial assessment. To date, 24 patients have completed full courses of treatment with sustained viral response in 13 patients. Results are awaited for seven patients. CONCLUSIONS: The development of outreach clinics for HCV in drug treatment centres can substantially improve clinic attendance and increase access to treatment in this marginalised group.

A pilot survey of dental health in a group of drug and alcohol abusers.

This study was designed to provide a broad estimate of the level of dental disease in a group of patients attending a Regional Addiction Unit, and outline some of the perceptions of this group with regard to the importance of dental health and gaining access to dental services. In a survey of consecutive patients admitted to a day Hospital Service at a Regional Addictions Psychiatry Unit, 50 patients were with either opiate or alcohol dependence were surveyed and asked a range of questions in relation to their dental health. A basic dental examination was carried out. The majority of patients had either moderate or severe dental disease. Disease levels were higher among opiate abusers compared to alcohol abusers. A large majority of patients had experienced dental problems within the preceding year and there was found to be a problem in accessing dental care for this group of patients. Improving dental care for this group of patients presents various challenges given the high rates of dental disease and poor access to dental services.

Family history, early adversity and the hypothalamic-pituitary-adrenal (HPA) axis: Mediation of the vulnerability to mood disorders.

The effect of early-life vulnerability factors on the subsequent pathophysiology of severe mood disorders has yet to be fully elucidated. This study examines the relationship between early adverse life experience, family history and hypothalamic-pituitary-adrenal (HPA) axis function. Childhood trauma questionnaire (CTQ) scores, family history data and the cortisol response to the dexamethasone/corticotrophin releasing hormone (dex/CRH) test were examined in 40 patients with severe mood disorder. Normative data for the CTQ was also obtained. The study demonstrated that mood disorder patients reporting high levels of childhood emotional neglect (n = 26) had an HPA axis response which did not differ from controls, whereas patients reporting low levels (n = 19) had an enhanced response (p = 0.011). A positive family history of mood disorder further enhanced this response. These data suggest that early adverse life events and genetic susceptibility have dissociable effects on glucocorticoid receptor-mediated negative feedback of the HPA axis in adult patients with severe mood disorders.

Effect of sub-chronic hydrocortisone on responses to amphetamine in normal male volunteers.

RATIONALE: Enhancement of dopamine (DA) release by corticosteroids may be of aetiological importance in substance misuse. OBJECTIVES: To examine the effect of sub-chronic administration of hydrocortisone on the response to amphetamine in healthy male volunteers. METHODS: Following baseline assessment, 20 volunteers were pretreated for 7 days with 20 mg of hydrocortisone or placebo at 0800 hours and 2000 hours in a double-blind, random order, cross-over design prior to receiving 0.15 mg/kg metamphetamine intravenously. Blood samples for cortisol and prolactin were taken every 15 min. Subjects also underwent tests of neuropsychological function including sustained attention using the rapid visual information processing test (RVIP), which has been shown to be sensitive to changes in DA function. RESULTS: Metamphetamine produced a substantial reduction in prolactin levels, and increased subjective mood ratings of "mind-race" and "buzz". Sub-chronic hydrocortisone administration had no effect on these neuroendocrine responses, subjective mood changes or neurocognitive performance on a task of sustained attention (RVIP). CONCLUSIONS: Despite measurable changes in neuroendocrine and affective functioning in response to metamphetamine, pretreatment with hydrocortisone did not significantly affect any of the variables measured. This suggests that this model of DA function is not affected by this regimen of corticosteroid administration.