Extended-release naltrexone versus standard oral naltrexone versus placebo for opioid use disorder: the NEAT three-arm RCT.

BACKGROUND

People recovering from heroin addiction need better treatments than are currently offered. The chronic relapsing nature of drug dependence means that helping a patient to achieve abstinence is often difficult. Naltrexone blocks the effects of ingested heroin; however, evidence is conflicting regarding the best delivery method.

OBJECTIVES

The primary purpose of the trial was to evaluate the clinical effectiveness and cost-effectiveness of extended-release naltrexone versus standard oral naltrexone versus relapse prevention therapy without medication for opioid use disorder (OUD).

DESIGN

This was a 3-year, definitive, three-centre, three-arm, parallel group, placebo-controlled, double-blind, double-dummy, randomised controlled trial.

SETTING

Two specialist NHS outpatient addiction clinics: one in London and one in Birmingham.

PARTICIPANTS

Planned study sample - 300 adult patients with OUD who had completed detoxification.

INTERVENTIONS

One iGen/Atral-Cipan Extended Release Naltrexone device (iGen/Atral-Cipan, Castanheira do Ribatejo, Portugal) (765 mg naltrexone or placebo) at day 0 of study week 1. Three weekly directly observed active or placebo oral naltrexone tablets (2 × 50 mg, Monday and Wednesday; 3 × 50 mg, Friday) at day 0 of study week 1 (for 4 weeks) and then an 8-week regimen of patient-administered dosing at the same dosing level.

MAIN OUTCOME MEASURE

The primary outcome measure was the proportion of heroin-negative urine drug screen (UDS) results at the end of the 12-week post-randomisation time point.

RESULTS

Six patients were recruited and randomised to receive study interventions. Two patients had no positive UDS samples for heroin during the 12-week treatment period, one patient had only one positive UDS sample and the remaining patients had two, six and eight positive UDS results for heroin. All patients had at least one missed clinic visit (range 1-14).

CONCLUSIONS

Considerable problems were encountered with (1) the stipulated requirement of a validated 'detoxified' status prior to the initiation of the study naltrexone, (2) the requirement for a consent cooling-off period and (3) delays awaiting the surgical implant procedure. Major upheaval to the organisation and delivery of NHS community treatment services across England led to extremely poor levels of actual entry of patients into the trial. Research-vital clinical and procedural requirements were, therefore, more challenging to implement. The potential therapeutic value of the opioid antagonist naltrexone still needs clear investigation, including comparison of the established oral form with the new ultra-long-acting depot implant formulations (for which no licensed products exist in Europe). Despite the small number of study participants, some tentative conclusions can be reached, relevant to potential future work. The blinding of the active/placebo medications appeared to be good. Self-report was not sufficient to detect instances of heroin use. Self-report plus UDS information provided a fuller picture. Instances of lapsed heroin use were not necessarily followed by full relapse, and future work should consider the lapse-relapse relationship. The prison release setting also warrants special consideration. In future, investigators should consider seeking ethics approval for studies in which clinical procedures to accelerate the treatment process are permitted, even if outside orthodox clinical practice, if they address a clinical need at the time of challenge and clinical risk. In addition, it may be appropriate to seek exemption from the ordinary requirement of a cooling-off period after securing consent because it is often essential to initiate treatment promptly.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN95809946.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

Déclaration de conflit d'intérêts

John Strang reports grants and others from Martindale Pharma, grants and others from Mundipharma, and grants and others from Braeburn Pharma, outside the submitted work. In addition, John Strang has a Euro-Celtique patent issued, and a King’s College London patent pending. Michael Kelleher reports grants from the National Institute for Health Research (NIHR) during the conduct of the study, others from South London and Maudsley NHS Foundation Trust, Public Health England, Braeburn Pharma and Reckitt Benckiser, personal fees from Mundipharma and non-financial support from Cephaid, outside the submitted work. Sarah Byford reports grants from NIHR Health Technology Assessment programme during the conduct of the study. John Marsden reports investigator-led, educational grant funding from Indivior (administered by Action-on-Addiction) for a study of personalised psychosocial intervention for non-response to opioid agonist treatment. He declares consultancy for the US National Institute on Drug Abuse Centre for Clinical Trials Network. In the past 3 years, he received honoraria from Merck Serono (2015; clinical oncology training), Martindale (2017; expert meeting on opioid use disorder), and Indivior (via PCM Scientific) as co-chairperson (2015, 2016) and chairperson (2017) for the conference on Improving Outcomes in Treatment of Opioid Dependence.