Introduction

Opioid overdose is a major cause of premature mortality 1. In Scotland, drugs‐related deaths (DRDs) averaged 500 per annum during 2006–10, nearly 80% of them opioid‐related 2, 3. Scotland has one of the European Union's highest DRD rates at 94 per million of population, and almost as high as the United States at 116 DRDs per million of population 4.

One‐third of receptions into Scottish prison custody test positive for opiates 5, and surveillance shows that in 2010 6, as in the 1990s, one‐third of inmates has a history of injection drug use. Scotland has some 60 000 problem drug users (PDUs) 7, 8, of whom two‐fifths are aged 35+ years. More than 20 000 clients receive opioid‐substitution therapy 5, 9, which is continued in Scottish prison custody 10.

The risk of DRD is particularly high for problem drug users after periods of relative abstinence, most notably soon after prison release 11-13, but also after hospital discharge 14, 15. The most probable reason is loss of tolerance of opioids, but prison release and hospital discharge may also mark transitions to vulnerability for other reasons. The first quantification of the high risk of DRD in the 2 weeks after prison release was made in Scotland for HIV‐infected injectors released from Edinburgh Prison in 1983–94 12. Bird & Hutchinson 13 showed that a seven times higher DRD risk in the first fortnight persisted for male releases from Scottish prison custody in 1996–99. International meta‐analysis 11 has demonstrated that prisoners' DRD risk is still elevated in the second 2 weeks post‐release. During 1996–10, White et al. 15 estimated 2.4 DRDs in the subsequent 4 weeks per 1000 hospital discharges of Scotland's drug treatment clients with a history of injection drug use, approximately half the DRD risk for ever‐injectors in the 4 weeks after prison release 16.

Bird & Hutchinson 13 had proposed a prison‐based randomized controlled trial of naloxone‐on‐release but it was not until 2005 that the opioid antagonist naloxone was added to the United Kingdom's exempt list of prescription‐only medicines that could be administered intramuscularly by anyone in an emergency to save life 17. Some long‐established naloxone services in America 18-23 gave a lead, and several editorials were published 24-26. Naloxone is now provided for at‐risk patients and other first responders 1 by selected services in several European countries, Australian states and Canadian provinces.

In 2008, the UK Medical Research Council funded the pilot phase of the individually randomized N‐ALIVE Trial to test the effectiveness of naloxone‐on‐release for reducing eligible prisoners' DRDs within 4 weeks of their prison release (by 30%) and during the next 8 weeks (by 20%) 16. The N‐ALIVE Trial had been due to begin in Scotland's adult prisons but, in January 2011, was pre‐empted when Scotland became the first country internationally to introduce a centrally funded, coordinated and evaluated National Naloxone Policy (NNP) 27, 28; see Supporting information.

Across Scotland, there is a standardized naloxone‐supply scheme, and a national Patient Group Directive for supplying take‐home naloxone 29. For lay administration to adults, Scotland followed the British National Formulary recommendation of ‘intramuscular injection of 400 micrograms repeated at intervals of 2–3 minutes (in subsequent resuscitation cycles if patient not breathing normally) until consciousness regained, breathing normally, medical assistance available, or contents of syringe used up'. After completing a brief intervention (10–15 minutes), individuals at risk of opioid overdose can be prescribed naloxone. Training is delivered by a range of staff: nurses, pharmacists, voluntary‐sector workers and peer trainers, and takes place typically in community substance misuse services and pharmacies. All 15 prisons in Scotland offer naloxone‐on‐release.

Evidence of naloxone's effectiveness in reducing fatalities from opioid overdose was rated as weak by the World Health Organization 30, and has been insufficient for policy change in America 4. Scotland's NNP makes it uniquely placed to address these important limitations on empirical knowledge about naloxone's effectiveness at a population level. In this paper, we: (1) summarize the power of Scotland's before/after evaluation of its National Naloxone Policy based on well‐defined primary and secondary outcomes; (2) appraise the evidence for NNP's effectiveness by comparing outcomes in the 5 years before NNP (2006–10) and in NNP's first 3 years (2011–13); (3) apply Hill's criteria for the assessment of causality; and (4) estimate the prescription cost per quality‐adjusted life‐year (QALY) gained by ORD prevention, alternatively for 1 or 10 years.