Introduction

Parts of this chapter have been reproduced from Jones et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Background

In England, over half of drug deaths involve opioids, and death by drug overdose has increased since 2012.2 In the UK, accidental overdose related to the misuse of opioid drugs (such as heroin, methadone, fentanyl and morphine) is an increasingly prevalent public health problem.3–5 The number of deaths involving heroin and/or morphine doubled between 2012 and 2015 to the highest on record.6 The rise in heroin-related deaths has not only caught the attention of the research community but has also received coverage from the popular press – in the UK7,8 and abroad.9

People who misuse either illicit or prescription opioids are at an increased risk of non-fatal overdose, subsequent hospital or emergency service (ES) utilisation, and death.10–12 Non-fatal opioid overdose is associated with long-term morbidity and increased demand on health services.13–15 ES contact for drug-related morbidity has been found to be a predictor of future episodes of poisoning or overdose.16,17

Naloxone is an effective fast-acting opioid antagonist used to treat opioid overdose.18 Naloxone blocks opioid receptors to counteract the effects of opioid drugs. It reverses the life-threatening effects of an overdose such as depressed breathing, and has no psychoactive properties or intoxicating effects.19

Naloxone can be supplied to people at risk of opioid overdose by paramedics or by laypeople in the form of take-home naloxone (THN).20 However, the safety of naloxone in community settings is unclear. Typically, a THN kit comprises one or more doses of naloxone, an intramuscular (IM) needle and syringe for injecting the dose, and written or pictorial instructions to explain how to prepare and administer the dose and perform basic life support, and the importance of calling the ES. These materials may also describe the duration of effect, and hence why it is important that paramedics attend the patient as soon as possible; the safety of naloxone in terms of adverse events and overdose; and the legality of bystander administration of naloxone.

Non-experimental studies suggest that THN programmes which involve the training of laypersons to administer a naloxone dose in cases of overdose emergency are safe and effective.21–23 THN kits can be used by people without formal medical training in the event of an opioid overdose. Increased access to THN kits via specialist drug services in the UK and internationally has been motivated by recommendations from influential bodies, including the World Health Organization (WHO) and the British Advisory Council on the Misuse of Drugs (ACMD).24,25

Numerous THN distribution programmes aiming to reduce death from opioid overdose have been implemented by drug service providers in the UK and internationally since the 1990s.26,27 However, a significant proportion of people at risk of opioid overdose do not engage with these services.28 Additionally, high-quality empirical evidence to demonstrate the safety and effectiveness of THN is sparse. Observational data suggest that non-serious adverse reactions to naloxone administration are common while serious adverse reactions are rare.29,30 However, the risks of inadequate response or return to a state of overdose following the administration of naloxone by laypeople remain poorly quantified.31,32 Moreover, the uptake of THN kits in at-risk populations remains low33,34 and appropriate THN intervention by peers and witnesses may not be optimal.35

Members of the research team (CM, HS) have previously conducted a randomised feasibility study of THN distributed through the emergency ambulance service (AS) in a single urban geographic area.36 Their experiences, consistent with those of other researchers,37,38 have demonstrated that using traditional methods (e.g. telephone or postal methods) for capturing follow-up outcomes of participants in receipt of a THN kit (and of those not in receipt of a THN kit despite eligibility) is not feasible.

Rationale

The theory underpinning THN provision as an intervention is that by distributing a readily administrable dose of naloxone to people likely to witness opioid overdose, naloxone would be administered to victims of overdose earlier post onset of symptoms than standard care (administration of naloxone by health professional on ambulance or in ED), thus improving survival. Currently, THN provision initiatives, primarily aimed at reducing incidence of fatal heroin overdose, usually take place in non-clinical environments such as third-sector drug services or prison, rather than in emergency care settings. This means that a proportion of those at risk of opioid overdose who do not attend drug services or who are not completing a sentence of imprisonment have limited access to THN kits. Based on figures from England, Wales and Scotland, it appears that this is a sizeable population. In 2017, it was estimated that there were 340,000 high-risk opioid users in England and Wales, and 149,420 people receiving opioid substitution treatment.39 Between 2017 and 2018 in Wales, 25,190 individuals accessed a needle exchange service, of which opioids was the primary use for 48%.40 In comparison, only 2896 THN kits were supplied for the same year, of which 1372 were supplied to individuals for the first time and 533 were reportedly used.41

In Scotland in 2017–8, a total of 6924 THN kits were issued in the community, of which 2458 were thought to have been issued to individuals for the first time.42 To put this into context, figures for 2015–6 in Scotland show an estimated 55,800 to 58,900 users of opioids and/or benzodiazepines.43 These data tell us that saturation of THN kits among opioid users in the general population remains low. However, the distribution and receipt of THN kits in communities around the country is increasing – for example, in 2019–20, Scotland had a 44.3% increase, England’s THN distribution increased by 13.8% whereas Wales’s distribution stayed the same at an average of 389 kits a month.44 This increase in uptake underlines the urgency of establishing the safety and effectiveness of THN provision. Despite the growth in THN provision initiatives and implementation programs, questions have been raised regarding potential harms associated with the administration of naloxone to lay people in non-clinical settings. Concerns include adverse events such as acute opioid withdrawal,31,32 and an increase in high-risk drug-taking behaviour (due to the availability of an apparent ‘safety net’) or other unforeseen methods of indirectly abusing naloxone.45 Furthermore, there is a possibility of naloxone dose being insufficient, or wearing off too quickly, resulting in patients requiring cardiopulmonary resuscitation (CPR) or further treatment and not receiving this.31,46 Tse et al.’s47 systematic review of 7 studies with 2578 participants found no evidence that THN provision increased opioid use. Of the included studies which reported overdose frequency, three of the studies saw no change in overdose rate and one found a decrease. Nonetheless, a previous study found no difference in the number of ambulance call outs before or after THN implementation, suggesting that community-based THN programmes do not result in a reduction in ambulance calls for overdose, that overdose rates do not increase, and that users do not become less likely to call 999.48 However, as the study used anonymised linked ambulance dispatch data, it was not possible to assess whether an increased number of overdoses took place where no 999 call was made.

There is currently limited published evidence regarding THN provision in emergency settings and, with little evidence from RCTs, the safety, wider effects on drug-taking behaviour, and cost-effectiveness of THN provision initiatives in the community are unknown. However, evidence suggests that THN provision programs in emergency settings are acceptable to our target population, and we can therefore expect favourable recruitment among paramedics.38 Members of our study team completed the recruitment phase of a feasibility study of THN provision to patients following attendance and resuscitation by emergency ambulance paramedics for opioid overdose.36 We used a cluster stepped wedge design and randomly selected paramedics in one urban centre in south Wales. We randomised paramedics to the week in which they would receive training and THN kits over the first 4 months of the 12-month recruitment period, so that all paramedics had the opportunity to deliver the intervention during the study. Eligible patients attended by participating paramedics during the period before they were trained and allocated THN kits were allocated to the control group, while eligible patients attended by paramedics who had received training and THN kits were allocated to the intervention group. We published preliminary results related to recruitment, follow-up and outcomes.49 Eighty-five of 102 eligible paramedics took part. The number of opioid-related emergency ambulance contacts (215) exceeded those predicted (100–120) in 12 months. Of 182 cases attended by study paramedics, 148 were attended by paramedics who had been trained and issued with THN kits (intervention group). Thirty-five of 55 patients eligible for the intervention (sufficiently recovered and able to consent) were offered it. Twenty-five accepted, received training from the paramedic, and were given a THN kit; a 71% acceptance rate. Follow-up of participants for self-reported outcomes proved challenging. Of the 215 events for which we have data, 58 were repeat episodes involving 25 individual users. The number of repeat encounters experienced by these individuals ranged from two to five. Six deaths were recorded during the study period.

In addition to this work, Kestler et al.50 carried out an anonymous survey study in the ED in which patients completed a questionnaire regarding opioid use and were offered THN kit plus training after completion. Two-thirds accepted THN, a similar proportion to that seen in our team members’ feasibility study, and multivariate analysis identified injecting drug use as a factor associated with acceptance of THN. In comparison, researchers at Boston University in the USA carried out a feasibility study of the distribution of intranasal (IN) THN via a drug outreach service based in an ED.37 They did not use linked data but took contact details for 415 participants seen by the service. Of these 415, 12.3% (n = 51) completed follow-up by telephone and 9% (n = 37) accepted the THN kit, using IM naloxone – a much lower acceptance rate than previously reported. Of those who had received a THN kit and completed follow-up, six reported administering the naloxone.

In summary, though the efficacy of naloxone in reversing opioid overdose is established, the effectiveness of THN provision as an intervention – in either community or ES settings – is unknown. This state of equipoise warrants investigation using experimental methods. We tested the feasibility of carrying out a definitive randomised trial to evaluate safety, clinical effectiveness and cost-effectiveness of THN provision to opioid users at risk of overdose in emergency settings. In this feasibility trial, at randomly selected sites, THN was distributed to patients identified by emergency ambulance paramedics or ED clinical staff as actively taking opioids. Using this approach, we aimed to reach the very highest-risk group, who may not be registered with drug services or general practitioners (GPs). Of drug users in the UK, opioid users have the lowest rates of GP referral to drug services and have been found to be most likely to report insecure housing arrangements,51 representing a barrier to GP access.52 The ES may be the only healthcare system that this vulnerable and underserved patient group ever access. Testing whether THN can be distributed through such settings to help minimise the risk of preventable death is an important step in establishing an evidence base for distribution of THN for peer administration of naloxone to people in an overdose.

Research aims and objectives

Feasibility study aim

To determine the feasibility of carrying out a fully powered RCT of THN in emergency settings using anonymised linked data to capture outcomes.

Feasibility study objectives

To establish:

1. the best form of THN kit, training and delivery, based on previous experience, evidence, specialist (addiction, emergency care) and service user advice
2. using agreed progression criteria, whether a trial clustered by ED catchment area and associated AS is deliverable.

In order to satisfy our study objectives, we answered the following questions:

1. Can we recruit paramedics and ED staff to trial participation?
2. Is the THN intervention acceptable to service users and practitioners?
3. Can we identify and retrieve (linked routine data) outcomes for two population groups:
   1. those eligible for THN kit provision by paramedics or ED staff?
   2. a further group who may receive (peer-administered) THN following an overdose?
4. What outcomes should we include in a full trial; how should its primary outcome be defined and in what form should it be presented for analysis?
5. What difference in primary outcome would be clinically important and justify the costs and burden on emergency care staff needed to facilitate widespread implementation of THN kit provision?
6. What sample size (and number of clusters) would we need to achieve in a full trial to be confident of detecting a specified THN intervention effect – should it exist – in this primary outcome?
7. Are there any important safety effects of distributing THN kits that we should consider (e.g. increase in risk-taking behaviour or non-fatal overdoses), and can we retrieve data on these?
8. What are the barriers and facilitators to implementation of this THN intervention in emergency settings?
9. What are the patient and peer experiences at intervention sites?

Progression criteria

We assessed whether or not to proceed to a fully powered RCT using the following progression criteria, informed by the previous Cardiff-based feasibility study (CM, HS),35,48 and the Trial Steering Committee (TSC). We used a ‘traffic-light’ system to judge progress against each criteria.

Green: indicates that we have either met a criterion (in which case no modifications to the relevant aspect of the study protocol may be needed), or we are within 10% of our stated progression targets (in which case we reviewed the reasons for this and considered appropriate modifications to study methods).

Amber: indicates that we are within 20% of our stated progression target, in which case we critically reviewed reasons for this and assess whether major changes to study methods are likely to realise significant improvements.

Red: indicates that we are more than 20% from our target, in which case we would not, in the absence of clear extenuating circumstances, consider progression to a full trial.

All percentage changes were measured as relative to target.

Intervention feasibility criteria

1. Sign-up of four sites, including ≥ 50% of eligible staff to complete training in delivering the intervention at each intervention site.
2. Identification of ≥ 75% of people who have presented to ED or associated AS with opioid overdose or an opioid use-related problem over a 12-month period.
3. THN kits issued to ≥ 50% of eligible patients over a 12-month period at intervention sites.
4. Serious adverse event rate [to be defined in agreement with the Data Monitoring and Ethics Committee (DMEC)] of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment.

Trial methods feasibility criteria

1. Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to ONS mortality data (previous ONS data suggest between 140 and 180 such deaths across the 4 participating sites during the study period).
2. Matching and data linkage in ≥ 90% of cases not dissented at the conclusion of quantitative data collection.
3. Retrieval of primary and secondary outcomes from NHS Digital and Digital Health and Care Wales (DHCW) within 6 months of projected timeline.