Take-home naloxone in multicentre emergency settings: the TIME feasibility cluster RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as award number 16/91/04. The contractual start date was in March 2018. The draft manuscript began editorial review in April 2023 and was accepted for publication in November 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Copyright statement

Copyright © 2024 Snooks et al. This work was produced by Snooks et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Snooks et al.

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 UK^7,8 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 low^33,34 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

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.

Study design

We carried out a randomised feasibility trial in the emergency care environment, involving study sites defined geographically as an ED and its catchment area within the local emergency AS.

We were unlikely to know if the naloxone dose included in any individual THN kit was administered to a peer of the recipient of the kit or to the recipient him/herself. Effects of the THN intervention could extend beyond recipients seen in the ED or by ambulance crews. In order to measure treatment effect in those likely to benefit from THN, we needed to define a wider population – those at high risk of death from opioid overdose in the general population at intervention and control study sites. We undertook work, therefore, to develop a discriminant function to identify cohorts to include in outcome comparisons.

Alongside this work, we carried out a RCT clustered by study site. We also collected qualitative data to gain an understanding of the processes of implementation of the intervention and experiences of service users and providers and assessed the feasibility of costing the intervention and its effects.

Study setting

We conducted the feasibility study in the emergency departments (EDs) and their catchment areas within the local emergency AS. The following sites were randomly allocated to intervention or control in ‘pairs’: Bristol Royal Infirmary and South Western Ambulance Service NHS Foundation Trust; Hull Royal Infirmary and Yorkshire Ambulance Service NHS Trust; Northern General Hospital Sheffield and Yorkshire Ambulance Service NHS Trust; Wrexham Maelor Hospital and Welsh Ambulance Service NHS Trust.

Development of the discriminant function

We intended to identify for inclusion in outcome follow-up people at high risk of fatal opioid overdose who may benefit from naloxone from a THN kit. We attempted to define a discriminant function, similar to a risk index, incorporating known and routinely recorded predictors of opioid-related deaths. We used existing linked data about opioid deaths in Wales, including ED and inpatient data, to select predictors closely associated with those who died from opioid poisoning. We then intended to use these predictors in our discriminant function to identify participants in the study site areas to be included in the ‘high-risk population’ for outcome analyses. We previously carried out scoping of NHS Wales ED and hospital routine datasets and linked ONS mortality records with these datasets. We found that we were able to describe circumstances of death for opioid overdose decedents who had visited EDs prior to their death, as well as describe service usage over a prolonged observation period. Mortality data were of high quality, as were data items on times and dates of attendances, outcomes of attendances and demographic characteristics of attendees. Diagnostic and treatment data were of lower quality.

Trial participants

Randomised controlled trial patient recruitment

Interventions

Intervention arm: administration of THN kits and training

The Take-home naloxone Intervention Multicentre Emergency setting (TIME) intervention is described here according to the guidance for intervention description and replication (TIDieR) checklist. 56 Prenoxad is a multi dose THN kit containing 2 mg naloxone hydrochloride in 1 mg/1 ml solution for IM injection. This kit contains simple textual and pictorial instructions which reiterated the face-to-face training each participant receives as part of the intervention. Participants were not able to receive part of the intervention only — for example the kit but not the training — and therefore needed to consent to the whole intervention or decline the whole intervention.

The kit is manufactured by Martindale Pharma (Woodburn Green, UK) and supported by ‘train-the-trainer’ materials for participating paramedics and ED staff developed by Stephen Malloy, an independent consultant. Each Prenoxad kit retails at £21.00 before value-added tax (VAT). The decision to use the Prenoxad kit, as opposed to an IN alternative, is supported by evidence regarding the bioavailability of naloxone following IM versus IN administration,^57,58 and the time taken for improvement in respiratory rate to be observable. 59 We also based our decision on feedback from drug service workers who were approached in the initial setting up of the study.

At intervention sites, participating healthcare professionals based in the specific ED or AS region and caring for patients eligible to receive the intervention offered these patients the THN kit, with an explanation of its purpose. Patients received TAU and then offered the intervention.

In the intervention arm, if the patient consented to receiving the kit, the healthcare professional provided training regarding the preparation and administration of the naloxone dose using the kit materials. The healthcare professional and the patient then completed a training checklist document which was stored as evidence that training was provided as part of the intervention.

Outcomes

We measured outcomes related to the feasibility of the study in terms of the intervention and methodology, as reflected in the progression criteria.

The proposed primary outcome for a future trial was mortality (all deaths and those known to be opioid-related). Secondary outcomes included intensive treatment unit (ITU) admissions, ED-visits, and inpatient admissions (all visits/attendances as well as those known to be opioid-related), further 999 calls as well as THN kits issued and costs. Our feasibility study was not adequately powered to detect statistically significant differences in these proposed outcomes between intervention and control arms.

Qualitative study methods

We used qualitative data to explore the feasibility and acceptability of THN from the perspective of service users, based upon their previous knowledge and experience of overdose. We also explored the feasibility and acceptability of the intervention from the provider perspective by undertaking interviews and focus groups with paramedics, clinical ED-staff, and health service managers at participating sites regarding THN in emergency settings. We explored awareness and experiences of naloxone, perceived benefits and challenges of THN, and views on the feasibility and acceptability of distributing THN via ambulance paramedics and hospital EDs. Interviews were recorded, with participants’ consent, and professionally transcribed prior to analysis. We used normalisation process theory (NPT) to guide analysis of the provider data and to help understand how the intervention can be optimised within the ED and prehospital settings, and to explore whether difficulties in implementation were due to the intervention itself or other factors. 61

Changes to study design

Following difficulty in recruiting staff to qualitative focus groups, it was decided to offer the £20 Amazon voucher to staff as an incentive to take part. Also, due to staff rotas, it was decided to conduct interviews for individual staff rather than focus groups as originally planned.

Due to delays in permissions for routine data access, and low numbers of THN kits distributed during the trial recruitment period, a decision was taken by the Trial Management Group (TMG) to not go ahead with the planned retrieval of datasets from English sites (originally planned to be used for testing of discriminant function and comparison of outcomes between trial arms).

Randomised controlled trial

Interim analysis and stopping guidelines

No interim analyses were planned or performed.

Health economics

We aimed to assess the feasibility of generating costs relating to staff training, distribution of the THN kits and the use of routine data sources to estimate healthcare costs.

We aimed to calculate training costs using records of completion of training and staff recall of patient training, and then combined with NHS salary data.

Qualitative data

Trial management

A TMG was established to manage the project and report to the independent TSC at appropriate intervals. The Chief Investigator chaired the TMG, which met quarterly. The TMG comprised of all co-applicants, named collaborators, public contributors and researchers.

The independent TSC oversaw the conduct and progress of the trial and adherence to the protocol, patient safety, and the consideration of new information of relevance to the trial. Two public contributors were members of the TSC.

A Data Monitoring Committee (DMC) monitored the study data at interim periods and made recommendations to the TSC on whether there are any ethical or safety reasons why the trial should not continue.

Routine data

The combined WDSD files comprise information on n = 5,640,113 individuals. No ALF_PE (unique patient identifier in SAIL) was recorded for n = 504 cases; a further n = 1,740,317 individuals had no recorded residency in Wales during the study window; and a further n = 151 individuals had a recorded date of death indicating death before the study window – although date of death is recorded in ADDE, only ADDE data on or after the beginning of the study window were available, and so could not determine whether people were alive or not at this timepoint. Excluding these individuals leaves for further consideration n = 3,899,140 individuals deemed to be alive and resident in Wales at the start of the study window.

Of these, we then excluded another n = 664,050 individuals with week of birth recorded as on or after 1 December 2003; these individuals would be < 18 years old at the end of the study window. A further n = 7694 individuals were aged 17 or under at their final date of residency in Wales, or at their date of death. Excluding these individuals leaves n = 3,227,396 individuals in our study population.

For our derived cohort of n = 3,227,396 individuals, we extracted basic demographic data and then assessed mortality and healthcare resource utilisation, as recorded in the available routine data sources. We start with mortality, which defines both our primary outcome (death from opioid overdose) and study end dates.

Summary

We have provided details on healthcare utilisation and proportion of decedents from opioid overdose with no such records up to 12 months prior to death. We found a small number of decedents, which is a limiting factor in the development and accuracy of the discriminant function. Predictive variables produced in this study have shown that there are statistically significant differences in the factors and covariates in opioid overdose decedents and other cohorts, however, at an individual level and not sufficiently different from members of the other cohorts.

In order to identify and include 75% of the high-risk population for 1-year follow-up, we would need to monitor approximately one-third of the population. As only 1–2% of the deaths within the follow-up period would be the result of opioid overdose, it follows that reducing substantially or even eliminating entirely such deaths would have little overall effect on mortality rates in the high-risk population. Given the weak predictive link between deaths from and healthcare events related to opioid overdose, using routine data to identify with sufficient precision those at high risk of death from opioid overdose currently seems infeasible.

Setting and recruitment

Site 2 AS was the first site to open to recruitment on 13 May 2019; Site 1 AS was the last on 10 October 2019.

Site 1 AS suspended recruitment on 28 November 2019 with concerns that paramedics could not supply THN under the agreed PGD – ‘our Pharmaceutical Advisor has raised the issue with her colleagues in the Specialist Pharmacy Service and been advised that administration under PGD by paramedics is not supported by the current legal framework’. Site 2 AS then paused recruitment as well. The Trial Office wrote to the MHRA to reassure the ASs that paramedics could supply THN under a PGD, and received this response on 4 December 2019: ‘Paramedics can supply Naloxone under a PGD. Naloxone is not usually supplied on a named patient basis. Once the Naloxone has been supplied an exemption in Section 17 of the Human Medicines Regulations 2012 would allow it to be administered by anyone in a medical emergency’. Site 2 AS recommenced recruitment the following day. Site 1 AS recommenced recruitment on 18 December 2019.

The recruitment period for TIME was also disrupted by COVID-19; all recruitment was paused on 17 March 2020 (except for Site 2 ED where study activity paused on 23 March 2020). Table 15 shows when each site originally opened; opened after the pause for COVID-19; and then closed to recruitment. Site 2 ED took the longest time to reopen as their research nurse had been redeployed during COVID-19 and recruitment could not recommence until he was reinstated.

Trial recruitment

In total, 277 patients were identified as eligible to receive a THN kit and training in this trial (see Figure 1). Sixty THN kits were supplied to eligible patients during the recruitment period (Site 1 ED = 36, Site 2 ED = 16, Site 1 AS = 4, Site 2 AS = 4). In 16 cases (all in Site 1 ED), the patient agreed to the THN kit and accompanying training but ultimately did not receive the kit (n = 4) or declined the THN kit because they already had one (n = 12). In 37 cases, the patient declined the THN kit for reasons other than already having one Site 1 ED = 25, Site 2 ED = 9, Site 1 AS = 1, Site 2 AS = 2. Eligible patients were not offered THN kits 164 times (Site 1 ED = 159, Site 1 AS = 2, Site 2 AS = 3). Reasons reported for not offering eligible patients kits were: staff forgot (n = 136); no kit available (n = 2); staff too busy (n = 15); suspected intentional overdose (n = 3); already given by drugs nurse (n = 4); and other (n = 3).

FIGURE 1.

CONSORT flow diagram. a, We are unable to report patient numbers by site due to small numbers of cases at some sites.

Over 90% of cases in Site 1 ED and Site 2 AS occurred between July 2019 and March 2020 – that is, before the start of the COVID-19 pandemic. In contrast, only a third of cases at Site 2 ED occurred before the pandemic, with two-thirds between February 2021 and July 2021. At Site 1 AS, equal numbers of cases were reported before and after the start of the pandemic, over the period from November 2019 to October 2020. We are unable to provide further details or more precise numbers due to the small numbers of cases at some sites.

We had no direct access to identifiable or other demographic data on patients presenting with opioid overdose or problems related to opioid use. Instead, some sites sent data to NHS Digital with the intention of generating demographic data from linked data. As no data linkage was undertaken, we are unable to report any characteristics of these patients.

Staff recorded 626 people as being considered for inclusion but found not to be eligible (Site 1 ED = 532; Site 2 ED = 4; Site 1 AS = 49; Site 2 AS = 41). Reasons given were: uncooperative including being abusive towards staff (n = 55); lack of capacity (n = 35); reduced consciousness level (n = 41); patient in custody (n = 21); patient admitted to hospital (n = 194, see Protocol deviations); 6); staff not trained (n = 29); locum staff (n = 14); already recruited (n = 64); other (n = 12).

Adverse events

No adverse events were reported.

Fulfilment of progression criteria

1. Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site.

   1. Assessment: RED: Four sites did recruit patients to the TIME trial. At the time of staff training, there were 132 eligible staff in Site 1 ED; 197 in Site 2 ED; 222 in Site 1 AS; and 136 in Site 2 AS. Both Site 1 ED and Site 1 AS trained more than 50% of their eligible staff (82.6% and 54.5%, respectively). Site 2 AS, however, trained only 33.8% (46/136) and Site 2 ED only trained 8.1% (16/197) of eligible staff. This progression criterion was not met.

2. Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period.

   1. We were unable to identify all those who presented to ED or the AS with opioid overdose or other related problem, so were not able to ascertain whether this criterion was met.

3. Take-home naloxone kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites.

   1. RED: Sixty kits were given to eligible patients, out of n = 277 identified by trial staff as eligible. As this is just 21.7% of eligible patients, we did not meet this progression criterion.

4. Serious adverse event rate (to be defined in agreement with DMEC) of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment.

   1. GREEN: No serious adverse events were reported; therefore, this criterion was met.

Trial method feasibility

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).

   1. RED: We were unable to identify this population to include in the 1-year follow-up.

2. Matching and data linkage of quantitative data collected.

   1. RED: The linkage of quantitative data was no longer pursued due to issues with NHS Digital approvals resulting in significant delays that did not allow for linkage and analysis to be possible within the timeframe of this project, as well as low distribution of THN kits at intervention sites. Therefore, we did not meet this criterion.

3. Retrieval of primary and secondary outcomes from NHS Digital and National Welsh Informatics Service within 6 months of projected timeline.

   1. RED: We did not retrieve primary and secondary outcomes from NHS Digital and NWIS within 6 months of our projected timeline; therefore, we did not meet this criterion.

Protocol deviations

There were 201 protocol deviations reported during the trial. One protocol deviation was reported to the Research Ethics Committee (REC) and Sponsor, both on 23 February 2021. There was miscommunication between the Trial Office and Site 1 ED, with the Trial Office being under the impression that Site 1 ED had stopped recruiting on 2 December 2020 as agreed. Site 1 ED actually continued to recruit until 5 February 2021 (a total of 61 weeks instead of 52). The underlying reasons for this miscommunication were reported as related to the COVID-19 pandemic (with research staff at site having not met in December 2020 or January 2021 as planned), and a change in Trial Manager at Swansea University (a new Trial Manager was appointed in December 2020). No further action was taken regarding this.

Other protocol deviations reported to the Trial Office were:

1. Site 1 ED: 194 protocol deviations were recorded for patients who were going to be admitted and were not offered a THN kit; this was not one of our exclusion criteria.

2. Site 1 AS: TIME Patient Information Leaflet not left with the patient 5 November 2019.

3. Site 2 AS: Reduced frequency of THN kit audit following reopening of recruitment after the pause for COVID-19. Prior to the pandemic, Site 2 AS audited there THN kits every fortnight. Subsequently, this was done once at reopening and once at closure (8 weeks apart). This was due to availability of staff members.

4. Site 2 AS: on three occasions, THN kits were not accounted for during audit. One of these was eventually located, two were not.

5. Site 2 AS: a THN kit was used on a patient on one occasion.

Naloxone kits

The data from the Naloxone Case Report Forms were complete.

Staff time to undergo training

Training data were collected from all four intervention Trusts.

Staff time to give training to patients

With the change in the format of qualitative data collection following the pandemic, and low recruitment, it was decided to drop the questions relating to patient training. Consequently, no data relating to this are available.

Associated health service contacts

Due to changes in the project, the request for routine data was abandoned, and so these costs could not be calculated.

Summary

The study has shown that the methods for collecting costs relating to the naloxone kits and the training of NHS staff are feasible and can take into account differences in the form of training (e.g. one-to-ones group, nominated trainers vs. cascade trainers). The unit costs used in our calculations are approximate, and further calculations are also needed to produce per-patient costs, but the feasibility of these changes is beyond doubt.

It should be noted, however, that there were some problems with the staff training data. One centre produced high-quality data, two centres generated data with some discrepancies and one centre failed to use the data collection tool at all. All of these problems are considered resolvable in any future trial. 70

We have been unable to assess the feasibility of collecting patient training times via staff recall. It is unlikely that this finding represents a serious barrier to the conduct of any future evaluation of THN. However, the precise method of collection of these data is still open to question; we planned to use practitioner recall, while other methods could include prospective collection as part of the Naloxone Case Report Form. It should be noted that a UK-based evaluation of THN demonstrated that cost-effectiveness is unlikely to be sensitive to uncertainties related to training costs,71 and so this should be recognised when designing future data collection; expensive or disruptive data collection is unlikely to be worthwhile.

We were also unable to test the costing of other health service contacts. However, as stated previous, this work wasn’t strictly an issue of feasibility; the approach is feasible, although the precise way in which the data would be used needs finalising.

Service user perspectives

Our findings suggested that service users had significant experience of overdose (their own or others) and were keen to maximise provision of THN which they perceived as an acceptable and easy-to-use intervention. They valued provision of THN via ambulance (ES) or ED staff in addition to community provision. Although they expressed concerns about risks of wanting to leave the ED or ambulance quickly after reversal, due to potential side effects of rapid withdrawal associated with naloxone, they valued its life-saving benefits. Service users spoke about THN training and provision giving them a sense of self-agency and empowerment and users perceived this as an opportunity to save lives. Users also felt there were opportunities for friends and family to also undergo training and receive the THN kits.

Service provider perspectives

In total we conducted 14 interviews (8 paramedics, 4 ED staff) plus one focus group with 8 ED staff (see Table 16 for details of characteristics of participants).

Public and patient involvement

We involved public contributors throughout this study in order to ensure research relevance, quality and accountability strengthen research rigour. 72

Our aim was to include people with experience of opioid addiction, as drug users or with a close connection to someone who used drugs. We identified individuals with experience of opioid addiction through family relationships, voluntary networks or individual circumstances. We involved them in designing the study proposal and in delivering the commissioned research. When designing this study, we sought the views of different groups linked to opioid use. When developing and designing the study we met with third-sector workers and individuals using a drug service, to discuss attitudes and experiences relating to overdose, THN and the proposed research. We also worked closely with individuals with experience within their family of opioid overdose who drew on personal experience to highlight the relevance of the research questions and comment on data collection methods and selection of outcomes. We wanted to be sure the research would be feasible so explored whether it seemed relevant and coherent to them and how likely people would be to take part. We also gained insight into personal experiences of overdose and THN, including how they perceived the services which respond to emergency overdose calls. These contacts enabled us to gain people’s views on the research question and the proposed methods. We also discussed how we could involve individuals in delivering the research and identified individuals and support groups interested in maintaining a relationship with the study team. The people we were in touch with gave their active support to the research aim to reduce death from opioid overdose. One was named a study co-applicant.

Throughout the process of delivering the TIME trial, we followed our intention to work closely with people with personal experience of opioid addiction and overdose. We sought their input to all stages of research implementation, oversight and dissemination.

Our public contributor co-applicant was a TMG member and included in all meeting discussions and communication. Her experience in relation to opioid overdose, which contributed to her commitment to the research, also interrupted her ability to routinely attend research meetings. We recognised her personal commitments. When domestic responsibilities limited her ability to attend meetings, the public and patient involvement (PPI) lead met with her at another convenient time to discuss project progress and obtain her feedback. We discussed other ways she could contribute to the study and agreed she would give comments and feedback by e-mail between meetings.

We wanted to supplement involvement in delivering the study by creating a second, more accessible route for linking with people with relevant experience. We recognised and had been advised by people we talked to when planning the study, that it would be challenging for people to join a formal research team meeting. We identified the Sheffield Addiction Research Recovery Panel (ShARRP), which is a group of people with experience of dependent/problematic drug and alcohol use, either personally or as carer, partner or relative of someone. Selected team members met periodically with ShARRP. The team members reported study progress and sought comments, suggestions and relevant experience from Panel members to inform research implementation. Through this route they also identified individuals to attend TMG meetings, to speak from the insight provided by membership of ShARRP. 73 These individuals joined some meetings but were not able to consistently attend, so the ShARRP meetings provided a useful supplement to accessing individuals and gaining feedback.

Personal commitments and circumstances made it difficult for any individual to sustain their involvement for the full study period. While the research team made regular efforts to involve people with relevant experience and enable their contributions, we did not have the opportunity to build long-term relationships. ^74,75 However, we minimised the lack of continuity by meeting public contributors in their settings and groups. Hearing their stories reinforced for us the challenging circumstances of experiencing, or associating with, opioid addiction. 76

We also recruited two public contributors to join the TSC to provide experience-based expertise alongside input from members with academic, clinical and methodological skills. They were involved in all the TSC meetings. We recruited these individuals through the Public Involvement Community in Wales supported by Health and Care Research Wales and through networks known to the study team. They had relevant experience and also skills which enabled them to be active members of the TSC.

We supported all public contributors in line with the UK Standards for Public Involvement. 72 We offered honoraria and reimbursement of all expenses. We sought flexible routes to seek public contributions and communicate with individuals with relevant experience. We named a co-applicant as PPI lead, who was supported by other team members able to use their skills and geographic location for this aspect of our collaboration. We have reported our experiences in line with best practice. 77

Equality, diversity and inclusion

The methods of participant recruitment for this study did not proactively target specific groups, but maintained an equitable approach. Due to the nature of this project, participants are often marginalised and from deprived socioeconomic backgrounds. We offered an honorarium to all people we invited to be involved as public contributors and provided access to a free Citizens Advice Bureau-supported helpline for advice on claiming this.

Key findings

Study limitations

1. Quality of coding: currently, many healthcare events have missing inadequate codes. There is a linked lack of granularity – currently events recorded in EDDS and PEDW have been categorised as opioid overdose-related or not. It is unclear that if there would be improvement in an extended classification of events.

2. We have noted above the major limitation that a considerable number of decedents from opioid overdose have no recorded events in routine data in the 12 months (or even in the 36 months) prior to the date of death. Our approach extends in principle to include further data sources, but we note the regulatory and logistical hurdles to doing so in practice. Further data sources include: the Welsh Longitudinal GP data set, potentially including data on smoking/alcohol usage; drug prescriptions; AS records (including records on reasons for emergency call, ambulance attendance and disposition; police and probation/justice data; and data from third-sector organisations working with opioid and other drug and substance users, and their peers.

3. The COVID-19 pandemic resulted in pauses in recruitment and an increase in strain on the ES which may have impacted recruitment of both staff and patients.

4. Unforeseen difficulties with Confidentiality Advisory Group (CAG) and NHS Digital approval to retrieve data for application of the discriminant function to a second population in England and to then retrieve outcomes for the population identified contributed to delays and the decision to discontinue this stage of the research. We were caught between CAG and NHS Digital for many months without clarity as to how to move forward. NHS Digital required detail of the discriminant function prior to approval; however, we were unable to produce the function without a means to test it on the English data.

5. We found some problems with variations in the quality of data. Regarding the staff training data, one centre produced high-quality data; two centres generated data with some discrepancies; and one centre failed to use the data collection tool at all. The number of patients identified as eligible for the trial was also vastly different across sites. While this may have been the case, it is more likely that some sites were more invested in the trial and proactively looking for eligible patients compared to others. In Site 2 ED, where the research nurse was redeployed following COVID-19 for several months, this seemed to be a particular issue. All of these problems are considered resolvable in any future trial.

6. Not all sites were able to provide staff for focus groups, which may have resulted in missing some perspectives of the service providers. It may have been that those who felt more positively towards the intervention were willing to take part in the qualitative aspect of the study. Within the study timetable and resources, and considering COVID-19 delays, we could not pursue this further.

Public and patient involvement

We involved public contributors throughout this study in order to ensure research relevance, quality and accountability and strengthen research rigour. We recruited two public contributors to join the TSC to provide experience-based expertise alongside input from members with academic, clinical and methodological skills. They were involved in all the TSC meetings. However, personal commitments and circumstances made it difficult for any individual to sustain their involvement for the full study period. To minimise the impact of the lack of continuity, we met public contributors in their settings and groups, allowing us to hear their stories, which reinforced for us the challenging circumstances of experiencing, or associating with, opioid addiction.

Interpretation

We found that THN kit administration was overall low in this study, with considerable variation between sites. Reasons given for this were related to the emergency care setting – staff were busy and under pressure; patients were undergoing emergency treatment, mainly for overdoses, and were often not fit or willing to consent to receipt of the kit or the training. There may be ways to overcome these barriers – the protocol for administration of kits could, for instance, be more flexible. A greater focus on relatives and friends may increase the chance of success of TNH provision in the emergency setting. Research conducted in the USA reported that nearly half of the kits distributed by ESs were given to family members with the patient themselves being the second largest group to receive the kit. 78 A study assessing the acceptance of nasal naloxone in the ED reported low uptake, with barriers such as difficulties identifying the ‘right’ patient, access to the kits and lack of clarity as to when to offer the kit due to the patient typically not waiting for formal discharge so they may not get a chance to be offered a kit. 79 The barriers mentioned are similar to those mentioned by service users and providers in this study and indicate that although there is a general consensus that the ED is a suitable setting to provide THN kits due to the contact with the patient group which may not receive contact with the health service in other means, there are issues with regard to the feasibility of the intervention. These findings are in line with other research which found the ED to be a suitable point for THN kit distribution and training but reported ED staff didn’t have enough time for training and patient identification workflow which could hinder the implementation of this intervention in the ED. ^38,80 A more recent study assessing methods of increasing THN prescribing in the ED found that although barriers remain, with improved, targeted staff training, the use of works aid such as best-practice advisory tools can increase the prescription of THN kits in the ED. 81 Interestingly, we found that both the service users and service providers believed in focusing on the relatives and friends of opioid users; however, a 2022 European study assessing the attitudes and likelihood of using THN kits reported that opioid users were significantly more likely to witness an overdose and use a THN kit compared to the family. 44 It may also be possible to identify patients for administration of a THN kit at the time of follow-up, rather than during the emergency episode.

There is overall support from both ED staff and opioid users to provide THN kits and training in the emergency setting. Further findings in this study highlighted issues with regards to recruiting eligible staff in some sites; we were unable to reach the target of training 50% or more of eligible staff in two of the four intervention sites, and therefore did not meet he progression criteria. It is however worth noting that Site 2 ED, which only recruited 8% of staff, and Site 1 ED, which recruited 55% of staff, are similar-sized EDs with similar throughputs and have used an identical approach to the recruitment of staff and contact with the academic research team, but have had very different outcomes in training staff, recording training data and were also unable to provide staff to contribute to focus groups. This indicates that the issues with regards to staff recruitment may lie within the EDs themselves, potentially including pressures of the department, staff support for the project and other factors which could not be accounted for in this study but may be work investigating for future research. It could be beneficial for future research to tailor recruitment and training to each ED and provide different support to each ED depending on their requirements. Furthermore, barriers in recruiting ED staff identified from this research have been documented and include general pressures of the ED including large numbers of patients with challenging circumstances of admittance and unpredictable working environment. Other barriers were identified to be specific to research including a lack of face-to-face communication between the academic research team and research nurses recruiting, as well as a lack of support for research nurses during recruitment which can cause a sense of unease and concern about their confidence in identifying eligible staff and patients. 70

Methodologically, this is a challenging area for research and evaluation. There are four main interrelated issues, some of which relate to the specific target population for the intervention, and some of which apply more generally to the conduct of trials in emergency care:

1. Identification of trial population: The THN kits are intended for peer administration. Therefore, the person who benefits from the naloxone may not be the recipient of the kit. Standard RCT recruitment strategies will not work, an alternative has to be found to capture outcomes. We tried to do this through attempting to identify a high-risk population to include in a trial; however, we found that sensitivity and specificity of a discriminant function were both low, and it would not be feasible to use this method in a trial.

2. Consenting patients to any trial in the emergency setting is challenging. In practice, with ethical approval, we often consent them to treatment at the point of recruitment, and to follow up at a later point. In this study we knew from our previous feasibility study49 that follow-up rates would be extremely low and we would not be able to count on consenting patients to follow up after the emergency episode itself.

3. Further to this point, it is very challenging to include self-reported outcomes in a trial in the population. For this reason, we proposed using anonymised linked routine data outcomes, but were unable to define the high-risk population to include in outcome comparisons.

4. With opioid-related death being a relatively rare event, and low THN administration levels, data linkage becomes problematic, as individuals may be at risk of becoming identifiable.

Recommendations for research

The evidence base for distribution of THN in terms of safety, costs and effects is very thin – in any setting, but particularly so in the emergency care environment. It remains the case that the safety and effectiveness of this intervention needs to be evaluated, and that those who suffer an opioid-related emergency may be at highest risk. However, in the light of our findings related to feasibility of the intervention as designed in this study, and our proposed trial methods, in order of priority we recommend the following research be undertaken:

1. What modifications could be made to the intervention to increase its uptake in the emergency setting?

   1. Could the intervention be distributed to family or friends of the opioid user?

   2. Could the intervention be distributed at follow up, rather than during the initial emergency episode?

   3. How can the rate of missed recruitments be reduced? – how could we make sure healthcare staff are more invested in trials? – particularly in this patient group.

2. Is there another setting in which THN could be distributed and evaluated? For example, could the intervention be feasible in the primary care setting?

3. What are the self-reported outcomes of patients who are given THN kits?

4. How can a randomised trial be designed for this population in this setting? How can those who may benefit from the naloxone in the THN kits be identified and followed up? Is there an alternative rigorous study design that could be used?

Conclusion

Rigorous research evidence about safety, costs and effectiveness of THN is still needed to inform policy and practice. We recognise the emergency setting may be a good starting point for identification of people at high risk of harm from opioids and, potentially, for THN kit provision. However, in this feasibility study we did not meet our preset progression criteria related to staff and patient recruitment and to the identification of high-risk patients for outcome comparisons. Therefore, we conclude that a full RCT based on the intervention and methods that we tested is not feasible.

Contributions of authors

Helen Snooks (https://orcid.org/0000-0003-0173-8843) (Professor of Health Services Research at Swansea University), chief investigator, led the development of the research question and study design, was responsible for trial delivery and conduct, led the drafting and editing of the final report, contributed to the writing of the report and approved the final version.

Jonathan Benger (https://orcid.org/0000-0001-6131-0916) (Professor of Emergency Care in the School of Health and Social Wellbeing at the University of the West of England, Bristol), co-applicant, contributed to the study design, protocol development and delivery of the trial at the Bristol Royal Infirmary, contributed to the writing of the report and approved the final version.

Fiona Bell (https://orcid.org/0000-0003-4503-1903) (Head of Research at Yorkshire Ambulance Service), principal investigator for Yorkshire Ambulance Service, contributed to the writing of the report and approved the final version.

Sarah Black (https://orcid.org/0000-0001-6678-7502) (Head of Research, Audit and Quality Improvement at South Western Ambulance Service NHS Foundation Trust) co-applicant, principal investigator for South Western Ambulance Service NHS Foundation Trust, contributed to the study design, supported the delivery of the trial at this site, contributed to the writing of the report and approved the final version.

Simon Dixon (https://orcid.org/0000-0001-7394-7009) (Health Economist based at the University of Sheffield) wrote the analysis plan for the health economic evaluation, analysed health economics data and led the drafting of the health economics chapter, contributed to the writing of the report and approved the final version.

Helena Emery (https://orcid.org/0000-0003-1890-4254) (Research Officer, Swansea University), project manager; co-ordinated the drafting and editing of final report, contributed to the writing of the report and approved the final version.

Bridie Angela Evans (https://orcid.org/0000-0003-0293-0888) (Research Officer, Swansea University), co-applicant, public and patient involvement lead, led the writing of the public involvement chapter, contributed to the writing of the report and approved the final version.

Gordon Fuller (https://orcid.org/0000-0001-8532-3500) (Consultant in emergency medicine and a NIHR fellow in health data science), co-applicant, contributed to the writing of the report and approved the final version.

Rebecca Hoskins (https://orcid.org/0000-0001-7883-437X) (Consultant Nurse and Senior Lecturer in the School of Health and Social Wellbeing at the University of the West of England, Bristol), co-applicant, principal investigator at the Bristol Royal Infirmary, contributed to the writing of the report and approved the final version.

Jane Hughes (https://orcid.org/0000-0003-1389-3402) (Site Researcher based at Sheffield University), service user involvement lead and qualitative support. Led writing of the service user chapter, contributed to the writing of the report and approved the final version.

Jenna Jones (https://orcid.org/0000-0002-1280-4941) (Research Officer and GP Registrar in Swansea Bay University Health Board), previous research manager, co-led the writing of the final report, contributed to the writing of the report and approved the final version.

Matthew Jones (https://orcid.org/0000-0002-6974-8725) (Research Officer at Swansea University and Psychotherapist), co-applicant, previous research manager, led the writing of the study protocol, contributed to the writing of the report and approved the final version.

Sasha Johnston (https://orcid.org/0000-0002-9904-8834) (Health Education England Clinical Fellow (Mental Health) and Research Paramedic with South Western Ambulance Service NHS Foundation Trust), PRSO for principal investigator for South Western Ambulance Service NHS Foundation Trust, contributed to the writing of the report and approved the final version.

Jaqui Long (https://orcid.org/0000-0002-6889-6195) (Researcher, Sheffield University) undertook some of the analysis for both of the qualitative chapters, contributed to writing the qualitative chapters, contributed to the writing of the report and approved the final version.

Chris Moore (https://orcid.org/0000-0002-2192-3002) (Head of Medicines Management and Principal Investigator for Welsh Ambulance Services NHS Trust), co-applicant, contributed to the writing of the report and approved the final version.

Rakshita Parab (https://orcid.org/0000-0003-1822-657X) (Research Officer at Swansea University) led the RCT recruitment data analysis, drafted chapter related to epidemiology and discriminant function, contributed to the writing of the report and approved the final version.

Richard Pilbery (https://orcid.org/0000-0002-5797-9788) (Research data analyst at Yorkshire Ambulance Service NHS Trust), PRSO for Yorkshire Ambulance Service NHS Trust, contributed to the writing of the report and approved the final version.

Fiona C Sampson (https://orcid.org/0000-0003-2321-0302) (Site Researcher, Sheffield University), service provider involvement lead and qualitative support, led writing of the service provider data chapter, contributed to the writing of the report and approved the final version.

Alan Watkins (https://orcid.org/0000-0003-3804-1943) (Professor of statistics at Swansea University), senior statistician, developed analysis plan, discriminant function and analysed data. Led draft of epidemiology and discriminant function chapter, contributed to the writing of the report and approved the final version.

Acknowledgements

This study was only possible thanks to the expertise and commitment of a wide range of people and organisations. Although we specifically acknowledge the following parties, we would like to extend our thanks to all of those who supported this work.

• All the participating hospitals, ASs and their staff.

• All patients and stakeholders who participated in the trial.

• NIHR HTA for funding and then supporting this research throughout.

• Anne Surman, Daniel Holohan, Neil Jenkinson and Hayley Dash for administrative support.

• Members of our DMC: Ranjit Lall (Chair), Andy Rosser, Dalya Marks and Matthew Reed.

• Members of our TSC: Kathy Rowan (Chair), Derin Omole, Ben Carter, Elwyn Thomas, Ian Mursell, Andrew McAuley and John Ryan.

• Our patient and public representatives: Jackie McCarthy and Rosita Wilkins.

• The SAIL Databank team at Swansea University.

• A special thanks to Jake Alhiliali, Penny Buykx, Timothy Driscoll, Adrian Edwards, Christopher Evans, Steve Goodacre, Kelly Hird, Ann John, Barbara Lawrence, Rosanna Oretti, Emma Parry, Robin Roop and Paul Williams for their support throughout the project.

Patient data statement

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives. You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Data-sharing statement

TIME data within SAIL is securely stored within the Databank. Applications to access data held within the SAIL Databank require approval following independent review by their Information Governance Review Panel (IGRP), and are subject to SAIL’s terms, conditions and data disclosure and dissemination policies and procedures. TIME data within the SAIL Databank are held in compliance with its data retention, archiving and data destruction policies. All other queries should be addressed to the Corresponding author.

Ethics statement

The TIME study was approved by the Health Research Authority on 8 January 2019 with a favourable opinion received from the Research Ethics Committee (reference number: 18/WA/0337) on 16 October 2018.

Information governance statement

Swansea University is committed to handling all personal information in line with the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679.

Under the Data Protection legislation, Swansea University is the Data Controller, and you can find out more about how we handle personal data, including how to exercise your individual rights and the contact details for our Data Protection Officer here: https://www.swansea.ac.uk/aboutus/compliance/data-protection/.

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/YNRC8249.

Primary conflicts of interest: Alan Watkins declares his role as a member of the NIHR HS&DR Funding Committee, 2018–present. Helen Snooks declares her role as a member of the NIHR HTA & EME Editorial Board, 2015–present. Swansea University is the study sponsor. The protocol is available at https://doi.org/10.1186/s40814-020-00626-w.

Publication

Snooks HA, Jones JK, Bell FB, Benger JR, Black SL, Dixon S, et al. Take-home naloxone administered in emergency settings: feasibility of intervention implementation in a cluster randomized trial. BMC Emerg Med 2024;24(1):155. https://doi.org/10.1186/s12873-024-01061-3

Disclaimers

This article presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.