Rebecca McDonald

Are take-home naloxone programmes effective?: Systematic review utilizing application of the Bradford Hill criteria

Abstract Background and Aims Fatal outcome of opioid overdose, once detected, is preventable through timely administration of the antidote naloxone. Take‐home naloxone provision directly to opioid users for emergency use has been implemented recently in more than 15 countries worldwide, albeit mainly as pilot schemes and without formal evaluation. This systematic review assesses the effectiveness of take‐home naloxone, with two specific aims: (1) to study the impact of take‐home naloxone distribution on overdose‐related mortality; and (2) to assess the safety of take‐home naloxone in terms of adverse events. Methods PubMed, MEDLINE and PsychINFO were searched for English‐language peer‐reviewed publications (randomized or observational trials) using the Boolean search query: (opioid OR opiate) AND overdose AND prevention. Evidence was evaluated using the nine Bradford Hill criteria for causation, devised to assess a potential causal relationship between public health interventions and clinical outcomes when only observational data are available. Results A total of 1397 records (1164 after removal of duplicates) were retrieved, with 22 observational studies meeting eligibility criteria. Due to variability in size and quality of the included studies, meta‐analysis was dismissed in favour of narrative synthesis. From eligible studies, we found take‐home naloxone met all nine Bradford Hill criteria. The additional five World Health Organization criteria were all either met partially (two) or fully (three). Even with take‐home naloxone administration, fatal outcome was reported in one in 123 overdose cases (0.8%; 95% confidence interval = 0.4, 1.2). Conclusions Take‐home naloxone programmes are found to reduce overdose mortality among programme participants and in the community and have a low rate of adverse events.

Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?

CONTEXT Take-home naloxone is increasingly provided to prevent heroin overdose deaths. Naloxone 0.4-2.0 mg is licensed for use by injection. Some clinicians supply improvised nasal naloxone kits (outside licensed approval). Is this acceptable? AIMS (1) To consider provision of improvised nasal naloxone in clinical practice and (2) to search for evidence for pharmacokinetics and effectiveness (versus injection). METHODS (1) To document existing nasal naloxone schemes and published evidence of pharmacokinetics (systematic search of the CINAHL, Cochrane, EMBASE and MEDLINE databases and 18 records included in narrative synthesis). (2) To analyse ongoing studies investigating nasal naloxone (WHO International Clinical Trials Registry Platform and US NIH RePORT databases). FINDINGS (1) Multiple studies report overdose reversals following administration of improvised intranasal naloxone. (2) Overdose reversal after nasal naloxone is frequent but may not always occur. (3) Until late 2015, the only commercially available naloxone concentrations were 0.4 mg/ml and 2 mg/2 ml. Nasal medications are typically 0.05-0.25 ml of fluid per nostril. The only published study of pharmacokinetics and bioavailability finds that nasal naloxone has poor bioavailability. QUESTIONS FOR DEBATE: (1) Why are pharmacokinetics and bioavailability data for nasal naloxone not available before incorporation into standard clinical practice? (2) Does nasal naloxone have the potential to become a reliable clinical formulation? (3) What pre-clinical and clinical studies should precede utilization of novel naloxone formulations as standard emergency medications? CONCLUSIONS The addictions treatment field has rushed prematurely into the use of improvised nasal naloxone kits. Evidence of adequate bioavailability and acceptable pharmacokinetic curves are vital preliminary steps, especially when effective approved formulations exist.

The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales

Objective To examine the population-wide overdose risk emerging from the prescription of methadone and buprenorphine for opioid substitution treatment in England and Wales. Design Retrospective administrative data study. Setting National databases for England and Wales. Participants/cases Drug-related mortality data were drawn from the Office for National Statistics, and prescription data for methadone and buprenorphine were obtained from the National Health Service for the years 2007–2012. During this 6-year period, a total of 2366 methadone-related deaths and 52 buprenorphine-related deaths were registered, corresponding to 17 333 163 methadone and 2 602 374 buprenorphine prescriptions issued. The analysis encompassed poisoning deaths among members of the wider population of England and Wales who consumed, but were not prescribed these medications, in addition to patients prescribed methadone or buprenorphine. Main outcome measures Mortality risk: substance-specific overdose rate per 1000 prescriptions issued; relative risk ratio of methadone in relation to buprenorphine. Results During the years 2007–2012, the pooled overdose death rate was 0.137/1000 prescriptions of methadone, compared to 0.022/1000 prescriptions of buprenorphine (including buprenorphine-naloxone). The analysis generated a relative risk ratio of 6.23 (95% CI 4.79 to 8.10) of methadone in relation to buprenorphine. UK Borders Agency data were taken into consideration and revealed that only negligible amounts of methadone and buprenorphine were seized on entering UK territory between 2007 and 2012, suggesting domestic diversion. Conclusions Our analysis of the relative safety of buprenorphine and methadone for opioid substitution treatment reveals that buprenorphine is six times safer than methadone with regard to overdose risk among the general population. Clinicians should be aware of the increased risk of prescribing methadone, and tighter regulations are needed to prevent its diversion.

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

Abstract Background and Aims Take‐home naloxone can prevent death from heroin/opioid overdose, but pre‐provision is difficult because naloxone is usually given by injection. Non‐injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability. Design Open‐label, randomized, five‐way cross‐over PK study. Setting Clinical trials facility (Croydon, UK). Participants Thirty‐eight healthy volunteers (age 20–54 years; 11 female). Intervention and comparator Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone. Measurements Regular blood samples were taken, with high‐frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration. Findings Mean peak concentration (Cmax) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (Tmax). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47–51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3‐minute intervals showed that comparable plasma naloxone concentrations would be anticipated. Conclusions Concentrated 2 mg intranasal naloxone is well‐absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post‐dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.

Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone

The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatins tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitols recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitols greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 μg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.

Heroin overdose resuscitation with naloxone: patient uses own prescribed supply to save the life of a peer

Opiate overdose is the primary cause of death among injection-drug users, representing a major public health concern worldwide. Opiate overdose can be reversed through timely administration of naloxone, and users have expressed willingness to carry the antidote for emergency use (take-home naloxone). In November 2014, new WHO guidelines identified that naloxone should be made available to anyone at risk of witnessing an overdose. We present the case of a 46-year-old man in opioid-maintenance treatment who used take-home naloxone to rescue an overdose victim. This is the first- ever account of a patient using dose titration of naloxone to restore respiratory function while minimising the risk of adverse effects. To improve the safety of take-home naloxone, the authors call for clinicians involved in the treatment of opiate users to: prescribe take-home naloxone to all patients; forewarn patients of potential side effects; and instruct patients in naloxone dose titration.

Paying participants in addiction research: is cash king?

ABSTRACT I know there’s some real scary, hardcore stories of people selling vouchers, but I’ve never experienced anything like that. If I got a voucher, I would often see it as a bonus. If it was for a shop I didn’t use, I would sell it to someone I knew for the same amount of money – them just doing me a favour really. I wouldn’t sell a voucher for less than its value.

A mapping review of take-home naloxone for people released from correctional settings

BACKGROUND People released from correctional settings are at an elevated risk of opioid overdose death in the weeks immediately following release. However, it is not well understood how this population, as a particularly high-risk group, is included in, and benefits from take-home naloxone (THN) programs. The objective of this review is to map research into THN for people released from correctional settings in order to identify further research needs. METHOD We searched electronic databases, grey literature, and conference abstracts for reports on THN for people in or released from correctional settings. Studies were categorised into themes defined by the studys aims and focus. Results from each study were summarised by theme. RESULTS We identified 19 studies reporting on THN programs for people released from correctional settings. Studies have examined attitudes towards naloxone among people in custody or recently released from custody (theme 1), and among non-prisoner stakeholders such as prison staff (theme 2). Evaluations and interventional studies (theme 3) have examined process indicators and approaches to naloxone training, including for contacts of prisoners, but there are challenges in assessing health outcomes of THN in the correctional context. Case reports suggest that training in correctional settings translates to action post-release (theme 4). CONCLUSION The feasibility of THN in the context of release from a correctional setting has been established, but there is a need for rigorous research into health outcomes and program implementation. This is an emerging field of study and ongoing assessment of the state of the literature and research needs is recommended.

Toxicity: exploring and expanding the concept

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Patient views of opioid pharmacotherapy biodelivery systems: Qualitative study to assist treatment decision making.

The technology for delivering opioid pharmacotherapy (OPT) is expanding. It is important to know what OPT patients think of these developments and to find ways of enabling patients and clinicians to make informed decisions about which biodelivery system to choose. We explored the views of current and former OPT patients with a history of heroin use to identify factors influencing their preferences regarding routes of OPT administration. Data were generated via seven focus groups conducted in London, United Kingdom. Participants (n = 44) considered standard biodelivery systems (liquid/linctus, tablet, injectables), emergent systems (implants, depot injections), and a hypothetical system (nasal sprays). Groups were audio-recorded, transcribed verbatim, coded using qualitative software, and analyzed inductively via iterative categorization. Participants were cautious of, but willing to consider, new ways of receiving OPT and they welcomed having more choice. Their preferences and decision-making processes were influenced by nine interconnected factors: (a) personal dislike of particular biodelivery systems, (b) desired feelings following OPT administration, (c) perceived effectiveness of OPT biodelivery systems, (d) concerns about side effects, (e) ability to control the OPT, (f) impact on daily lives, (g) concerns about OPT-related stigma, (h) need for psychosocial support, and (i) personal treatment goals. This complexity may make it difficult for patients and clinicians to evaluate the pros and cons of the expanding array of OPT biodelivery systems and to arrive at clear conclusions. We therefore use the findings to construct a checklist that may facilitate discussions with patients when decisions about OPT need to be made.