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

Strength of association

In 21 of the 22 studies, pre‐provision of naloxone was followed by use of the naloxone to reverse opioid overdose. After exclusion of four studies that possibly contained duplicate samples 30, 31, 32, 33, a total of 2336 THN administrations were found across 17 studies (see Table 3). Due the binary outcome (survival/death), the number of successful overdose reversals can be estimated by deducting the number of deaths from the number of THN administrations. By deducting the 20 confirmed deaths (1 + 1 + 2 + 6 + 10) where overdose victims did not recover following naloxone administration 12, 24, 25, 34, 35, we obtain an upper estimate of 2316 successful overdose reversals. If the four deaths where it was unclear if naloxone had been administered 23 and 63 cases (8 + 36 + 14 + 5) of naloxone administration with ‘unknown outcome’ 23, 24, 27, 34 are also counted towards fatalities following naloxone administration, a conservative, lower estimate of 2249 successful overdose reversals emerges. In the only study where THN provision did not lead to overdose reversals 11, nine of 46 programme participants witnessed a total of 16 overdoses at 6‐month follow‐up, but none administered naloxone to the overdose victims. The main reason for non‐administration was that participants did not have their naloxone supply available.

In summary, there is a strong association between THN programmes and overdose survival, as evidenced by at least 2249 successful overdose reversals [96.3%; 95% confidence interval (CI) = 95.5, 97.1] among 2336 THN administrations.

Temporality

In 21 of the 22 studies, training in overdose prevention and THN provision preceded overdose reversals. Two of these studies provide clear evidence in support of the temporality criterion. Supportive evidence comes from descriptive accounts of early THN distribution in Chicago and surrounding Cooks County 35: after a 135% increase in local overdose deaths from 1996 to 2000, the introduction of THN in 2001 led to reduction in fatal overdoses by 20% in 2001, 8% in 2002 and 6% in 2003 (compared to past‐year rate). While these data are indicative of a temporal sequence between THN introduction and reduced overdose mortality, no definite conclusion can be drawn, as the lack of control group means that other causes may have contributed to decreasing overdose mortality rates.

Stronger evidence comes from Walley et al. 20 who conducted an evaluation of a state‐funded THN programme in Massachusetts. Between 2006 and 2009, the Massachusetts Department of Public Health used a phased roll‐out to introduce THN in 19 communities, enrolling 2912 individuals in total. To evaluate the impact of THN, Walley et al. used an interrupted time–series analysis, where each community served as its own geographic control and communities without concurrent THN availability served as time control. For all 19 participating communities, overdose mortality rates in the time‐periods before and after THN implementation were compared. Overdose mortality rates were reduced significantly in communities where THN was implemented, compared to pre‐implementation rates and to communities without THN.

Consistency

Overdose reversals by means of THN have been documented in the selected studies by independent investigators under different circumstances in at least 15 different cities, states and countries: in Canada (Toronto and British Columbia), the United States (Baltimore, Boston/Massachusetts, Chicago, Los Angeles, San Francisco, New York, Pittsburgh, Rhode Island), the United Kingdom (England, Jersey, Scotland, Wales) and Germany (Berlin). Overdose reversals by THN have also been documented repeatedly in New York 26, 27 and San Francisco 14, 24, 25. In conclusion, there is substantial support for the consistency criterion.

Biological plausibility

This criterion addresses the therapeutic effect of naloxone. Naloxone is a pure opioid antagonist that binds to the μ‐opioid receptor and blocks competing agonists, such as heroin 36. All but one study 11 reported on THN administration in cases of suspected opioid overdoses, and the pharmacological effects of naloxone led to at least 2249 overdose reversals. In conclusion, there is strong empirical support to the biological plausibility criterion.

Coherence

Declining overdose rates in the absence of THN have been reported in the literature. The Australian heroin drought constitutes a prominent example, where between 2001 and 2002 overdose‐related mortality rates dropped in conjunction with a shortage in illicit heroin imports. THN could not have accounted for the decline in mortality, as it was introduced in Australia only in 2011 37, 38. However, the Australian example does not conflict with the presumed effect of THN on reduced overdose mortality. The cause‐and‐effect interpretation of our data is consistent with current understanding of the mechanisms of opioid overdose, and the 21 studies which reported overdose reversals provide strong support for the coherence criterion.

Specificity

The specificity criterion relates to efficacy of the intervention (the same as biological plausibility), rather than population‐wide effectiveness. THN exclusively reverses opioid‐induced overdoses, as illustrated by the following two cases: in the Dettmer et al. study 39, naloxone had zero effect when administered to a person suffering from cocaine intoxication. The Chicago Recovery Alliance reported one fatality after naloxone administration 35 where naloxone failed to revive an overdose victim with non‐opioids in their system. The mooted benefit from naloxone is specific to opioid overdose. In practice, THN may be primarily beneficial for the reversal of overdoses from heroin and other short‐acting opioids. (All 22 studies reported primarily on heroin overdoses, and one study specified that the long‐acting opioid methadone was involved in less than 5% of overdose reversals [33].) Overall, the evidence constitutes strong support for this criterion.

Dose–response relationship

Researchers estimate that THN distribution can only achieve maximum impact on overdose reduction if a certain volume of THN kits is available in the community. Among the 22 studies, only Walley et al. 20 assessed the impact of varying degrees of THN availability on overdose mortality by splitting the 19 participating communities into three groups based on volume of THN distribution: zero implementation, low implementation (1–100 programme enrolments per 100 000 inhabitants) and high implementation (>100 enrolments). Both low and high implementers had significantly reduced overdose mortality rates compared to communities without implementation, and there was a significant implementation dose‐relationship with overdose death rates, with greatest effect with greatest implementation.

To summarize, there is only this limited empirical evidence for a dose‐related impact of THN availability, and hence this criterion is only partially fulfilled.

Experimental evidence

While none of the 22 studies deliver experimental evidence, the interrupted time–series analysis by Walley et al. 20 provides quasi‐experimental evidence in support of causation. Importantly, even communities with low‐level THN implementation of THN (1–100 participants, see above) saw a reduction in overdose mortality, compared to communities without THN distribution. Interrupted time–series analysis is considered to be the strongest quasi‐experimental research design 40. The results of the study by Walley et al. 20 thus provide preliminary support for the experimental evidence criterion.

Analogy

THN is analogous to naloxone treatment for the same clinical indication in emergency medical care, and also to the prescription of other emergency medications (typically antidotes for overdose or poisoning) for peer administration: THN has been compared to the provision of adrenaline injection kits (e.g. EpiPen) to individuals with severe allergic reactions for family members to administer in the event of anaphylactic shock 15 or the provision of glucagon for insulin overdose 35. Similarly, THN has been likened to pre‐placement of defibrillators and cardiopulmonary resuscitation (CPR) training for lay people likely to witness cardiac arrest 41. For all these emergency interventions, timely delivery is crucial. We conclude that the analogy criterion is fulfilled.

Cost‐effectiveness

Separate modelling data from both the United States and Russia conclude that THN is cost‐effective even under conservative circumstances, i.e. when the cost of naloxone increases and the rate of observed overdoses decreases 42, 43. Bearing in mind the potential limitation that both studies were conducted by the same authors, there is consistent evidence for the cost‐effectiveness of THN.

Absence of negative consequences

In five of the 17 studies that did not contain duplicate samples, 20 overdose victims did not survive naloxone administration 12, 24, 25, 34, 35. In addition, Wagner et al. 23 reported four deaths where it was unclear if naloxone had been administered. Based on these observations, the following fatality rates emerge: 20 confirmed deaths per 2336 naloxone administrations (0.9%; 95% CI = 0.5, 1.2) or 24 deaths per 2336 naloxone administrations (1.0%; 95% CI = 0.6, 1.4) if we include the four fatalities where it was unclear if naloxone had been administered. If we limit the study selection to the nine papers with systematic follow‐up, a similar ratio of one confirmed death per 123 naloxone administrations (0.8%; 95% CI = 0.4, 1.2) was observed.

In six 15, 23, 24, 35, 39, 44 of the 17 studies, several adverse reactions were reported in conjunction with a total of 2336 naloxone administrations: at least 65 instances of withdrawal symptoms (2.8%), 52 cases of vomiting (2.2%), 50 cases of agitation (2.1%) and four seizures (0.1%).

In conclusion, THN programmes have a low rate of adverse events. Where adverse reactions occurred, these were most frequently symptoms of opioid withdrawal (including nausea/vomiting, agitation).

Feasibility of implementation, expansion and coverage

The 22 studies document THN implementation in a variety of settings across 16 geographical locations, and naloxone usage rates between 5 and 63% are reported. San Francisco is an example of rapid expansion, as the volume of THN kits distributed increased from 24 in 2001 to 2962 kits during the 6‐year period between 2003 and 2009 (i.e. approximately 494 kits/year) 24, and to 2500 kits from 2010 to 2013 (i.e. approximately 833 kits/year) 25. Outside the 22 studies included in this review, implementation in resource‐poor settings has been achieved in Kyrgyzstan and Tajikistan, with reported naloxone usage rates of 47 and 78%, respectively 45. These studies suggest that THN schemes are capable of implementation across a wide range of settings and cultures.

Unanticipated benefits

Four of the 22 studies reported unanticipated benefits. In THN programmes in California, 25% of participants in San Francisco entered treatment within 6‐month follow‐up 14 and 53% of participants in Los Angeles reported decreased drug use at 3‐month follow‐up 23. Similarly, Maxwell et al. reported anecdotal evidence of increased willingness among THN recipients to be tested for HIV and hepatitis C virus (HCV) 35. Strang et al. 15 found a secondary training effect: within a 3‐month follow‐up period, 28% of THN recipients had trained a family member or peer.

Special populations

THN provision has been implemented successfully in programmes targeting special populations with high risk of overdose: detox patients 11, 33, homeless users 23, 24, 25, 27, 46, methadone patients 33 and prison inmates 12. The Massachusetts THN programme 20 also enrolled attendees of HIV education centers, and a Los Angeles‐based programme recruited more than 50% HCV‐positive patients. Both represent particularly vulnerable groups due to their comorbid health issues and risk of blood‐borne virus transmission by needle‐sharing. From the perspective of implementation, THN schemes can be delivered to populations in special need.