Take-Home Naloxone in Opioid Dependency

An Intervention to Reduce Opioid-Related Deaths

Background: There were 2227 drug-related deaths in Germany in 2023, corresponding to a rise of 12% over the previous year and a doubling over the course of a decade. Approximately 60% of these deaths were related to opioid consumption. In this narrative review, we discuss whether take-home naloxone (THN) might lower the mortality of persons with opioid dependency.

Methods: This review is based on pertinent publications that were retrieved by a selective search in PubMed.

Results: Seven observational studies of the mortality of persons with opioid dependency were included in the analysis. The available evidence for the intervention is on a low level. The studies indicate an overall lowering of mortality even though a significant reduction in drug-related deaths was not always achieved. It was concluded in a meta-analysis of 9 observational studies that 9.2% (95% confidence interval, [5.2; 13.1]) of the THN kits provided were actually used in the first three months to prevent opioid overdose–related death. In a Canadian study, 43% [41; 45] of the naloxone kits that were handed out over a period of 8 years were used and successfully prevented opioid overdose-related death. The latter figures suggest that the use of THN may have been systematically underestimated to date.

Conclusion: Demonstrating the efficacy of THN is difficult because of the nature of the research topic. Current evidence implies that THN lowers the mortality of persons with opioid dependence. It is estimated that only about 1.3% of opioid dependent people have been provided with THN in Germany thus far. A major expansion of the provision and use of THN could contribute to a further reduction in opioid-related deaths.

Cite this as: Fleissner S, Stöver H, Schäffer D, Wodarz-von Essen H, Deimel D, Wodarz N: Take-home naloxone in opioid dependency: An intervention to reduce opioid-related deaths. Dtsch Arztebl Int 2025; 122: 240–4. DOI: 10.3238/arztebl.m2025.0030

In Germany, 2227 drug-related deaths were recorded in 2023. This corresponds to a year-on-year increase of 12% and a doubling in numbers over the course of the last decade (e1). In approximately 60% of these deaths, opioids played a role, a trend already noted in previous years (e1, e2, e3). Unintentional overdoses are a major contributor to the observed at least tenfold increased mortality among people who are opioid-dependent compared to people who are not opioid-dependent of the same age and sex (1). Around one in 50 of all emergency physician-staffed ambulance call-outs are related to drugs (not including alcohol) (2). People with opioid dependency are frequently treated in emergency departments, withdrawal or detox facilities, and prisons (e4), but also in other health care settings. In the case of the latter, this is particularly due to the fact that secondary or concomitant diseases, such as infections, are common among persons with opioid dependency (3, e4).

Opioid-agonist treatment (OAT) can lower mortality (e5); however, mortality rates remain significantly elevated in the first weeks after treatment initiation and especially after (unplanned) termination of OAT (e6). In Germany, only about 50% of the estimated 166 000 persons who are opioid-dependent are currently receiving OAT (3).Furthermore, mortality is significantly increased when a relapse occurs after withdrawal or detoxification treatment due to a reduction in tolerance to opioids (e7) or after imprisonment without OAT (e8). Abstinence-oriented treatments can be helpful, but the drop-out rate is high (e9, e10, e11). The experiences gained in the US should be taken into account to prevent them from being repeated. There, as the result of aggressive marketing, opioids were very liberally prescribed over prolonged periods of time for non-cancer pain (e.g., headache or back pain), even to young patients or even beyond the hospital stay to patients who underwent uncomplicated surgery (e12).

Take-home naloxone (THN) is harm-reducing treatment with the potential to reduce drug overdose-related deaths (4, 5, e13). A naloxone nasal spray has been available in Germany since 2018:

• It can antagonize the effect of opioids within minutes.
• It is suitable for use by non-professional persons.
• When used in the absence of opioids, it has no effect (6, 7, 8).
• It does not lead to riskier patterns of consumption (9, 10).

Each naloxone nasal spray has an effect equivalent to a dose of approx. 0.4 mg naloxone administered intramuscularly (i.m.), two single-dose sprays are equivalent to a total dose of approx. 2 mg intramuscular naloxone (11). One package contains two single-dose sprays (1.8 mg naloxone each); currently, it is classed as a prescription drug and eligible for reimbursement. It is approved for use in persons with opioid dependency. It is advisable to provide emergency training before distributing THN so that trained persons with opioid-dependency can help other persons suffering from an overdose by providing first aid, administering naloxone and attending to the person until the emergency service arrives at the scene. This seems to be particularly relevant, as in 70–90% of cases overdoses occur in the presence of third persons, typically other people who use drugs (e14). In this narrative review we present the available evidence in support of the potential of THN to lower mortality in people who are opioid-dependent.

Methods

This review is based on pertinent publications that were retrieved by a selective search in PubMed. Studies evaluating the effect of THN on the mortality of persons with opioid dependency were included. For ethical reasons, randomized controlled trials (RCTs) are not permitted in this situation. A total of seven observational studies were identified which met the above inclusion criterion (Table). To supplement these seven observational studies, publications on the use of THN in the management of overdose emergencies as well as model calculations on the effectiveness of THN were also included. Only peer-reviewed publications were considered. The results are reported in narrative form.

Table

Observational studies on the relationship between mortality and take-home naloxone

Results

Observational studies

If conducting an RCT is not feasible, an interrupted time series analysis is a suitable alternative for evaluating intervention effects (e15). Using this methodology, an analysis of 19 districts in Massachusetts showed that in districts with 1–100 people who are opioid-dependent provided with THN per 100 000 population the number of opioid-related deaths decreased by 27% (adjusted rate ratio [aRR]: 0.73; 95% confidence interval [0.57; 0.91]). In districts with > 100 people who are opioid-dependent provided with THN per 100 000 population, mortality decreased by 46% (aRR 0.54 [0.39; 0.76]) (12). Using a different methodology, but on a similar scale, the Scottish THN program showed an effect on opioid-related deaths that occurred within four weeks of release from prison or discharge from hospital in the period 2011–2013. For comparison, the deaths that occurred in the period 2006–2010 were used because no THN was available at that time. In the period during which THN was distributed, a decrease in the number of opioid-related deaths by 36% was observed after release from prison [20; 51] and by 22% after discharge from hospital [7; 33] (13).

During the opioid crisis in the USA, two studies investigated how opioid-related mortality varied with laws that regulate both easier access to THN and impunity for first responders. The studies compared US federal states with such legislation to states without such laws in various time periods. Opioid-related mortality was found to be lower in states with such legislation, particularly on making THN more accessible, albeit to varying degrees (14, 15). No significant difference in mortality was found between the median of opioid-related deaths in the period before (October 2015 to September 2017) and during (October 2017 to September 2019) a THN project in the state of Ohio (16), presumably due to inadequate study duration and number of cases (16).

A Swedish population study compared a period of large-scale THN distribution to people who are opioid-dependent (2019–2021) with a period without THN distribution (2013–2017) regarding the number of opioid-related deaths. Based on data from the National Cause of Death Register, the annual number of opioid-related deaths per 100 000 population decreased significantly from 3.9 to 2.8 (17). A cluster-randomized waiting group study investigated the effect of THN, OAT, safe prescription of opioids, and other strategies on the number of opioid-related deaths. No differences were found. However, the study was started shortly before the onset of the corona pandemic. In addition, 38% of the interventions had already been implemented and fentanyl increasingly became the drug of choice in the four states involved, with a correspondingly increased risk of (lethal) overdosing (18). The only attempt to conduct an RCT had to be terminated prematurely due to methodological difficulties (19); consequently, we did not include this study in our review.

Review articles

Other studies did not explicitly investigate mortality; instead, they inferred the effectiveness from the use of THN in cases of overdosing, as each THN used can potentially prevent one fatal outcome. In a systematic review, McDonald and Strang (4) analyzed the literature using the Bradford Hill criteria which can be applied if, as with THN, no RCTs but only observational studies are available. They arrived at the conclusion that THN can reduce opioid-related mortality. This conclusion is confirmed by another systematic review (20). In addition, over the following years, the successful use of THN was demonstrated in non-randomized observational studies, both internationally (21, 22, 23) and in Germany (2, 24). Addressing the question of how often trained people who are opioid-dependent actually use THN to treat an overdose, a descriptive meta-analysis of 9 observational studies from different settings in the US, UK and Canada found that 9.2% [5.2; 13.1] of the THN kits were successfully used within the first 3 months. In contrast, a study in British Columbia in Canada showed that 43%[41; 45] of the naloxone kits distributed between February 2015 and August 2023 were used, indicating that their use has been systematically underestimated so far (26).

Model calculations

Statistical models were used to calculate the reduction in mortality in relation to the distribution of THN. Based on their probabilistic base case in the US, Coffin and Sullivan (27) assumed a reduction in opioid-related deaths of 6.1% once 20% of the persons who are opioid-dependent had received THN. One death could be prevented per 227 [71; 716] distributed naloxone kits (number needed to treat) (27). Using the same model in the UK, Langham et al. (28) assumed a reduction in opioid-related deaths of 6.6% once 30% of people who are opioid-dependent had received THN. Coffin et al. (29) adapted the model to a distribution of fentanyl. The effectiveness decreases, but THN still prevents opioid-related deaths. The model calculation by Nielsen et al. (30) looked at the effectiveness of THN in people prescribed with opioids in Australia. When 90% of this population is reached by 2030, a 20% reduction in opioid-related deaths by 2030 can be assumed. Tatara et al. (31) showed in their model that especially THN distributed on release from prison can prevent opioid-related deaths.

Discussion

Evaluating the effect of THN on overdose-related mortality among people who are opioid-dependent is methodologically challenging. RCTs cannot be conducted for ethical reasons and practical experience in research has shown that the control group also benefits from THN in the intervention group (19). To further complicate matters, the basic population of people who are opioid-dependent can only be estimated and the data on the number of drug-related deaths is also influenced by various factors (e.g., proportion with toxicological expert opinions) (e17). Although increasing in numbers, deaths due to opioid overdosing are still a rare occurrence (in Germany: 2.7 per 100 000 population [e17]). Substantial sample sizes are therefore required, as the confidence intervals are typically very large (5).

Despite the fact that THN programs have been run for many years now (for example 32), the level of evidence of the available data on the effectiveness of THN is still only moderate to low. However, almost all of these studies indicate a reduction in opioid-related deaths. The reviews on the use of THN can provide further evidence that it is possible to prevent opioid-related deaths by administering THN (4, 20, 25). However, given that not every opioid overdose resulting in unconsciousness necessarily entails a fatal outcome, it remains unknown whether the affected person would have survived without the administration of THN and consequently to what extent mortality is actually reduced. At the same time, it was also shown that less than 1% of people with overdoses did not survive despite THN administration (4, 23). Thus, overdose-related fatal outcomes occur in particular in settings where no help, including THN, is available (33, 34, e14). The available modeling also shows a reduction in opioid-related deaths (27, 28, 29, 30, 31). Key elements of the database, such as the number of drug-related deaths, overdoses and THN uses, are dependent on various factors and are thus of limited validity. However, particularly conservative estimates are used in the models. Therefore, the effects tend to be rather overestimated despite the limited quality of the source data.

The Bradford Hill criteria (35) were also used as an alternative approach to evaluating the effectiveness of THN in reducing mortality, and, with this method, THN was found to be effective (4). The European Union Drugs Agency (EUDA) assumes a high level of evidence (e18). In the soon to be published S3-level clinical practice guideline of the Association of the Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) on opioid-related disorders, THN distribution to people who are opioid-dependent will receive the highest grade of recommendation. Thus, despite at best moderate evidence, THN after relevant training can be regarded as a standard of care in the treatment of people who are opioid-dependent, also in the case of OAT (36).

The benefits appear to clearly outweigh the possible side effects, such as withdrawal symptoms associated with naloxone administration, particularly in view of the potentially life-threatening nature of the situation. In addition, training content helps to adequately deal with the consequences of these side effects (37). Several studies have shown that trained people who use drugs are able to correctly use THN (2, 19, 26, 36). Furthermore, THN does not result in increased or riskier consumption (2, 9, 10). With regard to the aspect of quality-adjusted life years (QALY), it is reasonable to assume that THN is cost-effective (27, 28).

Take-home naloxone in Germany

In Germany, THN has been available in small local projects since 1998 (24). During the two model projects BayTHN (2018–2020) (2, 38) and NALtrain (2021–2024) (e19), drug emergency training with subsequent provision of THN was documented of almost 2000 people who are opioid-dependent; additionally 203 uses of THN were recorded. To a lesser extent, this is supplemented by training provided in other facilities and projects. However, no data has been published on these training events, but cautious estimates suggest that approximately 200 people who are opioid-dependent were also trained and provided with THN there. Based on 166 000 people living in Germany who are opioid-dependent (3), so far only about 1.3% (2200) of the persons with opioid dependency have been reached. The fixed organizational combination of drug emergency training (for example provided by trained instructors from drug help facilities), prescription (close collaboration with doctors) and prescription redemption makes it difficult to distribute THN more widely, thereby preventing that THN can significantly contribute to a reduction in opioid-related deaths.

Conclusion

Given the effectiveness of THN, nationwide implementation could prevent opioid-related deaths in Germany. Since only 1.3% of people who are opioid-dependent in Germany are reached, the harm-reducing potential of THN has hardly been utilized to date. Situations that are particularly suitable for the implementation of THN include the start and end of OAT (36, 39), discharge from or termination of a withdrawal or detoxification treatment (e20), release from prison (13, 31, 40), and in the emergency department after an opioids overdose (e21, e22, e23). However, THN can only prevent a certain proportion of opioid-related deaths and should be implemented in conjunction with other measures (e24, e25)..

Acknowledgement

We would like to thank the dedicated staff in the facilities of the Drug and AIDS Service Organizations as well as the contributing people who are opioid-dependent. Our thanks also go in loving memory to Dr. phil. Heike Wodarz-von Essen who sadly passed away far too early – without her, the BayTHN would not have been possible.

Funding

The federal model project “NALtrain” was funded by the German Federal Ministry of Health (BMG, Bundesministerium für Gesundheit) (ZMI1–2521DSM20A). The model project BayTHN was fund by the Bavarian State Ministry of Health and Care (G27C-G8434–2017/9–43).

Conflict of interest
HS is chairman of akzept e. V. – Federal Association for Accepting Drug Work and Humane Drug Policy.

The remaining authors declare no conflict of interest.

Manuscript received on 1 October 2024, revised version accepted on 10 February 2025

Translated from the original German by Ralf Thoene, M.D.

Corresponding author

Prof. Dr. med. Norbert Wodarz

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