Abstract
Background and aim
Opioid overdose is a public health crisis. Globally, ~ 600,000 deaths each year are attributable to drug use, and roughly three-quarters are linked to opioids. The rising prevalence of high-potency synthetic opioids like fentanyl necessitates comprehensive prevention and treatment strategies. This scoping review aims to map the published literature on the early detection and community management of opioid overdose and post-overdose care and identify research gaps. The aim was also to inform the potential research questions for updating the WHO and other international guidelines.
Methods
We systematically searched PubMed, EMBASE, PROSPERO, and the Cochrane Database for systematic reviews for studies published between January 2014 and March 2024. Inclusion criteria encompassed systematic reviews and review protocols, randomized clinical trials, and their secondary analysis, and guidelines published in those databases, addressing opioid overdose early detection and treatment strategies.
Results
A total of 3,057 unique records were screened, resulting in 105 studies meeting the inclusion criteria. Thirty studies examined the effects of the acute opioid overdose treatment. Among the preventive strategies, 46 studies focused on “Take Home Naloxone” strategies, reflecting a significant emphasis on naloxone distribution as a primary intervention. However, 11 studies examined post-overdose care, highlighting a notable gap in the literature. Additionally, research predominantly concentrated in the Americas (70 studies) and Europe (27 studies), with limited representation from Africa and Southeast Asia. There was a marked absence of studies on polysubstance use and ultrapotent opioids, with one systematic review addressing the treatment of fentanyl overdose.
Conclusion
Findings support future international guidelines, such as those of the WHO, to examine the effectiveness of take-home naloxone, peer training, and community-based distribution models, higher-dose naloxone protocols for ultrapotent opioids, and digital delivery models. This review identifies gaps in post-overdose care, fentanyl and polysubstance overdose management, and research from low-resource settings.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12954-025-01372-z.
Introduction
Opioid overdose has emerged as a critical public health crisis globally, with escalating rates of morbidity and mortality associated with opioid misuse. Globally, ~ 600,000 deaths each year are attributable to drug use, and roughly three-quarters are linked to opioids [1]. The US has witnessed a loss of life expectancy at birth, with a doubling of the years of life lost due to drug overdose deaths, between 2019 and 2022, across races/ethnicities and states [2]. Opioid overdoses that do not lead to death are several times more common than fatal overdoses [1]. This alarming trend underscores the urgent need for comprehensive strategies aimed at preventing and treating opioid overdose, which are essential components of a broader public health response to the opioid epidemic.
The opioid overdose crisis is characterized by an array of factors that contribute to both the onset and the escalation of opioid-related harm. Factors such as the availability of prescription opioids, the rise of illicit opioids like fentanyl and its synthetic analogs, and socio-economic disparities play significant roles in the landscape of opioid use and subsequent overdose [3–5]. These complexities necessitate an integrated approach to prevention and treatment, targeting the various dimensions of the crisis, including socio-cultural, economic, and healthcare system factors [6].
Prevention strategies are critical in addressing the opioid overdose crisis. These can be broadly categorized into primary, secondary, and tertiary prevention efforts. Primary prevention aims to reduce the incidence of opioid overdose before it occurs, often through prescription drug monitoring programs [7], improving access to treatment for opioid use disorder (OUD) [8], and public policy initiatives and access to harm reduction strategies [9, 10]. Secondary prevention focuses on early identification and management of individuals experiencing opioid overdose, including various community programs for naloxone distribution [11, 12]. Tertiary prevention addresses providing treatment for opioid overdose and support to prevent overdose recurrence and improve overall health outcomes [1, 13].
A comprehensive understanding of effective treatment options is also paramount. Evidence suggests that medication for OUD (MOUD), which combines pharmacological interventions with behavioral therapies, is one of the most effective strategies for treating OUD [14] and reducing overdose risk [15]. Medications such as methadone and buprenorphine have been shown to significantly reduce opioid use and the likelihood of overdose [15]. Moreover, the provision of naloxone, an opioid antagonist, either by injection or via intranasal routes, that can rapidly reverse opioid overdose, is the cornerstone of overdose treatment [1, 16]. The availability of naloxone in various settings, including pharmacies and community organizations, has been linked to reductions in overdose fatalities [17].
Despite the advances in prevention and treatment modalities, significant barriers hinder the effective implementation of these strategies. The stigma associated with OUD, coupled with insufficient access to treatment services, creates substantial obstacles for individuals seeking help [18, 19]. Moreover, the fragmented nature of healthcare systems often complicates the provision of comprehensive care, leading to gaps in service delivery and support for individuals at risk of overdose [20]. Addressing these systemic issues is crucial for creating an environment conducive to effective prevention and treatment efforts.
To address the limited access to the treatment of opioid overdose and to enhance response capabilities in overdose situations, the WHO guidelines on the community management of opioid overdose recommended that individuals likely to witness an overdose—particularly people who use opioids and their family members—be provided with naloxone and trained in its administration [21]. The guidelines also recommended that naloxone can be delivered via injection or nasal spray and has minimal effects on individuals who are not using opioids. While bystander administration of naloxone serves as a crucial, life-saving measure during an overdose, it is important to emphasize that it should not substitute for comprehensive medical care [21]. This approach aligns with the need for integrated strategies in overdose prevention and treatment, highlighting the importance of equipping individuals with the knowledge and tools to respond effectively in emergencies.
After ten years [21], there is a felt need to update the existing WHO guidelines in light of accumulated evidence of the significant evolution of the opioid crisis, marked by a dramatic increase in overdose prevalence and fatalities- in the US, from 47,500 in 2014 to crossing 100 000 in 2025, particularly attributed to the emergence of potent synthetic opioids [22]. Recent data indicate a surge in opioid-related deaths, necessitating a reassessment of existing guidelines to reflect current trends and risks. Additionally, advancements in naloxone distribution strategies and administration techniques, including intranasal formulations that enhance accessibility for laypersons, warrant updated recommendations on distribution and training protocols, and the application of telemedicine to improve and expedite access to naloxone [23–25]. The changing landscape of substance use, including polydrug use and the integration of overdose prevention within comprehensive substance use disorder treatment frameworks, highlights the need for a holistic approach to the guidelines [26]. An update would ensure that health professionals and community members are equipped with the most effective, evidence-based strategies to manage opioid overdoses, ultimately saving lives and fostering a proactive, community-oriented response to this ongoing public health emergency.
This scoping review aimed to conduct evidence mapping of the published systematic reviews and review protocols, primary randomized trials and their secondary analysis on the early detection and community management of opioid overdose and post-overdose care (secondary and tertiary prevention). The aim of the evidence mapping was to inform the potential research questions for the systematic reviews for updating the WHO and other international guidelines on the community management of opioid overdose [21].
Methods
Eligibility criteria
We included all systematic reviews (including scoping reviews, rapid systematic reviews) and systematic review protocols of clinical trials and observational studies, individual RCTs, and secondary analyses of RCTs on the prevention and treatment of opioid overdose (secondary and tertiary prevention) published between January 2014 and March 2024. Systematic reviews of observational and quasi-experimental studies were also included. We included any additional medical interventions (e.g., CPR). Overdose prevention models were added. “Model” refers to a defined service-delivery approach that specifies who delivers the intervention, to whom, where, what components are included (education, supplies, linkage), and how implementation is supported (training, protocols, workflows, data systems). This includes models that distribute prevention tools (e.g., naloxone distribution) and models that deliver overdose risk-reduction services (e.g., supervised consumption/overdose prevention centers). We did not exclude any population group, treatment settings (community vs. emergency/healthcare settings), or control group. Population included individuals experiencing or at risk of opioid overdose. At-risk of opioid overdose refers to individuals who, by virtue of their substance use patterns, medical history, or environmental exposure, are considered to have an elevated risk of experiencing an opioid overdose. This includes people who use opioids (prescription or illicit) and individuals with OUD.
We included and documented any outcomes assessed. We also included national guidelines on the pharmacological treatment of opioid overdose published in the searched databases.
We did not impose any language restrictions.
Information sources
The WHO guideline on Community Management of Opioid Overdose was released in 2014 [21]. To capture all systematic reviews/review protocols and RCTs published since its release, we systematically searched Pubmed, EMBASE, PROSPERO, and Cochrane Database for systematic reviews of studies published between January 2014 and Mar 2024.
Search strategy
Population: focused on individuals experiencing or at risk of opioid overdose, and service providers. Accordingly, we used search terms such as “opioid overdose”, “drug overdose”, and “opioid intoxication”.
Intervention: included both pharmacological and non-pharmacological approaches to overdose prevention and treatment. We used search terms such as “naloxone”, “injection naloxone”, “take-home naloxone”, “naloxone nasal spray”, “naloxone distribution”, and “overdose prevention” to reflect the range of interventions under review.
We did not impose any exclusion based on the controls or outcomes; hence, we did not have search terms related to these variables.
To ensure comprehensive retrieval of relevant studies, we deliberately used broad search terms related to opioid overdose, such as “opioid overdose,” “drug overdose,” and “opioid intoxication.” We did not restrict our search to specific opioid types (e.g., fentanyl, heroin, oxycodone) because such specificity risked missing relevant studies that use generalized or non-standardized terminology. Given the heterogeneity in how opioids and overdoses are described in the literature, this broader approach maximized sensitivity and inclusiveness—consistent with the aims of a scoping review. Similarly, for the intervention concept, we employed general terms. This was based on the recognition that intervention terminology varies across studies and jurisdictions, and overly specific search terms could omit studies that did not use standardized descriptors. Given our objective to map the full scope of literature on opioid overdose prevention and treatment, using broader terms was essential to ensure maximal retrieval across diverse study designs, populations, and geographic regions.
Detailed search strings available in Supplementary Table 1.
Selection of sources of evidence
We used evidence mapping software, EPPI Reviewer 6.0 to upload the sources of evidence. Two trained researchers screened the articles by title and abstract screening and generated the list for the full-text retrieval. The full texts were reviewed by two researchers independently, and a senior researcher resolved the discrepancies between the two professionals after discussion and finalized the list of the selected articles. All full texts were reviewed by at least two reviewers (AG/SC/TM) for evidence mapping.
Data charting process
We have developed a data extraction sheet to systematically capture and organize the relevant evidence regarding the prevention and treatment of opioid overdose. This extraction sheet was updated following feedback from WHO experts, collaborative discussions within our team, and the critical insights gleaned from the reviewed literature.
For each included study, we extracted the following variables:
Bibliographic details: author(s), year of publication, country or WHO region.
Study characteristics: study design (e.g., systematic review, randomized controlled trial, guideline), setting (e.g., emergency department, community, harm reduction), target population (e.g., individuals with opioid use, healthcare providers, laypersons).
Intervention details: type of intervention (e.g., naloxone administration, take-home naloxone, supervised injection sites, telemedicine, education/training, post-overdose care), route/formulation of naloxone if applicable.
Outcomes assessed: overdose reversal, mortality, safety/adverse effects, knowledge or skill acquisition, treatment engagement post-overdose, cost-effectiveness, patient-reported outcome measures (PROMs), healthcare provider and community perceptions.
Comparator (if applicable): e.g., placebo, usual care, alternative intervention.
Quality appraisal: AMSTAR-2 rating for systematic reviews; RoB-2 rating for RCTs.
Critical appraisal of individual sources
We employed the AMSTAR (A MeaSurement Tool to Assess Systematic Reviews)−2 checklist to evaluate the degree of confidence that can be attributed to systematic reviews [27]. It comprises 16 items that assess domains such as protocol registration, adequacy of the literature search, risk of bias assessment, and appropriateness of meta-analytical methods. Using AMSTAR-2, we classified these reviews into four distinct categories: high-quality (indicating no or one non-critical weakness), moderate quality (indicating more than one non-critical weakness), low quality (characterized by one critical flaw, with or without additional non-critical flaws), and very low quality (defined by more than one critical flaw, with or without additional non-critical flaws). Additionally, we utilized the Risk of Bias Assessment tool (RoB-2) version 2 to evaluate the quality of randomized controlled trials (RCTs) [28]. The RCTs were subsequently categorized as having low, high, or uncertain risk of bias according to the RoB-2 tool. In conclusion, we grouped the systematic reviews and RCTs into three overarching quality categories: high quality (indicating high quality according to AMSTAR-2 and low risk of bias per RoB-2), moderate quality (denoting moderate quality as per AMSTAR-2 and uncertain risk of bias according to RoB-2), and low quality (encompassing both low and very low quality according to AMSTAR-2 and high risk of bias as per RoB-2).
Synthesis of results
We compiled and analyzed the results by tallying the number of studies, including clinical trials, systematic reviews, and review protocols, associated with each specific intervention and categorizing them according to distinct outcomes and populations. To enhance data visualization, we created heat maps. This synthesis provided insights into the areas where systematic reviews/clinical trials have been conducted (or underway) over the past 10 years and identified existing evidence gaps. We utilized EPPI Reviewer 6.0 to manage the dataset, perform screening, removing duplicates, and facilitate evidence mapping. The initial evidence mapping was carried out by one reviewer, and subsequently, another team member verified and ensured the accuracy of the mapping.
Results
Selected reports
“PRISMA 2020 Flow Diagram: Treatment/Prevention of Overdose” (Fig. 1) outlines the systematic review process used to identify, screen, and include studies related to the treatment and prevention of drug overdose. Initially, 2,987 records were identified through database searches, along with an additional 150 records from registers. Before the screening process, 80 duplicate records were removed, resulting in 3,057 unique records. During the screening phase, 2,884 records were excluded based on predefined criteria, leaving 173 records for further retrieval and assessment. All 173 reports were successfully retrieved and underwent a thorough eligibility assessment. Of these, 68 reports were excluded for various reasons: 22 due to design issues, 17 based on outcome relevance, 17 were duplicates, 5 due to population criteria, and 9 because of intervention criteria. Consequently, 105 reports met the inclusion criteria and were incorporated into the final review. See the Supplementary for all included articles.
Fig. 1.
Identification of studies via databases and registers: Treatment/Prevention of overdose
Population
Most of the reports focused on the “individuals at risk of opioid overdose” (n = 72, 68.6%); there were 27 (25.7%) records of individuals with opioid overdose. Several studies focused on healthcare professionals (n = 27, 25.7%), and some studies on “lay persons (n = 13, 12.4%)” and “first responders (n = 9, 8.6%).” We did not find any systematic review or RCTs on the opioid and polysubstance overdose population. See Table 1.
Table 1.
Study Population for Opioid Overdose Treatment/Prevention (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/Population_Year.html)
| Year | Individuals with Opioid Overdose | Individuals at-risk for Opioid Overdose | First Responders | Healthcare Professionals |
Opioid and Polysubstance Overdose | Lay Persons |
|---|---|---|---|---|---|---|
| 2014- | SRs 4 | SRs 5 | CT 1 | SRs 2 | - | CT 2 |
| 2017 | SRP 2 | SRP 3 | MA 1 | SRs 1 | ||
| MA 1 | MA 1 | MA 1 | ||||
| GR 1 | SRP 1 | |||||
| 2018- | SRs 8 | SRs 18 | SRs 3 | SRs 14 | - | SRs 5 |
| 2021 | SRP 3 | SRP 6 | SRP 1 | SRP 2 | SRP 1 | |
| CT 2 | MA 4 | CT 1 | ||||
| GR 2 | CT 3 | GR 1 | ||||
| MA 1 | GR 1 | |||||
| 2022- | SRs 4 | SRs 17 | SRs 2 | SRs 5 | - | SRs 2 |
| 2024 | CT 1 | SRP 10 | SRP 2 | |||
| GR 4 | Clinical Trial 1 |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; SRP Systematic Review Protocol, OAMT: opioid agonist maintenance treatment
Intervention
Treatment of opioid overdose
Thirty studies examined the effects of the acute opioid overdose treatment. Among these reports, most studied the effectiveness of different naloxone routes/doses; there were eight records on different naloxone formulations. Three studies examined behavioral and other non-naloxone interventions. eleven records were retrieved for post-overdose care/treatment. See Table 2.
Table 2.
Acute treatment of opioid overdose> (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/Treatment_Year.html)
| Year | Naloxone Doses/Routes | Naloxone Formulations |
Any Other (Non- naloxone) Overdose Treatment |
Immediate Post- overdose Treatment | Delayed Post-overdose Treatment |
|---|---|---|---|---|---|
| 2014–2017 |
SRs 3 MA 1 SRP 1 |
SRs 2 SRP 1 |
- |
SRs 1 SRP 1 |
- |
| 2018–2021 |
SRs 5 SRP 2 CT 1 MA 1 GR 1 |
SRs 2 SRP 1 GR 1 |
CT 1 SRs 1 |
SRs 3 CT 1 MA 1 GR 1 |
CT 1 SRs 1 |
| 2022–2024 |
SRs 3 CT 1 |
SRs 1 | SRs 1 | SRs 1 |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; SRP Systematic Review Protocol
Prevention of opioid overdose
The ‘Take Home Naloxone’ strategy shows significant research, with 46 studies, including systematic reviews, protocols, meta-analyses, clinical trials, and guidelines reviews. ‘Community-based Naloxone/Overdose Prevention Centers/Supervised Injection Sites (SIS)’ has 25 (23.8%) studies, while ‘Pharmacy-based/Primary Care-based Naloxone’ accounts for 12 (11.4%) studies. ‘Naloxone and Overdose Education/Training’ has a notable total of 40 (38.1%) studies. The ‘Prescription Drug Monitoring/Regulation Programs’ strategy includes 10 (9.5%) studies, and ‘State Policies’ has 12 (11.4%) studies. The ‘Opioid Agonist Maintenance Treatment (OAMT)’ strategy comprises 10 (9.5%) studies, and ‘Telemedicine-based/digital Prevention’ has 11 (10.5%) studies. This broad range of prevention strategies, with a predominant focus on systematic reviews, highlights the diverse and growing body of research dedicated to preventing opioid overdose. There were three systematic review protocols on supervised consumption sites. See Table 3.
Table 3.
Preventative interventions for opioid overdose (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/Prevention_Year.html)
| Year | Take Home Naloxone | Community- based Naloxone/Overdose Prevention Centers/SIS | Pharmacy- based/Primary Care- based Naloxone |
Naloxone and Overdose Education/Training | Prescription Drug Monitoring/Regulation Programs |
State Policies | OAMT | Telemedicine - based Prevention |
|---|---|---|---|---|---|---|---|---|
| 2014–2017 |
SRs 6 SRP 1 |
SRs 3 SRP 2 MA 1 |
SR 1 SRP 1 |
SRs 3 SRP 4 CT 2 MA 1 |
SRs 1 SRP 1 GR 1 |
SRs 2 | MA 1 | CT 1 |
| 2018–2021 |
SRs 17 SRP 4 MA 2 CT 1 GR 1 |
SRs 3 MA 1 SRP 1 |
SRs 3 MA 1 |
SRs 16 Clinical Trial 2 SRP 2 GR 1 |
SRs 5 SRP 1 |
SRs 6 SRP 1 MA 1 |
SRs 4 CT 1 MA 1 SRP 1 |
CT 3 SRs 2 |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; SRP Systematic Review Protocol, OAMT: opioid agonist maintenance treatment; SIS: Safe injection sites
Study settings
In the Hospital Emergency setting, there are a total of 21 (20%) studies (2014–2024), predominantly systematic reviews. The Hospital (inpatient/outpatient/special pain clinic) setting features 16 (15.2%) studies, including systematic reviews, review protocols, and guidelines reviews. The Community/EMS/Pharmacy/Primary Care setting has the highest number of studies, totaling 55 (52.4%), with a significant focus on systematic reviews, review protocols, and meta-analyses. The Prisons (or post-prison release) setting has 9 (8.6%) studies, encompassing systematic reviews, clinical trials, and meta-analyses. Lastly, the Harm Reduction setting includes 22 (21%) studies, with a mix of systematic reviews, review protocols, clinical trials, and guidelines reviews. This diverse research landscape across multiple settings underscores the extensive efforts to address opioid overdose through varied prevention strategies, with a notable concentration of studies in community-based settings. Find further details in Table 4.
Table 4.
Study settings for opioid overdose Treatment/Prevention (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/Settings_Year.html)
| Year | Hospital Emergency | Hospital (inpatient/outpatient/special pain clinic) |
Community/EMS/Pharmacy/Primary Care | Prisons (or Post- prison Release) | Harm Reduction |
|---|---|---|---|---|---|
| 2014–2017 | SRs 3 |
SRs 1 SRP 1 GR 1 |
SRs 6 SRP 4 CT 1 MA 1 GR 1 |
SRs 2 CT 1 |
SRs 2 SRP 1 |
| 2018–2021 |
SRs 8 SRP 4 CT 1 MA 1 GR 1 |
SRs 7 SRP 2 MA 1 |
SRs 13 SRP 5 MA 2 CT 1 GR 1 |
SRs 3 CT 1 MA 1 |
SRs 4 SRP 2 CT 1 GR 1 |
| 2022–2024 |
SRs 3 SRP 1 |
GR 3 SRP 1 |
SRs 13 SRP 6 GR 2 |
SRP 1 |
SRs 6 SRP 5 CT 1 |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; SRP Systematic Review Protocol, EMS: Emergency medical service
Outcome measures
Overdose prevention outcomes have the most extensive body of research with 49 (46.7%) studies, including systematic reviews, review protocols, clinical trials, and meta-analyses. Cost-effectiveness/cost-analysis has 8 studies, all being systematic reviews. Health System outcomes encompass 40 (38.1%) studies, focusing primarily on systematic reviews and review protocols. The training knowledge/skill acquisition/use outcome was studied in 49 studies, including systematic reviews, review protocols, meta-analyses, clinical trials, and guidelines reviews. Overdose treatment outcomes show a total of 20 (19%) studies, featuring systematic reviews, review protocols, meta-analyses, clinical trials, and guidelines reviews. Lastly, the Safety outcome includes 23 (21.9%) studies, with a mix of systematic reviews, review protocols, meta-analyses, clinical trials, and guidelines reviews. This broad research distribution highlights a strong emphasis on training, overdose prevention, and health system outcomes, while cost-effectiveness remains relatively underexplored.
For Patient-Reported Outcome Measures (PROM), there are 20 (19%) studies, with a focus on systematic reviews and review protocols. The Healthcare workers/Trained lay workers category includes 22 (21%) studies, comprising systematic reviews and review protocols. The Community members category has 19 (18.1%) studies, featuring clinical trials, systematic reviews, review protocols, and guidelines reviews. This distribution indicates a substantial amount of research dedicated to understanding the perceptions of healthcare workers, community members, and patients, highlighting the importance of stakeholder perceptions in shaping effective opioid overdose prevention strategies. See Table 5.
Table 5.
Overdose outcome and year of publications (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/Outcome_Years.html)
| Year | Training Knowledge/Skill Acquisition/Use | Cost- effectiveness/Cost- analysis |
Health System Outcomes | Overdose Prevention Outcomes | Overdose Treatment Outcomes | Safety | PROM | Perceptions: healthcare workers/trained laypersons |
Perceptions: Community members |
|---|---|---|---|---|---|---|---|---|---|
| 2014–2017 |
SRP 3 CT 2 SRs 2 MA 1 |
SRs 1 |
SRs 5 SRP 1 |
SRs 3 SRP 3 MA 1 GR 1 |
SRs 4 MA 1 SRP 1 |
SRs 3 SRP 2 |
SRs 1 |
SRs 1 SRP 1 |
CT 1 SRs 1 SRP 1 |
| 2018–2021 |
SRs 15 CT 2 GR 1 |
SRs 2 |
SRs 14 CT 3 MA 2 |
SRs 15 MA 3 CT 2 SRP 2 GR 1 |
SRs 5 SRP 3 GR 2 CT 1 |
SRs 6 SRP 4 MA 2 CT 1 GR 1 |
SRs 7 SRP 4 CT 1 GR 1 |
SRs 7 SRP 4 |
SRs 6 SRP 5 GR 1 |
| 2022–2024 |
SRs 8 CT 1 SRP 1 |
SRs 4 SRP 1 |
SRs 11 SRP 3 CT 1 |
SRs 9 SRP 7 GR 4 |
SRs 2 SRP 2 |
SRs 2 SRP 2 |
SRs 5 SRP 1 GR 1 |
SRs 7 SRP 2 |
SRs 4 GR 1 |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; PROM: Patient related outcome measures
Study design
In the period from 2014 to 2017, there were a total of 19 (18.1%) studies: 2 (10.5%) clinical trials, 9 (47.3%) systematic reviews, 2 (10.5%) meta-analyses, 5 (26.3%) systematic review protocols, and 1 (5.2%) guideline review. The period from 2018 to 2021 saw an increase, with 49 (46.7%) studies: 5 (10.2%) clinical trials, 26 (53.1%) systematic reviews, 5 (10.2%) meta-analyses, 11 (22.4%) systematic review protocols, and 2 (4.1%) guidelines reviews. The most recent period, from 2022 to 2024, includes 41 (39%) studies: 2 (4.9%) clinical trials, 19 (46.3%) systematic reviews, 14 (34.1%) systematic review protocols, and 4 (9.8%) guidelines reviews. See Supplementary Table 2.
Study quality
Among Clinical Trials, there are a total of 9 (8.6%) studies: 3 (33.3%) of low quality, 4 (44.4%) of medium quality, and 2 (22.2%) of high quality. Systematic Reviews dominate the chart with 40 (38.1%) studies; out of these, 11 (27.5%) of low quality, 25 (62.5%) of medium quality, and 4 (10%) of high quality. Meta-analyses consist of 7 studies: 1 (14.3%) of low quality, 5 (71.4%) of medium quality, and 1 (14.3%) of high quality. Lastly, guidelines reviews have 2 (1.9%) studies, both of medium quality. The presence of high-quality studies is fewer than medium-quality studies. We did not perform a quality evaluation of scoping reviews. See Supplementary Table 3.
Study locations
In Africa, no studies are recorded. South East Asia features 4 (3.8%) records; among these, 3 systematic reviews and one meta-analysis. The Eastern Mediterranean Region has a minimal presence (n = 3, 2.9%) with 1 systematic review, 1 meta-analysis, and one clinical trial. The Americas lead in research output with 70 (66.7%) studies; out of these, 7 (10%) clinical trials, 56 (80%) systematic reviews, and 7 (10%) meta-analyses. Europe also shows substantial research activity with 27 (25.7%) studies, including 1 (3.7%) clinical trial, 21 (77.8%) systematic reviews, and 5 (18.5%) meta-analyses. The Western Pacific Region contributes 20 (19%) studies, consisting of 16 (80%) systematic reviews and 4 (20%) meta-analyses. See Table 6.
Table 6.
Opioid overdose Treatment/Prevention study regions (https://eppi.ioe.ac.uk/cms/Portals/35/Maps/PGIMER/StudyRegion_Design.html)
| Study Design | Africa | South-East Asia | Eastern Mediterranean Region |
Americas | Europe | Western Pacific Region |
|---|---|---|---|---|---|---|
| CT | 1 Record | 7 Records | 1 Record | |||
| SRs | - | 3 Records | 1 Record | 56 Records | 21 Records | 16 Records |
| MA | 1 Record | 1 Record | 7 Records | 5 Records | 4 Records | |
| SRP |
Please see an interactive Bubble Map by clicking the link above
CT Clinical Trials; GR Guidelines Review; MA Meta-analysis; SR Systematic Review; SRP Systematic Review Protocol
Other notable findings
We found 44 (41.9%) records testing the effectiveness of naloxone administration by “lay persons”, more than those testing its effectiveness when delivered by healthcare professionals. There were four studies on overdose surveillance either through data linkages or via electronic/digital methods. We found five systematic/scoping reviews on the social and structural determinants of opioid overdose deaths. There was one systematic review, one review protocol, and a single clinical trial on the effectiveness of potent/ultrapotent opioid overdose treatment.
Discussion
This scoping review on early detection and treatment of opioid overdose, and post-overdose care identified 105 studies published between January 2014 and March 2024. A predominant focus on naloxone-based interventions was observed—Take-Home Naloxone (THN) emerged as the most extensively studied strategy, with 46 studies, followed by community and pharmacy-based naloxone programs. However, 11 studies addressed post-overdose care, highlighting a critical gap in the continuum of treatment. Furthermore, there was limited research on polysubstance overdose and ultrapotent opioids, with one systematic review and a single trial specifically focused on fentanyl overdose treatment. The majority of studies were concentrated in high-income countries, particularly the Americas (n = 70) and Europe (n = 27), with minimal representation from Africa or Southeast Asia.
The strong emphasis on naloxone distribution programs, especially, the “Take Home Naloxone” strategy emerged as the most researched prevention intervention. This reflects a growing recognition of the necessity to equip individuals, particularly those at risk of opioid overdose and their families, with naloxone [17]. The evidence indicates that bystander administration of naloxone must be examined to see whether it significantly reduces overdose fatalities, highlighting the need for continued expansion of naloxone access in community settings, pharmacies, and through training initiatives [29, 30]. Yet, the significant number of reports (n = 21) focused on hospital emergency settings indicates a missed opportunity to bridge the gap between emergency care and community-level interventions. Future research should explore how emergency departments can better connect patients at risk of overdose with community resources and treatment options, thereby enhancing continuity of care [31]. While naloxone is a critical tool for overdose prevention, it should not replace comprehensive medical care and support services for individuals with OUD [32].
Our review identified 22 reports within harm reduction contexts, highlighting the opportunities of integrating naloxone distribution and education into existing harm reduction frameworks, such as needle exchange programs and supervised injection sites (SIS) [33]. These settings not only facilitate access to lifesaving interventions but also foster a non-judgmental atmosphere where individuals can receive comprehensive care [30, 34]. The evidence suggests that harm reduction approaches significantly reduce overdose fatalities by empowering individuals with the knowledge and tools necessary to respond effectively in emergencies [30]. Electronic harm reduction strategies were developed to address limited access due to structural and systemic barriers [35]. Furthermore, harm reduction strategies often extend beyond immediate overdose management, incorporating broader support services such as mental health counseling, housing assistance, and access to OUD treatment. However, challenges remain in ensuring that harm reduction services are adequately funded and accessible, particularly in regions with regulatory restrictions and high levels of stigma surrounding substance use.
The treatment of acute opioid overdose represents a critical area of focus in our review, with 30 reports. Not surprisingly, the administration of naloxone emerged as the cornerstone of acute overdose management, with multiple studies investigating different routes of administration and formulations. While naloxone is essential for acute overdose management, additional interventions are often required to stabilize patients’ post-overdose and to prevent recurrence [36]. 11 studies focused on post-overdose care, highlighting a significant gap in the literature regarding the follow-up treatment and support needed for individuals who have experienced an overdose. This gap is concerning, as effective post-overdose management can mitigate the risk of subsequent overdoses and facilitate entry into OUD treatment. Integrating post-overdose care protocols into emergency response strategies could enhance outcomes for individuals at risk and contribute to more comprehensive care pathways [37].
The quality of studies in our review shows significant variation. two (~ 22%) clinical trials were rated as high quality, with most classified as moderate or low. Systematic reviews also predominantly fell into moderate quality, with 30 (~ 64%) studies. These findings indicate an urgent need for more rigorous research methodologies in opioid overdose prevention and treatment to enhance the reliability and validity of results. Regional disparities further complicate the landscape of opioid overdose prevention and treatment. Our review revealed a pronounced concentration of research in the Americas and Europe, compared to limited representation from regions like Africa and Southeast Asia. This uneven distribution of research activity raises concerns about the applicability of findings to different contexts, particularly in underserved areas where opioid use and overdose may be increasing but remain under-studied.
Our review highlights several critical research gaps, particularly concerning populations experiencing polysubstance use [38], as evidenced by the absence of systematic reviews or RCTs addressing opioid and polysubstance overdose. This gap is concerning given the rising prevalence of polydrug use and its associated risks. While naloxone distribution emerged as a prominent intervention, with 46 studies examining the “Take Home Naloxone” strategy, there is limited research on the long-term outcomes of naloxone use and its integration into comprehensive treatment plans, especially post-overdose care. Additionally, a significant gap exists in research specifically addressing the impact of fentanyl and other ultrapotent opioids, with one systematic review and a simulation clinical trial focusing on tailored interventions for these substances [39, 40]. As fentanyl-related overdose deaths rise, future studies should prioritize understanding its effects, optimal treatment protocols, and effective prevention strategies. Addressing these gaps is essential for developing targeted interventions that meet the diverse needs of individuals at risk of overdose and for informing public health strategies to effectively combat this ongoing crisis.
This scoping review forms the initial step and indicates areas for updating international guidelines on the early detection and treatment of opioid overdose. First, upcoming guidelines might reflect the growing evidence for Take-Home Naloxone (THN) programs, including intranasal delivery, pharmacy-based distribution, and peer training models, which were examined by over 40 studies across diverse settings. Second, new guidance might also address post-overdose care, emphasizing the need for structured referral pathways to treatment for OUD following an overdose event—an area identified as critically under-researched. Third, the updated guidelines may examine the effects of strategies for responding to fentanyl and other ultrapotent synthetic opioid overdoses, including considerations and potential problems associated with higher-dose naloxone protocols and repeat dosing [33]. Fourth, WHO might like to promote research and implementation efforts in underrepresented regions, such as Africa and Southeast Asia, to ensure global relevance and equity in overdose response capacity. Finally, the incorporation of telemedicine and digital tools to support naloxone training, distribution, and overdose surveillance might also be examined in the updated guidelines, based on emerging data.
This scoping review is subject to several limitations. First, the inclusion criteria encompassed a wide range of study designs, which could introduce variability in the quality and rigor of the evidence assessed. While we utilized AMSTAR-2 and RoB-2 tools for quality evaluation, these were administered by a single researcher. Hence, there was a potential for subjective bias. Moreover, we considered individual RCTs; however, substantial evidence in overdose space comes from quasi-experimental and observational studies. Although the previous observational/quasi experimental studies should have been captured by the systematic reviews, recent non-RCTs might have been missed. Furthermore, the reliance on published literature may overlook ongoing or unpublished studies that could provide valuable insights. Finally, the dynamic nature of the opioid crisis necessitates regular updates to this review, as emerging trends and novel interventions evolve continuously, emphasizing the need for ongoing research in this rapidly changing landscape.
The review findings suggest a need for updated international guidelines (e.g., the WHO guidelines on community management of opioid overdose) to critically examine the evidence on naloxone distribution methods, post-overdose care strategies, digitally delivered strategies for early detection and treatment of opioid overdose, and tailored responses to fentanyl-related overdoses. These guidelines will guide evidence-informed policy and practice. There is also a need to assess evidence from diverse resource, regulatory, and cultural settings. Furthermore, fostering research in underrepresented regions is an important area for consideration. The evolving nature of the opioid overdose crisis necessitates ongoing research and timely updates to guidelines to ensure the most effective and comprehensive response to this global public health challenge. Addressing these gaps will be crucial for improving overdose prevention, treatment, and outcomes across diverse populations and settings.
Supplementary Information
Acknowledgements
The review was supported by the Alcohol, Drugs and Addictive Behaviours Unit of the Department of Mental Health, Brain Health and Substance Use, World Health Organization. Nandi Siegfried, PhD, Chief Specialist Scientist, South African Research Council, Cape Town, South Africa Disclaimer: The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.
Author contributions
DK, NC, AG: Concept AG, SC, TM, NC, DK: Methods and study conduct AG and SC wrote the main manuscript texts; NC, TM, and DK reviewed, edited, and commented on the final manuscript. All authors approved the final manuscript for submission.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.