We have followed PRISMA-P guidelines for the reporting of this protocol (Additional file 3) [64]. As we aim to address the limitations of recent systematic reviews that excluded data on ultra-potent opioids, we have tailored our methods to capture available data on these agents. We will document protocol changes as amendments adhering to PRISMA-P guidelines.

Eligibility criteria

Population

The population of interest are people who suffered from suspected or confirmed opioid toxicity (manifested by respiratory depression, depressed level of consciousness, and/or cardio-respiratory arrest) induced by suspected non-medical use of opioids and ultra-potent opioids in particular. We will not base inclusion on the specific type of opioid used and will include mixed intoxications, as information about specific agents ingested is usually unavailable to bystanders and medical personnel at the time of treatment. We will include data from children over the age of 12, as we suspect that teenagers who use opioids are close to adults in height and weight and would receive the same recommended treatment strategy as adults.

Intervention

The intervention of interest is the administration of an empiric naloxone dose (and possible additional naloxone doses) for the treatment of suspected or confirmed opioid toxicity from non-medical opioid use. We will include studies reporting naloxone use for any confirmed or suspected opioid ingestion by any route, which includes known ultra-potent opioids, opioids originally obtained by prescription, tampered with, and/or illicitly manufactured. We will examine naloxone use by all routes of administration and will include reports of naloxone administration by both lay and healthcare personnel in both out-of-hospital and in-hospital settings.

Comparator

None.

Outcomes

The three main outcomes after naloxone administration are as follows: (1) clinical reversal of opioid toxicity, defined by but not limited to the return of spontaneous breathing, an increase in respiratory rate, return of consciousness, or discharge alive from medical care; (2) occurrence of serious adverse effects, including but not limited to acute opioid withdrawal, pulmonary edema, and seizures; and (3) cumulative dose of naloxone administered.

Study design

We will include randomized and non-randomized controlled trials, non-comparator trials, prospective and historical cohort studies, cross-sectional studies, and case-control studies. Given the recently changing epidemiology of opioid use and the high likelihood that the treatment of ultra-potent opioid overdoses may not yet have been described in formal studies, we will also include case series, case reports, and reports from poison centers [65]. We will retain editorials, commentaries, letters, and reviews identified by our search: we will not formally include these in our systematic review, however, they will assist us in identifying additional relevant eligible studies and important relevant gray literature sources.

Search strategy

We will develop a systematic search strategy with a professional librarian (MDW) with two parallel aims: first, to capture the dosing, effectiveness, and adverse effects of naloxone in all opioid overdoses, and, second, to capture all available evidence specifically pertaining to ultra-potent opioids. Our three preliminary searches will be combined and include the following concepts: (1) naloxone AND drug overdose AND (adverse effects OR emergency treatment); (2) naloxone AND (adverse effects OR dosage/administration); and (3) naloxone AND ultra-potent opioids (see Additional file 1 Search Concepts). We will develop sensitive searches using applicable subject headings and keywords to capture as much of the relevant literature as possible. We have reviewed papers on naloxone for relevant subject headings and keywords to include in our search. We will also review the scope notes for all subject headings to ensure inclusion of all pertinent terms and prior indexing terms and will identify and include appropriate synonyms for all of the ultra-potent opioids identified so far (Table 1). A draft MEDLINE (Ovid) search is included (see Additional file 2, Draft MEDLINE (Ovid) Search Strategy) (Figs. 1 and 2). We will use our MEDLINE search as a starting point for adaptation to other databases and will iteratively refine and update our searches. We will not restrict our searches by language; we will examine abstracts in all languages but will only include studies published in English, French, or German for full-text review. We will include studies on naloxone and opioids published after 1972, as this is when naloxone and fentanyl entered the legal market.

Table 1 Opioids involved in overdose deaths in Canada [19] Full size table

Fig. 1 Search concepts for MEDLINE (Ovid) Full size image

Fig. 2 Draft MEDLINE (Ovid) search strategy Full size image

Information sources

We will search the following electronic reference databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE) all available through Ovid, Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, CINAHL - Cumulative Index to Nursing and Allied Health Literature through EBSCO, and the Science Citation Index (Web of Science Core Collection) from Clarivate Analytics. We also will review reference lists and trial registries for unpublished trials, including the ISRCTN Registry, ClinicalTrials.gov, EU Clinical Trials Register and South African National Clinical Trials Register, Open Trials, and the Quebec Pain Registry. We will search for studies meeting our inclusion criteria using the Web of Science Core Collection and ScienceDirect (Elsevier).

We will perform an electronic gray literature search using the search engine Google by combining relevant search terms from our bibliographic database search. In addition, we will search the websites of professional organizations, harm reduction initiatives, and of international, national, and provincial guidelines for the treatment of opioid overdose (Table 2). We will search conference proceedings through database searches in Embase (Ovid) and the Web of Science. Additionally, we will specifically search the conference proceedings of the International Society for the Study of Drug Policy (ISSDP), National Harm Reduction Conference, Issues of Substance (IOS), and the International Harm Reduction Conference. We will also hand search the table of contents of relevant journals, for example, the Canadian Journal of Emergency Medicine and International Journal of Drug Policy.

Table 2 List of relevant professional organizations Full size table

Study records

Data management

We will create a search report of all searches and their sources and will capture all identified titles in RefWorks. We will use unique folders for each step of the search process within a common team RefWorks account. For our gray literature searches, we will track the search terms and the date of the searches performed.

Selection of studies

Two reviewers will independently review the titles and abstracts of identified references for eligibility based on the inclusion and exclusion criteria. Both reviewers will pilot test the inclusion and exclusion criteria on a convenience sample of the first 15 titles in our search results, to ensure we have adequately described and are able to consistently apply our study selection criteria. All potentially relevant titles identified by both reviewers will be moved forward for full-text review. Any disagreements relating to the inclusion or exclusion of full-text articles between the two reviewers will be resolved through discussion or, if required, a third reviewer. We will document inclusion and exclusion decisions on a study selection form. We will record and report the reason for excluding records.

One reviewer will review the first 100 results of our Google search result pages for relevant reports and literature and will move the full texts of any relevant documents, reports, or websites identified in our Google search forward for full-text review. Two reviewers will then independently review all potentially relevant full texts as per our eligibility criteria.

Data collection process

Two reviewers will independently extract data from each included study using a study/data collection form. We will resolve any disagreements through discussion until achieving consensus or, if required, a third reviewer. Both reviewers will pilot test data collection on the first 15 included studies to ensure that the form does not require revision and that data extraction is consistent.

Data items

We will extract data on relevant information about the type of opioid ingested (if known), study date and location, the study participants, the geographic location and timing of patient enrolment (which we will use to estimate prevalence of ultra-potent opioids), the intervention (both experimental and control for experimental studies), including information about initial and subsequent doses, route, frequency, and sequence of naloxone administration, as well as the person and setting of its administration, and patient outcomes. We will collect information on study design, participants, setting, data quality, limitations, and funding sources. We will contact study authors for missing information or clarifications required for data synthesis. We will attempt to contact authors by email at least twice with emails sent three weeks apart.

Risk of bias in individual studies

Two reviewers will independently appraise each included study for potential sources of bias. We will appraise observational studies using an adaptation of the Downs and Black risk of bias assessment tool modified for observational studies. We will assess randomized controlled trials with the Cochrane Risk of Bias Tool to assess for selection, performance, attrition and reporting bias, and possible conflicts of interest. The two reviewers will resolve all disagreements by discussing until reaching consensus. If they cannot reach consensus, a third reviewer will adjudicate the study.

Data synthesis

Based on recent studies and systematic reviews in this field, we anticipate that many studies will report outcomes as proportions of patients who experience clinical reversal of opioid toxicity by dose level [63, 66]. In our meta-analysis (if performed), we will deconstruct any comparative studies into its one-arm components and use the aggregate results by arm. We will plot log (proportion) versus dose to graphically summarize the dose-response relationship for naloxone administration by similar route of administration; the symbol size will be proportional to the precision of the estimate. We will use a random effect, one-stage meta-regression to estimate the dose-response relationship. If we find a sufficient number of distinct doses, we will use a flexible method (splines) to model dose; with only a few distinct doses, we will adopt an unstructured dose trend treating dose as a categorical variable. We will adopt a similar strategy for the proportion of patients experiencing a serious adverse event. A sensitivity analysis will be conducted to exclude studies that are categorized as high risk of bias.

We will assess heterogeneity using the I2 statistic. Regardless of the magnitude of I2, we will explore clinical heterogeneity by adding covariates to the dose-response meta-regression. As we anticipate a limited number of studies, we will incorporate only one variable at a time. Variables to be investigated include the following: the type of opioid used (non-ultra-potent versus ultra-potent, mixed versus single agent), time, geographic location (with suspected high and low prevalence of ultra-potent opioids), the setting of naloxone use (e.g., hospital, pre-hospital, bystander), its route of administration (e.g., intravenous, intranasal, intramuscular), administering provider (layperson versus medical personnel), and frequency or schedule of naloxone administration. If we find insufficient studies for meta-analysis, we will synthesize the information qualitatively.

We will interpret our findings in light of the suspected prevalence of ultra-potent opioids based on year and geographic location of the studies examined. We will define effectiveness as the clinical reversal of opioid toxicity after naloxone administration as indicated, for example, by increased respiratory effort or rate, improved level of consciousness, return of spontaneous circulation, and/or discharge alive from medical care. We will define serious adverse events by the occurrence of adverse clinical responses to naloxone including but not limited to acute opioid withdrawal syndrome, pulmonary edema, and seizures. We will define the total dose used as the sum of all naloxone doses administered to a patient. We will perform subgroup analyses assessing the primary and secondary outcomes listed above within studies based on type of opioid ingested, by varying prevalence of ultra-potent opioids based on time and geographic location, by setting of naloxone administration (bystander, pre-hospital, hospital), by route of naloxone administration, and by frequency or schedule of naloxone administration.

Confidence in cumulative evidence

We will present the results of our meta-analysis (if performed) using a GRADE summary of findings table. This table will present the summarized naloxone dose-response relationship alongside a score for the quality of the evidence used to generate that value. We will assign the quality of evidence scores based on the number and quality of the component studies and the consistency and generalizability within them.

Knowledge translation

We will disseminate our results through traditional academic mechanisms, including abstracts to national and international meetings and open-access peer-reviewed publications. We will produce briefing notes from our findings to inform health care professionals, policy makers, and patient safety organizations. We will immediately disseminate our results to all emergency physicians in BC, where the epicenter of the current epidemic is, through the province-wide Emergency Medicine Network of which several of our authors are members. Furthermore, our results will be shared widely with emergency physicians in Canada through research bulletins published by the Canadian Association of Emergency Physicians. In addition, our results will inform the training, naloxone dosing, and administration schedule in BC Take Home Naloxone Kits being widely disseminated to people who use opioids, family and friends of people who use opioids, public bystanders, and staff involved in responding to opioid overdoses outside of acute care settings. Our results will also inform program training resources available to the public through the BC Centre for Disease Control’s “Toward the Heart” program (available at towardtheheart.com). These program training resources include manuals, brochures, posters, videos, online applications, and modules which train members of the public on how to effectively respond to opioid overdoses. Furthermore, results and knowledge translation resources will be presented and made available to the BC Drug Overdose & Alert Partnership (DOAP), a multi-sectoral committee that includes emergency health services and regional health authorities. Tailored information materials will be disseminated to Individuals in observed drug use settings, such as overdose prevention services and supervised consumption services sites.