Preventing Opioid Overdose Mortality in the United States
Phase: NA
Conditions: Opioid Overdose
Sponsor: RTI International

Official Title: Preventing Opioid Overdose Mortality in the United States  
Clinical Trial #: NCT03924505  
Unique Protocol ID: INOD  
Secondary IDs: R01DA046867 
Date of Document: November 14, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Scientific Background 
The United States (US) continues to face decades-long increases in opioid overdose 
mortality [1]. The Centers for Disease Control and Prevention (CDC) estimates nearly 775,000 
people have died of an opioid overdose since 1999 [2]. Between 2020 and 2021, overdose mortality 
rates involving heroin and synthetic opioids, other than methadone, increased 22%.  Overall, drug 
overdose deaths in the US increased for all genders; all age groups over the age of 25; American 
Indian/Alaskan Native, non-Hispanic White, non-Hispanic Black, Hispanic, and Native 
Hawaiian/Pacific Islander communities; all census regions; and urban, suburban, and rural 
settings [3]. 
Opioid overdoses involve a toxic dose of natural opioids like heroin, semi-synthetic opioids like 
oxycodone, and/or synthetic opioids like fentanyl. Naloxone, an opioid antagonist, is an evidence-
based biomedical intervention that effectively reverses opioid overdose when administered 
intranasally or intramuscularly [4-7]. Opioid antagonists bind to the brain’s opioid receptor sites, 
which displaces any opioid currently in the system and temporarily negates their effects, saving the 
individual’s life. Use of naloxone does not cause dependence or tolerance, and can, though not 
always, precipitate withdrawal [5-8]. Naloxone can dramatically reduce opioid overdose mortality 
when distributed to people likely to experience or witness an opioid overdose and packaged with 
education on its use, known as overdose education and naloxone distribution (OEND)[9-14]. 
Syringe services programs (SSPs) have a primary function of distributing safe drug use supplies, 
such as sterile syringes, pipes, injection-related equipment, wound care materials, etc., to 
facilitate the reduction of harms associated with drug use for their participants. Often, SSPs are the 
first to hear from their participants regarding changes in the unregulated drug market, drug use trends, 
and overdose experiences. Most SSPs provide a variety of other evidence-based interventions to 
improve the health of people who use drugs, including OEND [15-18]. SSPs reach people at high 
risk for experiencing or witnessing an opioid overdose, and pioneered the development of OEND 
[19-21]. With staff who are culturally competent in providing services for people who use opioids 
and pre-existing delivery systems designed to reach participants in their own environment, SSPs 
are an ideal venue for OEND. 
Research documenting OEND’s effectiveness (i.e., intervention effectiveness) for reducing 
opioid overdose mortality emerged over 15 years ago [7]. Only recently have studies begun to 
assess elements of OEND implementation effectiveness within SSPs [22-26]. As an organizational-
level construct, implementation effectiveness can be defined as the aggregated consistency and 
quality of intervention use within an organization [27]. Findings from recent research identify 
factors from both the external and internal context of SSPs that shape effective implementation of 
OEND [22-26]. Yet, to date, no studies have assessed whether implementation strategies (i.e., 
approaches to improve the adoption, implementation, or sustainment of evidence-based 
practices) can advance implementation effectiveness of OEND within SSPs.  
External facilitation-based implementation strategies have been identified as a promising 
approach to advance implementation outcomes [28-39]. Fundamentally, these approaches involve 
a person external to the organization providing interactive problem solving and support to assist 
implementation efforts. Often, their work is in conjunction with other implementation strategies. 
Whether such an approach can help SSPs, which often face substantial community, financial, and 
legal constraints [40], effectively implement OEND remains an important area of inquiry.  
 
Study Objective 
As such, we conducted a randomized controlled trial of 105 SSPs throughout the US to 
understand the effectiveness of a multifaceted, external facilitation-based implementation 
strategy at advancing OEND implementation effectiveness within SSPs.  

Scientific Methods  
Trial Design 
We conducted a randomized controlled trial of SSPs throughout the US and US Territories. 
SSPs were assigned to one of two implementation conditions using simple randomization. A 
standardized checklist aided this paper’s clarity and transparency for describing an intervention 
and reporting a randomized controlled trial [41, 42]. RTI International’s Institutional Review Board 
(IRB) approved and provided oversight for all research activities (STUDY00020448). This trial was 
registered at ClinicalTrials.gov as NCT03924505.  
 
Study Setting 
The target population was operators of SSPs located throughout the US and US Territories. 
Prior to launching the trial, 342 SSPs were known to be operating in the US and US Territories. 
Described elsewhere [25], our team launched a national survey of syringe services programs 
(NSSSP) in February 2019 of all known SSPs operating throughout the US and its Territories, 
receiving a response from 263 (77%) SSPs. NSSSP responding SSPs were located in the Northeast 
(13%), Midwest (21%), South (24%) and West (42%) census regions. Among the responding SSPs, 
247 (94%) were implementing OEND for their participants [25].  
 
Recruitment, Eligibility, and Enrollment 
 
To be eligible, an organization must have: 1) met the definition of an SSP – a program which 
primary function is to engage people who use drugs and provide them free drug use supplies to 
reduce harms associated with drug use, 2) implemented OEND for a minimum of 6 months, and 3) 
completed the NSSSP fielded from February to July 2019. We excluded organizations such as fire 
departments or emergency departments of hospitals that offered drug use supply distribution 
since it would be an ancillary function of these organizations and OEND programs that were not 
part of a SSP. 
A total of 243 SSPs participated in the survey and were determined to be eligible. SSPs were 
organized into a randomized list and were contacted sequentially for recruitment into the trial. We 
recruited SSPs from September 2019 to February 2021. Within that timeframe, we paused 
recruitment activities from March to July 2020 due to the onset of the COVID-19 pandemic. The 
pause in recruitment activities primarily provided an opportunity for SSPs to adapt to COVID-19 
changes, particularly for their adjustment to stay-at-home orders and adoption of delivery models 
that minimized close person-to-person contact. 
To recruit SSPs, our study team initially contacted people in leadership role(s) at each SSP 
via email to set up a call to explain the study and carry out enrollment activities for organizations 
that were interested. Organizational leadership included executive directors, program managers, 
and/or site coordinators. For organizations interested in participating in the trial, study staff would 
obtain electronic/written informed consent from the organization to join the study, carry out the 
organizational agreement for participation, and administer the baseline survey. Following the 
baseline survey, SSPs were randomized using simple randomization to two study arms: 1) 
dissemination of OEND best practice recommendations (i.e., Control SSPs), or 2) the Organize and 
Mobilize for Implementation Effectiveness (OMIE) approach along with dissemination of the OEND 
best practice recommendations (i.e., OMIE SSPs). Sequentially numbered sealed envelopes were 
used to implement the random allocation sequence, which were concealed until the point of 
randomization.  
 
OEND Best Practice Recommendations 

Study staff disseminated best practice recommendations to all SSPs enrolled in the trial. 
Details of OEND best practice recommendations can be found elsewhere [43]. Briefly, a Delphi 
study was carried out to develop a set of best practices for OEND implementation within SSPs. 
Experts for the Delphi study included people in paid and volunteer leadership and direct service 
positions in SSPs, OEND researchers, people who work in state or local health departments, and 
people who use drugs who deliver and access SSP/OEND services. All individuals had prior or 
current experience delivering OEND programming in community-based settings, and people with 
lived and living substance use experience were represented in each of the expert 
categories. Findings from this initiative were summarized into a best practices implementation 
guide (Appendix A).  
 
Organize and Mobilize for Implementation Effectiveness (OMIE) 
Table 1 defines and specifies the 8 discrete implementation strategies that comprised 
OMIE. The OMIE approach was based on the Implementation and Sustainment Facilitation (ISF) 
Strategy, which is grounded in the theory of implementation effectiveness [27], and added discrete 
strategies from the Addiction Technology Transfer Center (ATTC), which were considered 
necessary elements from the original trial. Both ISF and ATTC have been described extensively 
elsewhere [44, 45]. Overall, our multi-component approach used external facilitation as the 
overarching strategy, by which seven other strategies were leveraged to support SSP staff and 
leadership. In total, 4 out of 7 discrete strategies from ISF were combined with 4 out of 10 discrete 
strategies from ATTC, detailed in Table 1. In addition to external facilitation, our multi-faceted OMIE 
approach included: organize implementation team meetings, identify and prepare champions, 
develop and organize quality monitoring system, assess for readiness and identify barriers, 
distribute educational materials and resources, conduct educational meetings, and provide 
ongoing consultation. The study team, comprised of people who had delivered SSP-based OEND 
services in the past year, researchers with over 20 years of SSP and OEND research experience, 
and national OEND implementation experts, collaboratively decided upon the discrete strategies 
for the OMIE approach. Decisions were grounded in  shared understanding and discussion of 
implementation barriers SSPs faced generally and with OEND specifically.  
 
Table 1. Specification of Organize and Mobilize for Implementation Effectiveness 
Discrete 
strategy 
Definition, actor, action, action target and temporality specification 
1. External 
Facilitation  
Definition: provision of guidance, resources and coaching from an implementation 
expert who is external to the organization. 
Actor: individual with previous OEND implementation experience within SSP 
settings. 
Action: overarching mechanism by which the below strategies were delivered to SSP 
staff. 
Action Target: SSP staff, including naloxone implementation team and leadership. 
Temporality: Begins within 1 month of enrolling into the trial, occurs up to monthly 
for twelve months. 
2. Organize 
implementation 
team meetings 
Definition: develop and support implementation team who are implementing OEND, 
giving them protected time to focus on implementation efforts, share experiences 
and support one another. 
Actor: external implementation advisor (see above). 
Action: web-based meetings with direct interaction between external 
implementation advisor and SSP staff. 
Action Target: SSP staff, including naloxone implementation team and leadership. 

Temporality: Begins within 1 month of enrolling into the trial, occurs up to monthly 
for twelve months. 
3. Identify and 
prepare 
champions 
Definition: cultivate relationships with people who will champion and generate 
excitement within the organization regarding OEND best practice implementation. 
Actor: external implementation advisor (see above). 
Action: focused relationship building with SSP staff who are OEND implementation 
champion(s). 
Action Target: SSP staff, including OEND implementation team and leadership. 
Temporality: Begins with first organizational team meeting and continues as needed 
for 12 months 
4. Develop and 
organize quality 
monitoring system 
Definition: develop and introduce an electronic tool that can be used to assess and 
prioritize best practice implementation efforts. 
Actor: external implementation advisor (see above). 
Action: using the electronic tool, external implementation advisor works with SSP 
staff to assess OEND best practice implementation and prioritize areas for focused 
efforts. 
Action Target: SSP staff, including OEND implementation team and leadership. 
Temporality: begins with first organizational team meeting and continues up to 
monthly for 12 months 
5. Assess for 
readiness and 
identify barriers  
Definition: assess SSPs to determine degree of readiness for best practice 
implementation, and barriers that may impede implementation. 
Actor: external implementation advisor (see above). 
Action: focused conversation to discuss activities required for best practice 
implementation, readiness to carry out those activities and potential barriers that 
could impede those efforts. 
Action Target: SSP staff, including OEND implementation team and leadership 
Temporality: begins within 1 month of enrolling into the trial, occurs up to monthly 
for twelve months 
6. Distribute 
educational 
materials and 
resources 
Definition: distribute educational materials (manuals, online trainings, etc.) 
electronically with regards to OEND best practices 
Actor: external implementation advisor (see above). 
Action: electronically distribute OEND best practices manual and other resources 
including implementation manuals and online trainings 
Action Target: SSP staff, including OEND implementation team and leadership 
Temporality: begins with first organizational team meeting and continues as needed 
for 12 months 
7. Conduct 
educational 
meetings 
Definition: conduct educational sessions for providers and leadership with regards 
to OEND best practices 
Actor: external implementation advisor (see above). 
Action: web-based trainings with direct interaction between external 
implementation advisor and SSP staff. 
Action Target: SSP staff, including OEND implementation team and leadership 
Temporality: begins with first organizational team meeting and continues as needed 
for 12 months. 
8. Provide ongoing 
consultation 
Definition: provide implementers with continued consultation with with regards to 
OEND best practices. 
Actor: external implementation advisor (see above). 
Action:  web-based meetings with direct interaction between external 
implementation advisor and SSP staff. 
Action Target: SSP staff, including OEND implementation team and leadership 
Temporality: begins within 1 month of enrolling into the trial, occurs via web-based 
meetings up to monthly for twelve months and as needed via electronic 
communication 

SSP staff and organizational leadership in the OMIE arm were provided the opportunity to 
participate in 60-minute sessions once a month for up to 12 months. In addition to monthly 
sessions, facilitators were provided up to 2 hours to prepare for sessions and to identify and 
distribute resources to SSPs based on identified priorities. All sessions were offered virtually over 
audio-visual connections. Thus, the maximum possible dose for each SSP was 12 sessions or 36 
hours. To maximize the extent to which the approach was implemented with consistency and 
quality, the project’s lead and the study coordinator trained each facilitator, reviewed randomly 
selected facilitation session recordings, and held group supervisory meetings weekly to discuss 
successes, lessons learned, and emerging issues.  
 
Data Collection 
We carried out an interview-administered survey at SSPs baseline visit and at their 12-
month follow-up after all facilitation-based activities had occurred. SSPs were paid a $50 incentive 
for their time (~30 minutes) completing the baseline and the 12-month follow-up survey. In 
addition, the study coordinator tracked the number of sessions and the number of hours between 
external facilitators and SSP teams as part of a log of implementation activities. Follow-up to 
complete the 12-month follow-up survey ended in February 2022, marking the end of the trial 
approximately 12 months after the last SSP was enrolled. 
 
Trial Outcomes 
Our primary outcomes center on the multidimensional variable of implementation 
effectiveness (i.e., the consistency and quality of OEND implementation by SSP staff). 
Implementation effectiveness fit our broad objectives, by focusing on the extent to which our 
multifaceted, facilitation-based approach impacted OEND delivery at the organizational level. 
Accordingly, SSPs represent the primary unit of analysis. Proctor et al.’s taxonomy of 
implementation outcomes informs our operationalization of implementation effectiveness, 
focusing on the reach of SSPs’ naloxone distribution (i.e., consistency) and fidelity to OEND best 
practices (i.e., quality)[46]. As such, the primary outcomes were the number of naloxone doses 
distributed in the past 3 months; the number of SSP participants receiving naloxone in the past 3 
months, and the number of OEND best practices implemented. Importantly, prior research has 
shown that larger scale naloxone distribution has led to reductions in opioid overdose mortality, 
further supporting use of these measures as trial outcomes [17, 47, 48]. 
 
Covariates 
The baseline survey also collected information on region of operation, the number of staff 
and volunteers at the SSP, staff training in OEND, the prior year’s annual budget in dollars, the 
number of participant contacts at the SSP in the past 3 months.  
 
Masking 
Masking the SSP organizations and their staff to the assigned implementation strategy 
condition was not possible. Aside from the external facilitators who delivered the implementation 
strategies, research staff were blinded to all condition assignments, including the statistician 
throughout all analyses.  
 
Targeted Sample Size 
The targeted sample size was estimated using PASS software [49]. We estimated that a 
sample of 100 SSPs (50 per arm) would provide 80% statistical power to detect a statistically 
significant (p<0.05) medium effect size (Cohen’s d = 0.45)[50] between study arms, assuming an 

alpha of 0.05, standard deviation of 1.0 and two repeated measurements (baseline and 12-month 
follow-up) with a first-order autoregressive covariance structure and a correlation between 
observations on the same SSP of 0.3. 
 
Statistical Analysis Plan 
Statistical analyses were conducted using an intent-to-treat approach. Descriptive 
statistics were used to summarize continuous outcomes and covariates by experimental 
condition; frequencies and percentages were used to summarize categorical measures. Given the 
varying sizes of SSPs, counts of naloxone doses and individuals receiving naloxone were 
summarized as a rate per number of participant contacts for syringe services in the past 3 months.  
Negative binomial regression models were used to compare the number of naloxone doses 
distributed and contacts for naloxone refills or trainings by condition; the number of contacts for 
syringe services in the past 3 months was included as an offset. The model for naloxone doses was 
adjusted for baseline rate given the difference between conditions at baseline. The mean number 
of best practices adopted were compared by condition using a two-sample t-test. We also carried 
out a per-protocol dose response analyses, where OMIE SSPs were dichotomized at the median for 
the number of OMIE sessions (<10 sessions; 10+ sessions) and number of OMIE hours received 
(<12 hours; 12+ hours) and compared to Control SSPs. P-values <0.05 were considered statistically 
significant a priori. All analyses were conducted using Stata 16.1 (StataCorp LLC, Texas USA).