Commentary: Study Protocol for the Respond to Prevent Study: A multi-state randomized controlled trial to improve provision of naloxone, buprenorphine and nonprescription syringes in community pharmacies

Abstract

Access to the opioid antidote naloxone is a critical component of addressing the opioid crisis. Naloxone is a population-level prevention intervention associated with substantial reductions in overdose mortality and reduction of nonfatal overdose. Pharmacies’ pivotal role in dispensing medications like buprenorphine for the treatment of opioid use disorder and selling nonprescription syringes places them at the crossroads of opioid access and risk mitigation methods like naloxone provision. Testing ways to optimize pharmacy-based naloxone provision will be key as the country expands the implementation of naloxone through the medical system. In the Respond to Prevent Study, we conducted a large, practical study of a pharmacy-focused intervention in a sample of Washington, Oregon, Massachusetts and New Hampshire community chain pharmacies to increase naloxone dispensing and improve opioid safety. The intervention integrated two evidence-based educational toolkits and streamlined materials to enhance the focus on naloxone policy, stigma reduction, and patient communications around naloxone, nonprescription syringes and buprenorphine access. The real-world study implemented a stepped wedge, clustered randomized trial design across 175 community chain pharmacies to evaluate the effectiveness of the Respond to Prevent intervention in increasing: a) pharmacy based naloxone distribution rates, naloxone-related patient engagement, and pharmacist and technicians’ attitudes, knowledge, perceived behavioral control and self-efficacy toward naloxone; and b) pharmacy nonprescription syringe sales, and pharmacist and technicians’ attitudes, knowledge, perceived behavioral control and self-efficacy toward dispensing buprenorphine for opioid use disorder (secondary outcomes). This commentary provides a brief narrative about the study and presents insights on the design and adaptations to our study protocol, including those adopted during the unprecedented COVID-19 pandemic further compounded by Western wildfires in 2020.

Introduction

Pharmacies can play a critical role in the opioid crisis and in harm reduction by serving as access points to the overdose antidote naloxone,^1,2 the opioid partial agonist buprenorphine,^3,4 and infectious disease prevention tools like nonprescription syringes.^5,6 As the most accessible healthcare resource, community pharmacies are hubs providing medicines, counseling, and supplies to communities across the country, and they are staffed by trained health professionals. In addition, during the COVID-19 pandemic, pharmacies further expanded their public health imprint by pivoting to provide thousands of COVID-19 diagnostic tests and vaccinations across the age span.^7,8 Laws to permit pharmacist-facilitated naloxone provision quickly disseminated across all states and the District of Columbia from 2015 to 2018, and permission to sell nonprescription syringes at community pharmacies exist in all but 14 states presently.⁹ However, the attitudes and behaviors of pharmacists and other pharmacy staff,^10–17 stigma and discrimination against people who use drugs during pharmacy interactions,^18,19 and structural factors like stocking of medications^20–25 have been identified as key barriers to the dispensing or sale of naloxone, buprenorphine, and nonprescription syringes in pharmacies.

Study aims and intervention

Our study aimed to address these barriers through a four-state stepped wedge cluster randomized trial involving two large pharmacy chain businesses by implementing a multi-component intervention imbued with stigma reduction content specifically designed for the community pharmacy environment and for use by pharmacy staff. The first aim of our National Institute on Drug Abuse (NIDA)-funded study was to combine and adapt two recently completed evidence-based Agency for Healthcare Research and Quality (AHRQ)-funded interventions for opioid safety and naloxone provision, the MOON and RESPOND studies.^26–32 The MOON Study focused on implementing pharmacy naloxone, and formed the core component of the present study. The process employed in the development of the MOON intervention followed a multi-step, community-informed model. Briefly, 4 focus groups with chronic pain patients, people who use drugs, caregivers and community pharmacists to identify content areas and points of intervention before, during, and after the pharmacy visit.²⁸ Another set of focus groups was conducted with the same stakeholder groups to provide feedback on the developed materials. ³⁰ One-on-one interviews with people who had obtained naloxone at chain, independent, grocery chain, outpatient pharmacy or other community pharmacy further informed the trainings and the interactive tools developed. ²⁷ Components of the intervention were then piloted in independent, outpatient hospital and chain pharmacies over a series of week- or month-long trials to iteratively refine them. The finalized MOON intervention entails pharmacist academic detailing and places materials (available freely at prevent-protect.org) in the pharmacy both for the pharmacy team and for patients to improve naloxone access. To this core were added elements from another related intervention, RESPOND, which was developed with extensive pharmacist focus group input, and addresses opioid safety and the pharmacist’s use of the prescription drug monitoring program. ³² For the present study, the new intervention combined the two components and incorporated content to explicitly address nonprescription syringe and buprenorphine access as it relates to and reinforces naloxone provision at the pharmacy. To build the combined intervention, we again employed a participatory process of intervention adaptation, which included feedback from four external stakeholder advisory committees (one in each study state) and focus groups held in Massachusetts and Oregon with people who use drugs and with community pharmacists. The resulting new intervention, called Respond to Prevent, includes an online training for pharmacists, on-site peer-to-peer evidence-based educational sessions (i.e., academic detailing) for the pharmacy team, patient-facing materials for placement at the pharmacy (e.g., naloxone informational display pads), materials to offer to patients (e.g., personal syringe disposal containers), reference materials to store behind the counter (i.e., the pharmacy’s onsite overdose policy), and regional manager and site-level feedback summaries from experiences of intervention fidelity checks (i.e., secret shopping to verify quality of implementation) at the sites, along with practice improvement tips. Once readied for the trial, approved by all institutional review boards and reviewed by our data safety monitoring board (DSMB) and sponsor, we began the intervention implementation.

In the second aim of the study, we proposed, using a stepped wedge, clustered randomized trial design, to evaluate the effectiveness of Respond to Prevent in 175 community pharmacies in increasing: a) pharmacy based naloxone distribution rates, naloxone-related patient engagement, and pharmacists’ attitudes, knowledge, perceived behavioral control and self-efficacy toward naloxone (primary outcomes); and b) pharmacy syringe sales, and pharmacists’ attitudes, knowledge, perceived behavioral control and self-efficacy toward dispensing buprenorphine for opioid use disorder (secondary outcomes). Data sources for the primary and secondary outcomes include weekly store-level counts of naloxone dispensed, nonprescription syringes sold, and buprenorphine prescriptions filled. Naloxone-related patient engagement is measured by the research team through daily logs collected by phone or fax from the pharmacy at post-intervention and 6-months post intervention during a 2-week period. Pharmacist and technician self-reported outcomes are collected in baseline, 6- and 12-month online assessments. Attitudes, knowledge, perceived behavioral control and self-efficacy outcome measures were previously developed by the research team or adapted from prior studies. The supplemental materials detail the Institutional Review Board approved protocol, including further information about the procedures and variables collected. The Respond to Prevent Study is also registered on the public website clinicaltrials.gov (NCT03545321).³³ In this narrative, we provide insights into the application of the unique design and key decision points and adaptations to the protocol, in the hope that they may inform other and future pharmacy-centered practice-based research studies.

Designing a large pragmatic community pharmacy trial

The study employed a stepped-wedge quasi-experimental study design, set within two large pharmacy chain businesses located in Oregon, Washington, New Hampshire and Massachusetts. The states were chosen based on their rising opioid overdose trends, opportunity to contrast pharmacy naloxone policies (i.e., standing orders, prescriptive authority), corporate and practice environments, and mix of rural and urban communities. Many prior studies of pharmacy interventions relied upon academic research center connections (i.e., clinical trial network) or involved pharmacies within an integrated care network like the Veterans Health Administration. Our vision was to conduct a large pragmatic trial in a real-world community pharmacy environment. To do so, the stepped wedge design allowed for all study sample sites to eventually receive the intervention, with randomization of the timing of receipt rather than randomizing receipt of the entire intervention. This approach helped manage corporate partner expectations but also to clarify selection of sites to the pharmacies. Close collaboration and regular meetings with the pharmacy corporate leadership during implementation supported a total of 175 pharmacies (approximately 45 per state) to be involved. Pharmacists employed at least part-time from each site were invited to consent to participate in the year-long follow-up cohort study, and to receive the individual-level components of the intervention (i.e., continuing education credited online training modules).

Study Adaptations

Conducting a large research trial in real-world settings presented enormous opportunities but also substantial challenges. For both pharmacy retailers, time constraints on the pharmacy staff members and strained workflow requirements meant that detailers needed to adapt to detail quickly in some places or take time in others, and to be flexible whenever necessary. For one pharmacy retail partner, the onsite academic detailing was carefully scheduled, and the pharmacy retail corporation provided a “floater pharmacist” to join the study academic detailer in all initial visits, which allowed the staff pharmacist to step out of the workflow and devote attention to the intervention receipt. For the other retail partner, the study team worked to accommodate the pharmacies’ schedules, sometimes returning multiple days to the same remote areas to achieve the best windows of focused pharmacist time. By the second of five waves, we had fielded many requests from pharmacy technicians to take the online training modules, and study academic detailers similarly conveyed pharmacy technician heightened participation during detailing visits. Our team’s prior research suggested³⁴ that pharmacy technicians could be better integrated into opioid safety, naloxone provision, and syringe access conversations, prompting the team to carefully consider possible expansion of eligibility criteria to include technicians as participants in the study. Additionally, while we had anticipated recruiting two or more pharmacists at each site, enrollment was low, and we found on average one staff pharmacist per site consented to participate in the longitudinal study. After obtaining support from our DSMB and approval from the sponsor, we expanded the study eligibility to invite pharmacy technicians across the remaining waves four and five. We also created a technician-specific online training module, redesigned materials specific to technicians, obtained approval for technician continuing education credit, and adapted study assessments for technicians.

Two other study adaptations are notable. First, our initial design conceptualized the pharmacy and pharmacist as points of intervention, but many sites, especially among one retail partners, featured drive-through pharmacy windows. Because nonprescription syringes and naloxone can both be obtained in this extended pharmacy space, we adapted our intervention materials, procedures, and fidelity checking protocols to explicitly involve drive-through activities. For example, a large patient-facing “window cling” with a design and messaging consistent with other intervention materials was developed and provided to all sites for posting at drive-through windows or, when sites lacked a drive-through, other glass door entryways onsite. Procedural changes included orienting academic detailing content and conversations to confirm the permissibility of using the drive-through for naloxone access and syringe sales, affixing the “window clings” about naloxone availability to drive-through windows during site visits, and placing study syringe disposal containers and boxes of commonly sold syringe sizes close to the drive-through window. In terms of protocol execution, fidelity checking by the study team also adapted to verify whether the drive-through had adopted the intervention.

Adaptations during the COVID-19 pandemic and Western wildfires

A final yet critical set of protocol adaptations followed from the COVID-19 pandemic and the Oregon wildfires of 2020, both of which affected waves three through five of the study. During COVID-19, the timing of the implementation was slightly delayed across all sites, and the intervention period was prolonged in the three waves as pharmacies quickly pivoted to provide frontline essential services. Delays ranged from initial lockdowns, need for additional institutional approvals, state travel restrictions, staff testing or quarantining, and by request from both of the pharmacy chain businesses that were shifting personnel, reconstructing the pharmacy space to accommodate social distancing requirements, dealing with stocking challenges, filling high volumes of medications from patients, fielding higher than usual volume of inquiries from patrons, or shifting to massive scale-ups for COVID-19 testing and vaccination. Nevertheless, after each challenge, the pharmacies quickly adjusted to the “new normal.” Because pharmacists are essential workers, the core components of the intervention continued, including all in-person, socially distanced initial academic detailing sessions. Additionally, due to concerns about COVID-19 transmission, adaptations and additional cleaning protocols were implemented within intervention sites, occasionally resulting in study materials being misplaced, ruined from COVID-19 cleaning protocols, or discarded. To address evolving COVID-19 cleaning protocols the study team contacted intervention sites at multiple points throughout implementation to replace or restock study materials (e.g. stickers, signage). Due to institutional requirements and COVID-19 safety concerns, the research protocol in Pacific Northwest sites was required to shift from in-person to telephone-based fidelity checking. Also during the study period, when the Oregon wildfires forced the closure of one site where individual 12-month participation was active, we paused on telephone and email intervention reminders. Finally, as COVID-19 vaccinations became available in late 2020 and our Northeast partners began pharmacy-led vaccination programs in the final wave five, we worked closely with our corporate pharmacy chain partners to identify and successfully recruit pharmacy sites where vaccination rollout was not active. All five intervention periods concluded by September 2021.

Study and pharmacy resilience are strong. Flexible and adaptable study materials, well-trained staff, and partnering with community pharmacy practice leaders committed to public health provision permitted critical shifts to the intervention, design, and protocol that other settings or a less nimble design would have resulted in scientific loss. If the Respond to Prevent Study produced meaningful changes in the pharmacy team’s attitudes toward naloxone and people who use drugs and in the pharmacy’s naloxone provision, nonprescription syringe sales, and buprenorphine dispensing, the proposed and adapted real-world study protocol described here are strong starting points for the ability to detect these needed changes.