Addressing the Opioid Epidemic Through Community Pharmacy Engagement: Randomized Controlled Trial (Aim 2)
Phase: NA
Conditions: Naloxone
Sponsor: University of North Carolina, Chapel Hill

 
Addressing the Opioid Epidemic Through Community Pharmacy 
Engagement: Randomized Controlled Trial (Aim 2) 
 
 
NCT number NCT04677387 
Document Date 05/29/2024 
 

PROTOCOL: INTERVENTIONAL STUDY 
 
 
Complete Title: Addressing the Opioid Epidemic Through Community Pharmacy Engagement: Randomized 
Controlled Trial (Aim 2) 
 
 
 
 
Short Title: Nalox-Comm: Naloxone Communication Training for Pharmacists 
Drug or Device Name(s): N/A 
FDA IND/IDE (if applicable): N/A 
Sponsor: National Institutes of Health (NIH) 
Protocol Date: 5/29/24 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
National Institutes of Health (NIH) 
Bethesda, MD 20892 
USA 
Study Principal Investigator: Delesha Carpenter, PhD, MSPH 
1 University Heights, 114G Karpen Hall 
Asheville, NC 28804 
Phone: 828-250-3916 
Email: dmcarpenter@unc.edu  
 
 

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PROTOCOL TITLE:  
Addressing the Opioid Epidemic Through Community Pharmacy Engagement: Randomized 
Controlled Trial (Aim 2) 
Short Title:  
Nalox-Comm: Naloxone Communication Training for Pharmacists 
 
Lead Investigator: 
Delesha Carpenter, PhD, MSPH 
 University of North Carolina at Chapel Hill 
Version Date: May 29, 2024 
 
I confirm that I have read this protocol and understand it.    
Principal Investigator Name:  
 
 
Delesha Carpenter 
 
 
 
Principal Investigator Signature:  
 
 
 
 
 
 
 
Date:   
 
 
 
 
5/30/2024 
 
 
 
 
 
 
 

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Table of Contents 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................................... 4 
PROTOCOL SYNOPSIS .......................................................................................................................................................................................... 5 
BACKGROUND AND RATIONALE ......................................................................................................................................................................... 8 
1. 
STUDY OBJECTIVES .......................................................................................................................................................................... 9 
2. 
INVESTIGATIONAL PLAN ................................................................................................................................................................. 9 
3. 
STUDY PROCEDURES ..................................................................................................................................................................... 10 
4. 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................................................................. 11 
5. 
STATISTICAL CONSIDERATIONS .................................................................................................................................................... 13 
6. 
STUDY INTERVENTION .................................................................................................................................................................. 14 
7. 
SAFETY MANAGEMENT ................................................................................................................................................................. 15 
8. 
DATA AND SAFETY MONITORING ................................................................................................................................................. 15 
9. 
CONSENT PROCESS ....................................................................................................................................................................... 16 
10. 
REFERENCES .................................................................................................................................................................................. 16 
APPENDIX .................................................................................................................................................................... 18 
 
 
 

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Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
RCT 
Randomized controlled trial 
SP 
Simulated patient 
P2P 
Prescribe to Prevent 
GEE 
Generalized estimating equations 
DSMB 
Data and Safety Monitoring Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
  
Study Title 
Addressing the Opioid Epidemic Through Community Pharmacy 
Engagement: Randomized Controlled Trial (Aim 2) 
Funder 
National Institutes of Health (NIH) 
Study Rationale 
• From 1999 to 2015, the drug overdose death rate in non-
metropolitan rural areas increased by 325% and, by 2015, 
exceeded that of metropolitan urban areas2. 
• Naloxone, an opioid overdose reversal agent, is not readily 
accessible in many rural communities.  
• Community pharmacists are the most accessible healthcare 
professional in rural areas4-6 and are well-positioned to 
increase access to naloxone in rural areas7. 
• The amount of naloxone dispensed by pharmacists has 
increased steadily over the past five years8,9. 
• Multiple studies11-13 have shown that even when pharmacies 
stock naloxone, many pharmacists do not offer or dispense 
it. Reasons include barriers related to talking with patients 
and caregivers about the sensitive topic of overdose14-17. 
• Pharmacists’ comfort communicating about naloxone is 
significantly associated with how often they offer it13. 
• Existing online naloxone training resources do not 
sufficiently address communication barriers. 
• The objective of our 4-state collaboration is to develop an 
online module (Nalox-Comm) to increase rural pharmacists’ 
self-efficacy to engage in naloxone discussions and, 
ultimately, increase how often they dispense naloxone. 
• In Aim 1 (study #19-0998), we will gather and analyze 
formative data and engage in an iterative intervention 
development process to finalize Nalox-Comm content. 
• For Aim 2 (study #20-2192), which is described in this 
protocol, we will conduct a pilot randomized controlled trial 
with 60 pharmacists to evaluate whether Nalox-Comm 
increases the frequency with which pharmacists dispense 
naloxone (primary outcome). 
Study Objective(s) 
Primary  
• 
To evaluate whether Nalox-Comm increases the rate at which 
pharmacists dispense naloxone  
Secondary 
• 
To determine whether the Nalox-Comm module increases 
pharmacists’ willingness to dispense naloxone 

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• 
To determine whether the module increases pharmacists’ self-
efficacy to dispense naloxone 
• 
To determine whether the module improves the quality of 
pharmacists’ naloxone communication 
Test Article(s) 
 
The Nalox-Comm training developed for this study is ~30 mins in 
length. It is an online module with videos, didactic content, and 
reflection. Content includes: 
• The importance of naloxone and the role of the pharmacist 
• Non-stigmatizing language 
• How to initiate an offer of naloxone 
• How to respond to patient & caregiver naloxone requests 
• How to address specific communication barriers 
Study Design 
 
This is a cluster RCT with balanced randomization by pharmacy and 
two parallel groups (experimental and control), conducted with 
pharmacists from 62 pharmacies part of a single grocery store chain 
in rural counties of Georgia, North Carolina, South Carolina, and 
Tennessee. 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
1. Subjects age 18-99 years; 
2. currently work at a pharmacy that stocks naloxone; 
3. currently work at a rural community pharmacy; and 
4. speak English. 
Exclusion Criteria 
1. Non-staff pharmacists such as pharmacy "floaters" or fill-in 
pharmacists 
Number Of Subjects  
60 pharmacists  
Study Duration 
Each subject’s participation will last approximately 6 months. 
The entire study is expected to last approximately 3 years. 
Study Phases 
  
1. Enrollment by invitation: inviting select pharmacies via email, 
confirming eligibility of those interested, obtaining electronic 
informed consent, completion of baseline survey 
2. SP baseline observation: 3 SPs call each enrolled pharmacist to 
observe and rate the quality of their naloxone communication 
3. Study intervention: participants complete either the Nalox-
Comm module (experimental group) or the P2P training module 
(control group) based on previous randomization of 
pharmacies. They also complete a post-training survey. 
4. SP post-training observation: 3 SPs call each enrolled 
pharmacist to observe and rate the quality of their naloxone 
communication 

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5. Follow-up: 3 months post-intervention, participants complete a 
final follow-up survey to assess secondary outcomes 
Efficacy Evaluations 
Primary outcome: change in naloxone dispensing rates is measured 
by comparing pharmacy records of naloxone dispensed in the 3 
months prior to study participation to number of naloxone 
dispensed in the 3 months after study completion  
Secondary outcomes: 
• Willingness – 7 items measure willingness to dispense 
naloxone. Pharmacists rate their willingness to engage in 
each item from 1= “Not at all willing” to 4 = “Very willing.” 
• Self-efficacy – factors were identified that could impact 
counseling self-efficacy. On the study surveys, pharmacists 
rate their confidence to engage in 7 naloxone 
communication tasks. Response options range from 1 = “Not 
at all confident” to 4 = “Very confident.” 
• Quality of naloxone counseling – SPs use a validated 
observation guide with 6 items to rate the pharmacist’s 
quality of communication on a 5-point scale (1 = lowest 
score and 5 = highest score). 
Statistical And Analytic 
Plan 
Linear regression using GEE will be used to assess the effect of the 
intervention on naloxone dispensing rates (primary outcome) after 
adjusting for any imbalances between the treatment groups. Similar 
models will be used to assess the effect of the intervention on each 
secondary outcome. 
DATA AND SAFETY 
MONITORING PLAN 
The study PI will evaluate data collected by secret shoppers and 
through surveys. The PI will also meet weekly with her project 
director and monthly with the research team to discuss data 
collection, potential data quality issues if they arise, and study 
progress. Also, the DSMB will provide an independent and unbiased 
review of the study’s ongoing progress. 
 
 
 

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BACKGROUND AND RATIONALE 
 
In 2017, more than 49,000 of the 72,000 estimated drug overdose deaths in the U.S. involved opioid drugs1. 
From 1999 to 2015, the drug overdose death rate in non-metropolitan rural areas increased by 325% and, by 
2015, exceeded that of metropolitan urban areas2. Naloxone, an opioid overdose reversal agent, is not readily 
accessible in many rural communities because these communities often lack substance use treatment 
resources and are health professional shortage areas3. Community pharmacists (pharmacists who work in 
outpatient ambulatory care settings) are the most accessible healthcare professional in rural areas4-6 and, due 
to statewide standing orders that have granted pharmacists increased prescriptive authority to dispense 
naloxone to anyone who may benefit from it, are well-positioned to increase access to naloxone in rural areas7. 
 
The amount of naloxone dispensed by pharmacists has increased steadily over the past five years8,9. This 
increase is likely to continue since the Surgeon General’s (SG) Advisory on Naloxone and Opioid Overdose, 
which was released in April 2018, specifically encourages individuals to talk with their pharmacists about 
naloxone.10 Unfortunately, multiple studies11,12, including our own13, have shown that even when pharmacies 
stock naloxone, many pharmacists do not offer or dispense it. The reasons behind pharmacists’ reluctance to 
offer and dispense naloxone often include barriers related to talking with patients and caregivers (i.e., third 
parties who obtain naloxone for someone at risk of overdose) about the sensitive topic of overdose14-17. Our 
own work has shown that pharmacists’ comfort communicating about naloxone is significantly associated with 
how often they offer it13. Existing online naloxone training resources do not sufficiently address communication 
barriers that may influence pharmacists’ willingness to offer and dispense naloxone, particularly barriers that 
are common in rural areas, such as high stigma against drug use and fear of offending patients13,18. 
 
The objective of our 4-state collaboration is to develop an online module (Nalox-Comm) to increase rural 
pharmacists’ self-efficacy to engage in naloxone discussions and, ultimately, increase how often they dispense 
naloxone. For Aim 1 (study #19-0998), we will gather formative data on barriers to engaging in naloxone 
conversations and preferences for module content from rural pharmacists, patients, and caregivers (i.e., third 
parties who obtain naloxone for someone who takes opioids). We will then analyze formative data and engage 
in an iterative intervention development process with a stakeholder development panel and expert consultants 
to finalize Nalox-Comm content. For Aim 2 (study #20-2192), which is described in this protocol, we will conduct 
a pilot randomized controlled trial with 60 pharmacists to evaluate whether Nalox-Comm increases the 
frequency with which pharmacists dispense naloxone (primary outcome). We will also assess whether the 
module increases pharmacists’ willingness and self-efficacy to dispense naloxone and improves the quality of 
their naloxone communication (secondary outcomes). 
 
 
 
 
 
 
 

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1. STUDY OBJECTIVES 
We are conducting a RCT to evaluate whether Nalox-Comm training increases how often rural pharmacists 
dispense naloxone compared to completing a more basic online naloxone training that includes minimal 
communication content. We hypothesize that pharmacists who complete Nalox-Comm will dispense more 
naloxone in the three months post-intervention (primary outcome) and will report greater willingness to 
dispense naloxone, higher naloxone counseling self-efficacy, as well as demonstrate higher quality 
communication about naloxone (secondary outcomes). 
 
2. INVESTIGATIONAL PLAN 
2.1 Study Design 
This is a cluster RCT with balanced randomization by store and two parallel groups (experimental and 
control), conducted with pharmacists from 62 pharmacies part of a single grocery store chain in rural 
counties of Georgia, North Carolina, South Carolina, and Tennessee. These 62 pharmacies comprise all 
of the pharmacies in the grocery store chain that are in rural areas, defined by a Rural-Urban 
Commuting Area (RUCA) code of 4–10 and/or a county that is at least 33% rural according to the 2010 
U.S. Census Bureau data19. Figure 1 provides an overview of the study design, including completion of a 
baseline survey, simulated patient baseline observations, an online experimental or control naloxone 
training, a post-training survey, simulated patient post-training observations, and a three-month 
follow-up survey. 
2.2 Randomization and Allocation to Treatment Groups 
All 62 rural pharmacies were matched based on their county’s opioid prescribing rate and level of 
rurality (33% or greater). The county opioid prescribing rate for each pharmacy was identified using the 
Centers for Disease Control and Prevention’s opioid prescribing rates20. 
Pharmacies were first ordered by opioid prescribing rate (primary matching variable) and then level of 
rurality. Pharmacies with exact matches were paired first and then the rest of the pairs were matched 
using the closest value. Using computer-generated random numbers, one pharmacy in each matched 
pair was randomized to either the control or experimental group. 
 
2.3  Number of Subjects, Study Duration, and Enrollment 
60 pharmacists, 30 for the experimental group (Nalox-Comm) and 30 for the control group (Prescribe 
to Prevent) will participate. The overall time commitment for participants is less than 2 hours spread 
out over a 6 month period. We will keep the study active until all aims are completed (approximately 3 
years). The Clinical Coordinator for the grocery store pharmacy chain will distribute an email to the 62 
rural pharmacy stores to notify pharmacists that the chain is participating in an evaluation of naloxone 
training materials and introduce them to the study team. The study team will then email the 
pharmacies’ store email addresses with more information about the study and a link to an online 
baseline survey. The first page of the baseline survey contains a consent form, which notifies 
pharmacists that, should they choose to participate, they will be asked to complete surveys before and 

Page 10 of 19 
 
after completing the training and will be observed by simulated patients. Pharmacists who provide 
electronic informed consent and complete the baseline survey are considered to be enrolled in the 
study. Upon completion of the baseline survey, they automatically receive an email confirmation 
detailing next steps. 
 
2.4 Study Population 
The recruitment goal is 60 pharmacists. Each of the 62 pharmacies employs two full-time pharmacists, 
both of whom can participate. Thus, participants for the RCT (N = 60) will be recruited from a total 
sample of 124 pharmacists. Eligible pharmacists must meet the following criteria: 1) be age 18 years or 
older, 2) speak English, 3) work as a full-time pharmacist at one of the participating 62 rural grocery 
store chain pharmacies. In addition, individuals who are a floater, or non-staff, pharmacist are 
ineligible. 
 
3. STUDY PROCEDURES 
3.1 Simulated patient pre-training observation 
After completing the baseline survey and before receiving an invitation to complete the online 
naloxone training, three SPs who are blinded to group assignment call each enrolled pharmacist to 
observe and rate the quality of their naloxone communication. These SPs act as “Secret Shoppers”, 
whereby the pharmacist does not know the call is not a real patient. The SPs were trained using 
procedures that have been used in previous pharmacy SP studies21-23. SPs were trained to present one 
of three realistic naloxone cases (i.e., scenarios). SPs were provided with a script, which they reviewed 
and practiced with the study team until their presentation felt genuine. 
 
During and immediately after the interaction with the pharmacist, each SP rates several aspects of the 
encounter using an observation guide. SPs then enter their observation guide responses for each 
pharmacist into a secure Qualtrics survey where they do not have access to other SPs’ ratings for the 
same participant. 
 
3.2 Naloxone online training 
Once enrolled pharmacists have been observed by all three SPs, they receive an email invitation to 
complete either the Nalox-Comm module (experimental group) or the P2P training module (control 
group). The email includes a link to the respective training, instructions on how to navigate and 
complete the module, and the process for receiving continuing education (CE) credit. For those in the 
control group, the email also contains the link to the post-training survey, which is completed after 
training. The first question of this survey asks pharmacists if they completed the P2P training and will 
not allow them to continue the survey if they check “No.” Those assigned to the Nalox-Comm module 
(experimental group) are directed to the post-training survey within the module in order to coordinate 
CE credit and track completion. 
 
3.3 Simulated patient post-training observation 
Up to four weeks after pharmacists have completed training, the three blinded SPs observe their 
naloxone communication by phone a second time. In order to prevent pharmacists from recognizing 

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SPs, the three scenarios were adapted to be similar in nature to the pre-intervention scenarios, but 
different enough so as to not cause suspicion on the part of the pharmacist. SPs use the same 
observation guide to rate the pharmacists’ naloxone communication and enter their responses into a 
secure Qualtrics survey. 
 
To ensure SP scenarios are enacted with fidelity, research assistants observe two of each SP’s baseline 
observations and two of their post-intervention observations, using an SP assessment guide to rate the 
quality of the SP’s performance. Items in the guide were adapted from previously validated SP 
assessments24,25 and ask raters to indicate if all script content is covered and whether the SP sounds 
authentic and stays in his/her role. Additionally, research assistants describe any deviations and 
provide an overall rating from 1 to 9 of the SP’s portrayal, where low numbers indicate “needs 
improvement” and high numbers indicate a “great” portrayal. 
 
3.4 Three-month post-intervention follow-up 
When three months has passed since training, pharmacists receive an email invitation to complete 
their final follow-up survey, which assesses the study’s secondary outcomes. 
 
3.5 Remuneration and participant follow-up 
Participants can receive up to $150 in Amazon eGift cards for completing the study: $50 for completing 
each of the surveys (baseline, post-training, and three-month follow-up). To help reach the enrollment 
goal of 60 pharmacists, as well as ensure a 100% completion rate for those enrolled, up to five follow-
up email reminders are sent to non-completers of each survey. If no response is received after the 
reminder emails, pharmacists receive one phone call. Additionally, recruitment flyers were mailed to 
each pharmacy. 
 
4. STUDY EVALUATIONS AND MEASUREMENTS 
4.1 Primary outcome 
Our primary outcome is change in naloxone dispensing rates measured by comparing pharmacy 
records of naloxone dispensed in the three months prior to study participation to number of naloxone 
dispensed in the three months after study completion (Table 2). The grocery store pharmacy chain has 
agreed to provide us with these naloxone dispensing rates from each of the participating pharmacies at 
the conclusion of the study. We hypothesize that pharmacies in the experimental group will dispense 
more naloxone in the three months post-intervention compared to pharmacies in the control group. 
 
4.2 Secondary outcomes 
Willingness to dispense naloxone: Seven items measure willingness to dispense naloxone; 
four items came from the Nielsen et al. (2016) naloxone attitudes survey and two items from the 
Wilson et al. (2016) HOPE measure26,27. A seventh item was created to reflect initiating a conversation 
about naloxone. At baseline, immediately post-intervention, and three months post-intervention, 
pharmacists indicate how willing they are to engage in activities such as “proactively identify 
customers who are candidates for naloxone” and “dispense naloxone to patients and caregivers.” 

Page 12 of 19 
 
Response options range from 1 = “Not at all willing” to 4 = “Very willing.” Items are averaged to create 
a mean willingness score, with higher scores indicating more willingness to dispense naloxone. 
 
Naloxone counseling self-efficacy: There are no validated instruments to measure 
pharmacists’ naloxone counseling self-efficacy. Thus, we referred to the qualitative literature on 
pharmacists’ barriers to dispensing naloxone11,15-17,26,28,29 and identified factors that could impact 
counseling self-efficacy. On the baseline, immediate post-intervention, and three-month post-
intervention surveys, pharmacists rate their confidence to engage in seven naloxone communication 
tasks, including engaging in naloxone counseling when the pharmacy is busy and discussing naloxone in 
a way that does not offend customers. Response options range from 1 = “Not at all confident” to 4 = 
“Very confident.” Items are averaged to create a mean self-efficacy score (range = 1 to 4), with higher 
scores indicating greater naloxone counseling self-efficacy. 
 
Quality of naloxone counseling: SPs assess pharmacists’ quality of naloxone counseling at baseline and 
four weeks post-intervention. During a phone interaction with the pharmacist, SPs use a validated 
observation guide with six items to rate the pharmacist’s quality of communication on a 5-point scale 
(1 = lowest score and 5 = highest score). These items specifically assess satisfaction with 
communication (e.g., listened carefully, showed respect, and actively engaged with their case). This 
method for measuring impressions of communication has been used previously to assess the effect of 
training on pharmacists’ ability to communicate about antidepressants21. 
 
Three separate SPs rate each pharmacist both pre-intervention and post-intervention. The three 
ratings are averaged to create summary scores for quality of communication before and after training 
(range = 1 to 5), with higher scores indicating higher quality of communication. 
 
In addition to the six items, the observation guide asks if the pharmacist encouraged or made a 
personal recommendation for naloxone, what term the pharmacist used to describe naloxone’s use 
(e.g., overdose, opioid emergency), and which analogy or comparison was used to describe naloxone 
(e.g., EpiPen, fire extinguisher). 
 
4.3 Other measures 
Naloxone knowledge: Six multiple-choice questions and two true/false questions based 
on the content of the naloxone training modules assess participants’ naloxone knowledge. Correct 
answers are totaled to create a summary score (range = 0 to 6), with higher scores indicating greater 
naloxone knowledge. 
 
Attitudes toward dispensing naloxone: Eight items from the Wilson et al. (2016) HOPE 
measure assess participants’ attitudes toward naloxone27. Items relate to attitudes toward substance 
abuse (e.g., “I believe chemical dependency is a disease”) and naloxone (e.g., “Giving patients naloxone 
for overdose reversal will cause them to use more drugs”). Response options range from 1 = “Strongly 
disagree” to 4 = “Strongly agree”. Items are reverse scored as necessary and averaged to create a 
mean score (range = 1 to 4), with higher scores indicating more negative attitudes toward naloxone. 
 

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Barriers to dispensing naloxone: This construct is assessed using items from the HOPE measure27. 
Pharmacists report how much of a concern 10 attitudinal and environmental barriers are for 
dispensing naloxone, including not wanting to insult the patient and lack of time to counsel. Response 
options range from 1 = “Not at all concerned” to 5 = “Extremely concerned.” Items are averaged to 
create a mean score (range = 1 to 5), with higher scores indicating more barriers to dispensing 
naloxone. 
 
Previous naloxone training: At baseline, pharmacists indicate whether they have ever 
received naloxone training (yes/no) and on the three-month post-intervention survey whether they 
have received any naloxone training in addition to the training completed as part of the study (yes/no). 
 
Pharmacist characteristics: At baseline, pharmacists report their age, gender, race, 
ethnicity, how long they have worked in pharmacy practice and at their current pharmacy, and 
whether they have previously dispensed naloxone (yes/no). 
 
Pharmacy characteristics: At baseline, pharmacists report the number of pharmacists and technicians 
who are typically at the pharmacy at one time, as well as the estimated daily prescription volume at 
their pharmacy. 
 
Social desirability bias: The validated short version of the Marlowe-Crowne Social 
Desirability Scale, Cronbach alpha = 0.6530, assesses pharmacists’ social desirability bias. From 10 
statements such as “I’m always willing to admit when I make a mistake” and “I never resent being 
asked to return a favor”, respondents select statements that are true for them (coded as 1). 
Unchecked, or “false” statements, are coded as 0. Items are summed so that scores range from 0 to 10, 
with higher values indicating greater social desirability bias. 
 
5. STATISTICAL CONSIDERATIONS 
 
Characteristics of pharmacies and pharmacists will be presented by treatment group. Unadjusted 
statistical comparisons using two sample t-tests and chi-square tests will be made between treatment 
groups (control vs. intervention group). Generalized estimating equations, (i.e., the GEE method), will be 
used to analyze the effects of the intervention on the primary and secondary outcome variables, while 
accounting for the fact that pharmacists are nested within pharmacies. 
 
5.1 Primary outcome  
The GEE method will be used to detect a significant difference in our primary outcome variable of 
frequency of naloxone dispensing. Specifically, we will evaluate change in naloxone dispensing from 
the 3 months pre-intervention to the 3 months post-intervention. Our multivariable model will be 
nested by pharmacy and will include several covariates, including the county’s opioid prescribing rate, 
pharmacy rurality, average daily script fill rate, and demographic characteristics of the pharmacist. 
Alpha will be set at 0.05. 
 
5.2 Secondary outcomes 

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We will also conduct similar GEE models as the one described above to assess if the intervention 
improves our secondary outcomes of willingness to dispense naloxone, naloxone counseling self-
efficacy, and quality of naloxone counseling. 
 
5.3 Sample size and power 
Pharmacies in this grocery store chain dispense naloxone once for every 250 opioid prescriptions, on 
average. With 60 pharmacists, 30 per treatment arm, we have at least 80% power at the 0.05 
significance level to detect an increase in naloxone dispensing to 1 for every 100 opioid prescriptions 
dispensed, assuming a standard deviation of 0.008 (2 in 250 or 0.8 in 100) and depending on the 
intraclass (within pharmacy) correlation. In other words, we expect the intervention to increase the 
naloxone dispensing rate from 1 in 250 (0.4%) to 1 in 100 (1%), an increase of 0.6%. So, the sample size 
is based on a mean difference of 0.6%. 
 
6. STUDY INTERVENTION 
6.1 Control group: Prescribe to Prevent online module 
Participants randomized to the control group complete the 55-min online Prescribe to Prevent (P2P) 
module. P2P consists of videos, didactic content, and quizzes, covering the key naloxone topics listed in 
Table 1. Two videos included in P2P demonstrate a pharmacist communicating about a potentially fatal 
opioid drug interaction with: 1) a patient and 2) a provider. Of note, none of the P2P videos 
demonstrate effective naloxone communication with patients. Pharmacists in the control group can 
receive 0.125 continuing education units (CEUs) for completing the course. 
 
6.2 Experimental group: Nalox-Comm online module 
Pharmacists in the experimental group complete the approximately 30-minute Nalox-Comm online 
module. The module was developed during Aim 1 of the NIDA-funded study (study #19-0998). 
Formative data to guide Nalox-Comm content were collected from interviews with 40 pharmacists, 40 
patients at-risk of opioid overdose, and 40 caregivers of individuals at-risk of overdose from 
pharmacies located in rural counties with high rates of opioid-related overdose deaths in Alabama, 
Iowa, North Carolina, and Wisconsin. Logistical and attitudinal barriers to pharmacists engaging in 
naloxone counseling with their patients were identified, including: privacy (patients often do not want 
others to know they take prescription opioids), cost (patients may not be interested in something they 
cannot afford), safety (patients may be wary about new medications), and stigma (naloxone has some 
negative associations from news headlines or television shows). Thus, Nalox-Comm includes three 
separate, approximately 10-min lessons on how to initiate and conduct a conversation about naloxone 
that addresses these specific communication barriers. Throughout Aim 1 (study #19-0998), a 
stakeholder development panel of rural community pharmacists advised on module content to ensure 
relevancy for rural populations. 
 
Nalox-Comm includes multiple video examples of pharmacists conversing with patients about 
naloxone, in which they demonstrate a stepwise communication approach (C.A.R.E.). C.A.R.E. stands 
for: show that you Care or have Concern; Ask the patient for permission to counsel them about 
naloxone; Relate naloxone to patients by explaining their specific risk factors; and Encourage and 

Page 15 of 19 
 
Educate patients by making a personal and/or professional recommendation that they get naloxone. 
Pharmacists in the experimental group can receive 0.10 CEUs for completing the course. 
 
7. SAFETY MANAGEMENT  
The primary risk is breach of confidentiality. The study consent form will inform pharmacists that their 
responses to the surveys and secret shopper observations will not be shared with their employer, results 
will be reported in aggregate, and will not affect their employment. The online consent will include a check 
box that states, ‘I agree to participate in this research study.’ All data will be stored in a secure fashion 
with password-protected files and secure servers. 
 
We do not anticipate any adverse events (AEs) since the surveys and intervention assess naloxone 
knowledge, attitudes, and communication/training preferences and scenarios will be realistic and not 
outside the range of what pharmacists would be asked to navigate as part of their normal professional 
duties. However, the secret shopper interactions may still cause the pharmacist to feel uncomfortable, and 
thus potential mild AEs include pharmacist discomfort and possible emotional outburst when engaging in 
the secret shopper encounter. Secret shoppers will be trained to handle possible negative reactions from 
the pharmacist, although the likelihood of a negative reaction is low. Due to the nature of our study, we do 
not anticipate encountering situations in which confidentiality could be breached because of mandatory 
reporting. However, if the pharmacist reacts negatively to the scenario and it is clear that they need 
medical assistance or counseling, confidentiality may be breached to ensure the safety of the pharmacist. 
The consent form will state that confidentiality will be breached in the case that a pharmacist needs 
medical assistance or counseling. 
 
The study research team members are trained in confidentiality procedures. Identification numbers will be 
assigned to pharmacists and any information that could identify individuals participating in this project will 
not be included in any data sets. The data will only be given to the PI and research staff. Data will not be 
shared with the pharmacists’ employers. 
 
8. DATA AND SAFETY MONITORING  
The study PI will evaluate data collected by secret shoppers and through surveys. The PI will also meet 
weekly with her project director and monthly with the research team to discuss data collection, potential 
data quality issues if they arise, and study progress. These meetings will serve as a forum to discuss issues 
related to data collection and implementation of the data collection protocol. Meetings will be held more 
frequently if needed. 
 
Additionally, an independent and unbiased review of the study’s ongoing progress will be provided by the 
DSMB. The DSMB is well-qualified to comment on the appropriateness of the RCT protocol and make 
recommendations related to any AEs or adjustments to study procedures. The investigator(s) will appoint 
a DSMB chairperson. S/He is responsible for overseeing the meetings and developing the agenda in 
consultation with the investigator(s). The DSMB will meet at least once per year and will schedule 
additional meetings, if deemed necessary. A quorum of more than half the DSMB members is required in 
order to convene a meeting of the DSMB. 
  

Page 16 of 19 
 
9.  CONSENT PROCESS 
Informed consent documents for this study include a specific statement that information from the trial will 
be posted on ClinicalTrials.gov. Consent will be obtained on the online baseline survey. The first page of 
the baseline survey will contain a study consent form that includes the requirements, risks, and benefits of 
participation. The consent form will also include a checkbox stating that “I agree to participate in this 
research study” that pharmacists check to consent to participate in the study. Pharmacists will have the 
ability to opt out of the study. The consent form will notify pharmacists that secret shoppers will observe 
their communication over the 3-month study period. The consent form will also state that the secret 
shopper will not disclose their identity, but the pharmacist will be notified after the study has been 
completed of when the phone calls occurred. The consent form will also state that data collected during 
the secret shopper visit will not be shared with their employers. Pharmacists who do not wish to 
participate in the research study will not be penalized by their employer. 
 
10. REFERENCES 
1. Centers for Disease Control and Prevention. CDC WONDER. Retrieved from https://wonder.cdc.gov/. Accessed 
Nov 14, 2018. 
2. Mack KA, Jones CM, Ballesteros MF. Illicit drug use, illicit drug use disorders, and drug overdose deaths in 
metropolitan and nonmetropolitan areas—United States. American journal of transplantation. 
2017;17(12):3241-3252. 
3. Thomas KC, Ellis AR, Konrad TR, Holzer CE, Morrissey JP. County-level estimates of mental health professional 
shortage in the United States. Psychiatric Services. 2009;60(10):1323-1328. 
4. Knapp KK, Paavola FG, Maine LL, Sorofman B, Politzer RM. Availability of primary care providers and pharmacists 
in the United States. Journal of the American Pharmaceutical Association (1996). 1999;39(2):127-135. 
5. Casey MM, Klingner J, Moscovice I. Pharmacy services in rural areas: is the problem geographic access or 
financial access? The Journal of Rural Health. 2002;18(3):467-477. 
6. Lin SJ. Access to community pharmacies by the elderly in Illinois: a geographic information systems analysis. 
Journal of Medical Systems. 2004;28(3):301-309. 
7. Roberts AW, Carpenter DM, Smith A, Look KA. Reviewing state-mandated training requirements for naloxone-
dispensing pharmacists. Research in Social and Administrative Pharmacy. 2018. 
8. Morton KJ, Harrand B, Floyd CC, et al. Pharmacy-based statewide naloxone distribution: A novel “topdown, 
bottom-up” approach. Journal of the American Pharmacists Association. 2017;57(2):S99-S106.e105. 
9. Jones CM, Lurie PG, Compton WM. Increase in naloxone prescriptions dispensed in US retail pharmacies since 
2013. American journal of public health. 2016;106(4):689-690. 
10. U.S. Department of Health and Human Services. Surgeon General's Advisory on Naloxone and Opioid Overdose. 
2018. Retrieved from https://www.surgeongeneral.gov/priorities/opioid-overdoseprevention/naloxone-
advisory.html. Accessed June 11, 2018. 
11. Thornton JD, Lyvers E, Scott VGG, Dwibedi N. Pharmacists' readiness to provide naloxone in community 
pharmacies in West Virginia. Journal of the American Pharmacists Association. 2017;57(2):S12-S18.e14. 
12. Bailey AM, Wermeling DP. Naloxone for opioid overdose prevention: pharmacists’ role in community- based 
practice settings. Annals of Pharmacotherapy. 2014;48(5):601-606. 
13. Carpenter DM, Dhamanaskar AK, Gallegos KL, Shepherd G, Mosley SL, Roberts CA. Factors associated with how 
often community pharmacists offer and dispense naloxone. Research in Social and Administrative Pharmacy. 
2018. 

Page 17 of 19 
 
14. Cochran G, Field C, Lawson K, Erickson C. Pharmacists' knowledge, attitudes and beliefs regarding screening and 
brief intervention for prescription opioid abuse: a survey of Utah and Texas pharmacists. Journal of 
Pharmaceutical Health Services Research. 2013;4(2):71-79. 
15. Hagemeier NE, Murawski MM, Lopez NC, Alamian A, Pack RP. Theoretical exploration of Tennessee community 
pharmacists' perceptions regarding opioid pain reliever abuse communication. Research in Social and 
Administrative Pharmacy. 2014;10(3):562-575. 
16. Gamm L, Stone S, Pittman S. Mental health and mental disorders—A rural challenge: A literature review. Rural 
healthy people. 2010;1:97-114. 
17. Browne T, Priester MA, Clone S, Iachini A, DeHart D, Hock R. Barriers and Facilitators to Substance Use 
Treatment in the Rural South: A Qualitative Study. The Journal of Rural Health. 2016;32(1):92-101. 
18. Carpenter DM, Roberts CA, Westrick SC, et al. A content review of online naloxone Continuing Education courses 
for pharmacists in states with standing orders. Research in Social and Administrative Pharmacy. 
2018;14(10):968-978. 
19. United States Census Bureau, Percent Urban and Rural in 2010 by State and County. 
https://www.census.gov/programs-surveys/geography/guidance/geo-areas/urban-rural/2010-urban-rural.html.  
20. Centers for Disease Control and Prevention, Prescription Opioid Data. 
https://www.cdc.gov/drugoverdose/data/prescribing.html.  
21. Liekens S, Vandael E, Roter D, et al. Impact of training on pharmacists’ counseling of patients starting 
antidepressant therapy, Patient Educ. Couns 94 (1) (2014) 110–115.  
22. Alte D, Weitschies W, Ritter CA, Evaluation of consultation in community pharmacies with mystery shoppers, 
Ann. Pharmacother 41 (6) (2007) 1023–1030.  
23. Weiss MC, Booth A, Jones B, Ramjeet S, Wong E. Use of simulated patients to assess the clinical and 
communication skills of community pharmacists, Pharm. World Sci 32 (3) (2010) 353–361. 
24. Wind LA, Van Dalen J, Muijtjens AM, Rethans JJ. Assessing simulated patients in an educational setting: the 
MaSP (Maastricht assessment of simulated patients), Med. Educ 38 (1) (2004) 39–44.  
25. Cross WF, West JC, Crean HF, Rosenberg E, LaVigne T, Caine ED. Measurement of primary care providers’ suicide 
prevention skills following didactic education, Suicide Life Threat Behav (2022), 10.1111/sltb.12827. 
26. Nielsen S, Menon N, Larney S, Farrell M, Degenhardt L. Community pharmacist knowledge, attitudes and 
confidence regarding naloxone for overdose reversal, Addiction 111 (12) (2016) 2177–2186. 
27. Wilson JD, Spicyn N, Matson P, Alvanzo A, Feldman L. Internal medicine resident knowledge, attitudes, and 
barriers to naloxone prescription in hospital and clinic settings, Subst. Abus 37 (3) (2016) 480–487. 
28. Freeman PR, Goodin A, Troske S, Strahl A, Fallin A, Green TC. Pharmacists’ role in opioid overdose: Kentucky 
pharmacists’ willingness to participate in naloxone dispensing, Journal of the American Pharmacists Association 
57 (2) (2017) S28–S33. 
29. Mueller SR, Koester S, Glanz JM, Gardner EM, Binswanger IA. Attitudes toward naloxone prescribing in clinical 
settings: a qualitative study of patients prescribed high dose opioids for chronic non-cancer pain. J. Gen. Intern. 
Med 32 (3) (2017) 277–283. 
30. Strahan R, Gerbasi K, Short. Homogenous version of the Marlowe-Crowne social desirability scale. J. Clin. Psychol 
28 (191) (1972) 193. 
 
 

Page 18 of 19 
 
APPENDIX 
 
 
Figure 1: Study Design 
 
 
 
Table 1: Summary of the P2P and Nalox-Comm Modules 
Prescribe to Prevent 
Nalox-Comm 
Length 
55 minutes 
~30 minutes 
Format 
Online module with videos, 
didactic content, quizzes  
Online module with videos, didactic 
content, reflection 
Topics 
covered 
• 
Risk factors for overdose 
• 
How to respond to overdose 
• 
How naloxone works 
• 
Types of naloxone 
• 
How to administer naloxone 
• 
Medico-legal issues 
• 
How to stock, fill, and bill for 
naloxone 
• 
The importance of naloxone and 
the role of the pharmacist 
• 
Non-stigmatizing language 
• 
How to initiate an offer of naloxone 
• 
How to respond to patient & 
caregiver naloxone requests 
• 
How to address specific 
communication barriers 
 
 
 
 
 
 
 

Page 19 of 19 
 
Table 2: Study measures 
Variable 
Source 
# of 
items 
Baseline 
Immediate 
post- 
intervention 
Within 4 
weeks post- 
intervention 
3-month 
follow- 
up 
Primary Outcome 
Naloxone dispensing rate 
Pharmacy 
records 
- 
X 
 
 
X 
Secondary Outcomes 
Willingness to dispense naloxone 
Self-report 
survey 
7 
X 
X 
X 
Naloxone counseling self-efficacy 
Self-report 
survey 
7 
X 
X 
X 
Quality of naloxone counseling 
Direct 
observation 
6 
X 
X 
Other Measures 
Naloxone knowledge 
Self-report 
survey 
8 
X 
X 
X 
Attitudes toward dispensing 
naloxone 
Self-report 
survey 
8 
X 
X 
X 
Barriers to dispensing naloxone 
Self-report 
survey 
10 
X 
X 
X 
Previous naloxone training 
Self-report 
survey 
1 
X 
X 
Pharmacist characteristics 
Self-report 
survey 
7 
X 
Pharmacy characteristics 
Self-report 
survey 
3 
X 
Social desirability bias 
Self-report 
survey 
10 
X