Pain-related Anxiety Intervention for Smokers With Chronic Pain: A Comparative Effectiveness Trial of Smoking Cessation Counseling for Veterans
Phase: NA
Conditions: Smoking, Pain, Smoking Cessation
Sponsor: VA Office of Research and Development

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STUDY PROTOCOL: 
NCT02971137 
 
I. 
PRINCIPAL INVESTIGATOR:  
Principal Investigator: Lori Bastian, M.D., M.P.H. - VA Connecticut Healthcare System 
 
II. 
PROJECT TITLE 
Pain-related Anxiety Intervention for Smokers with Chronic Pain: A Comparative Effectiveness Trial of Smoking 
Cessation Counseling for Veterans 
 
III. 
Submission Date  
1/31/2022 
 
IV. 
Protocol 
Among Veteran smokers with chronic moderate to severe pain, a pain intensity ≥4 for 3 or more months, we 
are proposing a randomized comparative effectiveness trial to compare the effectiveness of a telephone-based 
smoking cessation intervention including CBI for pain to a standard telephone-based smoking cessation 
intervention. The goals of the study are: 1) Evaluate the impact of smoking cessation plus CBI (SMK-CBI) 
on cigarette abstinence rates among Veterans with chronic pain at 6 and 12-months compared to standard 
smoking cessation counseling (SMK-STD); 2) Evaluate the impact of SMK-CBI on pain intensity and pain 
interference among Veterans at 6- and12-months compared to SMK-STD; 3) Assess whether change in self-
efficacy and pain-related anxiety mediate the impact of SMK-CBI on smoking cessation in Veterans with pain 
at 6- and 12-months compared to SMK-STD. 
6. Research Plan:   
 
Study methods with proactive recruitment: Potentially eligible patients will be identified by administrative 
data pull of pain scores equal to or greater than 4 and current tobacco use.  We will oversample women 
Veterans to increase the diversity. Eligible patients will be sent the following components: Introductory letter: A 
letter from Dr. Bastian to introduce the study, make an appeal to the patient to quit smoking, and informs them 
that they will be called to complete a telephone survey unless they call a toll-free number to refuse 
participation; Informational Consent Document: A document providing all the information for informed consent 
into the study and will be sent along with introductory letter and that describes the study. 
 
Other recruitment methods: Recruitment will also occur via flyers posted in patient care areas, referrals by 
providers, and self-referrals from Clinicaltrials.gov at VACHS and VA Central Western Massachusetts 
Healthcare System (VACWM), and with the monthly pain recruitment table at West Haven and Newington. The 
anticipated goal for this VACHS study is to recruit 371 veterans, and VACWM will look to recruit 100 Veterans.  
 
Approximately seven days after the mailing, Veterans who have not opted out will receive a phone call from a 
research assistant (RA) to further assess inclusion criteria, obtain informed consent (if interested), and conduct 
the baseline survey. Eligible patients must be Veterans enrolled at VACHS or VACWM with current tobacco 
use, willingness to make a quit attempt in the next 30 days, significant pain defined as >4 on the pain intensity 
portion of the BPI, and report that their current pain has been present for 3 months or more. Veterans with any 
of the following will be excluded: active diagnosis of psychosis or dementia in their medical records, Non-
english speaking, refusal to provide informed consent, severely impaired hearing or speech, lack of telephone 
access, enrollment in another research study that might affect the main outcomes of this study, or terminal 
illness. Participants enrolled into PASS will have a research alert noted in their medical record. 
 
In this comparative effectiveness trial, both groups will receive 5 sessions of telephone counseling. Five 
counseling sessions will be completed over 10-12 weeks on an approximately bi-weekly schedule that will be 
tailored to the individual Veteran’s needs. Veterans will be mailed a reminder letter about their 6 month and 12 

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month follow-up surveys in order to improve retention. Both VA sites will utilize the same counselor for the 
telephone sessions. 
 
Data sharing plan: Electronic data will be stored on a VA protected SharePoint site or local network, both of 
which are secure systems that exists behind the VA firewall and access is granted by an administrator only to 
authorized users. A SharePoint website is established only for the purposes of this project and will serve as a 
repository for study documents, communication, and other important information to be shared between VA CT 
and VACWM. The site is private and can only be accessed by approved study personnel with permissions 
granted by the PI or Project Director. 
 
Smoking cessation counseling: Both groups will receive smoking telephone counseling and smoking 
cessation content delivered at parallel times. The protocol included in this application is based on standard 
techniques shown to be efficacious for smoking cessation and is informed by behavioral treatment principles,45 
Social Cognitive Theory,46 and Motivational Interviewing.47 The treatment protocol is consistent with the Public 
Health Service Clinical Practice Guide and was tailored to the Veteran population based on principles of 
evidence and consensus-based clinical practices.48  
 
Cognitive behavioral intervention: In the SMK-CBI arm, behavioral stress reduction pain management 
approaches will be integrated into the evidence-based smoking cessation counseling. The adjunctive cognitive 
behavioral intervention emphasizes psycho-educational and skills-based approaches and is informed by VHAs 
existing pain self-management program. Specifically, the CBI developed for the study includes a focus on 
increasing physical activity, identifying pleasurable activities, relaxation practices, and thought 
monitoring/restructuring. The CBI participant manual will also include PASS activity booklet. The main 
objective of the PASS activity booklet will be to provide Veterans with an opportunity to practice selected 
behavioral and cognitive skills of relevance for both smoking cessation and pain self-management. Participants 
in the SMK-CBI arm will be given pedometers. This group will be instructed to track and record their weekly 
steps in the PASS activity booklet, and will be asked to report their weekly steps to the PASS counselor during 
each of the 5 telephone counseling sessions.  
 
Counselor education: The PASS study counselor will be trained by a doctoral-level clinician on both SMK-
STD and SMK-CBI counseling sessions, will be provided with videos and readings on CBI, smoking-cessation, 
and pain, and will be audio-recorded using a mock patient. The PASS study counselor will be given the 
opportunity to ask questions about trainings, and will then be tested and rated by a doctoral-level clinician 
using the Fidelity Scale to establish proficiency. 
 
Standard of Care: 
At VA specialty-based smoking clinics, counseling sessions with NRT are standard care for assisting Veterans 
to quit smoking. At the first telephone counseling session, counselors will ask potential participants if they are 
interested in using NRT. Dr. Bastian will contact the patient’s PCP to facilitate a NRT prescription if the PCP 
agrees for those participants who are interested in using NRT.  
 
Table 1: Outline of Counseling Sessions 
Smoking Cessation  
Counseling SMK-STD 
Smoking Cessation Counseling plus Cognitive 
Behavioral Intervention SMK-CBI 
#1 
✓ Introduce counselor and study 
✓ Check in   
✓ Explore motivation to quit 
✓ Set quit date if appropriate 
✓ All components of SMK-STD Session 1 (to 
the left, less the quit date discussion), plus 
the following: 
✓ Introduce physical activity 
✓ Use pedometer to record weekly step 
count 
✓ Assign homework 

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#2 
✓ Check in  
✓ Check in on patient’s action plan on 
taking steps towards quitting  
✓ Discuss ways to manage cravings  
✓ All components of SMK-STD Session 2 (to 
the left), plus the following:  
✓ Pleasant activities  
✓ Set quit date  
✓ Record weekly step count 
✓ Assign homework 
#3 
✓ Check in  
✓ Check in on patient’s action plan on 
taking steps towards quitting  
✓ Discuss how to handle slips 
✓ All components of SMK-STD Session 3 (to 
the left), plus the following: 
✓ Introduce and practice progressive muscle 
relaxation  
✓ Record weekly step count 
✓ Assign homework 
#4 
✓ Check in  
✓ Check in on patient’s action plan on 
taking steps towards quitting  
✓ Discuss rewards 
✓ All components of SMK-STD Session 4 (to 
the left), plus the following: 
✓ Introduce Unhelpful Thoughts 
✓ Introduce Mini Practices  
✓ Record weekly step count 
✓ Assign homework 
#5 
✓ Check in  
✓ Check in on patient’s action plan on 
taking steps towards quitting  
✓ Develop a post-counseling action plan 
✓ All components of SMK-STD Session 5 
(to the left), plus the following: 
✓ Review skills learned in previous sessions 
✓ Record weekly step count 
 
V. 
Outcomes: 
Participants will be surveyed three times: enrollment, 6-months post-intervention and 12-months post-
intervention using VA RED Cap to collect these data. Baseline survey will assess demographics, smoking 
history, nicotine dependence, global self-efficacy to quit smoking, depression, pain intensity and other 
covariates related to pain and smoking, via telephone. Follow-up surveys will be administered at 6-months and 
12 months post-intervention. The follow-up surveys will assess smoking status, pain intensity, use of 
intervention materials (e.g., NRT, PASS activity booklet), and intervention acceptability (e.g., intervention 
appropriateness, suitability, effectiveness, and convenience). Participants will be compensated $25 per 
completed follow-up survey. We will abide by the patient’s preference since many patients may be reluctant to 
send their sensitive bank information or provide it over the phone for this telephone-based study. 
 
Saliva samples will be collected from participants who report not smoking in the last 7 days (7-day point 
prevalence) in order to biochemically validate their self-reported smoking status. This process has been shown 
to improve the validity of self-reported smoking cessation. Samples will be collected at next clinic visit following 
the telephone interview.49 Saliva samples will measure cotinine levels using NicAlert dipsticks with a standard 
cut point of 16 ng/ml to determine abstinence. Participants will receive $10 incentive for providing each saliva 
sample. 
 
Counseling session fidelity will be assessed using audio-taped recordings of sessions. We aim to record 
approximately 20% of sessions (all sessions in the first 3 months of the study and then one week every 2 
months for the remainder of the study). Investigators will rate 10% of the sessions to ensure protocol fidelity 
and lack of drift of information from the SMK-CBI to SMK-STD over time. 
 
Outcome 1: Prolonged abstinence: In keeping with the SNRT recommendations for measuring abstinence, we 
will use prolonged abstinence as our main outcome and allow for a grace period around quit date. During the 
6- and 12-month follow-ups, patients will be asked about prolonged abstinence, “In the past 6 months, have  

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you smoked at least a part of a cigarette on each of 7 consecutive days?” and “In the past 6 months, have you 
smoked any cigarettes in each of 2 consecutive weeks?”50 
 
Outcome 2: Point prevalent abstinence: At each follow-up (6-and 12-month), patients will be asked whether 
they have smoked a cigarette, even a puff, in the past 7 days and, if no, will be asked whether they have 
smoked a cigarette, even a puff, in the past 30 days.   
 
Outcome 3: Pain intensity (usual) and pain related functional interference: Participants will complete the BPI, 
which includes 2 multi-item scales measuring pain intensity and pain-related functional interference. Pain 
intensity in the past 24 hours is measured in 4 items—worst, least, current and usual-- each using a validated 
11-point numerical rating scale (0-10). A rating of 0 indicates no pain while 10 indicates the worst pain 
imaginable. A score of 4 or above is considered a clinically significant pain level according to VHA treatment 
guidelines.51 The functional interference subscale consists of 7 items measuring self-rated pain interference 
related to general activity, mood, walking ability, normal work (inside or outside the home), relations with other 
people, sleep and enjoyment of life. Respondents rate how much pain has interfered with these aspects of 
their lives in the past 24 hours on a 0 (does not interfere) to 10 (completely interferes) point scale. 
 
VI. 
Statstical Protocol: 
Data Summary. Descriptive statistics, including graphical displays, will be used to summarize all study 
variables, both overall and by intervention group. Evidence of imbalance in baseline characteristics will be 
noted and discussed as to whether they are clinically significant. As recommended by Committee for 
Proprietary Medicinal Products (CPMP) guidelines, we will consider sensitivity analyses adjusting for these 
baseline characteristics to ensure that an observed intervention effect is not due to this baseline imbalance. 
We will construct individual and mean trajectory plots of the longitudinal outcome variables (e.g., BPI) to 
understand their general trends over the study period. In addition, we will explore the variability and correlation 
structure of the longitudinal outcome variables. All statistical analyses will be performed using the SAS 
software package; the VACHS Center of Innovation maintains the current SAS release on our system. 
 
Intent-to-Treat Analysis. All primary and secondary analyses focus on the effect of SMK-CBI as compared to 
SMK-STD. We, therefore, plan to use the intent-to-treat assumption for all analyses; participants will be 
analyzed as part of the group to which they are randomized, regardless of intervention adherence. 
 
Analyses 
Hypothesis 1.1: Prolonged abstinence rates will be significantly higher among Veterans in the SMK-CBI group 
compared to those in the SMK-STD group. 
Hypothesis 1.2: The 7-day point prevalence abstinence rates will be significantly higher among Veterans in 
the SMK-CBI group compared to those in the SMK-STD group. 
 
Rates of cigarette abstinence (prolonged abstinence) will be assessed at 6- and 12-month follow-up. 
Abstinence will be measured as a dichotomous variable that indicates whether patients have been abstinent or 
not. The same analysis approach will be used to test both prolonged and 7-day point prevalence abstinence 
rates. Self-report of abstinence will be validated with cotinine saliva testing.  
 
We will use logistic regression to test for a between-group difference in abstinence rates at 6 months.  This 
logistic regression model can be written as: Logit(pi) = 0 + SMK-CBIi*1 , where pi represents the probability 
that patient i has abstained from smoking  at the 6-month follow-up. In this model, SMK-CBIi is the intervention 
group indicator; therefore, 1 represents the log-odds ratio of smoking abstinence in the SMK-CBI group as 
compared to the SMK-STD group. For each of the abstinence outcomes, we will formally evaluate the 
intervention effect by testing that 1 differs from zero and report the odds ratio (exp(1)) and 95% CI of the 
odds ratio. An odds ratio significantly greater than 1.0 provides evidence that SMK-CBI group patients have 
higher prolonged abstinence rates. The model will also include stratification variables (gender) as 
recommended in the CPMP guidelines.  
  

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Sustainability, or longer term effects of the intervention, will be examined by comparing abstinence rates 
between groups at 12 months. We will model change in abstinence rates at baseline, 6, and 12 months using 
generalized linear models with a logit link fit with generalized estimating equations. The regression coefficients 
from this model have essentially the same interpretation as those from a cross-sectional regression analysis 
(e.g. logistic regression) but are more appropriate as they properly incorporate the within-subject correlation 
that is inherent in the longitudinal structure of the data. The model will be fit using the SAS procedure 
GENMOD (SAS Institute, Cary, NC).  
 
Hypothesis 2.1: Veterans in the SMK-CBI will report significantly lower usual pain intensity and pain 
interference compared to the SMK-STD group. 
 
We will use linear mixed effects models procedure for analyzing repeated measures data with fixed and 
random effects to evaluate study group assignment effects on our continuous and repeated outcomes (pain 
intensity and pain interference). The Mixed Models procedure is designed for unbalanced repeated measures 
with missing data, allowing for intra-participant serial correlation and unequal variance and covariance 
structure across time.  It provides tests of the overall between-participant effects, repeated measures (time) 
effects, tests of fixed and random effects, and analysis of reduced models that can provide detailed tests of 
specific pattern of results. A repeated measures analysis of variance in the Mixed Models procedure takes into 
consideration differences that may emerge over time; we will use this procedure to test for a significant effect 
of the two treatments on the primary outcome measure, time, and the interactions between time and each of 
the two treatments. Random effects will also be included to account for intra-participant correlation of repeated 
measures. Additionally, the model will include the stratification variables. We plan to estimate the parameters 
in the model using the SAS procedure MIXED (SAS Version 9.2, Cary, NC).  
 
Hypothesis 3.1: The relationship between pain-related anxiety intervention and smoking cessation will be 
mediated by self-efficacy and pain-related anxiety. 
 
If there is a significant intervention effect on smoking cessation (i.e., if 1 is significantly different from zero in 
the first model above in Hypothesis 1.1), then we also plan to examine whether change in self-efficacy and 
pain-related anxiety mediate the impact of the intervention. This aim can be addressed under the general 
framework of mediation. We propose to conduct this mediation analysis using the MacArthur approach, a 
modification of the traditional Baron & Kenny criteria, developed for use specifically in randomized clinical 
trials.90,91 By the MacArthur definition, the potential mediator must be evident during or post-treatment; 
therefore, for example, the change in patient self-efficacy measures between baseline and 6-months will be 
considered as potential mediators. The outcome will be patients’ abstinence at 12-months. We will first fit a 
model to examine the correlation between the mediator (C) and the SMK-CBI group: C = 0 + 1*SMK-CBI. We 
also fit a model that examines the relationship between the mediator and the probability of abstinence (p): 
logit(p) = 0 + SMK-CBI*1 + C*2 + C*SMK-CBI*3. Improvements in patient self-efficacy or pain-related 
anxiety will be considered to account for improvements in abstinence rates if there is evidence that 1 is not 
equal to zero, and if either 2 or 3 are not equal to zero. 
 
E.12.4. Missing Data. Because the main predictors of interest are collected at baseline, we do not anticipate 
much missing data in these variables. We do, however, anticipate missing values in the longitudinal outcomes 
owing to dropout, death, an inability to reach the patient by phone, or item non-response. If the missing values 
are related to other measured patient factors, such as age, gender, or employment status, then multiple 
imputation (MI) provides a framework for incorporating information from these auxiliary variables while still 
preserving a parsimonious main treatment effect mode: this framework is described as a significant advantage 
in recommendations from the Panel on Handling Missing Data in Clinical Trials. We will follow multiple 
imputation methods presented in Hedeker et al for missing abstinence outcomes. Depending on the type and 
scope of missing data for other longitudinal variables, MI will be conducted via the SAS procedure PROC MI or 
the SAS macro IVEware (http://www.isr.umich.edu/src/smp/ive/).