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. Author manuscript; available in PMC: 2025 May 1.
Published in final edited form as: J Subst Use Addict Treat. 2024 Jan 24;160:209296. doi: 10.1016/j.josat.2024.209296

Cognitive Behavioral Therapy for Anxiety and Opioid Use Disorder: Development and Pilot Testing

R Kathryn McHugh 1,2, Garrett M Fitzmaurice 1,2, Victoria R Votaw 1,2, Rachel B Geyer 1,2, Kael Ragnini 1,2, Shelly F Greenfield 1,2, Roger D Weiss 1,2
PMCID: PMC11060910  NIHMSID: NIHMS1962277  PMID: 38272120

Abstract

Introduction:

Anxiety disorders are highly prevalent among people with opioid use disorder (OUD), and they have a negative impact on disorder course and treatment outcomes. The objective of this Stage 1A/1B behavioral treatment development trial was to develop a novel cognitive-behavioral therapy (CBT) protocol for co-occurring anxiety disorders and OUD.

Methods:

Following a period of iterative manual development involving patient interviews and feedback from content experts, we tested a 12-session individual CBT protocol in a small, open pilot trial (N=5). This was followed by a small, randomized controlled trial (N=32), comparing the new protocol to 12 sessions of manualized Individual Drug Counseling. All participants also received medication for OUD.

Results:

Overall, support for feasibility and acceptability was strong, based on recruitment and retention rates and patient satisfaction ratings. Within-subjects results identified 11-point reductions in anxiety symptom severity (on a 0–56 point scale); these gains were sustained through 3 months of follow-up. However, these changes did not differ between randomized conditions. With respect to opioid outcomes, 85% of participants were abstinent in the prior month at the end of treatment. Opioid use outcomes also did not differ by treatment condition.

Conclusions:

These results support the feasibility and acceptability of a CBT protocol for co-occurring anxiety and OUD. However, in this small pilot trial results do not show an initial benefit over an evidence-based psychosocial treatment targeted to OUD alone, in combination with medication for OUD.

Keywords: anxiety disorder, opioid use disorder, cognitive-behavioral therapy, individual drug counseling

1. Introduction

Among people with opioid use disorder (OUD), co-occurring mental health conditions are associated with worse treatment outcome (McHugh, Hilton, et al., 2021; Zhu et al., 2021) and increased risk for discontinuation of medication (Litz & Leslie, 2017). Anxiety disorders are among the most common co-occurring diagnoses with OUD (Conway et al., 2006; Gros et al., 2013; Lister et al., 2022). In people with OUD, anxiety and anxiety-related vulnerabilities are associated with higher rates of suicidal ideation, greater severity of OUD, and fear of opioid withdrawal (Archambault et al., 2022; Stathopoulou et al., 2021). Furthermore, anxiety is associated with the misuse of benzodiazepines, which is a risk factor for overdose in people with OUD (McHugh, Votaw, Bogunovic, et al., 2017). Treatment with medication for OUD (MOUD), such as buprenorphine and extended-release injectable naltrexone, alone appears to confer only modest improvements on anxiety symptoms (Latif et al., 2019). Accordingly, there is a need for novel treatments for anxiety in people with OUD.

Behavioral therapies may be particularly well-suited for addressing anxiety disorders in people with OUD for several reasons. First, numerous meta-analytic reviews demonstrate that behavioral therapies are effective for the treatment of anxiety disorders (Carpenter et al., 2018; Cuijpers et al., 2014; Hofmann & Smits, 2008; Papola et al., 2022). Second, behavioral therapies can target shared and interactive mechanisms that maintain both disorders. For example, maladaptive responses to distress—characterized by avoidance or escape behaviors—are factors implicated in the development and maintenance of both anxiety and OUD and can be modified in a behavioral treatment (Leyro et al., 2010; McHugh, Taghian, et al., 2021). Third, although medication for anxiety may be indicated for some people with OUD, certain medications (e.g., benzodiazepines) come with additional risks in this population (e.g., overdose) and thus require careful safety consideration (DuPont, 2017; Park, 2017). Furthermore, although behavioral therapies targeting OUD have not shown reliable benefits when added to buprenorphine for opioid outcomes (Carroll & Weiss, 2017), there is evidence that the addition of behavioral therapy may offer benefits to people with co-occurring psychiatric disorders (McHugh, Hilton, et al., 2021).

Consistent with the Stage Model of Behavioral Therapy Development (Rounsaville et al., 2001), the objective of this Stage 1A/1B trial was to develop a cognitive-behavioral treatment for people with co-occurring OUD and anxiety disorders and to conduct preliminary tests of feasibility, acceptability, and efficacy. The trial consisted of three phases: manual development, a pilot open trial, and a small, pilot randomized controlled trial (RCT) of CBT compared to an existing evidence-based treatment for OUD, Individual Drug Counseling (IDC). In a prior report, we described the treatment development process (McHugh, Votaw, Barlow, et al., 2017). This paper will focus on feasibility, acceptability, and clinical outcomes from the open trial and the RCT.

As MOUD is the standard of care for opioid use disorder (Committee on Medication-Assisted Treatment for Opioid Use Disorder, 2019), the study tested the addition of behavioral therapy to ongoing MOUD. Co-primary outcomes were interviewer-rated anxiety symptoms and urine-confirmed self-report of opioid use. We hypothesized that those who received CBT would demonstrate (a) greater reductions in interviewer-rated anxiety symptom severity, and (b) fewer opioid-positive weeks compared to those who received IDC.

2. Materials and Methods

This trial was registered on clinicaltrials.gov (NCT02252068) and was funded by the National Institute on Drug Abuse. The local Institutional Review Board approved study procedures. A previously published overview of the study methods provides additional detail on study rationale and design choice points (McHugh, Votaw, Barlow, et al., 2017).

2.1. Participants

We enrolled a total of 42 participants in the open pilot and RCT, both of which we conducted in an outpatient setting at an academically affiliated psychiatric hospital. In the open pilot, 5 participants enrolled and initiated treatment. In the RCT, 37 participants enrolled and 6 discontinued prior to randomization and treatment initiation. Detailed demographic and clinical characteristics are in Table 1.

Table 1.

Demographics and Baseline Opioid Use Characteristics

Mean (SD) or %
Pilot (n=5) RCT (n=26)
CBT (n=13) IDC (n=13)
Age, years 31.8 (8.2) 31.8 (7.4) 33.9 (12.2)
Sex (% female) 20.0% 30.8% 23.1%
Race (% White) 100.0% 100% 100%
Ethnicity (% Hispanic/Latino) 0.0% 7.7% 0%
Education
High school or equivalent 0.0% 15.4% 30.8%
Some college 40.0% 30.8% 46.2%
Associate’s degree 0.0% 7.7% 0%
Bachelor’s degree 60.0% 30.8% 23.1%
Graduate degree 0.0% 15.4% 0%
Marital status
Married 20.0% 23.1% 23.1%
Never married 80.0% 61.5% 69.2%
Living with a partner 0.0% 15.4% 7.7%
Employment
Unemployed 60.0% 53.8% 15.4%
Temporarily laid off/on leave 0.0% 0% 15.4%
Part time 20.0% 7.7% 0%
Disabled 0.0% 7.7% 0%
Student 0.0% 0% 7.7%
Full time 20.0% 30.8% 61.5%
Primary opioid problem
Opioid analgesic misuse 20.0% 38.5% 16.7%
Heroin 20.0% 53.8% 58.3%
Both 60.0% 7.7% 25.0%
Anxiety Disorder Diagnoses
Panic Disorder 20% 7.7% 0%
Social Anxiety Disorder 80% 84.6% 69.2%
Generalized Anxiety Disorder 100% 76.9% 92.3%
Specific Phobia 40% 7.7% 7.7%
Met Criteria for >1 Anxiety Disorder 80% 76.9% 61.5%
Other Psychiatric and Substance Use Diagnoses
PTSD/Acute Stress Disorder 0% 30.8% 7.7%
Obsessive-compulsive Disorder 20% 23.1% 7.7%
Other Specific Obsessive-compulsive or related
disorder 0% 0% 7.7%
Major Depressive Disorder 60% 61.5% 61.5%
Persistent Depressive Disorder 20% 15.4% 15.4%
Bipolar disorder/cyclothymia 20% 0% 7.7%
Substance-induced mood disorder 0% 7.7% 7.7%
Other Specified Depressive Disorder 0% 7.7% 0%
Alcohol Use Disorder 20% 7.7% 46.2%
Cannabis Use Disorder 0% 15.4% 15.4%
Cocaine Use Disorder 0% 7.7% 15.4%
Stimulant Use disorder 20% 7.7% 0%
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We recruited participants for a study of treatment of opioid use disorder and anxiety from local treatment settings (primarily through the continuum of outpatient through inpatient care at an academically affiliated psychiatric hospital) through clinician referral or self-referral between 2015 and 2019. Members of the study staff provided clinicians with flyers as well as presentations. Staff also presented information on the study prior to the start of group therapy to facilitate self-referral. Most participants who were screened were either directly referred by a clinical provider or informed about the study from a provider (130 of the 144 screened).

Adults aged 18 years and older with current Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association, 2013) diagnosis of OUD and at least one DSM-5 anxiety disorder were eligible for the trial. Additional inclusion criteria included a current prescription for MOUD (either opioid agonist/partial agonist or antagonist medications), use of opioids in the previous 90 days, a score above the clinical cut-off of 14 on the Hamilton Anxiety Rating Scale (Hamilton, 1959; Shear et al., 2001), intention to remain in the geographical area for the duration of the study, and ability to read English and to provide informed consent. We excluded participants if they had a current psychiatric or medical condition that would preclude the ability to participate (e.g., acute psychosis), required inpatient care for a substance use or psychiatric disorder, were currently receiving cognitive-behavioral therapy (CBT), had initiated a new psychiatric medication or changed dose of a medication in the previous 4 weeks, had a current as-needed (i.e., PRN) benzodiazepine prescription, or were currently receiving treatment on a non-voluntary basis.

In the open pilot study, most (80%) participants had used heroin in their lifetime, and all had misused opioid analgesics. In addition, 3 of the 5 participants reported a lifetime history of injecting heroin and 2 of the 5 reported lifetime opioid analgesic injection. The most common primary anxiety disorder diagnoses were social anxiety disorder (n = 2) and generalized anxiety disorder (n = 2), followed by panic disorder (n = 1).

In the RCT, most participants had misused prescription opioids in their lifetime (92%), and 77% had used heroin. A lifetime history of injection heroin use was common (62% of the sample) and 27% of the sample reported lifetime history of injection of opioid analgesics. The most common primary anxiety disorder was generalized anxiety disorder (69%), followed by social anxiety disorder (42%); of note, some participants were assigned co-primary anxiety disorder diagnoses. Mean days of prescription opioid use in the 30 days prior to enrollment was 8.7 (SD = 12.1) and mean days of heroin use was 13.7 (SD = 12.2). The mean age of onset of opioid analgesic misuse was 20.8 years (SD = 6.1) and age of onset of heroin use was 23.7 years (SD = 5.2). The average duration of use was 3.3 years (SD = 5.5) for heroin and 4.4 year (SD = 3.8) for opioid analgesics. Prior treatment episodes were common, with 36% of the sample reporting prior treatment for alcohol problems and 100% reporting prior treatment for drug problems (mean number of drug treatment episodes 3.9, SD = 4.5).

2.2. Design Overview

All participants first completed a baseline assessment and then study staff assigned them to a study therapist. In the RCT, randomization occurred after the baseline assessment session and was stratified by MOUD type (agonist/partial agonist vs. antagonist) and lifetime presence of heroin use. We selected these strata because of their established association with outcomes in other OUD trials (Dreifuss et al., 2013; Lee et al., 2018). Outcome assessors were blind to study condition throughout the trial. We collected self-report assessments using an electronic data capture method (REDCap; Harris et al., 2009). Study staff collected interviewer-administered measures suing paper forms, which they later entered into REDCap to allow for monitoring of data quality and export to data analysis software.

Participants received 12 sessions of treatment within 14 weeks to allow for some flexibility with respect to missed sessions (e.g., holidays). Participants then completed a post-treatment assessment at the end of treatment (after week 12), as well as 1-month and 3-month post-treatment follow-ups. In addition, participants provided a urine drug screen and self-reported past-week substance use and anxiety symptoms at each weekly session.

Participants received compensation for their time and effort completing each major assessment and received study treatments free of charge (participants did not receive compensation for their time in treatment sessions). Payment included $45 for the baseline assessment, $70 for the end-of-treatment assessment, $40 for the 1-month follow-up and $50 for the 3-month follow-up.

2.3. Study Treatments

The Integrated CBT for Anxiety and Opioid Use Disorder protocol (CBT) is a 12-session, manualized cognitive-behavioral therapy designed to modify behavioral and cognitive processes posited to maintain symptoms of anxiety and OUD. Content for the manual integrated evidence-based principles for the behavioral treatment of substance use disorders (Carroll, 1998) and anxiety disorders (Barlow et al., 2011; Otto & Pollack, 2009).

Sessions were 45–60 minutes in length and consisted of review of the prior session, the session topic and exercises, and assignment of homework. In addition to an initial psychoeducational session and a final relapse-prevention session, the treatment consisted of practice in 5 skills (e.g., responding to triggers, modifying maladaptive cognitions) and 5 sessions of fear exposure and skills practice. The fear exposure and skills practice sessions focused on conducting an in-session fear exposure, with the application of a treatment skill from the first half of the treatment. For example, an in-session exposure to anxiety about assertiveness may be combined with the use of refusal skills. The details of manual development have been reported previously (McHugh, Votaw, Barlow, et al., 2017).

The first author administered Protocol Version 1.1 to 5 participants in the open pilot trial. Following this trial, the study made further modifications and consultants reviewed the subsequent version (Version 1.2) administered in the RCT. Experiences in this pilot trial informed revisions between CBT manual versions 1.1 and 1.2. First, we reduced the content of some sessions due to difficulty covering all concepts in 45–60 minutes. Removal of content focused on reducing the number of exercises or examples, rather than removing any topics. Additionally, we re-ordered sessions to introduce two foundational skills earlier (identifying and responding to triggers and cognitive interventions) than in Version 1.1 due to their relevance to later, more complex skills (e.g., interpersonal skills). Finally, consistent with the Stage Model, we expanded the manual to include more detail and guidance on the application of each session to facilitate the training of new clinicians.

Individual Drug Counseling (IDC) (Mercer & Woody, 1999) is a structured drug counseling treatment that has been extensively tested in the treatment of substance use disorders, including OUD (Fiellin et al., 2006; Woody et al., 1977). IDC focuses on recovery from addiction with an emphasis on the role of mutual help treatments (e.g., Narcotics Anonymous, SMART Recovery) and the identification and implementation of concrete behavioral changes to facilitate recovery. Example content topics include identification of triggers for craving and/or drug use, structuring time, managing social pressures to use, and managing relationships in recovery. In other studies, IDC has demonstrated similar efficacy for substance use outcomes to CBT-based treatments (McGovern et al., 2011; Otto et al., 2014). Consistent with prior studies comparing IDC to CBT-based treatments (Crits-Christoph et al., 1999), we matched sessions in duration and quantity to CBT (12, 45–60-minute sessions).

2.4. Treatment Fidelity Monitoring

Six providers with a master’s or doctoral degree administered the study treatments. All providers received training in both study treatments, and assignment to treatment was roughly equivalent between conditions within each therapist (i.e., therapists administered both treatments) to attempt to mitigate provider effects. The first author of the study provided the treatment for all participants in the open pilot study and for some participants in the RCT and trained and supervised all other therapists, which included an initial didactic training and weekly supervision.

Study therapists audiotaped all sessions for fidelity monitoring. One RCT participant declined audiotaping consent. We developed a fidelity monitoring measure for the CBT protocol for the purpose of this study using the Yale Competence and Adherence Scale Guidelines (Carroll et al., 2000). We rated IDC sessions using the rating scale accompanying the IDC manual, following published guidance (Carroll et al., 2000). Both fidelity monitoring scales assessed separately for competence (i.e., skillfulness of the therapist in administering the intervention component) and adherence (i.e., the frequency and extensiveness with which the intervention component was administered). In this Stage 1A/1B treatment development study, the study first piloted the CBT fidelity scale in the open trial for ease of use. Following this pilot, we made minor wording modifications for clarity and added one item to assess the degree to which the therapist administered the content in a patient-centered manner (e.g., using the patient’s own examples, ensuring patient comprehension of content). The range of scores on each item was 1 to 7, with a rating of 4 reflecting adequate competence/adherence, and higher scores reflecting stronger competence/adherence. We then averaged scores for competence and adherence, separately. For this preliminary Stage 1A/1B treatment development trial, the first author completed all fidelity ratings.

2.5. Measures

Participants self-reported demographic and historical clinical variables. The first author made psychiatric diagnoses using the Anxiety Disorders Interview Schedule for DSM-5 (Brown & Barlow, 2014) at the baseline assessment.

2.5.1. Feasibility, Acceptability, and Satisfaction

The 8-item Client Satisfaction Questionnaire (CSQ) (Larsen et al., 1979) assessed participant satisfaction with the treatment. The CSQ is an 8-item self-report measure of patient satisfaction with treatment services. Possible scores range from 8 to 32, with higher scores reflecting greater treatment satisfaction.

The Credibility/Expectancy Questionnaire (CEQ) (Borkovec & Nau, 1972) is a 6-item measure of the credibility of a therapy (how logical or believable it is) and expectancy of its effects. This was a secondary index of acceptability. The CEQ has demonstrated strong psychometric properties and a 2-factor structure, corresponding to credibility and expectancy subscales (Devilly & Borkovec, 2000). We split one item in this questionnaire into two separate questions to assess credibility for improvement in anxiety symptoms and for substance use symptoms, separately (“At this point, how successful do you think this treatment will be in reducing your [anxiety or drug use]?”). Consistent with a prior study (Thompson-Hollands et al., 2014), we averaged the items of the credibility scale and used a single item for expectancy (“By the end of the therapy period, how much improvement do you think will occur?”). We administered this measure at sessions 3 and 7. The range of possible scores was 1–9 for credibility and 0–100% for expectancy, with higher scores reflecting greater perceived credibility and more positive expectancy, respectively.

2.5.2. Clinical Outcomes

For this trial of treatment for co-occurring disorders, we used co-primary outcomes of anxiety symptom severity and a count of weeks of opioid use in the previous 4 weeks. The Hamilton Anxiety Rating Scale (HARS)measured Past-week severity of anxiety symptoms at each assessment (Hamilton, 1959). We utilized the Structured Intervention Guide for the HARS, which provides additional standardization by including anchor points (a description of the severity and functional impact of each symptom) for each possible item (Shear et al., 2001). Following structured training with the first author, bachelor’s-level independent raters, who were blind to treatment condition (in the RCT) administered the HARS. Scores ranged from 0 to 56, with higher scores representing more severe anxiety symptoms.

Urine-confirmed self-report assessed the number of weeks of opioid use (Donovan et al., 2012). A week was coded as positive for opioid use if the participant either self-reported opioid use or provided a urine drug screen positive for a non-prescribed opioid. Urine drug screens assessed the following substances: amphetamine, cocaine, marijuana, methamphetamine, opioid, phencyclidine, benzodiazepines, barbiturates, oxycodone, propoxyphene, methadone, and buprenorphine. The Timeline Follow-back Method assessed self-report of opioid use(Sobell & Sobell, 1996) at each weekly treatment session and each major assessment point. Of note, participants reported at each week whether they had a current prescription for opioids to ensure as-prescribed use was not being captured. No participants reported a current opioid analgesic prescription during the study. This method has been extensively validated for the assessment of substance use behaviors in clinical trials (Donovan et al., 2012).

2.6. Data Analysis

We first screened data for skewness and univariate outliers and to determine whether transformations were necessary; no transformations were required. To characterize feasibility and acceptability (Aim 1) we focused on three indicators: retention (defined as both % of sessions attended and treatment discontinuation rate), treatment satisfaction (Client Satisfaction Questionnaire total score and % of participants scoring above “ambivalent” on average), and presence of adverse events related to study participation. Due to the typical treatment response rate and course of OUD (i.e., a 50% relapse rate among people on MOUD; Lee et al., 2018; Weiss et al., 2011), we expected adverse events related to relapse and increased level of care. We used descriptive statistics to characterize these outcomes. We report statistical comparisons of conditions (using independent-samples t-tests chi-square tests), with the caveat that such tests would only be powered to detect large effects.

To characterize clinical improvement (Aim 2) we first used descriptive statistics to characterize changes in the open pilot. Intent-to-treat analyses were used for all clinical outcomes, with all open pilot participants and all randomized participants in the RCT included in outcomes analyses. We conducted two separate longitudinal analyses, using generalized estimating equations (GEE), for the co-primary outcomes, anxiety symptom severity, and weeks of opioid use in the past month. Due to a significant skew in the opioid use variable, we used an ordinal proportional odds model; we used a linear model anxiety symptom severity. Both models controlled for the two stratification factors (lifetime heroin use, type of MOUD at the time of randomization) as well as age and gender, which were identified a priori as covariates of interest; the model for anxiety symptom severity also controlled for the baseline assessment of the outcome. The dependent variables for the anxiety analysis were the changes in anxiety symptom severity from baseline to post-treatment (week 12), 1-month and 3-month follow-up. In this model, the treatment condition effect is the treatment group difference in the adjusted mean change from baseline to post-treatment. We mean centered all covariates; the estimated intercept can be interpreted as the adjusted mean change from baseline to post-treatment in the reference group. Models included an effect of treatment, (post-baseline) time and treatment by time interactions. All models appropriately accounted for the correlation among repeated measurements within subjects through the use of robust or so-called “sandwich-based” standard errors.

3. Results

Five participants enrolled in the open pilot, and 32 participants enrolled in the RCT, 6 of whom discontinued participation prior to randomization (i.e., did not attend the scheduled first appointment and were unable to be recontacted). The CONSORT diagram is in Figure 1. Among 31 participants enrolled across the open pilot and the RCT, 18 people received at least one session of CBT, and 13 received at least one session of IDC.

Figure 1.

Figure 1.

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CONSORT Flow Diagram

3.1. Open Trial

Of the 5 participants enrolled, 2 discontinued treatment early; the other 3 completed at least 11 of 12 sessions. Satisfaction was very high, with a mean CSQ score of 30.5 (SD = 0.6; n = 4) out of a maximum possible score of 32 at mid-treatment, and 32 (SD = 0; n = 3) at week 12. All 5 participants reported that they expected at least a 50% improvement in symptoms at week 3, and credibility (range of scale = 1–9) was rated highly at both week 3 (mean = 7.7, SD = 0.4, n=5) and week 7 (mean = 6.4, SD = 2.4, n = 2).

The 2 participants who discontinued treatment early were lost to follow-up and thus clinical outcomes data are only available for 3 participants. For the 3 participants with complete data, HARS scores improved substantially from baseline (mean = 30.0, SD = 4.0) to post-treatment (mean = 9.3, SD = 1.8), with a small average increase at 3 month-follow-up (mean = 12.7, SD = 2.0). This reflects, on average, reductions from severe anxiety to mild anxiety (Matza et al., 2010).

With respect to opioid outcomes, based on urine-confirmed self-report of weeks of opioid use, 2 of the 3 participants with complete data were abstinent from opioids in the last 4 weeks of treatment, and one participant used opioids in 3 of the last 4 weeks. At 3-month follow-up, 2 of 3 participants were abstinent and 1 participant reported 1 week of opioid use in the prior 4 weeks (the same participant who reported opioid use at post-treatment).

3.2. Randomized Trial

3.2.1. Treatment Fidelity

Of the 252 total sessions conducted in the RCT, 248 had an available tape and the first author reviewed 50 for fidelity, divided evenly between IDC and CBT. This included 20% of sessions for each study clinician. We used a random number generator to chose study for review (within clinician and study condition).

Fidelity for CBT sessions was adequate and similar to prior trials of CBT for SUDs (Kiluk et al., 2018). Mean ratings of adherence for each category of intervention (e.g., symptom assessment, session topic, and skills practice) ranged from 3.2 to 4.15 (scale of 1–7, with 4 reflecting adequate adherence). Mean competence ranged from 3.95 to 4.51 (scale of 1–7, with 4 reflecting adequate competence). All IDC intervention categories also evidenced adequate adherence and competence; all individual components had a frequency higher than 3.5, with the exception of the “miscellaneous” category (which includes optional intervention components, such as addressing anger and discussing family issues) and all components had quality exceeding 4.5, on average.

3.2.2. Feasibility, Acceptability and Satisfaction

For participants receiving CBT, the average number of sessions attended was 8.7 (SD = 4.1), with 54% of participants completing more than 10 of the 12 sessions and 38.5% (5 out of 13) ending treatment early. Of those who discontinued early, 2 discontinued prior to the start of exposure sessions and 3 after exposures started (sessions 6, 8, and 9, respectively). In IDC, the average number of sessions attended was 11 (SD = 1.7), with 77% of participants completing more than 10 of the 12 possible sessions. The number of sessions attended was not significantly different between conditions (t[24] = 0.81, p = .42).

Client satisfaction was very strong for those in the CBT condition at both the week 6 (mean CSQ = 27.9 out of a maximum possible score of 32, SD = 3.2, n = 11) and week 12 (mean CSQ = 27.1, SD = 4.6, n = 12) session in treatment. These scores were similar to participants completing IDC (week 6 mean CSQ = 27.7, SD = 7.8, n = 12; week 12 mean CSQ = 29.4, SD = 3.4, n = 10), with no significant differences at either week (ps > .20).

Participants completed ratings or credibility and expectancy at weeks 3 and 6. In the CBT condition, mean credibility scores were 7.3 out of a maximum possible score of 9 (SD = 1.2) at week 3 and 7.5 (SD = 1.0) at week 7. Expectancy for improvement was also strong, with 9 of 10 participants reporting at least a 50% expected symptom improvement at session 3, and 9 of 11 reporting at least 50% expected improvement at week 7.

Likewise, in the IDC condition, participants reported mean credibility scores of 6.8 (SD = 1.2) at week 3 and 7.6 (SD = 1.1) at week 7. In the IDC condition, 7 of 11 participants reported an expectation of at least a 50% symptom improvement at session 3, and 10 of 11 reported at least 50% expected improvement at session 7. There were no significant differences in credibility or expectancy between conditions at either time point (ps > .13).

3.2.3. Clinical Outcomes

There were 12 adverse events in the trial, we deemed 11 of these to be expected (due to the typical course of OUD) and unrelated to study participation. This included 10 increases in level of care (inpatient detoxification/stabilization or partial hospitalization) due to return to or escalation of substance use and 2 increases of level of care due to psychiatric symptoms. In addition, there was one opioid overdose fatality in the study; this was deemed unrelated to study participation. One adverse event occurred in someone enrolled, but not yet randomized; 23% of participants who received IDC had at least one adverse event and 38% of participants who received CBT had at least one adverse event. This difference was not statistically significant (χ2= 1.51, p =.22).

Consistent with these data on increased level of care, changes in other treatments were common. In the first 6 weeks of the trial, most participants had at least one change in treatment, including new medications (25%) or other treatments (42%) as well as discontinued medication (42%) or other treatment (25%). Between week 6 and the end of treatment, 27% of participants started a new medication, 27% discontinued a medication, 35% started a new treatment, and 19% discontinued treatment.

Figure 2 depicts independent evaluator-rated mean anxiety scores over time by treatment condition. As evident in this figure, symptoms improved significantly in both groups, with an adjusted change from baseline (based on the longitudinal models) of almost 12 points in both treatment conditions. There was no effect of randomized condition (Wald Chi-Square =.09) or evidence for a treatment by time interaction at any follow-up time point (Wald Chi-Square =.06). The linear model for the longitudinal analysis indicated that improvements in anxiety were mostly sustained at both 1-month follow-up and 3-month follow-up. Full model results are in Table 2.

Figure 2.

Figure 2.

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Independent Evaluator-Rated Anxiety Change in Mean Over Time (note full range of scale is 0–56; scores >23 are severe). IDC = Individual Drug Counseling, CBT = Cognitive-Behavioral Therapy

Table 2.

Longitudinal Linear Regression Model Examining Change in Anxiety Over Time

Variable B SEB 95% CI Upper 95% CI Lower p
− 1.89 −15.41 −7.98 0.00
Intercept 11.69
Time (3-MFU vs. post-treatment) 3.09 1.93 −0.70 6.87 0.11
Time (1-MFU vs. post-treatment) 2.03 1.99 −1.88 5.93 0.31
Treatment (reference = IDC) −0.20 2.90 −5.88 5.48 0.95
Baseline HARS (centered) −0.43 0.14 −0.71 −0.15 0.00
Age (centered) −0.13 0.12 −0.36 0.10 0.27
MOUD type (centered; reference = buprenorphine) −5.06 2.21 −9.40 −0.73 0.02
Lifetime heroin (centered; reference = no) −6.58 3.10 −12.65 −0.52 0.03
Gender (centered; reference = male) −0.28 2.87 −5.90 5.33 0.92
Treatment by 3-MFU Interaction −0.80 3.46 −7.58 5.97 0.82
Treatment by 1-MFU Interaction −0.71 3.29 −7.16 5.74 0.83
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Note. MFU = month follow-up; IDC = Individual Drug Counseling; HARS = Hamilton Anxiety Rating Scale; MOUD = medication for opioid use disorder

Opioid use was low among those with available data, with 85% of participants reporting no opioid use in the prior month at post-treatment (n = 26; 85% of IDC participants; 85% of CBT), 80% reporting no use at 1-month follow-up (n = 20; 82% in IDC; 78% in CBT), and 67% reporting no use at 3-month follow-up (n = 18; 75% in IDC; 60% in CBT). There was again no effect of treatment condition (Wald Chi-Square = 0.16) or treatment by time interactions (Wald Chi-Square = 1.24). Full model results are presented in Table 3.

Table 3.

Longitudinal Ordinal Proportional Odds Model for Opioid Use Outcomes

Variable B SEB 95% CI Upper 95% CI Lower p
Time (3-MFU vs. post-treatment) .12 .48 −.83 1.06 .81
Time (1-MFU vs. post-treatment) .08 .20 −.32 .48 .70
Treatment (reference = IDC) .08 1.10 −2.07 2.24 .94
Age .04 .05 −.06 .13 .46
Gender (reference = male) .12 .92 −1.68 1.92 .90
Lifetime heroin (reference = no) .36 1.08 −1.76 2.48 .74
MOUD type (reference = buprenorphine) −.42 .95 −2.27 1.44 .66
Treatment by 3-MFU Interaction .84 1.16 −1.43 3.10 .47
Treatment by 1-MFU Interaction .00 .95 −1.86 1.86 1.00
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Note. MFU = month follow-up; IDC = Individual Drug Counseling; MOUD = medication for opioid use disorder

4. Discussion

As even the gold standard OUD treatments (i.e., MOUD combined with medication management or behavioral therapy) are associated with an approximately 50% relapse rate (Lee et al., 2018; Weiss et al., 2011), the development of novel interventions to enhance treatment response is a critical need. In this trial, we examined the feasibility, acceptability, and preliminary efficacy of a newly developed cognitive-behavioral treatment for co-occurring anxiety and OUD. Overall, feasibility, satisfaction, and acceptability were high. Most participants were satisfied with the treatment and the average number of sessions completed was higher than many reports in the literature of behavioral therapy added to medication for OUD (Carroll & Weiss, 2017). Nonetheless, consistent with other behavioral therapy trials in this population, early discontinuation was not uncommon (Fiellin et al., 2013; Weiss et al., 2011).

Although we observed no statistically significant differences in the number of sessions attended between those in CBT and IDC, further consideration of in tolerability and satisfaction will be important in future, larger trials. Nonetheless, attendance was higher than in typical OUD studies for both conditions (Fiellin et al., 2013). Furthermore, also consistent with other OUD trials, adverse events were common—particularly related to OUD or other substance use disorder symptom exacerbations (e.g., worsening alcohol use) and consistent with the typical course of OUD, even among people receiving medication. There were no significant differences in such events between conditions; however, in this preliminary study, only large effect sizes would be detectable statistically.

In the full sample, we observed significant clinical improvement on average in both co-primary outcomes. On average, the level of anxiety reported reduced from severe to mild, and this was mostly sustained through 3-months post-treatment. Likewise, most participants were abstinent from opioids at the end of treatment. There was no evidence of differences between groups in either outcome. This suggests that well-structured psychosocial treatment, when given in addition to MOUD, may offer benefits for psychiatric symptoms in people with OUD, even when not specifically targeting the psychiatric disorder. This is consistent with a previous trial that found that people with posttraumatic stress disorder benefited from the addition of IDC to buprenorphine, whereas this addition did not confer benefit for people without posttraumatic stress disorder (McHugh, Hilton, et al., 2021). Notably, IDC contains components that may also provide psychiatric symptom or overall functioning benefit (e.g., structuring time, engaging in positive non-drug activities, managing family stressors). Also of note, although we had several restrictions with respect to concomitant treatment at the time of enrollment, we did not restrict other treatments during the trial. As would be expected for this population, changes in other treatments were very common, which may have also influenced outcomes. Our findings also indicate that exposure-based treatment did not worsen symptoms relative to standard treatment, consistent with a growing body of evidence supporting the safety of fear exposure in people with substance use disorders (Back et al., 2019; Mills et al., 2012; Tripp et al., 2020).

These results raise the important—and to date unanswered—question about who may benefit from targeted psychiatric treatment and who may experience significant improvement in psychiatric symptoms (e.g., anxiety) through engagement in substance use disorder care alone. Significant amelioration of depressive and anxiety symptoms occur following several weeks of abstinence from substance use (Liappas et al., 2002). Nonetheless, for many people with OUD, medications to promote abstinence might be inadequate to reduce psychiatric symptoms, as evidenced by subgroups of individuals receiving MOUD who have persistent depressive symptoms (Vest et al., 2023) and only modest improvements in anxiety symptoms during MOUD treatment (Latif et al., 2019). This may indicate that the skills provided, even in substance-specific behavioral treatments, may offer benefits for co-occurring symptoms that are not afforded by MOUD with medical management alone. One important future direction will be the identification of who responds adequately to substance use disorder treatment alone (e.g., MOUD combined with SUD-focused behavioral therapy or other SUD-focused psychosocial support) and who may benefit from the addition of targeted care for co-occurring other psychiatric disorders (e.g., medication, behavioral therapy). Indeed, stepped care models may be a useful approach for further study, in which some people receive substance use disorder treatment alone whereas others receive or progress to additional, targeted treatment. Particularly given worsening mental healthcare workforce gaps, such models may assist individuals with co-occurring disorders to receive the treatment they need from a single provider.

There are several limitations to the current study. Most notably, our sample was entirely White with only one participant identifying as Hispanic/Latinx; testing in more diverse samples and consideration of any needed cultural adaptations in such testing is an essential need. Similarly, although our population was diverse with respect to education level, employment, age and marital status, in a small sample, potential subgroup differences in acceptability and efficacy are difficult to detect. This highlights the importance of larger samples that allow for consideration of different preferences, perspectives, and outcomes across domains of individual differences. As we selected the sample size based on guidance for Stage 1 behavioral therapy development trials, any conclusions related to efficacy should be considered very preliminary and indicative of the early stages of treatment development. Of note, the target sample size for this trial (N = 54) was not achieved due to unanticipated delays in recruitment (e.g., closing of a local buprenorphine program). For Stage 1 trials, the development and refinement of fidelity rating scales is an important component. In this study these measures were developed and refined by the first author, with feedback from other investigators. Future, larger (e.g., Stage 2 trials) will benefit from the use of independent fidelity evaluators who complete ratings masked to condition. Another limitation relates to the evolving nature of the opioid drug supply. We did not systematically evaluate fentanyl use, as the drug supply at the time in the location that the study was conducted consisted almost exclusively of opioid analgesics (diverted or illicitly produced) and heroin. Future studies will be needed that are representative of continued evolution of the drug supply (e.g., predominance of fentanyl), the changing population of people with OUD (e.g., a greater representation of people of color), and the addition of new medication formulations for the treatment of OUD (e.g., injectable formulations).

5. Conclusions

Overall, CBT was associated with strong feasibility, satisfaction, and acceptability in adults with co-occurring OUD and anxiety disorders. Participants improved substantially with respect to both OUD and anxiety clinical symptoms. However, in this small preliminary trial, this improvement was not significantly better than an existing evidence-based treatment for OUD alone. Future research on who may not require intensive or anxiety-specific care and who may benefit from adjunctive services will be an important next step toward improving outcomes for this population. Nonetheless, these results suggest there may be substantial clinical improvement and high treatment satisfaction with the addition of a structured psychosocial treatment to medication for OUD.

Highlights.

  • We developed a 12-session cognitive-behavioral treatment (CBT) for anxiety and opioid use disorder.

  • We compared CBT to Individual Drug Counseling (IDC), both added to medication for opioid use disorder (MOUD).

  • The treatment had very strong participant-reported satisfaction and acceptability.

  • In a preliminary study, participants in both the CBT and control conditions reported significant improvement in anxiety.

  • More than 80% of participants were abstinent from opioids at post-treatment (week 12).

  • CBT+MOUD did not outperform IDC+MOUD.

Acknowledgments

The authors would like to acknowledge the contributions of Dr. Kathleen M. Carroll to this work. Dr. Carroll was a brilliant and deeply generous mentor and colleague and her seminal work on cognitive-behavioral therapy for substance use disorders was the foundation for much of this work.

Funding Sources

This work was supported by the National Institutes of Health (K23 DA035297).

Footnotes

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