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Abstract: Buprenorphine and other medication treatments for opioid use disorder (OUD) in general medical settings are effective in preventing drug overdoses related to opioid use, although treatment retention is often challenging. Real-world data indicate high medication discontinuation rates at 6 months or greater following treatment initiation, partially indicative of a common failure to optimize medication dosing to minimize side effects, maximize therapeutic effects, and sustain treatment engagement and adherence. These barriers hinder the achievement of optimal clinical outcomes in managing conditions like OUD, which is often a chronic relapsing condition and frequently associated with mood disorders. Measurement-based care (MBC) may be defined as an evidence-based healthcare approach in which systematic outcome monitoring of disease severity and symptomatology over time yields actionable feedback to providers to guide their clinical decision-making on how to customize medication dosing promptly to improve patients’ treatment outcomes. This opinion piece describes a proposed research agenda evaluating measurement-based care for opioid use disorder among patients with co-occurring depressive disorders that emphasizes pragmatic, multisite effectiveness-implementation trials to operationalize MBC in real-world, community-based, and primary care settings. The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) is positioned as a potential platform for advancing this agenda, leveraging its experience in bridging research and practice.

Abstract:

Objective: This study evaluated whether depressive symptom severity improved early with extended-release naltrexone and bupropion combination (naltrexone bupropion) compared to a placebo in individuals with moderate/severe methamphetamine use disorder and predicted subsequent use of methamphetamine.

Methods: This secondary analysis from the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2, CTN-0068) trial, which was conducted from May 23, 2017-July 25, 2019, included 326 individuals with a 9-item Patient Health Questionnaire (PHQ-9) score =5 at baseline. Repeated-measures mixed model analyses evaluated early (baseline-to-week-4) changes in depressive symptom severity with naltrexone-bupropion versus placebo and provided slope estimates for PHQ-9 change. Additional depression outcomes included response (=50% reduction in PHQ-9 from baseline) and remission (PHQ-9 =4). Methamphetamine treatment response was ascribed if 3 out of 4 urine drug screens were negative during weeks 5 and 6. Logistic regression analyses evaluated whether changes in depression predicted methamphetamine treatment response. Covariates included age, sex, race, ethnicity, and baseline PHQ-9.

Results: There was a greater reduction in PHQ-9 scores at week 4 with naltrexone-bupropion versus placebo (estimate = -2.52; standard error = 0.81). At week 4, depression response (odds ratio [OR] = 2.54; 95% confidence limit [CL], 1.42-4.55) and remission (OR = 3.04; 95% CL, 1.57-5.87) were more likely with naltrexone-bupropion versus placebo. Greater baseline-to-week 4 reduction in PHQ-9 was associated with a higher likelihood of methamphetamine treatment response (OR = 3.74, 95% CL, 1.28-10.93) and explained 24.8% (95% CI, 6.7%-60.3%) of the effect of naltrexone-bupropion on methamphetamine treatment response.

Conclusion: Use of naltrexone bupropion was associated with early reduction in depressive symptom severity compared to a placebo, which was associated with a higher likelihood of reduction in subsequent methamphetamine use.

Related protocols: CTN-0068

Abstract:

Background and aims: Amphetamine-type stimulants are the second-most used illicit drugs globally, yet there are no US Food and Drug Administration (FDA)-approved treatments for amphetamine-type stimulant use disorders (ATSUD). The aim of this study was to utilize a drug discovery framework that integrates artificial intelligence (AI)-based drug prediction, clinical corroboration and mechanism of action analysis to identify FDA-approved drugs that can be repurposed for treating ATSUD.

Design and setting: An AI-based knowledge graph model was first utilized to prioritize FDA-approved drugs in their potential efficacy for treating ATSUD. Among the top 10 ranked candidate drugs, ketamine represented a novel candidate with few studies examining its effects on ATSUD. We therefore conducted a retrospective cohort study to assess the association between ketamine and ATSUD remission using US electronic health record (EHR) data. Finally, we analyzed the potential mechanisms of action of ketamine in the context of ATSUD.

Participants and measurements: ATSUD patients who received anesthesia (n = 3663) or were diagnosed with depression (n = 4328) between January 2019 and June 2022. The outcome measure was the diagnosis of ATSUD remission within one year of the drug prescription.

Findings: Ketamine for anesthesia in ATSUD patients was associated with greater ATSUD remission compared with other anesthetics: hazard ratio (HR) = 1.58, 95% confidence interval (CI) = 1.15-2.17. Similar results were found for ATSUD patients with depression when comparing ketamine with antidepressants and bupropion/mirtazapine with HRs of 1.51 (95% CI = 1.14-2.01) and 1.68 (95% CI = 1.18-2.38), respectively. Functional analyses demonstrated that ketamine targets several ATSUD-associated pathways including neuroactive ligand-receptor interaction and amphetamine addiction.

Conclusions: There appears to be an association between clinician-prescribed ketamine and higher remission rates in patients with amphetamine-type stimulant use disorders.

Related protocols: CTN-0114

Abstract:

The goal of this study, part of CTN-0140 (Cannabis Use Among Pregnant Women with Polysubstance Use and Psychiatric Problems), was to estimate the strength of association between psychiatric disorders and substance use disorders (SUD), and cannabis use and cannabis use disorder (CUD) during early pregnancy. Participants were 299,496 pregnancies from 227,555 individuals screened for cannabis use by self-report and a urine toxicology test at entrance to prenatal care in Kaiser Permanente Northern California during January 2011-December 2021 (excepting year 2020). The sample was 62.5% non-White, with a mean (standard deviation) age of 31.1 (5.5) years; 6.8% used cannabis; 0.2% had a CUD.

Exposure variables included electronic health record-based psychiatric diagnoses of attention deficit hyperactivity, anxiety, bipolar, depressive, personality, posttraumatic stress and psychotic disorders; and alcohol, opioid, stimulant and tobacco use disorders, during the two years prior to pregnancy up to the day before the prenatal substance use screening date. Outcome variables were any cannabis use, frequency of self-reported cannabis use and CUD during early pregnancy.

Psychiatric disorder prevalence ranged from 0.2% (psychotic) to 14.3% (anxiety), and SUD ranged from 0.3% (stimulant/opioid) to 3.8% (tobacco). Psychiatric disorders were associated with cannabis use and CUD, with the strongest association for any use found for bipolar disorder (adjusted odds ratio [aOR] = 2.83; 95% confidence interval [CI] = 2.53-3.17) and the strongest association for CUD found for psychotic disorders (aOR = 10.01, 95% CI = 6.52-15.37). SUDs were associated with cannabis use and CUD, with the strongest association for any use found for tobacco use disorder (aOR = 4.03, 95% CI = 3.82-4.24) and the strongest association for CUD found for stimulant use disorder (aOR = 21.99, 95% CI = 16.53-29.26). Anxiety, bipolar, depressive disorders and tobacco use disorder were associated with greater odds of daily than monthly or less cannabis use.

Conclusions: Psychiatric disorders and substance use disorders appear to be associated with elevated odds of any and frequent cannabis use as well as cannabis use disorder during early pregnancy. In most cases, the associations with cannabis outcomes were stronger for substance use disorders than other psychiatric disorders.

Related protocols: CTN-0140

Abstract:

To inform clinical practice, researchers identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment. Participants were 474 adults in a 24-week treatment trial for OUD. Depression symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D) at nine-time points. This was a secondary analysis of the Clinical Trials Network Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (X:BOT, CTN-0051) trial using a growth mixture model.

Three distinct depression trajectories were identified: Class 1 High Recurring-10% with high HAM-D with initial partial reductions (of HAM-D across time), Class 2 Persistently High-5% with persistently high HAM-D, and Class 3 Low Declining-85% of the participants, with low HAM-D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse.

Conclusions: In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment. This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment.

Related protocols: CTN-0051

Abstract:

Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial (CTN-0051).

This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables.

Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use.

Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

Related protocols: CTN-0051

Abstract:

The concept of “deaths of despair” (suicide, overdose, and alcohol-related liver disease) highlights the importance of detecting and understanding the course of co-occurring depression in patients with opioid use disorder (OUD). To that end, this study examined the prevalence of depression (assessed with the Hamilton Depression Rating Scale [HDRS]) at baseline and after 4 weeks of treatment, as well as the association between depression and relapse to opioid use, using data from CTN-0051, a 24-week trial of 570 patients with OUD randomized to buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX).

Among 473 patients who initiated medication, 14.2% (67/473) had moderate/severe depression (HDRS ≥ 17) and 34.9% (165/473) had mild depression (8 ≤ HDRS ≤ 16) at baseline. Patients with moderate/severe depression had more frequent histories of anxiety disorders and suicidal ideation. After 4 weeks of treatment, approximately two-thirds of participants with depression either responded (HDRS reduced ≥ 50% from baseline) ore remitted (HDRS ≤ 7), with no significant differences between medication treatment groups. Those with moderate/severe depression were less likely to remit (52.8%; 28/53) compared to those with mild depression (76%; 98/129) at week 4 (OR=0.43, 95% CI=0.21-0.89, P=0.02). Further, those who remitted at week 4 had lower, but not significantly different, risk of relapse to opioids compared to those who did not remit (OR=0.55, 95% CL=0.28-1.08, P=0.08).

Conclusions: Depression is common among patients with OUD and often remits after initiation of BUP-NX or XR-NTX, although when it does not remit it may be associated with worse opioid use outcomes. Depression should be screened and followed during initiation of treatment and, when it does not remit, specific depression treatment should be considered.

Related protocols: CTN-0051

Abstract:

Individuals with pain prescribed opioids experience high rates of comorbid depression. The aim of this study was to characterize pain, substance use, and health status as a function of depressive symptom level in individuals filling an opioid prescription at a community pharmacy.

Participants (N=1268) filling an opioid prescription enrolled in a study (CTN-0093) validating a prescription drug monitoring metric completed an online survey assessing sociodemographics, depressive symptoms, substance use, prescription opioid misuse, overdose history, general health, and pain severity and interference.

Approximately one-fifth (19.3%) had a positive depression screen result. In covariate-adjusted logistic regression analyses, individuals with a positive depression screen result were more likely to have moderate/high substance use risk scores for prescription opioids (adjusted odds ratio [AOR]=2.06; 95% confidence interval [CI], 1.51–2.79); street opioids (AOR = 7.18; 95% CI, 2.57–20.01); cannabis (AOR = 2.00; 95% CI, 1.34–3.00); cocaine (AOR = 3.46; 95% CI, 1.46–8.22); tobacco (AOR = 1.59; 95% CI, 1.18–2.15); methamphetamine (AOR = 7.59; 95% CI, 2.58–22.35); prescription stimulants (AOR = 2.95; 95% CI, 1.59–5.49); and sedatives (AOR = 3.41; 95% CI, 2.43–4.79). Individuals with a positive depression screen were more likely to misuse prescription opioids (AOR = 3.46; 95% CI, 2.33–5.15), experience a prior overdose (AOR = 2.69; 95% CI, 1.76–4.11), report poorer general health (AOR = 0.25, 95% CI, 0.18–0.35), and report moderate/severe pain severity (AOR = 4.36, 95% CI, 2.80–6.77) and interference (AOR = 6.47, 95% CI, 4.08–10.26).

Conclusions: Individuals prescribed opioids with heightened depression were more likely to report other substance use, prescription opioid misuse, prior overdose, greater pain, and poorer health.

Related protocols: CTN-0093

Abstract:

Abstinence is rarely achieved in clinical trials for cannabis use disorder (CUD). Cannabis reduction is associated with functional improvement, but reduction endpoints have not been established, indicating a need to identify and validate clinically meaningful reduction endpoints for assessing treatment efficacy.

In this study, data from a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (CTN-0053, ACCENT) were analyzed. Participants (N = 225) were treatment-seeking adults, M = 30.6 (8.9) years old, 70.2% male, and 42.2% non-white, with CUD who completed 12 weeks of treatment. Frequency (days of use per week) and quantity (grams per using day) were used to define high-, medium-, and low-risk levels. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and cannabis-related problems were assessed using the Marijuana Problems Scale. General linear models for repeated measures tested associations between the magnitude of risk reduction and functional outcomes from baseline (BL) to end-of-treatment (EOT).

Results found that cannabis risk levels were sensitive to reductions in use from BL to EOT for frequency- and quantity-based metrics. Magnitude reduction in frequency-based risk level was associated with magnitude decrease in depression, anxiety, and cannabis-related problems. Magnitude reduction in quantity-based risk level was associated with magnitude decrease in anxiety and cannabis-related problems.

Conclusions: Cannabis use risk levels, as operationalized in this study, captured reductions in use during a clinical trial. Risk level reduction was associated with functional improvement suggesting that identifying risk levels and measuring the change in levels over time may be a viable and clinically meaningful endpoint for determining treatment efficacy.

Related protocols: CTN-0053

Abstract:

This study examined the associations of multiple psychiatric and chronic conditions with the self-reported history of major depressive disorder (MDD) among patients with opioid use disorder (OUD) and tested whether the associations differed by gender. Using data from CTN-0027 (START), a clinical trial including 1,646 participants with OUD, of which 465 had MDD, a variable cluster analysis was used to classify chronic medical and psychiatric conditions. Multivariate logistic regression analyses were used to estimate their associations with MDD in subjects with OUD.

Nine variables were divided into three clusters: cluster 1 included heart condition, hypertension, and liver problems; cluster 2 included gastrointestinal (GI) problems and head injury; and cluster 3 included anxiety disorder, bipolar disorder, and schizophrenia. The overall prevalence of MDD in participants with OUD was 28.3% (22.8% for males and 39.5% for females). Gender, anxiety disorder, schizophrenia, liver problems, heart condition, GI problems, and head injury were significantly associated with MDD. Gender-stratified analyses showed that bipolar disorder, liver problems and individuals with one chronic condition were associated with MDD only in males, whereas heart condition, hypertension, and GI problems were associated with MDD only in females. In addition, anxiety disorder, head injury, individuals with one or more than two psychiatric conditions, and individuals with more than two chronic conditions were associated with MDD regardless of gender.

Conclusions: This study showed a high prevalence of MDD in individuals with OUD as compared to the general population. In those with OUD, there is a significant association between MDD and gender, anxiety disorder, liver problems, heart condition, GI problems, and head injury. Furthermore, multiple psychiatric and chronic conditions were significantly associated with MDD. Additionally, gender-stratified analyses showed that bipolar disorder, liver problems and one chronic condition was associated with MDD in males, while heart condition, hypertension, and GI problems were associated with MDD only in females. Treatment plans in patients with OUD should not only address MDD but also co-morbid psychiatric and chronic medical conditions that occur with MDD.

Related protocols: CTN-0027

Abstract:

This study examined the associations of polysubstance use, mood disorders, and chronic conditions with the history of anxiety disorder among patients with opioid use disorder (OUD). Researchers performed a secondary analysis of the baseline data from NIDA-CTN-0027 (“Starting Treatment with Agonist Replacement Therapies (START)”), a clinical trial that included 1,645 individuals with OUD, of which 513 had anxiety disorder. Substance use disorder (SUDs) included alcohol, amphetamines, cannabis, cocaine, and sedative use disorders. Mood disorders included major depressive disorder (MDD) and bipolar disorder (BD). Chronic conditions were allergies, gastrointestinal problem(s), skin problem(s), and hypertension. Sedative use disorder, MDD, BD, skin problems, and hypertension were significantly associated with anxiety disorder. Additionally, more than two SUDs, two mood disorders, and more than two chronic conditions were significantly associated with anxiety disorder.

Conclusions: These findings highlight the comorbid mental health and physical health problems in individuals with OUD, as well as the need for integrated multidisciplinary treatment plans. Future areas of research should focus on not only OUD, but also patients presenting with other comorbidities to identify more vulnerable groups, discover effective solutions, and reduce the prevalence of OUD.

Related protocols: CTN-0027

Abstract:

This study aimed to evaluate the longitudinal treatment effect on depression measured by Hamilton Depression Rating Scale (HAM-D) score in a randomized clinical trial for the treatment of opioid use disorder (OUD). The authors conducted a secondary data analysis of data from the National Institute on Drug Abuse’s Clinical Trials Network protocol CTN-0051. Patients with OUD (N=570) were randomized to receive buprenorphine/naloxone (BUP-NX, n=287) or extended-release naltrexone injection (XR-NTX, n=283). The HAM-D score was completed at baseline and follow-up visit up to 36 weeks. A linear mixed model analysis was performed for log transformed HAM-D score and the generalized linear mixed model analysis was conducted for depression status.

Compared with BUP-NX, subjects randomized to XR-NTX had higher HAM-D scores at weeks 1 and 3 (p<0.05). There were significant interactions between treatment and visit on HAM-D score and depression status during the first four weeks of treatments in individuals without lifetime major depressive disorder (MDD). Past year cocaine use was associated with HAM-D score and depression status just in individuals without MDD, whereas past year cannabis use was associated with HAM-D score and depression status just in individuals with MDD. Past year amphetamine use was associated with HAM-D score just in individuals without MDD, however, lifetime anxiety was associated with HAM-D scores regardless of MDD.

Conclusion: When prescribing XR-NTX, particularly in the first month of treatment, it is essential to monitor for depressive symptoms. Screening for depression and multiple substance uses may help clinicians identify appropriate treatment.

Related protocols: CTN-0051

Abstract:

Individuals treated for opioid use disorder (OUD) have high rates of psychiatric disorders potentially diminishing treatment outcomes. This study examined long-term treatment experiences and outcomes by type of psychiatric disorder among participants in the NIDA Clinical Trials Network Starting Treatment with Agonist Replacement Therapies (START) study (CTN-0027) and its follow-up study (CTN-0050).

Researchers categorized the 593 participants who completed the Mini-International Neuropsychiatric Interview (MINI) during the START follow-up study into four mutually exclusive groups to indicate current psychiatric diagnosis: 1) bipolar disorder (BPD; n=51), 2) major depressive disorder (MDD; n=85), 3) anxiety disorder (AXD; n=121), and 4) no comorbid mental disorder (NMD; n=336). Participants’ baseline characteristics and treatment outcomes were then compared.

Groups with mental disorders had worse substance use outcomes and poorer psychosocial functioning than the NMD group. Participants with BPD had significantly more self-reported days using opioids (mean: 8.6 for BPD vs. 3.4 days for NMD) and heroin (mean: 6.4 for BPS vs. 2 for MDD, 3.1 days for NMD) in the 30 days prior to the final interview. Compared to patients without mental disorders, patients with MDD spent more time engaged with OUD pharmacotherapy during the ~16 month period between MINI and final interview (mean: 71.6% vs. 50.6%).

Conclusions: Results show that treatment outcomes in individuals with OUD vary by psychiatric comorbidity groups, which supports the need for mental health assessment and treatment for psychiatric conditions in the context of pharmacotherapy for patients with OUD.

Related protocols: CTN-0027, CTN-0050

Abstract:

Cannabis use is common among individuals with pain who are prescribed opioids, occurring in approximately 10% of this population. This study aimed to explore the relationship between non-medical cannabis use and other health risks among individuals filling opioids at community pharmacies.

This study was an exploratory secondary data analysis of a National Drug Abuse Treatment Clinical Trials Network (CTN)-sponsored study, Validation of a Community Pharmacy-Based Prescription Drug Monitoring Program Risk Screening (CTN-0093), examining the relationship between risky cannabis use and depressive symptoms, pain, overdose, and other substance misuse among individuals filling opioid prescriptions in community pharmacies (N = 1440).

Participants reporting moderate- to high-risk compared to low-risk cannabis use were more likely to report depressive symptoms (adjusted OR = 1.67, 95% CI = 1.11–2.56), history of overdose (adjusted OR = 2.15, 95% CI = 1.34–3.44), and moderate- to high-risk use of alcohol (adjusted OR = 2.10, 95% CI = 1.28–3.45), opioids (adjusted OR = 2.50, 95% CI = 1.67–3.76), sedatives (adjusted OR = 2.58, 95% CI = 1.72–3.86), stimulants (adjusted OR = 4.79, 95% CI = 2.83–8.01), and tobacco (adjusted OR = 3.60, 95% CI = 2.47–5.24).

Conclusion: Community pharmacies may be valuable sites for identifying, studying, and intervening with substance use problems.

Related protocols: CTN-0093

Abstract:

In the multi-site NIDA Clinical Trials Network Prescription Opioid Addiction Treatment Study (POATS), the best predictor of successful opioid use outcome was lifetime diagnosis of major depressive disorder. The primary aim of this secondary analysis of data from POATS was to empirically assess two explanation for this counterintuitive finding.

The POATS study was a national, 10-site randomized controlled trial (N=360 enrolled in the 12-week buprenorphine-naloxone maintenance treatment phase) sponsored by the NIDA CTN. This study evaluated how the presence of a history of depression influences opioid use outcome (negative urine drug assays). Using adjusted logistic regression models, researchers tested the hypothesis that 1) a reduction in depressive symptoms and 2) greater motivation and engagement in treatment account for the association between depression history and good treatment outcome.

Analysis found that although depressive symptoms decreased significantly throughout treatment, this improvement was not associated with opioid outcomes. Reporting a goal of opioid abstinence at treatment entry was also not associated with outcomes, however, mutual-help group participation was associated with good treatment outcomes. In each of these models, lifetime major depressive disorder remained associated with good outcomes.

Conclusions: Findings are consistent with the premise that greater engagement in treatment is associated with good opioid outcomes. Nevertheless, depression history continues to be associated with good opioid outcomes in adjusted models. More research is needed to understand how these factors could improve treatment outcomes for those with opioid use disorder.