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Abstract: Introduction: Prescription opioid dose reductions can raise the risk of adverse events for patients on long-term opioid therapy for non-cancer pain. Evidence on whether risks differ by age or sex is needed to support tailored clinical decision-making. Methods: In 2024, a secondary analysis of an observational cohort study (NIDA-CTN-0084) was conducted across 8 U.S. healthcare systems analyzing electronic health record and claims data from a prescription opioid registry (excluding buprenorphine prescriptions) between 1/1/2012 and 12/31/2018, including adults with stable prescription opioid use and a subsequent =2-month dose reduction period (n=60,040), yielding 600,234 dose reduction periods as the analytic sample. Differences in the association between dose reduction level (1-<15%, 15-<30%, 30-<100%, 100% from baseline) and potential adverse events (emergency department visits, opioid overdose, all-cause mortality, benzodiazepine prescription fills) in the month after dose reduction by sex and age group were examined by including interaction terms in logistic regression models. Results: Of the 600,234 dose reduction periods, 346,733 were among women, with a mean age of 57.5 [SD=13.2] years for women and 56.7 [SD=12.1] years for men. Associations between dose reduction levels and potential adverse events did not differ significantly by sex, but differed by age for emergency department visits: patients 40-64 and =65 years with dose reductions of 30-<100% had lower odds compared to those aged 19-39 (adjusted ratio of odds ratios [aROR]=0.87, CI 0.80, 0.96; aROR=0.82, CI 0.74, 0.91; respectively). Conclusions: Patients under 40 may benefit from closer monitoring in the month after dose reduction, given their higher odds of an emergency department visit. Related protocols: CTN-0084

Abstract:

Background: A majority of the 8.9 million Americans with opioid misuse have mild or no symptoms of opioid use disorder (OUD), but they may be at elevated risk of developing more severe OUD, overdose, or other health consequences of opioid use. The “Subthreshold Opioid Use Disorder Prevention”(STOP) Trial is evaluating a collaborative care intervention for risky opioid use in primary care. Here, we describe baseline characteristics of participants to understand their needs and assess the generalizability of the sample.

Methods: Recruitment at five primary care sites spanned March 2021-May 2023. Adult patients who screened positive for subthreshold OUD (current illicit or non-medical opioid use without meeting DSM-5 criteria for moderate-severe OUD) were eligible. Baseline assessments measured self-reported demographic characteristics, other substance use, pain, and physical and mental health symptoms. Descriptive statistics summarize characteristics of the enrolled sample across sites.

Results: Among the 202 participants, the majority identified as female (63.4%), white (70.8%), and non-Hispanic (96.5%), with mean age 55.7 (SD: 12.7) years. Nearly half (49.0%) had problem or high-risk use of prescription opioids, and most received a prescription for opioid medication in the past six months (74.8%). Many participants reported current problem use or high-risk use of alcohol (47.0%) or cannabis (31.2%). Approximately one-third endorsed mental health symptoms, including moderate-severe anxiety (35.6%), depression (31.2%), or sleep disturbance (29.7%), and 20.3% reported a past suicide attempt. In the prior six months, 14.7% had experienced a nonfatal overdose. Moderate-severe pain was reported by 63.4%, and 60.4% rated their general health as fair or poor.

Conclusions: Patients with subthreshold OUD had high rates of polysubstance use and comorbidities that may present challenges to reducing risky opioid use. The STOP trial presents an opportunity to detect and address subthreshold OUD in a cohort with considerable medical and social needs, within primary care settings.

Related protocols: CTN-0101

Abstract:

The aim of this qualitative study, part of CTN-0115 (Developing an Intervention to Address Intersecting Prescription Opioid and Chronic Pain Stigma in Cancer Survivors), was to characterize opioid stigma in cancer remission using the Opioid Stigma Framework as a grounding theoretical framework.

Researchers conducted in-depth qualitative interviews with cancer survivors in remission who are currently or were previously prescribed opioids for moderate-to-severe pain related to their cancer diagnosis (n=17) and clinicians who routinely treat chronic cancer-related pain (n=20). Interviews occurred at a single institution from 05/2021-12/2021. The primary focus of this analysis was to describe perceived stigma from a patient perspective, as relayed by either survivors or treating clinicians.

Survivors and clinicians perceived externalized stigma in a variety of healthcare settings, sometimes influenced by survivors’ sociodemographic characteristics (e.g., race). Survivors and clinicians also reported stigmatizing behaviors from a variety of personal relationships, including family and community members, which then impacted decisions around prescription opioid use. Finally, survivors and clinicians described a pervasive sense of internalized stigma related to prescription opioid use in survivorship, including shame, embarrassment, and fear of addiction. Survivors and clinicians also reflected on known disparities in pain management, which in turn may have influenced experiences with opioid stigma.

This research extends the Opioid Stigma Framework’s concepts — previously described in patients with active cancer — to opioid stigma in cancer survivors. Given the frequency of opioid prescribing across the cancer continuum, it is crucial to develop targeted and tailored interventions to de-stigmatize clinical care and improve safe, effective chronic cancer pain management.

Related protocols: CTN-0115

Abstract:

Background: The opioid epidemic presses on as a significant public health issue in the U.S., with particularly high overdose death rates in the Southeast. Naloxone is the standard of care for reversing opioid overdose; however, many people who use drugs (PWUD) experience barriers to naloxone use. This cross-sectional survey study aims to describe awareness of, experience with, willingness, barriers, and distribution strategies for naloxone among PWUD in the Southeast.

Methods: Data were obtained from a larger implementation survey study (CTN-0082). Descriptive analyses focused on N = 381 people in substance use treatment programs, syringe services programs, and sexually transmitted infection clinics who reported non-prescription opioid use in the past 12 months and completed a naloxone-related questionnaire.

Results: Most PWUD reported using opioids daily (60–62 %). 82 % had previously heard of naloxone, but only 43 % reported having received any type of training to use it. On a 5-point scale, PWUD without prior training (n = 219) reported being very willing to be trained to use naloxone on someone who overdoses (Mdn=5.00, IQR=2.00). Among all PWUD, not knowing where to go for naloxone training was the only barrier to using naloxone that was endorsed with certainty (Mdn=4.00, IQR=2.00). PWUD endorsed three strategies to improve naloxone distribution, including wanting their site to offer naloxone training (Mdn=4.00, IQR=1.00), increased access to naloxone education (Mdn=4.00, IQR=1.00), and connecting people to training programs (Mdn=4.00, IQR=1.00).

Conclusion: This study suggests that improvements are still needed in the saturation of naloxone training and distribution among PWUD, including in settings that provide non-opioid related services.

Related protocols: CTN-0082

Abstract:

Objective: This secondary analysis evaluated the validation results of the Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) tool for older adults.

Methods: Researchers performed a subgroup analysis of older adults aged =65 (n = 184) from the TAPS tool validation study conducted in 5 primary care clinics (CTN-0059). They compared the interviewer and self-administered versions of the TAPS tool at a cutoff of =1 for identifying problem use with a reference standard measure, the modified World Mental Health Composite International Diagnostic Interview.

Results: The mean age was 70.6 ± 5.9 years, 52.7% were female, and 49.5% were non-Hispanic Black. For identifying problem use, the self-administered TAPS tool had sensitivity of 0.91 (95% CI: 0.75–0.98) and specificity of 0.91 (95% CI: 0.85–0.95) for tobacco; sensitivity of 0.68 (95% CI: 0.45–0.86) and specificity of 0.88 (95% CI: 0.82–0.93) for alcohol; and sensitivity 0.86 (95% CI: 0.42–1.00) and specificity 0.94 (95% CI: 0.90–0.97) for cannabis. The interviewer-administered TAPS tool had similar results. Researchers were unable to evaluate its performance for identifying problem use of individual classes of drugs other than cannabis in this population due to small sample sizes.

Conclusions: While the TAPS had excellent sensitivity and specificity for identifying tobacco use among older adults, the results for other substances lack precision, and we were unable to evaluate its performance for prescription medications and individual illicit drugs in this sample. This analysis underlines the critical need to adapt and validate screening tools for unhealthy substance use, specifically for older populations who have unique risks.

Related protocols: CTN-0059

Abstract:

The Centers for Disease Control and Prevention’s 2022 Clinical Practice Guideline for Prescribing Opioids for Pain cautioned that inflexible opioid prescription duration limits may harm patients. Information about the relationship between initial opioid prescription duration and a subsequent refill could inform prescribing policies and practices to optimize patient outcomes. We assessed the association between initial opioid duration and an opioid refill prescription.

Using data drawn from a multi-site prescription opioid registry developed by CTN-0084, conducted a retrospective cohort study of adults =19 years of age in 10 US health systems between 2013 and 2018 from outpatient care with a diagnosis for back pain without radiculopathy, back pain with radiculopathy, neck pain, joint pain, tendonitis/bursitis, mild musculoskeletal pain, severe musculoskeletal pain, urinary calculus, or headache. Generalized additive models were used to estimate the association between opioid days’ supply and a refill prescription.

Overall, 220,797 patients were prescribed opioid analgesics upon an outpatient visit for pain. Nearly a quarter (23.5%) of the cohort received an opioid refill prescription during follow-up. The likelihood of a refill generally increased with initial duration for most pain diagnoses. About 1 to 3 fewer patients would receive a refill within 3 months for every 100 patients initially prescribed 3 vs. 7 days of opioids for most pain diagnoses. The lowest likelihood of refill was for a 1-day supply for all pain diagnoses, except for severe musculoskeletal pain (9 days’ supply) and headache (3-4 days’ supply).

Conclusions: Long-term prescription opioid use increased modestly with initial opioid prescription duration for most but not all pain diagnoses examined.

Related protocols: CTN-0084

Abstract:

In response to the opioid crisis in the United States, population-level prescribing of opioids has been decreasing; there are concerns, however, that dose reductions are related to potential adverse events. The purpose of this study was to examine associations between opioid dose reductions and risk of 1-month potential adverse events (emergency department (ED) visits, opioid overdose, benzodiazepine prescription fill, all-cause mortality).

This observational cohort study used electronic health record and claims data from eight United States health systems in a prescription opioid registry (Clinical Trials Network protocol CTN-0084). All opioid fills (excluding buprenorphine) between 1/1/2012 and 12/31/2018 were used to identify baseline periods with mean morphine milligram equivalents daily dose of = 50 during six consecutive months. Researchers identified 60,040 non-cancer patients with = one 2-month dose reduction period (600,234 unique dose reduction periods). Analyses examined associations between dose reduction levels (1-<15%, 15-<30%, 30-<100%, 100% over 2 months) and potential adverse events in the months following a dose reduction using logistic regression analysis, adjusting for patient characteristics.

Overall, dose reduction periods involved mean reductions of 18.7%. Compared to reductions of 1–<15%, dose reductions of 30–<100% were associated with higher odds of ED visits (OR 1.14, 95% CI 1.10, 1.17), opioid overdose (OR 1.41, 95% CI 1.09–1.81), and all-cause mortality (OR 1.39, 95% CI 1.16–1.67), but lower odds of a benzodiazepine fill (OR 0.83, 95% CI 0.81–0.85). Dose reductions of 15–<30%, compared to 1–<15%, were associated with higher odds of ED visits (OR 1.08, 95% CI 1.05–1.11) and lower odds of a benzodiazepine fill (OR 0.93, 95% CI 0.92–0.95), but were not associated with opioid overdose and all-cause mortality.

Conclusions: Greater dose reductions were associated with elevated odds of potential adverse events, relative to smaller dose reductions. Dose reductions for patients on long-term opioid therapy require careful planning and monitoring, particularly soon after a reduction.

Related protocols: CTN-0084

Abstract:

Screening for substance use in rural primary care clinics faces unique challenges due to limited resources, high patient volumes, and multiple demands on providers. To explore the potential for electronic health record (EHR)-integrated screening in this context, researchers conducted an implementation feasibility study with a rural federally-qualified health center (FQHC) in Maine. This was an ancillary study to a NIDA Clinical Trials Network study of screening in urban primary care clinics (CTN-0062).

Researchers worked with stakeholders from three FQHC clinics to define and implement their optimal screening approach. Clinics used the Tobacco, Alcohol, Prescription Medication, and Other Substance (TAPS) Tool, completed on tablet computers in the waiting room, and results were immediately recorded in the EHR. Adult patients presenting for annual preventive care visits, but not those with other visit types, were eligible for screening. Data were analyzed for the first 12 months following implementation at each clinic to assess screening rates and prevalence of reported unhealthy substance use, and documentation of counseling using an EHR-integrated clinical decision support tool, for patients screening positive for moderate-high risk alcohol or drug use.

Screening was completed by 3749 patients, representing 93.4% of those with screening-eligible annual preventive care visits, and 18.5% of adult patients presenting for any type of primary care visit. Screening was self-administered in 92.9% of cases. The prevalence of moderate-high risk substance use detected on screening was 14.6% for tobacco, 30.4% for alcohol, 10.8% for cannabis, 0.3% for illicit drugs, and 0.6% for non-medical use of prescription drugs. Brief substance use counseling was documented for 17.4% of patients with any moderate-high risk alcohol or drug use.

Conclusions: Self-administered EHR-integrated screening was feasible to implement, and detected substantial alcohol, cannabis, and tobacco use in rural FQHC clinics. Counseling was documented for a minority of patients with moderate-high risk use, possibly indicating a need for better support of primary care providers in addressing substance use. There is potential to broaden the reach of screening by offering it at routine medical visits rather than restricting to annual preventive care visits, within these and other rural primary care clinics.

Related protocols: CTN-0062-Ot

Abstract:

While polysubstance use has consistently been associated with higher rates of relapse, few studies have examined subgroups with specific combinations and time course of polysubstance use (i.e., polysubstance use patterns). This study aimed to classify and compare polysubstance use patterns and their associations with relapse to opioid use in 2637 participants in three large opioid use disorder (OUD) treatment trials in the NIDA Clinical Trials Network (CTN-0027, CTN-0030, and CTN-0051).

Researchers explored the daily patterns of self-reported substance use in the 28 days prior to treatment entry. Market basket analysis (MBA) and repeated measure latent class analysis (RMLCA) were used to examine the subgroups of polysubstance use patterns, and multiple logistic regression was used to examine associations between identified classes and relapse.

MBA and RMLCA identified 34 “associations rules” and 6 classes, respectively. Specific combinations of polysubstance use and time course (high baseline use and rapid decrease of use prior to initiation) predicts a worse relapse outcome. MBA showed individuals who co-used cocaine, heroin, prescription opioids, and cannabis had a higher risk for relapse (OR=2.82, 95%CI=1.13, 7.03). In RMLCA, higher risk of relapse was observed in individuals who presented with high baseline prescription opioid (OR = 1.9, 95% CI = 1.3, 2.76) or heroin use (OR = 3.54, 95%CI = 1.86, 6.72), although use decreased in both cases prior to treatment initiation.

Conclusions: Our analyses identified subgroups with distinct patterns of polysubstance use. Different patterns of polysubstance use differentially predict relapse outcomes. Interventions tailored to these individuals with specific polysubstance use patterns prior to treatment initiation may increase the effectiveness of relapse prevention.

Related protocols: CTN-0027, CTN-0030, CTN-0051

Abstract:

Benzodiazepines and opioids are used alone or in conjunction in certain care settings, but each have the potential for misuse. This longitudinal observational study, developed with CTN support through the Ohio Valley Node “base” award, evaluated substance use and mental health outcomes associated with providing opioids with or without benzodiazepine to treat traumatic injury in the emergency department (ED) setting.

Researchers analyzed a limited dataset obtained through the IBM Watson Health Explorys. Matched cohorts were defined for: 1) patients treated with opioids during the ED encounter (ED-Opioid) vs. neither opioid or benzodiazepine treatment (No medication) (n = 5372); 2) patients treated with opioids and benzodiazepines during the ED encounter (ED-Opioid+Benzodiazepines) vs. No Medication (n = 2454); and 3) ED-Opioid+Benzodiazepines vs. ED-Opioid (n = 2454). Patients consisted of adults with an emergency department encounter in the MetroHealth System (Cleveland, Ohio) with a chief complaint of traumatic injury and medical records for five years following the encounter. Control patients for each cohort were matched to the exposure patients on demographics, body mass index, and residential zip code median income. Outcomes were five-year incidence rates for alcohol, substance use, depression, and anxiety-related diagnoses.

Results indicated that, although receiving opioids during the ED visit predicted a relatively lower likelihood of subsequent substance use and mental health diagnoses, the brief co-use of benzodiazepines was strongly associated with poorer outcomes.

Conclusions: Even brief exposure to co-prescribed opioids and benzodiazepines during emergency traumatic injury care may be associated with negative substance use and mental health consequences in the years following the event.

Abstract:

This is the primary outcomes article for CTN-0084.

This project aimed to develop and implement a prescription opioid registry in 10 diverse health systems across the U.S. and describe trends in prescribed opioids between 2012 and 2018.

Using electronic health record and claims data, researchers identified patients who had an outpatient fill for any prescription opioid, and/or an opioid use disorder diagnosis, between January 1, 2012 and December 31, 2018. The registry contains distributed files of prescription opioids, benzodiazepines and other select medications, opioid antagonists, clinical diagnoses, procedures, health services utilization, and health plan membership. Rates of outpatient opioid fills over the study period, standardized to health system demographic distributions, are described by age, gender, and race/ethnicity among members without cancer.

The registry includes 6,249,710 patients and over 40 million outpatient opioid fills. For the combined registry population, opioid fills declined from a high of 0.718 per member-year in 2013 to 0.478 in 2018, and morphine milligram equivalents (MMEs) per fill declined from 985 MMEs per fill in 2012 to 758 MMEs in 2018. MMEs per member declined from 692 MMEs per member in 2012 to 362 MMEs per member in 2018.

Conclusions: This study established a population-based opioid registry across 10 diverse health systems that can be used to address questions related to opioid use. Initial analyses showed large reductions in overall opioid use per member among the combined health systems. The registry will be used in future studies to answer a broad range of other critical public health issues relating to prescription opioid use.

Related protocols: CTN-0084

Abstract:

The objectives of the presentation are to 1) Quantify receipt of addiction treatment and retention in care among youth with opioid use disorder (OUD); 2) List common facilitators and barriers to receipt of addiction treatment from the perspective of clinicians, youth, and family members; and 3) Describe approaches to improving clinical services for youth with OUD.

Abstract:

Watch recording on YouTube.

Presented by Erin Bonar, PhD

Dr. Bonar presents results from pilot work on behavioral interventions delivered via telemedicine and a patient portal-like system the are now being testing in a large RCT as part of the NIH Heal Prevention Initiative. The interventions are rooted in Motivational Interviewing, include an emphasis on cognitive-behavioral skills, and are highly tailored for adolescents and young adults. These promising interventions build on prior efficacious behavioral interventions that showed reductions in primary substance use outcomes and secondary effects on prescription drug misuse.

Abstract:

This is the primary outcomes paper for CTN-0093.

Prescription drug monitoring programs (PDMPs) are critical for pharmacists to identify risky opioid medication use. This study, an independent evaluation of the PDMP-based Narcotic Score (NS) metric, was a one-time, cross-sectional health assessment within 19 pharmacies from a national chain among adults picking up opioid medications. The NS metric is a 3-digit composite indicators. The WHO Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) was the gold-standard to which the NS metric was compared. Machine learning determined optimal risk thresholds; Receiver Operating Characteristic curves an Spearman (P) and Kappa (K) coefficients analyzed concurrent validity. Regression analyses evaluated participant characteristics associated with misclassification.

The NS metric showed fair concurrent validity (area under the curve=0.70; K=0.35; P = 0.37, p < 0.001). The ASSIST and NS metric categorized 37% of participants as low-risk (i.e., not needing screening/intervention). Further, 17.2% were categorized as low ASSIST risk but moderate/high NS metric risk, termed false positives. These reported disability (OR=3.2), poor general health (OR=0.66), and/or greater pain severity/interference (OR=1.12/1.09; all p < 0.05; i.e., needing unmanaged-pain screening/intervention). A total of 13.4% were categorized as moderate/high ASSIST risk but low NS metric risk, termed false negatives. These reported greater overdose history (OR=1.24) and/or substance use (OR=1.81-12.66; all p < 0.05).

Conclusions: The NS metric could serve as a useful initial universal prescription opioid-risk screener given its: 1) low burden (i.e., no direct assessment); 2) high accuracy (86.5%) of actionable data identifying low-risk patients and those needing opioid use/unmanaged pain screening/intervention; and 3) broad availability.

Related protocols: CTN-0093

Abstract:

This article examines age differences across genders in clinical characteristics in emerging adult (25 years or less) vs. older adult patients (26 years or older) with opioid use disorder (OUD). Participants included 570 people (30% female) entering a comparative effectiveness medication trial of buprenorphine vs. extended-release naltrexone (CTN-0051, X:BOT).

Analysis revealed similar differences across genders in clinical characteristics in emerging adult vs. older participants. However, women who were 26 years old or older reported more mental health problems compared with women 25 years old or younger, while men 25 or younger reported more mental health problems compared with men 26 or older.

Conclusions: Different strategies for emerging adult and older patients seeking OUD treatment may be necessary to address psychiatric comorbidities that differ across genders in this population. Comprehensive psychiatric assessment should be systematically included in OUD treatment for all genders. Treatment should focus on the emerging adult development phase when appropriate, with psychiatric treatment tailored for women and men, separately, across the lifespan.

Related protocols: CTN-0051