Most people with moderate to severe substance use disorder do not use a single substance. They combine opioids, stimulants, and alcohol, a pattern the research team identifies as the predominant form of the condition, and one associated with increased mortality and morbidity risk and worsened clinical treatment outcomes. Yet the evidence base guiding treatment was built largely one substance at a time: medications for opioid use disorder and alcohol use disorder, and contingency management for stimulant use disorder, have each been tested in trials that rarely addressed multiple substances.
A study protocol published in Addiction Science & Clinical Practice describes an effort to close that gap in the setting where many of these patients actually receive care, the primary care clinic. The trial, called CoCare, short for Collaborative Care for Polysubstance Use in Primary Care Settings, is a cluster-randomized controlled trial registered at ClinicalTrials.gov under identifier NCT06116266 on October 31, 2023. Randomization occurs at the level of the primary care provider rather than the individual patient, so entire provider panels are assigned to the intervention or to a comparison condition of enhanced usual care.
The study will be conducted across six distinct geographic sites and will enroll adult primary care patients with moderate to severe opioid, stimulant, and/or alcohol use disorder who report concurrent use of at least two of these substance classes. The trial is designed to test the efficacy of the CoCare intervention in decreasing polysubstance use over a six-month intervention period. CoCare assembles four roles around each patient.
A practice-embedded nurse care manager manages medications for opioid and alcohol use disorder, conducts contingency management, links patients to mental health and addiction treatment, and provides general care management. The patient's own primary care provider prescribes medications and manages medical conditions. A remote health coach delivers patient-centered counseling, motivational enhancement, and cognitive behavioral therapies.
Finally, an addiction specialist advises the nurse care manager and health coach on evidence-based patient care, using population health management tools to guide those recommendations. The primary outcome is deliberately practical: the total number of self-reported days of opioid use, stimulant use, and heavy alcohol use, summed over months four through six. Heavy alcohol use is defined as four or more drinks per day for women and five or more drinks per day for men.
These outcomes are assessed monthly via text messages using items drawn from the Addiction Severity Index, a structured assessment instrument. On the analysis side, the primary outcome data will be examined with a mixed-effects negative binomial model with a log link, a statistical approach suited to count outcomes such as days of use. Secondary outcomes reach beyond substance use itself.
The investigators plan to track progress in treatment and recovery, substance use frequency and severity, mental health, quality of life, healthcare utilization, overdose risk, and pain, along with primary care provider attitudes and behaviors. The choice of primary care as the setting is grounded in who seeks treatment: according to the protocol, only a minority of individuals with active polysubstance use disorder enter specialty addiction treatment, but these patients frequently visit primary care. As a protocol publication, the article describes the trial's design rather than its results, and no efficacy findings are yet available.
The registered design does, however, lay out a detailed technical blueprint: cluster randomization by provider, six geographic sites, a six-month intervention with four defined roles, monthly text-message assessment using Addiction Severity Index items, and a prespecified statistical model for the primary outcome. The investigators state that, given the importance of addressing polysubstance use disorder in primary care settings, this trial of collaborative care offers a blueprint for a feasible and effective approach.
Subject of Research: Study protocol for a cluster-randomized controlled trial of collaborative care for polysubstance use disorder in adult primary care patients
Article Title: Collaborative care for polysubstance use in primary care settings (co-care): protocol for a cluster randomized controlled trial
Article References: Liebschutz, J. M., Subramaniam, G. A., Stone, R., Appleton, N., Beers, D., Bradley, K., Bui, E., Case, A., Gauthier, P., Gelberg, L., Hefner, K., Kline, M., Lovejoy, T. I., McCormack, J., Otterstatter, M., Park, T., Scott, D., Mazel, S., & McNeely, J. (2026). Collaborative care for polysubstance use in primary care settings (co-care): protocol for a cluster randomized controlled trial. Addiction Science & Clinical Practice. https://doi.org/10.1186/s13722-026-00727-6
Image Credits: AI Generated
DOI: 10.1186/s13722-026-00727-6
Keywords: polysubstance use, substance use disorder, collaborative care, primary care, cluster randomized trial, opioid use disorder, alcohol use disorder, stimulant use disorder, nurse care manager, contingency management, Addiction Severity Index, study protocol
News Source: Ophelia Keating. (October 23, 2026). CoCare Trial Protocol Tests Collaborative Care for Polysubstance Use in Primary Care. Scienmag.
