CARES (Comprehensive Analgesic, Recovery, and Education Support) for Surgery Trial

This is a Type 1 hybrid effectiveness-implementation, three-arm, parallel randomized controlled trial (RCT) evaluating a behavioral-pharmacologic intervention for postoperative opioid management in patients with preoperative long-term opioid use (LTOU). A total of 375 participants will be enrolled across four academic medical centers:

• Stanford University Medical Center,
• Harvard University- Brigham and Women's Hospital,
• Wake Forest University- Atrium Health Wake Forest Baptist Medical Center, and
• University of Kansas Medical Center.

Eligible participants will be randomized in equal allocation to one of three study conditions:

• Motivational Interviewing-Guided Opioid Taper combined with tizanidine (MI-Opioid Taper + Tizanidine),
• MI-Opioid Taper with placebo, or
• Enhanced Usual Care (EUC). Participants will be followed for 12 months following surgery, with structured assessments of opioid use, pain outcomes, and related behavioral and clinical measures.

The primary endpoint is time to return to baseline opioid use. Secondary endpoints include time to opioid cessation, time to opioid dispensing cessation, time to pain cessation, and incidence of postoperative opioid misuse. Additional exploratory analyses will examine behavioral and clinical mediators of treatment effects, including motivation for change, change talk, and pain reduction.

Effect modification analyses will assess whether baseline participant characteristics are associated with differential treatment engagement and outcomes. Implementation outcomes will be evaluated using a mixed-methods approach guided by the RE-AIM framework, focusing on barriers and facilitators to future dissemination and scalability of the MI-Opioid Taper intervention.

This project addresses a critical gap in postoperative care for patients with long-term opioid use in need of precision postoperative pain care to minimize opioid-related harms.

Inclusion criteria

• 18 to 75 years of age
• Able to speak, write, and read fluently in English
• Scheduled for elective surgery at

• Stanford University Medical Center,
• Brigham and Women's Hospital (Harvard University),
• Atrium Health Wake Forest Baptist Medical Center (Wake Forest University), or
• University of Kansas Medical Center
• Preoperative long-term opioid use (Defined as ≥ 60-day supply of opioids in the 180-day period prior to surgery), identified via self-report, state Prescription Drug Monitoring Program (PDMP), or Electronic Medical Records (EHR). Days may be nonconsecutive, and actual use of opioid supply is not required.
• Willing and able to complete online assessments and study calls independently
• On the preoperative Baseline assessments, least one of the following:

• Current Opioid Misuse Measure (COMM-17): score ≥ 9
• Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS-1): Reported use more frequent than "Never" on any item except Tobacco; for Tobacco, "Yes" to at least one item on the TAPS-2 for Tobacco
• Alcohol Use Disorders Identification Test (AUDIT-C): score ≥4 (men), ≥3 (women)
• Modified Brief Pain Inventory (mBPI): "Yes" to at least one of the following:

• Over the past 24 hours have you needed to take your pain medication to help you sleep?
• Have you taken any pain medications for any reason other than your pain, such as to reduce anxiety or improve mood?
• Have you taken more pain medication than was prescribed to you in the past 24 hours?
• At the Post-Operative Call (7-13 days post-op): Postoperative daily opioid dose ≥ preoperative daily opioid dose (identified during the Pre-Surgery Call 5-1 day before surgery), measured in Morphine Milligram Equivalents (MME).

Exclusion criteria

• Infection, tumor, or fracture at the operative site
• Allergy or intolerance to tizanidine
• Current use of tizanidine
• Renal impairment (Creatinine Clearance [CrCl] < 25 ml/min)
• Hepatic impairment, including cirrhosis or elevated liver enzymes
• Concurrent use of other α2-adrenergic agonists, skeletal muscle relaxants
• Concurrent use of: fluvoxamine, ciprofloxacin,zileuton, fluoroquinolones, antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, oral contraceptive pills, acyclovir, ticlopidine, and fexinidazole
• Pre-existing hypotension, sedation, dizziness, severe respiratory insufficiency.
• Opioid Use Disorder
• Suicidality as assessed by the Patient Health Questionnaire-9 (PHQ-9) Question 9 score ≥ 1
• Pregnancy, breastfeeding, or planning to conceive
• Planned cancer treatment in the < 3 months following surgery
• Conditions causing inability to complete assessments (education, cognitive ability, mental status, medical status)
• Participating in another clinical trial with an active treatment arm