Abstract 51 million Americans undergo surgery annually and 10-20% present for surgery with long-term opioid use (LTOU) far exceeding the national prevalence. These patients on LTOU are at overwhelmingly increased risk of postoperative complications, morbidity, mortality, increased pain, persistent postoperative LTOU, and opioid- related harms. Surgery is a critical point-of-care for patients with LTOU as opioids are prescribed regardless of prior problematic opioid use, opioids are acutely escalated for prolonged durations compounded opioid-related harms, and patients are at heightened risk for a myriad of negative postoperative outcomes adversely impacting QOL. Research examining postoperative opioid tapering and non-opioid acute pain management often excludes these vulnerable patients. Our proposal addresses this critical knowledge gap in acute to chronic postoperative pain care for patients with LTOU. Patients are receptive to changes in pain therapy and opioid tapering after surgery, representing a key intervention opportunity. Also, safer alternatives are needed to reduce serious risks of respiratory depression associated with concomitant use of certain common non-opioid and opioid pain medications. This proposal builds off the PI’s research (K23, R01) developing postoperative Motivational Interviewing and guided Opioid Tapering support (MI-Opioid Taper) and demonstrating feasibility and initial empiric support in promoting postoperative opioid cessation without adversely affecting pain even among patients with preoperative opioid use. Tizanidine has analgesic, muscle relaxant, anxiolytic and opioid- sparing effects, and potential to relieve opioid withdrawal symptoms as an 2-agonist. We directly address the HEAL MIRHIQL initiative by examining the combined effects of MI-Opioid Taper (behavioral) and tizanidine (pharmacologic) interventions among patients with preoperative LTOU exhibiting impaired return to baseline opioid use after surgery where harms may outweigh benefits of continued use. In this Type 1 hybrid effectiveness-implementation three-arm parallel RCT, 375 patients with preoperative LTOU undergoing spine surgery will be recruited across 4 sites (Stanford, Harvard, Wake Forest, U. of Kansas) and randomized to 1 of 3 groups (MI-Opioid Taper and tizanidine, MI-Opioid Taper and placebo, enhanced usual care) and followed for 12 months. The primary outcome is time to baseline opioid use. Secondary outcomes are time to opioid cessation, opioid dispensing cessation, pain cessation, and risk of postoperative opioid misuse. We will examine motivation for change, change talk, and reduction in pain as mediators of treatment effects and characterize treatment interactions with participant attributes in predicting both treatment engagement and efficacy. A mixed-methods evaluation using the RE-AIM framework will explore barriers and facilitators to future larger-scale implementation of MI-Opioid Taper. The project will address the unmet needs...