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This systematic review reports the potential for withdrawal, pain level, treatment success, adverse events, and other outcomes of discontinuing long-term opioid therapy and switching to buprenorphine., Key Points Question Is rotation to buprenorphine from full μ-opioid receptor agonists associated with improved pain-related outcomes and acceptable adverse effects in patients with chronic pain and long-term use of opioids? Findings In this systematic review of 22 studies that addressed prespecified outcomes of rotation to buprenorphine, low-quality evidence suggested that buprenorphine rotation was associated with reduced pain without precipitating opioid withdrawal or other serious adverse effects. Meaning These findings suggest that buprenorphine rotation may be a viable option for mitigating the harms of long-term opioid therapy in individuals with chronic pain who were receiving unsafe opioid analgesic regimens; further studies are needed to examine the best way to accomplish buprenorphine rotation., Importance Individuals with chronic pain who use long-term opioid therapy (LTOT) are at risk of opioid use disorder and other harmful outcomes. Rotation to buprenorphine may be considered, but the outcomes of such rotation in this population have not been systematically reviewed. Objective To synthesize the evidence on rotation to buprenorphine from full μ-opioid receptor agonists among individuals with chronic pain who were receiving LTOT, including the outcomes of precipitated opioid withdrawal, pain intensity, pain interference, treatment success, adverse events or adverse effects, mental health condition, and health care use. Evidence Review PubMed, CINAHL, Embase, and PsycInfo were searched from inception through November 3, 2020, for peer-reviewed original English-language research that reported the prespecified outcomes of rotation from prescribed long-term opioids to buprenorphine among individuals with chronic pain. Two independent reviewers extracted data as well as assessed risk of bias and study quality according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Findings A total of 22 studies were analyzed, of which 5 (22.7%) were randomized clinical trials, 7 (31.8%) were case-control or cohort studies, and 10 (45.5%) were uncontrolled pre-post studies, which involved 1616 unique participants (675 female [41.8%] and 941 male [58.2%] individuals). Six of the 22 studies (27.3%) were primary or secondary analyses of a large randomized clinical trial. Participants had diverse pain and opioid use histories. Rationale for buprenorphine rotation included inadequate analgesia, intolerable adverse effects, risky opioid regimens (eg, high dose and/or sedative coprescriptions), and aberrant opioid use. Most protocols were adapted from protocols for initiating treatment in patients with opioid use disorder and used buccal or sublingual buprenorphine. Very low-quality evidence suggested that buprenorphine rotation was associated with maintained or improved analgesia, with a low risk of precipitating opioid withdrawal. Steady-dose buprenorphine was better tolerated than tapered-dose buprenorphine. Adverse effects were manageable, and severe adverse events were rare. Only 2 studies evaluated mental health outcomes, but none evaluated health care use. Limitations included a high risk of bias in most studies. Conclusions and Relevance In this systematic review, buprenorphine was associated with reduced chronic pain intensity without precipitating opioid withdrawal in individuals with chronic pain who were receiving LTOT. Future studies are necessary to ascertain the ideal starting dose, formulation, and administration frequency of buprenorphine as well as the best approach to buprenorphine rotation.