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In patients prescribed stable, long-term, high-dose opioid therapy, is dose tapering associated with an increased risk of overdose or mental health crisis?
In this retrospective cohort study that included 113 618 patients prescribed stable, high-dose opioid therapy, patients in periods following dose tapering, compared with patients before or without tapering, had an adjusted incidence rate ratio of 1.68 for overdose and 2.28 for mental health crisis; both risks were statistically significant.
Opioid dose tapering was associated with increased risk for overdose and mental health crisis, but interpretation of these findings is limited by the study design.
Opioid-related mortality and national prescribing guidelines have led to tapering of doses among patients prescribed long-term opioid therapy for chronic pain. There is limited information about risks related to tapering, including overdose and mental health crisis.
To assess whether there are associations between opioid dose tapering and rates of overdose and mental health crisis among patients prescribed stable, long-term, higher-dose opioids.
Design, Setting, and Participants
Retrospective cohort study using deidentified medical and pharmacy claims and enrollment data from the OptumLabs Data Warehouse from 2008 to 2019. Adults in the US prescribed stable higher doses (mean ≥50 morphine milligram equivalents/d) of opioids for a 12-month baseline period with at least 2 months of follow-up were eligible for inclusion.
Opioid tapering, defined as at least 15% relative reduction in mean daily dose during any of 6 overlapping 60-day windows within a 7-month follow-up period. Maximum monthly dose reduction velocity was computed during the same period.
Main Outcomes and Measures
Emergency or hospital encounters for (1) drug overdose or withdrawal and (2) mental health crisis (depression, anxiety, suicide attempt) during up to 12 months of follow-up. Discrete time negative binomial regression models estimated adjusted incidence rate ratios (aIRRs) of outcomes as a function of tapering (vs no tapering) and dose reduction velocity.
The final cohort included 113 618 patients after 203 920 stable baseline periods. Among the patients who underwent dose tapering, 54.3% were women (vs 53.2% among those who did not undergo dose tapering), the mean age was 57.7 years (vs 58.3 years), and 38.8% were commercially insured (vs 41.9%). Posttapering patient periods were associated with an adjusted incidence rate of 9.3 overdose events per 100 person-years compared with 5.5 events per 100 person-years in nontapered periods (adjusted incidence rate difference, 3.8 per 100 person-years [95% CI, 3.0-4.6]; aIRR, 1.68 [95% CI, 1.53-1.85]). Tapering was associated with an adjusted incidence rate of 7.6 mental health crisis events per 100 person-years compared with 3.3 events per 100 person-years among nontapered periods (adjusted incidence rate difference, 4.3 per 100 person-years [95% CI, 3.2-5.3]; aIRR, 2.28 [95% CI, 1.96-2.65]). Increasing maximum monthly dose reduction velocity by 10% was associated with an aIRR of 1.09 for overdose (95% CI, 1.07-1.11) and of 1.18 for mental health crisis (95% CI, 1.14-1.21).
Conclusions and Relevance
Among patients prescribed stable, long-term, higher-dose opioid therapy, tapering events were significantly associated with increased risk of overdose and mental health crisis. Although these findings raise questions about potential harms of tapering, interpretation is limited by the observational study design.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Alicia Agnoli, MD, MPH, MHS, Department of Family and Community Medicine, University of California, Davis, 4860 Y St, Ste 2300, Sacramento, CA 95817 (firstname.lastname@example.org).
Accepted for Publication: June 21, 2021.
Author Contributions: Drs Agnoli and Fenton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Agnoli, Magnan, Jerant, Fenton.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Agnoli, Jerant, Fenton.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Xing, Tancredi, Magnan, Fenton.
Obtained funding: Agnoli, Fenton.
Administrative, technical, or material support: Agnoli, Magnan, Jerant.
Supervision: Agnoli, Magnan, Jerant, Fenton.
Conflict of Interest Disclosures: Dr Agnoli reported receiving grants from the University of California Davis School of Medicine Dean's Office (scholar in women's health research; BIRCWH/K12) during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was supported by a University of California–OptumLabs Research Credit and the Department of Family and Community Medicine, University of California, Davis. Dr Agnoli was supported by the University of California, Davis School of Medicine Dean’s Office (Dean’s Scholarship in Women’s Health Research).
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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