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Tapering Opioids May Drive Overdose, Mental Health Crises

September 26, 2021
Individuals with chronic pain tapered off opioids after long-term treatment could be at higher risk for depression. How to manage opioid reduction safely.

with Beth Darnall, PhD

Tapering of opioids was significantly associated with increased risk of overdose and mental health crisis in patients prescribed long-term, stable, higher-dose therapy, based on data from a retrospective study of more than 100,000 adults aged 18 years and older.

Opioid tapering was defined in this study as a relative reduction in mean daily dose by at least 15% during any of 6 overlapping 60-day tapering windows as part of a 7-month follow-up period. (Image: iStock).

Deprescribing Opioids

Although CDC guidelines and other organizations have advised tapering doses of opioids in patients on long-term therapy, studies suggesting increased risk of suicidal ideation, overdose, and transition to illicit opioids prompted the FDA to issue a prescriber warning on the potential hazards of rapid tapering, wrote Alicia Agnoli, MD, of the University of California, Davis, Sacramento, and colleagues.1

“As clinicians and patients face difficult decisions about whether and how to de-prescribe opioids, there is a need to elucidate the potential harms of stopping or decreasing these medications,” they wrote in the article.

In their study, published in JAMA, Dr. Agnoli et al identified 113,618 adult patients who were prescribed stable higher doses of opioids for a 12-month baseline period with at least 2 months’ follow-up between 2008 and 2018. Higher dose was defined as an average of at least 50 mg/day of morphine milligram equivalents. Opioid tapering was defined as a relative reduction in mean daily dose by at least 15% during any of 6 overlapping 60-day tapering windows as part of a 7-month follow-up period.

A total of 29,101 patients underwent tapering, and 84,517 had no tapering. Baseline demographics including age, education, insurance status, proportion of urban vs. rural residence, were similar between the groups. The average age was approximately 54 years, and half were women. However, patients in the tapering group had significantly higher baseline opioid doses, and significantly higher rates of depression and anxiety, as well as higher baseline rates of overdose and drug use disorder.

Opioid Tapering Risks

The primary outcomes were overdose and mental health crisis following a tapering period. In their first analysis, the researchers compared the risk of overdose and mental health crisis in patients who underwent tapering during their tapered and non-tapered periods. Mental health crisis was a composite of depression, anxiety, and attempted suicide.

During tapered periods, the adjusted incidence rate of overdose events was 9.3 events per 100 person-years, vs. 5.5 events per 100 person-years during non-tapering periods, for an adjusted incidence rate ratio (aIRR) of 1.68. The adjusted incidence rate ratio of mental health crisis was 7.6 events per 100 person-year during tapering vs. 3.3 events per 100 person-years in non-tapered periods for an aIRR of 2.28.

Opioid Tapering and Mental Health

Tapering also was associated with increased risk for each of the components of the mental health crisis outcome: depression events (aIRr 2.46), anxiety events (aIRR 1.79), and suicide attempts (aIRR 3.30).

The researchers analyzed maximum monthly dose reduction velocity, and found that a 10% increase in maximum monthly dose reduction velocity was associated with increases in both overdose and mental health crises (incidence rate ratios of 1.09 and 1.18, respectively).

The study findings were limited by several factors, mainly by the observational design, which limits interpretation of the results, the researchers noted. Other limitations included possible confounding from unmeasured variables that might have impacted adverse events in the tapering patients, the inability to assess tapering circumstances, and the lack of accurate measures of race and ethnicity, they added.

However, the results were strengthened by the large sample size and consistent with those of other recent studies of opioid discontinuation, they said. The absolute differences of approximately 3 to 4 per 100 person-years in rates of both overdose and mental health crisis in tapering vs. non-tapering patients “suggest that adverse events associated with tapering may be relatively common and support HHS recommendations for more gradual dose reductions when feasible and careful monitoring for withdrawal, substance use, and psychological distress,” the team wrote. More research is needed to inform clinical guidance on patient selection, optimal dose reduction rates, and strategies for patient monitoring and support, they concluded.

Opioid Tapering and Risk Reduction Merits More Research

“Risks associated with opioid prescribing are fairly well appreciated, but far less appreciated are the risks associated with opioid reduction,” said Beth Darnall, PhD, director of the Stanford Pain Relief Innovations Lab at Stanford University, California, in an interview. (More on Dr. Darnall’s role in the pain management field.)

“This study highlights important potential harms that are associated with prescription opioid tapering in people with chronic pain,” Dr. Darnall told PPM. “The large dataset of more than 100,000 patients suggested associations with tapering and patient distress, mental health crises, and suicidality,” she noted. “While work remains to understand these associations in greater detail, these findings reveal that patients with chronic pain need better protections within the healthcare system.”

Dr. Darnall noted that the findings “align with increasing reports of iatrogenic harms associated with opioid tapering, forced tapering, including psychological distress, suicidality and suicides. Involuntary tapering may carry greater risks.” A previous study in a population of veterans documented risks and harms from opioid tapering, and the authors suggested monitoring patients not only during a taper, but also up to three months later, Dr. Darnall added.

How to Taper Opioids Safely

A take-home message for clinicians is to “Apply patient-centered care that focuses on the needs of the individual person rather than on an opioid dose or an algorithm,” advises Dr. Darnall. “Taper at the pace that is comfortable and acceptable to the patient. Closely monitor patient response closely during an opioid taper and for at least three months after a taper,” she emphasized. “Have a plan in place for managing the patient’s pain and distress and have systems that support rapid action and flexibilities to address patient needs,” she adds. “While very slow tapering is best, we must allow ‘no taper’ for some patients. Not all patients need to be tapered or should be tapered. Appreciating the heterogeneity of patients and chronic pain requires we appreciate the heterogeneity in opioid response.”

Opioid Tapering and the EMPOWER Study: Progress to Date

In the Stanford Pain Innovations Research Lab, Dr. Darnall and colleagues are conducting the EMPOWER study “a 4-state voluntary prescription opioid tapering study that is embedded into clinical care in pain and primary care clinics,” said Dr. Darnall. The EMPOWER study is funded by the Patient-Centered Outcomes Research Institute.2,3 “We enhance patient agency and control during the taper. Patients determine the pace of the taper, they may pause the taper if they wish, they can stop their taper; we do not taper to zero unless patients choose that goal, and clinicians may decide to increase opioid doses for patients for whom that seems to be the best course for analgesia,” she explained. “We follow patients weekly during their taper with e-surveys, and we follow each patient for 12 months,” she said.

“We need research to study patients for whom opioids work well, including research that focuses on voluntary and supportive methods for opioid reduction when that is the desired goal,” Dr. Darnall emphasizes. “Patients at high risk for iatrogenic harms during tapering require careful considerations and a much higher level of care than they are currently receiving,” she added.

Other research gaps include tracking of opioid policy implementation “to ensure our policies are not harming some patients,” Dr. Darnall says. “We need research that focuses less on the opioid dose and more on the needs of the person with pain who is taking medication for pain relief.”



Agnoli’s 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 disclosed grant support from the University of California, Davis School of Medicine Dean’s Office.

Dr. Darnall has served on the CDC Opioid Workgroup, and she is the principal investigator for pain and opioid reduction research awards from the Patient-Centered Research Outcomes Research Institute and from the National Institutes of Health. Dr. Darnall also disclosed consultant fees in 2019 from Axial Healthcare related to physician education for opioid prescribing and deprescribing. Dr. Darnall is a scientific member of the NIH Interagency Pain Research Coordinating Committee and a member of the Pain Advisory Group of the American Psychological Association. She is Chief Science Advisor at AppliedVR (personal fees) and receives royalties for four pain treatment books she has authored. Dr. Darnall also serves on the Board of Directors for the American Academy of Pain Medicine and on the Board of Directors for the Institute for Brain Potential.

Last updated on: October 12, 2021
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