Is Dose Tapering Linked to Mental Health Crises in Setting of Long-Term, High-Dose Opioid Therapy?

A man pouring out many tablets from a prescription bottle
A man pouring out many tablets from a prescription bottle
Opioid dose tapering may be linked to increased risk for overdose and mental health crises in patients taking long-term, high-dose opioids.

Opioid tapering may be associated with an increased risk for overdose and mental health crises in patients prescribed long-term, higher dose opioid therapy, according to research results published in JAMA.

Using deidentified medical and pharmacy claims data from 2007 to 2019, researchers conducted a retrospective cohort study to evaluate the potential associations between opioid tapering and rates of overdose and mental health crisis in patients prescribed long-term and higher-dose opioids.

Primary study outcomes include emergency or hospital encounters for drug overdose or withdrawal and mental health crisis, including depression, anxiety, or attempted suicide, during the 12-month follow-up period.

The total cohort included 113,618 patients who had been prescribed a stable, long-term, higher-dose of opioid therapy for at least 12 months; a total of 203,920 baseline periods were contributed (mean per patient, 1.8; median per patient, 1.0). Within this cohort, 54.3% of patients underwent opioid dose tapering were women (vs 53.2% of those who did not).

In total, 18.2% of baseline periods were followed by tapering for 37,170 tapering events; 20.5% were discontinued at some point during the follow-up period. Median maximum velocity of dose reduction was 22.7% (interquartile range [IQR], 15%-41.3%) per month for tapered periods and 3.2% (IQR, 1.7% to-5.9%) per month without tapering.

Researchers found that those who underwent tapering had significantly higher baseline opioid doses. These patients were also more likely to be coprescribed benzodiazepines and had significantly higher baseline rates of overdose, drug use disorder, depression, and anxiety.

During periods after dose tapering investigators identified an adjusted incidence rate of 9.3 overdose events per 100 person-years, vs 5.5 events per 100 person-years in nontapered periods (adjusted incident rate difference [aIRD], 3.8 per 100 person-years; 95% CI, 3.0-4.6; adjusted incidence rate ratio [aIRR], 1.68; 95% CI, 1.53-1.85).

Opioid tapering was associated with an adjusted incidence rate of 7.6 mental health crises per 100 person-years, vs 3.3 events in nontapered periods (aIRD, 4.3 per 100 person-years; aIRR, 2.28 per 100 person-years; 95% CI, 3.2-5.3 and 1.96-2.65, respectively).

In patients who underwent opioid tapering and had 1 or more outcome event during follow-up, median time to first event was 6 months for both outcomes. Results of secondary analyses of individual components for the mental health crisis outcome showed that tapering was associated with depression, anxiety, and suicide attempts (aIRR, 2.46, 1.79, and 3.30, respectively).

Results of analyses of interaction terms between tapering status and other key covariates indicated informative and statistically significant interactions between baseline dose category and tapering status. For both of these outcomes, patients who were prescribed a higher baseline dose had greater risks associated with tapering compared with those prescribed lower baseline doses.

Further analyses of maximum monthly dose reduction velocity in 109,599 patients followed up over 139,941 person-years showed that an incremental increase in maximum monthly dose reduction velocity of 10% was associated with an increased aIRR for both overdose and mental health crisis (aIRR, 1.09 and 1.18, respectively). In higher maximum monthly dose reduction velocity categories, associations were noted for higher event rates for overdose and mental health crisis.

Study limitations include unmeasured factors that may contribute to an increase in the risk of adverse events in the tapering population, an inability to assess tapering circumstances, and the lack of an accurate measure of race in the study population.

“These findings suggest that adverse events associated with tapering may be relatively common and support [Health and Human Services] recommendations for more gradual dose reductions when feasible and careful monitoring for withdrawal, substance use, and psychological distress,” the researchers concluded.


Agnoli A, Xing G, Tancredi DJ, Magnan E, Jerant A, Fenton JJ. Association of dose tapering with overdose or mental health crisis among patients prescribed long-term opioids. JAMA. 2021;326(5):411-419.