High Dose, Prolonged Opioid Use Associated with Adverse Events and Death


A daily opioid dose higher than 90 MME is associated with 3-fold risk increase, compared to 90 MME or lower.

Siyana Kurteva, BSc

Siyana Kurteva, BSc

A recent study aimed to estimate the harms associated with opioid use, related to dose and duration of use and whether the risk is modified by treatment indication and age.

Investigators, led by Siyana Kurteva, BSc, Clinical and Health Informatics Research Group, Department of Medicine, McGill University, found that opioid use for prolonged duration and at high doses were associated with an increased risk of opioid-related adverse event or death.


Kurteva and colleagues used an ad hoc cohort study to follow up with patients enrolled in a cluster randomized trial of medical reconciliation at the McGill University Health Centre (MUHC) 12 months after discharge from a medical or surgical unit.

The study used data from patients enrolled in October 2014 – November 2016.

Patients were required to have filled at least 1 opioid prescription in the 90 days after discharge. Exclusions included patients with a history of using methadone hydrochloride or buprenorphine hydrochloride.

Investigators used multiple data sources with demographic, clinical, health care use, and prescription claims retrieved from the Régie de l’Assurance Maladie du Québec (RAMQ) and data on medications at admission, in hospital, and discharge from the MUHC Data Warehouse.

The team used time-varying measures of opioid use including current use (no or yes, daily morphine milligram equivalent (MME) dose (90 MME or >90 MME), cumulative use duration (1-30, >30-60, >60-90, and >90 days), and continuous use duration (0, 1-30, 30-60, and >60 days).

Investigators also collected data on the type of ingredient in prescription opioid, including codeine sulfate, morphine sulfate, oxycodone hydrochloride, hydromorphone, hydrochloride, fentanyl citrate, or multiple opioid products.

Primary outcomes included opioid-related emergency department visits, hospital readmission, or all-cause death in the year after discharge. It was collected through RAMQ medical services claims and hospitalization databases.

Investigators used multivariable marginal structure Cox proportional hazards regression models to identify an association between time-varying opioid use and risk of outcome.


From a total of 3486 participants in the cluster randomized trial, 1511 patients were included in the ad hoc cohort study.

During discharge from the hospital, 202 of 392 patients (51.5%) from the medical unit and 987 of 1119 patients (88.2%) from the surgical unit were prescribed opioids.

Investigators noted out of the 348 patients who did not receive an opioid prescription at discharge, 178 (51.2%) filled an opioid prescription in the 7 days after discharge.

The team also found in patients with ≥1 opioid dispensation, 241 (15.9%) had an opioid related ED visit, hospital readmission, or death.

Most frequent adverse events found were fractures (51.8%), nausea and vomiting (15.6%), and dizziness (18.4%).

Further, the team found that current opioid use was associated with a 71% increased risk of opioid-related adverse events (adjusted hazard ratio AHR 1.71; 95% CI, 10.04 – 2.82).

In comparison to exposure of 1 – 30 days, investigators found longer past use of more than 60 to 90 days (AHR, 2.45; 95% CI, 1.18 - 5.09) and more than 90 days (AHR, 2.56; 95% CI, 1.25-5.27) were associated with a 2-fold increase in risk of adverse events.

The team found a 3 times higher risk increase in a daily dose higher than 90 MME (AHR 3.51; 95% CI, 1.58 – 7.82), compared to 90 MME or lower.


Investigators concluded the data show opioid use for prolonged durations and higher doses are associated with an increased risk of adverse events or death.

The team noted that treatment indications and accounting for alternative opioid consumption patterns may help quantify the risk of adverse events in patients.

“These results can inform policies or strategies for minimizing the harms and risks associated with opioid-related morbidity,” investigators wrote. “Opioid use duration and opioid doses may need to be adjusted for patients who are transitioning from acute postoperative to chronic pain.”

The study, “Association of Opioid Consumption Profiles After Hospitalization with Risk of Adverse Health Care Events,” was published online in JAMA Network Open.

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