Opioid Dose, Treatment Length Linked to Adverse Health Care Events and Outcomes

The researchers’ goal was to estimate the risk of harm associated with opioid dose and duration of use and then to determine whether the risk is modified by the patients’ treatment indication and age.

Adverse health care events and outcomes are associated with higher opioid doses used over a longer treatment period, according to research results published in JAMA Network Open.

Researchers conducted a prospective cohort study that included patients 12 months after discharge from a medical or surgical unit to estimate the risk of harm associated with both opioid dose and duration of use, as well as whether treatment indication and age modify this risk. Patients were originally enrolled in a cluster randomized trial of medication reconciliation at the McGill University Health Centre in Montreal, Quebec, Canada, between 2014 and 2016.

Investigators measured opioid use 1 year after discharge using Quebec Health Insurance Plan (RAMQ) pharmacy claims data. The primary study outcome was the time from the first opioid dispensation to the earliest first opioid-related emergency department visit, hospital readmission, or death from any cause during the 12 months following discharge.

The original study included 3486 participants (57.7% men; mean age, 69.9±14.9 years), of whom 1511 were included in the current study. Within this cohort, 74.1% underwent surgery and 25.9% received care in a medical unit. At discharge, 88.2% and 51.5% from each unit, respectively, received an opioid prescription.

Of the 348 patients who did not receive an opioid prescription at discharge, 51.2% filled an opioid prescription within the 1-week period following discharge.

Investigators found that fewer surgical patients used opioids prior to admission compared with medical patients (30.7% vs 72.2%); 48.1% and 42.9% of patients in each unit, respectively, had documented cancer diagnoses.

In the 1-year period following discharge, 15.9% of all patients had an opioid-related emergency department visit or hospitalization or died. The most frequent opioid-related adverse events noted were fractures, dizziness, and nausea and vomiting, seen in 51.8%, 18.4%, and 15.6% of patients, respectively.

Current opioid use — defined as patients who had an active prescription on a given day during the follow-up period — was associated with a 71% increased risk for experiencing opioid-related adverse events (adjusted hazard ratio [aHR], 1.71; 95% CI, 1.04-2.82).

Compared with patients who had a shorter cumulative exposure (1-30 days), longer use of more than 60 to 90 days and more than 90 days (aHR, 2.45 and 2.56, respectively) were both associated with a 2-fold increase in adverse event risk (95% CI, 1.18-5.09 and 1.25-5.27). Up to 60 days of uninterrupted, continuous use was associated with a 3-fold increased risk of adverse health care events related to opioid use (aHR, 3.73; 95% CI, 1.83-7.60).

For the few patients who exceeded 60 continuous days of use, investigators found no evidence of an increased adverse event risk (aHR, 0.86; 95% CI, 0.37-1.96).

Opioid-related adverse event or death risk was 3 times higher in patients with a current daily dose >90 morphine milligram equivalents (MME; aHR, 3.51; 95% CI, 1.58-7.82) compared with doses ≤90 MME. Only morphine demonstrated a statistically significant risk increase (aHR, 4.04; 95% CI, 1.02-15.9) vs codeine.

Two statistically significant interactions were found between surgery and current opioid use, and between surgery and more than 90 days of opioid use (aHR, 3.35 and aHR, 7.80). Within patients discharged from a surgical unit, current and cumulative use duration of more than 90 days were associated with a statically significant increased risk of opioid-related adverse events or death (aHR, 3.35 and aHR, 7.80). These associations were not statistically significant for patients discharged from a medical unit.

After excluding previous opioid users, results changed only slightly. In the first month after discharge, 90% of these patients reported using their dispensed opioids as prescribed, with 12% discontinuing their initial dispensation and 5% filling their prescription but never using it. Bias sensitivity analysis results found that patients with a daily opioid dose higher than 90 MME were still at a significantly increased risk of opioid-related adverse health care events, even following adjustment for a “moderately strong unobserved confounder.”

Study limitations include potential exposure mismeasurement, potential unmeasured confounding and confounding by indication, and potential bias due to the selected patient population, as well as an inability to account for opioid medications obtained through either diversion or other illicit avenues.

“We found that using opioids for prolonged duration and at high doses was associated with increased risk of opioid-related adverse events or death,” the researchers concluded. “These results can inform policies or strategies for minimizing the harms and risks associated with opioid-related morbidity. Opioid use duration and opioid doses may need to be adjusted for patients who are transitioning from acute postoperative to chronic pain.”


Kurteva S, Abrahamowicz M, Gomes T, Tamblyn R. Association of opioid consumption profiles after hospitalization with risk of adverse health care events. JAMA Netw Open. 2021;4(5):e218782. doi:10.1001/jamanetworkopen.2021.8782