Can Opioid Duration of Action Predict Unintentional Overdose Risk?


In a study published in JAMA Internal Medicine, researchers examined whether opioid duration of action is related to risk of unintentional overdose (OD) injury.

Misconceptions of opioid abuse and overdose rooted in media coverage highlight a need for pharmacists to educate both prescribers and patients about this issue.

Researchers recently examined whether opioid duration of action is related to risk of unintentional overdose injury. To answer this question, they studied patients receiving care within the US Department of Veterans Affairs (VA) Healthcare System.

The investigators conducted a propensity score-adjusted cohort study to ensure that the outcome stemmed from the difference in opioid duration of action, rather than the patients’ observed characteristics.

Patient Characteristics

The study population was limited to new users of opioids and patients with chronic, noncancer pain. “New user” was defined as a patient with a minimum of 6 months without opioid use before the first day on which an opioid prescription was filled.

Opioid Exposure

The opioids included in the study were those most commonly prescribed in the VA system.

Long-acting opioids:

  • Sustained-release morphine sulfate
  • Methadone hydrochloride
  • Controlled-release oxycodone hydrochloride
  • Levorphanol tartrate
  • Fentanyl patch

Short-acting opioids:

  • Codeine phosphate
  • Hydrocodone
  • Oxycodone

Injectable opioids and opioids combined with other agents in elixirs were excluded.

All opioid doses were converted to morphine-equivalent mean daily doses to ensure that any observed overdoses were related to the drug’s formulation and not the dose administered.

Study Results

Of 840,606 eligible patients, 19,000 were excluded for receiving opioids other than those specified above.

Of the remaining patients, 801,729 (97.7%) received short-acting opioids, while 18,887 (2.3%) received long-acting ones.

A total of 319 unintentional overdose events were observed, about half of which occurred within the first 60 days of therapy initiation. Of the events, 282 were seen among patients taking short-acting opioids, and 37 occurred among those taking long-acting opioids.

Overdose rates were higher for both groups during the first 2 weeks of therapy, and they remained 2.5 times higher for the group receiving long-acting opioids even after adjustment for age, sex, and dose. Risk for overdose was 5-fold higher during the first 2 weeks of therapy for long-acting group and decreased to 2-fold afterwards.

Overdose Risk Factors

Patients receiving long-acting opioids were more likely to have baseline risk factors for unintentional overdose injury, which include substance abuse disorder, psychiatric morbidity, and concomitant use of barbiturates, antidepressants, and sedative-hypnotics.

Even after adjustment for these factors, overdose risk remained high for those receiving long-acting agents, particularly soon after initiation. Recipients of long-acting formulations were also more likely to receive higher daily doses and have back or neck pain, depression, anxiety, and substance abuse disorders.

Study Limitations

Pharmacists must always keep in mind the applicability of study results and whether the study population is reflective of their patient community. In this study, the typical patient was a white male aged older than 50 years who had chronic medical conditions and received care within the VA health system.

Key Takeaways for Pharmacists

  • Consider both the daily opioid dose prescribed and its duration of action.
  • Favor short-acting opioids over long-acting agents when possible, especially during the first 2 weeks of therapy.
  • Assess patients for baseline risk factors for unintentional overdose injury.


Miller M, Barber CW, Leatherman S, Fonda J, Hermos JA, Cho K, Gagnon DR. Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. JAMA Intern Med. 2015 April; 175(4): 608—615. doi: 10.1001/jamainternmed.2014.8071.

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