Pain Management

Short-Acting Opioids Decrease Risk of Overdose

A new study concludes that injured workers are at significantly higher risk for unintentional overdose when prescribed long-acting opioids.
By: | March 23, 2015

Injured workers in chronic pain who are prescribed opioids would likely have fewer risks with short-acting drugs, suggests a new study. Researchers found a higher risk of unintentional overdoses among pain patients taking long-acting medications.

Researchers evaluated chronic pain patients in the Veterans Administration Healthcare System prescribed many of the opioids used in the workers’ comp system. They evaluated the connection between an opioid’s duration of action and unintentional overdose.

Long-acting agents were said to be those that have “either an inherently long serum half-life or a delivery vehicle that allows less-frequent administration (i.e., at most, twice daily),” according to the study. “The long-acting opioids in the present study included orally administered sustained-release morphine sulfate, methadone hydrochloride, controlled-release oxycodone hydrochloride, levorphanol tartrate, and fentanyl patches.” Short-acting opioids used in the study — codeine phosphate, hydrocodone, and oxycodone — were packaged as single agents or combination products containing acetaminophen or aspirin.

Researchers reported their findings in the Journal of the American Medical Association.

“Patients who initiated opioid therapy with long-acting agents were at significantly higher risk of unintentional overdose events compared with those given prescriptions for shorter acting agents,” the study says. “Risk was especially high shortly after opioid therapy began (5-fold higher) and remained elevated throughout the 1-year study period (relative risk was approximately 50 percent higher for patients receiving long-acting opioids beyond 60 days of continuous opioid use).”

The Study

The researchers set out to analyze whether the risk of unintentional overdose was associated with the duration of opioid action, long-acting vs. short-acting formulations. They looked at clinical and pharmacy data involving more than 840,000 chronic pain patients in the VA system, mostly men over the age of 50.

“To our knowledge, the findings of the present study provide the first evidence that the risk of unintentional overdose injury is related to the prescribed opioid’s duration of action,” the report says. “The relationship between particular opioid regimens and the risk of overdose remains poorly understood for several reasons.”

Most randomized clinical trials have been too small to generate meaningful results. Many of the studies have focused on the actual dose rather than modified attributes of prescriptions such as whether the opioid agent or type used matters when the dose is controlled. Additionally, previous studies have typically been limited, for example, failing to distinguish between intentional and unintentional overdoses.

The veterans included in the study received care during a 10-year period from Jan. 1, 2000, to Dec. 31, 2009. Patients studied included only new users of opioids, meaning each had at least six months without the use of an opioid.

Only noncancer pain patients were included in the study. Chronic pain was generally limited to things such as general chronic pain, headaches, atypical face pain, back and neck pain, arthritis, arthropathies, and neuropathies.

Of the 840,606 eligible patients in the study, most — 801,729 — received short-acting agents. There were 18,887 new users of long-acting opioid monotherapy.

The patients given prescriptions for long-acting opioids generally received higher daily doses than those receiving short-acting opioids, and were more likely to have back and neck pain, depression, anxiety, post-traumatic stress disorder, and substance use disorders. They also were more likely to receive concomitant antidepressants and benzodiazepines. The researchers converted each opioid agent to the morphine-equivalent dose to assess and control for the effect of the opioid dose.


There were 319 unintentional overdose events among the sample during the study period of which 282 received short-acting opioids and 37 took long-acting opioids. About half the events occurred within the first two months after the start of the opioid therapy.

“The crude rate of overdose events observed for both short-acting and long-acting opioids was higher during the first 2 weeks after opioid initiation than thereafter, but the heightened risk immediately after initiation therapy was far more marked among patients initiating therapy with long-acting opioids than for patients initiating therapy with short-acting opioids,” the study says. “The crude hazard ratio of unintentional overdose events during the study period was more than 2.5 times higher for persons initiating therapy with long-acting opioids (35 per 10,000 person-years) compared with persons initiating therapy with short-acting opioids (14 per 10,000 person-years). After adjustment for age, sex, and opioid dose, the patients receiving long-acting opioids still had a 2.5-fold higher risk of overdose.”

In terms of the dosages prescribed, the researchers found the risk of overdose among patients receiving higher dose therapy was greater. Those receiving more than 50 mg equivalents of morphine were at more than twice the risk of those receiving 1 to 20 mg equivalents.

The researchers said the event rates they reported were probably underestimates because unintentional overdoses may go unreported for a variety of reasons such as:

  • The person died before seeking medical attention.
  • The patient did not seek medical attention for a nonfatal event.
  • The person received medical attention outside the VHA system.

Despite any limitations of the study, the authors believe the findings are the first clear evidence to associate unintentional opioid overdoses with a prescribed opioid’s duration of action.

“If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regiments should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first two weeks of therapy.”

Nancy Grover is the president of NMG Consulting and the Editor of Workers' Compensation Report, a publication of our parent company, LRP Publications. She can be reached at [email protected].

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