Higher doses of opioids – the equivalent of 50 mg/dL or more of morphine – are more likely than are lower doses to lead to unintentional overdose, according to a report in the April 6 issue of JAMA.
However, the practice of adding a prescription for as-needed opioids to an existing prescription for regularly scheduled opioids, which allows patients to deal with acute exacerbations of pain, does not raise the risk of unintentional overdose in most patients, as some experts have feared, said Amy S.B. Bohnert, Ph.D., of the Department of Veterans Affairs and the University of Michigan, both in Ann Arbor, and her associates.
Citing a "troubling and dramatic" 124% increase in unintentional deaths from opioid overdose in the United States in recent years, the investigators examined the relationship between opioid-prescribing patterns and opioid-related deaths using a nationally representative sample of 155,434 cases in the VA’s National Patient Care Database.
The study subjects included patients taking opioids for cancer pain, chronic bodily pain, headache, neuropathy, and injuries; the prescribed opioid analgesics included codeine, morphine, oxycodone, hydrocodone, oxymorphone, and hydromorphone.
There were 750 deaths attributed to unintentional overdose, for an overall rate of 0.04% among all patients treated with opioids. The risk of overdose increased when the opioid dose was equivalent to 50 mg/dL of morphine, and there was a dose-response relationship in which increasing daily prescribed doses of opioids correlated with increasing risk of overdose death.
As an example, prescribed doses of 100 mg/dL or higher were associated with a hazard ratio of approximately 12.
Dr. Bohnert and her colleagues described their study as the first to assess concurrent prescribing of regularly scheduled opioids plus as-needed opioids. With the exception of cancer patients, participants treated with this strategy showed no excess risk of overdose. "Recent treatment guidelines have indicated that the long-term safety of this strategy for pain exacerbations has not been established, [but] in [this] study we did not find evidence of greater overdose risk associated with this treatment practice, after accounting for maximum daily dose and patient characteristics," they noted (JAMA 2011;305:1315-21).
The researchers also said theirs is the first study of this issue to include patients with cancer. The overall rate of opioid overdose was lower in cancer patients, compared with other subjects, but clinicians should be mindful that renal and liver impairment in this patient group can interfere with the metabolism of opioids and that high doses can place cancer patients at risk.
Cancer patients also were at increased risk of overdose if they were prescribed as-needed opioids alone, rather than regularly scheduled opioids. "Pain for patients with cancer can be particularly rapid in onset, unpredictable, and severe, and taking opioid doses as needed may result in [sudden] high doses being taken without the benefit of tolerance developed through a regularly scheduled opioid," the investigators said.
In a research letter accompanying this report, Dr. Nora D. Volkow, director of the National Institute on Drug Abuse, and her associates presented data from their study of prescription practices, which was aimed at identifying possible contributors to the high rate of opioid abuse. They drew on information in a national prescription database that included about 80 million prescriptions for opioid analgesics.
The main prescribers were general, family medicine, and osteopathic physicians, who accounted for 29% of these prescriptions, followed by internists (15%), dentists (8%), and orthopedic surgeons (8%).
Across all specialties, more than half of these prescriptions (56%, or 45 million) were given to patients who had already filled another opioid prescription during the preceding month. The data could not show whether such prescribing was "justified" or rather "suggests the need to improve information infrastructures that could enhance the safety of prescribed opioid analgesics and minimize diversion," Dr. Volkow and her colleagues said (JAMA 2011;305:1299-1301).
In addition, they found a fivefold increase in drug-treatment admissions for pharmaceutical opioids, from 19,941 to 121,091 in the past 10 years. Emergency department visits related to opioid overdose rose from 144,644 to 305,885 between 2004 and 2008. And deaths from unintentional opioid overdose have quadrupled, from approximately 3,000 in 1999 to 12,000 in 2007.
"Opioid overdose is now the second leading cause of unintentional death in the United States, second only to motor vehicle crashes," they noted.
The study by Dr. Bohnert and her colleagues was supported by the U.S. Department of Veterans Affairs’ Office of Mental Health Services and Office of Patient Care Services. One of Dr. Bohnert’s associates reported ties to Purdue Pharma. Dr. Volkow and her colleagues reported no disclosures.