Use of long-acting, vs short-acting, opioids for chronic pain was linked to unintentional overdose Clinical impact ratings:



Miller M, Barber CW, Leatherman S, et al. Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. JAMA Intern Med. 2015;175:60815.




In veterans with chronic noncancer pain (CNCP), is the use of long-acting, compared with short-acting, opioids associated with unintentional overdose? If so, does this association vary with duration of continuous opioid use?

Clinicians in North America are too familiar with the epidemic of dependence, abuse, and death associated with the rapid increase in opioid prescription over the past 2 decades (1, 2). They may be surprised to learn that Canada and the USA now rank first and second, respectively, in the world for opioid use per capita (3). Opioid-related harm becomes even more tragic when juxtaposed with the absence of evidence of benefit in terms of function or quality of life in CNCP (4).

Methods Design: Retrospective cohort study with linkage of Veterans Health Administration (VHA) databases. Setting: USA. Patients: 840 606 veterans with CNCP (mean age 60 y, 94% men) who filled new prescriptions (≥ 6 mo with no opioid use before index prescription) for short- (n = 801 729) or long-acting (n = 18 887) opioids and had ≥ 1 inpatient or outpatient encounter with the VHA in the year before the index prescription. Exclusion criteria included enrolment in hospice in the year before the index prescription or ineligibility for VHA benefits. Risk factors: Duration of opioid action and duration of opioid use. Outcomes: Unintentional overdose (events coded as drug or medication poisonings of accidental or undetermined intent, without accompanying code for external cause of injury).

Main results Compared with short-acting opioids, use of long-acting opioids was associated with increased risk for unintentional overdose overall, with the risk seeming to be highest in the first 14 days (Table).

Conclusion In veterans with chronic noncancer pain, use of long-acting opioids was associated with unintentional overdose events compared with short-acting opioids, especially in the first 14 days of use.

Miller and colleagues' well-done, propensity-matched cohort study of VHA patients compared newly prescribed long- and short-acting opioids, a recent area of focus. Despite methodologic concerns related to unmeasured confounders, more psychiatric morbidity, and more psychoactive drug use in the longacting opioid user group, and the restricted VHA population (older male veterans), the study provides strong evidence that long-acting opioids (slow-release morphine, controlled-release oxycodone, levorphanol, nonliquid methadone, and fentanyl patches) prescribed to opioid-naı¨ve patients increase the risk for unintentional overdose. More data on the clinical outcomes and resource utilization related to these events would have been helpful. What should clinicians do in the face of well-meaning, but not strictly evidence-based, guidelines; aggressive pharmaceutical promotions; patients who are often desperate for pain relief; a dearth of high-quality randomized trials; and not a single highly effective and safe analgesic to prescribe? For now, starting opioid therapy in CNCP with long-acting agents should be completely avoided. Current evidence also supports avoiding longacting agents altogether, not co-prescribing other sedating drugs, keeping morphine-equivalent doses < 80 mg/d, and maintaining strict control of quantity and interval of dispenses and protocols to taper or stop opioids. Anne Holbrook, MD, PharmD McMaster University Hamilton, Ontario, Canada

Source of funding: Centers for Disease Control and Prevention. For correspondence: Dr. M. Miller, Northeastern University, Boston, MA, USA. E-mail [email protected] 

References 1. Dhalla IA, Mamdani MM, Sivilotti ML, et al. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ. 2009;181:891-6.

Association between use of long- vs short-acting opioids and unintentional overdose in veterans with chronic noncancer pain* Duration of opioid use

Event rates/10 000 person-y Long-acting


Adjusted hazard ratio (95% CI)†




2.33 (1.26 to 4.32)



5.25 (1.88 to 14.72)

15 to 60 d



2.30 (0.67 to 7.90)

> 60 d



1.50 (0.68 to 3.33)

≤ 14 d

2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305: 1315-21. 3. Pain & Policy Studies Group. (accessed 12 May 15). 4. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of longterm opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015:162: 276-86.

*CI defined in Glossary. †Adjusted for all available covariates.

21 Jul 2015

Annals of Internal Medicine

ACP Journal Club

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姝 2015 American College of Physicians

ACP Journal Club. Use of long-acting, vs short-acting, opioids for chronic pain was linked to unintentional overdose.

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