Patient Safety Tip of the Week

February 24, 2015

More Risks with Long-Acting Opioids



For quite some time now we have highlighted the dangers of long-acting and/or extended-release opioids (see our Patient Safety Tips of the Week for June 28, 2011 “Long-Acting and Extended-Release Opioid Dangers” and  July 24, 2012 “FDA and Extended-Release/Long-Acting Opioids”). Unintentional overdoses with prescription opioids have escalated over the past two decades as prescriptions for all types of opioids have increased. Undoubtedly the development and marketing of multiple opioid preparations has contributed to the increase in prescribing of opioids.


A 2013 CDC report (CDC 2013) showed that fatal overdoses of prescription opioids more than quadrupled between 1999 and 2010 and now exceed fatal overdoses of illicit drugs like heroin and cocaine.


Now a new study further emphasizes the dangers of long-acting opioids in producing unintentional overdoses. Miller and colleagues (Miller 2015) analyzed clinical and pharmacy data from a large VA population over a 10-year period. They identified those patients with non-cancer chronic pain who were newly begun on opioids (having received no opioids for at least the preceding 6 months) and created a propensity-matched cohort for comparison. After adjustment for multiple variables, those patients on long-acting opioids were more than twice as likely to suffer an unintentional overdose than those taking short-acting opioids (hazard ratio 2.33). The risk was especially high during the first two weeks of therapy, where those taking long-acting opioids were more than 5 times more likely to suffer an unintentional overdose. After the first two weeks the risk for unintentional overdose remained twice as high in the group on long-acting opioids. These findings also likely represent an underestimate of the actual occurrence of unintentional overdose.


Opioids in the long-acting group included sustained-release oral morphine sulfate, methadone hydrochloride, controlled-release oxycodone hydrochloride, levorphanol tartrate, and fentanyl patches (they excluded liquid methadone hydrochloride because that is typically used in the VA system for treating opioid addiction).


Though the study had limitations (retrospective design, use of claims database, predominantly male veteran population, inability to exclude unidentified confounders) it nevertheless drives home several important points.


First and foremost is that these long-acting and extended-release opioid formulations are not intended for use as first-line agents in opioid-naοve patients. The newer opiate formulations are either more potent or designed to produce a longer peak action, two characteristics that lead to some of the greatest dangers that have been popping up. We are referring to the long-acting and extended-release forms of opiates. These have been designed to be used in patients who are opioid-tolerant and have pain of a chronic nature that has not been controlled with more conventional opiates. They were not intended to be used for treatment of acute pain nor to be used as first line agents in patients with pain. But in practice they are often being (mis)used in that way.


A second significant factor related to the association between long-acting opioids and overdoses is dosage. The amount of morphine equivalents in these preparations is higher than that found in most short-acting formulations and many prescribers are not appreciative of this. Of course, the issue of dose is not unique to the long-acting opioids. We’ve highlighted the same problem with HYDROmorphone in our September 21, 2010 Patient Safety Tip of the Week “Dilaudid Dangers” and the other columns on HYDROmorphone safety issues listed below. It is also problematic that when switching from short-acting opioids to long-acting or extended-release opioids it is very common to see misunderstandings of the relative potencies of the various opiate preparations.


A third important factor is use of concomitant medications. In the Miller study those patients in the long-acting group were more likely to be also taking benzodiazepines and antidepressants. The increased risk for the long-acting group held up even after adjustments for such variables. However, multiple studies have shown that opioid overdoses, particularly fatal ones, often involve drugs in addition to the opioids. A study of fatal overdoses (Jones 2013) showed many cases had concomitant use of benzodiazepines, antidepressants, antiepileptic agents, antiparkinsonism agents, and antipsychotic or neuroleptic medications. Conversely, fatal overdoses primarily due to these other medications also commonly involved opioids.


Note that long-acting opioid formulations are also now frequent causes of accidental overdoses, including those for whom they were not prescribed such as children and pets (see our September 13, 2011  Patient Safety Tip of the Week “Do You Use Fentanyl Transdermal Patches Safely?” and our May 2012 What’s New in the Patient Safety World column “Another Fentanyl Patch Warning from FDA”).


CPOE (computerized physician order entry) and electronic prescribing probably have the greatest potential to reduce the inappropriate prescribing of long-acting or extended-release opioids. Alerts during CPOE can help prevent their use in opioid-naοve patients and ensure there is a legitimate indication for use of such agents. Similarly, clinical decision support tools during CPOE can help physicians better understand the dosing equivalency issues for each opioid formulation. But we also need to be aware that we do not unintentionally encourage use of such drugs during CPOE. We have seen standardized order sets that have included these formulations as options for pain management for some conditions.


Linking electronic prescribing to prescription databases maintained by state health departments also has great potential to prevent overdoses related to prescription opioids. A study done in Tennessee identified significant risk factors for opioid-related overdose deaths (Gwira Baumblatt 2014). Those risk factors included receiving opioid prescriptions from 4 or more providers, using 4 or more pharmacies, and having a total dose of more than 100 morphine milligram equivalents per day. The authors estimate that about half of the patients could have been identified using these criteria before their deaths.


Our October 2013 What’s New in the Patient Safety World column “Opioid Safety Actions and Resources” provided links to some valuable resources from the FDA, ISMP Canada, SAMHSA, and some state health department resources to help prevent prescription opioid overdoses. The SAMHSA Opioid Overdose Prevention Toolkit includes not only recommendations for physicians regarding opioid prescribing and management but also resources for patients and families, first responders, and community members. It even has resources for survivors of opioid overdose and family members. It has good discussions about recognizing signs and symptoms of opioid overdose and treating overdoses. It also discusses consideration of prescribing a naloxone kit (for emergency treatment of overdose) at the time the opioid prescription is made.


You are probably aware that many communities have begun providing education and naloxone kits to emergency response personnel (eg. police). An observational study in Massachusetts showed that death rates from opioid overdose were reduced in communities where overdose education and naloxone distribution was implemented compared with not implemented (Walley 2013).


The decision to prescribe opioids should not be made without careful consideration of potential risks and benefits and individual patient circumstances. The decision to prescribe long-acting or extended-release opioids requires consideration of even more detailed factors and should not be undertaken lightly.



Our prior articles pertaining to long-acting and/or extended release preparations of opioids:



Our prior columns on patient safety issues related to Dilaudid/HYDROmorphone:







CDC. Addressing prescription drug abuse in the United States: current activities and future opportunities. Atlanta: Centers for Disease Control and Prevention, 2013



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; Published online February 16, 2015



Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA 2013; 309: 657-659



Gwira Baumblatt JA, Wiedeman C, Dunn JR, et al.  High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med 2014; 174(5): 796-801



SAMHSA (Substance Abuse & Mental Health Services Administration).

Opioid Overdose Prevention Toolkit. Updated 2014



Walley AY, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ 2013; 346 doi: (Published 31 January 2013)





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