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What’s New in the Patient Safety World

February 2020

The FDA and Long-Acting Opioids

 

 

In multiple columns we have highlighted the dangers of long-acting and/or extended-release opioids (see especially our Patient Safety Tips of the Week for June 28, 2011 “Long-Acting and Extended-Release Opioid Dangers”, July 24, 2012 “FDA and Extended-Release/Long-Acting Opioids” and February 24, 2015 “More Risks with Long-Acting Opioids”, and our February 2017 What's New in the Patient Safety World column “FDA Approves Even More Long-Acting Opioids”).

 

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. 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. And, unfortunately, these preparations became a prime driver of the opioid epidemic in the US.

 

Recognizing that ER/LA opioids were associated with greater risk of addiction, unintentional overdose and death than their immediate-release counterparts, the FDA in 2012 developed the concept of Risk Evaluation and Mitigation Strategy (REMS) programs. These were intended to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics.

 

So how did these REMS do? Not so good, according to a new study (Heyward 2019). Heyward et al. reviewed 9739 pages of FDA documents obtained through a Freedom of Information Act request. Their aim was to investigate whether the FDA and ER/LA manufacturers were able to assess the effectiveness of the ER/LA Risk Evaluation and Mitigation Strategy (REMS) program by evaluating manufacturer REMS assessments and FDA oversight of these assessments.

 

The documents show that the FDA’s REMS program was largely implemented as planned, and that tens of thousands of physicians took CE courses approved through the REMS, and that the courses generally included the content sought by the FDA.

 

The FDA’s goal was for 60% of ER/LA prescribers to take REMS-adherent continuing education (CE) between 2012 and 2016; Only 27.6% of prescribers had done so by 2016. Nonrepresentative cross-sectional surveys of self-selected prescribers suggested modestly greater ER/LA knowledge among CE completers than noncompleters, and claims-based surveillance indicated slowly declining ER/LA prescribing, although the contribution of the REMS to these trends could not be assessed.

 

The effectiveness of the REMS program for reducing adverse outcomes also could not be assessed because the analyses used nonrepresentative samples, lacked adequate controls for confounding, and did not link prescribing or clinical outcomes to prescribers’ receipt of CE training. Although the FDA had requested studies tracking adverse outcomes as a function of CE training, the FDA concluded that these studies had not been performed as of the 60-month report in 2017.

 

The authors conclude that, five years after initiation of the REMS program, the FDA and ER/LA manufacturers could not conclude whether the ER/LA REMS had reduced inappropriate prescribing or improved patient outcomes.

 

Retired FDA senior executive William Hubbard wrote the editorial accompanying the Heyward study (Hubbard 2019). He notes that actions at the federal level to combat the opioid epidemic have been “underwhelming”. He notes that more effective interventions are available, pointing to Florida’s restriction on prescribing. Florida had become known for its “pill mills”. In banned pain management clinics from dispensing drugs and established requirements for medical examinations and follow-ups before and after prescribing opioids for chronic pain. That resulted in a two-thirds reduction in pain clinics. Johnson et al. (Johnson 2014) described the multiple events that took place in Florida in response to a proliferation of pain clinics and a 61% increase in overdose death from 2003 to 2009. Pain clinic regulations were further expanded later in 2010. In February 2011, law enforcement conducted statewide raids, resulting in numerous arrests, seizures of assets, and pain clinic closures. In July of that year, coinciding with a public health emergency declaration by the Florida Surgeon General, the state legislature prohibited physician dispensing of schedule II or III drugs from their offices and activated regional strike forces to address the emergency. Mandatory dispenser reporting to the newly established prescription drug monitoring program began in September 2011. Finally, in 2012, the legislature expanded regulation of wholesale drug distributors and created the Statewide Task Force on Prescription Drug Abuse and Newborns.

 

Many states have implemented restrictions on prescriptions for opioids, for example, limiting initial prescriptions of opioids to a specified time period (eg seven days) for treatment of acute pain.

 

Long-acting and extended-release opioid preparations have clearly played a role in the opioid epidemic that has plagued the US. The crisis has been fed not only by an oversupply of opioids that often gets them into the wrong hands, but also by opioids being prescribed by healthcare professionals. Much of the FDA’s approach has been to focus on abuse-deterrent formulations to discourage abuse (see our February 2017 What's New in the Patient Safety World column “FDA Approves Even More Long-Acting Opioids”).

 

But our concerns over ER/LA opioid preparations extend well beyond just the issues of abuse, illicit use, and addiction. One significant factor related to the association between long-acting opioids and overdoses is dosage equipotency. The amount of morphine equivalents in these preparations is typically 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.

 

We’ve also seen patients develop delayed-onset coma after attempting suicide. If the specific formulation they took is unknown, they may be evaluated in an ER prior to admission to a behavioral health unit, at which time they lack clinical signs of opioid intoxication and may have very low toxicology levels. They are given “medical clearance” and admitted to the behavioral health unit. Overnight they get further release of the opioid into their bloodstream and the following morning they may be comatose.

 

Another important issue for these long-acting and extended release opioids is the phenomenon of re-narcotization. The effect of the reversal agent naloxone may wear off long before the effect of the opioid wears off, raising the danger of recurrence of respiratory depression.

 

We’ve also seen rare cases in which patients on these long-acting opioid formulations have developed acute opioid withdrawal symptoms following naloxone injections.

 

Note that long-acting opioid formulations (particularly those in transdermal patches) 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”).

 

These are all issues that should be addressed in the ER/LA REMS programs, but not all of them are. We find it particularly bothersome that the Heyward study has shown that, five years after initiation of the REMS program, the FDA and ER/LA manufacturers could not conclude whether the ER/LA REMS had reduced inappropriate prescribing or improved patient outcomes.

 

 

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:

 

 

Some of our other Patient Safety Tips of the Week regarding fentanyl and fentanyl patches:

 

 

 

 

References:

 

 

Heyward J, Olson L, Sharfstein JM, Stuart EA, Lurie P, Alexander GC. Evaluation of the Extended-Release/Long-Acting Opioid Prescribing Risk Evaluation and Mitigation Strategy Program by the US Food and Drug Administration: A Review. JAMA Intern Med 2019; Published online December 30, 2019

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2757791

 

 

Hubbard WK. Getting Serious About Opioid Regulation. JAMA Intern Med 2019; Published online December 30, 2019

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2757786

(Hubbard 2019)

 

 

Johnson H, Paulozzi L, Porucznik C, et al. Decline in Drug Overdose Deaths After State Policy Changes — Florida, 2010–2012. MMWR Morb Mortal Wkly Rep 2014; 63(26): 569-574; Published online July 4, 2014.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584904/

(Johnson 2014)

 

 

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