A Brief History of the FDA’s Role in the Ongoing Effort to Ensure Safe Opioid Use
The Centers for Disease Control and Prevention (CDC) estimates that 1 out of 5 patients with noncancer pain receive a prescription for opioids.1 The Food and Drug Administration (FDA) divides prescription opioids into 2 categories according to their duration of action: immediate-release (IR) and extended-release/long-acting (ER/LA).2 Immediate-release products can usually be taken every 4 to 6 hours, while ER/LA products are generally taken once or twice a day.
The federal law governing the prescribing and distribution of opioid medications is the Controlled Substance Act, which was put into place in 1970 as part of the Comprehensive Drug Abuse Prevention and Control Act.3 Currently, the Drug Enforcement Agency (DEA) classifies controlled substances into 1 of 5 schedules based on their potential for abuse. The majority of opioids have been classified as Schedule II, indicating that they have an extremely high potential for abuse. Schedule II products are the most strictly regulated controlled substances and have the most extensive rules regarding their prescribing and distribution. Some combination pain medications, such as codeine-acetaminophen, are considered to have a lower abuse potential and are classified as Schedule III.
Prescription opioid abuse and overdose have become serious public health problems in the United States. According to a recent CDC report, 63.1% of the drug overdose deaths that occurred in the United States in 2015 involved an opioid; between 1999 and 2014, the number of drug overdose deaths nearly tripled, reaching a record 52,404 deaths in 2015.4
The Substance Abuse and Mental Health Services Administration (SAMHSA) estimates that almost 2 million Americans abused or were dependent on prescription opioid drugs in the year 2014, while over 1,000 people are treated in emergency departments each day for misusing prescription opioids.5 In response to this growing problem, the FDA has attempted to implement a variety of measures to limit opioid misuse and encourage judicious prescribing of these medications (see timeline).
One of the most recent actions by the FDA was a change to the labeling of opioid medications. On August 31, 2016, a new boxed warning was added to the labels of all opioid analgesics, opioid-containing cough products, and benzodiazepines.6,7 The warning describes the serious risks of taking opioids and benzodiazepines together, which include extreme sleepiness, respiratory depression, coma, and death. This additional warning was a result of 2 new studies that indicated an increase in concomitant opioid and benzodiazepine prescribing, along with a simultaneous increase in the number of overdose deaths involving the 2 medication classes.
A study published in 2015 found that the number of overdose deaths involving both opioids and benzodiazepines had nearly tripled between 2004 and 2011.7,8 Benzodiazepines were involved in 31% of opioid overdose deaths in 2011, up from 18.4% of opioid overdose deaths in 2004.8 A separate study found that the rate of opioid and benzodiazepine co-prescribing rose 41% between 2002 and 2014; approximately half of the patients who received prescriptions for both drugs received them from the same prescriber on the same day.7,9 The FDA hopes that the addition of this stronger warning to opioid labels will encourage prescribers to carefully consider the risks before prescribing opioids and benzodiazepines together.
This warning is just the latest step in a larger effort by the FDA to reverse the growing problem of opioid abuse and overdose. In an effort to heighten awareness of the risks associated with opioids, the FDA has been updating the labeling and strengthening the boxed warnings on opioid medications in recent years.10-12
Opioid Action Plan
In early 2016, the FDA announced a comprehensive Opioid Action Plan that aims to reduce prescription opioid abuse while still allowing patients with chronic pain to access effective pain-management options.7,13,14 This plan is designed to approach the issue from multiple angles and complement the efforts of other federal agencies.14 As part of the plan, the FDA intends to:
- Expand the use of advisory committees in decisions regarding opioid formulations that do not possess abuse-deterrent properties
- Enhance safety labeling for IR opioid formulations
- Require more post-marketing studies for ER/LA opioids
- Update the Risk Evaluation and Mitigation Strategy (REMS) program for ER/LA opioids
- Expand access to abuse-deterrent opioid formulations
- Support better treatment options for opioid overdose and pain
- Reassess the risk-benefit paradigm for opioids
Long-Acting and Abuse-Deterrent Formulations
The FDA has had a long history of implementing efforts to minimize the risks associated with opioid use. One of the 1st such efforts was the 1995 approval of OxyContin, a controlled-release formulation of oxycodone.12 The FDA hoped that OxyContin would decrease abuse due to its slower absorption rate. However, the crushing of OxyContin became a widespread practice, and high levels of abuse were subsequently seen.
In the early 2000s, reports of prescription-drug overdoses rose dramatically, with OxyContin being commonly linked to emergency room visits and prescription drug-related deaths.12 Long-acting formulations alone were no longer a guaranteed way to prevent opioid abuse, and interest grew in creating formulations that would not be so easy to misuse or abuse.
In 2009, Embeda, an extended-release combination of morphine sulfate and naltrexone, was approved.12 Naltrexone, an opioid antagonist, was included in the formulation to prevent users from experiencing a high if they crushed the medication and tried to inject it. Embeda was one of the first opioid pain medications with properties specifically designed to deter abuse.
In 2010, the FDA approved a new formulation of OxyContin designed to help discourage misuse and abuse of the medication.12 According to Coplan et al,15 following the introduction of the reformulated OxyContin, abuse of the drug decreased by 36%; however, abuse of “single-entity oxycodone increased by 20% [and] abuse of heroin increased 42%.” The study authors noted that the reformulation of OxyContin did reduce the number of calls to poison centers, but did not stem the abuse of other opioids or heroin.