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12 Articles in Volume 17, Issue #1
A Brief History of the FDA’s Role in the Ongoing Effort to Ensure Safe Opioid Use
Distinguishing Neuropathic, Non-Neuropathic, and Mixed Pain
How Can Healthcare Providers Better Advocate for Patients With CRPS?
Ketamine for the Treatment of CRPS?
Letters to the Editor: Opioid Calculator; Metformin
Living With CDC Opioid Guidelines
Neurohormones in Pain and Headache Management: New and Emerging Concepts
Optimizing Neuropathic Pain Relief With Scrambler Therapy
Pain Management and the Elderly
Spinal Cord Stimulation: What Clinicians Need to Know
The Association Between Depressive Disorder and Chronic Pain
Updates in Management of Complex Regional Pain Syndrome

A Brief History of the FDA’s Role in the Ongoing Effort to Ensure Safe Opioid Use

Given the recent focus on the opioid abuse epidemic, Practical Pain Management asked the authors to review what efforts the FDA has taken to help combat abuse of these medications.

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.

FDA action plan to combat opioid abuse.

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).

Boxed Warnings

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.

In 2011, the White House Office of National Drug Control Policy issued a report regarding the growing prescription drug abuse crisis: in this statement, it tasked the FDA with encouraging the development of abuse-deterrent formulations and creating an industry guidance for these products.16

In 2013, the FDA released this guidance, which describes different types of abuse-deterrent formulations and delineates the types of studies required to demonstrate a formulation’s abuse-deterrent properties.17 According to this guidance, abuse-deterrent products must be designed to prevent abuse by known or suspected methods of abuse (eg, crushing, snorting, or injecting). These products may utilize physical or chemical barriers to abuse, or they may combine opioid agonists and antagonists in such a way that the product no longer produces euphoric effects when manipulated. Abuse-deterrent products may also contain a substance that produces an unpleasant effect when the product is used in an unapproved manner.

The FDA has since approved several opioid pain medications with labeling that designates them as “abuse-deterrent formulations.” Examples of these products include Hysingla ER (extended-release hydrocodone), Xtampza ER (extended-release oxycodone), and Troxyca ER (extended-release oxycodone/naltrexone).12 These abuse-deterrent formulations are not yet available as generic medications, so their impact on practice has likely been limited due to cost concerns. In March 2016, the FDA issued a similar guidance for generic abuse-deterrent formulations.18  [Editor’s note: As of press time, the FDA has approved 2 generic opioids with abuse-deterrent formulations in 2017: Arymo ER (morphine sulfate, Egalet Pharma) and Vantrela ER (hydrocodone bitartrate, Teva).]

Risk Evaluation and Mitigation Strategy (REMS) Programs

The FDA has also attempted to use REMS programs to mitigate the risks associated with opioid use. In 2007, the FDA gained the authority to require REMS programs for specific medications.12 These REMS programs require manufacturers to implement various safety measures in order to maintain a favorable risk-benefit ratio. These measures typically include the development of mandatory educational materials, such as medication guides for patients and providers; they may also involve the implementation of “elements to ensure safe use,” such as registries or mandatory certification of healthcare providers.19

The first opioid medication to be approved with a required REMS program was Onsolis, a fentanyl buccal film, in 2009.12 In March 2012, a mandatory REMS program was implemented for all transmucosal IR fentanyl products. In July of the same year, a REMS program for all ER/LA opioid medications was approved. The ER/LA REMS program requires manufacturers to offer voluntary opioid training programs for prescribers.

Unlike with the REMS program for transmucosal IR fentanyl products, the REMS program for ER/LA opioids does not require prescribers to complete this education or become specially certified.20 Unfortunately, the true impact of REMS programs has not been well studied. The FDA is legally required to assess REMS program effectiveness, but inadequate reporting by manufacturers and limited resources are major barriers to the performance of comprehensive follow-up reviews.19,20 The effectiveness of the individual components of REMS programs remains unclear. One study found that the mandatory medication guides may be ineffective for patient education due to the complexity of language used.21

Medication Safety Initiatives

Other broad safety initiatives include the FDA’s Safe Use Initiative and the safe disposal program. The Safe Use Initiative, launched in 2009, sought to reduce opioid misuse and abuse by studying ways to use urine drug testing in the management of patients who abuse prescription opioids.22 This initiative is also responsible for the development of the opioid patient-prescriber agreement model, which is designed to encourage patients to use opioids responsibly.

According to a recent study, the incidence of hospitalizations for opioid poisoning among children ages 1 to 4 years has increased by over 200% between 1997 and 2012.23 The safe disposal program focuses on ensuring that unused medications are disposed of in a manner that prevents accidental ingestion.24 These methods for opioid disposal include DEA take-back programs, flushing down the toilet (for certain medications only), or mixing of opioids with unpalatable substances (eg, coffee grounds, cat litter) and placing the mixture in a sealed bag with household trash. While both the FDA and the Environmental Protection Agency (EPA) have noted that take-back programs are the preferred method for opioid disposal, the FDA maintains that flushing is permissible for certain opioid medications because the risk posed by accidental ingestion is greater than the risk that flushing may potentially pose to the environment.25,26 The evidence to support the efficacy of these programs is limited.27

Rescheduling Hydrocodone

Out of all the changes to opioid regulation and labeling, the rescheduling of hydrocodone combination products (eg, Vicodin) from Schedule III to Schedule II was perhaps the most practice-changing. While the DEA initiated this move in response to a citizen petition, the FDA played a crucial role in reviewing the evidence and making a recommendation for rescheduling.12 In January 2013, the FDA’s Drug Safety and Risk Management Advisory Committee voted in favor of the rescheduling, and on October 6, 2014, all hydrocodone-containing products were moved from Schedule III to Schedule II.12,28 The restrictions on prescribing Schedule II controlled substances are much stricter than those on the prescribing of Schedule III controlled substances; most significantly, no refills are allowed on Schedule II controlled substances, while Schedule III controlled substances can be prescribed with a maximum of 5 refills.28,29

A recent study of prescription data examined the impact of this rescheduling on the prescribing habits of providers.28 This study found that in the 12 months after rescheduling, dispensed prescriptions for hydrocodone combination products fell by 22%. During the same time period, the dispensed prescriptions for other non-hydrocodone combination opioid analgesics increased by 4.9%. How this rescheduling will impact prescribing in the long run or how it might impact the ability of patients to access these medications is still unknown at this point.

Summary

While many policy and labeling changes have been implemented, the impact of these changes has not been fully examined.27 All of these interventions have the potential to help turn the tide against prescription opioid abuse, but whether or not they have made a meaningful impact remains an open question. Further studies are needed to determine which interventions are effective and where future efforts should focus. However, even in the absence of high-quality evidence, the high rate of drug overdose deaths involving opioids calls for actions or programs to reverse this trend in the United States. The FDA’s Opioid Action Plan is still ongoing in its implementation, and other government agencies have developed new initiatives as well. Only time will tell if these new initiatives are successful in preventing opioid abuse.

Last updated on: March 5, 2019
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Distinguishing Neuropathic, Non-Neuropathic, and Mixed Pain

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