In accordance with new actions by the U.S. Food and Drug Administration (FDA), healthcare professionals and consumers will soon find updated class-wide labeling for extended-release and long-acting (ER/LA) opioid analgesics to help ensure safe and appropriate use. Besides emphasizing prescribing of these agents only for severe pain, the FDA will stress avoidance of opioids during pregnancy and is requiring manufacturers to study risks when these drugs are used long-term.
Douglas Throckmorton, M.D., deputy director of regulatory programs in FDA's Center for Drug Evaluation and Research stated in an announcement [here], “The new labeling requirements and other actions are intended to help prescribers and patients make better decisions about who benefits from the use of these medications. They also are meant to reduce problems associated with their use,” and “to make opioids as safe as possible for those who need them.”
These actions come after the FDA’s careful analysis of new safety information, including reviews of medical literature, and consideration of input from patients, experts, and many other interested parties. Currently, labeling on ER/LA opioids indicate that they are for “the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time.” However, the updated indication for prescribing these medicines will, when finalized, emphasize that other treatment options should be considered first.
The FDA is requiring that revised labeling states the drugs are “indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.” Furthermore, the updated labeling will retain language indicating that the drugs are not intended for use on a PRN, or “as-needed,” basis.
The revised labeling also adds: “Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve [these analgesics] for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.”
This updated labeling language emphasizes that patients in pain should be assessed not only by their ratings on a pain intensity scale, but also based on a more thoughtful determination that their pain — however it may be defined — is “severe enough” to require daily, around-the-clock, long-term opioid therapy. This framework is expected to better enable prescribers to make decisions based on patients’ individual needs, against a backdrop of alternatives such as immediate release (IR) opioids and nonopioid analgesics. Additionally, it expectedly allows prescribers to make an assessment of pain relative to a patient's ability to perform daily activities or to enjoy a reasonable quality of life.
As for use during pregnancy, currently approved FDA labeling describes effects of opioid analgesics on newborns resulting from exposure to these drugs while in the mother's womb, and warns against use by women during pregnancy and labor or while nursing. The new labeling, will provide more detail and elevate the risk of neonatal opioid withdrawal syndrome (NOWS) to the most prominent position in labeling — a boxed warning.
Finally, recognizing the need for more scientific data about the risks of ER/LA-opioids when used during extended time periods, the FDA also decided to require manufacturers to conduct longer term studies and trials of ER/LA-opioid pain relievers presently on the market. The companies must evaluate long-term opioid use, with the goal of assessing a variety of known serious risks, including misuse, abuse, addiction, overdose, and death, as well as the risks of developing increasing sensitivity to pain (hyperalgesia).
Once the labeling changes are implemented, educational materials for healthcare providers and patients will be modified accordingly. Along with that, presently available ER/LA-Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS) education programs also will be updated. These voluntary courses, from accredited continuing education sources, teach about risks and safe prescribing practices regarding these medications [see list of online courses here].
After a long process of thorough deliberation it appears that the FDA has arrived at prudently conservative changes in addressing concerns about ER/LA-opioid therapy for chronic pain. While there still may be some points of confusion or misinterpretation, the label changes probably reflect how competent and conscientious practitioners are already managing the prescribing of these analgesics.
Of interest, the FDA announcement comes about one year after a petition was submitted to the agency by members of Physicians for Responsible Opioid Prescribing (PROP), several other individual healthcare providers, and the advocacy group Public Citizen, requesting changes to the labeling of ER/LA-opioids [first discussed in an UPDATE here]. However, the FDA apparently judged only 1 of several requests in what has become known as the “PROP petition” as meriting attention (see below).
There are a number of points in the FDA’s recent announcement that are of special interest and importance…
- The new indication for ER/LA-opioids is for managing pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. How pain that is “severe enough” could/should be objectively assessed is left open-ended; although, the original allowance for also treating “moderate” pain with these analgesics was removed. In many cases, however, it seems that persistently troublesome moderate pain may be classified as severe enough to merit ongoing, daily opioid therapy.
- The PROP petition had requested the elimination of “moderate pain” as an indication, which technically was accepted by the FDA, and also that there be limits on ER/LA-opioid dosing (≤100 mg morphine-equivalent) and duration of continuous therapy (≤90 days). Apparently, the FDA did not find suitable evidence to accept and implement the dose/duration requests.
- The label clause “….for which alternative treatment options are inadequate” may be problematic, depending on how it is interpreted. It implies that other therapies should (or must) be applied first, before ER/LA-opioids are acceptable, but it does not provide specific guidance in this regard. Does this include both pharmacologic and nonpharmacologic therapies? Will insurance companies deny coverage unless certain step-therapies or other remedies precede an ER/LA-opioid prescription?
- There are no distinctions made in the new FDA labeling and associated documents between cancer pain and chronic noncancer pain (CNCP) — in fact, these terms are not mentioned. This is important because all of the discussions and debates regarding the appropriateness of ER/LA-opioids have centered on CNCP; now it appears that the etiology of the pain and even whether or not it is of a certain duration (eg, chronic) are not limiting factors.
- During the course of the past year, a great deal of evidence regarding ER/LA-opioids has been put forth by PROP members and many other groups and individuals for FDA consideration; some of it good, but mostly poor quality evidence. In some cases, a lack of evidence in support of long-term opioid therapy was, itself, proposed as evidence.
In a letter to manufacturers [PDF here] the FDA wisely reached a conclusion that more data are needed on ER/LA-opioid risks and benefits, and manufacturers are being required to conduct further research. The target date for final research reporting is June 2018; however, there are intermediate stages that require studies to validate appropriate research methodologies. Along with that, the FDA is downplaying the use of administrative databases for research purposes — eg, data-mining, which we have eschewed in the past — and emphasizing the importance of clinical trials and other more direct approaches to data gathering.
- A question is, with so many manufacturers involved, will there be a costly redundancy of research efforts and/or a proliferation of small and inadequate studies? In their letter, the FDA is encouraging manufacturers to work together on the studies and clinical trials to gather the best information possible. Hopefully, a pooling of effort and funding will result in high quality, definitive research that resolves many of the concerns about ER/LA-opioids for pain management.
- Finally, an issue of some concern is that these latest announcements from the FDA — including label changes and calls to action by manufacturers — seem heavily weighted toward risks of misuse, abuse, hyperalgesia, addiction, overdose, and death associated with ER/LA-opioids. While these problems are certainly of critical importance, it also should be imperative that new research ventures assess clinical efficacy — in terms of pain relief, functionality, and quality of life — of these analgesics for various pain conditions and in different subsets of patients.
In sum, in reaching a decision the FDA does appear to have devoted considerable time to hearing all sides of the ER/LA-opioid debate and carefully examining the evidence (or lack thereof). There are some who may feel that the FDA took too long in their deliberations and then arrived at an overly restrained approach to addressing the issues. While certain prescribing points still appear to be rather vague — eg, defining “severe enough” pain and “alternative options” — the updated labeling surely seems consistent with sound medical practice and provides necessary leeway for practitioners who are so motivated and educated to provide adequate care for patients with pain.