Tuesday, September 10, 2013

FDA Issues ER/LA-Opioid Prescribing Changes

FDAIn 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].


Opioid FearAfter 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…

  1. 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.

  2. 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.

  3. 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?

  4. 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.

  5. 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.

  6. 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.

  7. 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.

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Bruce Scott said...

I'm particularly glad to see the nonsensical distinction between cancer and noncancer pain dismissed. The mere idea was absurd on the face of it. The distinction might be understandable if argued by a poorly-educated lay audience; however, there is no excuse when made by theoretically well-educated professionals. Cancer isn't magic. The term encompasses a very broad range of only vaguely related diseases. It is difficult to actually define, and there is currently a debate raging about renaming some of the things we have previously called "cancer".

Regarding the issue of research (including redundancy and small/inadequate studies), this is part of a larger problem. Without a massive overhaul of how we fund medical research, how much industry influence we allow (and how it gets reported), whether we push for pre-registration of all trials, and whether we allow for suppression of negative data, we will continue to face questions regarding research into all pharmaceuticals, including opioids.

SB. Leavitt, MA, PhD said...

Thank you, Dr. Scott, for your comments. As for research, it is interesting that the FDA is actually asking for -- make that requiring -- industry-sponsored research, despite all of the limitations and potential biases of such endeavors. More so, the FDA is encouraging the various companies to collaborate on this, which seems questionable.

Husband of a 14 year pain patient said...


Anonymous said...

I am so glad to hear that the FDA has made a very hard decision based mainly on no research of these drugs. I am a chronic pain patient and have tried many other therapies to control my pain, pain pump, ESI's, racz procedure.After going through all of these it was determined opioids were my only choice of pain relief. This was 8 yrs ago and I find that this medicine truly helps me live a somewhat normal life. If I did not have access to these medications I would be bed bound. Thank You Dr. Throckmorton

Anonymous said...

Thank you FDA for your bold decision on opioids label changes for non cancer patient. You understood that there are patients who have tried everything over the years and can only find relief with opioid medication. Until there is a cure for intractable pain, patients must have access to opioid medication. Thank you for understanding.

Janice Reynolds said...

I also was generally pleased with the FDA’s decisions. I do have some problems with the “alternative treatment options are inadequate” for some of the reasons Dr. Leavitt mentioned but also because the best pain plans for many people are a combination of opioids, adjuvants, and non-pharmacological interventions the use of the latter two will reduced the amount of opioid needed. The insurance issue continues to be a huge one as many insurances will not pay for non-pharmacological interventions or ones that work for that person and without insurance many adjuvants and non-pharma therapies are too expensive (my daughter’s Lyrica-which works well for her –is over $600 a month). Sometimes a generic LA morphine is the cheapest route even if it is not the best choice. Also “pain “ does not encompasses one entity but rather many different syndromes and combinations as well as individual response make this more complicated than a ladder approach can justify.
The letter sent to PROP from the FDA made for really great reading: http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-0818-0793. I was most impressed though with the stance on cancer pain vs. chronic pain (as Dr. Levitt has pointed out). This artificially imposed differentiation has long troubled me (my example recently has been if my brain tumor had been cancerous my persistent post craniotomy pain would be legitimate where as it was not cancerous my pain is somehow less legitimate-you will notice I don’t say benign-there is nothing benign about a brain tumor cancerous or not). The quote from the letter is
It is the FDAs view that a patient without cancer, like a patient with cancer, may suffer from chronic pain, and PROP has not provided scientific support for why labeling should recommend different treatment for such patients. In addition FDA knows of no physiological or pharmacological basis upon which to differentiate the treatment of chronic pain in a cancer setting or treatment of a patient with chronic pain in the absence of cancer, and comments to the Petition docket reflect similar concerns. FDA therefore declines to make a distinction between cancer and non-cancer chronic pain in opioid labeling. [The italics are mine.]
PROP unfortunately is not done yet in a National Pain Report article “Kolodny says he is considering legal action against the FDA to compel the agency to comply with the federal Food, Drug and Cosmetic Safety Act, which requires drug companies to prove their products are safe and effective before putting them on the market.” Funny he does not feel this way about NSAIDs and other medications (there is a medication for partial seizures which under side effects says “it will cause blindness”!).

SB. Leavitt, MA, PhD said...

Thank you, Janice, for your comments. Here is an easy link to the FDA’s response letter to PROP: Click Here for PDF. It is a long document, but very telling -- the FDA certainly did their homework on this issue.

Patient in Virginia said...

Thre issues: in the letter the FDA makes a distinction between long-acting opiods and "rescue" medication. If I read the statement correctly, the FDA makes this distinction because one is easier for people to abuse, etc. I am fighting my insurance company about a new breakthrough medication -- the first one that actually helps - and they are using the standard arguments beginning with, "not cancer" and then saying that I have not tried ALL other methods for breakthrough medication. In my case, I had tried all but one. The insurance company continues to battle. Other than in the letter to PROP, is there a mention of cancer pain vs non-cancer pain? I could not find that specific citation. Finally, my pain doctor said he had just been at a conference and no one was discussing the outcome of this ruling. Instead, they were focusing on the continuing problems with DEA. Any possibility that DEA and FDA will "talk" to each other? Thank you for all your help! Diana

Patricia Martinez said...

After injuring my cervical spine I had surgery which then left me with broken screws; this was in addition to interstitial cystitis which I suffer from! It took me many months and finally 9 trips in ten days to finally get an x-ray which finally led to me being diagnosed with the broken screws! Although I finally found help with regards to treating my pain, my spine has continued to get worse from what has been suggested was long term "steroid" use used to treat an auto immune disease!

We are now in this age that I will describe as "a war on drugs" which is aimed at doctors who treat chronic pain and patients who need these medications to live any kind of life at all!

If I told you what I have been though over the last year you would not believe me but know that I went 10 days without my fentanyl patches last month because the pharmacy which had been filling for me all of a sudden refused to fill my prescription because my pain specialist was not in the same county that I live in! (Please know my insurance company set me up with this pain specialist and even supplied transportation for me to get to his office because they had no one in-network that could handle my morphine pump which has just recently had its battery die!) I could find no pharmacy or pharmacist that would fill my prescription for fentanyl from my pain specialist and my insurance company could find no one either!! The office of my pain specialist offered no help to me either except to keep looking; I was told to stick to small pharmacies which also did not help me! In desperation after 10 days without my fentanyl patches I went to my primary care doctor who took the prescription from my pain specialist and re-wrote the exact prescription which had been for me by my pain specialist in hopes that I could get it filled since my primary care doctor is in the same county that I live in! After going 10 days without this medication, I took the new prescription to the same pharmacy and they filled it in 30 minutes! NOW THE PROBLEM! My primary care doctor explained that he is worried for his family and practice ... mentioning DEA! He will no longer see me!
The pain specialist also refuses to see me any longer saying that I did something wrong by having my primary care doctor re-write the prescription after I had went 10 days without my medication when I could get no help from his office! !

So here I sit without a pain specialist, without a primary care doctor, and on my last patch! I have had no luck in locating any doctors because my insurance company is going out of business as of the 31st of December which I just found out!

I have been baker acted by a pharmacist who refused to fill my medication for me after a doctor called to be sure they had my medication! I was unable to get my break thru meds before what I am going though now and have finally become despondent!

This morning I lye here after putting on my last patch ... without any more medication, no doctors or an insurance company trying to help me since they are insolvent and going out of business as of the 31st of this month! Again I find myself in a in a catch 22! I would go to ER but I have had plenty of experience here in the past year and they too are afraid to help with pain!

All out of answers and in desperation; I have planned an exit strategy which involves the use of HELIUM! The bottom line is that I am not ready to go but when you can not tolerate the pain and there is no help available; you do what you don't want to do because there is no other options available! While everyone is celebrating a new year; I will be exit with many regrets but with the knowledge that I will no longer suffer at the hands of our medical community! May god forgive me and may my death bring awareness of what we are being forced to endure so that others have better options than what I had!