FDA Rules on Petition to Restrict Opioid Prescribing: Mostly Good News
Last year a group calling themselves Physicians for Responsible Opioid Prescribing (PROP) submitted a citizen petition to the FDA with three requests:
Strike the term ‘moderate’ from the indication of opioid analgesics for non-cancer pain.
Add a maximum daily dose, equivalent to 100 milligrams of morphine for non-cancer pain.
Add a maximum duration of 90 days for continuous daily use for non-cancer pain.
This month the FDA responded to the PROP petition. In short, they approved the first request, with two caveats, but denied the other two requests.
The FDA did remove the term ‘moderate.’ However, the two caveats were:
The new FDA ruling only applies to the labeling of extended-release/long-acting (ER/LA) opioids - not to labels for immediate-release opioids.
The FDA declined to make a distinction between cancer and non-cancer pain in opioid labeling. (More on this later in this article)
The updated indication states that ER/LA opioids 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. It further clarifies that, because of the risks of addiction, abuse, and misuse, even at recommended doses, and because of the greater risks of overdose and death, these drugs should be reserved for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain; ER/LA opioid analgesics are not indicated for as-needed pain relief.
Request 2: Add a maximum daily dose, equivalent to 100 milligrams of morphine for non-cancer pain.
The FDA agreed that adverse events and substance abuse of opioids does occur at high doses, but they noted that adverse events can also occur at doses lower than 100 mg. While they acknowledged that available data do suggest a relationship between increasing opioid dose and risk of certain adverse events, they pointed out that there is no evidence that the relationship is necessarily a causal one. Therefore, the FDA denied PROP’s request that a maximum daily dose for opioids be specified.
Request 3: Add a maximum duration of 90 days for continuous daily use for non-cancer pain.
In support of this request, PROP cited the American Pain Society-American Academy of Pain Medicine Opioids Guidelines. However the FDA rightly pointed out that "these guidelines state that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients. The guidelines recommend individualized care, management plans, and monitoring–not a maximum duration of treatment." They also pointed out that there was not adequate clinical data to support establishing a threshold for maximum duration of use. For those reasons and more, the FDA denied PROP’s request for a maximum duration specification.
Additional Studies Required
There are very few studies that look at either the effectiveness or the dangers of long-term opioid use. Therefore, in addition to the labeling changes, the FDA is requiring ER/LA opioid drug sponsors to conduct post-marketing research "to assess the known serious risks of misuse, abuse, hyperalgesia, addiction, overdose, and death associated with the long-term use of opioid analgesics." These studies are expected to be completed between 2015 and 2018.
Cancer vs. Non-Cancer Pain
I have long thought there should not be a distinction between pain caused by cancer and pain that comes from other sources. (See "Opioid Treatment for Cancer vs. Non-Cancer Pain: Is There Really a Difference?") Pain is pain - regardless the initial cause. Finally, it seems the FDA agrees with me.
In its response to the PROP petition, the FDA letter states, "All of PROP’s labeling change requests are limited to "non-cancer" pain, a distinction that is not made in current ER/LA opioid analgesic labeling. It is FDA’s 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 patient from the treatment of 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 pain in opioid labeling."
I don’t really have any major objections to the labeling changes made by the FDA. The long-term use of extended-release opioids should be carefully considered and only used when other treatments are not effective. The changes don’t impose any actual restrictions; they only point out the conditions under which the opioids should be used.
I’m very relieved the FDA declined PROP’s requests to limit the dosage and length of treatment for opioids. How much medication and how long it should be taken are decisions that should only be made by each patient’s doctor based on that patient’s individual need - not a government agency.
My only complaint about the post-marketing studies being required is that in the list of things drug makers are supposed to assess, there is no mention of effectiveness - only hyperalgesia, abuse, misuse, etc. It seems to me if the FDA is going to evaluate whether there is a "point at which the risks of opioid use at escalating doses and longer durations of treatment may outweigh the benefits of opioid analgesic therapy," they need to study the benefits. Since it would be to the drug makers’ advantage to show effectiveness, I’m hopeful their studies will include that parameter.
Finally, I applaud the FDA for refusing to differentiate between cancer and non-cancer pain. That’s not a distinction that is relevant when it comes to the need for pain relief.
For more details as to the reasoning behind the FDA’s response, you can download the pdf of their response letter: FDA CDER Response to Physicians for Responsible Opioid Prescribing Partial Petition Approval and Denial