FDA Adds New Safety Warning to Rx Opioids
/By Pat Anson, PNN Editor
Opioid-induced hyperalgesia (OIH) is a controversial medical theory, built on the premise that long term opioid therapy can heighten pain sensitivity and cause pain to grow worse.
Often confused with opioid tolerance, there is no clear medical definition for OIH and most of the research about it has been conducted on animals. Only a few dozen human cases of OIH have reported, even though millions of people take opioids every day. Perhaps most telling of all, there is no specific diagnostic code for OIH – meaning doctors can’t bill for it.
All of which makes it puzzling why the Food and Drug Administration has decided to add hyperalgesia to its “black box” warning label for opioids. In an 18-page Drug Safety Communication that was quietly released on Thursday, the FDA urges doctors to decrease the dose if they suspect a patient has OIH or switch them to another opioid product.
“Based on our review of available data, FDA has also determined that a new warning is needed about opioid-induced hyperalgesia (OIH),” the FDA said. “Although OIH can occur at any opioid dosage, it may occur more often with higher doses and longer-term use. This condition can be difficult to recognize and may result in increased opioid dosages that could worsen symptoms and increase the risk of respiratory depression.”
What is the data that prompted the FDA alert? The agency said it identified 46 patients with symptoms of OIH, after searching through years of medical literature and the FDA Adverse Event Reporting System. That’s all they could find, although the FDA meekly claims “there may be cases about which we are unaware.”
In those 46 patients, cancer pain was the most common condition being treated. The FDA said patients reported improvement in pain after they stopped taking opioids, before admitting it had no real understanding of why they did.
“Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been suggested,” the FDA said.
‘Insufficient Evidence’
“I am surprised the FDA is including a black box warning of OIH in the label with such flimsy data,” says Lynn Webster, MD, a pain management expert and past president of the American Academy of Pain Medicine. “My clinical experience suggests OIH exists, but clinically it is very difficult to differentiate it from pain-induced central sensitization.”
Webster is concerned the FDA’s updated warning label could lead to patients being diagnosed with OIH and taken off opioids without their consent.
“Misdiagnosing OIH can lead to forced tapering, which they warn against because it can cause serious harm. This will undoubtedly occur with the new label,” Webster told PNN. “I recognize that the FDA wants to provide prescribers with as much information as possible about the potential risks of opioids. That is good, but mentioning OIH in the box warning has a risk of overstating a disorder that is yet not well characterized or even accepted as clinical disorder.”
Other doctors and researchers share Webster’s doubts about the frequency and clinical significance of OIH. A 2021 review of dozens of published studies of hyperalgesia found only 72 patient cases of OIH, all of which were easily managed.
“At present, there is insufficient evidence from well-designed clinical trials that OIH is a clinically relevant phenomenon. Hence, while there are other reasons to avoid long-term use of opioids, the potential for the development of hyperalgesia during chronic opioid treatment is not a sound rationale for deprescribing these drugs in patients with chronic pain,” Craig Svensson, PharmD, Dean Emeritus of the Purdue College of Pharmacy said in an op/ed recently published in the International Journal of Pharmacy Practice.
A large survey conducted over a decade ago found a “significant knowledge gap” among physicians on how to diagnose and manage OIH. One reason hyperalgesia is so poorly understood is that it is often mistaken for drug tolerance, the tendency of patients on any medication to develop a tolerance over time. In many of those cases, the solution is to increase the dose, not decrease it.
Coincidentally, the FDA’s label change comes just days before an April 19 public meeting of an FDA Advisory Committee, which is considering a requirement that drug makers evaluate the long-term efficacy and risk of OIH in new drug applications for extended-release and long-acting opioids. Such an evaluation would include a post-marketing analysis of a new drug once it is approved.
Even though opioid prescribing has been cut in half over the past decade and the vast majority of overdose deaths involve street drugs, the FDA remains under pressure from politicians and anti-opioid activists to further restrict opioid prescriptions.
“I'm sure because of the past problems associated with opioids, the FDA regulators feel it best to advise prescribers of every possible potential risk, even if the science is weak. You might say they are between a rock and a hard place,” Webster said.
