Last Friday the FDA announced that Xanodyne Pharmaceuticals had agreed to withdraw propoxyphene – better known by the brand names Darvon and Darvocet – from the U.S. market due to new data showing that the drug can cause serious toxicity to the heart, even when used at therapeutic doses.
The FDA concluded that the safety risks of propoxyphene outweighed its benefits for pain relief at recommended doses. They also requested that the generic manufacturers of propoxyphene-containing drugs remove their products as well.
The FDA said their recommendation “is based on all available data including data from a new study that evaluated the effects that increasing doses of propoxyphene have on the heart... The results of the new study showed that when propoxyphene was taken at therapeutic doses, there were significant changes to the electrical activity of the heart: prolonged PR interval, widened QRS complex and prolonged QT interval. These changes can increase the risk for serious abnormal heart rhythms.”
There was also a concern that the elderly and patients with renal insufficiency would be more suseptible to the heart-related risks of propoxyphene.
The FDA further recommended that healthcare professionals:
- Stop prescribing and dispensing propoxyphene-containing products to patients.
- Contact patients currently taking propoxyphene-containing products and ask them to discontinue the drug.
- Inform patients of the risks associated with propoxyphene.
- Discuss alternative pain management strategies with patients.
Patients were advised to dispose of unused propoxyphene in household trash by following the recommendations outlined in the Federal Drug Disposal Guidelines.
In My Opinion...
Propoxyphene is an opioid analgesic that has been used in the U.S. for more than five decades. It was approved by the FDA in 1957 for the treatment of mild to moderate pain. As opioid pain relievers go, it is relatively weak – about half as potent as codeine. It's analgesic effect is said to be comparable with high-dose NSAIDs (non-steroidal anti-inflammatory drugs).
Even though there are many other pain relieving options available, for some patients propoxyphene seems to work better than anything else. People are different and what works well for one patient may not work at all for another. Perhaps propoxyphene shouldn't be the first choice for pain relief, but I really hate to see it totally removed as an option.
One of the things that really bothers me about the FDA's decision is that it was apparently made based primarily on the results of one study called the MAD (Multiple Ascending Dose) study. What they don't mention about that study is that only 18 healthy subjects took part – hardly a representative sampling of the patients who would be prescribed propoxyphene. And while a few of the participants showed “statistically significant” cardiac changes, many did not – something else they neglected to mention.
The FDA won't even consider approving a new drug without multiple clinical trials involving thousands of patients, yet they withdraw a drug that has helped millions of people for over 50 years based on a study of 18 people. That just doesn't seem right to me.
In an excellent commentary on Pain-Topics.org about the FDA's action, Dr. S.B. Leavitt pointed out that, according to their estimate, the propoxyphene-associated mortality rate over the past 53 years was only about 0.0001% – that's one ten-thousandth of one percent. Not exactly a huge number. I suspect there may be many other drugs which are considered to be safe that have a higher mortality rate.
So with what appears to me to be relatively weak data, why did the FDA choose to pull propoxyphene? There's no way of knowing for sure. We can only speculate. My personal guess is that it was probably a combination of fear and follow-the-leader. I say this based on the following:
- The investigation into propoxyphene started with a Citizen's Petition to remove it from the market. There have been two such petitions since 1978 based mostly on concerns about people overdosing. The FDA may have been afraid of the repercussions if they didn't act and one or more person's death was linked to propoxyphene.
- In 2005 England mandated a phased discontinuation of propoxyphene due to the rising rates of its use in suicides.
- In mid-2009, the European Medicines Agency recommended that the marketing authorization for propoxyphene be withdrawn across the European Union.
The FDA didn't ask me for my opinion, but if they felt something had to be done, I would much rather have seen recommendations that other pain relievers be tried first before prescribing propoxyphene, that it not be given to high-risk populations like the elderly and patients with renal insufficiency, that a stronger black-box warning be used, and/or even that more stringent REMS be developed. Taking it off the market completely seems to me to be an extreme over-reaction.
What do you think?
Propoxyphene: Withdrawal - Risk of Cardiac Toxicity. U.S. Food and Drug Administration. 11/19/2010.
Leavitt SB. Propoxyphene Products Withdrawn in USA. Why? Pain-Topics.org News/Research UPDATES. 11/19/2010.
Published On: November 24, 2010