Tuesday, November 30, 2010

Are You Glad Darvocet Got Pulled by the FDA? Are You Sure?

I know many palliative care practitioners were cheering the news that the world's least effective opioid propoxyphene (Darvocet (w/ APAP) /Darvon)  (similar efficacy to acetaminophen) is being pulled off the market by the FDA.  Along with meperdine (Demerol) I am not sure if a medicine exists that produces as much disdain as propoxyphene amongst palliative care clinicians.

But let's look a little closer as to why this happened.  The FDA cites the increasing cardiotoxicity and risk of heart arrythmias in a post-market study conducted by Xanodyne.  It is a little difficult to find out more exact information since the study is not published but lets do a little Scooby Doo-like sleuthing.

  • Propoxyphene is a synthetic derivative of methadone.
  • Methadone causes QT prolongation of questionable clinical significance in palliative care patients.
  • QT prolongation is a risk factor for ventricular arrhythmias.

Searching beyond just the press releases and news articles I found this FDA memo from Dr. Sharon Hertz *(Deputy Division Director Division of Anesthesia and Analgesia Products) noting that Xanodyne was asked to do a Thorough QT study. Never heard of that before? Well all new drugs since 2005 have had to pass through one before being approved. Given this increased risk of QT prolongation and the fear of resulting ventricular arrhythmias, the risk of the drug started to overwhelm the very minimal benefit it offered.
Interestingly the FDA has no evidence of QT Prolongation Adverse Event related deaths with Propoxyphene. Here is a quote from the memo: (emphasis mine)
At the 2009 advisory committee meeting, FDA staff shared postmarket data that have been suggestive, but inconclusive, about the risk for propoxyphene-related cardiac toxicity when used at therapeutic doses. No cases of torsades de pointes (TdP) causally associated with propoxyphene have been reported despite extensive use for many years. In an analysis of serious adverse events reported to the Adverse Event Reporting System (AERS) covering the period from marketing to February 2, 2005 (approximately 33 years), there were 91 U.S. deaths associated with Darvocet, the most commonly dispensed formulation of propoxyphene.  Most of the reports identified opioid drug overdoses in individuals with profiles of drug dependency, in which there was coingestion of multiple medications, or in those attempting suicide.
What is really interesting about this memo is section on page 20, where they discuss QT studies of other opiate agonists. 6 lines of the report are redacted and in the whole 20 pages there is not one mention of methadone despite nearly all other opioids being mentioned. Redaction? Should we call Wikileaks founder Julian Assange?

So in the end I am not sure if propoxyphene being removed is really about cardiotoxicity and QT, minimal effectiveness, abuse and overdose potential or a combination of all of the above.

Well all this may be a whole lot of nothing but my real concern is that methadone may be a drug in the crosshairs of the FDA soon. It already has four strikes against it:
1) documented QT prolongation
2) stigma of heroin treatment programs
3) accelerating percent of all deaths related to opioids
4) methadone could be considered an orphan drug

And evidence of  methadone being a very useful medication is possibly not strong enough to overcome these issues. So while we can cheer propoxyphene disappearing we should also be cautious and gather better evidence for the medications we wish to keep in our arsenal to ensure good pain control for years to come.

ResearchBlogging.orgBeaver, W. (1984). Analgesic Efficacy of Dextropropoxyphene and Dextropropoxyphene-containing Combinations: a Review Human and Experimental Toxicology, 3 (1 suppl), 191-220 DOI: 10.1177/096032718400300118

Collins, S., Edwards, J., Moore, R.,  McQuay, H. (1998). Single-dose dextropropoxyphene in post-operative pain: a quantitative systematic review European Journal of Clinical Pharmacology, 54 (2), 107-112 DOI: 10.1007/s002280050430

Ripamonti, C., Bianchi, M., Bruera, E. (2004). Methadone: An Orphan Drug? Journal of Palliative Medicine, 7 (1), 73-74 DOI: 10.1089/109662104322737278

** Yes the Deputy Direcotr in charge of pain medicine at the FDA is Dr. Hertz. Ha!

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