[LEFT]Written Statement for the January 30, 2009 Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee
Statement of Sidney M. Wolfe, M.D.
Director, Health Research Group at Public Citizen
Hearing on Propoxyphene
Before FDA’s Anesthetic, Analgesic and Rheumatologic Drugs and Drug Safety and Risk Management Advisory Committees
There is little doubt that were propoxyphene and propoxyphene-containing products to come before these committees today for approval, based on what is now known, they would be rejected because of one of the most unfavorable benefit-to-risk ratios ever seen for a drug. This is not to say that there was insufficient evidence for a ban 30 years ago when we first petitioned the FDA to withdraw the approval. But the forceful and successful war then waged by Lilly in opposition to such a ban tended to drown out evidence of minimal benefit and rapidly growing evidence of life-threatening, often lethal harm.
Propoxyphene-related deaths: DAWN
The Federally-funded Drug Abuse Warning Network (DAWN) collects data from both emergency rooms and from medical examiners concerning drugs which have been determined to be related to emergency room visits or deaths. This medical examiner data has changed, over the years, in that the number of entities reporting has increased and definitions such as accidental death, have been modified or combined. In 2006 and 2007, the same definitions were used. DAWN Reporters are trained to report only those drugs related to the death.
SOURCE: Office of Applied Studies, SAMHSA, Drug Abuse Warning Network 2008 (9/2008)
It can be seen that there was an increase in propoxyphene-related death cases from 446 in 2006 to 503 in 2007 but there was a concomitant increase in the number of jurisdictions reporting. The cases in which the death was categorized as accidental outnumbered those in which the manner of death was stated as suicide in both years. The DAWN data do not imply causality but rather that the death was related to the drug.
It must be noted that these data represent only a fraction of the U.S. population.
In 2007, the population covered by DAWN was approximately 109,048,573. That’s about 36% of the total population for 2007 which the U.S. Census estimated at 301,290,332. However, the population covered by the DAWN mortality component is primarily from metropolitan areas, and is not based on a statistical sample. Thus the DAWN data must not be used to extrapolate to the Nation. As of 2007, there was complete state reporting from only 10 states, not including Florida.
Propoxyphene-caused deaths: Florida
The system of collecting and recording Medical Examiner data in Florida provides more details than the DAWN data. The presence of a drug in a decedent is categorized as “cause” if the Medical Examiner concluded that there was enough of the drug present to have been either the sole cause or a contributory cause of the death. Other drugs are listed as merely “present” if the Medical Examiner did not conclude that the drug played a role in the patient’s death. In their words: “The state’s medical examiners were asked to distinguish between the drugs being the “cause” of death or merely “present” in the body at the time of death.”
SOURCE: Office of Applied Studies, SAMHSA, Drug Abuse Warning Network 2008: (9/2008)
From: Drugs Identified in Deceased Persons by Florida Medical Examiners: 2007. Report by the Florida Department of Law Enforcement
The chart below shows the total propoxyphene-related deaths in Florida and the subset in which the drug was found to be a cause, for the years 2003 through 2007.
It can be seen that in 2007, for example, of a total of 314 propoxyphene-related deaths reported in Florida, 85, or 25%, were cases in which the medical examiner concluded that the drug was a “cause of death”.
The next table examines, for 2007, the categories into which the 85 propoxyphene-caused deaths were divided.
Of the total 85 deaths in which propoxyphene was listed as a cause, in 25 cases it was the only causal drug and in another 60 cases, there was one or more other drugs also judged to be causal to the deaths, along with propoxyphene. Of these 85 deaths, 66 were judged to be accidental and 16, suicidal. The further breakdowns of these data can be seen in the chart above. It should be noted that with 18.7 million people, Florida constitutes 1/16 of US population.
FDA Review of Efficacy
The conclusion of the FDA’s extremely comprehensive and carefully done review of propoxyphene efficacy states:
“there is evidence that propoxyphene possesses weak analgesic effects in patients with acute pain compared to placebo….While most of the studies show that in combination with acetaminophen, the propoxyphene component appears to contribute little or no additional analgesic effect beyond the efficacy of the acetaminophen when studied in patients with acute pain, there is at least one study that does support the contribution of propoxyphene to the efficacy of the combination.”
The FDA review not only included the NDA data submitted to the agency but a series of meta-analyses and individual published randomized trials.
One of the published studies reviewed by the FDA (Hopkinson-1973) found that:
“A global evaluation at the end of treatment (4 hours) showed no difference between the PPX/APAP combination and the single-ingredient APAP in the percentage of patients reporting “effectiveness:”
• 64% in the combination group
• 62% in the single-ingredient APAP group
• 34% in the single-ingredient propoxyphene group
• 30% in the placebo group”[1]

An additional finding here, noted in some other studies, was that single ingredient APAP was more effective than single ingredient propoxyphene which, itself, was not distinguishable from a placebo. In some other studies, propoxyphene was superior to a placebo.
The FDA review stands on its own merits and, in essence, finds that a/ the addition of propoxyphene to acetaminophen does not result in a statistically significant improvement in pain relief compared with acetaminophen alone and
b/ that propoxyphene alone has only “weak analgesic effects”.

Statement by Dr. Steven B. Karch

I am a former assistant medical examiner in San Francisco where my practice was confined mainly to the investigation of deaths involving drug toxicity. I am a member of the Royal Academy of Physicians, Faculty of Forensic and Legal Medicine (London). My textbook, Karch’s Pathology of Drug Abuse (4th Edition published December 15, 2008), is widely used by pathologists and medical examiners in the United States and Europe. It is generally considered authoritative. This textbook contains a subsection specifically devoted to propoxyphene-related deaths.
I have been asked to confine my analysis to the cardiologic and toxicological issues of the Current Prescribing of Propoxyphene in the U.S.
Despite the evidence for the serious dangers of this drug and its marginal effectiveness, for most of the past 35 years or more, propoxyphene-containing drugs, now mainly the combination of propoxyphene and acetaminophen, have been among the top 25-selling drugs in the U.S. The data for the most recent eight years shows the continuation in top-25 status for the generic combination of propoxyphene and acetaminophen (similar to brand-name Darvocet): In the most recent year for which data are available, 2007, there were 21.3 million prescriptions filled for the generic combination of propoxyphene and acetaminophen, making it the 21st most-prescribed generic drug in the country.
Other top 25 drugs with vastly different benefit risk ratios
Two other top-25 generic drugs, oxycodone (16th) and warfarin (22nd), are worth mentioning because although they, too, have significant risks, they have clear and significant benefits, in the case of warfarin, a unique benefit. Because of proven, important efficacy, it would not be sensible to even consider removing either oxycodone or warfarin from the market. Risk mitigation strategies for such drugs, including the criminal prosecution of Perdue for mis-promoting Oxycontin and proper cautions for doctors and patients for both drug are necessary. For propoxyphene, market withdrawal is the only rational alternative.
Recent overview articles concerning propoxyphene
In a review entitled, Propoxyphene (Dextropropoxyphene): A Critical Review of a Weak Opioid Analgesic That Should Remain in Antiquity, the authors, all members of the Barkins family, concluded that “propoxyphene offers no therapeutic advantages over any other opioid. The propoxyphene-induced iatrogenic events and risk outweigh any perceived benefits that could be achieved. Any therapeutic benefit from this drug has long been overdue for disuse. The time has arrived for its imminent disposal into antiquity. More suitable therapeutic agents are available with a better risk-benefit ratio and less end organ damage such as those with CNS, cardiac, and pulmonary systems.”[6]
In another review, focusing on efficacy, Sachs found that “propoxyphene has poor efficacy and significant side effects. A meta-analysis of 26 trials involving 2,231 patients compared the combination of acetaminophen and propoxyphene with acetaminophen alone or placebo. The narcotic combination offered little benefit over acetaminophen alone. Another systematic review found that the NNT for a single 65-mg dose of propoxyphene to achieve at least 50 percent pain relief
was 7.7 (95 percent CI, 4.6 to 22) when compared with placebo. For the combination of propoxyphene and acetaminophen (650 mg), the NNT was 4.4 (95 percent CI, 3.5 to 5.6) when compared with placebo, similar to the NNT for acetaminophen alone….Thus, propoxyphene provides minimal if any additional analgesia to acetaminophen alone and is associated with significant adverse effects. It cannot be recommended for routine use.”
Conclusion:
When we first petitioned the FDA to ban propoxyphene-containing drugs 30+ years ago, our petition for a ban was supported by a number of medical examiners from around the country. Our more recent petition was prompted by the conclusion of the UK government, after a commission reviewed all of the evidence, that efficacy of this product “is poorly established and the risk of toxicity in overdose, both accidental and deliberate, is unacceptable.” They further said that “It has not been possible to identify any patient group in whom the risk-benefit [ratio] may be positive.”
In response to an article by former Mayo Clinic Chief of Oncology, Dr. Charles Moertel, attacking the use of propoxyphene 36 years ago by stating that “It appears that factors other than intrinsic therapeutic value are responsible for the commercial success of propoxyphene,”[7] a representative of Lilly wrote: “Darvon products have won a remarkable acceptance by patients and physicians since their introduction.”[8] In a letter in response to the Lilly letter, Dr. Moertel replied,
“The implication that general acceptance of a therapeutic procedure by physicians in a given era constitutes obligate proof for effectiveness is not tenable. If this were true, we would still be bound to the mummy dust, unicorn’s horn, leeching, purgatives and mustard plasters universally endorsed by our forebears. We must constantly offer challenge to all our sacred cows, so that our patients may afforded the highest care a the most reasonable cost.”[9]
Finally, I contacted Dr. Donald Kennedy who was FDA Commissioner when we originally filed our petition to ban propoxyphene in 1978. When I asked him, after sending him our 2006 petition to ban the drug, if he would now support our petition to ban the drug, he replied, “You can sign me up!!”
As I said in the beginning, propoxyphene has one of the most unfavorable benefit-to-risk ratios I have ever seen for a drug. This committee will hopefully agree with this and recommend the beginning of a two-year phased withdrawal of these products.
Thank you for taking the time to listen to my presentation.[/LEFT




continueeeeeeeeeeeeee]