FDA Right in Not Banning Propoxyphene Analgesics

Last week (July 7), the FDA decided to allow continued marketing in the United States of medications containing the pain reliever propoxyphene. However, they are requiring stronger label warnings regarding overdose, a Medication Guide for patients, and further study of possible harmful cardiac effects [see FDA info].

This decision came after the acetaminophen debacle just a week earlier [see our blog post], and after an FDA expert panel last January recommended discontinuing propoxyphene products (including Darvon® and Darvocet® brands). It also was bad news for the watchdog group “Public Citizen,” which had petitioned the FDA more than 3 years ago to ban propoxyphene. In a lengthy, research-filled, albeit highly biased, document, Public Citizen contended that risks associated with propoxyphene far outweighed any benefits [see petition document].

Weak But Popular Opioid Analgesic

Propoxyphene, in clinical use since 1957, is considered a fairly weak synthetic opioid (1/2-1/3 as potent as codeine) for treating mild-to-moderate pain. Despite this, it remains very popular; there are about 25 million prescriptions written for propoxyphene drugs annually in the U.S. Propoxyphene’s primary metabolite, norpropoxyphene, is strong, long acting, and toxic — it can accumulate in harmful amounts if propoxyphene is taken in excess and/or with alcohol or other CNS depressant drugs. Both propoxyphene (sometimes designated as “dextropropoxyphene”) and norpropoxyphene have been shown to alter cardiac electrical conduction and contraction, at least in animal experiments. However, to this day, it is unknown whether the cardiac effects found in nonclinical studies occur in patients exposed to therapeutic concentrations of propoxyphene drugs, according to FDA data. The FDA intends to study this issue further; although, if cardiotoxicity was a prominent, frequent, and fatal adverse effect it should have been apparent long ago.

Overdose, Suicide Deaths a Prime Concern

The FDA’s admirable restraint in not banning propoxyphene was somewhat surprising in that health authorities in the UK had ordered a phased removal of the analgesic in 2005. In the UK, “co-proxamol” (propoxyphene + acetaminophen) had been associated with nearly a fifth of all drug-related suicides, according to a recent report [Hawton et al. 2009]. With the ban there have, indeed, been reductions in co-proxamol-related suicides during the past few years, but with a corresponding shift to increased deaths with other analgesics and drugs overall.

The FDA had reports of 1,400 propoxyphene-related deaths since 1957, although there was no proof that the analgesic had directly caused all deaths. Most fatalities were drug overdoses and suicides, involving multiple agents in up to 93% of cases. On an annualized basis, the per-prescription incidence rate of propoxyphene-related mortality could be as low as 0.0001% ([1,400 deaths / 52 years] divided by 25-million-Rx/year). In other words, 99.99% of the time propoxyphene has been used without deadly effect. (The Public Citizen group’s petition claimed a higher annualized rate of roughly 338 deaths, which still results in a tiny 0.001% mortality incidence per year.)

Keeping Pain Relief Options Available

While propoxyphene drugs have been in clinical use for more than 50 years, and some clinicians consider these analgesics of questionable value today, they apparently still offer important pain relief options for many patients. In fact, after discontinuation in the UK, one study found that nearly half of patients previously taking propoxyphene were unable to find a suitable alternative [Ottewell and Walker 2008]. So the FDA’s decision to keeping this pain-relief option available in the U.S. is commendable.

Furthermore, in contrast to what the Public Citizen group described as “propoxyphene’s deadly nature,” the analgesic has had a remarkable record of safety when used as directed. There is no inherent evil lurking in propoxyphene molecules; on the other hand, case-series studies of propoxyphene-related overdose deaths have found a history of depression in more than half (55%), undetermined mental illness in a further 21%, and chronic alcohol abuse in up to a third of victims [Dywer and Jones 1984].

Quite possibly, with propoxyphene, as well as with other opioids, the incidences of related overdoses and suicides reflect failures of the mental healthcare and addiction treatment systems. Solving such problems would be beyond FDA purview but are, nonetheless, vital issues to take into account if significant increases in analgesic safety are to be achieved. Of potentially lesser value are “black box” warnings and Medication Guides [blog-post coming on this], or, worse yet, banning or restricting access to certain opioids.

What do you think? Click on the “comments” link below to share your opinions.

References [noted but not linked above]:
> Dywer PS, Jones IF. Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination. Hum Toxicol. 1984;3(Suppl.):145–174S.
> Hawton K, Bergen H, Simkin S, et al. Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis. BMJ. 2009;338 (online ahead of print).
> Ottewell L, Walker DJ. Co-proxamol: where have all the patients gone? Rheumatology. 2008;47(3):375.