Valium / Diazepam News Blog

WASHINGTON,Feb. 28, 2006-Public Citizen today petitioned the U.S. Food and Drug Administration (FDA) to immediately begin to phase out the widely prescribed pain reliever propoxyphene (Darvon, Darvocet and generic versions) from the market because the drug has been associated with more than 2,000 accidental deaths, is physically addictive and is no more effective than safer alternatives.

Data from the Federal Drug Abuse Warning Network, which provides autopsy information from medical examiners in the United States, has found that 5.6 percent of all drug-related deaths were related to propoxyphene during the past 19 years. In 2004, 23 million prescriptions for propoxyphene were filled, making it the 12th most commonly prescribed generic drug in the United States. Four companies – Mylan, Mallinkrodt, Teva and QLT – account for more than 91 percent of U.S. prescriptions.

Propoxyphene has been associated with 2,110 reported accidental deaths in the United States since 1981. A large proportion of these deaths occur because most of the drug is converted into a metabolite that is highly toxic to the heart and lasts longer in the body than the original compound, resulting in cardiac depression. Adverse cardiac events associated with propoxyphene include an interruption of heart transmission of electrical impulses, slowed heartbeats and a decreased ability of the heart to contract properly.

“The number of deaths involving propoxyphene in the U.S. alone is striking,” says the petition, filed by Public Citizen and two Swedish experts on propoxyphene, Drs. Ulf and Birgitta Jonasson. The entire petition can be viewed at www.WorstPills.org.

Last year, the British government announced a phased withdrawal of the drug because of its negligible effectiveness and the high risk of overdose and death. “It has not been possible to identify any patient group in whom the risk-benefit [ratio] may be positive,” the British government stated.

In addition, popoxyphene has been deemed inappropriate for prescription for the elderly because of central nervous system-related adverse events – such as sedation and confusion – that have been found to increase the likelihood of falls and fall-related fractures in the elderly. Studies have shown that propoxyphene use is widespread in the institutionalized population, in emergency rooms and in community-dwelling older people, populations in whom propoxyphene is most dangerous.

Public Citizen is calling for the drug to be phased out, rather than banned immediately, because of its addictive quality.

Explaining the background for removing propoxyphene products from the market, the British Committee on the Safety of Medicines pointed out, in January 2005, that “Each year there are 300-400 fatalities following deliberate or accidental drug overdose involving co-proxamol [propoxyphene/acetaminophen] in England and Wales alone. Approximately one-fifth of these deaths [60-80] are considered to be accidental.” Thus in those two countries alone, with a population of 53 million people---approximately 18% of the size of the U.S.-- there were an estimated 60 to 80 accidental deaths a year from co-proxamol or propoxyphene/acetaminophen.

Because it continues to be so widely prescribed in the U.S. (the 12th highest-selling generic drug in 2004 with 23 million prescriptions filled and sales that year of $291 million[1]) and because toxicity develops at only slightly above the recommended daily dose – especially in combination with alcohol and other central nervous system depressants – propoxyphene is consistently mentioned as one of the top 10 drugs found in the subject’s system during autopsies.[2] Medical examiners note its presence in more deaths each year than most other prescription drugs. Data from the Drug Abuse Warning Network (DAWN), which provides autopsy information from medical examiners nationwide, has implicated propoxyphene in 5.6% of all drug-related deaths (including prescription, over-the-counter, and illicit drugs) in just over 19 years (1981-1999). This amounts to 7,109 total reported U.S. deaths since 1981 merely for the counties covered by DAWN, which account for only approximately one-third of the population of the country.

Propoxyphene is implicated in a high proportion of accidental deaths each year, because the majority of the drug is converted into a metabolite that is even more toxic and has a longer half-life than its parent compound. From 1981 to 1999, DAWN reported 2,110 accidental propoxyphene-related deaths, or 38.6% of the total number of propoxyphene-related deaths. (DAWN no longer details manner of death but the total number of propoxyphene-related deaths has remained relatively the same since data collection on manner of death stopped in 1999—see Figure 1 for total death data through 2002). Because DAWN reports data only from medical examiners in counties whose total population makes up one-third of the country, it is reasonable to conclude that the true number of accidental propoxyphene-related deaths since from 1981 through 1999 may be three times greater than the 2,110 deaths actually reported.

In November 1978, the Health Research Group (HRG) of Public Citzen proposed significantly altering propoxyphene’s regulatory status in either of two ways: HRG petitioned the Department of Health, Education and Welfare (HEW) to ban the drug as an “imminent hazard.” As an alternative, HRG asked HEW to tighten restrictions on the drug’s use by placing it in Schedule II of the Controlled Substances Act. A key factor in the HEW decision to reject the HRG proposals was Eli Lilly’s commitment to an “educational program” intended to sensitize prescribers and patients to the hazards of propoxyphene products. In a 1978 HEW appraisal of Lilly’s efforts, the following was reported: “Lilly has not conducted its campaign to prescribers as FDA had expected. Detail persons visiting physicians failed to emphasize the user warnings in the majority of visits, left samples of Darvon in 50-75 percent of visits, and on the average spent less than half of the time on Darvon during the visits.”[11] It appears that Eli Lilly converted its education program into a marketing initiative.

In fact, even though Lilly no longer manufactures these drugs, having sold the rights to Darvon/Darvocet to aaiPharma several years ago, propoxyphene-containing compounds, mostly generic versions, remain among the top-selling drugs on the market.[14] This high level of prescribing persists despite propoxyphene’s eventual placement in Schedule IV of the Controlled Substances Act (which includes drugs with limited potential for dependence such as diazepam [Valium] as opposed to Schedule II, which includes drugs with a high potential for dependence such as codeine). Lilly’s half-hearted attempts to comply with the weak restrictions enacted the last time the government considered the dangers of propoxyphene have clearly allowed this drug to remain as a viable analgesic in the minds of doctors throughout the nation, despite its inappropriateness for treating pain and the serious dangers it presents to patients.

Although some have claimed that propoxyphene may be effective in chronic pain such as that from cancer,[20] there exist no randomized controlled trials that indicate any such effect. Dr. Charles Moertel, a well-known former cancer specialist at the Mayo Clinic, noted that “for the treatment of severe pain, the use of Darvon either alone or in combination is grossly inadequate treatment and is really inhumane to the patient.” Dr. Moertel also stated that “it is possible to maintain good medical practice without the use of Darvon.”[21] Further, even were propoxyphene shown to be effective for this kind of pain, chronic usage increases the likelihood of adverse events due to buildup of the cardiotoxic propoxyphene metabolite, norpropoxyphene.

Beyond the questionable wisdom of prescribing a drug with severe adverse effects that provides little benefit, the relative ineffectiveness of propoxyphene translates into an additional kind of increased danger to patients. When the recommended dose fails to alleviate their pain, patients may choose to take additional pills, exceeding the recommended daily dose. It does not require much additional drug beyond the daily dose to generate either dependency or toxicity, as the following section demonstrates.

Henry, et al., report that the cardiac toxicity of propoxyphene may derive from membrane stabilization, the depression of excitability in nerve and heart tissue.[26] Whitcomb et al. similarly found that propoxyphene acts as a potent sodium channel blocker, which depresses the action potential of myocytes.[27] There is a significant relationship between the dose of propoxyphene and prolongation of the QRS complex, representing an increase in the time required for the ventricles to depolarize. This relationship is not seen with other opioids.[28] The prolongation of the QRS complex associated with sodium channel blockade can be a precursor to ventricular arrhythmia, which is often fatal.

The margin of safety of propoxyphene, the ratio between the dose that contains 99% of the effectiveness of the drug and that which kills 1% of those who use it,[34] is extremely low, especially given its relative inefficacy as an analgesic. The dose of propoxyphene necessary for cardiac toxicity to occur overlaps significantly with the increased dose which a user, dissatisfied with the analgesic effects and still in pain, may ingest. The margin of safety is even worse when other drugs are involved, especially alcohol. The recommended dose for both chronic and acute pain is one pill every four hours, or six pills per day. Young, et al., found that death can occur with 20 pills while Whittington found that as few as 6-15 pills can cause death.[35],[36] The lower number reflects the ability of alcohol to potentiate the toxicity of propoxyphene. Similarly, Obafunwa, et al., found that as little as 0.168% blood alcohol content (BAC) can potentiate lethality within the propoxyphene limit of toxicity of 0.75 ?g/g.[37] A study analyzing over 1000 fatal intoxications (both intentional and accidental) due to alcohol, a single drug, or both, found that the median post-mortem blood alcohol concentrations -sufficient to cause death - were much lower when propoxyphene was found in combination with alcohol (3.3 parts per thousand BAC without propoxyphene, 1.7 parts per thousand with propoxyphene).[38] Thus, propoxyphene is particularly dangerous when combined with alcohol.

A Swedish study further highlights the dangers and prevalence of propoxyphene and alcohol consumption. Jonasson, et al., identified 766 propoxyphene-related suicides in Sweden from 1992-1996 and an additional 1,016 non-suicide deaths. Alcohol was present in 425 of those non-suicides and of those, 220 were classified as having been caused directly by propoxyphene. Among the fatally intoxicated, the mean blood propoxyphene concentration was only 2 ?g/g – less than three times the blood level typically found after the recommended, therapeutic dose. Further, the authors concluded that the majority of those who died from an accidental poisoning were not part of the “drug addict population.”[39] The same team of authors concluded in a separate study that suicides were generally over-reported in propoxyphene-related deaths and that accidents were under-reported.[40] The authors concluded that “probably more than 40 individuals die from accidental poisonings due to a combination of propoxyphene and alcohol each year” in Sweden alone[41] – and since accidents are under-reported, this may not even reflect the true dangers of accidental poisoning from propoxyphene.

Data from Sweden, where propoxyphene was not required to be prescribed on a special prescription form like other narcotic drugs in the country until 2001, suggest that the drug is one of the deadliest of all those heavily prescribed. Jonsson et al. determined the number of deaths from fatal intoxications found during autopsy from 1992-2002 at the Department of Forensic Chemistry in Lingkoping, which has complete national coverage of Sweden’s population of 8.9 million. Out of 6998 fatal intoxications, propoxyphene was found in 1863 – 27% - of cases, second only to ethanol. Toxic levels of propoxyphene (defined by the authors based on Druid, et al.,[45] as 0.8 ?g/g) were found in 1370– 74% of the 1863--more than any other prescription drug.

The study also measured the fatality ratio, which relates the number of fatal intoxications with toxic concentrations of the substance to the number of defined daily doses per 1000 inhabitants of the country per day. Thus, a drug with a fatality ratio of 1 would cause one fatal intoxication per dose per 1000 inhabitants per day. Using this measure of the lethality of a drug, the authors determined a fatality ratio of 10.8 for propoxyphene, almost five times as high as that for acetaminophen (2.3), the drug with the next highest number of absolute deaths. In other words, for a given number of prescriptions, propoxyphene was involved in almost five times as many deaths as acetaminophen.[46] This study highlights the deadliness of the combination of high lethality and massive prescribing that characterizes propoxyphene.

Propoxyphene and combinations including it constitute one of the most prescribed prescription drugs in the country. In 2004, propoxyphene was the 12th most prescribed generic drug with over 23 million prescriptions sold.[47] Over the past 47 years, it has also been one of the deadliest drugs on the market, being associated with well over 10,000 confirmed deaths in the United States alone.

In the United States, DAWN collects data from medical examiners and emergency rooms in approximately 40 metropolitan areas. As of 2002, 94 million people lived in counties that reported to DAWN. Given a 2000 US population of 293 million, this means that the network represents approximately 1/3 of the total population. Although data from DAWN cannot be directly extrapolated, multiplying its results by three gives a general idea of the enormity of the damage this relatively ineffective yet dangerous drug has wrought.

Data regarding propoxyphene-related deaths for the past 20 years of DAWN are presented in figure 1.[48] While these numbers do not necessarily implicate propoxyphene as the direct or sole cause of death, since other drugs were found with it in 93.3% of the 459 cases in 1999, its toxicity makes causation likely. Furthermore, a large proportion of deaths involving propoxyphene involved alcohol and/or acetaminophen as having been used in combination. Alcohol was one of the drugs involved in 33.8% of propoxyphene deaths involving two or more drugs and acetaminophen was in 19.6%. Alcohol is not particularly lethally toxic on its own, but has been shown to potentiate propoxyphene lethality. When we originally petitioned the FDA to ban propoxyphene in 1978, the Chief Coroner of San Francisco, Dr. Boyd Stevens, told Public Citizen that, based on autopsy findings, “if you double the Darvon dosage and take just one or two [bar] drinks, you can get into the toxic or lethal range.” In some cases, acetaminophen was likely found in autopsies due to its presence in propoxyphene/acetaminophen preparations. Since propoxyphene has been shown to have a fatality ratio almost five times as great as that for acetaminophen[49], it can be concluded that propoxyphene represents the cause of death in a significant proportion of these cases.

The number of deaths involving propoxyphene in the US alone is striking. Although in 1981, propoxyphene was implicated in over 8% of drug deaths mentioned in DAWN, that number has declined to around 4% as of 1999. Nevertheless, the actual number of propoxyphene-associated deaths in absolute terms has been creeping steadily upwards since 1981. Whereas 227 deaths were reported in 1981, a high of 459 was reported in 1999. The cumulative deaths since 1981 have, at last count, reached 7,109 through 2002. As propoxyphene has been on the market since 1957, there are many more deaths, occurring before 1981 and after 2002 that have not even been calculated. Further, these numbers represent only those cases in which an autopsy was performed.

From 1981 to 1999, the Drug Abuse Warning Network reported 2,110 propoxyphene-related accidental deaths, 38.6% of the total number of 5,462 deaths involving propoxyphene. There has been a slight trend towards an increasing number of accidental deaths reported, such that in the five years from 1995-1999, an average of 40.3% of the deaths were accidental. Although DAWN did not release the breakdown for manner of death in 2000-2002, assuming 199 accidental deaths (as there were in 1999) yearly during this time period yields 2,707 propoxyphene-related accidental deaths for the period from 1981-2002 out of a total of 7,109 propoxyphene-related deaths.

Lastly, these data represent only deaths in which the index of suspicion was high enough that the case was sent to a medical examiner. Cases in which an autopsy was performed in a hospital are not reported. Further, the autopsy rate in the US has been declining steadily since the 1950s from around 50% to between 5-10% today.[50],[51] Since autopsies are now much less likely to be routinely performed, the true number of accidental propoxyphene poisonings is almost certainly much higher than the 2,110 confirmed cases from medical examiners’ offices in the past twenty years alone.

Related to the above issue of autopsies, under-reporting of accidental deaths may be an especially significant problem in the elderly. Autopsies are performed at particularly low rates in nursing homes – Katz, et al., found an autopsy rate of only 0.8% from 1980-1984.[52] Propoxyphene is widely prescribed in the elderly, making up over 18% of prescribed analgesics in nursing homes[53], and the highly cardiotoxic and long-lasting propoxyphene metabolite norpropoxyphene is extremely prone to building up to high levels in the elderly. Since high levels of norpropoxyphene can occur at low doses of propoxyphene (as mentioned earlier, Inturrisi reports a case where a norpropoxyphene level of 5.07 ?g/g was found where the propoxyphene level was only 0.513 ?g/g – significantly under the level considered lethally toxic[54]), such a death from a ventricular arrhythmia in an infirm elderly decedent is unlikely to raise an index of suspicion sufficient to perform an autopsy. All this evidence points to a significantly higher number of accidental deaths related to propoxyphene than that reported by DAWN.

Nevertheless, in the most recent five years with such information, DAWN has reported that approximately one-third of deaths involving propoxyphene have been suicides (see figure 2 above). It could be argued that banning propoxyphene would have no effect on these deaths – those intent on suicide will choose another route and no net benefit will be produced. Indeed, a Lilly representative stated in 1980 that transferring propoxyphene to Schedule II, a less stringent restriction than our proposed complete banning of the drug, would have “negligible impact on the suicide rate” since abusers would merely “move to another drug.”[55] However, the restriction of several drugs typically involved in suicides demonstrates this not to be the case. For example, figure 3 shows that restricting the availability of barbiturates by imposing Schedule II controls had a marked positive effect on reducing the number of barbiturate suicides.[56] Although the number of total drug suicides did not drop as steeply as the number of barbiturate suicides, indicating that there was some substitution of other drugs for barbiturates, this substitution was clearly not 100%. Note that the steep drop in prescriptions and suicides began in 1970 when Congressional hearings regarding barbiturates began and dropped again in 1975, when the drugs were controlled in Schedule II. The graph shows that people intending to commit suicides did not completely turn to other drugs for suicides, as the total number of drug suicides decreased along with the number of barbiturate suicides. Given that we propose removing propoxyphene from the market rather than merely restricting its use by placing it in Schedule II, the resulting drop in total suicides would be predicted to be even more significant.

Further, many suicides are cries for help, not truly wishes for death. However, with the low margins of safety of propoxyphene due to its high toxicity, these attention-seeking attempts—often called suicidal gestures—are more likely to be “successful” when this drug is used. Thus, as a drug implicated in a large number of suicides yearly and one with few redeeming benefits, the ban of propoxyphene will likely result in a significant reduction in the total number of drug-related suicides.

Evidence of dependence on propoxyphene is well-documented in the literature. Clinical trials and published case histories illustrate that propoxyphene can produce physical addiction, as manifested by withdrawal symptoms, strong psychological dependence, and tolerance. Reports on propoxyphene dosage suggest addiction can occur at less than the maximum recommended daily dose of 390 mg. and unequivocally confirm addiction at just twice the recommended daily dose. Particularly for the elderly, the long-term use consequent to addiction can have devastating consequences because of the greater build-up of the cardio-toxic metabolite, norpropoxyphene in older people.

A more recent study by Ng, et al., reports that propoxyphene is a drug of primary abuse. Of the records of 73 propoxyphene abusers from a detoxification unit, 67% revealed that propoxyphene was the first opiate ever abused. The authors concluded that propoxyphene abuse is not secondary to heroin dependence.[66] Thus, propoxyphene poses a serious addiction risk.

Propoxyphene is still a major drug of abuse, as can be seen by the yearly number of emergency room visits reported by the Drug Abuse Warning Network (DAWN). Data from 1994-2002 indicate approximately 5,000 emergency room visits related to propoxyphene each year. In 2002, 1680 out of 4676 or 36% of people with an emergency room visit related to propoxyphene indicated that either psychic effects or dependence on propoxyphene were the reason for the emergency room visit.[67] Thus, propoxyphene abuse remains a major problem.

The Health Research Group urges, by this petition, the immediate implementation of a phased withdrawal from the U.S. prescription drug market of all propoxyphene-containing products. This should be initiated immediately because this drug has considerable human toxicity, addiction potential, abuse liability, but very limited therapeutic usefulness. That this drug, which has been associated with at least 7109 reported deaths including 2110 in which the death was accidental and many times more emergency room visits since September 1972, is a serious public health problem is not disputable. Only by banning propoxyphene can this danger be eliminated.

We agree with the January 2005 decision of the U.K. to phase out this dangerous drug because efficacy of this product “is poorly established and the risk of toxicity in overdose, both accidental and deliberate, is unacceptable” and find it inexcusable that the U.S. FDA is lagging so far behind in taking this important, life-saving public health regulatory action.

[1]The top 200 generic drugs in 2004 (by units and by retail dollars). Drugtopics.com [online]. Using IMS data from December 2005, four companies (Teva, Mylan, Mallinckrodt, and QLT) out of a total of 13 selling propoxyphene-containing products, sold 91% of the 2.15 million prescriptions that month, with two, Teva and QLT accounting for 54% of the 2.15 million prescriptions filled that month.

[2]Substance Abuse and Mental Health Services Administration: Office of Applied Studies. Drug Abuse Warning Network Annual Medical Data 1999.

[3]Beers MH, Ouslander JG, Rollingher I, Reuben DB, Brooks J, Beck JC. Explicit criteria for determining potentially inappropriate medication use by the elderly. Arch Intern Med Jul 1997;151:1531-36.

[4]Won AB, Lapane KL, Vallow S, Schein J, Morris JN, Lipsitz LA. Persistent nonmalignant pain and analgesic prescribing patterns in elderly nursing home residents. J Am Geriatr Soc. 2004 Jun;52(6):867-74.

[5]Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to acetaminophen. BMJ. 1997 Dec 13;315(7122):1565-71.

This is cache, read story here