effects of dextropropoxyphene (DPX) in clinical practice from the viewpoint of a death-investigator interested in evidenced-based medicine.
Dextropropoxyphene received FDA approval more than 50 year ago, at a time when it was impossible to measure propoxyphene metabolite directly, at a time when the family of CYP450 polymorphisms had not yet been discovered, when the ion channels in the heart had not yet been characterized (or, in some cases even discovered), and at a time when unintended drug reactions were difficult to identify and often went unnoticed.
The principal oxidation product of DPX is norpropoxyphene (NPX); it has a much longer half-life than DPX and tends to accumulate. In itself, that might not be a problem, but NPX accumulates in the heart where it exerts disruptive toxicity.

Use of this drug involves important safety issues. It is widely used, around the world, in suicidal gestures and for frank suicide. The physical properties of this drug make it particularly well fitted since it is widely available, rapidly absorbed, can exert toxicity even when the plasma concentration is within the “therapeutic range.” Indeed, most who attempt suicide with DPX die before they reach the hospital.

Simple DPX poisoning is straightforward and easy to understand. Even though DPX is a very weak mu agonist, when present in sufficient quantities, or taken with alcohol, it can cause respiratory depression.
However, the most dangerous aspect of DPX is that its cardio toxic oxidative metabolite, norpropoxyphene (NPX), is very long acting, and is also 2.5 times more potent than its parent compound in producing cardiac depression. It has a half-life (time before ½ of the substance is cleared from the body) of approximately 36 hours. In other words, the half-life of NPX is nearly three times longer than that of propoxyphene, which means that it will accumulate.
DPX accumulates particularly in the heart and liver. Because NPX also accumulates in the liver, it can cause disruption in the metabolism of many of the most important drugs now in use.
In the heart, NPX blocks both the IK and hERG currents. Blockade of the former can cause conduction delay and even heart block. Blockade of hERG (slow rapid depolarizing K channel) may cause QT interval prolongation leading to torsades des pointes and sudden death.
Patients who have overdosed with DPX have widening of the QRS complex, and the degree of widening is dose dependent. These findings have clinical relevance to the management of patients with DPX poisoning; heart block must be anticipated.
Disruption of liver function may be even more profound. CYP3A4 is the major CYP enzyme catalyzing DPX metabolism. The variability in pharmacodynamic and pain relieving effectiveness of DPX is likely due to large inter-subject genetic variability in hepatic CYP3A4 expression and/or drug-drug interactions.

DPX is also a competitive inhibitor of CYP3A4 and this enzyme oxidizes a large number of other important drugs. These include, calcium channel blocking agents, macrolide antibiotics, isonazid, and proton pump inhibitors. Perhaps most importantly, if the breakdown of carbamazepine, a commonly used anticonvulsant, is slowed because of propoxyphene, toxic levels may accumulate.

Strong evidence suggests that DPX is also an inhibitor of another drug-metabolizing enzyme, CYP2D6. This opens up the possibility for other types of drug interactions. Most beta blockers are metabolized by CYP2D6. A report of bradycardia in a user of metoprolol (a beta-blocker) suggest that symptomatic drug interactions are, in fact, occurring.
DPX toxicity increases in the presence of alcohol. When DPX is co-administered with Etoh, first pass hepatic metabolism is decreased, which means that DPX concentrations increases. Etoh is frequently present in DPX-related deaths. In a study of 123 DPX-related suicides in the UK, alcohol was found to be involved in 58.5% of the cases. In addition, these individuals generally had lower blood propoxyphene levels, and consumed fewer tablets.
Unless DPX is the only drug present, determining the cause of death can be problematic. When confronted with a decedent who has taken multiple drugs, including DPX, it is often impossible to tell which, if any of the drug was the cause of death, and the diagnosis is usually polypharmacy. As a consequence, many DPX-related deaths go unreported, where death is simply listed as a consequence of “polypharmacy,” and the risk posed by use of this drug goes under-estimated.
There are numerous reasons for banning this drug:
(1) It is a dangerous drug: Large amounts of DPX are rapidly absorbed from the GI tract very quickly, making attempted suicide difficult to treat.
(2) Even modest amounts of this drug can cause lethal cardiac arrhythmias in any individual with an undiagnosed hERG genetic polymorphism.
(3) Use of DPX can lead to toxic levels of antibiotics and anticonvulsants
(4 The drug is not particularly effective. For far less money, patients would get more pain relief if they took aspirin or acetaminophen.

Clinical Pharmacology Data

Because there are very little clinical data on patients found with the unexpected deaths typical of coroners’ cases, it is useful to examine clinical data from patients who lived after their overdoses of propoxyphene. A very unique series of 222 consecutive patients admitted over a six-year period to just one Danish hospital provides extremely useful data confirming what the FDA has referred to in the pre-clinical studies they described.[2]
The first figure below describes the findings on admission of these patients.

As can be seen, 48% of patients had heart failure/impaired circulation, 15% had a cardiac arrest (asystole), 9% had abnormally slow pulse and 41% had an abnormal electrocardiogram, including 19 patients with a ventricular arrhythmia.
The authors commented on experimental evidence of a negative chronotropic effect (slower pulse) and negative inotropic effect (weaker heart contraction) with propoxyphene that would explain some of these clinical findings, including the fact that only a few of the patients with circulatory failure exhibited a compensatory tachycardia (faster pulse) to make up for the decreased circulation because of the negative chronotropic effect..
The chart below illustrates further life-threatening clinical findings on admission:
44% of patients were in acute respiratory failure and had to be placed on a ventilator, 10% of patients had convulsions and 73% of patients were in a stupor or in a coma.
The final slide from this study concerns the 17 patients (8% of all 222 patients) who died despite apparently excellent care in the ICU.
Nine (53%) of the deaths were from heart failure, a total of 13 (76%) of deaths were from all cardiovascular causes and 4 deaths (24%) were from brain damage.
Pharmacokinetics
As we discussed in our petition, there is a very narrow margin of safety with propoxyphene, partly because of the accumulation, even at normal doses, of the cardio toxic metabolite, norpropoxyphene. This is borne out by pharmacokinetic studies, especially the findings with multiple doses over time and more so in older patients (age 70-79).[3]
The median maximum blood levels (and ranges) for a single dose in healthy elderly people were 156 (39-366) micrograms per liter for propoxyphene and 193 (112-283) for norpropoxyphene. For multiple sequential doses (the equivalent of just three 65 milligram doses of propoxyphene a day) for one week, the median level for propoxyphene was 239 (151-509) micrograms per liter and, for norpropoxyphene, it was 1100 (775-1500). Thus, although blood levels of the shorter half-life propoxyphene increased from 156 to 239, from the single to multiple doses (an increase of 1.5 times), levels of the longer half-life cardio toxic norpropoxyphene increased from a median value of 193 to 1100, an increase of 5.7 times when the drug was used over time in elderly people..
In our petition, we had cited data from patients being given chronic doses of propoxyphene having similar blood levels, in many cases using doses such as those in the data above.
Pills/day Type of Subject Duration of Drug Use Maximum Blood Concentration (μg/l)
DXP NPX
3 (HCl) Cancer patient 60 days 746 (2) 3010
3 (HCl) Cancer patient 14 days 275 (2) 750
3 (HCl) Normal vol. 4 days 241 (2) .600
6 (HCl) Normal vol. 4 days 849 (2) 1240
9 (N) Addict 28 days 519 (3) 3830
11 (N) Addict 42 days 567 (3) 4940
11 (N) Addict 84 days 513 (6) 5070
12 (N) Addict 84 days 424 (6) 1830
12 (HCl) Cancer patient 365 days 866 (2) 3230
Mortality Compared to codeine-containing combinations with acetaminophen: Effect of UK Ban
A recent study estimated the frequency of overdose and death for the three most popular acetaminophen-opioid compound analgesics: propoxyphene and acetaminophen and two different codeine preparations and acetaminophen. Adjusting for relative amounts of prescriptions of the three drugs, overdoses involving propoxyphene and acetaminophen Scotland were 10 times more likely to be fatal (24.6 (19.7, 30.4)) when compared with cocodamol (2.0 (0.88, 4.0)) or co-dydramol (2.4 (0.5, 7.2). The authors estimated from this study that withdrawal of propoxyphene and acetaminophen would prevent 39 excess deaths per annum in Scotland alone.[4]
A very recently published study measured the effect of the UK announcement of the ban of propoxyphene and acetaminophen (called co-proxamol in the UK) on suicides in Scotland.[5] The study showed early evidence of a reduction even before the ban was finalized in January, 2008. In the 5 years pre-legislation (2000–2004), there was a mean of 37 co-proxamol deaths per year. In the first year after the legislation was announced, 2006, the number had fallen to 10 per year in Scotland. The average number of total Scottish drug poisoning deaths in the 2000-2004 interval was 171 per year. Rather than any compensation for the decrease in co-proxamol use by increases in other drugs which could result in suicide, there was an actual decrease in all poisoning deaths to 126 in 2006.
In a personal communication with Dr. Nick Bateman, of the Royal Infirmary of Edinburgh, an author of both of the studies described above, he informed me that in England, unpublished data show that there has been a 90% decrease in co-proxamol deaths in that country since the ban was announced. He also stated that he supports the efforts to ban these products in the U.S.