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Approximately 10% of reported fatal poisonings with propoxyphene have blood concentrations exceeding 10 mg/L. A few have concentrations exceeding 100 mg/L. It is evident, therefore, that the blood does not reach propoxyphene "saturation" at either concentration. The ratios of propoxyphene to norpropoxyphene do not appear to differ markedly between drug abuse deaths and nonabuse deaths.

Dextropropoxyphene is a widely prescribed synthetic opiate-like drug of uncertain analgesic efficacy which, in acute overdosage, manifests all the features of opiate toxicity. It is rapidly absorbed and, in association with other central nervous system depressants such as alcohol or benzodiazepine drugs, may be rapidly fatal. Seriously overdosed patients are comatose with respiratory depression, vomiting, seizures and circulatory collapse; small pupils are a useful diagnostic marker. The first priority is to establish the airway and treat convulsions, if present. All the features of overdosage are then rapidly and safely reversed by the specific opiate antagonist naloxone given intravenously. High tissue concentrations and slow elimination of dextropropoxyphene metabolites make continued and intensive monitoring after resuscitation essential because sudden unpredictable deterioration may occur for up to 24 hours. Other more slowly toxic co-ingestants such as paracetamol (acetaminophen) are often present and should be detected and treated as necessary. Dextropropoxyphene poisoning is now probably one of the most common causes of self-poisoning death because, although there is an effective antidote, subjects frequently succumb before treatment can be made available.

The clinical course and the drug kinetics are described in a patient who ingested 1.35 g dextropropoxyphene chloride, 17.5 g aspirin, 7.5 g phenazone, 2.5 g butenemal, and 250 mg of a phentiazine derivative. Within 1 h the intoxication caused deep unconsciousness, severe respiratory depression, moderate circulatory failure, and slight quinidine-like changes in the ECG. Despite very high serum concentrations of dextropropoxyphene (peak 1010 micrograms/l at 2 h) and norpropoxyphene (871 micrograms/l at 8 h) the patient responded well to naloxone. No clear signs of the saturation of drug metabolism were found in this patient despite the high serum concentrations of dextropropoxyphene, salicylate, phenazone, and butenemal.

Liver damage in a woman who had taken an overdose of paracetamol and dextropropoxyphene was assessed by monitoring serum prealbumin concentrations and by routine plasma enzyme determinations. The plasma aspartate aminotransferase returned to normal levels after 3 days, alkaline phosphatase was slow to show increases in activity, and serum albumin concentration was in the normal range throughout. Prothrombin-time, although initially very high, returned almost to normal as a result of the administration of plasma. In contrast, serum prealbumin concentration decreased significantly after 36 h and continued to decrease, showing the course of failing liver function, until the patient's death 15 days after presentation. Prealbumin, a functional plasma protein synthesised in the liver, has a short half-life, is a true index of liver function, and seems to be a more reliable indicator of liver function in drug overdose than plasma enzymes, prothrombin-time, or plasma drug concentration.

Propoxyphene and its major metabolite, norpropoxyphene, have been quantitated in tissue specimens obtained from autopsies of people suspected of dying from propoxyphene overdosage. Gas-chromatographic determination of both propoxyphene and norpropoxyphene is essential because the blood concentration of the parent drug should be about 1.0 mg/liter or greater to attribute a death to the drug. The metabolite concentration in blood may help to establish when the drug was ingested. Concentrations in the blood after high oral therapeutic doses are about 0.3 mg of propoxyphene per liter, and norpropoxyphene concentrations may be as high as 3 mg/liter. Methods of determining propoxyphene are discussed.

Data from 30 fatal cases of dextropropoxphene poisoning occurring in Northern Ireland over three years have been studied. All the victims had ingested more than therapeutic amounts, and many had also taken alcohol or other drugs. Most of the deaths were probably suicides. Death occurred very rapidly suggesting that the narcotic effects of dextropropoxyphene predominated, and this may explain the scarcity of clinical reports, It is suggested that many doctors are unaware of the danger of dextropropoxyphene in overdosage and that the problem of dextropropoxyphene poisoning in the United Kingdom has not been fully appreciated. This supposition, if correct, highlights the absence of a satisfactory early-warning system for serious drug effects including death.

This retrospective study compares number and type of self-poisonings admitted to the intensive care units (ICU) at Sahlgren's Hospital, Gothenburg, during 1972 and 1976. The total number of patients requiring intensive care was unchanged, but a change in the pattern of self-poisoning was seen. In 1976 the number of patients requiring intensive care following acute alcohol intoxication had increased, whereas the number of barbiturate and methaqualone poisonings decreased. Tricyclic antidepressants formed the largest group in both years. Fewer patients needed endotracheal intubation and IPPV in 1976 than in 1972. Also, fewer complications were seen, and the death rate among ICU-treated patients decreased. In the Gothenburg area barbiturates accounted for one half of all deaths due to self-poisoning and tricyclic antidepressants for one fifth. Any expected decrease in intensive care as a result of fewer barbiturate and methaqualone poisonings was obscured by an increase in severe alcohol intoxication.

All admissions for analgesic self-poisoning to a district poisons unit over a 15-year period have been reviewed. During this time overdose with analgesic drugs increased to represent almost half of all admissions for self-poisoning. The types of analgesics taken in overdose also changed significantly during the period of this review. Aspirin and Distalgesic poisoning declined in incidence and more cases of self-poisoning by paracetamol and non-steroidal anti-inflammatory agents were seen. The impact of these changes on the medical management and outcome of deliberate self-poisoning is analysed. The reasons behind the trends described in this paper are assessed and their implications for future prevention and treatment are discussed.

Described is the case of a patient who developed left bundle branch block following acute propoxyphene hydrochloride overdosage. The left bundle branch block was transient and associated with no permanent sequelae. Previously documented cardiac abnormalities, specific narcotic antagonist therapy, and animal studies correlating cardiac toxicity of propoxyphene hydrochloride with its potent local anesthetic action are discussed.

Six patients suffering from cardiovascular failure due to acute propoxyphene overdose, were treated with dopamine infusion in doses of 2-17 microgram/kg/min. All patients responded with increased systolic arterial blood pressure, increased urinary output and decreased central venous pressure. The two most severely poisoned patients showed no increase in heart rate in spite of dopamine infusion in positively chronotropic doses. In two out of three patients the initially abnormal ECGs normalised during treatment. It is concluded that dopamine seems suitable for reversal of propoxyphene induced circulatory failure.

Despite the widespread use of propoxyphene products as analgesics, there is no profile of a typical abuser of propoxyphene. Propoxyphene is structurally related to methadone and has central nervous system effects similar to those of opioids. The patient with dependence needs professional help in withdrawing from propoxyphene, in finding an alternative regimen for management of pain and in connecting with self-help programs focusing on life without chemical dependence.

Propoxyphene and its major metabolite norpropoxyphene have been determined in blood and liver in 29 cases of death in which propoxyphene, either as the hydrochloride or as the napsylate salt, was involved. The use of propoxyphene napsylate (Darvon-N) contributed to the deaths of 4 persons, 3 of whom were former heroin addicts receiving large amounts of this drug in connection with propoxyphene substitution programs. In the majority of cases the norpropoxyphene blood concentrations exceed the propoxyphene concentrations, although brain determinations in several instances indicate that norpropoxyphene does not cross the blood-brain barrier with the same ease as propoxyphene. On the basis of the comparative toxicities of propoxyphene and norpropoxyphene in animals and the high tissue concentrations of norporpoxyphene in man after propoxyphene administration, it is conceivable that norpropoxyphene contributes to the toxic effects of propoxyphene.

The effects of continuously administered intravenous propoxyphene chloride (15 mg X min-1) on ECG, systemic, pulmonary and coronary circulations and myocardial oxygenation were investigated in eight pentobarbital-anesthetized pigs. Circulatory shock, defined as a systolic blood pressure below 60 mmHg (8.0 kPa) and a cardiac output of approximately 2.0 l X min-1 X m-2, occurred after 675 to 2025 mg propoxyphene chloride. At the time when shock occurred plasma concentrations of propoxyphene ranged from 9.6 to 15.3 micrograms X ml-1 which is within the range of the lethal concentration observed in man. Statistically significant decreases were observed for the following variables: maximum rate of rise of left ventricular pressure dP/dt (-90%), mean arterial pressure (-73%), heart rate (-46%), cardiac index (-58%), stroke volume index (-22%), left ventricular stroke work index (-85%), right ventricular stroke work index (-63%) and systemic vascular resistance (-50%). Mean pulmonary arteriolar occlusion pressure increased (+42%), whereas mean right atrial pressure and pulmonary vascular resistance remained unchanged. The arteriovenous oxygen difference increased (+53%) and total body oxygen consumption decreased (-35%). The following coronary variables decreased: coronary sinus blood flow (-57%), coronary vascular resistance (-65%), myocardial oxygen consumption (-68%), myocardial oxygen extraction (-26%) and myocardial lactate extraction (-28%). Prolongation of the ECG PQ and QRS intervals were recorded shortly before shock appeared, and all animals were in sinus rhythm till the last minute before death. The results indicate that intravenously administered propoxyphene besides being a powerful negative inotropic and chronotropic agent, is also a potent systemic and coronary vasodilator.

From 1971 through 1980, 1115 deaths were ascribed by the Dallas County Medical Examiner's Office to poisoning of some type. An analysis of these deaths, with emphasis on the substances involved, is the purpose of this study. Relatively few agents or groups of agents accounted for 87% of these deaths: carbon monoxide, barbiturates, propoxyphene, narcotics, tricyclic antidepressants, ethyl alcohol, and inhalants (gases and solvents). Twenty-five percent of the deaths were classified as mixed intoxications, resulting from combinations of agents. Two major trends were observed: in the second five-year period, barbiturate-induced deaths decreased considerably (58%) and deaths from tricyclic antidepressants increased more than four times as compared with the first five-year period. Yearly statistics have been compiled for deaths from each agent.