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PubMed1983

In vitro metabolism of propoxyphene in rat liver: reaction of a carbinol metabolite with acetaldehyde.

The metabolism of the analgesic drug propoxyphene (alpha-d-propoxyphene) has been investigated in the rat liver 9,000 X g supernatant fraction. The incubations were analyzed by HPLC. The major metabolite was norpropoxyphene carbinol, obtained through demethylation and ester hydrolysis. The demethylated metabolite of propoxyphene, norpropoxyphene, was also detected. Addition of acetaldehyde to the incubation mixture decreased the metabolism of propoxyphene. Reactions between norpropoxyphene carbinol and acetaldehyde resulted in a fast disappearance of the carbinol and the formation of a reaction product, the significance of which is discussed.

Acetaldehyde↗

PubMed1991

Dopamine and dobutamine reduce myocardial d-propoxyphene content in experimentally intoxicated rats.

The effect of sympathomimetic intervention with dopamine or dobutamine on the myocardial uptake of d-propoxyphene was investigated experimentally in rats. The d-propoxyphene (19 mg kg-1 h-1) was continuously infused, intravenously, over 45 min. After 20 min of infusion the rats were given either dopamine (12.5 micrograms kg-1 min-1 or 25 micrograms kg-1 min-1), dobutamine (25 micrograms kg-1 min-1 or 45 micrograms kg-1 min-1) or normal saline (control). Each group consisted of eight rats. The myocardial d-propoxyphene content was significantly lower in the two groups given dopamine and in the group given dobutamine 45 micrograms kg-1 min-1 than in the control group (P less than 0.05). This finding indicates the benefit of early sympathomimetic intervention with either dopamine or dobutamine in d-propoxyphene intoxication.

Animals↗

PubMed1976

Propoxyphene napsylate.

Propoxyphene napsylate differs from the hydrochloride salt in several ways. It is much less soluble and bitter and poses few stability problems when capsulated or tableted with aspirin. There is some evidence in several animal species that the pattern and severity of poisoning may be different with the two salts. Equimolar doses of the two salts are probably interchangeable in the relief of pain. The role of propoxyphene in clinical medicine and the questions of propoxyphene abuse and propoxyphene-related fatalities are discussed.

Analgesics↗

PubMed1977

Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals.

alpha-d-Propoxyphene and its principle metabolite, alpha-d-norpropoxyphene, were compared pharmacologically to establish their relative opioid profiles as defined by naloxone reversal. Propoxyphene exhibited opioid activity in the following tests: mouse abdominal constriction and rat tail heat analgesic tests, inhibition of the twitch of the guinea-pig ileum and acute lethality in rodents. Norpropoxyphene also showed opioid activity in the rat tail heat and guinea-pig ileum tests, but exhibited nonopioid activity in the mouse abdominal constriction and acute toxicity studies. Jumping in mice, precipitated by naloxone, suggests the following order for liability to produce physical dependence after repeated administration: morphine greater than codeine greater than propoxyphene greater than norpropoxyphene approximately saline. Propoxyphene and norpropoxyphene depressed axonal conduction in isolated peripheral nerve and were comparable in potency to standard local anesthetic agents. The nonopioid actions of norpropoxyphene might be due in part to its local anesthetic properties.

Analgesics, Opioid↗

PubMed1985

Propoxyphene dependence and withdrawal.

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.

Adult↗

PubMed1984

Assessment of biotransformation during transfer of propoxyphene and acetaminophen across the isolated perfused human placenta.

The purpose of this investigation was to assess the extent of biotransformation of drugs by the human placenta during their transfer from the maternal to the fetal circulation. Propoxyphene was used to determine N-demethylation, and acetaminophen served as a substrate for glucuronide and sulfate conjugation. Human full-term placentae were dually perfused in vitro, with one or the other drug being added to the maternal circulation. Propoxyphene and acetaminophen concentrations reached an essentially constant fetal/maternal ratio within 1 hour, with a half-time of about 20 minutes. The concentrations of both drugs in the placental tissues were higher than in the perfusion fluids; this accumulation was particularly pronounced in the case of propoxyphene. No metabolites of either drug were found in the maternal or fetal circulations, but norporpoxyphene, the N-demethylated metabolite of propoxyphene, was detected in placental tissue.

Acetaminophen↗

PubMed1983

Deaths related to propoxyphene or codeine or both.

Ninety-nine deaths involving propoxyphene or codeine or both were investigated through interviews with surviving relatives and associates. The criterion for admission to this study was the presence of propoxyphene or codeine in the body fluids or tissues, determined analytically. The codeine-related group included more ethnic minority persons, more histories of primary drug addiction, more users of street drugs, and more accidental deaths. In the propoxyphene-related group there were fewer histories of drug addiction and more persons with mental illness and more suicides. Most victims had considerable past experience with one or both of the drugs and other drugs as well. Propoxyphene was usually obtained by physician prescription. Codeine was often obtained illegally.

Adult↗

PubMed1981

Propoxyphene in postmortem toxicology 1976-1978.

A total of 1859 cases provides the basis for this study in which propoxyphene, and often its major metabolite, was demonstrated by toxicological analysis in the blood or tissues of the deceased at 27 medical examiner or coroner's offices across the United States and Canada. The study period includes the last five months of 1975 through December 1978. The cases describe a clearly defined adult population with a marked tendency toward hypochondria, chronic minor illness, and severe psychiatric problems. The high proportion of suicides (44.1% of the total cases and 54.0% of the drug-caused deaths) and multiple-drug toxicities (88.6%) suggests that the involvement of propoxyphene in many of these fatalities may be of less significance than the phenomenon of "polypharmacy" and self-medication without appropriate medical supervision. This evaluation of propoxyphene provides no evidence that propoxyphene is responsible for "street-drug" fatalities. Its appearance in postmortem toxicological examinations has been declining sharply since 1977, but it continues to be dangerous when used excessively, particularly in combination with alcohol and other central nervous system depressant drugs.

Adolescent↗

PubMed1981

Propoxyphene form maintenance treatment of narcotic addiction.

Two studies compared propoxyphene napsylate (Darvon-N) with methadone hydrochloride as maintenance treatment for narcotic addicts. Most measures indicated that methadone was more effective than propoxyphene as a maintenance drug. Patients receiving propoxyphene reported more withdrawal-related symptoms early in treatment, tended to drop out sooner than patients receiving methadone, and were more likely to abuse heroin. Nevertheless, follow-up interviews at one and six months after treatment indicated no between-group differences in adjustment.

Adult↗

PubMed1975

Heroin detoxification. A comparison of propoxyphene and methadone.

Propoxyphene napsylate and methadone hydrochloride were each administered under double-blind conditions to 36 outpatients for 21-day heroin detoxification. The initial dosage was 24 mg/day for methadone hydrochloride and 800 mg/day for propoxyphene napsylate. At these dosages, methadone more effectively suppressed the opiate-withdrawal syndrome, and patients remained in treatment longer in the methadone group (P greater than .05). In regard to heroin abstinence, however, results were not statistically significant in either group, as indicated by the number of patients whose urine was positive for morphine on admission and became negative during treatment, and the number who had morphine-negative urine at the conclusion of 21-day treatment. A one-month follow-up of patients showed that more patients given methadone had entered long-term medical maintenance while more patients given propoxyphene were heroin-abstinent. This study indicates that 21-day heroin detoxification, regardless of chemotherapeutic agent, yields a low rate of heroin abstinence.

Adolescent↗

PubMed1976

Propoxyphene: pathways of metabolism in man and laboratory animals.

Through the combined use of stable isotope labeling and gas chromatographic mass spectrometric analysis, the metabolic patterns for propoxyphene have been determined in laboratory animals and man. The rat and dog eliminated propoxyphene and its metabolites principally via the bile, while the rabbit more closely resembled man in excreting the metabolic products into urine. Metabolites in rat and rabbit existed as conjugates, whereas in dog and man the metabolites were excreted as a mixture of the free and unconjugated forms. The primary route of metabolism in all species studied was N-demethylation. However, the rat and rabbit extensively hydroxylated propoxyphene and its metabolites prior to elimination. Metabolites arising from ester hydrolysis were found in rat and man. N-acetylated products were identified in all four species. A metabolite formed from cyclization and dehydration of dinorpropoxyphene was isolated in urine and was further identified as a circulating metabolite in dog plasma.

Acetylation↗

PubMed1975

Determination of propoxyphene and norpropoxyphene by chemical ionization mass fragmentography.

The kinetics of propoxyphene and its primary metabolite, norpropoxyphene, have been simultaneously re-evaluated in man by using gas-liquid chromatography/mass spectrometry, deuterium-labeled mass internal standards, and multiple ion monitoring. Plasma concentrations in 4 volunteers determined for as long as 240 hr after single oral doses of 2 propoxyphene salts indicate the overall half-life of propoxyphene to be 11.8 hr and of norpropoxyphene to be 36.6 hr.

Adult↗

PubMedDate not supplied

Plasma protein binding of d-propoxyphene in normal subjects and anephric patients.

The free fraction of d-propoxyphene in the plasma of normal subjects is 0.24 +/- 0.02 (mean +/- S.D.) and is not concentration dependent in the usual therapeutic and toxic conentration range. Renal failure and relatively high concentrations of d-norpropoxyphene, the major metabolite of d-propoxyphene, have no significant effect on the plasma protein binding of d-propoxyphene.

Adult↗

PubMed1980

Propoxyphene and norpropoxyphene: influence of type of controlled-release formulation on intra- and intersubject variations.

Two types of controlled-release formulations of propoxyphene hydrochloride, one with a buffer system in the pellet core, were studied with regard to intra- and intersubject variations of Cmax and Tmax of propoxyphene as well as propoxyphene plus norpropoxyphene in 35 volunteers after administration of a single 150-mg dose. Statistically significant differences between the formulations in intrasubject variance were revealed, and the availability rate of the buffered product showed significantly better reproducibility, presumably due to the established low sensitivity of its release rate to the in vitro environment.

Adolescent↗

PubMed1977

Enhancement of propoxyphene-induced analgesia by doxepin.

The activity of the centrally acting analgesic, propoxyphene, either alone or combined with the tricyclic antidepressant, doxepin, has been studied. Doses of doxepin, in themselves lacking any analgesic effect, remarkably enhanced the analgesic activity of propoxyphene, either by the oral or intraperitoneal route. On the other hand, oral toxicity data prove that doxepin does not alter significantly propoxyphene acute toxicity.

Analgesia↗

PubMed1979

Effects of propoxyphene, ethoheptazine, and azabicyclane on schedule-controlled responding: attenuation by pentobarbital but not naloxone.

The effects of propoxyphene, ethoheptazine, and azabicyclane, alone and in combination with 1 mg/kg naloxone, were studied in pigeons responding under a multiple fixed ratio, fixed interval schedule of food presentation. Low doses of pentobarbital (3, 5.6, and 10 mg/kg) attenuated the rate-decreasing effects produced by 20 mg/kg propoxyphene, ethoheptazine, and azabicyclane. Naloxone antagonized the rate-decreasing effects produced by 10 mg/kg azabicyclane but did not antagonize the rate-decreasing effects of propoxyphene or ethoheptazine.

Analgesics, Opioid↗

PubMed1984

D-propoxyphene kinetics in man: significance of a deep third compartment.

Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5-10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15-30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.

Adult↗

PubMed1999

Utilisation of codeine and propoxyphene: geographic and demographic variations in prescribing, prescriber and recipient categories.

OBJECTIVES: To assess (1) whether the utilisation of codeine or propoxyphene differs among the three major Swedish cities (Stockholm, Göteborg and Malmö) and between urban and semirural areas; (2) if so, whether it co-varies with the utilisation of other potentially dependence-promoting drugs, benzodiazepines; (3) what influence age, gender and socioeconomic factors have on the prescribing of the two narcotic analgesics; and (4) whether different codeine-prescriber categories have different prescribing habits. METHODS: In Sweden, all pharmacies are owned by one corporation, Apoteket AB. This corporation collects, stores and compiles statistics on all drug sales in Sweden, and data are available both on national, regional, county and municipal levels. The employed unit is defined daily dose (DDD) per 1,000 inhabitants per day. Using the pharmacy computer system while dispensing a drug, prescription patterns can be elucidated. This system describes the number of drug items dispensed, drug amounts and age and gender of patients. Furthermore, data from another, ecological study were used to relate codeine and propoxyphene utilisation to that of benzodiazepines and to various socioeconomic data available from records of the city of Malmö. RESULTS: The utilisation of analgesics in Sweden has increased during a 10-year period. The withdrawal of over-the-counter combinations containing aspirin and low-dose codeine in 1990 resulted only in a transient decrease of codeine use. The utilisation of codeine in Malmö and Göteborg was considerably higher than that in Stockholm and in the rest of Sweden, including the surroundings of Malmö. In Malmö and Göteborg, codeine was most often prescribed by private physicians to middle-aged persons, particularly women. Districts in Malmö with a high utilisation of codeine were associated with unfavourable socioeconomic conditions and a high utilisation of benzodiazepines. The utilisation pattern of propoxyphene showed less or no such deviations. CONCLUSION: The results suggest an inappropriate use of codeine in two major cities in Sweden.

Adolescent↗