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PubMed1977

Propoxyphene: a review.

A critical analysis of information on propoxyphene that has been published since the drug's introduction is presented. Propoxyphene is discussed with regard to its chemistry, metabolism and pharmacokinetics, analgesic efficacy, analgesic efficacy of combination products, nonanalgesic uses, adverse effects, overdosage, and dependence and abuse. Both the hydrochloride and napsylate salts are covered. It is doubtful that propoxyphene hydrochloride 65 mg provides an analgesic effect equal to that of aspirin 650 mg. There is no conclusive evidence that combinations of propoxyphene with other analgesics are more effective than propoxyphene or other analgesics alone.

Acetaminophen↗

PubMed1985

Influence of (+)-propoxyphene on the hexachlorobenzene-induced porphyria of rats.

The increased urinary porphyrin excretion after hexachlorobenzene (HCB) could be reduced by simultaneous application of (+)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate ((+)-propoxyphene) to female Wistar rats over a period of 60 days. Total porphyrin excretion and predominantly the higher carboxylated porphyrins, such as uroporphyrin were reduced under the influence of (+)-propoxyphene. (+)-Propoxyphene led to an increase of hepatic cytochrome P-450 content and the cytochrome P-450 dependent enzymes arylhydrocarbon-hydroxylase- and aminopyrine-N-demethylase activities, whereas the 7-ethoxycoumarine-deethylase activity was not changed. The simultaneous treatment of rats with HCB and (+)-propoxyphene decreased the HCB induced cytochrome P-450 content and the aminopyrine-N-demethylase activity. The arylhydrocarbon-hydroxylase activity, however, was increased, whereas no influence on the 7-ethoxycoumarine-deethylase activity could be demonstrated by (+)-propoxyphene treatment of HCB exposed rats. It is under discussion that a reduction of aminopyrine-N-demethylase activity by the drug in the liver alters the HCB metabolism resulting in a reduced production of a probable ultimative porphyrogenic agent.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1978

Interaction of d-propoxyphene and diphenylhydantoin in rat liver microsomal preparation.

Inhibition of diphenylhydantoin biotransformation by d-propoxyphene and the ihibition of d-propoxyphene metabolism by diphenylhydantoin was studied in rat liver microsomal 9000 x g supernatant preparations. The parahydroxylation of diphenylhydantoin was inhibited 98% by 5 x 10(-4)M concentration of d-propoxyphene in a noncompetitive manner with a Kj of 3.2 +/- 1.6 x 10(-5)M. Only 18% inhibition of the N-demethylation of d-propoxyphene was observed at clinically unrealistic diphenylhydantoin concentrations of 10(-3)M. The in vitro studies suggest that the inhibition of diphenylhydantoin metabolism by d-propoxyphene may result in toxicity when the two drugs are chronically administered together.

Animals↗

PubMed1981

Separation and characterization of standard propoxyphene diastereomers and their determination in pharmaceutical and illicit preparations.

Due to the existence of 2 asymmetric carbon atoms in the propoxyphene molecule, there are 4 diastereomers: alpha dextro, alpha levo, beta dextro, and beta levo. Only alpha-d-propoxyphene is included under the federal Controlled Substances Act. Baseline separations of propoxyphene from various incipients (aspirin, caffeine, phenacetin, and acetaminophen) present in pharmaceutical and illicit preparations, and between the alpha and beta diastereomers, were achieved by high pressure liquid chromatography. The column eluant was collected and propoxyphene was extracted. The optical isomers were differentiated and characterized by melting points and by chemical microcrystalline tests. Using hot stage thermomicroscopy, the eutectic melting points of binary isomeric mixtures of propoxyphene bases and salts were found to be depressed about 10 degrees and 15-30 degrees C, respectively, below the individual isomer melting points. The characteristic microcrystals formed with the alpha racemic mixtures by using a glycerin-aqueous gold chloride reagent were not produced by the beta racemic mixtures.

Chromatography, High Pressure Liquid↗

PubMed1980

Cardiopulmonary, behavioral, and pharmacokinetic effects of propoxyphene in horses.

The acute behavioral cardiopulmonary and pharmacokinetic effects of propoxyphene hydrochloride were studied in seven adult horses. Each horse was given three different dosages of propoxyphene (0.5, 1.0, 2.2 mg/kg) IV. Fourteen days was allotted between each drug administration. The lower IV dosages of propoxyphene (0.5, 1.0 mg/kg) resulted in no changes in indices of cardiopulmonary function. Four horses demonstrated a transient period of muscle fasciculations when given 0.5 mg of propoxyphene/kg. Horses given 1.0 mg/kg demonstrated a brief period of euphoria, ataxia, and muscle fasciculations followed by a period of increased motor activity lasting for approximately 30 minutes. Horses given 2.2 mg of propoxyphene/kg demonstrated significant (P less than 0.05) increases in heart rate and arterial blood pressure and, after a brief period of ataxia and disorientation, displayed increased motor and locomotor activity lasting several hours. These behavioral effects were less apparent in three of four horses 4 hours after their appearance by the IV administration of naloxone. Propoxyphene exhibited a dose dependent half-life of from 61 to 135 minutes and an apparent volume of distribution of from 2.54 to 4.26 L/kg. Total body clearance was 21.9-28.4 ml/min/kg. In the adult pain-free horse, propoxyphene causes dose dependent excitatory effects similar to the narcotic analgesics.

Animals↗

PubMed1976

Propoxyphene and norpropoxyphene concentrations in blood and tissues in cases of fatal overdose.

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.

Adult↗

PubMed1977

Therapeutic usefulness of propoxyphene napsylate in narcotic addiction.

The maximum doses of propoxyphene napsylate used to treat heroin addicts produce a degree of morphine-like activity equal to that produced by 20 to 25 mg/day of subcutaneously given morphine or 10 mg/day orally given methadone. This degree of activity wound be sufficient to ameliorate abstinence even in patients dependent on large doses of narcotics--an observation that supports the utility of propoxyphene napsylate in detoxification. On the other hand, only patients taking 10 mg/day or less of parenterally administered heroin could be maintained on maximum subtoxic levels of propoxyphene napsylate without abstinence signs or symptoms suggesting that propoxyphene napsylate would be less useful in maintenance therapy.

Administration, Oral↗

PubMed1975

Hemodialysis in an infant with propoxyphene intoxication.

A 10-month-old infant was treated with intensive supportive care and hemodialysis for severe propoxyphene intoxication. Dialysis clearance studies demonstrated that propoxyphene was removed from the serum at approximately 50% of the rate of blood urea nitrogen removal. Possibly because of tissue binding of the drug, the absolute quantity of propoxyphene removed by dialysis was small. The child survived the acute episode of intoxication but died of pulmonary complications several days later. The role of dialysis in propoxyphene intoxication remains to be established.

Blood Urea Nitrogen↗

PubMed1979

d-Propoxyphene kinetics after single oral and intravenous doses in man.

d-Propoxyphene kinetics was studied in 8 healthy male subjects after single oral doses of d-propoxyphene at 65, 130, and 190 mg and after slow intravenous infusion of 65 mg. Total urinary excretion (7 days) indicated complete oral absorption but systemic availability was reduced corresponding to fist-pass elimination of 30% to 70%. There was linearity between oral dose and the corresponding area under the plasma concentration/time curve of d-propoxyphene and the metabolite norpropoxyphene. The kinetic measurements showed 2- to 3-fold interindividual variations: oral clearance, 1.3 to 3.6 1/min; systemic clearance, 0.6 to 1.2 1/min; apparent volume of distribution, 700 to 1,800 1; d-propoxyphene half-life (t1/2), 8 to 24 hr; and norpropoxyphene t1/2, 18 to 29 hr. There were pronounced intraindividual dose-dependent variations in oral clearance in some subjects. The intravenous concentration curves indicated a 3-compartment distribution model.

Administration, Oral↗

PubMed1977

Propoxyphene overdosage: a study of cases involving analgesic preparations containing dextropropoxyphene.

Propoxyphene and paracetamol concentrations have been determined in blood, urine, liver blood and stomach contents from 17 post mortem cases in which Distalgesic (a propoxyphene and paracetamol compound preparation) was involved. Five patients admitted to hospital with suspected Distalgesic poisoning have also been investigated. In most cases the propoxyphene concentrations, but not the paracetamol concentrations, exceeded the minimum lethal levels reported. On the basis of our results it appears that of the constituents of Distalgesic, propoxyphene has a far more immediate and dangerous effect than paracetamol.

Acetaminophen↗

PubMed1987

Effect of pretreatment with acetaminophen-propoxyphene for oral surgery pain.

To determine the effect of pretreatment and multiple doses on postsurgical pain, a study of the relative analgesic efficacy of placebo, acetaminophen 650 mg, and propoxyphene napsylate 100 mg alone and in combination was conducted. Forty-five patients undergoing surgical removal of impacted third molar teeth under local anesthesia were randomly allocated to the four treatment regimens under double-blind conditions. The first oral dose was administered one hour preoperatively and the second dose when the pain became moderate or severe, following the dissipation of the local anesthesia. Pain intensity and pain relief were assessed using standard verbal descriptor scales at 30 minutes and hourly for four hours after the postoperative dose. Measures of total effect, peak effect and duration of their effect were derived from these descriptors. Acetaminophen was no better than placebo. For peak and total effects, propoxyphene alone and the propoxyphene-acetaminophen combination were substantially superior to both placebo and acetaminophen alone. Duration of analgesia was also significantly longer with both propoxyphene-containing treatments. No side effects were reported. The results suggest that pretreatment with a narcotic agonist markedly improves postoperative analgesia.

Acetaminophen↗

PubMed2006

Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene.

Pharmacokinetic studies demonstrate that propoxyphene is a potent inhibitor of cytochrome P450 (CYP) 2D6. Clinically significant sequelae have not been previously reported. We report a case of this inhibition manifested by life-threatening bradycardia in a patient receiving a CYP2D6 substrate, metoprolol. A 48-year-old man came to the emergency department complaining of dizziness 3 hours after ingesting metoprolol, at his usual dose, and 2 tablets of propoxyphene, newly begun postoperatively. Four hours after ingestion of both drugs, the patient was noted to have a ventricular rate of about 30 beats/min with underlying atrial fibrillation. The patient's ventricular response returned to normal within 11 hours of ingestion. We have demonstrated the clinical importance of the interaction between propoxyphene and metoprolol likely resulting from inhibition of hepatic clearance of metoprolol by propoxyphene. Underscoring the clinical relevance of CYP2D6 inhibition by an analgesic of questionable efficacy should proscribe its use.

Acetaminophen↗

PubMed1992

Opioid analgesics and the risk of hip fracture in the elderly: codeine and propoxyphene.

We studied the risk of hip fracture in elderly persons receiving prescriptions for two commonly prescribed opioid analgesics--codeine and propoxyphene. Using automated prescription and hospitalization data, we identified 4,500 residents of Saskatchewan, Canada, aged 65 or older, who sustained a hip fracture between 1977 and 1985, and 24,041 age- and sex-matched controls. Compared to nonusers, the relative risk (95% CI) of hip fracture in current users of codeine or propoxyphene was 1.6 (1.4-1.9). There was no difference between relative risks of fracture among current users of codeine [1.6 (1.3-1.9)] and propoxyphene [1.6 (1.2-2.2)]. In new users of these opioids, the relative risk of fracture was 2.2 (1.7-2.8), compared to 1.3 (1.0-1.6) in users who received at least one additional prescription for codeine or propoxyphene in the 90-day period prior to the index date. Concurrent users of these opioids and psychotropic drugs (sedatives, antidepressants, or antipsychotics) had a risk of fracture 2.6 (2.0-3.4) times that of nonusers of either drug class. Review of a sample of medical records for 701 cases suggested this finding was not due to confounding by body mass, ambulatory status, functional status, or dementia. Given the essential role of opioids in the management of pain in geriatric practice, further study is needed to determine the psychomotor effects of opioid analgesics in older adults.

Age Factors↗

PubMed1990

d-Propoxyphene is a potent inhibitor of debrisoquine, but not S-mephenytoin 4-hydroxylation in vivo.

The debrisoquine and S-mephenytoin 4-hydroxylation phenotyping tests were performed in 14 healthy subjects. All were extensive metabolizers of both drugs. After at least 4 weeks, they received a 150 mg tablet of d-propoxyphene and 5 h later the debrisoquine-mephenytoin test was repeated. This single dose of d-propoxyphene caused no change in mephenytoin S/R ratio, but increased the debrisoquine metabolic ratio (MR) in each subject (p less than 0.025). The four subjects with a relatively high MR (5.1-8.3) in the first test had an MR of debrisoquine in the second test ranging between 22 and 40, falsely classifying them as "poor metabolizers" of debrisoquine. This shows that d-propoxyphene is a potent inhibitor of debrisoquine, but not of S-mephenytoin 4-hydroxylase in vivo. A previous in vitro study has shown that d-propoxyphene inhibits the hydroxylation of desipramine, which is a substrate of the debrisoquine hydroxylase.

Administration, Oral↗

PubMed1985

Pharmacokinetic interaction of propoxyphene with ethanol.

In order to study the effects of ethanol on the pharmacokinetics of propoxyphene, six healthy male volunteers were each given (1) propoxyphene 65 mg p.o. preceded by 1 h by ethanol 0.9 g/kg lean body weight and followed for 7.5 h by ethanol dosed to maintain breath ethanol at 800-1000 mg/l; and (2) propoxyphene 65 mg p.o. with orange juice in the same volume and frequency as ethanol. Ethanol did not induce any significant changes in apparent t 1/2 or Cmax of propoxyphene or norpropoxyphene. The average norpropoxyphene/propoxyphene ratio decreased by a mean 36%.

Adult↗

PubMed1985

Circulatory shock following intravenous propoxyphene poisoning. An experimental study of cardiac function and metabolism in pentobarbital-anesthetized pigs.

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.

Anesthesia, General↗

PubMed1985

The effects of cardiac pacing on central hemodynamics in experimental propoxyphene-induced cardiac failure.

Coronary sinus pacing was evaluated in 10 pigs during propoxyphene-induced cardiac failure. From baseline, propoxyphene chloride 15 mg . min-1 was infused until circulatory shock developed. Cardiac pacing was evaluated at different dose levels expressed as % of the shock dose of propoxyphene: at intoxication levels below 50% of the shock dose, cardiac pacing improved cardiac performance. At dose levels above 50% of the shock dose cardiac performance deteriorated further during pacing. The results are consistent with a severe negative inotropic effect of propoxyphene in overdose.

Animals↗

PubMed1985

The effects of naloxone on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced circulatory shock.

The courses of the hemodynamic and cardiometabolic effects of naloxone were evaluated in propoxyphene-induced shock in eight pentobarbital-anesthetized pigs. Circulatory shock was induced by an infusion of propoxyphene chloride 15 mg . min-1 i.v. At shock, i.e. MAP less than 60 mmHg and/or CI less than 2.0 l . min-1 . m-2, naloxone was administered at 0.75, 1.5 and 3.0 mg . kg-1 with an interval between increments of 8 min. The propoxyphene infusion of 15 mg . min-1 was continued throughout the study. Following the injection of naloxone 0.75 mg . kg-1, increases were observed (% of baseline value) in MAP (41%), i.e. deficit to baseline 59%, HR (66%), CI (67%) and SVI (108%), whereas MPAP and MPAOP were unchanged. dP/dt increased (34%). In the coronary circulation naloxone initiated the following changes: CSF increased (69%) as did MVO2 (48%) with unchanged MO2-extraction, but CVR decreased further (36%). The maximum effects of naloxone were registered 2-3 min after 0.75 mg . kg-1. Following 1.5 and 3.0 mg . kg-1, no changes in hemodynamics were observed other than those caused by progressing propoxyphene intoxication.

Animals↗