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PubMed1983

Ethanol interaction with propoxyphene and norpropoxyphene metabolism in isolated rat hepatocytes.

Suspensions of isolated rat hepatocytes (approximately 7.5 X 10(5) cells/ml) metabolized added propoxyphene and norpropoxyphene rapidly. At 2 microM, the metabolism of both drugs obeyed first-order elimination kinetics. Increasing propoxyphene concentrations (1, 2, 4 and 8 microM) gradually increased the medium concentrations of norpropoxyphene. The total propoxyphene metabolism was the same at 4 and 8 microM. The effect of ethanol (10 and 60 mM) on propoxyphene (2 microM) and norpropoxyphene (2 microM) metabolism in suspensions of isolated rat hepatocytes was studied. The half-lives of propoxyphene were 7.1 +/- 5.5 min in absence and 6.7 +/- 2.8 min in presence of 10 mM ethanol, but increased to 10.7 +/- 5.8 min in presence of 60 mM ethanol (p less than 0.05). The half-lives of added norpropoxyphene increased from 17.9 +/- 4.1 min to 26.0 +/- 7.3 min at 10 mM ethanol (p less than 0.05) and 29.3 +/- 5.9 min at 60 mM ethanol (p less than 0.05). Ethanol (60 mM) reduced the elimination rate constant of propoxyphene and norpropoxyphene by 31 +/- 25% and 38 +/- 15%, respectively.

Animals↗

PubMed1985

Interaction of propoxyphene with diazepam, alprazolam and lorazepam.

Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.

Adult↗

PubMed1982

Propoxyphene and acetaminophen. Possible effects on the fetus.

Propoxyphene (Darvon) and acetaminophen (Tylenol) are widely prescribed analgesic agents. Both can cross the placenta, and propoxyphene can produce serious withdrawal symptoms in newborns. Neither propoxyphene nor acetaminophen is considered a teratogen, yet, three malformed infants who were antenatally exposed to propoxyphene have previously been reported. We report a fourth case of an infant, with withdrawal symptoms and cranial-facial and digital malformations, born to a women who used propoxyphene and acetaminophen throughout her pregnancy. We suggest that possibility that the antepartum use of propoxyphene and acetaminophen, in combination, may be teratogenic.

Abnormalities, Drug-Induced↗

PubMed1977

Reduction of levopropoxyphene N-oxide to propoxyphene by dogs in vivo and rat liver microsomal fraction in vitro.

1. When l-propoxyphene-N-oxide was given orally to dogs, reduction occurred in vivo resulting in substantial plasma levels of l-propoxyphene. 2. When l-propoxyphene-N-oxide was given intravenously, near peak plasma levels of propoxyphene occurred in 10 minutes. This suggests that reduction is occurring at least in part in mammalian tissue rather than in gut flora. 3. Levopropoxyphene oxide was also readily reduced anaerobically in a rat liver microsomal fraction. 4. Results from this study explain our early observation that while l-propoxyphene-N-oxide is demethylated in vivo, demethylation does not occur in vitro when the oxide is incubated in air with liver homogenate. Thus demethylation of the oxide can occur only after reduction of the oxide to the tertiary amine. While reduction occurs readily in vivo it is completely inhibited by oxygen present in the usual microsomal incubation. 5. These studies further confirm that the N-oxide is not an intermediate in the demethylation of propoxyphene.

Administration, Oral↗

PubMedDate not supplied

Propoxyphene-induced hypoglycemia in renal failure.

OBJECTIVE: To present a case of symptomatic hypoglycemia induced by propoxyphene. METHODS: The historical features, results of laboratory evaluations, and clinical course of a man with end-stage renal disease in whom hypoglycemia developed during treatment with propoxyphene are described. RESULTS: A 54-year-old man with chronic renal failure had recurrent episodes of hypoglycemia (plasma glucose level, 40 mg/dL). While he continued treatment with propoxyphene, 58 hours into a 72-hour fast the plasma glucose concentration was 38 mg/dL, in conjunction with a beta-hydroxybutyric acid level of 0.9 mmol/L and inappropriately elevated plasma insulin, serum C-peptide, and proinsulin levels. A plasma drug screen was negative for sulfonylureas. A selective arterial calcium stimulation test yielded negative results. A 72-hour fast after discontinuation of propoxyphene therapy resulted in no hypoglycemia, and he experienced no hypoglycemic episodes for at least 2 years after withdrawal of the propoxyphene treatment. CONCLUSION: The importance of obtaining a thorough medication history in a patient with renal failure and hypoglycemic episodes is highlighted by this case of propoxyphene-induced hypoglycemia. The mechanism of this effect is not known, although non-micro receptor agonism or noncompetitive N-methyl-D-aspartate receptor antagonism may have a role in causing hypoglycemia.

Dextropropoxyphene↗

PubMed1983

The peripheral analgesic effect of morphine, codeine, pentazocine and d-propoxyphene.

The prostaglandin hyperalgesia and tail immersion tests were used to evaluate the analgesic action of morphine, codeine, d-propoxyphene and pentazocine following intraperitoneal, intraplantar and intracerebroventricular administration to rats. In the prostaglandin hyperalgesia test, all drugs produced a dose-dependent analgesia by the various routes. The rank order of potency after intraperitoneal administration was morphine (100) greater than d-propoxyphene (4) greater than pentazocine (2) greater than codeine (1). Although morphine (ID50 = 4 micrograms) was a very potent analgesic when given intracerebroventricularly, very shallow dose-response curves were obtained with the other substances which promoted less than 30% of inhibition at doses up to 250 micrograms. In the paw, morphine (ID50 = 5 micrograms) was only 5-8 times more potent than pentazocine, propoxyphene and codeine. Thus, in contrast with morphine, intraplantar administration of codeine, pentazocine and d-propoxyphene is much more effective than intracerebroventricular administration. In the tail immersion test the smallest intraperitoneal doses which affected the reaction time were 9 mg/kg morphine, 16.2 mg/kg codeine and pentazocine and 48.6 mg/kg d-propoxyphene. When injected intracerebroventricularly morphine (10 micrograms) was the only opiate that caused a detectable analgesic effect. In the prostaglandin hyperalgesia test, a small dose of naloxone (1 micrograms) given into the rat paw significantly antagonized the analgesic effect of d-propoxyphene, codeine and pentazocine administered either intraperitoneally or intraplantarly. These results clearly indicate that a method involving or mimicking inflammatory hyperalgesia is much more sensitive in detecting opiate analgesia than a method which uses heat as a nociceptive stimulus. Furthermore, our results support the proposition that part of the overall analgesia which follows the systemic administration of opiates is due to a peripheral antinociceptive action.

Analgesia↗

PubMed1983

Propoxyphene in children with iatrogenic morphine dependence.

In four children with iatrogenic morphine sulfate tolerance and dependence, narcotic withdrawal was successfully accomplished using propoxyphene napsylate. The patients showed signs and symptoms typical of narcotic withdrawal, which resolved with morphine administration and increased during attempts to lower the daily morphine dose. Propoxyphene napsylate at total daily doses of 25 to 65 mg/kg, administered at four-hour intervals, allowed rapid reduction of the morphine dosage, with few withdrawal signs and symptoms, and lessened respiratory depression. This treatment enabled patients to be rapidly weaned from the respirator. One child experienced increasing lethargy and respiratory depression and responded to naloxone hydrochloride and a decrease in the dose of propoxyphene; another had transient agitation, which may have been related to high levels of propoxyphene. Our treatment used alternating doses of propoxyphene and morphine, which allowed the child to be morphine free after four days and narcotic free after nine days.

Child↗

PubMed1981

d-Propoxyphene acts differently from morphine on opioid receptor-effector mechanisms.

The actions of d-propoxyphene and morphine on opioid receptor mechanisms were compared. In assay measuring receptor binding selectivity in vitro, with dihydromorphine, naloxone and an enkephalin analogue as radioactive ligands, d-propoxyphene differed from morphine in having a higher relative affinity for sites occupied by the peptide. Naloxone was more potent in antagonizing morphine- than d-propoxyphene-induced antinociception in the mouse hot-plate test. In morphine-tolerant mice showing three-fold lower morphine sensitivity the antinociceptive efficacy of d-propoxyphene was unchanged. The results indicate differences in receptor-effector mechanisms between d-propoxyphene and morphine.

Animals↗

PubMed1981

The effect of hematin on the development of microsomal enzyme induction and physical dependence in mice following repeated oral propoxyphene administration.

Male ICR mice (25 - 30 g) were pretreated with bovine hematin (20, 40 or 50 mumoles per kg per day, i.p.) for three days. During the next six-day period, animals received either 50 mg per kg per day propoxyphene-HCl or saline, p.o., in addition to the daily hematin injections. Only the highest hematin regimen depressed the induction of propoxyphene-N-demethylase activity significantly in the drug-treated animals. A similar depression below control levels was noted in the animals receiving only saline (p.o.) and hematin (i.p.). While hematin treatment abolished the metabolic tolerance to propoxyphene analgesia such treatment failed to generate any appreciable degree of physical dependence to propoxyphene as assessed by a challenge with naloxone. These findings may be helpful in assessing the risk factors associated with the widespread use of propoxyphene.

Analgesia↗

PubMed1977

Gas chromatographic determination of propoxyphene and norpropoxyphene in plasma.

Propoxyphene and its major metabolite norpropoxyphene have been determined simultaneously by using gas chromatography. In order to avoid the on-column decomposition of the propoxyphene, derivatives were formed with the aid of lithium aluminium hydride, which cleaves the propionic acid ester of propoxyphene and reduces the norpropoxyphene amide. Promethazine was used as an internal standard. Propoxyphene and norpropoxyphene levels in plasma were determined in samples from six male volunteers receiving a single oral dose of 150 mg of propoxyphene hydrochloride in a sustained-release form (Abalgin Retard).

Chemical Phenomena↗

PubMed1980

Nefopam and propoxyphene in episiotomy pain.

To evaluate relative efficacy, safety, and time course of analgesia, nefopam (45 and 90 mg), a new centrally acting nonnarcotic analgesic, was compared with propoxyphene (65 mg) and placebo in a single oral dose, parallel, stratified, randomized, double-blind trial with 100 hospitalized postpartum women with medium or severe episiotomy pain. Using subjective reports as indices of response, patients rated pain intensity and side effects at periodic interviews for 6 hr. After 45 and 90 mg nefopam, 21 of 25 and 20 of 25 patients (p less than 0.01) reported more than 50% reduction of pain, whereas after 65 mg propoxyphene 18 of 25 (p less than 0.05) and after placebo 11 of 25 reported reduction in pain. Relative efficacy, based on summed pain intensity differences, showed measurable but modest dose-dependent analgesia with nefopam, suggesting that the effectiveness of 65 mg propoxyphene lay between 45 mg nefopam and placebo. Side effects included mild dizziness and hypothermia after nefopam and mild elevation of diastolic arterial pressure after nefopam and propoxyphene. Our results suggest that 45- and 90-mg doses of nefopam induced more analgesia than 65 mg propoxyphene in the relief of episiotomy pain.

Adolescent↗

PubMed1980

Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient.

The widely used analgesic propoxyphene is subject to extensive presystemic (first-pass) biotransformation after oral administration. There have been indications that presystemic biotransformation of a drug may be less in anephric patients than in healthy subjects. Plasma concentrations of propoxyphene (a drug with dangerous adverse effects at high concentrations) and its major and pharmacologically active metabolite norpropoxyphene have been compared in 7 anephric patients and 7 healthy subjects after oral administration of a 130-mg dose. Maximum propoxyphene concentrations were much higher (177 +/- 16 vs 81 +/- 35 ng/ml, mean +/- SD, p less than 0.001), and areas under the concentration-time curve over 12 hr were much larger (4,310 +/- 1,520 vs 2,250 +/- 1,050 ng hr/ml, p less than 0.02) in the anephric patients than in the normal subjects. These differences were statistically significant even after normalization for dose per body weight. Norpropoxyphene concentrations were also higher and more persistent in the anephric patients. These differences, which appear to result from decreased presystemic biotransformation of propoxyphene and decreased elimintation of norpropoxyphene, indicate that propoxyphene should be used cautiously and at reduced doses in patients with renal failure.

Absorption↗

PubMed1977

Fatal poisoning with propoxyphene: report from 100 consecutive cases.

The first 100 deaths caused by propoxyphene and recorded by the Chief Medical Examiner of North Carolina were studied. Victims ranged evenly in age from the second to the seventh decade. Over 65% were suicides with a female to male ratio of 2:1. Blood propoxyphene concentrations of 0.2 mg/dl were fatal, representing rapid ingestion of approximately ten capsules. In North Carolina, deaths due to propoxyphene have increased from five in 1969 to 49 in 1975. Raising physician-awareness of propoxyphene's toxicity and placing the drug in Schedule II are two of the author's recommendations for reducing the number of propoxyphene deaths.

Adolescent↗

PubMedDate not supplied

Propoxyphene (dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity.

Propoxyphene (dextropropoxyphene) is a synthetic weak opioid introduced into the United States in 1957. It is most frequently prescribed in combination with acetaminophen and/or aspirin. After its ubiquitous introductory phase, it was soon discovered that this drug's iatrogenic events (cardiotoxicity, seizures, etc.) far outweighed any perceived therapeutic benefit. Propoxyphene analgesia was equated with that of merely acetaminophen or aspirin independently. The propoxyphenes euphorigenic component has created a problem in its prescribing. Use of this agent in the elderly should be avoided because of its complex pharmacokinetics and pharmacodynamics. The pharmacokinetics, pharmacodynamics, and pharmacology of this drug are discussed thoroughly in this article, including its arrhythmogenicity. Additional noncardiovascular pharmacotherapies that produce QTc prolongation or arrhythmogenicity are described. A list of the cytochrome P450 2D6 pharmacotherapies that will interact with propoxyphene is provided in the article. The use of this agent is highly discouraged. The rationale for this is discussed fully within this article. The toxicity of this drug is partially related to nor-propoxyphene a non-opioid cardiotoxic metabolite. The mere warnings of fatalities within the package insert should alert any cautious prescriber on the dangers of this agent and dampen its prescribing potential.

Analgesics, Opioid↗

PubMed1985

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

The hemodynamic and cardiometabolic effects of dopamine were evaluated in propoxyphene-induced circulatory 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. CI less than or equal to 2.0 l . min-1 . m-2 and/or MAP less than or equal to 60 mmHg, dopamine was infused at 10, 20, 40, 80 and 160 micrograms . kg-1 . min-1 with an interval between increments of 8 min. After 30 min at 160 micrograms . kg-1 . min-1, the infusion rate was reversibly decreased. The propoxyphene infusion of 15 mg . min-1 was continued throughout the study. Dopamine improved the circulation in seven animals; one animal died in refractory shock during dopamine infusion. Dopamine infusion at shock level resulted in an increase of the following variables (% of baseline value): MAP (69%), HR (109%), CI (138%) and SVI (129%). Normalisation was seen in MRAP (120%) and in MPAOP (100%). A profound decrease in systemic vascular resistance was unchanged. Increases were seen in left and right ventricular stroke work index, to 88% and 176% of baseline, respectively. Left ventricular dP/dt increased (170%). In the coronary circulation myocardial blood flow increased (133%) as did myocardial oxygen consumption (65%) concomitant with a decrease in myocardial oxygen uptake (41%), but coronary vascular resistance progressively decreased (38%). The myocardial propoxyphene extraction changed from +54% to -86% during peak dopamine infusion. In conclusion, dopamine reversed cardiac failure in propoxyphene overdose by a marked positive inotropic stimulation restoring contractility. A marked positive chronotropic stimulation maintained a sufficient cardiac index and a normal blood pressure in spite of a profound vasodilatation which was unresponsive to dopamine.

Animals↗

PubMed1987

Effects of prenalterol on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced shock.

The hemodynamic and cardiometabolic effects of prenalterol were evaluated in propoxyphene-induced circulatory shock in 10 pentobarbital-anesthetized pigs. Circulatory shock (i.e. a systolic arterial blood pressure below 60 mmHg (8 kPa) and/or a cardiac index of less than 2.0 1 X min-1 X m-2) was induced by intravenous propoxyphene chloride 15 mg X min-1. Circulatory shock occurred after 26 +/- 3 mg X kg-1 of propoxyphene. During continuous infusion of propoxyphene, consecutive doses of prenalterol 0.5, 1.0, 2.0 and 4.0 mg i.v. were injected with an interval between increments of 8 min. The maximum effect of prenalterol was seen following the 2 mg dose. Increases were observed in mean arterial blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, right ventricular stroke work index, maximum rate of rise of ventricular pressure, and total body oxygen consumption. Decreases were observed in pulmonary artery occlusion pressure, mean right atrial pressure and systemic vascular resistance, whereas heart rate and pulmonary vascular resistance remained unchanged. The cardiometabolic parameters: coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and extraction, remained low. Due to profound vasodilation, normal perfusion pressures were not reestablished. In conclusion, prenalterol improved cardiac performance by a significant positive inotropic action. However, pure inotropic stimulation was not sufficient to counteract the circulatory shock state during severe propoxyphene intoxication.

Animals↗

PubMed1983

Long-term comparison of suprofen and propoxyphene in patients with osteoarthritis.

The analgesic efficacy and safety of suprofen, 200 mg q.i.d., and propoxyphene, 65 mg q.i.d., were compared in 114 patients with chronic pain due to osteoarthritis. Both analgesic agents decreased pain intensity after only 1 week of treatment and considerable pain relief was apparent by week 2 to week 3 of treatment. These beneficial effects persisted with long-term therapy and improvement continued throughout the 24-week treatment period. Overall, the response to suprofen and propoxyphene was good to excellent in most of the patients treated. Long-term administration of suprofen was at least as well tolerated as that of propoxyphene. Only 24% (13 of 55) of suprofen-treated patients and 34% (20 of 59) of propoxyphene-treated patients discontinued therapy, primarily due to gastrointestinal complaints. It was concluded that suprofen, 200 mg q.i.d., is comparable in terms of efficacy to propoxyphene, 65 mg q.i.d., in relieving pain due to osteoarthritis.

Aged↗

PubMed1987

Effect of government and commercial warnings on reducing prescription misuse: the case of propoxyphene.

We analyzed trends in prescribing and overdose deaths related to propoxyphene (e.g., Darvon) before and after a 1978-80 informational campaign carried out by the US Food and Drug Administration and the drug's manufacturer through mailed warnings, face-to-face education of prescribers, press releases, and labeling changes. The goals included a reduction in propoxyphene use with alcohol or other CNS depressants, reduced prescribing of refills, and cessation of prescribing for patients at risk of abuse and misuse (suicide). We conducted time-series analyses of nationwide propoxyphene use data 1974-83 and analyzed data on drug overdose death rates covering a combined population of about 83 million. Segmented regression methods were used to determine if the informational program was associated with changes in trends of prescribing or overdose deaths. Comparison drug series were analyzed to control for other secular trends in prescribing. Nationwide propoxyphene use during the warnings continued a pre-existing decline of about 8 per cent per year, but this decline halted after the warnings. The no-refill recommendation had no impact on refill rates. The risk of overdose death per propoxyphene prescription filled has remained about constant since 1979. Sharper declines in misuse of such drugs will require stronger, more sustained regulatory or educational measures.

Dextropropoxyphene↗