Propoxyphene Research Articles

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

Two types of controlled-release formulations of propoxy-phene 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, i.e., pH.

Thermal decomposition of propoxyphene during GLC analysis

The decomposition products of propoxyphene during GLC were prepared on a larger scale by heating propoxyphene hydrochloride in the presence of glass wool They were identified by mass spectrometry and NMR spectroscopy as two isomeric diphenylbutenes and two isomeric products formed by loss of propionic acid. On-column decomposition of propoxyphene can be prevented by injection of the compound in solution in a silylating agent.

Addiction to Distalgesic (dextropropoxyphene)

Addiction to Distalgesic (dextropropoxyphene)

Propoxyphene dependence treated with thioridazine

Propoxyphene dependence treated with thioridazine

Evaluation of New Analgesics

Two new strong analgesics, butorphanol tartrate and nalbuphine hydrochloride, have recently become available. The pharmacologic actions of these mixed agonist-antagonist-type analgesics resemble those of pentazocine lactate, but the relative agonist and antagonist potencies of the drugs differ. They are effective analgesics in moderate to severe pain associated with conditions for which morphine or other opiates are used. The most commonly reported adverse reactions are those usually noted with agonists-antagonists; psychotomimetic effects seem to occur less frequently than with pentazocine. Although the abuse potential of these newer agents has been determined to be less than that of codeine or propoxyphene hydrochloride, physicians should prescribe them with the same cautions used for narcotics to prevent their possible abuse. ( JAMA 243:1465-1467, 1980)

Effect of hemodialysis on propoxyphene and norpropoxyphene concentrations in blood of anephric patients*

Our purpose was to determine whole-blood hemodialysis clearances and the effect of hemodialysis on blood propoxyphene concentrations and of its major metabolite, norpropoxyphene, in anephric patients under apparent steady-state conditions with respect to propoxyphene. Propoxyphene hydrochloride 130 mg was given orally every 8 hr for 7 doses to 4 patients. Blood propoxyphene and norpropoxyphene levels were determined repeatedly during the sixth dosing interval (before hemodialysis) and during the seventh dosing interval (during hemodialysis). There were no statistically significant differences in the areas under the blood level/time curves of propoxyphene and norporopoxyphene during the sixth and seventh dosing intervals, indicating that hemodialysis contributes negligible to their total clearance from the body. The low hemodialysis clearances of propoxyphene and norpropoxyphene were confirmed by direct in vivo determination of their hemodialyzer extraction ratios. Propoxyphene produces much higher propoxyphene plasma levels and higher as well as more persistent norpropoxyphene plasma levels in anephric patients than in normal subjects. In view of their substantive cumulation during repeated propoxyphene administration, their central nervous system and cardiac toxicity at high concentrations, their low hemodialysis clearance, and the apparent sensitivity of patients with renal failure to narcotics, propoxyphene should be used cautiously in anephric patients.

Problems with propoxyphene

Problems with propoxyphene

Naloxone Use in Newborns

Naloxone hydrochloride (Narcan) is a pure narcotic antagonist that is the drug of choice in the treatment of central nervous system and cardiores-piratory depression due to narcotic agonist drugs. It has virtually no agonist activity and therefore produces no narcotic effect even when administered in greater than recommended doses, in contrast to nalorphine hydrochloride and levallorphan tartrate, which have mixed agonist-antagonist activity. In 1975 the FDA approved a dosage form of naloxone in a concentration of 0.02 mg/ml that was specifically designed for use in newborns whose mothers receive narcotic analgesics during labor and who are born with narcotic-induced respiratory depression; this drug was marketed for general prescription use. Three years after its introduction, the role of naloxone in the management of the depressed newborn merits clarification. In addition, recent information regarding opiate receptors and endogenous opioids raises questions concerning the long-term safety of naloxone in neonates. A review of available published and unpublished data pertaning to naloxone use in the newborn infant by the Committee on Drugs forms the basis for the following commentary and recommendations. EFFICACY The potent narcotic antagonist activity of naloxone is well documented in infants and children as well as in adults. Naloxone has been effectively used postoperatively to reverse respiratory depression in infants and children who received narcotics for analgesia.1,2 Additional cases have been reported in which naloxone was successfully and safely used to treat children who were poisoned with narcotic agonists such as diphenoxylate hydrochloride (Lomotil),3,4 methadone hydrochloride, 57 and propoxyphene hydrochloride (Darvon).8 Most of the controlled clinical trials to study the safety and efficacy of naloxone in treating respiratory depression in the narcotic-exposed newborn have been carried out on full-term, healthy infants whose mothers received morphine or meperidine hydrochloride during labor, but who showed no overt clinical evidence of respiratory or CNS depression at birth.

Naloxone

A case of propoxyphene hydrochloride (Darvon) poisoning was unresponsive to therapeutic doses of naloxone hydrochloride in a 2 1/2-year-old girl. Following prolonged coma and artificial ventilation for three hours, the patient responded immediately to the intravenous administration of 2 mg of naloxone hydrochloride, which is 20 times the manufacturer's recommended dosage. Naloxone is the agent of choice in reversing the effects of narcotics and synthetic opiate derivatives, such as propoxyphene and pentazocine. The manufacturer's present recommended dosage may not be sufficient to reverse the effects of large narcotic ingestions. We therefore recommend that if there is no response within two minutes of the initial 0.01 mg/kg dosage of naloxone hydrochloride, a second dose 0.1 mg/kg (ten times the manufacturer's suggested dose) be given.

PROBLEMS WITH DEXTROPROPOXYPHENE PROLIFERATE

PROBLEMS WITH DEXTROPROPOXYPHENE PROLIFERATE

Propoxyphene: an example of the need for increased pharmacist/patient interaction.

Propoxyphene: an example of the need for increased pharmacist/patient interaction.

Plasma concentrations and electrocardiographic alterations after repetitive administration of propoxyphene to dogs

Propoxyphene hydrochloride was administered orally to four dogs every 8 hr for 19 days. Initial doses of 20 mg/kg were increased to 60 mg/kg in 5 to 15 mg/kg increments every 3 to 4 days. At the conclusion of the experiments animals were ambulatory although signs of toxicity including anorexia, sedation, tremors, and emesis were noted periodically throughout the study. Slight elevations in alkaline phosphatase and serum glutamate pyruvate transaminase values were also observed. Plasma concentrations of propoxyphene (P) (2.3±0.5 μg/ml) and norpropoxyphene (NP) (18.4±4.7 μg/ml), its major metabolite, were markedly elevated over those observed with a single near-lethal dose administered to naive dogs (P, 0.83 μg/ml; NP, 2.56 μg/ml). Tissue concentrations of P and NP were in excess of plasma concentrations showing marked tissue accumulation of both compounds. Electrocardiograms (ECG) showed an increase in PR interval after the first dose of propoxyphene. Doses from 20 to 45 mg/kg produced no further lengthening of the PR interval. Only when dogs were receiving 60 mg/kg (three times daily) were further changes in this interval observed, along with alterations in the QRS complex and T wave portions of the ECG. The average heart rate of these dogs was not significantly altered during the course of the study. At necropsy, mild superficial focal erosions in the mucosa of the stomach and upper small intestine were noted. No other histological changes were observed. These results demonstrated that in the dog, high plasma and tissue concentrations of P and NP can occur without causing significant toxic or lethal effects.

Lilly to provide consumer leaflet on Darvon

In the continuing saga of the widely used pain-killing drug propoxyphene hydrochloride, Eli Lilly and Company, the principal manufacturer of the drug, has agreed to voluntarily distribute a warning on the hazards of using its product (Darvon) in excess or in combination with other drugs. The Food and Drug Administration has announced that the new consumer leaflet will be available from pharmacists when prescriptions for Darvon are filled. "Darvon is a safe drug when used properly," said acting FDA Commissioner Sherwin Gardner. He added, however, that there is a "potentially lethal" risk involved when the drug is used with alcohol, tranquilizers, or sedatives. On his last day in office, however, former HEW Secretary Joseph Califano criticized the warnings as inadequate. He said that they fail to mention such things as the maximum recommended dose or the signs of drug dependency. Lilly manufactures at least 80% of the propoxyphene used in

The use of ascorbic acid and mineral supplements in the detoxification of narcotic addicts.

Since its inception in 1968, the San Francisco Drug Treatment Program, Inc., has responded to the mental and physical health needs of narcotic addicts. The search for safer, cost-effective detoxification alternatives grew from the controversial use of methadone and propoxyphene napsylate (Darvon N R) and has led to an exploration of nontraditional methods of detoxification which would address the poor nutritional habits of narcotic addicts. The present pilot study investigated the use of megadoses of ascorbic acid as sodium accurate, multivitamins, and mineral supplements in the treatment of drug withdrawal symptoms. A total of 227 subjects were compared; 30 subjects utilizing the ascorbic detoxification procedure, 186 subjects utilizing symptomatic relief medications,

Evaluation of Acetaminophen, Propoxyphene, and Their Combination in Office Practice

Thirty-two patients with chronic painful disease treated in office practice willingly participated in a double-blind, crossover analgesic study. They were informed about (1) the medications--placebo, 650 mg acetaminophen, 100 mg propoxyphene napsylate, and the combination of the two active drugs; (2) the regimen--four to six single-tablet doses per day for two days, crossover; (3) the reporting system--estimates of pain intensity and scores for other symptoms to be reported daily by telephone; and (4) return of the unused medication on the next office visit. In comparison to placebo, propoxyphene provided statistically significant analgesia, but acetaminophen did not. Significant adverse effects were not present with any test drug when compared to test placebo.

Acute poisoning with Distalgesic.

Acute poisoning with Distalgesic.

Points: Acute poisoning with Distalgesic

Points: Acute poisoning with Distalgesic

Anxiety and Pain over Valium, Darvon

Anxiety and Pain over Valium, Darvon

Propoxyphene-Associated Fatalities in Ontario: Incidence and Forensic Toxicologic al Aspects

The incidence of propoxyphene-associated fatalities in Ontario has been steadily increasing since 1974, with the increase being still evident at the end of 1977. In 1977, propoxyphene had become the third most frequently encountered drug on the drug-induced fatality scene in Ontario, and propoxyphene-associated fatalities comprised 16.3% of all ethanol and drug deaths in the Province. Propoxyphene was infrequently implicated alone; in a great majority of the fatalities propoxyphene was found together with ethanol and/or other drugs.The minimal lethal blood level of propoxyphene found was in the order of 0.1 mg/dl. This blood level is generally cohsistent with an acute ingestion of 8–14 capsules containing 65 mg propoxyphene hydrochloride or 100 mg of the napsylate. Combinations of propoxyphene with ethanol and/or other depressant drugs can cause dangerous drug inter-actions due to the mutual enhancement of effects; death can result accidentally at blood levels of drugs well below their respective fatal ranges.

Acute poisoning with Distalgesic

Acute poisoning with Distalgesic