A controlled study of two preparations, paramethasone, propoxyphene, and aspirin and propoxyphene and aspirin in the treatment of arthritis.
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Arthritis, Rheumatoid↗
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Results for “PROPOXYPHENE”
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Acute propoxyphene self-poisoning--with special reference to propoxyphene cardiotoxicity and treatment.
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Animals↗
Propoxyphene hydrochloride--a review article towards its proper usage. Need for a rational approach to the use of Darvon (propoxyphene hydrochloride).
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Dextropropoxyphene↗
Lack of evidence of increased lethality due to propoxyphene overdose in the presence of ethanol in male Wistar rats.
The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Propoxyphene use and risk for hip fractures in older adults.
BACKGROUND: Published guidelines have identified propoxyphene as an inappropriate medication for use in aged patients. It is no more effective than acetaminophen, yet has been associated with the same adverse effects (AEs) associated with other opioid drugs. In particular, its central nervous system-related AEs, dizziness and sedation, may increase the risk for fracture resulting from falls in older adults. Nonetheless, US studies have reported widespread use of propoxyphene in the elderly US population. OBJECTIVE: The aim of this study was to examine the risk for fracture associated with propoxyphene use in older adults. METHODS: This prospective cohort study used a large administrative claims data set from adults aged > or =65 years. A time-varying (lagged) covariate defined each person as a propoxyphene user or nonuser based on propoxyphene exposure in the 14 days before each fracture event in the cohort. Another time-varying measure stratified propoxyphene users based on their mean daily dose of propoxyphene (high dose = >260 mg; low dose = < or =260 mg of propoxyphene hydrochloride or equivalent napsylate salt). Time-dependent Cox regression models were used to estimate the association between propoxyphene exposure and occurrence of hip fracture (using International Classification of Diseases, Ninth Revision, Clinical Modification code 820.xx). RESULTS: A total of 362,503 patients were included in the analysis. During a mean follow-up of 464 days, approximately 10% (37,569) of the sample had > or =1 propoxyphene prescription filled and approximately l% (5065) sustained a hip fracture. Propoxyphene users had a 2-fold higher risk for hip fracture (hazard ratio [HR] [95% CI], 2.05 [1.87-2.25]) compared with nonusers of analgesics. Multivariate analysis found a dose-response relationship between propoxyphene and hip fracture risk (low dose, HR [95% CI], 1.45 [1.26-1.67]; high dose, HR [95% CI], 2.05 [1.85-2.29]). Other opioid analgesics were associated with an increased risk for hip fractures. CONCLUSIONS: The results of this cohort database study suggest that propoxyphene use among adults aged > or =65 years is associated with increased risk for hip fracture and suggest a need for interventions to reduce propoxyphene use in older adults. Clinicians should be aware of the risk for hip fracture with other opioids as well and weigh them against potential benefits when prescribing for older adults.
Aged↗
Ethanol does not increase lethality due to propoxyphene in rats.
Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats received either of the following drug treatments: Propoxyphene; ethanol + propoxyphene; naloxone + propoxyphene; and naloxone + ethanol + propoxyphene. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene as compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. A rise in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. Although these pharmacokinetic data indicate impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests antagonism between the two drugs, probably in the central nervous system.
Animals↗
National trends in and predictors of propoxyphene use in community-dwelling older adults.
BACKGROUND: Several pain management guidelines and explicit medication-use criteria identify propoxyphene as an inappropriate medication for use in older adults. OBJECTIVE: This study was conducted to estimate trends in propoxyphene use among community-dwelling elderly (age > or = 65 years) Medicare beneficiaries from 1993 through 1999 and to determine whether beneficiaries' drug coverage and specific characteristics of their physicians were associated with receipt of propoxyphene in 1999. METHODS: Data from the Medicare Current Beneficiary Survey (MCBS) were used to examine the prevalence of propoxyphene use in cross-sections of nationally representative samples of community-dwelling elderly Medicare beneficiaries from 1993 through 1999. The 1999 MCBS was linked with the 1999 Area Resource File to examine patient and physician factors associated with propoxyphene use in the community-dwelling elderly at the county level. RESULTS: Rates of propoxyphene use were generally stable over the 7-year period, from an annual prevalence of 6.8% in 1993 to the slightly decreased prevalence of 6.6% in 1999. No protective effects against propoxyphene use were observed based on beneficiaries' drug coverage or type of drug coverage. Rather, Medicaid beneficiaries were more likely to receive propoxyphene than those without drug coverage (odds ratio [OR] = 1.40; 95% CI, 1.02-1.92). Among physician characteristics, male sex (OR = 1.34; 95% CI, 1.02-1.75) and medical specialty (OR = 0.81; 95% CI, 0.65-1.00) were strongly correlated with prescribing of propoxyphene. CONCLUSION: This study found a continuing high prevalence of propoxyphene use in the community-dwelling elderly Medicare population from 1993 through 1999, with > 2 million beneficiaries receiving the drug in 1999.
Activities of Daily Living↗
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.
Adult↗
Characterizing the subjective, psychomotor, and physiological effects of oral propoxyphene in non-drug-abusing volunteers.
BACKGROUND: The subjective, psychomotor, and physiological effects of a widely prescribed prescription opioid, propoxyphene, have not been studied in a population of non-drug-abusing people. The drug also has potential for abuse and it was of interest in the present study to determine if the drug had any abuse liability-related subjective effects in this population. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo; 50 mg propoxyphene napsylate; 100 mg propoxyphene napsylate; 200 mg propoxyphene napsylate; 40 mg morphine sulfate; and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. RESULTS: Both morphine and lorazepam produced subjective effects. There were no statistically significant subjective effects obtained with any dose of propoxyphene in the group as a whole, but approximately 30-50% of the subjects did appear to experience subjective effects from the drug. Drug liking was not consistently observed in this subset. Propoxyphene, unlike lorazepam, did not impair psychomotor or cognitive performance. Both propoxyphene and morphine produced miosis. CONCLUSIONS: There was a lack of statistically significant subjective effects of propoxyphene in the group as a whole, including a propoxyphene dose that was twice as high as the typical clinically-prescribed dose of 100 mg. However, there were some subjects who did report effects, consistent with the notion that patients differ in their sensitivity to opioid effects.
Adult↗
Propoxyphene use by community-dwelling and institutionalized elderly Medicare beneficiaries.
OBJECTIVES: To provide the first comparable national prevalence estimates on use of propoxyphene, a potentially inappropriate drug, by elderly Medicare beneficiaries living in the community and institutions and to determine whether institutionalized beneficiaries are at a greater risk for receiving propoxyphene than community-dwelling beneficiaries. DESIGN: Cross-sectional study. SETTING: U.S. representative sample of elderly using Medicare database. PARTICIPANTS: Nationally representative sample of community-dwelling (n = 9,851, weighted n = 32.5 million) and institutionalized (n = 1,099, weighted n = 2.3 million) Medicare beneficiaries aged 65 and older. MEASUREMENTS: National estimates on prevalence of propoxyphene use and the odds of receiving propoxyphene were the two main outcome measures. RESULTS: Annual prevalence of propoxyphene use in 1998 was 6.8% by all community-dwelling elderly beneficiaries and 15.5% by institutionalized elderly beneficiaries. Beneficiaries in long-term care facilities had almost 40% higher odds of receiving propoxyphene (odds ratio = 1.38, 95% confidence interval = 1.1-1.8) than beneficiaries in the community even after controlling for other factors in a logistic regression. Other risk factors include female, rural residence, poor health, and history of osteoporosis or hip fracture. Beneficiaries residing in regions in the midwest and south were more than twice as likely to receive propoxyphene as those in the mid-Atlantic area. CONCLUSION: These results show that propoxyphene use by U.S. community-dwelling seniors is high but is much higher in the institutionalized population. These findings suggest that prescribing for older adults with pain could be improved, especially for vulnerable long-term care residents.
Aged↗
Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine.
The opiate analgesic propoxyphene produces cardiac toxicity when taken in overdose. We recently observed a patient with propoxyphene overdose in whom marked QRS widening was reversed by lidocaine. The reversal is apparently paradoxical as both agents block the inward sodium current (INa). We examined possible mechanisms of the reversal by measuring INa in rabbit atrial myocytes during exposure to propoxyphene and the combination of propoxyphene and lidocaine (60 and 80 microM, respectively). Propoxyphene caused use-dependent block of INa during pulse train stimulation. Block recovered slowly with time constants of 20.8 +/- 3.9 s. Block during lidocaine exposure recovered with time constants of 2-3 s. During exposure to the mixture, block recovered as a double exponential. The half time for recovery during exposure to the mixture was 1.6 +/- .9 s compared with a half-time of 14.3 +/- 2.9 s during exposure to propoxyphene alone. During pulse train stimulation, less steady-state block was observed during exposure to the mixture than during exposure to propoxyphene alone when the interval between pulses was greater than 0.95 s. Both drugs compete for a common receptor during the polarizing phase. The more rapid dissociation of lidocaine during the recovery period leads to less block during the mixture than during exposure to propoxyphene alone. The experiments suggest a mechanism for reversal of the cardiac toxicity of drugs which have slow unbinding kinetics.
Adult↗
Decreased absorption of propoxyphene by activated charcoal.
In 1968 we first suggested that activated charcoal (AC) should be administered in the emergency treatment of propoxyphene overdosage. The dramatic increase in recent years of deaths involving propoxyphene has prompted us to again evaluate the efficacy of AC in preventing absorption of propoxyphene from the GI tract. Male rats (100-125 g) were administered propoxyphene hydrochloride (P-HCl, 350 mg/kg) or propoxyphene napsylate (P-N, 825 mg/kg) either dissolved or suspended in 5% acacia in H2O. After 30 min the rats were administered either AC at 10 times the drug dose or water. Surviving rats were sacrificed at 1, 2, 4, 8, 12, and 24 h; the brain, liver, and both kidneys were removed intact, weighed, and stored at -70 degrees C. After lyophilization, the tissues were analyzed for propoxyphene and its metabolite, norpropoxyphene, by GLC. There were significantly less deaths in rats that received P-HCl + AC or P-N + AC than rats that received either P-HCl or P-N alone (9 vs 19, p less than .01 and 5 vs 10, p less than .05 respectively). Tissue levels of propoxyphene and norpropoxyphene were similarly significantly reduced. These studies provide further evidence of the efficacy of AC in propoxyphene overdosage.
Animals↗
Acute effect of ethanol on hepatic first-pass elimination of propoxyphene in rats.
The purpose of this investigation was to determine if ethanol enhances the acute toxicity of propoxyphene not only by its central nervous system depressant effect but also by inhibiting the otherwise pronounced presystemic biotransformation of the analgesic. Administration of propoxyphene to adult male rats by injection into either the systemic (jugular vein) or hepatic portal circulation (pyloric vein) revealed that 40 +/- 12% (mean +/- S.D.) of a 12 mg/kg dose reached the systemic circulation intact after injection of the drug into the portal circulation. This estimate, based on the area under the plasma concentration time curve, was confirmed by the relative amounts of propoxyphene excreted unchanged in the urine. Acute infusions of ethanol, 1.5 ml/kg/hr from -3 to 0 hr and 0.5 ml/kg/hr from 0 to +3 hr into the portal circulation, increased the total systemic clearance of propoxyphene from 64 to 95 ml/min/kg on the average (P less than .02), probably due to increased hepatic blood perfusion rate. The same rate and route of ethanol administration caused an increase in the average systemic availability of propoxyphene from 28 to 56% (P less than .001) after injection of 8 mg/kg into the portal circulation. Since orally administered propoxyphene is ordinarily subject to extensive presystemic biotransformation in humans, the frequent association of ethanol intake with fatal propoxyphene intoxication may be due, at least in part, to an increased systemic availability of propoxyphene when taken with ethanol.
Animals↗
Naltrexone and beta-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene.
RATIONALE: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. OBJECTIVE: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, beta-funaltrexamine (beta-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through muu opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. METHODS: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. RESULTS: Naltrexone (0.01-1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. beta-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. beta-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. CONCLUSIONS: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through mu opioid receptors. Overall, high doses of beta-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by beta-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects.
Animals↗
Effect of repeated oral propoxyphene administration on analgesia, toxicity and microsomal metabolism in the mouse.
Induction of hepatic propoxyphene N-demethylase and aniline hydroxylase activities resulted following repeated oral administration of 25, 50 and 100 mg d-propoxyphene hydrochloride per kg daily in the mouse over a six-day period. A significant elevation in both enzyme activities was noted after a single dose of propoxyphene (100 mg/kg). A dose-related response characterized the observed induction of each microsomal enzyme activity. Pentobarbital sleeping times (a measure of in vivo microsomal activity) also exhibited dose-related decrements in hypnosis with increasing doses of propoxyphene. These effects appeared to correlate with the development of tolerance to both the analgesic and lethal properties of propoxyphene. Pretreatment with SKF-525A, a potent microsomal enzyme inhibitor, abolished this tolerance in each case. Furthermore, a lack of central nervous system cellular tolerance was demonstrated by the finding that intracerebroventricular LD50 values for propoxyphene in propoxyphene- and water-treated mice were identical to the value derived from naive mice. Thus, the observed tolerance seems to be the result of dispositional (metabolic) and not central nervous system tolerance.
Administration, Oral↗
Deaths related to propoxyphene overdose: a ten-year assessment.
Of 81 fatal overdoses of propoxyphene identified over a ten-year period, suicide accounted for 76.5% and accidents for 23.5%. The incidence sharply increased in 1973 and the death rate has remained constant since then. In two thirds of the suicidal overdose deaths, additional drugs were encountered. Alcohol was detected in an additional 15%, and propoxyphene preparations alone were used in 19%. In the 19 deaths from accidental overdose, six resulted from recreational abuse, and additional drugs were detected in all. Five who dief of propoxyphene preparations alone had significant medical illnesses. Eight nonrecreational users died after taking other drugs or alcohol along with propoxyphene. Only one individual in the entire series was found to be dependent on propoxyphene. Although propoxyphene cannot be regarded as a harmless drug, the study indicates a very low rate of dependency and a low potential for recreational abuse. As with other drugs, adequate warnings concerning dosage abuse and the concurrent use of alcohol and other drugs must be stressed. The suggestion to reclassify propoxyphene to a Schedule II drug does not appear justified.
Adolescent↗
The effect of ethanol intake on propoxyphene absorption and biotransformation in dogs.
The effect of ethanol (0.5 and 1.0 g/kg) on gastrointestinal absorption and presystemic biotransformation of propoxyphene (4 mg/kg) was studied in dogs in a crossover design. Low ethanol doses (0.5 g/kg) had no effect on the bioavailability of propoxyphene. High ethanol doses (1.0 g/kg) enhanced the bioavailability of orally administered propoxyphene significantly (p less than 0.05). With this dose of ethanol, the area under the blood concentration versus time curve (AUC)0-5 h of propoxyphene was approximately 200% of the control value. The level of norpropoxyphene, a major metabolite of propoxyphene, was significantly decreased (p less than 0.05) after administration of high ethanol doses. In all blood samples, after propoxyphene administration, an unidentified metabolite of propoxyphene was found, which formation was dose dependently inhibited by ethanol.
Administration, Oral↗
Enhancement of propoxyphene bioavailability by ethanol. Relation to psychomotor and cognitive function in healthy volunteers.
The interaction between a single oral dose of 130 mg propoxyphene and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by 9 objective performance tests, 8 visual analogue self-rating scales and the measurement of plasma propoxyphene, norpropoxyphene and ethanol concentrations, using a double-blind threeway crossover design. Volunteers were each given one of three treatments, propoxyphene + ethanol, placebo + ethanol and propoxyphene alone, separated by a two week interval. The performance tests were completed before and 1.25 and 4 h after drug intake, and the self-rating scales before and 1.25, 4 and 10 h after it. Ethanol was shown to enhance the bioavailability of propoxyphene by 25% probably by reducing its first-pass metabolism. However, despite this pharmacokinetic effect no pharmacodynamic interaction was found. Subjective ratings disclosed that the effect of ethanol on physical and mental sedation predominated over the effects of propoxyphene.
Biological Availability↗