Relative abuse liability of diazepam and oxazepam: Behavioral and subjective dose effects

The effects of diazepam (10–160 mg) and oxazepam (30–480 mg) were studied in volunteers with histories of drug abuse. Oral doses were administered every third day under double-blind and counterbalanced conditions. Dose-effects with area under the time-action curve data (AUC) showed diazepam to be 2.6-5.7-times more potent than oxazepam on various psychomotor, cognitive, staff-rated, and subjective measures. Comparison of relative potencies showed diazepam to be relatively more potent in producing liking than in producing psychomotor and cognitive effects. Diazepam produced greater peak effects than oxazepam on a number of staff- and subject-rated measures, including liking. Onset of effect was more rapid and time to maximal effect was shorter (1–2 h versus 4–12 h) with diazepam than oxazepam, while time to offset of effect was similar for the two drugs. Diazepam was categorized as producing barbiturate-like subjective effects (38.3%) more frequently than was oxazepam (13.8%), while oxazepam was identified as placebo more often than diazepam. Repeated administration of 160 mg diazepam and 480 mg oxazepam showed that AUC liking was greater for diazepam than oxazepam and that tolerance to psychomotor and cognitive effects occurred with oxazepam but not diazepam. This study suggests that diazepam may have a higher abuse liability than oxazepam.     

A comparative study on the clinical effects of oxazepam and diazepam: Relationship between plasma level and effect.

The clinical effects of oxazepam and diazepam as oral premedicants were tested in a double-blind study of 60 children and 50 adults. The gas chromatographically measured concentrations of the active unconjugated forms of oxazepam and diazepam in the plasma were correlated to their clinical effects, as assessed both subjectively and objectively (sleep, sedation, apprehension, excitement, dizziness, emetic effect, headache, increase or decrease in systolic blood pressure, increase in pulse rate, venepuncture). No significant difference in the effects of these two benzodiazepine derivatives were observed, nor was there any obvious relationship between the plasma concentration and clinical effect.     

Oxazepam: update 1989

Oxazepam is an anxiolytic with established clinical efficacy. Compared to other benzodiazepines it may offer advantages in some patient populations, such as the elderly. Oxazepam has not been associated with more or different risks than other benzodiazepines, and there is no evidence that physiological dependence occurs more frequently with oxazepam than other benzodiazepines. Available evidence suggests that oxazepam may be associated with a lower risk of seizure-induction than lorazepam and alprazolam, and that compared to diazepam, oxazepam may have lower abuse potential.     

A death due to self-administered fentanyl

A fatality resulting from the self-administration of fentanyl is described. The decreased was a health care professional with a known history of drug abuse. At the scene, a syringe partly filled with red fluid was found. Pathological findings disclosed pulmonary congestion, hemorrhage, and aspiration of gastric contents and passive congestion in the liver and kidneys. Initial drug screening revealed the presence of fentanyl in the fluid from the syringe and diazepam/oxazepam in the urine. Fentanyl, diazepam, nordiazepam, and oxazepam in the submitted samples were simultaneously quantitated using a gas chromatograph equipped with a nitrogen-phosphorus detector. The fentanyl concentrations (micrograms/L or micrograms/kg) in serum, blood, urine, bile, liver, kidney, brain, lung, and stomach tissue were 17.7, 27.5, 92.7, 58.2, 77.5, 41.5, 30.2, 83.4, and 31.6, respectively. The tissue levels of diazepam and its metabolites were lower than the reported lethal concentrations. The fentanyl concentration in the syringe contents was 2,800 micrograms/L. The toxicological findings and circumstantial evidence of the case indicate that the death resulted primarily from fentanyl overdose.     

Kinetics of Drug Action in Disease States. XXXI. Effect of Experimental Hyperthyroidism on the Hypnotic Activity of a Benzodiazepine (Oxazepam) in Rats

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug.     

Plasma concentrations of diazepam and its metabolites after peroral, intramuscular, and rectal administration. Correlation between plasma concentration and sedatory effect of diazepam.

Plasma levels of diazepam, N-demethyldiazepam and free oxazepam were measured gaschromatographically in ten healthy volunteers after 5 mg of diazepam perorally, intramuscularly and rectally (with three different kinds of suppositories). The best absorption of diazepam was found after peroral administration. After an intramuscular injection a delayed absorption with low plasma concentrations of diazepam was found. The basal component of a diazepam suppository seems to have a great effect on the rectal absorption of diazepam. Two of the three different kinds of diazepam suppositories caused higher plasma diazepam concentrations than the intramuscular injection of the drug. There were no great differences in the amount of the metabolites of diazepam after different kinds of administration. The subjective sedatory effect of diazepam lasted approximately as long as the fast distribution of diazepam from plasma took place. A very highly significant correlation between plasma concentration and subjective sedatory effect of diazepam after a single dose was found.     

Biliary Excretion of Diazepam and its Metabolites in Man

Abstract: Ten mg diazepam was given intravenously to 12 patients with a T-tube in the common bile duct after choledochotomy (Group I) and to 10 patients after cholecystectomy (Group II). The concentrations of diazepam, of its main metabolite, N-demethyldiazepam, and of free oxazepam in the plasma of both groups and the conjugated and free concentrations of diazepam, N-demethyldiazepam, and oxazepam in the bile in the Group I were measured by gas chromatography. In Group I significantly lower plasma diazepam concentrations were obtained as compared with Group II indicating an enterohepatic circulation of diazepam. There was no significant difference in the concentrations of N-demethyldiazepam in the plasma between the two groups. In Group I the patients had frequently more free oxazepam in their plasma than in Group II. The main conjugated metabolite in the bile was N-demethyldiazepam (about 74 %). Traces of diazepam were in the conjugated form, but no conjugated oxazepam was found in the human bile. The enterohepatic circulation of diazepam and its metabolites may be partly responsible for the prolonged effects of diazepam.     

The urinary elimination profiles of diazepam and its metabolites, nordiazepam, temazepam, and oxazepam, in the equine after a 10-mg intramuscular dose

A method for the extraction of diazepam and its metabolites (nordiazepam, temazepam, and oxazepam) from equine urine and serum and their quantitation and confirmation by liquid chromatography-tandem mass spectrometry is presented. Valium, a formulation of diazepam, was administered at a dose of 10 mg intramuscularly to four standard-bred mares. Diazepam is extensively metabolized in the horse to nordiazepam, temazepam, and oxazepam. Diazepam urinary concentrations were found to be less than 6 ng/mL. Nordiazepam was found to be mainly in its glucuronide-conjugated form and was measured out to a collection time of 53-55 h. Oxazepam and temazepam were entirely conjugated, and their urinary concentrations were measured out to collection times of 121 h and 77-79 h, respectively. Diazepam and nordiazepam were measured in equine postadministration serum out to collection times of 6 and 54 h, respectively. Oxazepam and temazepam were not detected in postadministration serum.     

Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam,lorazepam, and oxazepam

Groups of male CF-1 mice received 3 and 10 µmol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using³H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30–60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity.) Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.Supported in part by grants MH-34223, DA-05258, and AG-00106 from the United States Public Health Service     

Toxicological determination of benzodiazepines in serum: methods and concentrations associated with high-dose intravenous therapy with diazepam.

This paper describes a rapid and simple procedure for the determination of benzodiazepines in biological samples. Five common benzodiazepines (diazepam, oxazepam, clorazepate, flurazepam, and chlordiazepoxide) and/or their major metabolites are extracted from a buffered serum sample at pH 9.2 by a mixture of toluene, hexane, and isoamyl alcohol. The phases are separated by centrifugation, and a small aliquot of the organic layer is injected into a gas chromatograph equipped with an electron-capture detector. The drugs are identified and quantitated by comparison with standards simultaneously processed similarly. A sample can be analyzed in about 30 min. The technique is illustrated by its application to sequential samples from a patient being treated for delirium tremens with large intravenous doses of diazepam. Serum diazepam, N-desmethyldiazepam, and oxazepam concentrations several times higher than usually encountered therapeutically were observed.     

Diazepam has no beneficial effects on stress-induced behavioural and endocrine changes in male tree shrews

The present study evaluated the effect of subchronic oral treatment of psychosocially stressed male tree shrews with diazepam on locomotor activity, marking behavior, avoidance behavior, and urinary cortisol and noradrenaline. To mimic a realistic situation of anxiolytic intervention, the treatment started 14 days after the beginning of psychosocial stress; at that time, the stress-induced behavioral and endocrine alterations had been established. The drug (5 mg/kg/day) was administered orally in the morning, while the psychosocial stress continued during the whole treatment period; the therapeutic action of diazepam treatment was followed across 7 days. Twenty-four hours after the last application serum concentrations of diazepam and its major metabolites were determined via HPLC. The results revealed concentrations of 7 ng/ml for diazepam, 106 ng/ml for nordiazepam, 22 ng/ml for temazepam, and 30 ng/ml for oxazepam. Treatment of subordinate animals with diazepam did not reveal a beneficial effect to any of the parameters studied. This contrasts to earlier findings showing that the behavioral and neuroendocrine alterations produced by this stress paradigm are sensitive to chronic treatment with the tricyclic antidepressant clomipramine. The present results support the view that in male tree shrews the state induced by psychosocial stress might be more depression related than anxiety related.     

Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake

Abstract: Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison to healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol-free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N-demethyl-diazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15% in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N-demethyldiazepam.     

Induction Effect of Diazepam on its Own Metabolism

Abstract: In the 7 psychiatric patients 10 mg diazepam administered intravenously, during continuous therapy, caused a significantly lower increase of diazepam concentrations in the plasma (at 15 min. P < 0.01; 1 hour P < 0.001; 3 and 6 hours P < 0.05; 24 hours P < 0.001) than in 13 healthy volunteers as an indicator of the increased elimination rate of diazepam. As a sign of the increased formation of the main metabolite, the increase in the concentration of N-demethyldiazepam was significantly higher in the psychiatric patients on continuous diazepam therapy (at 15 min. P < 0.05; 1 hour P < 0.01) than in healthy volunteers. The intravenous injection of 10 mg diazepam caused in 7 psychiatric patients on continuous diazepam therapy a significantly lower mean increase of diazepam concentrations in the plasma (at 15 min., 1 hour, 3 and 6 hours P < 0.01; 24 hours P < 0.001) than in 12 psychiatric patients treated without diazepam and significantly higher increase in the concentrations of N-demethyldiazepam (at 1 hour P < 0.05). No measurable amounts of free oxazepam was found in the plasma.     

Intravascular factors affecting diazepam binding to human serum albumin.

The binding of a benzodiazepine derivative (diazepam) to human serum albumin was studied by equilibrium dialysis. The influence on this interaction of various endogenous substances (fatty acids, uric acid and bilirubin) and the metabolites of diazepam (desmethyldiazepam and oxazepam) were investigated. Binding studies were analyzed by fitting a model which utilizes the two independently measured quantities, the free drug concentration and the total amount of drug, to the experimental data points with a least squares method. Oleic acid decreases the binding of diazepam at all molar ratios of fatty acid:albumin. In contrast, palmitic acid at ratios of < 1:1 enhanced diazepam binding. Both uric acid and bilirubin had negligible effects on diazepam binding. The metabolites were bound to a less extent than diazepam (diazepam > desmethyldiazepam > oxazepam), and both metabolites reduced diazepam binding to albumin. In vivo, the absolute ratio of specific fatty acids to each other is probably as important a source of variations as the quantitative changes in total fatty acids or metabolites.     

On the Mechanism of Hepatocarcinogenesis of Benzodiazepines: Evidence that Diazepam and Oxazepam are CYP2B Inducers in Rats,and both CYP2B and CYP4A Inducers in Mice

The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, diazepam and oxazepam induced both CYP2B and CYP4A at dietary doses associated with liver tumor formation. It remains to be determined why diazepam and oxazepam induce CYP4A in mice but not rats and whether this difference accounts for the apparent species difference in the tumor-promoting activity of diazepam and oxazepam.     

Multiple oral doses of diazepam, oxazepam and phenobarbital to dogs--behavioural effects and correlation with antipyrine half-life.

The effects of prolonged treatment with phenobarbital, diazepam, and oxazepam on behaviour and on the plasma half-life of antipyrine have been studied in the dog. In this species the biotransformation of diazepam and oxazepam is known to be very similar to man. After equipotent doses of phenobarbital (25 mg/kg) and diazepam (35 mg/kg), antipyrine half-life was found to decrease 80 and 40%, respectively, while after treatment with oxazepam (150 mg/kg) there was an increase of 20%. The behavioural effects declined in the dogs during the course of treatment with diazepam but were rather constant during treatment with oxazepam.     

On the mechanism of hepatocarcinogenesis of benzodiazepines: evidence that diazepam and oxazepam are CYP2B inducers in rats, and both CYP2B and CYP4A inducers in mice

The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, diazepam and oxazepam induced both CYP2B and CYP4A at dietary doses associated with liver tumor formation. It remains to be determined why diazepam and oxazepam induce CYP4A in mice but not rats and whether this difference accounts for the apparent species difference in the tumor-promoting activity of diazepam and oxazepam.     

Lack of pharmacokinetic interaction between vinpocetine and oxazepam.

The influence of multiple doses of vinpocetine (10 mg three times daily) on the steady state plasma concentrations of oxazepam (10 mg three times daily) was studied in 16 healthy subjects. The mean (+/- s.d.) AUC (ng ml-1h-1) of oxazepam over 24 h during combined treatment was 4716 +/- 2296 and for oxazepam treatment alone it was 4737 +/- 2448 (95% confidence intervals for ratio of means = 95.4-103.7%). The degree of plasma protein binding of oxazepam was 98.11 +/- 0.32% and was not affected by vinpocetine. Independent of vinpocentine treatment a significant diurnal change in the plasma binding of oxazepam was observed; the free drug fraction was 20% higher during the night than during the day. Cmax and AUC values based on total oxazepam in plasma were 10% lower during the night. The results indicate a lack of influence of vinpocetine on oxazepam kinetics. Diurnal changes in the plasma binding of oxazepam probably have no clinical consequences.     

Kinetics and mechanisms of hydrolysis of 1,4-benzodiazepines II: oxazepam and diazepam.

The hydrolysis kinetics of oxazepam and diazepam leading to a benzophenone product and a glycine derivative were quantified from pH 1 to 11. For oxazepam, two intermediates were isolated and identified, indicating a parallel consecutive reaction mechanism. The hydrolysis occurred uncatalyzed and demonstrated acid-base catalysis for both reaction steps. One intermediate was observed by TLC for diazepam hydrolysis. This intermediate, resulting from breakage of the azomethine linkage, was different than the major intermediate isolated for oxazepam hydrolytic degradation (amide hydrolysis preferred). Stability parameters involving rate constant-temperature dependence are reported.