Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.

This paper describes a rapid and sensitive method for analysis of lorazepam and its glucuronide metabolite in plasma and urine following therapeutic doses of lorazepam in humans. After addition of the structurally related benzodiazepine derivative, oxazepam, as the internal standard, 1-ml samples of plasma or urine are extracted twice at neutral pH with benzene (containing 1.5% isoamyl alcohol). The combined extracts are evaporated to dryness, reconstituted, and subjected to gas chromatographic analysis using a 3% OV-17 column and an electron-capture detector. Lorazepam glucuronide in urine is similarly analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of lorazepam per ml of original sample, and the variability of identical samples is 5% or less. The applicability of the method to pharmacokinetic studies of lorazepam is demonstrated.

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.

Combinations of metoclopramide and dexamethasone given intravenously control vomiting caused by high doses of cisplatin. Lorazepam and diphenhydramine are useful adjuncts to antiemetics. In a double-blind trial, 120 patients receiving high-dose cisplatin (120 mg/m2) for the first time were randomly assigned to receive either lorazepam (1.5 mg/m2) or diphenhydramine (50 mg) intravenously, 45 minutes prior to cisplatin. In addition, all patients received intravenous dexamethasone (20 mg) 40 minutes prior to chemotherapy along with metoclopramide (3 mg/kg) 30 minutes before and 90 minutes after cisplatin. Patients were directly observed in the hospital after cisplatin administration and completed a subjective assessment questionnaire. Overall, 60% of patients experienced no vomiting, and 83% had two or fewer emetic episodes during the study. There were no significant differences in objective antiemetic control between the two regimens. Only 3% of patients receiving lorazepam experienced treatment-related restlessness as opposed to 19% given diphenhydramine (P = 0.007). Less recall of chemotherapy administration (P less than 0.001), more sedation (P = 0.003), and transient enuresis while sedated (P = 0.0002) were characteristic of patients receiving lorazepam. Patient-generated ratings revealed less anxiety (P = 0.0001) for those individuals given the lorazepam-containing combination. Both regimens were well accepted, with 89% of patients receiving the lorazepam combination and 83% of those given the diphenhydramine regimen wishing to receive the same drugs in the future. Some degree of delayed vomiting occurred in 85% of patients during the 4-day period following this study. During the time that patients are at the greatest risk for emesis, the 24 hours immediately following cisplatin, three drug antiemetic combinations of either lorazepam or diphenhydramine with metoclopramide plus dexamethasone stopped cisplatin-induced emesis for the majority of patients and lessen other treatment-related side effects. Less restlessness and anxiety were observed among individuals receiving the lorazepam-containing combination.

Four baboons were trained to discriminate lorazepam (1.0 mg/kg i.m.) and two baboons were trained to discriminate pentobarbital (5.6 mg/kg i.m.) in a two-lever drug discrimination procedure. Food delivery depended on 20 consecutive responses on one lever in sessions preceded by an injection of the training drug and on 20 consecutive responses on the other lever after no drug. All baboons reliably completed 100% of the response runs on the appropriate lever in training sessions. Test sessions were conducted in which a drug dose different from the training dose was injected and 20 consecutive responses on either lever produced food. Drug lever responding occurred after a range of lorazepam and diazepam doses in both lorazepam- and pentobarbital-trained baboons. Drug lever responding also occurred after a range of doses of pentobarbital in the pentobarbital-trained baboons but in only one of the four lorazepam-trained baboons. Ro 15-1788 (0.1-1.0 mg/kg p.o.) antagonized the effect of lorazepam but had no effect on the pentobarbital discriminative stimulus. The asymmetrical generalization with lorazepam and pentobarbital suggests a specificity of discriminative stimulus effects that heretofore have not been documented in drug discrimination experiments with benzodiazepines and barbiturates. The selective antagonism of lorazepam by the benzodiazepine-receptor antagonist Ro 15-1788 suggests that the lorazepam but not the pentobarbital discriminative stimulus is mediated at the benzodiazepine receptor.

We report a case of gamma-hydroxybutyrate (GHB) withdrawal resulting in severe agitation, mental status changes, elevated blood pressure, and tachycardia hours after stopping chronic use of GHB. The patient admitted to substantial GHB abuse on a daily basis for 2.5 years. Previous attempts at cessation reportedly resulted in diaphoresis, tremors, and agitation. The patient's symptoms, negative polypharmacy history, and negative urine and blood toxicological analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances suggested the diagnosis of GHB withdrawal. Later analysis of a patient drug sample confirmed the presence of GHB. The patient required 507 mg of lorazepam and 120 mg of diazepam over 90 h to control agitation. This is one of the few reported cases of GHB withdrawal and one of the most severe. Given the increasing use of GHB, more cases of severe GHB withdrawal should be anticipated.

Ten healthy volunteers received single 2-mg doses of lorazepam on five occasions in random sequence. Modes of administration were: A, intravenous injection; B, deltoid intramuscular injection; C, oral tablets in the fasting state; D, sublingual dosage of oral tablets in the fasting state; and E, sublingual dosage of specially formulated tablets in the fasting state. Kinetic variables were determined from multiple plasma lorazepam concentrations measured during 48 hr postdose. After intravenous lorazepam, mean (+/- SE) values were: elimination half-life (t 1/2 beta), 12.9 (+/- 0.8) hr; volume of distribution, 1.3 (+/- 0.07) liters/kg; total clearance, 1.21 (+/- 0.1) ml/min/kg. Absorption of intramuscular lorazepam was rapid. Peak plasma levels were reached at 1.15 hr after dosage, with absorption half-life averaging 14.2 (+/- 4.7) min. Absorption or oral and sublingual lorazepam tended to be less rapid than intramuscular injection, although differences were not significant. Times of peak concentration were 2.37, 2.35, and 2.25 hr postdose for trials C,D, and E, respectively; values of absorption half-life were 32.5, 28.5, and 28.7 min. Absolute systemic availability for trials B, C, D, and E averaged 95.9, 99.8, 94.1, and 98.2%, respectively; none of these differed significantly from 100%. Values of t1/2 beta were highly replicable within individuals regardless of the administration route. Thus, sublingual lorazepam is completely absorbed and is a suitable administration route in clinical practice.

Twelve subjects (8 male) took part in a randomised double blind four way crossover design study comparing four treatments:(i) morphine sulphate 10 mg,(ii) morphine sulphate 15 mg,(iii) lorazepam 1 mg (positive control) and (iv) placebo. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam produced a marked impairment in the tests of attention and memory. CFFT was reduced from 1-4 h but this only reached significance at 4 hours. The subjective measures suggested impaired alertness but this did not reach significance. The effects of morphine were less dramatic; both doses of morphine produced significant impairment at 1 hour on tests of secondary memory retrieval (delayed word recall and picture recognition sensitivity). CFFT was reduced for the whole observation period (6 h) achieving statistical significance at 4 hours. Morphine 15 mg produced a significant improvement in accuracy on the choice reaction time test at the 2, 4 and 6 h assessments. These results show minimal impairment of cognitive and psychomotor function after single oral doses of morphine and with possible improvement in one test. Further studies are required to examine the effect of repeated doses.

The effects of single doses of CL284,846 (20 mg), lorazepam (2 mg) and placebo on psychomotor performance, memory function and subjective feelings were assessed in 12 normal, healthy male volunteers. Each subject received each treatment in balanced order and a minimum of 6 days was left between treatments. The subjects performance on a comprehensive battery of tests of psychomotor performance, memory function and subjective ratings was assessed pre-treatment and at 1, 3 and 5 h post-treatment. In general, the effects of CL284,846 on memory were similar to those of lorazepam at 1 h post-treatment but, recovery was rapid with CL284,846. Impairments induced by lorazepam persisted throughout the post-drug testing sessions. This pattern of effects was repeated across most of the variables tested. However, at 1 h, CL284,846 produced less marked psychomotor impairment than lorazepam. The results of this study suggest that CL284,846 is a safe, rapid acting and effective sedative with some clear advantages over lorazepam with respect to unwanted cognitive and psychomotor impairments.