Evaluation of lorazepam as an oral preanaesthetic medication. A comparative double-blind study with diazepam and placebo

Summary

A series of 143 patients scheduled for minor or moderate surgical procedures received, in double-blind fashion, a single preanaesthetic dose of either 4?mg. lorazepam, 20?mg. diazepam, or placebo 1 hour preoperatively. Blood pressure, heart rate, and respiratory rate, as well as the apparent sedative state of the patient, were determined the evening before surgery and again in the operating room an hour after premedication.

After premedication, 18 lorazepam patients (37%), 7 diazepam patients (15%), and 3 placebo patients (6%) were considered well sedated. Results with lorazepam were significantly better than with either diazepam or placebo. Increased sedation after premedication was noted in 55% of lorazepam patients, 39% of diazepam patients, and 23 % of placebo patients.

Changes in blood pressure, heart rate, or respiratory rate with either active drug were not appreciably different from placebo.     

Differences among nine 1,4-benzodiazepines: an ethopharmacological evaluation in mice

The present study explored whether the profiles of action of benzodiazepines on intraspecies conflict behavior in mice are different. The occurrence of seven behavioral elements was observed in aggressive and timid singlyhoused male mice treated with drugs in paired interactions with untreated non-aggressive males. At low doses, some benzodiazepines (alprazolam, oxazepam and diazepam) inhibited defenses, escapes, or attacks, but did not reduce other activities (social sniffing, walking, rearing), and actually increased most of them. At comparable doses, other benzodiazepines (flunitrazepam, nitrazepam, clonazepam and chlordiazepoxide) stimulated only social sniffing, but reduced rearing or walking. Further benzodiazepines (triazolam and lorazepam) reduced defenses, escapes and attacks only at doses that suppressed most of the remaining activities as well. Thus, the nine benzodiazepines tested exhibited different profiles of action in the present study. Alprazolam, oxazepam and diazepam appeared least sedative, while triazolam and lorazepam were most sedative.     

Reinforcing properties of lorazepam in normal volunteers

These experiments were designed to test the positive reinforcing property of a benzodiazepine in normal volunteer subjects. A choice procedure was used to measure preference for lorazepam, a benzodiazepine with a relatively short plasma half-life, over placebo. In separate experiments, subjects were given a choice between three doses of lorazepam (0.5, 1.0 and 2.0 mg, p.o.) and placebo, and in a fourth experiment subjects were given a choice between lorazepam (1.0 mg) and a therapeutically equipotent dose of diazepam (5 mg). Subjective effects of the drugs were monitored using an experimental version of the Profile of Mood States and a shortened version of the Addiction Research Center Inventory. Subjects showed no preference for 0.5 mg lorazepam over placebo (49% drug choice) or for 1.0 mg lorazepam over diazepam (46% lorazepam choice). However, subjects preferred placebo to both 1.0 and 2.0 mg lorazepam (32% and 16% drug choice for 1.0 and 2.0 mg, respectively). Subjective effects were consistent with the drug's known sedative and anxiolytic properties. Relative to diazepam, lorazepam had a longer duration of effect than might be expected from its plasma half-life. Differences in the pharmacokinetic properties of the two drugs account for the results. The results showed that lorazepam is not an effective positive reinforcer in these subjects, suggesting that it also does not have high dependence potential in this population.     

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.     

Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory

The effects of diazepam and lorazepam on explicit memory and perceptual priming were studied 50, 130 and 300 min after drug administration. Sixty healthy volunteers were randomly assigned to one of five parallel groups (placebo, diazepam 0.2 or 0.3 mg/kg, lorazepam 0.026 or 0.038 mg/kg). The corresponding doses of benzodiazepines exerted a similar negative effect on explicit performance. Lorazepam markedly impaired priming performance, whereas the effect of diazepam was intermediate between that of placebo and that of lorazepam 0.038 mg/kg. The impairment was maximal at the theoretical peak plasma concentration. Contamination by explicit memory could account for the decrease in priming performance observed in the diazepam groups.     

Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users

The subjective, psychomotor and cognitive effects of oral doses of lorazepam (0, 1.5, 3 and 6 mg) and diazepam (0, 10, 20 and 40 mg) were studied under double-blind conditions in 14 volunteers with histories of 'recreational' benzodiazepine use/abuse. For each subject, drug was administered over 4 test days in a 2 (drug) by 4 (dose level) mixed design. Drug was the between-groups factor while dose was the within-subjects factor. Test days were separated by at least 1 week. The results showed that subjective ratings of drug 'liking' and the psychomotor and cognitive effects of lorazepam were generally similar to those of diazepam over the range of doses studied. Lorazepam, however, tended to produce effects of longer duration than diazepam. Since previous studies have shown that diazepam has a relatively high abuse liability among the benzodiazepines, the present findings suggest that lorazepam shares this property with diazepam is subjects with a history of 'recreational' drug use/abuse.     

Differential effects of diazepam and lorazepam on repetition priming in healthy volunteers

The effects of two benzodiazepines, diazepam (15 or 20 mg orally) and lorazepam (1.75 or 2.5 mg orally), and a placebo on explicit memory, lexical priming and perceptual priming were assessed using a freerecall, a word-completion and a picture-completion test. The picture-completion test included two different study conditions intended to manipulate the magnitude of the priming effect. Sixty healthy volunteers took part in this double-blind study. Free-recall performances were altered by both drugs. Lorazepam impaired word-completion and picture-completion performance, whereas diazepam only exhibited a deleterious effect on the more sensitive of the two measures of the picture-completion test. These results indicate that the two benzodiazepines have differential amnestic effects. It is suggested that these differential effects could be accounted for by a different cortical distribution of the two benzodiazepines.     

Rate of entrance of benzodiazepines into the brain determined by eye movement recording.

1 Peak saccadic velocity of horizontal eye movements, saccade duration at 30 degrees of amplitude and saccade reaction time were measured in six drug free male subjects. 2 In two separate experiments, intravenous doses of diazepam (5 mg), lorazepam (2 mg), chlordiazepoxide (25 mg) and placebo were given, and eye movement recordings were made before and at frequent intervals after drug administration. 3 All the benzodiazepines produced a significant impairment of peak saccadic velocity and saccade duration. Only lorazepam significantly affected saccade reaction time. 4 Time to achieve maximum effect was 10 min after diazepam, 29 min after lorazepam and 42 min after chlordiazepoxide.     

Relative abuse liability of different benzodiazepines in drug abusers

There is a convergence of data from various sources suggesting that there are meaningful differences among the benzodiazepines with respect to their attractiveness as drugs of abuse for drug abusers. Laboratory studies of subjective and reinforcing effects in drug abusers, interviews with drug abusers, clinical judgment of medical professionals, and epidemiological studies all indicate that diazepam, in particular, has a greater abuse liability than many of the other benzodiazepines. Some of the available data also suggest that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard. These differences in abuse liability among benzodiazepines are analogous to the widely recognized differences in abuse liability within the barbiturate class that have proved to be important in helping guide clinicians' drug prescribing practices.     

Antagonism by exifone,a new cognitive enhancing agent,of the amnesias induced by four benzodiazepines in mice

Exifone is a novel compound proposed for treating cognitive decline associated with age and shows corrective effects in animal models of memory dysfunction. The present experiments examined the antagonism by exifone of the amnesias induced in mice in a passive avoidance test by four benzodiazepines: bromazepam, diazepam, lorazepam and triazolam. Subsequent experiments investigated the specificity of exifone's antagonism of benzodiazepine-induced amnesia by examining its interaction with the effects of the benzodiazepines in the staircase test (anxiolytic/sedative activity) and the electroshock test (anticonvulsant activity). The results indicated that exifone clearly antagonised the amnesias induced by the four benzodiazepines, but was without intrinsic effects in the staircase or electroshock test and did not antagonise the effects of the benzodiazepines in these two tests. These results suggest that exifone might be useful for decreasing the amnesias induced by commonly used benzodiazepines without affecting their anxiolytic or anticonvulsant activity.Adlone^c: marketed by Laboratoires Pharmascience, F-92400 Courbevoie, France     

Lorazepam and diazepam impair true, but not false, recognition in healthy volunteers

RATIONALE: The deleterious effects of benzodiazepine on memory are well documented. However, their effects on false memories are unknown. OBJECTIVE: The aim of this study was to investigate the effects of lorazepam and diazepam on false memories and related states of awareness in healthy volunteers. METHODS: The Deese/Roediger-McDermott procedure was used in 36 healthy volunteers randomly assigned to one of three parallel groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg). Subjects studied lists of words semantically related to a non-presented theme word (critical lure). On a recognition memory task with both previously presented words and non presented critical lures, they were asked to give Remember, Know or Guess responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. RESULTS: The proportions of studied words correctly recognized and the proportions of Remember responses associated with true recognition were lower in the benzodiazepine groups than in the placebo group. In contrast, benzodiazepines did not significantly influence the proportions of critical lures falsely recognized or the proportions of Remember responses associated with false recognition. CONCLUSION: These results indicate that diazepam and lorazepam impair conscious recollection associated with true, but not false, memories.     

Sequelae after the intravenous injection of three benzodiazepines--diazepam, lorazepam, and flunitrazepam.

The occurrence of thrombosis and phlebitis after intravenous injection of 10 mg diazepam, 4 mg lorazepam, or 1-2 mg flunitrazepam was studied on the second or third and the seventh to 10th days. A significantly higher incidence occurred with all drugs on days 7 to 10 than on days 2 and 3. Painless thrombosis occurred much more often with diazepam than with the other two benzodiazepines. Its incidence was greater in small hand or arm veins than in large antecubital vessels. Lorazepam and flunitrazepam therefore have clear advantages over diazepam.     

Comparative amnesic and sedative effects of lorazepam and oxazepam in healthy volunteers

Oxazepam and its chlorinated derivative, lorazepam, have similar half-lives but differing potencies. This study compared the effects of these two benzodiazepines with a placebo on memory, mood and psychomotor function. Thirty six volunteers took part in a double-blind, independent groups design. Subjects completed a battery of tests before and 2.5 h after drug administration. Lorazepam 2 mg produced more profound subjective and motor sedation than oxazepam 30 mg, and this in turn produced a similar, global pattern of impairments across a wide range of tasks. However, lorazepam produced greater decrements than oxazepam on a task involving episodic memory even when sedative effects were partialled out. We suggest that this finding may reflect either differential task sensitivities or a contribution of priming to performance on the explicit memory task.     

The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry

The present study used a radiotelemetric method to compare the muscle relaxant, hypothermic and locomotor depressant actions of the imidazopyridine zolpidem, with those of the benzodiazepines lorazepam and diazepam. Rats, n=7 per group, were divided into 3 dose-dependent treatment groups (highest, middle, and lowest). Each rat within a treatment group received a single dose of diazepam, lorazepam, zolpidem and vehicle. All three drugs induced dose-dependent decreases in body temperature, locomotor activity and electromyographic (EMG) activity. Administration of zolpidem (5 and 10 mg/kg) resulted in maximal decrements in locomotor activity that were comparable to those elicited by both diazepam (10 and 20 mg/kg) and lorazepam (12.5 and 25 mg/kg). Zolpidem (10 mg/kg) decreased EMG activity levels to approximately 45% of vehicle treated controls; a value similar to that induced by diazepam (2.5 mg/kg). These data suggest that the imidazopyridine zolpidem has a similar profile of acute effects in comparison to the benzodiazepines diazepam and lorazepam. However, the relative magnitude of the effects differed, with zolpidem producing less hypothermia and muscle relaxation than the two benzodiazepines.     

Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory,psychomotor performance and mood

The effects on memory, psychomotor functions and mood of intramuscular scopolamine (0.3 mg, 0.6 mg) were compared with those of oral lorazepam (2 mg) and placebo. Thirty-six volunteers took part in a doubleblind, independent groups design. Subjects completed a battery of tests 1 and 3 h after drug administration. Both doses of scopolamine produced levels of sedation comparable to that produced by lorazepam. The time course of effects of scopolamine and lorazepam differed but the pattern of psychomotor impairments and amnestic effects produced was very similar. In terms of mood, lorazepam had an anxiolytic effect whereas scopolamine increased ratings of anxiety. Levels of sedation, indexed by either subjective ratings or motor retardation (tapping speed), were related more to psychomotor performance than to performance on memory tasks. The results suggest that benzodiazepines and scopolamine have similar amnestic and sedative effects and as such may not offer distinct models of memory dysfunction.     

Behavioral effects of ethyl loflazepate and its metabolites

The behavioral effects of ethyl loflazepate and its metabolites were investigated in mice and rats, and they were compared with those of diazepam, nitrazepam and lorazepam. Locomotor activity of rats in open-field situation was increased with a wide range of doses of ethyl loflazepate and with large doses of nitrazepam. The anticonflict effect of ethyl loflazepate was slightly more potent than that of diazepam and much more potent than that of lorazepam. In suppressing muricide of both olfactory bulbectomized and raphe lesioned rats, ethyl loflazepate was approximately as potent as diazepam and much less potent than nitrazepam and lorazepam. Ethyl loflazepate was more potent than diazepam, nitrazepam and lorazepam in preventing pentetrazol-induced convulsion. In potentiating thiopental anesthesia in mice and impairing rotarod performance in mice and rats, ethyl loflazepate was less potent than diazepam, nitrazepam and lorazepam. The pharmacological activities of CM6913 and CM7116, metabolites of ethyl loflazepate, were approximately as potent as that of ethyl loflazepate. The duration of action of ethyl loflazepate was longer than those of the metabolites. These results indicate that ethyl loflazepate possesses pharmacological properties characteristic to benzodiazepines, and it is approximately equal to diazepam in potency and has a longer duration of action than diazepam, nitrazepam and lorazepam.     

The pharmacological profile of chlordesmethyldiazepam and other benzodiazepines

The pharmacological profile of chlordesmethyldiazepam was studied in mice and compared with that of other benzodiazepines (diazepam, lorazepam, clonazepam, nitrazepam, oxazepam, flunitrazepam, medazepam and chlordiazepoxide). All the drugs were administered perorally and their anticonvulsive activity (antagonism towards pentetrazole-induced clonic convulsions), anxiolytic action (the four-plate test), myorelaxant activity (the rota-rod test), sedative effect (inhibition of the locomotor activity) and neurotoxic effect (abolition of the righting reflex) were estimated. Chlordesmethyldiazepam revealed an anticonvulsive action (ED50 = 0.11 mg/kg), anxiolytic activity (MED = 2 mg/kg), myorelaxant action (ED50 = 17.5 mg/kg), sedative effect (ED50 = 34 mg/kg) and neurotoxic action (NTD50 = 190 mg/kg). Considering the potency of action (ED50) in respective tests and the therapeutic indices (NTD50/ED50 ratio), chlordesmethyldiazepam in respect of its profile resembles most lorazepam and diazepam.     

Buspirone and lorazepam abuse liability in humans: behavioral effects, subjective effects and choice

This study compared behavioral and subjective effects of two anxiolytics, the benzodiazepine lorazepam and the azaspirodecanedione buspirone, in healthy male volunteers with histories of sedative drug abuse. Placebo, lorazepam (1, 2, 4, 8mg/70kg) and buspirone (15, 30, 60, 120mg/70kg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. Lorazepam, but not buspirone, decreased psychomotor/cognitive performance. Both drugs produced similar increases in ratings of drug strength, however the onset and offset times for lorazepam were later than for buspirone. Lorazepam increased ratings of liking in contrast to buspirone which produced negative mood-related subjective effects (e.g. increases in ratings of disliking, bad/unpleasant effects, and tension-anxiety). Lorazepam was categorized by subjects as producing effects similar to barbiturates or benzodiazepines in contrast to buspirone which was not. When subjects were given a choice between self-administering an intermediate dose of lorazepam (4mg/70kg) or buspirone (60mg/70kg), which produced similar ratings of drug strength, eight out of nine subjects chose lorazepam. This study provides the clearest human experimental evidence to date that the abuse liability of buspirone is lower than that of a prototypic benzodiazepine, even at supratherapeutic doses.     

Effects of lorazepam and diazepam on conscious and automatic memory processes

Recent studies exploring benzodiazepine memory effects have used the distinction between explicit and implicit tasks. There is now increasing evidence that implicit tasks can be “contaminated” by conscious uses of memory and that unconscious (automatic) use of memory can contaminate explicit tasks, leading to mistaken estimates of their respective influences on memory performance. The aim of the present double-blind, double-placebo study was to assess the memory effects of diazepam and lorazepam using a process-dissociation procedure in a stem-completion task, this procedure providing uncontaminated estimates of conscious and automatic memory processes. The memory task was administrated to 60 healthy volunteers randomly assigned to one of three parallel groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg). Lorazepam markedly reduced conscious as well as automatic influences of memory. Diazepam also reduced conscious uses of memory, albeit to a lesser extent than lorazepam, but did not decrease the influence of automatic memory. Secondary analyses showed that when the deleterious effect on conscious uses of memory was equated between a diazepam subgroup and the lorazepam group, only lorazepam impaired the automatic use of memory. This study strongly suggests a qualitative difference in the memory effects of the two benzodiazepines. It has some implications regarding the relationships between states of consciousness and memory processes.     

Differential effects of oxazepam and lorazepam on aggressive responding

Two doses of two very similar benzodiazepines (oxazepam 15 and 30 mg: lorazepam 1 and 2 mg) and placebo were compared 4 h post-administration on a competitive reaction time task designed to measure behavioural aggression. Forty-five subjects were assigned randomly to five independent drug groups. Subjective ratings of mood, anxiety and aggression were completed pre- and post-drug and post-task. Oxazepam and lorazepam had very similar subjective effects, but the higher dose of lorazepam increased aggressive responding on the task more than any other treatment. This may be related to the different ceiling efficacies of the two benzodiazepines.