MIDAZOLAM AND OXAZEPAM IN THE TREATMENT OF INSOMNIA IN HOSPITALIZED PATIENTS

Transcription

1 Br. J. clin. Pharmac. (1983), 16, 145S-149S MIDAZOLAM AND OXAZEPAM IN THE TREATMENT OF INSOMNIA IN HOSPITALIZED PATIENTS 'Clinique des Maladies Infectieuses, H6pital Houphouet Boigny, Marseilles, France 1 Fifty-nine hospitalized patients participated in a double-blind study: 19 received 15 mg midazolam, 2 received 5 mg oxazepam, and 2 placebo. The three groups were comparable with regard to age, sex, height, weight, and degree and type of insomnia. 2 The sleep-onset latency was shorter with midazolam than with placebo or oxazepam (Mann- Whitney test, a <.5). 3 With regard to total sleep duration and the number of nocturnal awakenings, there was no difference between the midazolam and oxazepam groups, whereas there was a difference between these two groups and placebo. 4 More of the midazolam group felt calm and refreshed on awakening. 5 Safety, assessed by clinical examination and laboratory tests, was excellent. 6 This study confirms the usefulness of midazolam in treating 'early' insomnia, i.e. difficulty in falling asleep. Introduction The aim of the present study was to compare the efficacy and safety of 15 mg midazolam, 5 mg oxazepam, and placebo in a double-blind procedure with parallel groups. in this dosage has been described as an effective, well-tolerated hypnotic (Lupolover & Buch, 1981; du Cailar et al., 1981). is well established as an anxiolytic but opinion is divided as to its suitability as a hypnotic. In the USA, it is not intended for use as a sleep-inducing agent, whereas in Sweden it is classified as an anxiolytic but used as a hypnotic. In Germany and in Switzerland, it is registered as a hypnotic and prescribed in a dose range of 15-3 mg. In these latter two countries, on rare occasions a dose of 5 mg may be used, while in France this dose is quite commonly used. Earlier studies (Helcl et al., 1981) report that sleepdisturbed patients will fall asleep more rapidly after receiving 15 mg midazolam than after 15 mg oxazepam. For this reason, we decided to compare 15 mg midazolam with 5 mg oxazepam in order to determine whether this slower onset of effect can be accelerated by dosage increase or whether this is an intrinsic property, typical for oxazepam. Methods Patients We treated 59 hospitalized with insomnia, both male and female, with a mean age of years, who spontaneously requested a hypnotic. We routinely excluded pregnant women, patients with serious somatic illnesses (renal or hepatic insufficiency, heart failure), with a known allergy to benzodiazepines, and patients being treated with, for example, psychotropic or sedative agents. Before inclusion in the study, patients were informed about the aims and possible risks of the study, according to the terms of the Declaration of Helsinki, and their consent obtained. Protocol The study was comparative, double-blind with double-dummy involving three parallel treatment groups: 15 mg midazolam (n = 19), 5 mg oxazepam (n = 2), and placebo (n = 2). Each patient was studied for 8 nights: on the first night, they all received placebo (single blind). On nights 2, 3, 4, 5, and 6, they received either 15 mg midazolam, 5 mg oxa- 145S

2 146S zepam or placebo. On nights 7 and 8, no hypnotic was administered. As it was not possible to provide the three compounds in dosage forms of identical appearance, we employed a double-placebo technique, in which the patient received 2 tablets each evening, of which at least one contained placebo. Patients who had a positive reaction to placebo on the first night were not admitted to the double-blind phase. The patients were randomly attributed to one of the three treatment groups. Every night (nights 1-8), the following parameters were noted: (a) By the night staff: time taken to fall asleep (sleeponset latency), total sleep duration, number of nocturnal awakenings, and sleep quality. (b) By the patient: occurrence of dreams, state on awakening, side-effects, and overall assessment. Safety was assessed clinically by asking the patients if they had experienced any side-effects and by laboratory analyses on days 1 and 7 or 8: red blood count, white blood count, differential white blood count, platelets, haemoglobin, total bilirubin, creatinine, BUN, blood sugar, alkaline phosphatase, SGOT, SGPT, and urinalysis (glucose, protein). In no case was it necessary to open the double-blind code before the end of the study. Results Amongst the 59 hospitalized suffering from insomnia within the context of different somatic conditions, 19 received midazolam, 2 oxazepam, and 2 placebo. The three groups of patients were comparable with regard to sex, age, height, weight (Table 1), and type of insomnia. It was not possible to complete the study in all patients. In six cases, treatment had to be stopped prematurely because of insufficient effect: in one patient receiving midazolam, in two receiving oxazepam, and in three receiving placebo. In two cases in both the placebo and the oxazepam groups, the treatment had to be discontinued for administrative reasons (early discharge, transfer to another department). Sleep-onset latency Table 2 summarizes the baseline values. All patients were experiencing difficulty in falling asleep. In the initial placebo phase, three-quarters of the patients required over 4 min to fall asleep, two-thirds in fact requiring more than an hour to fall asleep. Before the start of treatment, there was no significant inter-group difference with regard to this parameter (Table 2). Table 2 Sleep-onset latency under placebo (night 1) Latencv < 2 min 2-4 min 4-6 min > 6 min Groups The results of all five therapy nights were averaged for each patient to provide a mean score for the time taken to fall asleep. Sleep-onset latency was shorter with midazolam than with oxazepam or placebo (Mann-Whitney test, a <.5), there being no difference between oxazepam and placebo (Figure 1). Duration ofsleep During the selection phase, there was no difference amongst the three groups and the mean sleep duration was 5 h. During the treatment phase, both oxazepam and midazolam increased the mean sleep duration to 7 h (P <.5). There was no difference between the midazolam group and the oxazepam group in this respect (Figure 2). Number ofawakenings With regard to number of awakenings, the three groups did not differ markedly from one another during the selection phase: at least half the patients awoke more than twice in the night and one-third had one or two awakenings. During the treatment there Table 1 Stratification of groups according to age and sex. There were no significant age and sex differences between groups Number and age (years) offemales n x s.d. Min Max Number and age (years) of males n x s.d. Min Max

3 MIDAZOLAM AND OXAZEPAM IN INSOMNIA 147S Figure 1 Sleep-onset latency averaged over 5 treatment nights. were significantly fewer awakenings in the oxazepam and midazolam groups than in the placebo group (Kruskal-Wallis test, a <.5). There was no difference between the midazolam and oxazepam groups (Figure 3). Safety The following clinical side-effects were reported: headache, lethargy, nausea, and drowsiness (rare). These effects were distributed equally amongst the three groups. Laboratory tests revealed no changes not attributable to the condition for which the patient was originally hospitalized. Discussion Several authors have already demonstrated that sleep-onset latency after 15 mg midazolam is significantly shorter than that after 15 mg oxazepam. In our present study comparing 15 mg midazolam, 5 mg Figure 2 Total sleep duration averaged over 5 treatment nights.

4 148S 1 L More than twice 8 F - 8- ~~~~~~~~~~Once 2 LS i g 1g1 twice ENone Figure 3 Number of nocturnal awakenings: first treatment night compared with selection night. Narrow column = selection night, broad column = first treatment night. oxazepam, and placebo, sleep latency in the midazolam group was confirmed as being shorter than that in the other two groups. Despite the higher oxazepam dosage, sleep latency in this group did not improve compared with placebo. The slow onset of oxazepam effect is therefore not related to the dose and is more ptobably attributable to specific physicochemical properties of the molecule. In comparison with other benzodiazepines, oxazepam possesses relatively limited lipophilicity. and oxazepam were shown in the present study to be equally effective in increasing sleep duration towards normal values. Since midazolam in a dose of 15 mg has been shown to possess no pharmacological effect in man at around 6 h after administration (Ziegler et al., 1983; Gudgeon & Hindmarch, 1983), the increase in sleep duration must be due to an indirect mechanism. In addition to fast sleep onset, midazolam results in rapid attainment of deep sleep stages (Krieger et al., 1983; Scollo-Lavizzari, 1983) and, in low doses, has scarcely any effect on sleep architecture. These conditions would appear to favour the smooth transition to spontaneous sleep. In insomnia that is fundamentally due to nocturnal awakenings spread through the night, oxazepam in a dose as high as 5 mg may be useful when impaired performance next morning is acceptable, as in hospital conditions. Thus, it can be concluded that, while 15 mg midazolam is as effective as 5 mg oxazepam with regard to lengthening sleep duration and reducing the number of nocturnal awakenings, it is superior in reducing sleep latency. would appear to be equally as well suited for hospitalized patients as for out-patient treatment of sleep disturbances in a working population. in a dose of 5 mg would be more appropriate for the treatment of insomnia in hospitalized patients, particularly when rapid sleep onset is not overly important, as there is strong evidence that, in such a dose, residual effects on performance will be present (Nicholson & Stone, 1978a, 1978b). References DU CAILAR, J., CADI, N., JULLIEN, Y. & GRIFFE,. (1981). Etude en double aveugle du midazolam sur le sommeil pre-operatoire. Arzneimittel-Forsch., 31, GUDGEON, A.C. & HINDMARCH, I. (1983). : effects on psychomotor performance and subjective aspects of sleep and sedation in normal volunteers. Br. J. clin. Pharmac., 16, 121S-126S. HELCL. 1.. LUPOLOVER, R., BUCH, J.-P. & AMREIN. R. (1981). Evaluation of the efficacy and tolerance of orally administered midazolam as hypnotic agent compared with oxazepam in the treatment of insomnia of mild to moderate severity. Arzneimittel-Forsch., 31, KRIEGER, J., MANGIN, P. & KURTZ, D. (1983). Effects of midazolam on sleep in normal. Br. J. clin. Pharmac., 16, 79S-8S.

5 MIDAZOLAM AND OXAZEPAM IN INSOMNIA 149S LUPOLOVER, R. & BUCH, J.-P. (1981). Evaluation of efficacy and safety of midazolam administered orally in sleep disorders. Arzneimittel-Forsch., 31, NICHOLSON, A.N. & STONE, B.M. (1978a). Hypnotic activity of 3-hydroxy, N-desmethyldiazepam (oxazepam). Br. J. clin. Pharmac., 5, NICHOLSON, A.N. & STONE, B.M. (1978b). Effectiveness of diazepam and its metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy, N-desmethyldiazepam (oxazepam) for sleep during the day. Chronobiol., 5, 191. SCOLLO-LAVIZZARI, G. (1983). Hypnotic efficacy and clinical safety of midazolam in shift-workers. Br. J. clin. Pharmac., 16, 73S-78S. ZIEGLER, W.H., SCHALCH, E., LEISHMAN, B. & ECKERT, M. (1983). Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites. Br. J. clin. Pharmac., 16, 63S-69S.