Zopiclone Versus Nitrazepam: A Double-Blind Comparative Study of Efficacy and Tolerance in Elderly Patients with Chronic Insomnia

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1 Sleep lo(suppl. 1):73-78, Raven Press, Ltd., New York 1987 Association of Professional Sleep Societies Zopiclone Versus Nitrazepam: A Double-Blind Comparative Study of Efficacy and Tolerance in Elderly Patients with Chronic Insomnia H. D. Klimm, *J. F. Dreyfus, and *M. Delmotte Lehrbeauffragter fur Allgemeinmedizin an der Universitiit Heidelberg, Kuppenheim, F.R.G. and RluJne-Poulenc-Sante, Courbevoie, France Summary: A randomized, double-blind, comparative trial of zopiclone versus nitrazepam was conducted in 74 geriatric chronic insomniac patients. Following a 7-day wash-out period, two parallel groups successively received a placebo for 7 days, then either 7.5 mg zopiclone or 5 mg nitrazepam for another 7-day period. Efficacy on sleep was assessed by a sleep analogue scale and the Spiegel Sleep Questionnaire, residual effects by psychometric tests and tolerance by a standardized question, as well as by clinical and laboratory tests. Zopiclone and nitrazepam were more active than placebo on all tests of efficacy. In contrast with nitrazepam, zopiclone was devoid of ettect on neurological function. In addition, the condition on awakening was better with zopiclone. Key Words: Zopiclone-Nitrazepam-Chronic insomnia-elderly patients. Zopiclone is a new hypnotic with an original chemical structure not related to that of the benzodiazepines. Numerous studies have shown that it is highly effective in adult insomniac patients and has minimal residual effects (1). Over 30% of patients taking hypnotics are elderly and, in this population, nitrazepam is very frequently prescribed. Since elderly patients represent a large proportion of the potential users of any new hypnotic, a comparison between zopiclone and nitrazepam should provide useful information on the effects in this age group. The aim of this study was to compare the efficacy and tolerance of the two compounds in elderly patients with chronic insomnia. METHODS Patients A total of 74 geriatric patients (>65 years of age; mean age 73.2 ± 1.54 years), 15 men and 59 women who were residing in a community for social reasons and were Address correspondence and reprint requests to Dr. H. D. Klimm at Lehrbeauffragter fur Allgemeinmedizin an der UniversiHit Heidelberg, Ringstrasse 20, D-7554 Kuppenheim, F.R.G. 73

2 74 H. D. KLIMM ET AL. suffering from chronic insomnia, agreed to take part in this double-blind, comparative, randomized trial On entry, all patients were free from severe organic and psychiatric disorders. However, 71 had concomitant diseases; the most frequent conditions were arthritis, circulatory disorders, hypertension, and cardiac insufficiency. All patients continued to receive their regular medication throughout the study provided that it was initiated > I week before the first consultation of the study and that the regimen continued unchanged throughout the trial. Patients presenting contraindications to benzodiazepines or painful conditions, those with a history of drug allergy or chronic alcoholism, those receiving drugs liable to affect metabolism, those refusing to give their consent, those who might have been unable to complete the trial, those already involved in another trial, and those considered unlikely to cooperate were excluded. From the beginning of the wash-out period and during the whole study, no psychotropic or centrally active drugs were administered. For the purpose of this trial, chronic insomnia was defined as the presence of two of the following criteria: hypnotics taken five times a week for the last 3 months, sleep onset latency> I h, total duration of sleep <6 h, and waking more than three times during the night. The patients' mental capacity, as measured by Intellectual Quotient (2) and memory tests (Syndrom Kurztest) (3), was to be within the normal range for their age. Two patients were lost to follow-up (one in each group). Two patients stopped taking capsules before the end of the study, one in the nitrazepam group due to side-effects (confusion) and one in the zopiclone group because he no longer experienced insomnia; these two patients were included in the statistical analysis. There were 36 patients in each group. Treatment Following a 7-day, wash-out period for subjects taking psychotropic drugs, all patients received placebo for 7 nights, then either 7.5 mg zopiclone (group Z) or 5 mg nitrazepam (group N) in identical capsules for 7 additional nights. They were randomly allocated to the treatment groups according to a parallel group design and were asked to take one capsule and one capsule only as close to bedtime as possible. Concomitant treatments were administered in 34 cases in group Z and 35 in group N; this included antihypertensives, non-steroidal anti-inflammatory drugs, hypoglycemic agents, uricosuric agents, anti-anginal agents, and hypolipidaemic agents. Assessments Every day during the placebo and active drug periods (14 days), patients were asked to fill a diary. This diary comprised three analogue scales [covering sleep onset (very fast-very slow), quality of sleep (very bad-very good), and feeling upon awakening (very sleepy-very alert)] and the Spiegel Sleep Questionnaire [comprising 7 items (time taken to fall asleep, quality of sleep, duration of sleep, awakenings during the night, dreams, condition in the morning, and general evaluation) scored from I to 5]. A standardized question concerning tolerance was also included. At the initial visit and after weeks 1 and 2 of treatment (week 1, placebo; week 2, randomized active treatment), the physician and the psychologist performed a brief systematic neurological examination, scored the Syndrom Kurztest (3), obtained the Sleep, Vol. 10. Suppl. J, 1987

3 ZaP/CLONE VERSUS NITRAZEPAM IN ELDERLY PATIENTS 75 standing systolic and diastolic blood pressures, and recorded events elicited in response to a standard question: "Did you have any problems taking the capsule?". A battery of laboratory tests were performed before and after the study. Only patients with no abnormal values or abnormal values not unusual in the opinion of the investigator for elderly patients with not presently severe concomitant diseases, at the initial visit were included. The Syndrom Kurztest was used to determine the effects of the hypnotics on shortterm memory and concentration. This test consists of nine subtests. Subjects are shown a set of 12 objects that they are asked to name as quickly as possible (subtest I). The pictures are then taken away and the subjects immediately asked to recall as many objects as they can (subtest II-immediate memory). For subtest III, they are asked to read a series of 10 numbers. Subtest IV involves arranging the same numbers in ascending order. For subtest V, one of the numbers is obscured and the subjects are asked to find which it is by comparison with the complete duplicate set. In subtest VI, subjects are asked to count how many times a given symbol appears in a total of 126 units consisting of three different symbols. Subtest VII is an interference test; subjects are shown a list of As and Bs and are asked to read the list aloud substituting A for B and B for A. In subtest VIII, subjects are asked to recall as many of the objects shown in subtest I as possible (recall), and in subtest IX, they are asked to find the original 12 objects from a set of 48 shown (recognition). RESULTS No difference was found between treatment groups at the end of the baseline placebo period with the exception of one item in the neurological examination (Romberg'S test standing with heels together and eyes closed). On day 7, 24 patients in the group N failed the Romberg's test, whereas 16 patients in the group Z did not succeed (p < 0.05). Therefore, the two groups may be considered as suitably similar. Analogue Scales When the scores obtained on the last day of placebo treatment were compared with those obtained on the first day under active treatment, it was found that both products led to significantly improved quality of sleep (zopiclone, p < 0.006; nitrazepam, p < 0.002) and that zopiclone decreased sleep onset latency (p < 0.04; Table 1). When the scores obtained on the first day and on the last day of active treatment were compared, no significant difference was found. The comparison between the two drug conditions showed only two significant differences: patients receiving zopiclone TABLE 1. Analogue scales: Difference between first day of active treatment and last day of placebo (mm) Zopiclone Nitrazepam Sleep onset latency (Very fast, 0; very slow, 100) Quality of sleep (Very bad, 0; very good, 100) Feeling on awakening (Very sleepy, 0; very alert, 100) a p < b P < C P < ± 48.3 a 24 ± 4S.6 b -S.7 ± 48.S -IS.6 ± 49.S 23.1 ± 37.8 c 6.8 ± 49.4 Sleep, Vol. 10, Suppl. 1, 1987

4 76 H. D. KLIMM ET AL. felt more alert in the morning than those receiving nitrazepam on days 9 (p < 0.02) and 11 (p < 0.01). Spiegel Sleep Questionnaire (rated by patients) Upon introduction of active treatment, sleep onset latency, quality of sleep, duration of sleep, awakening at night, condition in the morning, and general evaluation improved significantly in both groups as compared with their placebo baseline values. The frequency of dreaming decreased significantly with both drugs (Table 2). The improvement of sleep parameters was maintained throughout the trial as there were no significant differences between scores obtained on the first and on the last day of active treatment. Only one significant difference was found between the two treatment groups: Nitrazepam produced a greater reduction in sleep onset latency on day 12 (p < 0.001). Neurological examination Performance in Romberg's test deteriorated significantly from baseline in group N (six patients given nitrazepam compared with no patients receiving zopiclone deteriorated). Syndrom Kurztest Compared to the placebo baseline, an improvement in several results were noted: reading (p < 0.02), interference (p < 0.1), recalling (p < 0.01), and recognition (p < 0.04) tests improved significantly under zopiclone and immediate memory (p < 0.03) and recalling (p < 0.005) under nitrazepam. No significant difference was found between the treatment groups. Blood pressure Comparison between compound, and between active drug and placebo baseline showed no statistically significant differences. Laboratory tests No significant differences were noted between the two groups in the pre- or posttreatment laboratory tests. Intragroup significant differences between pre- and post-treatment were found. In the zopiclone group, the red blood cell (p < ) and neutrophil counts (p < 0.008) decreased and )'-GT (p < 0.002), urea (p < 0.03), and cholesterol levels (p < 0.02) increased as did the lymphocyte count (p < 0.02). In the nitrazepam group, the red blood cell (p < ), basophil (p < 0.02), and thrombocyte counts (p < 0.01), as well TABLE 2. Spiegel Sleep Questionnaire: Comparison between the last day of placebo and the first day 0.1' active treatment (p values) Sleep onset latency Quality of sleep Duration of sleep Awakenings at night Dreams Condition in the morning General evaluation Zopiclone Nitrazepam Sleep, Vol. /0, Suppl. 1, 1987

5 ZOPICLONE VERSUS NIT~AZEPAM IN ELDERLY PATIENTS 77 as the hemoglobin level (p < ) decreased, while,),-gt (p < 0.001) and serum glutamic-pyruvic transaminase (p < 0.01) increased. Side-effects From the different comparisons performed there was only one significant difference: The incidence of complaints in answer to the standardized question on tolerance (patient diary) was increased in the nitrazepam group (p < ) as compared with placebo. Both drugs were well tolerated throughout the study although one patient in the group N was withdrawn because of severe confusion (Table 3). DISCUSSION In this study, zopiclone and nitrazepam were equally effective in 74 elderly patients with chronic insomnia: Both groups received better scores than placebo on the analogue scales and sleep questionnaire. Nitrazepam led to a deterioration in the Romberg's test in six patients, whereas no impairment was noted in the zopiclone group. Nitrazepam, but not zopiclone, also led to an increase of complaints in daytime. In the elderly, the pharmacokinetics of the benzodiazepines differ from the pharmacokinetics in adults. The elimination half-life values are generally higher and this, in practice, may lead to accumulation and increase of both pharmacological and toxic effects. It has been shown that the bioavailability of zopiclone is greater in elderly subjects but that repcatcd dosing should not lead to accumulation (4). Furthermore, it was considered that the increase in bioavailability is not sufficiently large to affect daytime functioning. This conclusion is supported by the results of this study which show that neurological function was maintained despite the administration of zopiclone. Improvement of the Syndrom Kurztest may be attributable to the disappearance of insomnia and its consequences on performance, to practice, to the patient's evident desire to improve their performance for their own sake and to please the investigator. However, these factors do not account for the differences between the two treatment groups. Memory and concentration continued to improve with zopiclone while with nitrazepam, only memory did so. It probably implies that condition in the morning was better with zopiclone, which was indeed the case during the initial days of treatment. Tolerance was good throughout the study, however one patient in the nitrazepam group was withdrawn because of severe confusion. TABLE 3. Side-effects reported during the study Dry mouth Bitter taste 2 Dizziness Confusion Fatigue Gastralgia 3 Sleep disturbances 7 Placebo Zopiclone Nitrazepam Sleep, Vol, 10, Suppl. 1,1987

6 78 H. D. KLIMMET AL. RESUME Une etude randomisee en double aveugle destinee it comparer la zopiclone 7.5 mg au nitrazepam 5 mg a ete entreprise sur 74 patients ages insomniaques chroniques. Apn!s une periode de wash-out de 7 jours, deux groupes paralleles de patients ont re'!u un placebo pendant 7 jours, puis soit la zopiclone soit Ie nitrazepam pendant une nouvelle periode de 7 jours. L'efficacite des produits sur Ie sommeil a Me evaluee au moyen d'une echelle analogique et du questionnaire de Spiegel, les effets residuels au moyen de tests psychometriques et la tolerance par une question standard posee aux patients ainsi que par des examens cliniques et biologiques. La zopiclone et Ie nitrazepam se sont reveles plus actifs que Ie placebo dans tous les tests d'efficacite. Contrairement au nitrazepam, la zopiclone s' est montree depourvue d' effets residuels sur les fonctions neurologiques. De plus, la qualite du reveil a Me meilleure avec la zopiclone. REFERENCES I. Nicholson AN, Schlosberg A, Dreyfus JF, eds. Zopic/one: A Third generation of Hypnotics. Basel: Karger, Lehrl S, Gallwitz A, Blaha L. Kurztest filr Allgemeine Intelligenz, KAI. Vaterstetten, Erzigkeit H. Syndrom Kurztest, Formen A-E, Vaterstetten, Gaillot J, Le Roux Y, Houghton GW, Dreyfus JE Critical factors for pharmacokinetics of zopic\one in the elderly and in liver and renal insufficiency. Present issue. Sleep, Vol. 10, Suppl. I, 1987

Chronic Administration of Zopiclone and Nitrazepam in the Treatment of Insomnia

Sleep lo(suppl. 1):63-72, Raven Press, Ltd., New York 1987 Association of Professional Sleep Societies Chronic Administration of Zopiclone and Nitrazepam in the Treatment of nsomnia T. Tamminen and *P.