Sleep
lO(Suppl. 1):48-53, Raven Press, Ltd., New York
© 1987 Association of Professional Sleep Societies
Residual Effects of Zopiclone (Imovane)
A. Broadhurst and *R. C. Cushnaghan
West Suffolk Hospital, Bury Saint Edmunds, and *May and Baker Ltd., Dagenham,
Essex, U.K.
SUMMARY: A double-blind, randomized, cross-over study has been conducted with zopiclone (lmovane), a new cyclopyrrolone hypnotic in ten
healthy volunteers. Hypnotic efficacy has previously been demonstrated at a
dose of 7.5 mg. The present study was designed to determine the overnight
residual effects of different doses of the drug ranging from 2.5 to 10 mg. Measurement of complex reaction time was used as an objective test of impairment
of psychomotor function. To supplement this, the volunteers were asked to
report, by means of visual analogue scales, any perceived changes in their
performance in the complex reaction time test, in their mood, and in the onset
and quality of sleep. Complex reaction time testing revealed no significant
impairment except at 12 h after the 10 mg dose. Subjective assessments of
onset of sleep showed a dose-dependent shortening of sleep latency, confirming the hypnotic action of the drug. Volunteers were aware of a decline in
psychomotor performance, of some sleepiness on awakening, and decreased
alertness after previous night doses of 7.5 and 10 mg. It is concluded that a
dose of 7.5 mg is optimal, producing significant hypnotic effect with minimal
residual impairment. Key Words: Zopiclone-Performance-Dose response
-Reaction time.
Zopiclone (Imovane) is a novel compound, a member of the cyclopyrrolone group
that possesses tranquillizing and sedative properties (1,2). When the present study was
conducted, zopiclone had been shown to possess hypnotic activity. Sleep studies with
electroencephalographic (EEG) monitoring had revealed the duration of sleep to be in
the region of 7 h following 7.5 mg (3). At this dose, there was improvement in sleep
over the first 6 h, and although the onset of REM sleep was delayed and reduced over
this period, the proportion of REM over the whole night was unchanged (4).
In evaluating the properties of a hypnotic, consideration must be given not only to its
sleep-production properties but also to its duration of action. In particular, it should
not produce any significant hangover effects the following morning. The profile for
zopiclone with an elimination half-life of 4-5 h and no active metabolites suggested
that it might meet such a requirement (5).
Assessment of residual effects after hypnotic usage may be done by subjective or
objective means. In this study, complex reaction time was selected as an objective
Address correspondence and reprint requests to Dr. A. D. Broadhurst at West Suffolk General Hospital,
Bury St. Edmunds, Suffolk, U.K.
48
RESIDUAL EFFECTS OF ZOP/CLONE
f)
49
measure of residual effects. Choice reaction time is regarded as a sensitive laboratory
analogue of real-life performance in situations such as car driving (6). Complex reaction time, as used in this study is a refinement of choice reaction time; it takes into
account other significant factors, such as vigilance, discrimination, and accuracy (7).
The apparatus is simple to operate; a major practice effect is considered unlikely to
introduce serious experimental error since most subjects acceptably achieve uniform
reaction times after a minimum offive runs (8).
The primary objective of the study was to determine the dose range that was free
from residual effects 12 h after an evening drug intake of 2.5-10 mg of zopiclone by
comparison to a placebo. A secondary objective was to obtain sUbjective assessments
of residual effects and modification of mood by such doses and also to confirm previous findings on acceptability of zopiclone as a hypnotic.
METHODS
Ten healthy volunteers (seven men and three women), aged 20-36 years (mean age
28.2 ± 4.9 years) were included in this study. Pregnant women and women of childbearing potential, volunteers with a previous history of severe somatic or psychiatric
disease, and subjects requiring concomitant medication were excluded from the study.
The study was performed in accordance with the Declaration of Helsinki and verbal
informed consent was obtained from each of the volunteers.
Previously screened subjects were allocated to treatment in a balanced design in
which each subject received single, nightly, oral doses of zopiclone, 2.5, 5, 7.5, and 10
mg, and placebo as tablets under double-blind conditions. Each of the five administrations was followed by a wash-out of at least 1 week's duration.
During each test period, for 24 h preceding administration of the drug, subjects were
instructed to refrain from alcohol, to avoid excessive exercise, and to avoid naps. They
were instructed to take the medication at the same time each night (~2300 h) and to
retire to bed immediately. The morning following ingestion, they were requested to rise
at the normal time, have their usual breakfast, and report to the laboratory for testing.
The following assessments were performed 12 h after ingestion of each of the trial
preparations (placebo and 2.5, 5, 7.5, and 10 mg of zopiclone).
Objective assessment of residual effects by means of the complex reaction time test.
Prior to the first formal tests of psychomotor function, each subject was allowed to
familiarize himself with the operation of the apparatus in order to minimize any
learning effect.
Subjective self-assessment by means of 100 mm visual analogue scales. Assessments included (a) opinion on performance of complex reaction time test (from useless
to perfect); (b) feeling on awakening (from very sleepy to very alert); (c) mood as 16
components grouped into alertness, contentedness, or calmness (9); (d) sleep as onset
(from very abrupt to very slow) and quality (from very bad to very good).
Each measure was analyzed by the mixed model analysis of variance for repeated
measurements (10,1 I) and further comparisons were made using a t test. For the subjective assessments, standardized differences (t values) were used instead of actual
measured differences in cm. This allowed for comparison of results between all subjective assessments.
Sleep, Vol. 10, Suppl. 1,1987
A. BROADHURST AND R. C. CUSHNAGHAN
50
TABLE 1. Mean values for complex reaction time measured in milliseconds and suhjective
assessments measured in em on visual analogue scales
Zopiclone (mg)
Assessment
Mean reaction time
Self-assessment of reaction time
Feeling on awakening
Onset of sleep
Quality of sleep
Mood ratings
Factor I-Alertness
1.1 Alertness
1.2 Attentiveness
1.3 Physical feeling
1.4 Clarity of mind
1.5 Coordination
1.6 Mental ability
1. 7 Strength
1.8 Interest
1.9 Competence
Factor II-Contentedness
II.I Happiness
11.2 Amicability
II.3 Tranquility
II.4 Contentment
II.5 Personality
Factor III-Calmness
Ill.! Calmness
1I1.2 State of relaxation
Mean
placebo
437.4
7.4
7.9
(i.3
7.7
1.4
1.2
8.6
9.0
1.7
8.8
2.5
1.4
8.5
2.5
5
7.5
10
p
424.4
7.6
7.5
5.4
8.3
429.7
6.7
6.4
4.4
8.4
456.1
5.5
4.4
3.9
7.4
473.0
4.8
2.7
3.6
7.9
<0.01
<0.01
<0.01
<0.01
>0.01
1.7
2.2
2.1
7.3
8.0
2.5
7.6
2.9
1.6
7.3
4.1
4.5
5.4
5.4
4.1
5.1
4.4
2.8
5.5
4.5
4.7
5.2
5.0
4.4
5.1
5.1
3.5
5.1
<0.01
<0.01
<0.05
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
3.2
6.7
7.5
3.3
5.8
3.4
6.7
5.9
5.1
5.7
>0.05
>0.05
>0.05
<0.01
>0.05
2.1
7.9
2.3
7.2
>0.05
<0.05
1.2
8.7
8.6
1.5
8.6
2.8
1.4
8.7
2.4
7.6
7.5
2.6
7.0
1.4
8.6
8.7
7.1
2.0
8.0
7.4
2.6
7.0
1.7
8.1
1.6
8.5
1.8
8.5
1.5
RESULTS
There was a significant variation in the mean reaction time and the majority of subjective assessments with different doses of zopiclone (Table l). This is illustrated
graphically for four of the measures in Figure I. Compared with placebo, only a dose of
10 mg gave a significant increase in mean response time to the objective test, complex
reaction time. The subjective awareness of being less good on the complex reaction
time test and feeling more sleepy on awakening were both significant at dose levels 7.5
and 10 mg when compared with placebo.
Results for the mood assessment scales grouped under "contentedness" and "calmness" showed no significant differences between any of the dose levels and placebo
except for the scales Contentment and Relaxation, which were both "less marked"
after 10 mg. For all nine scales grouped under "alertness," there was a significant
dose-dependent effect (Table 1). Compared with placebo, there was a decrease in alertness from a dose level of 7.5 mg onwards, the mean differences against placebo were
significant at 1% level for all but one scale. The onset of sleep was rated more abrupt
with rising dose level. The difference against placebo reached 1% significance from
dose level of 5 mg onwards (Fig. 1). There was no difference in the quality of sleep
between any dose level and placebo (Table 1).
Sleep, Vol. 10, Suppl. I, 1987
51
RESIDUAL EFFECTS OF ZOP/CLONE
MEAN REACTION TIME
SELF·ASSESSMENT OF REACTION TIME TEST
I (Standard units)
I \Standard units)
5
5
Dose (mg)
Dose (mg)
10.0
-1
-2
-3
Mean
difference
significant
at
-5
)1
t
= 5%
= 2.0
t
=
Q
-6
Less perfect
1%
27
-7
FEELING ON AWAKENING
ONSET OF SLEEP
(I (Standard units)
t (Standard Units)
5
5
More abrupt
Dose (mg)
5.0
7.5
Dose (mg)
10.0
2.5
50
7.5
10.0
-1
-2
-3
-4
-5
-6
-7
-3
I
1
Mean
difference
significant
at
-4
5%
t = 2.0
-5
Q=
a= 1%
t =
Mean
difference
significant
at
1
Q=
2.7
-6
5%
t = 2.0
Q=
t =
1%
2.7
Less alert
-7
FIG. 1. Psychometric assessments 12 h after ingestion of medications; t values for each dose level of zopiclone are presented.
Sleep, Vol. 10, Suppl. I, 1987
52
A. BROADHURST AND R. C. CUSHNAGHAN
DISCUSSION
Objective assessment of complex reaction time shows significant impairment only
after the 10 mg dose when compared with placebo. The subjective impressions of residual effects (opinion on performance in the complex reaction time test and feeling on
awakening), the measures of hypnotic efficacy, and assessment of mood should be
considered in the light of the fact that the subjects were healthy volunteers.
Considering first the measures of sleep, onset duration is dose related showing significant shortening following 5 mg and higher doses of zopiclone when compared with
placebo, which supports previous findings of the hypnotic effect of the drug. The absence of improvement in sleep quality is what could be expected in volunteers of this
age group, who usually sleep well (12).
The subjective assessment of residual effects-impression of complex reaction time
performance, sleepiness on awakening, and each of the nine alertness scales-showed
impairment following 7.5 and 10 mg doses. Patients suffering from insomnia could
present with a lower baseline for residual effects due to lack of sleep (13), and improvement, due to improved quality of sleep, could be expected. Thus, significant residual
effects might be seen only at a higher dose in insomniac patients. The therapeutic dose
in such patients should lie somewhere between 5 and 10 mg. In the volunteers who had
none of the mood disturbances commonly associated with insomnia, absence of change
in the measures for calmness and contentedness was to be expected.
The findings in this study are in agreement with a similar study with EEG recordings
(taken at 10 and 13 h after drug intake) and assessment of residual effects by means of
digit symbol substitution test and symbol copying, reaction time, tapping rate, and
mood rating scale (14). Subsequent double-blind, placebo-controlled, clinical studies of
at least one week's duration in over 500 patients support the efficacy of a 7.5 mg dose;
at this dose of zopiclone, morning drowsiness was less than found with 15 mg flurazepam in a geriatric population and less than found with 5 mg nitrazepam in a nongeriatric population.
Considering the primary objective of the trial, the optimum effective dose of zopiclone producing minimal residual effects should be 7.5 mg in insomniac patients.
Taking into account the subjective assessments, a dose of 5 mg might be indicated in
healthy subjects using a hypnotic sporadically.
RESUME
La zopiclone (Imovane), nouvelle cyclopyrrolone hypnotique, a fait I'objet d'une etude
croisee randomisee en double aveugle chez 10 volontaires sains. L'efficacite hypnotique du produit a la dose de 7.5 mg ayant ete etablie, cette etude avait pour but d'evaluer les effets residuels
Ie lendemain de prises vesperales allant de 2.5 a 10 mg. La mesure du temps de reaction complexe a ete prise comme indice objectif d 'une alteration eventuelle des fonctions psychomotrices.
De plus, on a demande aux volontaires de noter, a l'aide d'echelles analogiques visuelles, toutes
les modifications qu'ils percevaient au test du temps de reaction complexe, dans leur humeur et
dans la latence et 1a qualite de leur sommeil. Le temps de reaction complexe n'a montre une
modification significative que 12 heures apres la dose de 10 mg. L'evaluation subjective de l'endormissement a revele une diminution significative de la latence de sommeil confirm ant ainsi
l'action hypnotique du produit. Les sujets ont ressenti une diminution de leurs performances
psychomotrices, une certaine somnolence au reveil et une diminution de leur vigilance Ie lendemain de prises de 7.5 mg et de 10 mg. En conclusion, la dose de 7.5 mg est optimale; eUe produit
un effet hypnotique important suivi d'effets residuels minimes.
Sleep, Vol. 10, Suppl. 1, 1987
RESIDUAL EFFECTS OF ZOPICLONE
53
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Sleep. Vol. 10, Suppl. 1,1987