Current Drug Safety, 2011, 6, 209-218 209 Zopiclone as Positive Control in Studies Examining the Residual Effects of Hypnotic Drugs on Driving Ability

Joris C. Verster*,1, D. Warren Spence2, Azmeh Shahid3, Seithikurippu R. Pandi-Perumal4 and Thomas Roth5

1Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands 2323 Brock Avenue, Toronto, Ontario M6K-2M6, Canada 3Department of psychiatry, University of Toronto, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada, Youthdale Treatment Center, 227 Victoria Street, Toronto, Canada 4Somnogen Canada Inc, College Street, Toronto, ON M6H 1C5, Canada 5Sleep Disorders and Research Center, Henry Ford Health System, Detroit, Michigan, USA

Abstract: Zopiclone (7.5 mg) is frequently used as a positive control in studies that examine the residual effects of hypnotic drugs on driving ability and related skills. This review summarizes studies examining the effects of zopiclone, and discusses its usefulness as a comparator drug for investigations of residual effects of novel sleep medication. A literature review (Pubmed and Embase) was conducted searching for studies that tested zopiclone on driving. Cross- references were checked for additional papers. Eight studies utilizing the standardized on-the-road driving test consistently showed that in the morning following bedtime administration zopiclone (7.5 mg) significantly impaired driving performance. A total of 191 healthy volunteers were tested after placebo and zopiclone (7.5 mg). Meta analyses showed no significant differences in driving performance after zopiclone (7.5 mg) between adult and elderly healthy volunteers. The combined effect size (ES) and 95% confidence interval (95%CI) for healthy volunteers was 0.782 (0.620, 0.944). Relative to placebo, an average increment of 3.0 cm in Standard Deviation of Lateral Position (SDLP) was observed when treated with zopiclone (7.5 mg). This deviation was higher than the increment in SDLP reported for drivers with a blood alcohol concentration of 0.05% (+2.4 cm). Results from driving simulators and psychometric tests are consistent with the on-road driving test results. In conclusion, zopiclone (7.5 mg) is a reliable positive control, that consistently shows significant and meaningful impairment on the on-the-road driving test. Keywords: Zopiclone, driving, SDLP, comparator, active control, clinical trials.

INTRODUCTION concentration [3]. Part of the task of evaluating a hypnotic agent however is to determine its effects on various A challenge faced by clinicians when treating patients cognitive skills, which affect not only driving but also job with insomnia is how to evaluate the comparative risks and performance, social relations, and general problem solving. benefits of hypnotic agents, many of which have residual In this regard a Canadian armed forces study has shown that effects which can impair next-day alertness and differences exist among several hypnotic agents (zaleplon, performance. Of particular concern are daily activities with zopiclone, and temazepam ), with all but melatonin showing significant consequences if impaired, such as driving a car. differential adverse effects on serial reaction time, logical Various tests of driving performance (on-the-road driving, reasoning, serial subtraction, and multitask performance [4]. closed road tests, and driving simulator studies) have shown that the impairing effects of traditional benzodiazepines can In terms of their effects on driving skills, the non- be severe, with reductions in driving ability persisting for up benzodiazepines zaleplon and zolpidem in fact appear to be to 16-17 hours after administration [1,2]. The introduction of fairly safe when taken, as indicated, at bedtime [5-7]. When the newer non-benzodiazepine alternatives, in particular the taken “off label” zaleplon 10 mg has been shown to have no “Z-drugs” (zopiclone, zolpidem and zaleplon), was residual effect on on-road driving driving when administered accompanied by the hope, given their shorter half lives, that, in the middle of the night, 4 h before driving [8]. Zolpidem compared to benzodiazepines, their adverse effects were 10 mg did significantly impair driving 4 hours after middle- fairly benign, or at least limited to only their peak period of of-the-night administration. In contrast, zopiclone (7.5 mg) significantly impairs next-morning driving performance,

when administered both in the middle of the night, as well as *Address correspondence to this author at the Utrecht Institute for when administered at bedtime [5-7]. Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands; Tel: +31 30 253 The review which follows focuses on zopiclone, and its 6909; E-mail: [email protected] usefulness as positive control in the Dutch on-the-road

1574-8863/11 $58.00+.00 © 2011 Bentham Science Publishers 210 Current Drug Safety, 2011, Vol. 6, No. 4 Verster et al. driving test. This standardized test is performed on a primary comparison was calculated, using standardized mean SDLP highway in normal traffic [9-12]. To ensure safety during the differences. That is, when computing the effect size, SDLP test, a licensed driving instructor having access to dual differences between treatment and placebo were weighted controls accompanies the subject. Subjects are instructed to according to the number of subjects that participated in each drive 100 kilometer with a steady lateral position between study. In addition, the ninety-five percent confidence interval the delineated boundaries of the right (slower) traffic lane (95% CI) was computed for each ES. If the confidence while maintaining a constant speed of 95 km/h. A camera interval does not include zero, the ES is considered mounted on the roof of the car continuously records the statistically significant. Homogeneity/heterogeneity analyses position of the car within the traffic lane, by measuring the were performed to determine if all individual ES have the relative distance of the car from the left lane delineation. The same distribution as the combined overall ES. In a speed and lateral position of the car are continuously homogenous distribution, the dispersion of effect sizes recorded, digitally sampled at 2 Hz, and edited off-line, blind around their mean is not greater than that expected from as to treatment, to remove data that were disturbed by sampling error alone. If the Q statistic resulting from this extraneous events (e.g. overtaking maneuvers, traffic jam). analysis is not significant (p > 0.05), a homogenous The standard deviation of lateral position (SDLP), i.e. the distribution can be assumed and using a fixed effects model amount of weaving of the car, is the primary outcome to perform the meta-analysis is justified. However, if the Q measure. statistic is significant (p < 0.05), variation in effect size is greater than would be expected from subject-level sampling The inclusion of a positive control in clinical trials is error alone, and a random effects model should be applied important to demonstrate assay sensitivity. Furthermore, as a correcting for additional variation between the studies [35]. direct comparator, the magnitude of impairment produced by Due to the variety of tests, variable time of testing after the drug under investigation can be put into perspective. To administration, and incompletely reported data, no meta- this extent an appropriate positive control produces a clinically relevant difference from placebo. In order to analyses were attempted for driving simulator tests and psychometric tests that examined the residual effects of interpret the data, SDLP differences between drug treatment zopiclone. and placebo are often compared with data obtained with alcohol [13]. Relative to placebo, SDLP increments of 2.4 cm were found with a blood alcohol concentration (BAC) of RESULTS 0.05% (and 4.1 cm for a BAC of 0.08%). Since a BAC of On-the-Road Driving tests in Normal Traffic 0.05% represents the legal limits for driving of many countries, SDLP differences exceeding 2.4 cm are regarded In The Netherlands, zopiclone (7.5 mg) has been tested in as a clinically relevant impairment. Since zopiclone is often 8 on-the-road driving studies [6-7, 36-41]. In each study, used as positive control (verum), the research evidence Standard Deviation of Lateral Position (SDLP) was the reviewed here evaluates whether zopiclone consistently primary outcome measure. The results of these studies are produces clinically relevant impairment on the on-the-road summarized in Table 1. driving test, and tests that examine related skills and Volkerts et al. examined driving performance after abilities. bedtime administration of zopiclone (7.5 mg) [36]. On-the- road driving tests were performed in the morning (10-11 h METHODS after intake) and afternoon (16-17 h after intake) in 16 female subjects. Zopiclone significantly impaired driving A literature search on PubMed and Embase was performance in the morning (p<0.003). In the afternoon no performed using the keyword ‘zopiclone’. This yielded 792 significant differences from placebo were found. Vermeeren articles of which the abstracts were evaluated. In addition, et al. (1998) tested driving performance after intake of cross-references were checked. Studies were included in this zopiclone (7.5 mg) at bedtime, or taken during the night [6]. report if the research papers were written in English, and if the design was double-blind, crossover, and placebo- On-the-road driving tests were performed 10-11 or 5-6 hours after intake. 28 healthy subjects participated in the study. controlled. The review was aimed at finding studies that Driving was significantly impaired: SDLP decrements measured next morning performance after bedtime relative to placebo for evening or nightly administration of administration of zopiclone, i.e., 8-12 hours after intake. As zopiclone equaled 4.5 cm and 9.1 cm, respectively. In a a consequence, most articles were not covered in this review. subsequent study, Vermeeren et al. examined the residual Other papers were not included because they administered and tested zopiclone during the daytime in order to measure effects of zopiclone (7.5 mg) on driving performance of 30 healthy volunteers [7]. Subjects performed an on-the-road acute effects [4,14-26]. Additionally, two studies were not driving test 10-11 hours after intake. When compared to included because they tested performance during the night placebo, driving was significantly impaired after [27-28]; three other studies were not included because they administration of zopiclone (18.2 cm versus 21.6 cm, were performed in shift workers [29], in sleep-deprived respectively, p<0.001). Mets et al. examined the effects of subjects [30], or among subjects whose sleep was disturbed by noise [31]. Finally, two studies were omitted because they zopiclone (7.5 mg) in 30 healthy volunteers, 8.5 to 9.5 hours after bedtime administration [37]. Relative to placebo, examined interaction effects of zopiclone with alcohol [32- zopiclone significantly impaired driving performance (SDLP 33]. increment of 2.9 cm). Ramaekers et al. also used zopiclone For the on-the-road driving test results, meta-analyses were (7.5mg) as positive control [38]. 32 healthy volunteers performed using Comprehensive Meta-analysis [34]. The performed the on-the-road test 11 hours after treatment effect size (ES) for each treatment-versus-placebo Zopiclone as Positive Control in Studies Examining the Residual Effects Current Drug Safety, 2011, Vol. 6, No. 4 211

Table 1. Results from On-the-Road Driving Studies with Zopiclone (7.5 mg)

Placebo Zopiclone References Subjects Type Time of Test
SDLP SDLP (SE) SDLP (SE)

[36] 16 hv 10-11h 20.5 (0.8) 23.2 (1.1) +2.7 cm [6] 24 hv 10-11h 22.3 (0.6) 26.8 (0.7) + 4.5 cm [7] 30 hv 10-11h 18.2 (0.5) 21.6 (0.8) + 3.4 cm [37] 30 hv 8.5-9.5h 18.7 (0.7) 21.6 (0.8) + 2.9 cm [38] 32 hv 11h 18.3 (0.5) 20.6 (0.6) +2.3 cm [39] 25 hv 10-11h 17.8 (0.6) 20.3 (0.7) + 2.5 cm [40] 18 he 10-11h 17.8 (0.8) 19.8 (1.0) + 2.0 cm [41] 16 he 10-11h 17.8 (0.6) 21.4 (1.0) + 3.6 cm [41] 16 epf 10-11h 19.7 (1.0) 21.3 (1.2) +1.6 cm [41] 16 epi 10-11h 18.2 (0.9) 20.3 (1.0) + 2.1 cm [6] 24 hv 5-6h 22.3 (0.6) 31.4 (0.6) + 9.1 cm [36] 16 hv 16-17h 20.9 (1.0) 22.0 (1.0) +1.1 cm All differences from placebo were significant (p<0.05), except when zopiclone was tested 16-17 hours after administration [36]. All studies were placebo-controlled, double blind, and had a crossover within subject design Abbreviations: h = hours after treatment administration, hv = healthy volunteers (18-65 years old), he = healthy elderly volunteers (>65 years old), epf = elderly insomnia patients who frequently use zopiclone, epi = elderly insomnia patients who use zopiclone infrequent. administration. SDLP values after zopiclone (20.6 cm) From Table 2 it is evident that all on the road highway differed significantly from placebo (18.3 cm). driving studies reported significant residual impairment of zopiclone (7.5 mg) on driving ability. In healthy volunteers, Leufkens et al. tested 25 healthy adult volunteers, 10-11 hours after intake of zopiclone (7.5 mg) [39]. Subjects zopiclone has a similar impairing effect on driving in adult and elderly subjects. The combined effect size (ES) and 95% received their treatment at 23:00 h and were awakened at confidence interval (95%CI) is 0.782 (0.620, 0.944). 04:00 h to receive a placebo treatment. The following Comparing the data from bedtime administration studies morning, subjects performed an on-the-road driving test. with those that administered in the middle of the night [6], or When compared to placebo, driving was significantly tested driving in the afternoon [36], indicates that the impaired (p<0.001). Mean (SE) SDLP after placebo was 17.8 (0.6) cm, and 20.3 (0.7) cm after zopiclone, an magnitude of driving impairment depends on the time of testing after administration of zopiclone. In healthy increment of 2.5 cm. Leufkens et al. also tested 18 elderly volunteers, the average increase in SDLP the morning healthy volunteers, 10-11 hours after intake of zopiclone (7.5 following bedtime administration is 3.0 cm. The repeated mg) [40]. When compared to placebo, driving was findings that zopiclone (7.5 mg) administration is associated significantly impaired (p<0.002). Mean (SE) SDLP after with mean SDLP increments of more than 2.4 cm, i.e. legal placebo was 17.8 (0.8) cm, and 19.8 (1.0) cm after zopiclone, an increment of 2 cm. limit for driving in many countries, confirms that zopiclone is an appropriate active control for on-the-road driving test Leufkens et al. compared the effects of zopiclone (7.5 research. mg) in three groups of elderly participants, (1) 16 elderly insomniacs who frequently use zopiclone (on average 6.6 Driving Simulators days a week for the last 7 years), (2) 16 elderly insomniacs who infrequently use zopiclone (4.5 days per month for the Five studies using different versions of driving simulators last 7.8 years), and (3) 16 matched healthy elderly who do have examinined the residual effects of zopiclone (7.5 mg) not use hypnotic drugs [41]. Zopiclone (7.5 mg) or placebo on driving. Bocca et al. examined driving performance in 16 was administered at bedtime, and driving tests were healthy volunteers, 10 and 12 hours after intake of zopiclone performed the following morning (10-11 hours after intake). (7.5 mg) [42]. In a driving simulator, subjects performed a Relative to placebo, zopiclone significantly impaired driving 90-minute highway test. Lateral position variability was the performance in each group. The magnitude of impairment primary parameter. Ten hours after intake, zopiclone among infrequent zopiclone users (+2.1 cm) did not differ significantly impaired performance (p<0.001). Twelve hours significantly from healthy matched controls (+3.6 cm). after intake the difference from placebo was no longer Frequent zopiclone users showed significantly less significant. Berthelon et al. examined simulated driving impairment (+1.6 cm) than controls, suggesting that performance of 10 healthy subjects, 10 hours after bedtime tolerance develops after chronic treatment. administration of zopiclone (7.5 mg) [43]. In a simulated collision anticipation test, driving scenarios of intersections Table 2 summarizes results of the meta-analyses were shown to the subjects. Subjects had to estimate as conducted for the healthy volunteer data.

212 Current Drug Safety, 2011, Vol. 6, No. 4 Verster et al.

Table 2. Meta-Analyses Results of On-the-Road Driving Studies with Zopiclone (7.5 mg) Conducted in Healthy Volunteers

95% CI 95%CI Reference ES SE Variance Z-Value p-Value Lower Limit Upper Limit

[36] 0.683 0.278 0.077 0.139 1.227 2.460 0.014 [6] 0.959 0.242 0.058 0.485 1.432 3.968 0.0001 [7] 0.902 0.217 0.047 0.477 1.326 4.164 0.0001 [37] 0.731 0.199 0.040 0.341 1.121 3.672 0.0001 [38] 0.702 0.204 0.042 0.302 1.101 3.443 0.001 [39] 0.813 0.231 0.053 0.361 1.265 3.524 0.0001 Overall healthy adults 0.796 0.091 0.008 0.617 0.975 8.701 0.0001 [40] 0.257 0.240 0.057 -0.212 0.727 1.074 0.283 [41] 0.162 0.252 0.063 -0.332 0.655 0.642 0.521 Overall healthy elderly 0.720 0.195 0.038 0.338 1.102 3.694 0.0001 Combined (N=192) 0.782 0.083 0.007 0.620 0.944 9.447 0.0001 Abbreviations: ES = Effect Size, SE = Standard Error, CI = Confidence Interval. P-values are significant if p<0.05. quickly as possible whether the other vehicle would reach insensitive for other drugs known to produce residual the intersection before or after their car. No significant impairment such as flunitrazepam (1 mg). The relevance of differences were found between zopiclone and placebo. break reaction time testing to normal driving is unclear as Staner et al. tested driving ability in 23 patients with primary emergency stops, while important, are not a part of “normal insomnia [44]. Patients drove a 60-minute highway scenario driving”. Therefore, this test provides little information in the FAROS driving simulator, 9-11 hours after bedtime about regular vehicle control, but should be regarded as a administration of zopiclone (7.5 mg). A significant increase variant of a reaction time test. As such, the absence of a in the number of collisions was observed, but zopiclone did significant effect was probably caused by a combination of not affect SD speed, speed limit deviation, or route small sample size and the small number of trials as well as deviation. Meskali et al. failed to find significant effects of the selection of the primary endpoint (i.e. mean reaction zopiclone (7.5 mg) on the number of collisions or mean time). speed in 16 elderly drivers, tested 10 hours after intake [45]. The driving simulator test consisted of two 7-minutes Driving Related Skills and Abilities scenarios, in which a maximum of 5 collisions could be made. This low number of potential crash scenarios probably A number of studies have examined the residual effects precluded differentiating between zopiclone and placebo. of zopiclone (7.5mg) on tests measuring cognitive Bocca et al. examined driving performance of 16 adult functioning, memory and psychomotor performance. subjects (55-65 years old), 10 hours after bedtime Although the results from these tests do not directly predict administration of zopiclone (7.5 mg) or placebo [46]. In this actual driving performance measured by SDLP, they do study, the simulator test comprised 60 minutes of measure skills and abilities that are related to daytime monotonous highway driving with no other traffic on the functioning and possibly some aspects of driving [12]. road. Road breath and speed variability were measured. The Therefore, these tests may support findings obtained in on- test was similar to the one used by Meskali et al. [44]. the-road studies. Zopiclone significantly impaired performance on the test. Twenty-one placebo-controlled double-blind clinical Although most of these studies used different driving trials were identified that tested the residual effects of simulator tests and different outcome measures, zopiclone zopiclone on cognitive, psychomotor, and memory typically showed significant impairment. functioning in healthy adult volunteers (18-65 years old); three additional trials were performed in healthy elderly subjects. Brake Reaction Time Test Lader & Denney examined cognitive and psychomotor Harrison et al. examined the residual effects of zopiclone functioning 10 and 13 hours after bedtime administration of (7.5 mg) on a brake reaction time test on a closed driving zopiclone (2.5, 5, 7.5, 10 mg) or placebo in ten healthy male circuit [47]. Ten healthy females (24-40 years old) volunteers [48]. The tests included an auditory reaction time, participated in the study. The test was performed 10 hours tapping test, Digit Symbol Substitution Test (DSST), and a after bedtime administration. Subjects drove on a closed symbol copying test. Performance on the DSST was course (72 km/h) and had to brake as quickly as possible significantly impaired 10 and 13 hours after intake of when a red light on the dashboard was illuminated. The zopiclone (7.5 mg and 10 mg). Symbol copying was outcome measure was the mean reaction time to a total of 12 impaired 10 hours after intake (zopiclone 7.5 mg) and 13 emergency braking situations. No significant difference hours after intake (zopiclone 10 mg). Reaction time was between zopiclone and placebo was found. This test was also Zopiclone as Positive Control in Studies Examining the Residual Effects Current Drug Safety, 2011, Vol. 6, No. 4 213 significantly impaired 13 hours after intake of zopiclone 10 performance on the DSST was significantly worse (p<0.05) mg, but not after 10 hours. The tapping rate was significantly after zopiclone 10 mg when compared to the 5 mg dose. impaired 10 hours after intake of zopiclone 10 mg. These Mizuki et al. tested psychomotor performance in 9 inconsistent results were likely due to the small sample size. healthy young men, 9, 12 and 15 hours after bedtime Nicholson & Stone examined DSST and symbol copying 9 administration of zopiclone (10 mg) [55]. At all hours after bedtime administration of zopiclone (2.5, 5, 7.5 measurements, CFFT was significantly impaired when or 10 mg) and placebo in 6 healthy male volunteers [49]. compared to placebo. No significant effects were found on Performance on the DSST was significantly impaired for tapping rate, a pursuit rotor task, choice reaction time test, or zopiclone 7.5 mg and 10 mg. Symbol copying was on a working memory test. significantly impaired for the 10 mg dose. Fossen et al. (1983) examined memory functioning in 12 healthy Rettig et al. tested the residual effects of zopiclone (7.5 volunteers who received zopiclone (7.5 mg) or placebo for mg) in 20 patients who entered the hospital for elective 28 days [50]. On days 1, 7, 8, 14, 15, 21, 22, and 28 they surgery [56]. Nine hours after bedtime intake, zopiclone did performed a recall test, paired associates test, and a visual not impair performance on a letter cancellation test. memory test (immediate and delayed recall), 11 hours after Significant impairment was found on a measure of ocular treatment. A second study in 15 healthy volunteers tested the imbalance (the Maddox Wing test). Whitehead et al. also residual effects of zopiclone (7.5 mg) on digit learning, examined the residual effects of zopiclone (7.5 mg) in 20 memory for position, and a visual memory test 10 hours after patients who entered the hospital for minor surgery (e.g. intake. Although some impairment was seen on day 1, dental extraction and tonsillectomy) [57]. Results were zopiclone did not significantly impair performance on any compared to those of a placebo group (N=21). At bedtime test when compared to placebo. The authors suggested that they received treatment, and tests were performed the the absence of effects was probably caused by a lack of following morning, 10-11 hours after intake. Zopiclone statistical power attributable to the small sample size used in significantly impaired performance on the CFFT (p<0.01), their study. but no impairment was found on two memory tasks (object recall and a paired associate test). Subhan & Hindmarch examined performance on the Sternberg memory scanning test 1 and 10 hours after Tafti et al. examined psychomotor and physical skills in bedtime administration of zopiclone (7.5 mg) [51]. Ten 8 athletes, the morning following bedtime administration of healthy females (24-40 years old) participated in the study. zopiclone (7.5 mg) [58]. Tests included a choice reaction After 1 hour, RT was significantly impaired (p<0.05), but no time test, eye-hand coordination test, CFFT, a standing jump significant impairment was found on the test 10 hours after test, and a running time test were performed 9, 14 and 19 drug ingestion. Harrison et al. examined the residual effects hours after intake. Zopiclone did not significantly impair of zopiclone (7.5 mg) on a variety of tests, including Critical performance on any test. Flicker Fusion Test (CFFT), choice reaction time, Sternberg Vermeeren et al. tested performance after intake of memory scanning, and a tracking test. Performance of ten zopiclone (7.5 mg) at bedtime, or taken during the night, in healthy volunteers, 10 hours after administration of 28 healthy volunteers [6]. When administered at night, zopiclone, did not differ significantly from placebo on any of significant impairment was found on all tests (5-6 h after the tests [47]. intake). Bedtime administration of zopiclone significantly Broadhurst & Cushnaghan examined performance of 10 impaired delayed recall of the word learning test, and healthy volunteers on a complex reaction time test, 12 hours performance on a syntactic reasoning test (10-11 h after after bedtime intake of zopiclone (2.5, 5, 7.5 or 10 mg) or intake). Performance on a spatial memory test and semantic placebo. A dose-related increase in RT was observed for verification test was not significantly impaired. zopiclone. Performance after zopiclone 10 mg differed In 17 healthy volunteers, Bocca and Denise conducted significantly from placebo [52]. two ocular saccade tests, 10 hours after bedtime Billiard et al. tested 6 healthy subjects (20-39 years old) administration of zopiclone (7.5 mg) [59]. They found 1.45 h after an evening intake of zopiclone (3.75 mg or 7.5 significant impairment on one of the tests, indicating deficits mg) or placebo and the following morning (9.45 and 13.45 in disengagement of spatial attention. hours after intake) [53]. Tests included an eye-hand Grobler et al. examined the effects of zopiclone (7.5 mg), coordination test (Purdue pegboard), a choice reaction time 10 h after intake [60]. Twelve healthy regular sportsmen test, DSST, and immediate word recall. Zopiclone 7.5 mg performed an eye-hand coordination test, pegboard test, a (but not the 3.75 mg dose) significantly impaired 30-meter sprint test, and a treadmill run-to-exhaustion test. performance on the eye-hand coordination test 9.45 hours Zopiclone did not significantly impair performance on any of after intake. No significant differences from placebo were the tests. found 13.45 hours after intake of zopiclone. On the other tests, no significant performance differences between Vermeeren et al. examined the residual effects of zopiclone and placebo were found. zopiclone (7.5 mg) in 30 healthy volunteers on tests measuring cognitive, memory and psychomotor Nicholson et al. tested 6 middle-aged healthy volunteers performance, which were administered 9-10 hours after (45-52 years old), 9 hours after bedtime administration of intake [7]. No significant impairment was found on a critical zopiclone (5, 7.5 or 10 mg) or placebo [54]. Tests included a tracking test, but tracking as part of a divided attention test choice reaction time test, DSST, and symbol copying. No tracking was significantly impaired. Immediate recall, significant differences from placebo were found, but 214 Current Drug Safety, 2011, Vol. 6, No. 4 Verster et al. delayed recall and recognition of the word learning test were significantly increased 8.45 h after intake of zopiclone. At all significantly impaired when compared to placebo. 11.45h after intake, significant impairment was found on a stop signal task. At both 8.45 and 11.45 h after intake Silva et al. tested the effects of zopiclone (7.5 mg) on delayed recall and recognition (but not immediate recall) of memory storage during sleep [61]. Eight healthy volunteers learned a list of 15 words, 1 hour before treatment the word learning test were significantly impaired. administration. The following morning (12 hours after Taken together, clinical trials in healthy volunteers show intake) subjects recalled as many words as possible (delayed that zopiclone (7.5 mg) produces significant impairment, recall). When compared to placebo, after zopiclone subjects albeit not consistently found, on a variety of cognitive, remembered significantly fewer words (14.4 versus 12.4, memory and psychomotor tests. respectively). Performance on the DSST did not differ significantly between the treatments. Clinical Trials Testing Patients with Insomnia Leufkens et al. examined 25 healthy volunteers, 8.5 to Seven clinical trials tested the effects of zopiclone in 9.5 hours after intake of zopiclone (7.5 mg) [40]. Subjects patients with insomnia. Treatments were administered for received their treatment at 23:00 h and were awakened at several days, and a variety of laboratory tests were 04:00 h to receive a placebo treatment. Significant conducted. Dehlin et al. examined 68 geriatric patients with impairment was found on delayed recall and recognition (but chronic insomnia (mean age 81 years old) who received not immediate recall) in the word learning test. In a divided zopiclone (3.75, 5, 7.5 or 10 mg) or placebo for 14 days [64]. attention test, reaction speed and number of errors were The morning following the first night of treatment, and after significantly increased. Significant impairment was also 1 and 2 weeks of treatment, patients performed the DSST found on the DSST, but not on a critical tracking test. and a letter cancellation test. No significant differences from Ramaekers et al. examined the effects of zopiclone (7.5 placebo were found. Klimm et al. examined memory mg) on a word learning task, stop-signal task, critical functioning (using the Syndrom Kurztest) in 34 geriatric tracking task, and divided attention task in 32 healthy patients with insomnia who received zopiclone (7.5 mg) for volunteers, approximately 13 to 14 hours after 1 week [65]. Performance significantly improved relative to administration. At this time, no significant differences from placebo baseline on several outcome measures of the placebo were found [38]. memory test, perhaps reflecting the regimen’s effectiveness for treating insomnia. Mets et al. examined the residual effects of zopiclone (7.5 mg), 9 to 11 hours after bedtime administration in 30 Malmelack et al. examined the effects of zopiclone (7.5 healthy volunteers [37]. Zopiclone produced significant mg) in 10 patients with insomnia after 10-12 days of impairments on reaction time in the Sternberg Memory treatment [66]. DSST and tracking performance were not Scanning Test, DSST, slow and fast tracking, reaction speed significantly impaired. Tamminen and Hansen examined and tracking in the Divided Attention Test, and delayed psychomotor performance in 49 patients with insomnia who recall in the Word Learning Test. No significant differences were treated with zopiclone (7.5 mg) for 6 weeks [67]. The 6 between zopiclone and placebo were observed for percentage weeks of treatment were preceded by a 1-week placebo of errors on the Sternberg Memory Scanning Test and wash-out week. Before treatment, and after 2, 4 and 6 weeks, Divided Attention Test, and immediate recall of the word patients performed a symbol copying test, DSST, tapping learning test. test, and an auditory reaction time test. No significant differences from placebo (pre-treatment) were found. A Three trials were performed on healthy elderly subjects significant learning effect was found on the DSST. Ngen and (>65 years old). Hemmeter et al. tested cognitive Hassan examined cognitive performance in patients with performance after administering zopiclone (7.5 mg) to 12 insomnia who received zopiclone 7.5 mg (N=15) or placebo healthy elderly subjects (60-70 years old) [62]. Tests were (N=10) for 2 weeks [68]. Tests were performed at baseline performed during the night (5 hours after bedtime and on day 7 and 14. Tests included a choice reaction time administration; subjects were awakened for 30 minutes), and test, CFF, and a letter cancellation test. After 1 and 2 weeks the following morning (9 and 12 hours after intake). Relative of treatment, no significant differences were found between to baseline (pre-treatment measurement), zopiclone did not patients who received zopiclone or placebo. Ponciano et al. significantly impair next morning choice reaction time, examined cognitive and psychomotor performance in 8 CFFT, word recall, prose recall, digit span, nor procedural patients with sleep disturbances who received zopiclone (7.5 memory. Performance on the letter cancellation test however mg) for 3 weeks [69]. A test battery was completed on day 7, was significantly impaired. Farber and Burke examined the 14 and 21 and included CFF, a choice reaction time test, effects of zopiclone 4 to 8 hours after middle-of-the-night letter cancellation, and digit span. Results were compared administration [63]. Elderly subjects (65-80 years old) with those of 8 patients who had received placebo. No received half the dose of adult healthy volunteers (3.75 and significant differences were found. Leufkens et al. compared 7.5 mg, respectively. In elderly healthy volunteers, the effects of zopiclone (7.5 mg) in elderly insomniacs who significant performance impairment was found after both 4, frequently (N=16) or infrequently (N=16) use zopiclone and 6 and 8 hours on the DSST and a symbol copying test. In compared their performance with matched healthy elderly adults, performance did not differ from placebo. who do not use hypnotic drugs (N=16) [41]. Zopiclone (7.5 Leufkens et al. tested 18 elderly healthy volunteers, 8.45 mg) or placebo was administered at bedtime. After a single and 11.45 hours after intake of zopiclone (7.5 mg) [40]. No night of treatment, tests were performed 8.5 hours after significant impairment was found on a critical tracking test. bedtime administration. Significant impairment was found On a divided attention test, the number of errors was Zopiclone as Positive Control in Studies Examining the Residual Effects Current Drug Safety, 2011, Vol. 6, No. 4 215 on the word learning test, but not on the psychomotor Regarding simulated driving tests, the choice of test vigilance task. parameters is very important. While SDLP is an established and thoroughly examined parameter in actual traffic [10-12], The limited data from clinical trials of patients with other parameters are much less well studied. It is important insomnia show that impairment is less frequently demonstrated with zopiclone. Also, when it is found, to determine what one wants to measure, and at what level of driving behavior these skills are conducted. For example, tolerance develops after repeated administration of there is an essential difference between tests measuring basic zopiclone. The main difficulty with these primarily negative vehicle control (such as lane-keeping in the on-the-road studies is that there is no positive control to demonstrate driving test) or tests that measure higher order driving skills assay sensitivity. (e.g., emergency braking or route finding). Although this is sometimes misinterpreted in the literature, measurement of DISCUSSION brake reaction time on a closed course does not provide The on-the-road highway driving studies presented in this important information on basic vehicle control, nor does it review consistently show that basic vehicle control is give any information on interaction with other traffic (i.e., significantly impaired the morning following bedtime use of essential in actual driving). 7.5mg of zopiclone. The results from the meta-analyses The relationship between psychometric tests and actual confirm these findings. No significant difference in the driving is not clear [12]. Tests should have a clear rationale magnitude of impairment was observed between young and as to the psychological or behavioral skills and abilities that elderly healthy volunteers. The meta analysis on healthy are measured, and as to whether they are driving-related. For volunteers yielded a significant effect size (95%CI) of 0.782 many tests, such as the DSST and CFFT, this relationship is (0.620, 0.944). Since mean SDLP increment after zopiclone unclear. Most studies examining cognitive, psychomotor, (7.5 mg) of 3.0 cm exceeds + 2.4 cm, i.e. the legal limit for and memory functioning suffer from small sample sizes and driving in many countries, the data confirm that zopiclone is are therefore suffer from lack of adequate power to allow suitable as an active control for on-the-road driving test firm conclusions about potential residual impairing effects of research. zopiclone. As a result, mixed results have been found. Most The data from on-the-road driving studies are consistent negative findings (no significant effects) were found in with epidemiological evidence revealing that people who use studies with small sample sizes (less than 20 subjects), zopiclone have a four-fold increased risk of becoming lacking sufficient power to show significant effects. Given involved in a traffic accident [70]. The results are also the frequency of failure to detect drug effects, a positive supported by studies using driving simulators. Although control would help put the results in context. zopiclone showed significant impairment in most of these Unfortunately, in patients psychometric tests were not studies, the current usefulness of driving simulators in administered after one night of administration. Therefore, no evaluating driving impairment has not been clearly direct comparisons can be made with data obtained from established. This is because driving simulators as well as the healthy volunteers. Instead, most of these studies tested driving scenarios they employ are not standardized. Thus it patients only after one or more weeks of daily treatment. No is hard to compare study results from different sites. Trials in effects were reported, possibly because tolerance to the healthy volunteers show that zopiclone (7.5 mg) also impairing effects of zopiclone had developed. produces significant impairment on a variety of cognitive, memory and psychomotor tests. In many of these trials, It remains unknown to what extent performance would laboratory tests are conducted before or after the driving test have been impaired one or two days after treatment to provide additional evidence of performance impairment. initiation. Since many patients use hypnotic drugs However, in the studies that assayed both performance test intermittent (as needed), more clinical trials examining first as well as on-road driving [6-7, 37-38], the driving results or second day effects in the intended patient population are more consistently demonstrated an impairment relative to the needed. performance test. In no instance there was a performance Most of the psychometric tests were of short duration. In decrement in the absence of as driving impairment. tests that require only a few minutes to complete, subjects The studies summarized in this review have several may have compensated for drug-induced impairment by limitations. First, studies employing the on-the-road driving increasing mental effort to perform well on the test. In tests are limited to one or two nights of treatment contrast, the on-the-road driving test takes 1 hour to administration. Data on driving impairment after sub-acute complete. In this test, performance gradually worsens over and chronic use of zopiclone is currently not available. This the distance traveled [10]. Tests of short duration (e.g., less data is important for determining if and how tolerance that 10 minutes) often fail to measure this vigilance effect. develops after daily use of zopiclone. Second, on-the-road Regarding the time of testing, from approximately 13 to 14 driving studies with different dosages of zopiclone have not hours after administration of zopiclone (7.5 mg), no been performed. This is unfortunate, because elderly subjects significant performance impairment was observed [38]. may use half the typical dose of zopiclone (3.75 mg). It Also, after repeated dosing tolerance develops to the would also be important to determine the effects of impairing effects of zopiclone. This should be taken into zopiclone 3.75 mg after middle-of-the-night administration. account when designing clinical trials. When developing a Future studies should resolve these gaps in our current clinical trial, the possibility of learning effects should be knowledge on the effects of zopiclone on driving taken into account. Studies with repeated administration of performance. simple tests such as choice reaction speed and the DSST sometimes report significant learning effects [53]. Due to 216 Current Drug Safety, 2011, Vol. 6, No. 4 Verster et al. these learning effects, subjects improve their performance on [3] Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L. New each subsequent test day. Although this improvement is also drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003, 26:261-82. seen in the placebo condition, it may mask the actual [4] Paul MA, Gray G, MacLellan M, Pigeau RA. Sleep-inducing impairment caused by a drug. pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Aviat Space Environ Med 2004, 75: 512-519. Taken together, this review and meta-analysis shows that [5] Vermeeren A, O’Hanlon JF, DeClerck AC, Kho L. Acute effects of zopiclone (7.5 mg) is an effective positive control for clinical zolpidem and flunitrazepam on sleep, memory and driving trials that use the on-the-road driving test. Driving simulators performance, compared to those of partial sleep deprivation and and psychometric tests also report performance impairment placebo. Acta Ther 1995; 21: 47-64. after administration of zopiclone. However, their application [6] Vermeeren A, Danjou PE, O’Hanlon JF. Residual effects of evening and middle-of-the-night administration of zaleplon 10 and is limited by the fact that in contrast to the on-the-road 20 mg on memory and actual driving performance. Hum driving test they have less ecological validity, are generally Psychopharmacol 1998; 13 (Suppl 2):S98-S107. not standardized across research sites, and sometimes have [7] Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat an unclear relationship with actual driving. The fact that A. Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002; 25: epidemiological studies show an increased prevalence of car 224-31. accident among individuals using zopiclone validates the on- [8] Verster JC, Volkerts ER, Schreuder AHCML, et al. Residual the-road driving studies. It however also raises questions effects of middle-of-the-night administration of zaleplon and about the inconsistent results seen on psychometric tests, zolpidem on driving ability, memory functions and psychomotor especially those carried out in insomniacs. performance. J Clin Psychopharmacol 2002; 22: 576-83. [9] O’Hanlon JF, Haak TW, Blaauw GJ, Riemersma JB. Diazepam impairs lateral position control in highway driving. Science 1982; CONFLICTS OF INTERESTS 217: 79-81. [10] Verster JC, Roth T. Standard Operation Procedures for conducting Joris Verster has received research funding from Takeda the on-the-road driving test, and measurement of the Standard Pharmaceuticals and Red Bull GmbH, and was scientific Deviation of Lateral Position (SDLP). Int J Gen Med 2011; 4: 359- 71. advisor for Takeda, Sanofi-Aventis, Transcept, Sepracor, [11] Verster JC, Roth T. Drivers can poorly predict their own driving Red Bull GmbH, Deenox, and CBD. impairment: a comparison between measurements of subjective and objective driving quality. Psychopharmacology 2011 [Epub ahead S. R. Pandi-Perumal is a stockholder and the President of print]. and Chief Executive Officer of Somnogen Inc., a New York [12] Verster JC, Roth T. The relation between psychometric tests that Corporation. measure driving related skills and actual driving performance. Psychopharmacology 2011, in revisions Thomas Roth has received grants/research support from [13] Louwerens JW, Gloerich ABM, De Vries G, Brookhuis KA, Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, O’Hanlon JF. In: Noordzij PC, Roszbach R Eds, The relationship Sanofi, Schering-Plough, Sepracor, Somaxon, Syrex, between drivers’ blood alcohol concentration (BAC) and actual Takeda, TransOral, Wyeth and Xenoport; has acted as a driving performance during high speed travel. Alcohol, Drugs and Traffic Safety. Amsterdam, Excerpta Medica. 1987; pp. 183-192. consultant for Abbott, Acadia, Acoglix, Actelion, [14] Mattila ME, Mattila MJ, Nuotto E. Caffeine moderately Alchemers, Alza, Ancil, Arena, AstraZeneca, Aventis, antagonizes the effects of triazolam and zopiclone on the AVER, BMS, BTG, Cephalon, Cypress, Dove, Elan, Eli psychomotor performance of healthy subjects. Pharmacol Toxicol Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, 1992; 70: 286-89. [15] Mattila MJ, Vanakoski J, Mattila-Evenden ME, Karonen S-L. Intec, Intra-Cellular, Jazz, Johnson – Johnson, King, Suriclone enhances the actions of chlorpromazine on human Lundbeck, McNeil, MediciNova, Merck, Neurim, psychomotor performance but not on memory or plasma prolactin Neurocrine, Neurogen, Novartis, Orexo, Organon, in healthy subjects. Eur J Clin Pharmacol 1994; 46: 215-20. Prestwick, Procter – Gamble, Pfizer, Purdue, Resteva, [16] Mattila MJ, Mattila-Evenden ME. Effects of alcohol and Roche, Sanofi, Schering-Plough, Sepracor, Servier, Shire, hypnosedative drugs on digit-symbol substitution: comparison of two different computerized tests. J Psychopharmacol 1997; 11: Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, 313-17. Wyeth, Yamanuchi, and Xenoport. [17] Mattila MJ, Vanakoski J, Kalska H, Seppälä. Effects of alcohol, zolpidem, and some other sedatives and hypnotics on human performance and memory. Pharmacol Biochem Behav 1998; 59: ABBREVIATIONS 917-23. [18] Saano V, Hansen PP, Paronen P. Interactions and comparative BAC = Blood Alcohol Concentration effects of zopiclone, diazepam and lorazepam on psychomotor CFFT = Critical Flicker Fusion Test performance and on elimination pharmacokinetics in healthy volunteers. Pharmacol Toxicol 1992; 70: 135-39. DSST = Digit Symbol Substitution Test [19] Kuitunen T, Mattila MJ, Seppälä T, Aranko K, Mattila ME. Actions of zopiclone and carbamazepine, alone and in combination, ES = Effect Size on human skilled performance in laboratory and clinical tests. Br J Clin Pharmacol 1990; 30: 453-61. SDLP = Standard Deviation of Lateral Position [20] Kuitunen T, Mattila MJ, Seppälä T. Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol. Int Clin Psychopharmacol 1990; 5 REFERENCES (supplement): 115-30. [1] Verster JC, Veldhuijzen DS, Volkerts ER. Residual effects of sleep [21] Aantaa R, Salonen M, Nyrke T. Difference in action between oral medication on driving ability. Sleep Med Rev 2004, 8:309-25. triazolam and zopiclone. Eur J Clin Pharmacol 1990, 38: 47-51. [2] Verster JC, Veldhuijzen DS, Patat A, Olivier B, Volkerts ER. [22] Gorenstein C, Tavares SM, Gentil V, Peres C, Moreno RA, Hypnotics and driving safety: meta-analyses of randomized Dreyfus JF. Psychophysiological effects and dose equivalence of controlled trials applying the on-the-road driving test. Curr Drug zopiclone and triazolam administered to healthy volunteers. Saf 2006, 1: 63-72. Methodological considerations. Braz J Med Biol Res 1990; 23: 941-51. Zopiclone as Positive Control in Studies Examining the Residual Effects Current Drug Safety, 2011, Vol. 6, No. 4 217

[23] Warot D, Bensimon G, Danjou P, Puech AJ. Comparative effects and placebo on driving performance and ocular saccades. of zopiclone, triazolam and placebo on memory and psychomotor Psychopharmacol 1999; 143: 373-79. performance in healthy volunteers. Fundam Clin Pharmacol 1987; [43] Berthelon C, Bocca ML, Denise P, Pottier A. Do zopiclone, 1: 145-52. zolpidem and flunitrazepam have residual effects on simulated task [24] Griffiths AN, Jones DM, Richens A. Zopiclone produces effects on of collision anticipation? J Psychopharmacol 2003; 17: 324-31. human performance similar to flurazepam, lormetazepam and [44] Staner L, Ertle S, Boeijinga P, Rinaudo G, Arnal MA, Muzet A, triazolam. Br J Clin Pharmacol 1986; 21: 647-53. Luthringer R. Next-day residual effects of hypnotics in DSM-IV [25] Channer KS, Dent M, Roberts CJC. The effects of posture at the primary insomnia: a driving simulator study with simultaneous time of administration on the central depressant effects of the new electroencephalogram monitoring. Psychopharmacology 2005; hypnotic zopiclone. Br J Clin Pharmacol 1984; 18: 879-86. 181: 790-98. [26] Parker G, Roberts CJC. Plasma concentrations and central nervous [45] Meskali M, Berthelon C, Marie S, Denise P, Bocca M-L. Residual system effects of the new hypnotic agent zopiclone in patients with effects of hypnotic drugs in aging drivers submitted to simulated chronic liver disease. Br J Clin Pharmacol 1983 ; 16: 259-65. accident scenarios: an exploratory study. Psychopharmacology [27] Allain H, Patat A, Lieury A, le Coz F, Janus C, Menard G, Gandon 2009; 207: 461-67. JM. Comparative study of the effects of zopiclone (7.5 mg), [46] Bocca ML, Marie S, Lelong-Boulouard V, et al. Zolpidem and zolpidem, flunitrazepam and placebo on nocturnal cognitive zopiclone impair similarly monotonous driving performance after a performance in healthy subjects, in relation to pharmacokinetics. single nighttime intake in aged subjects. Psychopharmacology Eur Psychiatry 1995; 10 (Suppl 3): 129s-35s. 2011; 214: 699-706. [28] Allain H, Bentué-Ferrer D, Tarral A, Gandon J-M. Effects on [47] Harrison C, Subhan Z, Hindmarch I. Residual effects of zopiclone postural oscillation and memory functions of a single dose of and benzodiazepine hypnotics on psychomotor performance related zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in to car driving. Drugs Exp Clin Res 1985; 11: 823-29. elderly healthy subjects. A randomized, cross-over, double-blind [48] Lader M, Denney SC. A double-blind study to establish the study versus placebo. Eur J Clin Pharmacol 2003; 59: 179-88. residual effects of zopiclone on performance in healthy volunteers. [29] Moon CA, Hindmarch I, Holland RL. The effect of zopiclone 7.5 Pharmacol 1983; 27 (suppl 2): 98-108 mg on the sleep, mood and performance of shift workers. Int Clin [49] Nicholson AN, Stone BM. Zopiclone: sleep and performance Psychopharmacol 1990; 5 (suppl): 79-83. studies in healthy man. Pharmacology 1983, 27 (suppl 2): 92-97 [30] Wickstrøm E, Gotlibsen OB, Bredesen JE, Jensen MH. [50] Fossen A, Godlibsen OB, Loyning Y, Dreyfus JF. Effects of Performance and mood following partial sleep deprivation: a hypnotics on memory. Pharmacology 1983; 27 (supplement 2): randomized, double-blind, cross-over study of zopiclone, triazolam, 116-26 flunitrazepam, ethanol and placebo. Hum Psychopharmacol 1988; [51] Subhan Z, Hindmarch I. Effects of zopiclone and benzodiazepine 3: 3-11. hypnotics on search in short-term memory. Neuropsychobiology [31] Stone BM, Turner C, Mills SL, Paty I, Patat A, Darwish M, Danjou 1984; 12: 244-48. P. Noise-induced sleep maintenance insomnia: hypnotic and [52] Broadhurst A, Cushnaghan RC. Residual effects of zopiclone residual effects of zaleplon. Br J Clin Pharmacol 2002; 53: 196-02. (Imovane). Sleep 1987; 10 (supplement 1): 48-53. [32] Seppälä T, Nuotto E, Dreyfus JF. Drug-alcohol interactions on [53] Billiard M, Besset A, de Lustrac C, Brissaud L. Dose-response psychomotor skills: zopiclone and flunitrazepam. Pharmacology effects of zopiclone on night sleep and on nighttime and daytime 1983; 27 (supplement 2): 127-135 functioning. Sleep 1987; 10 (suppl 1): 27-34. [33] Hindmarch I. Immediate and overnight effects of zopiclone 7.5 mg [54] Nicholson AN, Stone BM. Efficacy of zopiclone in middle age. and nitrazepam 5 mg with ethanol, on psychomotor performance Sleep 1987; 10 (suppl 1): 35-39. and memory in healthy volunteers. Int Clin Psychopharmacol 1990; [55] Mizuki Y, Hirano H, Miyoshi A, et al. Residual effects of 5 (suppl): 105-13. zopiclone on subsequent daytime functions in normal humans. [34] Borenstein M, Rothstein H. Comprehensive Meta-analysis. A Hum Psychopharmacol 1987; 2: 119-26. computer program for research synthesis. Biostat, Inc. USA, 1999. [56] Rettig HC, de Haan P, Zuurmond WWA, van Leeuwen L. Effects [35] Lipsey MW, Wilson DB. Practical meta-analysis. Applied Social of hypnotics on sleep and psychomotor performance. A double- Research Methods Series, Sage Publications, Inc.2001; Vol. 49. blind randomised study of lormetazepam, midazolam and [36] Volkerts ER, Louwerens JW, Gloerich ABM, Brookhuis KA, zopiclone. Anaesthesia 1990; 45: 1079-82. O’Hanlon JF. Zopiclone’s residual effect upon actual driving [57] Whitehead C, Sanders L, Appadurai I, Power I, Rosen M, performance versus those of nitrazepam and flunitrazepam. Traffic Robinson J. Zopiclone as a preoperative night hypnotic: a double- Research Centre, Groningen, The Netherlands. Report VK 84-10. blind comparison with temazepam and placebo. Br J Anaesth 1994; 1985. 72: 443-446. [37] Mets MAJ, de Vries JM, de Senerpont Domis LM, Volkerts ER, [58] Tafti M, Besset A, Billiard M. Effects of zopiclone on subjective Olivier B, Verster JC. Next-day effects of ramelteon (8 mg), evaluation of sleep and daytime alertness and on psychomotor and zopiclone (7.5 mg), and placebo on highway driving performance, physical performance tests in athletes. Prog Neuro-Psychopharm memory functioning, psychomotor performance and mood in Biol-Psychiatry 1992; 16: 55-63. healthy adult subjects. Sleep 2011; 34: 1327-34. [59] Bocca ML, Denise P. Residual effects of hypnotics on [38] Ramaekers JG, Conen S, de Kam PJ, Braat S, Peeters P, disengagement of spatial attention. J Psychopharmacol 2000; 14: Theunissen EL, Ivgy-May N. Residual effects of esmirtazapine on 401-5. actual driving performance: overall findings and an exploratory [60] Grobler LA, schwellnus MP, trichard C, Calder S, Noakes TD, analysis into the role of CYP2D6 phenotype. Psychopharmacology Derman WE. Comparative effects of zopiclone and loprazolam on 2011; 215: 321-32. psychomotor and physical performance in active individuals. Clin J [39] Leufkens TR, Lund JS, Vermeeren A. Highway driving Sport Med 2000; 10: 123-28. performance and cognitive functioning the morning after bedtime [61] Silva A, Collao A, Orellana M, Meléndez J, Caviedes P, Cárdenas and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. AM. Zopiclone, but not brotizolam, impairs memory storage during J Sleep Res 2009; 18: 398-96. sleep. Neurosci Res 2003, 47: 241-243. [40] Leufkens TR, Vermeeren A. Highway driving in the elderly the [62] Hemmeter U, Müller M, Bischof R, Annen B, Holsboer-Trachsler morning after bedtime use of hypnotics. J Clin Psychopharmacol E. Effects of zopiclone and temazepam on sleep EEG parameters, 2009; 29: 432-38. psychomotor and memory functions in healthy elderly volunteers. [41] Leufkens TR, Ramaekers JG, de Weerd AW, Riedel WJ, Psychopharmacology 2000, 147: 384-96. Vermeeren A. Residual effects of zopiclone 7.5 mg on highway [63] Farber RH, Burke PJ. Post-bedtime dosing with indiplon in adults driving performance in elderly insomnia patients: a placebo and the elderly: two placebo-controlled, active comparator controlled crossover study. In: Leufkens TR. Hypnotics and crossover studies in healthy volunteers. Curr Med Res Opin 2008; anxiolytics: field laboratory measures of drug safety in driving 24: 837-46. performance and cognitive functioning. Thesis. Maastricht, The [64] Dehlin O, Rundgren Å, Börjesson L, et al. Zopiclone to geriatric Netherlands, 2009. patients. A parallel double-blind dose-response clinical trial of [42] Bocca ML, le Doze F, Etard O, Pottier M. Residual effects of zopiclone as a hypnotic to geriatric patients – a study in a geriatric zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg hospital. Pharmacology 1983; 27 (suppl 2): 173-78 218 Current Drug Safety, 2011, Vol. 6, No. 4 Verster et al.

[65] Klimm HD, Dreyfus JF, Delmotte M. Zopiclone versus nitrazepam: [68] Ngen CC, Hassan R. A double-blind placebo-controlled trial of a double-blind comparative study of efficacy and tolerance in zopiclone 7.5 mg and temazepam 20 mg in insomnia. Int Clin elderly patients with chronic insomnia. Sleep 1987; 10 (suppl 1): Psychopharmacol 1990; 5: 165-71. 73-78. [69] Ponciano E, Freitas F, Camara J, Faria M, Barreto M, Hindmarch I. [66] Malmelack M, Buck L, Csima A, Price V, Smiley A. Effects of A comparison of the efficacy, tolerance and residual effects of flurazepam and zopiclone on the performance of chronic insomniac zopiclone, flurazepam and placebo in insomniac outpatients. Int patients: a study of ethanol-drug interaction. Sleep 1987; 10 (suppl Clin Psychopharmacol 1990; 5 (suppl): 69-77. 1): 79-87. [70] Barbone F, McMahon AD, Davey PG et al. Association of road [67] Tamminen T, Hanssen PP. Chronic administration of zopiclone and traffic accidents with benzodiazepine use. Lancet 1998; 352: 1331- nitrazepam in the treatment of insomnia. Sleep 1987; 10 36. (supplement 1): 63-72.

Received: July 10, 2011 Revised: September 28, 2011 Accepted: September 29, 2011