Psychopharmacology (1999) 143 : 373379
© Springer-Verlag 1999
O R I G I NA L I N V E S T I G AT I O N
M.L. Bocca · F. Le Doze · O. Etard · M. Pottier J. LHoste · P. Denise
Residual effects of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades Received : 30 April 1998 / Final version : 2 December 1998
Abstract Rationale : Studies report contradictory results concerning the residual e¤ects of zolpidem and zopiclone. Moreover, residual e¤ects of these compounds on healthy subjects have not yet been simultaneously assessed. Objective : The present study with healthy subjects investigated the residual e¤ects of zolpidem 10 mg and zopiclone 7.5 mg on driving performance and on ocular saccade and compared them to those under ßunitrazepam 1 mg and placebo. Methods : The study involved 16 subjects divided into two groups, a 9 : 00 a.m. group and a 11 : 00 a.m. group, in a balanced, double-blind, cross-over design. Results : In the 9 : 00 a.m. group, zolpidem had no residual e¤ects while zopiclone and ßunitrazepam both impaired driving performance (P < 0.001 for both) and increased saccadic latency (P < 0.005; P = 0.052, respectively). Zopiclone impaired driving performance 5 times less than did ßunitrazepam. In the 11 : 00 a.m. group, zolpidem and zopiclone had no residual e¤ects, while ßunitrazepam increased saccadic latency (P = 0.065) but did not impair driving performance. Conclusions : Zopiclone and ßunitrazepam had residual e¤ects in the Þrst part of the morning, whereas zolpidem had no residual e¤ects. The hierarchical character of the e¤ects of the molecules di¤ered according to the test administered. This is probably linked more to drug-
M.L. Bocca (*) · O. Etard · M. Pottier · P. Denise Laboratoire de Physiologie, Faculté de Médecine, CHU-avenue de la Côte de Nacre, F-14032 Caen Cedex, France e-mail :
[email protected], Fax: +33-2-31-06-82-19 F. Le Doze Laboratoire de Pharmacologie, Faculté de Médecine, CHU-avenue de la Côte de Nacre, F-14032 Caen Cedex, France M.L. Bocca · J. LHoste Laboratoire de Psychologie de la conduite, INRETS, 2 avenue du Général Malleret-Joinville, F-94114 Arcueil Cedex, France
induced speciÞc alterations than to di¤erent sensitivities of the tests. Key words Zolpidem · Zopiclone · Flunitrazepam · Driving performance · Residual e¤ect · Saccadic eye movement
Introduction The consumption of benzodiazepine hypnotics has a statistically signiÞcant association with hospital admissions due to tra¦c accidents (Neutel 1995). The highest risk of accidents occurs within 1 or 2 weeks after the start of treatment. Furthermore, the risk of involvement in injurious crashes increases with the dose and with concurrent use of two or more di¤ering benzodiazepines (Ray et al. 1992). Unfortunately, the reason for prescribing benzodiazepine may be a confounding factor leading to the increase of accident risk. It has been largely demonstrated, nevertheless, that benzodiazepine hypnotics impair: memory (Vermeeren et al. 1995), psychomotor performance in various tasks (Mamelak et al. 1987; Mizuki et al. 1987; Bensimon et al. 1990) and driving performance (OHanlon 1984; OHanlon and Volkerts 1986; Brookhuis et al. 1990; Laurell and Tornros 1991). In order to reduce these residual e¤ects, pharmaceutical companies have developed new classes of hypnotics structurally unrelated to the benzodiazepines, such as the imidazopyridines (zolpidem) or cyclopyrrolones (zopiclone). Zopiclone and zolpidem are two molecules with short elimination half-lives, 36 h for zopiclone (Fernandez et al. 1995) and 1.52.4 h for zolpidem (Salva and Costa 1995). Zopiclone exhibits a pharmacological spectrum of activity that resembles that of benzodiazepines with, however, weaker muscle relaxant properties and stronger sedative hypnotic
374
properties. The principal action of zolpidem is sedative hypnotic; it is devoid of signiÞcant muscle relaxant, anxiolytic, and anticonvulsant activity when administered in clinically relevant doses (Zivkovic et al. 1988). Zopiclone di¤ers from the benzodiazepines in that it binds to regions or domains of the benzodiazepine binding site which are di¤erent from the benzodiazepine binding domain (TriÞletti and Snyder 1984; Byrnes et al. 1992; Doble et al. 1992). Zolpidem has a selective action with respect to the di¤erent GABA-A receptor subtypes (high a¦nity for omega-1 subtypes) which may be responsible for its more speciÞc pharmacological action. A few preceding studies have evaluated the residual e¤ects of zolpidem and zopiclone. The results obtained have sometimes been contradictory. These divergencies can be linked to the tests employed, which are di¤erent from one laboratory to another. No residual e¤ects of zolpidem were found with psychomotor tests (Nicholson and Pascoe 1986; Gieschke et al. 1994) and with a real driving test on insomniac women (Vermeeren et al. 1995). In contrast, residual e¤ects of zolpidem were found based on a simulated driving test performed at 9 : 00 a.m. but not at 11 : 00 a.m. (Etard et al. 1993). With a MSLT, Clodore et al. (1990) have observed a risk of somnolence and greater di¦culty in Þghting o¤ drowsiness at 10 : 00 a.m., while no e¤ects were observed from 12 : 00 p.m. to 6 : 00 p.m. No residual e¤ects of zopiclone were found with psychomotor tests (Subhan and Hindmarch 1984; Tafti et al. 1992), whereas residual e¤ects were observed with a real driving test on insomniac women (Volkerts et al. 1984). Numerous studies have shown that saccadic eye movements were altered by drugs acting at the GABA benzodiazepine receptor complex (for review, see Glue 1991). Saccadic eye movements have been used to assess the daytime e¤ects of compounds (for review, see Glue 1991) and the residual e¤ects of ßunitrazepam (Ho¤erberth 1986; Salonen et al. 1986) and zolpidem (Richens et al. 1993). They have been described as providing a more sensitive measurement of performance impairment than some psychomotor tests (Mercer et al. 1990; Glue 1991). The residual e¤ects assessed by saccadic eye movements have not yet been compared to those assessed by simulated or real driving tests. No study of the same design has assessed the residual e¤ects of zopiclone and zolpidem, so it is di¦cult to compare the e¤ects of those two hypnotics. The Þrst purpose of this study was to assess and compare in the same design the residual e¤ects of zolpidem and zopiclone. Residual e¤ects were assessed with a simulated driving test and with an ocular saccade test in a Þrst group of eight subjects studied at 9 : 00 a.m. The second purpose of this study was to evaluate the duration of the residual e¤ects of zolpidem and zopiclone, if these existed. Indeed, Etard et al. (1993) have shown, for zolpidem, a disappearance of residual e¤ects
from the end of the morning on. A second group of eight subjects performed both tests at 11 : 00 a.m. This group was introduced to test the hypothesis of a possible lack of residual e¤ects of these compounds beginning from late morning. For two reasons, we chose to test eight subjects at 9 : 00 a.m. and eight subjects at 11 : 00 a.m. and not 16 subjects both at 9 : 00 and 11 : 00 a.m. First, subjects would have been too tired to undergo two series of tests in a row, and the results at 11 : 00 would have been inßuenced by the Þrst series of tests at 9 : 00. Second, we would avoid having healthy subjects take the same hypnotics twice, which would have led to rather long periods of wash-out. We chose healthy subjects and a single nighttime dose to determine residual e¤ects. The daytime e¤ect of a single nighttime dose is justiÞable, since a large segment of the population uses hypnotics only occasionally for a single night. Moreover, in clinical practice, zolpidem and zopiclone are given for transitory insomnia i.e. for one to a few nights. Since negative results could arise from insensitive measurements, ßunitrazepam was introduced into the study as a positive control to validate the testing procedures.
Materials and methods Subjects The study was granted ethical approval by the Ethics Committee, CHU Côte de Nacre, Caen. All subjects provided written informed consent after the study procedures were explained in detail. The study was carried out on 16 healthy volunteers (nine men and seven women) recruited from among a student population. Their mean age was 24.5 years (2030 years). Inclusion criteria were the possession of a drivers license for at least 2 years and driving experience of at least 5000 km per year. Non-inclusion criteria were sleeping, alertness, neurological, cardiovascular, respiratory, hepatic, renal, or metabolic disorders; chronic or transitory use of oral medication except contraceptives during the 2 years prior to the experiment; cigarette consumption >15 cigarettes per day and alcohol consumption >28 units per week.
Drugs, doses All hypnotics were administered at the lowest therapeutic dose. All subjects received at 11 : 00 p.m. the day before each session the following treatments for a single night : zolpidem 10 mg, zopiclone 7.5 mg, ßunitrazepam 1 mg or a placebo in identical capsules.
Design The study was conducted according to a balanced, double-blind, cross-over design. Each subject followed four sessions held at intervals of at least 2 weeks. One group of eight subjects (four men and four women) was tested at 9 : 00 a.m. and another group of eight subjects (Þve men and three women) was tested at 11 : 00 a.m.; all subjects rose at the same time (7 : 30 a.m.). The two groups were composed with respect
375 to the circadian pattern of the subjects according to the morningness-eveningness questionnaire of Horne and Ostberg (1976). Eight subjects were morning type and eight subjects were evening type. Subjects with the same score for the questionnaire were paired o¤, with one placed in each of the two groups; thus, each group contained four morning types and four evening types. The experiments took place from Tuesday to Friday. Subjects performed their four driving tests on the same day of the week and at the same time of day so as to permit comparison of the di¤erent conditions and to avoid any possible interference with changes in biological rhythms from one day of the week to the next. The medication was administered at the subjects home under the supervision of an experimenter. Then, an actimeter was placed by the experimenter on the non-dominant arm for monitoring the motor activity under medication during the night. The subject was required to retire to bed within half an hour. The next day, the subject was brought to the simulator site.
Car driving Simulator The driving simulator comprises a car seat together with steering wheel and pedals, a video projector and a PC. The movements of the steering wheel and actions on the pedals are detected by means of potentiometers. The resulting signals are transformed by means of an analog to a digital converter card. A simulator software program (Animate, Cachan, France) calculates the new position of the vehicle using its dynamic characteristics. The resulting image is then prepared through a database and projected onto a screen using the video projector. The entire cycle is repeated approximately 25 times a second. This apparatus has no system that enables simulation of the movements of the car or engine noise. During each cycle, the computer records the complete set of variables characterizing the movement of the car and the actions of the driver.
The test drive The test involved driving for 90 min along a two-lane road in a rural environment. No other vehicle or pedestrian was represented. Driving was performed in daylight. The instructions were as follows : (1) to ensure maximum lateral stability of the vehicle; (2) to drive as quickly as possible while complying with instruction 1. At no time during the session did the subjects receive stimulation by actions external to the driving operation. One week prior to the Þrst trial session, subjects received a training session lasting 45 min. This training session was long enough while no training e¤ect was detected with statistical analysis.
Statistical analysis The variables given by the simulation software were instantaneous frame-by-frame values of the vehicles position relative to the center line of the road as well as the vehicles speed. As the purpose of this study was to demonstrate impaired vehicle control after ingestion of a hypnotic, the variables we adopted for analysis were the mean variance of lateral position (m)2 and the mean variance of vehicle velocity (m / s)2. The mean variance of lateral position is an index of vehicle control. This is the most accurate measurement and has been described as such by all studies in real driving conducted by the Tra¦c Research Center at the University of Groningen. The null hypothesis, whereby there is no di¤erence in mean variances among the four groups, was tested with the Bartlett test (Zar 1984). For four groups (df = 3), the signiÞcance threshold
was at P = 0.05 is χ2 = 7.81. Discovery of a signiÞcant treatment e¤ect was followed by an F test to compare the mean variances 2 by 2; the signiÞcance threshold at P = 0.05 is F(7,7) = 3.79. Eye movements The ocular saccade test was realized immediately after the driving test.
Materials and saccade test Horizontal eye movements were recorded binocularly using Ag / AgCl-electrodes in complete darkness. Electrodes were taped to the outer canthus of each eye and a ground electrode was taped to the middle of the forehead. The eye-position signal was sampled on-line at 100 Hz. Before the recording session, a 15-min period was allowed for adaptation to darkness. The eye movement recording session was conducted in a room with a constant dim light. The recording session began and ended with a calibration test. It was composed of light emitting diode (LED) jumps with amplitudes of 5°, 10°, 15°, 20°, 25° to and from the center position, in both directions. In the saccade task, the subjects were asked to look at the central LED illuminated for 3.5 s and move their eyes to the new position when that LED was extinguished just prior to the illumination for 0.5 s of the lateral LED. They were instructed to watch the illuminated LED as quickly as possible and not to preempt the movement of the LED. Sixty lateral LEDs were randomly illuminated either 15° to the right or left of the central LED on the horizontal meridian.
Analysis Before tests subjects had no training session; no signiÞcant training e¤ect was found with ANOVA. As many saccades are undershot, in order to calculate the peak velocity for an amplitude of saccade of 15°, we plotted peak velocity as a function of the amplitude of saccades. For the amplitude of saccades under 20°, this may be approximated by a straight line (Bahill et al. 1975). The peak velocity from this curve, corresponding to a 15° saccade, served as the dependent measure. Saccadic latency was measured from laterally illuminated LEDs to the initiation of eye movement. Saccadic duration was measured from initiation to end of saccadic eye movement. The e¤ect of the treatments was assessed with respect to the saccades parameters : latency (ms); duration (ms); peak velocity (°/ s).
Statistical analysis All saccade parameters were separately analyzed by a two-factor (treatment × subject) ANOVA. When a signiÞcant main e¤ect of treatment was found, post hoc multiple comparisons were conducted using the Dunnett test. SigniÞcance was accepted at the P < 0.05 level.
Results The motor activity records enabled us to verify good protocol respect from subjects, i.e. the time of sleeponset in the evening, and of awakening in the morning. Thus, all subjects completed this study.
376
Fig. 1 Residual e¤ects on driving performance. Results are expressed as mean variances. SigniÞcant comparisons to placebo using Fisher test are depicted. n 9 : 00 a.m group, 11 : 00 a.m group
Results and signiÞcant comparisons are depicted in Figs. 1 and 2. 9:00 a.m. group Simulated driving test (Fig. 1) No signiÞcant main e¤ect of the treatment on the variance of vehicle velocity was found with the Bartlett test [Bc(3,7) = 1.04; 0.9 < P
