Hypnotics drugs residual effects on monotonous simulated driving in elderly drivers

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1 Hypnotics drugs residual effects on monotonous simulated driving in elderly drivers ML Bocca 1-2, S Marie 2, C. Berthelon 3*, A. Coquerel 2, V. Lelong-Boulouard 2, M. Moessinger 4, P. Denise 2 1 : Paris Sud-11 University, UPRES EA 4142, Orsay Cedex, France 2 : Caen Basse-Normandie University, UPRES EA 3917, UFR Médecine, Caen Cedex, France 3 : INRETS (the french National Institut for Transport and Safety Research), Chemin de la Croix Blanche, Salon de Provence, France 4 : LAB (Laboratoire d'accidentologie, de biomécanique et d'étude des comportements humains) Renault-PSA, 132 rue des Suisses, Nanterre, France * : poster presenter INTRODUCTION Elderly people, and particularly women, already represent a large part of drivers and the proportion will increase in the future in most occidental countries. It was demonstrated that, motor, cognitive and sensory changes occuring with age alter driving performance. Moreover, these changes could interact with pathologies and pharmacokinetic modifications due to age and thus explain the increased risk of driving accidents in this population. Paradoxically, while insomnia is more frequent in elderly, most experimental studies assessing drugs effects are conducted on healthy young subjects. To date, no comparisons between young and elderly subjects have been made examining hypnotics effects on driving performance. The purpose of this work is to characterise the residual effects of zolpidem and zopiclone on monotonous car driving assessed using a driving simulator in elderly subjects. Monotonous car driving is widely used to assess residual effects of drugs, and previously showed residual effects of zopiclone in particular, in healthy young subjects. MATERIALS AND METHODS Sixteen healthy volunteers (8 men and 8 women) participated in this study. They were aged between 55 and 65 years. At p.m. the day before each session, the subject took a tablet of either zolpidem 10mg (Zd), zopiclone 7.5mg (Zc), flunitrazepam 1mg (Fln) or a placebo (C). The study was conducted according to a balanced, double blind, cross-over design. Each subject followed four sessions held at intervals of at least two weeks. All the subjects were required to arise at 7.00 a.m.. The medication was administered at the subject's home under the supervision of an experimenter. The subject was required to retire to 1

2 bed within half an hour. The next day, the subject was brought to the simulator site. CAR DRIVING Simulator and test drive: The driving simulation was performed on a mono-screen INRETS- FAROS driving simulator. The test drive involves driving for 1 hour along a two-lane road in a rural environment. No other vehicle or pedestrian is represented. Driving is performed in daylight. The instructions were as follows: 1./ to ensure maximum lateral stability of the vehicle, 2. / to respect driving at 110 km/h. At no time during the session did the subjects receive stimulation by actions external to the driving operation Subjects were trained to obtain baseline performance on monotonous driving. The amount of weaving of the car measured by the standard deviation of the lateral position (SDLP, m) is an index of driving safety. Other parameters analysed were the standard deviation of speed (SDS, km/h), the mean lateral position (mlp) and mean speed (ms). Some subjects drove out the allowed traffic lane to both left and right repeatedly. For analysis of SDLP, we only keeped lateral position data to those between the left and right traffic lane (i.e. road breadth). When subjects crossed the left or the right lane, a road exit was counted. The number of road exits was analysed too (data not presented). After conclusion of the driving test, retrospective self-assessment data were obtained from the subjects in order to assess subjective driving quality and mental effort during driving (data not presented). Statistical analysis: Statistical analysis were done employing the Statistica 7.1 statistical program. ANOVA for repeated measurements was performed in order to compare the active treatments zolpidem, zopiclone and flunitrazepam to placebo. Because recordings problems occured with two subjects for one session each, the repeated measures ANOVA was performed on 14 subjects (7 men and 7 women). Post-hoc comparisons were assessed with Dunnet s test. P-values less or equal to 0.05 were considered statistically significant. RESULTS The ANOVA performed on the SDLP (fig.1) showed a significant treatment effect [F(3,39) = 11.55; P = ]. Dunnett s test showed that zolpidem (P = ) and zopiclone (P = 0,000067) significantly increased SDLP. A trend was observed with flunitrazepam (P = 0.1). On SDS, ANOVA showed a significant main effect of treatment [F(3,39)= 4.35; P = 0.009]. Post-hoc comparisons revealed significant effect of zolpidem (P = 0.01) and zopiclone 2

3 (P = 0.009). Flunitrazepam had no effect (P = 0.33). No treatment effect was observed on ms and mlp. Hypnotics effects on SDLP 0,75 0,70 SD lateral position (m) 0,65 0,60 0,55 0,50 0,45 P < P < ,40 Zp Zc Fln Pla Fig.1: residual effects on SDLP (m). Hypnotics effects on SDS SD speed (km/h) 10,00 9,00 8,00 7,00 6,00 5,00 4,00 3,00 2,00 1,00 0,00 P < 0.01 P < 0.01 Zp Zc Fln Pla Fig.2: residual effects on SDS (km/h). 3

4 DISCUSSION SIMULATOR The main result of this study is that zolpidem 10mg has residual effects in elderly subjects more than 10 hours after intake. Our study is the first one showing residual effects of zolpidem 10 mg. It reveals that elderly subjects were differently sensitive to this drug than young subjects who participated in similar drug effects studies. Moreover, this work confirms zopiclone s residual effects already observed in younger subjects (Bocca and al. 1999; Vermeeren and al. 2002). Surprinsingly, flunitrazepam 1 mg did not affect driving performance in the morning. These results probably indicate that hypnotics effects were delayed in elderly people compared to young people. This could probably explained the lack of residual effects of flunitrazepam in the morning. Two women were strongly affected by zopiclone and zolpidem as after 10 minutes driving, they were unable to drive correctly and crossed the left and right lane more than 50 times each. For such driving behaviour which affect calculation of SDLP we have reduced our analysis to the size of the traffic lane. Opposite is represented individual changes from placebo in SDLP (see fig.3). Fig.3 : individual changes from placebo in SD lateral position ΔSDLP (cm) placebo0-10 men women Individual changes from placebo in SD lateral position Zp Zc Fln Nevertheless, women and men were not differently affected by hypnotics as no treatment*gender interaction were found by ANOVA. Women sensitivity to zolpidem was already evoked by Verster and al (2002) who related that 3 young women were unable to drive after taking zolpidem in the middle of the night. 4

5 CONCLUSION Healthy elderly people were differently affected by hypnotics than healthy young people. Our results indicate therefore that hypnotics effects should not only be lead on healthy young subjects in drugs driving studies. REFERENCES Bocca ML, Le Doze F, Etard O, Pottier M, L'Hoste J, Denise P. (1999) Residual effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades. Psychopharmacology 143(4): Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat A. (2002) Residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 25(2): Verster JC, Volkerts ER, Schreuder AH, Eijken EJ, van Heuckelum JH, Veldhuijzen DS, Verbaten MN, Paty I, Darwish M, Danjou P, Patat A. (2002) Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 22(6):