A Methodical Comparative Study of Over-the-road and Simulated Driving Performance after Nocturnal Treatment with Lormetazepam 1 mg and Oxazepam 50 mg

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1 A Methdical Cmparative Study f Over-the-rad and Simulated Driving Perfrmance after Ncturnal Treatment with Lrmetazepam 1 mg and Oxazepam 50 mg Vlkerts, Dr. E.R./ van Laar, Dr. M.W./ van Willigenburg, Dr. A.P.P. Intrductin Studies f hypntics have generally fcussed n their effects n sleep. Hwever, it is als clear that they have effects which can extend beyund the usual sleep perid. Amng the risks assciated the use f hypntics, the mst prminent effect is decreased perfrmance during the day fllwing ncturnal administratin (Vlkerts & O Hanln, 1986; Hindmarch, 1980). This hangver r residual effect is nt a side effect, but merely the extensin f the drug s primary effect. It ccurs because hypntics prduce sleepiness, reduce alertsness, and thereby reduce perfrmance efficiency. This pses a crucial prblem fr hypntic users wh must perate a mtr vehicle r ther dangerus machinery. The purpses f this study were (1) t examine the sensitivity and cncurrent criterin validity f a driving simulatr test mdel (TS2), in cmparisn with a standard ver-the-rad driving test, after ne night treatment with lrmetazepam 1 mg, xazepam 50 mg (as a verum) and placeb; and (2) t measure the effects f the intended drugs and placeb in the same subjects sample, after tw treatment nights in the mrning and in the afternn, n ver-the-rad driving perfrmance. Methds Eighteen healthy male vlunteers aged between 25 and 31 years (mean yrs) and varying in weight frm 66 t 84 kg (mean 76.83), were admitted t the study. Each subject received the three treatments exactly at hrs, during tw cnsecutive nights accrding t a duble-blind, 3-way crssver design. An ver-the-rad driving test and a simulatr test were cnducted in the mrning fllwing the first night. After the secnd treatment night, ver-therad driving tests were perfrmed in the mrning and in the afternn. 664 A lchl, D rugs and Traffic S afety - T92 Ed. by U tzelm ann / B erghaus / Krj Verlag TÜV Rheinland GmbH, Köln -1993

2 The primary perfrmance parameter f the ver-the-rad driving test was the standard deviatin f lateral psitin (SDLP). Parameters f the simulatr (TS2) test were the number f crrectly executed tracking cntrl maneuvres (TC), and reactin time (RT)(see van Laar et al. in this vlume fr a full discriptin f bth tests). RESULTS DAY 1 O ver-the-rad driving Lateral psitin parameter Grup means (±SE) f SDLP fr the entire test ride (100 km), fr each treatment cnditin are shwn in Figure 1. c w Figure a re 1 9 i_ a> *-» r e 1 8 a ( / ) LOR OXA Mean (±SE) f SDLP in cnditins P, LOR and OXA It is evident frm the figure that -the verum- xazepam 50 mg had a mre prnunced effect n mean SDLP than lrmetazepam 1 mg and placeb. Individual SDLP values were analyzed by MANOVA. The factrs tested fr significance were treatment cnditins (3), treatment rder (3) and their interactin. The analysis revealed a significant (F2i4=5.59; p<.02) multivariate effect f treatment cnditins. Univariate analysis shwed that the verall effect was prduced by bth OXA (F, 15=8.70; p<.01) and LOR (FU 5=7.77; p<.01). The effects f treatment rder and f its interactin with treatment cnditins were nt significant (F < 1). 665

3 Speed parameter Neither mean nr SD speed was significanly affected by treatment cnditins. Sim ulated Driving Prir t their entry in the study the subjects were extensively trained in the TS2 simulatr test t attain stable criterin scres (TC > 400 and RT < 1500 ms). The mean number f bserved crrect respnses n TC frm the 18 vlunteers and crrespnding predicted values are pltted in Figure 2 fr the successive training sessins. The duratin f each sessin was 30 minutes. As in every individual case perfrmance had reached a plateau-level and satisfied the criterin scres, the TS2 test was thereafter perfrmed after treatment with lrmetazepam 1 mg, xazepam 50 mg and placeb. TC (number f Crrect respnses) Training Sessins «Observed Values Predicted Values Figure 2. Learning-curve: Mean Observed and Predicted [f(x)=b+c(l-e'ax)] scres frm 18 subjects in 6 successive training sessins. A=0549; B= ; C Tracking Cntrl Grup means (SE) were calculated fr the ttal time-n-task. The results fr each treatment cnditin are shwn in Figure

4 Individual scres were analyzed by MANOVA. The multivariate effect f treatment cnditins was nt significant (F<1). Univariate analysis revealed n significant effects neither fr lrmetazepam (F<1) nr fr xazepam, relative t placeb. Treatment rder and its interactin with treatment cnditin were als nt significant. Figure 3. Mean (±SE) f crrect respnses in cnditins P, LOR and OXA Reactin Time Grup mean values and standard errrs were calculated and the results are shwn in Figure 4. Individual values were analyzed by MANOVA. The multivariate verall effects were nt significant (F<1). Als, univariate analysis did nt shw any significant differential effect f bth LOR (F<1) and OXA relative t P. Figure 4. Mean (±SE) RT in cnditins P, LOR and OXA 667

5 DAY 2 O ver-the-rad Driving Lateral psitin parameter Mean (±SE) f SDLP is shwn in Figure 5 fr each cnditin and bth times f testing, separately. It is evident frm the figure that there were treatment effects in the mrning. Hwever, they seemed t equal P in the afternn. Mrever, mean SDLP values in P were almst the same in mrning and afternn tests n day 2, and bth mrning tests n day 1 and day 2. E c 3 'in C L TO k. <u TO Mrning ( hrs pa) n = u Afternn n = (16-17 hrs pa) E in Q. TO i a> TO O w ^ 17 D I P LOR OXA LOR OXA Figure 5. Mean (±SE) f SDLP in cnditins P, LOR and OXA in the mrning and afternn n day 2 The nly data that entered analyses n day 2 were thse cllected accrding t the within factrs f the design. Individual SDLP values were analyzed by MANOVA. The multivariate effect f treatment cnditins was nt significant (F216= 2.52; p=.12); cnsidered tgether the drugs did nt prduce a significant elevatin in SDLP relative t placeb when mrning and afternn data were cmbined. Hwever, the verall effect f time-n-testing was highly significant (FU7= 20.95; p<.0001) which means that when cnsidered tgether, drug effects n SDLP differ significantly ver the day. The interactin between these tw factrs was als significant (F216= 8.47; pc.001) indicating that the drugs prduced higher SDLP elevatin in the mrning than in the afternn. 668

6 Univariate analysis revealed that xazepam impaired perfrmance significantly (FU7 = 5.35; p<.03) when mrning and afternn data were cmbined. This effect was mre prnunced in the mrning than in the afternn, as was shwn by a significant (F, n= 18.01; p<.001) interactin between treatment cnditin and time-f-testing. Lrmetazepam did nt shw a significant (Fj 17= 2.43; p=.14) effect n SDLP when bth times f testing were cmbined. Hwever, the interactin between treatment cnditin and time-f-testing was significant (F, 17= 4.45; p<.05), indicating that there was a reductin in the effect f this treatment ver the day. Speed parameter As n day 1, neither mean speed nr SD speed was significantly affected by treatment cnditins r time-f-testing. Predicting ver-the-rad driving perfrmance frm the simulatr test parameters Our attempt t cmpare the residual effects f the tw hypntics n simulated and ver-the-rad car driving perfrmance within the same subject sample is apparently unprecedented. The main finding f this study is the prved sensitivity f the standard ver-the-rad driving test cncerning the sedative hangver effects f lrmetazepam 1 mg and xazepam 50 mg as measured by the primary parameter f the test, the standard deviatin f lateral psitin. This test repeatedly demnstrated the sedative effects f many drugs (hypntics, anxilytics, antidepressants, antihistamines and ethanl) n actual driving perfrmance during high-speed uninterrupted vehicle peratin. Mrever, in several cnsecutive studies the methd determined stable dserespnse relatinships between varius dsages f benzdiazepine hypntics and anxilytics. Over the years, varius driving simulatr studies have been carried ut. The driving simulatrs differ widely in simulating the visual scene r dynamics f real car driving. The TS2 simulatr test can be cnsidered as a cmpsitin f tw labratry tasks since the primary perfrmance measure is the number f successfully cmpleted trials within a cnstant time perid. Sme mre advanced simulatrs prvide measurements that pssess a mre reasnable degree f face validity (Ziedman et al., 1979). The subjects perate nrmal vehicle cntrls t interact with a cmputer that in turn cntrls large-scale prjectins f a dynamic rad scene. Tasks include lane and speed maintenance, car fllwing, curve fllwing, rute sign recgnitin, car passing 669

7 and emergency decisin making. The mre advanced simulatrs have in additin t an interactive visual display, a crdinated mving base t prvide prpriceptive mtin cues. The fremst is the Daimler - Benz driving simulatr, built in Berlin, which allws a particularly realistic simulatin f real traffic (Friedel et al., 1991). Hwever, fr all driving simulatr perfrmance measures it remains t be shwn if they are valid predictrs f unsafe vehicle peratin. The realism f driving simulatin n the ne hand, and the mtivatin f the subjects n the ther hand, are factrs which can determine the validity f driving simulatrs. Real driving seems t be superir t simulated driving nt nly because f the real task but als because f the real mtivatin, including accident risks which influences perfrmance. Willumeit (1984) recgnized the influence f mtivatinal factrs and tried t bring them under cntrl by giving an acustic signal whenever the subject makes an errr "...as a feedback prcess t reprt his driving perfrmance and increase his mtivatin". Hwever, this can be interpreted as a rather artificial cnstruct. The TS2 simulatr test develped by Willumeit and his clleagues was als applied in the present investigatin. In cntrast t the btained results frm the SD lateral psitin parameter f the ver-the-rad driving test, nne f the tw parameters (TC and RT) f the simulatr test shwed any significant difference between the drug treatment cnditins, and placeb. These results indicate that the TS2 simulatr test parameters were nt sensitive with respect t the residual sedative effects f the treatments. Relatinships between SD lateral psitin data and thse f TC and RT tgether, cllected in the drug cnditins and placeb were determined by cefficients f crrelatin calculated between the raw values in each treatment cnditin (see van Laar et al. in this vlume, particularly the results sectin). In cnclusin, the results f this study finally demnstrated that results btained with the TS2 driving simulatr cannt be translated t actual driving perfrmance and, frm there, be extraplated t driving safety. It wuld be premature t generalize these results t all simulatr studies as there are majr differences between them, hwever the ne crucial aspect they have in cmmn is the lack f real traffic. This fact will prbably be the reasn fr the superirity f testing drug effects n driving perfrmance in the field with a standard ver-the-rad driving test. 670

8 References Friedel, B J, S. & Hartman,R.(1991). Testing Drivers taking diazepam in the Daimler-Benz Driving Simulatr. Jurnal f Traffic Medicine, 19,(1) Hindmarch, I. (1980). Psychmtr functin and psychactive drugs. British Jurnal f Cinical Pharmaclgy, 10, Vlkerts, E.R. & O Hanln, J.F. (1986). Hypntics residual effects n driving perfrmance. In: J.F. O Hanln & J.J. de Gier (Eds.). Drugs and Driving (pp ). Lndn: Taylr and Francis. Willumeit, H.P., Ott, H. & Neubert, W. (1984). Simulated car driving as a useful technique fr determinatin f residual effects and alchl interactin after shrt- and lngacting benzdiazepines, In I. Hindmarch, H. Ott & T. Rth (Eds.). Sleep, benzdiazepines and perfrmance. Berlin: Springer-Verlag. Ziedman, K Smiley, A. & Mskwitz, H. (1979). Effects f drugs n driving: Driving simulatr tests f diazepam and secbarbital. Prceedings f the Human Factrs Sciety (23 rd An.M.Bstn, Mass). 671