Eur J Clin Pharmacol (1992) 42:363-369
©
Springer-Verlag 1992
Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving J. G. Ramaekers, M. M. C. Uiterwijk, and J. E O'Hanlon Institute for Drugs, Safety and Behavior, Maastricht, The Netherlands Received: March 15, 1991/Accepted in revised form: September 2, 1991
Summary. Sixteen healthy male and female volunteers took part in a 6-way, double-blind cross-over trial to compare the effects of single doses of cetirizine 10 rag, loratadine 10 mg and placebo, with and without alcohol (0.72 g.kg 1, lean body mass). Performance was measured in two repetitions of a psychometric test battery, and a standard, over-the-road driving test. E E G was also measured during driving. Alcohol significantly affected almost every performance measure and altered the E E G energy spectrum during driving whilst the blood concentrations declined from 0.37 to 0.20 rag. ml- 1.The effects of cetirizine of on driving performance resembled those of alcohol. It caused the subjects to operate with significantly greater variability in speed and lateral position ('weaving' motion). The effects of alcohol and cetirizine appeared to be additive. Certain cetirizine-placebo differences in subjective feelings and test battery performance were also significant. Loratadine had no significant effect on any performance parameter. It was concluded that cetirizine, but not loratadine, generally caused mild impairment of performance after a single 10 mg dose. Key words: Cetirizine, Loratadine; alcohol, driving, psychomotor performance, E E G
Loratadine and cetirizine are structurally distinct, as derivatives of cyproheptadine and piperazine, respectively, but are similarly potent and selective Hi-receptor antagonists. Their pharmacokinetic profiles are also similar. Mean tm~xand tl/2~ are 1.5 and 11 h for loratadine and 1.0 and 7-10 h for cetirizine [Hilbert et al., 1987; Campoli-Richards et al., 1990]. The potencies and pharmacokinetic profiles of the drugs permit once a day dosing with the same recommended dose of 10 mg. Both drugs are polar, which retards their passage through the blood-brain barrier. As a consequence, neither possesses the marked sedative activity, which characterized older, more lipophilic antihistamines. Both are said to be "nonsedating" when taken in the recom-
mended doses. Whether they actually are is currently a matter of controversy. There appears to be no indication in the clinical literature that loratadine 10 mg produces significantly more complaints of sedation than placebo. However, there is some indication that cetirizine 10 mg does so. Analyses of pooled clinical trial data in the United States and Europe, from 1500 and 1400 patients, respectively, revealed a significantly higher incidence of reported sedation after cetirizine 10 or 20 mg than placebo [Spector et al., 1987; Monroe, 1988]. Neither author concluded that cetirizine 10 mg was likely to produce sedation of practical consequence, but if the suggestion were correct, it could not be said that the drug was free from all sedative potential. Any even low level potential of a drug to produce sedation is important, since it might add to or potentiate the sedative effect of another drug or alcohol taken concomitantly. The expression of single or combined sedative drug effects in causing inadequate performance of an inherently dangerous task, such as car driving, is a matter of common concern. The present investigation was primarily undertaken to measure and compare the influence of loratadine and cetirizine on the actual driving performance, of the same subjects in a standardized, over-the-road test. The effects were determined with and without the co-administration of a moderate dose of alcohol. Further, supporting evidence was sought by assessing the psychometric testing of subjects before and after driving, and by analysing subj ective feelings, and E E G measurements made during driving.
Subj ects and methods
Subjects and design Sixteen healthy subjects 8 men and 8 women, aged 22-35 y, were selected. Inclusion criteria were the possession of a valid driver's licence for the previous three years, and driving experience of at least 8000 km per year. Exclusion criteria, applied followinga medi-
364 cal examination, were a history of severe mental or physical disorders, alcohol or drug abuse, excessive smoking or caffeine consumption, body weight 10% outside the population norm, requirement for chronic medication (except oral contraceptives) and known allergic reactions to antihistamine drugs. The study was conducted according to a 6-way, double-blind, cross-over design, in which single doses of loratadine 10 mg, cetirizine 10 mg and placebo were administered with and without alcohol, on separate occasions at least one week apart. Sixteen different treatment orders were constructed, so that a given condition occurred either 2 or 3 times at each ordinal position in the series. The treatments were randomly assigned to the respective subjects. The study protocol was approved by the institutional Ethics Committee.
Drug administration Subjects fasted for at least 3h before ingesting drugs and placebo, which were formulated in identical gelatine capsules. For half of the group ingestion was at 10.00 h and for the others, at 11.15 h. One hour later they drank orange juice containing a weight-calibrated dose of ethanol (99.8 % ), or the juice alone, within 15 min. The dose of ethanol was 0.72 g/kg-~ lean-body-mass [LBM, Froentjes, 1968]. A standard low-fat meal was consumed with the beverage to slow alcohol ab sorption. Blood alcohol concentrations (BAC) were estimated from expired alveolar air, using a Lion SD-3 "Breath Analyzer", before and after each period of continuous performance testing. Prior to the administration subjects were individually trained to stable performance criteria in each of four psychometric tests. They also undertook an entire "dress rehearsal" of the standard driving test. Psychometric testing began on treatment days with the first repetition of the battery 1.5-2.5 h after drug or placebo administration. It continued with the driving test after 3 4 h, and the second battery of tests after 4.5-5.5 h.
Driving test The driving task was operation of a vehicle over a 100 km circuit on a primary highway while attempting to maintain a constant speed (95 ka~.h -~) and steady lateral position between the delineated boundaries of the right (slower) traffic lane. Subjects were accompanied during all the tests by a licenced driving instructor, who couldintervene if necessary by using duplicate controls at his position in the front passenger seat. The test vehicle was a specially instrumented 1989 Volvo 240 GL station wagon. An electro-optical device was used to measure the lateral position of the vehicle relative to the paint-stripe delineation. This analogue signal, plus those for speed and steering wheel angle, were sampled at 4 Hz and were digitized. The resulting data were filed in an on-board microcomputer system. Later, they were edited to remove sections containing incomplete data due to signal loss, or which arose during relatively infrequent overtaking manoeuvres. Afterwards a program was applied which calculated the mean and standard deviations of all directly measured parameters for successive 5 km segments of the ride, and over the test as a whole. The primary measure of road tracking ability was the standard deviation of lateral position (SDLP). The method was standardized and has repeatedly been applied to measure the sedative effects of drugs [O'Hanlon et al., 1986]. An additional analytical procedure [Godthelp, 1988] was used to obtain another measure of road tracking ability. Simultaneous samples of speed, lateralposition, heading angle and steeringwheel angle were used to derive an integrated measure, Time to Line Crossing (TLC). The calculation predicted the interval before the left or right front wheel of the vehicle would cross the appropriate lane boundary line if the driver did not take any corrective action. A TLC value was derived at each data sampling time and the distribution of values over time in both directions was calculated. They range from short intervals when the angle subtended between the projected path of the re-
hicle and the boundary was most acute to the infinitely high value which occurred momentarily when the path was exactly parallel to the boundary lines. The 15 th percentile TLC value, averaged over both left and right distributions, was taken as the performance measure over successive 5 km segments and for the test as a whole.
EEG E E G recordings were taken throughout every test ride from bipolar leads, O2-Pz, referred to the right mastoid, according to the International 10-20 System [Jasper, 1958]. E O G recordings were taken from electrodes above and below the left eye, referred to the left mastoid, in order to detect eye- and head movement artifacts. Electrodes were attached by short cables to preamplifiers (system gain 2 x 10~) mounted on a headband. The latter was connected by shielded cable to an A/D converter and computer. The E E G system frequency response was essentially flat between 0.4 Hz and 130 Hz (-3 db points). Frequency attenuation beyond those points was 3 db per octave. The time constants of the E E G and E O G filters were 0.3 s and 3 s respectively. The two analogue signals passed through a low pass filter with a cut-off frequency of 20 Hz and were sampled at a rate of 50 Hz. The data were segregated into consecutive 2.5 s epochs. The data sets were then automatically screened to remove those containing head or eye movement artifacts. Those remaining were subjected to Fast Fourier Analysis with cosine tapering to yield corresponding energy spectra with 1 Hz resolution between 4 and 20 Hz. Energy spectra (50-65) in successive 3 min periods of the driving test, excluding those occurring during the mid-test turning manoeuvre, were averaged. For analytical purposes, the 10 average spectra measured before the turning manoeuvre, and the 10 subsequent spectra were themselves averaged to yield representations of E E G during the first and second halves of the test. Total log energies within each of the following contiguous frequency bands were than calculated as the parameters to show treatment effects: theta: 4--7 Hz; slow-alpha: 8-10 Hz; fast-alpha: 11-13 Hz; and beta: 14-20 Hz.
Psychometric tests The battery included the following tests administered in the order given: Critical Tracking [CTI', Jex et al., 1966], Divided Attention [DAT, Moskowitz, 1973], Choice Reaction Time [CRT, Sternberg, 1969] and Response Competition [RCT, Erikson and Erikson, 1974]. CTF measures the ability to control an inherently unstable error signal in a P*-order compensatory tracking task. The subject uses a joy-stick to control the direction and velocity of a cursor, which tends to diverge horizontally from the centre of a display with progressively increasing velocity. The compensatory response of the subject increasingly lags the error signal until the point comes where the two frequencies are 180 ° out of phase. At that response frequency, called the °'critical frequency" or "lambdac", control is lost. The average lambda~ obtained in five consecutive trials was the performance measure. Theoretically, the reciprocal of lambdac is a direct measure of the subject's minimum perceptual-motor delay-lag during closedloop operation. D A T measures the ability to divide attention between tracking and monitoring tasks performed simultaneously. The former subtask is similar to that described above, except that the error signal velocity was fixed at a constant 50 % of that which was just controllable by the particular subject. Tracking error was measured as the average absolute distance (mm) between the position of the cursor and display centre over the entire 12 min test. The latter subtask was to monitor 24 peripheral LED display fixed to both sides of the main display. The displays presented the numerals 0-9, which changed asynchronously every 5 s. The subject had to remove his foot from a pedal-switch as quickly as possible after detecting the target numeral "2". A target occurred twice at each location over the course of a
365 Possible adverse-effects were measured after the driving test on separate visual analogue scales between the endpoints "none" and "severe". The items included drowsiness, lack of concentration, dizziness, headache, stomach ache, nausea, perspiration and dry mouth. A final scale was added to score any affective reaction from "pleasurable" to "unpleasurable".
SDLP (crn) 26,
24-
No Alcohol
Statistical analysis
22
18
PLA
LOR
CET
PLA
LOR
CET
Fig. 1. Mean (SEM) Standard Deviation of Lateral Position (SDLP) after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
12-min test. Within this constraint, target locations were random. The interval between target occurrences varied randomly between 5 and 25 s. Average reaction time was the second response measure. The two responses were usually analyzed separately, but in this study they were combined after separate T-score transformation of each subtask measures, according to the formula, Q = (T2TR+ T2RT)~/2, where TT~ and TaT are the T-scores for the tracking and reaction times, and Q is a combined performance quality score. The Q measure is a vector in a circular coordinate system. The angle subtended by the vector measures the performance bias in favour of one or the other subtask. Tile y-axis corresponds to performance in the tracking subtask and the x-axis to that in the monitoring subtask, so angles below and above 45 ° indicate biases in favor of relatively better scores in the tracking and monitoring dimensions, respectively. The usual trigonometric formula for calculating angles was used - @ (Bias) = Arctan (T~/TRT) CRT was based on the Sternberg memory search paradigm and lasted for 10 rain. The subject was shown a set of letters ("memory set") and was told to memorize them. Then a series of 90 letters was presented at intervals of 2 s. After each one the subject had to decide whether or not the presented letter was contained in the memory set, and to respond as quickly and accurately as possible using corresponding push-buttons. The presented letters comprised equal numbers of members and non-members of the memory set, in random order. Memory sets of 1, 2 and 4 letters were given, each followed by its respective series. Average (RT) and standard deviation (SDRT)both of correct "yes" and "no" reaction times were measured for each memory set. RCT measures the ability to ignore distracting stimuli while responding to a target stimulus. Prior to this task, subjects were informed that the displayed target stimuli, "K" and "H", required a leftward joystick deflection and "S" and "C" the opposite movement. They were told that a target stimulus would always be present on a given presentation, either singly or flanked by two letters on each side (visual angle = 2.5 °). The flankers were either the same as the target (e. g. KKKKK), different but compatible (e. g. HHKHH) or different and incompatible (e. g. SSKSS). Finally, subjects were told to concentrate on responding to the target as quickly as possible and to ignore the flankers, as their influence could delay the response. During the task, the subject was shown a random sequence of 384 patterns, comprising equal numbers of all types, at a rate of one every 2 s. They were given in five blocks, with 30 s rest pauses in between (total time 15 min). Average reaction time (RT) and error frequency (i. e. "misses") normally depend upon the type of pattern presented, and are normally lowest after singleqetter presentations. They increase progressively with redundant, compatible and incompatible presentations. Treatment effects can cause similar or differential increases in RT and misses over all categories.
All variables were tested first in separate applications of repeatedmeasures multivariate analysis of variance (MANOVA). The gender of the subjects was included as a between-group factor in this analysis. Although this factor occasionally produced significant differences, it failed to do so as an interaction either with Drugs of Alcohol, i. e. males and females responded similarly to the treatments. The effects of gender have been ignored therefore. The factor is mentioned to explain why degrees of freedom appearing in the text are less than might have been expected. Driving parameters were tested according to a 3 x 2 factorial model for the main effects of Drugs (Ioratadine-cetirizine-placebo)and Alcohol (present-absent) and their interaction. EEG and psychometric parameters were analyzed in a 3 x 2 x 2 model for the same main effects and Time, and their interactions. The additional factors of Memory Set ( x 3) and Response Category ( x 4) were added to analyse data obtained from the CRT and RCT, respectively. The purpose in both cases was to determine whether treatment effects were the same or different depending upon the type of stimulus presentation in the tests. When MANOVA revealed a significant (P < 0.05) overall difference between drugs and placebo conditions, data obtained after cetirizine and loratadine were separately compared with those obtained after placebo using parallel repeated-measures analysis of variance (ANOVA). Such comparisons allow identification of the specific drug-placebo differences that contribute most to the overall effect. All analyses were conducted by microcomputer employing the SPSS PC + statistical program series [Norusis, 1986].
Results
Blood Alcohol Concentration (BA C) M e a n B A C did n o t differ significantly b e t w e e n c o n d i t i o n s i n v o l v i n g the a d m i n i s t r a t i o n of alcohol with drugs or placebo, n o r b e t w e e n m a l e a n d f e m a l e subjects. T h e g r o u p m e a n B A C s before a n d after the three c o n s e c u t i v e testing periods were 0 . 0 5 7 ~ . 5 3 , 0.37-0.20 (driving) and 0.12-0.2 rag. ml -~.
Drivingperformance T h r e e driving tests were s t o p p e d b y the instructor, who c o n s i d e r e d that the subjects were b e c o m i n g too drowsy to c o n t i n u e safely. T h e y o c c u r r e d twice after the c o m b i n a tion of p l a c e b o a n d alcohol a n d once after cetirizine a n d alcohol, w h e n the c o r r e s p o n d i n g j o u r n e y s had b e e n 80, 35 a n d 55 % c o m p l e t e d . M e a n ( S E M ) s t a n d a r d deviations of lateral p o s i t i o n ( S D L P ) a n d speed (SDSP) in every c o n d i t i o n are s h o w n in Figs. 1 a n d 2. M A N O V A i n d i c a t e d significant effects of D r u g s o n b o t h measures: S D L R F2,13 = 4.31; P < 0.04; and, SDSP, F2, t3 = 4.37; P < 0.04. A N O V A i d e n t i f i e d the separate effect of cetirizine as significant: S D L R F1, 14= 7.99; P < 0,02; and, SDSR F1,14 = 7.07; P < 0.02. T h e s e p a r a t e effects of l o r a t a d i n e were n o t significant; F1, 14= 0.65 a n d 0.02, respectively. B o t h m e a s u r e s were also significantly
366 SDSP(kin/h) 3.0-
Alcohol
No Alcohol
2.B-
2.6
2.4
2.2
2.0 PLA
LOR
CET
PLA
LOR
CET
Fig.l, Mean (SEN) Standard Deviation of Speed (SDSP) after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
affected by Alcohol: SDLP, F1. 14= 17,6; P < 0.001: and, SDSR F1, 14----6.73, P < 0.03. In neither case was the interaction of Drugs and Alcohol significant. TLCls was significantly affected by Alcohol (F1, 14----11.0; P < 0.005), although not by drugs or the interaction of the two factors.
EEG during driving Geometric mean difference spectra were obtained in the following manner. After all energy values recorded at i Hz frequency points were transformed into logarithms, those obtained at a given elapsed driving time in the placebo condition were subtracted from the corresponding values in each of the drug and/or alcohol conditions. The differences
were averaged across subjects per frequency, time and condition. The resulting values were transformed into antilogs (geometric means) for presentation in Fig. 3. Fig. 3 is divided into six parts, A - E The first shows the loratadine-alone difference spectra as a function (z-axis) of elapsed driving time. Those spectra were relatively flat and sometimes negative in the theta and alpha regions, indicating no drug-induced slow-wave activity. In contrast, Part B shows that cetirizine-alone produced considerably more slow-wave activity than placebo, which generally increased as a function of driving time. The effects of alcohol alone, shown in Part C, were similar to although larger, than those of cetirizine. The effects of loratadine and cetirizine, plus alcohol, are shown in Parts D and E, respectively. There was little to distinguish the effect of either on the difference spectra from that of alcohol alone, except perhaps for an earlier rise in slow-wave activity following the combination of cetirizine and alcohol. All energy spectra measured over driving time in each condition were averaged to provide a single spectrum per condition (Part F). It is apparent that loratadine-alone had the least effect on the average difference spectrum. Progressively greather effects were apparent after cetirizine-alone, alcohol-alone, loratadine plus alcohol and cetirizine plus alcohol. Statistical analysis generally confirmes the impressions given by the figure. The effects of Time measured by M A N O V A as the difference between the first and second halves of the test were significant for energies in every frequency band (F1,14 > 800). The effects of Alcohol were significant on energies in both the slow- and fast-alpha bands ( F I , 14 = 6.51 & 5.71, respectively; P < 0.05). The overall Drugs effect on slow-alpha energy was nearly significant (FI, 13--3.72; P = 0.053). Separate ANOVA's revealed a significant effect of cetirizine on slow-alpha (F1, 14= 5.31; P < 0.05) but not of loratadine (F1, z4= 2.32). There was
Fig.3. Geometric mean difference EEG energy spectra (drug and/or alcohol minus placebo) in separate time series ((~60 min) after each of the following; loratadine (A), cetirizine (B), alcohol (C), loratadine + alcohol (D) and cetirizine+ alcohol (E); and, the average mean difference spectra, collapsing across time, for each of those conditions (F). Colour coding is used to indicate EEG frequency bands; red = theta (4-7 Hz), yellow = slow-alpha (8-10 Hz), green - fast-alpha (11-13 Hz), blue = beta (14-20 Hz)
367 Table 1. Major results from MANOVA and ANOVA of the psychometric variables. Significant F-ratios are shown with the associated P-value (*, < 0.05 and **, < 0.01) CTT
DAT a
Lambda c TR
RT
Drugs ( d r = 2,13)
CRT b
RCT c
Q
Q
RT
SDRT R T
-
4.60*
-
4.35*
9.67**
C E T v. PLA
MISS
8.46**
L O R v. PLA (1,14) Alcohol
4.47*
5.85* -
5.60*
4.78*
6.21"
18.5"*
12.0" -
5.10"
11.0"*
5 39*
7.29*
-
6.46*
7.79* 6.68*
(l,t4) Time (1.14) DxA (2,13) DxT (2,13) AxT
ordinate system. Poorer combined subtask performance increases the vector length. Relatively better performance in the tracking subtask than the monitoring subtask rotates the vector counterclockwise from 45 ° (vertical in the figure). The opposite bias rotates the vector clockwise. The effect of alcohol is shown by an extension of the vector in every condition where it was given in combination with drug or placebo in comparison to conditions where the latter were given alone. Yet the length of the vector was not affected by either drug relative to placebo. Instead, both drugs at times caused the vector to rotate in the clockwise direction, particularly cetirizine during the second test replication. This suggests the occurrence of a bias in favor of relatively better performance in the monitoring subtask at the expense of tracking.
Subjective feelings
(1,14) DxAxT (2,13)
'~ Degrees of freedom associated with error variance for these variables is reduced by (1) owing to loss of one subject's data " Effects of memory-load on RT and SDR,rwere, as expected, highly significant (p < 0.001), but there was no significant interaction between memory-load and either drugs or alcohol c Effects of stimulus-type on RT and Misses were, as expected, highly significant (p < 0.001) but there was no significant interaction between stimulus-type and either drugs or alcohol
one significant interaction, an effect of Drugs x Alcohol x Time on fast alpha (F2. i,~= 4.27; P < 0.05). Judged from the data in Fig. 3, this was attributable to the unique rise in fast alpha after cetirizine plus alcohol. The components of the interaction were tested in separate ANOVA's; that involving cetirizine was almost significant (F~, 14= 4.01; P = 0.065), but that involving loratadine was not (F~, ~4= 0.00).
Psychometric performance Significant results in the psychometric tests are summarized in Table l. Alcohol affected most performance measures in the expected directions. The Alcohol x Time interaction was significant for lambdac as obtained in the CTT, and the general performance quality score (Q), obtained in theDAT. In both cases, the greatest impairment was measured in the first test replication. The overall effect of Drugs was significant in only two tests, CRT and DAT. In both cases, separate drug-placebo comparisons showed that cetirizine was primarily responsible for the overall effect. Cetirizine significantly increased the variability of the reaction time (SDRT) in the CRT, although not the mean reaction time (RT). Cetirizine also significantly affected performance in the D A T the way illustrated in Fig. 4, which presents the mean D A T performance quality and bias of the subjects by, respectively, vector length and angular rotation in a circular co-
Among the side effects rated by the subjects only "drowsiness" showed a significant treatment effect. This feeling was influenced by Drugs (F2, 13= 4.30; P < 0.04) as well as Alcohol ( F 1 , 14 = 5 . 1 1 ; P < 0 . 0 4 ) . Separate comparisons of drowsiness scores after cetirizine and loratadine versus those following placebo revealed an almost significant effect of the former (F1,14 = 4.40; P = 0.055), but none of the latter (F,. ~4= 0.17). As shown in Fig. 5, the greatest feelings of drowsiness occurred after the combination of cetirizine and alcohol, when the mean score was about midway between "none" and "severe".
Discussion and c o n d u s i o n
The results of the study consistently demonstrate that cetirizine 10 mg possesses acute sedative activity. It significantly impaired driving performance, altered E E G energy spectra in the direction of electrocortical deactivation and caused marked feelings of drowsiness during driving. On the other hand, loratadine 10 mg had no significant effect on any of the measured variables. The conclusion appears inescapable: after single recommended doses cetirizine is sedative and impairing whereas loratadine is not. The difference between the effects of the antihistamines on performance, E E G and subjective feelings during the driving test cannot easily be attributed to pharmacokinetic factors. According to the data cited above, the peak plasma concentrations of both drugs should have occurred well in advance of the driving test. The slightly faster absorption and elimination of cetirizine should have led to lower plasma concentrations as a proportion of its Cm~×than those of loratadine during the test. The apparently greater sedative activity of the former may instead be attributed to more rapid penetration of the blood-brain barrier, or greater affinity for central histamine receptors, or to both. The practical relevance of these results should not be exaggerated. The sedative activity of cetirizine might diminish due to tolerance developing during the course of therapy. Even if the observed degree of performance im-
368 otSt /r ~ -
Alcohol • NoA[cohol /X
/
PLA - -
f
•
',
o
l
&.
.
-
:
,
~
6
45
36
~S
35
56
Fig.4. Mean performance quality (vector) and subtest bias (angle) in the Divided AttentionTest (DAT) for the first (left) and second (right) test repetitions after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
BIAS (o)
Subjective drowsiness (max=10) 8
61
Alcohol
No Alcohol
o
PLA
LOll
CET
PLA
LOR
CET
Fig. 5. Mean (SEM) reported drowsiness after driving after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
pairment were to persist, it would not necessarily constitute an important safety hazard for patients engaged in potentially dangerous tasks, such as driving. The mean elevations in speed and lateral position variability after cetirizine alone were less than those following alcohol alone while the mean blood concentrations in the subjects declined from 0.37 to 0.20 mg. ml- 1. Alcohol but not cetirizine significantly reduced the time available for the subjects to correct the course of the vehicle before it would stray from the traffic lane (i. e. TLC). Even such low blood alcohol concentrations had a greather influence on driving performance than cetirizine 10 mg. The effects of cetirizine on driving in this study were not very different from those of other "nonsedating" antihistamines given in multiple, higher than normal doses to healthy volunteers [Riedel et al., 1990]. Loratadine 20 mg OD and terfenadine 120 mg b.d. significantly elevated SDLP in the standard test on the first and fourth day of separate treatments to almost the same extent as did cetirizine here. It appears as if every modern antihistamine penetrates the blood brain barrier. Whether its brain concentration exceeds a threshold causing sedation and per-
formance impairment depends on the administered dose and the pharmacokinetic factors responsible for accumulation of the drug. The only apparent difference between cetirizine and the other antihistamines is that the former has a lower ratio of the sedative to recommended therapeutic doses. This simply means that sedation is more likely to occur when patients take cetirizine, as it is ordinarily prescribed, than the other antihistamines. The present study appears to have been the first to demonstrate the capacity of cetirizine to impair performance after a single 10 mg dose. Ostensibly well conducted studies by Gengo et ai. (1987) and Seidel et al. (1987), among others, failed to show any significant effects in various short-term psychometric tests. Betts et al. (1989) were able to measure significant impairment in certain staged driving manoeuvres 2-3 h after a single 20 mg dose but none after a 10 mg dose. The question is why acute impairment by the drug was observed here but not previously. The answer may lie in the duration and monotonous nature of the highway driving test. It lasted 6-12 times longer than most conventional psychometric tests used to assess drug effects. It is not unreasonable to suppose that some sort of decrement in vigilance normally occurs in subjects performing the driving test and that it is accelerated by drug-induced sedation. It might have been difficult to discriminate between the effects of cetirizine and placebo in a driving test lasting only for 5-10 min, just as it was to measure significant differences between those conditions using the present test battery. All that was found after cetirizine was an increase of reaction time variability within individuals in the CRT and a change in how they chose to divide their attention between subtasks in the DAT. No overall impairment of performance occurred in either test. Without the diverse and mutually supportive results obtained during the driving test, we would have had to join previous investigators in concluding that cetirizine 10 mg had little or no effect on performance. Alcohol not only served as a challenging agent to evaluate antihistamine effects, it also served as the positive control. Changes in driving performance after alcohol alone were as expected on the basis of a previous dose-effect study by Louwerens et al. (1987). Those authors derived an empirical equation for predicting the change in
369 S D L P f r o m p l a c e b o levels with i n c r e a s i n g b l o o d a l c o h o l c o n c e n t r a t i o n s . T h e p r e d i c t e d effect at 0.40 m g - m l - ~ was a m e a n rise o f 2.1 cm, close to t h e significant m e a n eleva t i o n of 2.6 c m actually o b s e r v e d . E E G a l p h a activity was also significantly a f f e c t e d b y alcohol. E v e r y o n e of the p s y c h o m e t r i c tests a d m i n i s t e r e d while t h e B A C s of t h e subjects w e r e b e t w e e n 0.60 a n d 0,50 r a g - m l - 1 in the first r e p e t i t i o n , a n d a b o u t 0.10 m g . m l - 1in the s e c o n d , s h o w e d s o m e significant effect. N e i t h e r a n t i h i s t a m i n e p o t e n t i a t e d the effect of alcohol. H a d t h a t b e e n the case, a significant D r u g x A l c o h o l i n t e r a c t i o n w o u l d h a v e b e e n e x p e c t e d in the results. T h e lack of a n y such i n t e r a c t i o n i n d i c a t e s t h a t t h e two factors w e r e i n d e p e n d e n t . W h e n b o t h factors c a u s e d significant imp a i r m e n t in t h e s a m e test (e. g. driving), t h e i r effects w e r e additive.
References Betts T, Kenwood C, Dalby G, Hull B, Wild J (1988) A comparison of the effects of two non-sedating antihistamines (terfenadine and cetirizine) on tests of CNS function (including driving). Paper presented at the joint annual meeting of the Canadian College of Neuropsychopharmacology and the British Association for Psychopharmacology. Cambridge, UK Campoli-Richards DM, Buckley MM-T, Fitton A (1990) Cetirizine: a review of its pharmacological properties and clinical potential in allergic rhinitis, pollen-induced asthma, and chronic urticaria. Drugs 40:762-781 Eriksen BA, Eriksen CW (1974) Effects of noise letters upon the identification of a target letter in a nonsearch task. Percept Psychophysics 16:143-146 Froent]es W (1968) Factoren van invloed op de hoogte van her bloedalcoholgehalte. In: Buikhuisen (ed) Alcohol en verkeer. Boom, Meppel Gengo FM, Gabos C, Mechtler L (1990) Quantitative effects of cetirizine and diphenhydramine in mental performance measured using an automobile driving simulator. Ann Allergy 64:520-526
Godthelp J (1988) The limits of path error neglecting in straight lane driving. Ergonomics 31:609-615 Hilbert J, Radwanski E, Weglein R, Luc van GP, Symchowicz S, Zampaglione N (1987) Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmaco127:694~98 Jasper HH (1958) The ten twenty electrode system of the International Federation. Electroenceph Clin Neurophysio110:371-376 Jex HR, McDonnell JD (1966) Critical tracking task for manual control research. IEEE Trabs Fac Electron HFE 7:138-145 Louwerens JW, Gloerich ABM, Vries de G, Brookhuis KA, O'Hanlon JF (1987) The relationship between drivers' blood alcohol concentration (BAC) and actual driving performance during high speed travel. In: Noordzij PZ, Roszbach R (ed) Alcohol, drugs and traffic safety. Elsevier Science Publishers B.V. (Biomedical Division) Monroe EW (1988) Chronic urticaria: Review of nonsedating H, antihistamines in treatment. J Am Acad Dermatology ] 9:842-849 Moskowitz H (1973) Laboratory studies of the effects of alcohol on some variables related to driving. Safety Res 5:185-199 Norusis MJ (1986) SPSS/PC + Advanced Statistics. McGraw-Hill, New York O'Hanlon JF (1984) Driving performance under the influence of drugs, a rationale for, and application of, a new test. Br J Clin Pharmacol 18:121-129 Riedel WJ, Ramaekers JG, Uiterwijk M, O'Hanlon JF (1990) Higher doses of terfenadine and loratadine; acute and subchronic effects on psychomotor and actual driving performance. Institute for Drugs, Safety and Behavior IGVG 90 08 Seidel WE Cohen S, Bliwise NG, Dement WC (1987) Cetirizine effects on objective measures of daytime sleepiness and performance. Ann Allergy 59:58-62 Spector SL, Altman R (1987) Cetirizine, a novel antihistamine. Am J Rhinology 1:147-149 Sternberg S (1969) Memory scanning: mental processes revealed by reaction time experiments. Am Sci 57:421~t57
Dr. J. G. Ramaekers Institute for Drugs, Safety and Behavior Beeldsnijdersdreef 85 NL-6216 EA Maastricht The Netherlands
©
Springer-Verlag 1992
Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving J. G. Ramaekers, M. M. C. Uiterwijk, and J. E O'Hanlon Institute for Drugs, Safety and Behavior, Maastricht, The Netherlands Received: March 15, 1991/Accepted in revised form: September 2, 1991
Summary. Sixteen healthy male and female volunteers took part in a 6-way, double-blind cross-over trial to compare the effects of single doses of cetirizine 10 rag, loratadine 10 mg and placebo, with and without alcohol (0.72 g.kg 1, lean body mass). Performance was measured in two repetitions of a psychometric test battery, and a standard, over-the-road driving test. E E G was also measured during driving. Alcohol significantly affected almost every performance measure and altered the E E G energy spectrum during driving whilst the blood concentrations declined from 0.37 to 0.20 rag. ml- 1.The effects of cetirizine of on driving performance resembled those of alcohol. It caused the subjects to operate with significantly greater variability in speed and lateral position ('weaving' motion). The effects of alcohol and cetirizine appeared to be additive. Certain cetirizine-placebo differences in subjective feelings and test battery performance were also significant. Loratadine had no significant effect on any performance parameter. It was concluded that cetirizine, but not loratadine, generally caused mild impairment of performance after a single 10 mg dose. Key words: Cetirizine, Loratadine; alcohol, driving, psychomotor performance, E E G
Loratadine and cetirizine are structurally distinct, as derivatives of cyproheptadine and piperazine, respectively, but are similarly potent and selective Hi-receptor antagonists. Their pharmacokinetic profiles are also similar. Mean tm~xand tl/2~ are 1.5 and 11 h for loratadine and 1.0 and 7-10 h for cetirizine [Hilbert et al., 1987; Campoli-Richards et al., 1990]. The potencies and pharmacokinetic profiles of the drugs permit once a day dosing with the same recommended dose of 10 mg. Both drugs are polar, which retards their passage through the blood-brain barrier. As a consequence, neither possesses the marked sedative activity, which characterized older, more lipophilic antihistamines. Both are said to be "nonsedating" when taken in the recom-
mended doses. Whether they actually are is currently a matter of controversy. There appears to be no indication in the clinical literature that loratadine 10 mg produces significantly more complaints of sedation than placebo. However, there is some indication that cetirizine 10 mg does so. Analyses of pooled clinical trial data in the United States and Europe, from 1500 and 1400 patients, respectively, revealed a significantly higher incidence of reported sedation after cetirizine 10 or 20 mg than placebo [Spector et al., 1987; Monroe, 1988]. Neither author concluded that cetirizine 10 mg was likely to produce sedation of practical consequence, but if the suggestion were correct, it could not be said that the drug was free from all sedative potential. Any even low level potential of a drug to produce sedation is important, since it might add to or potentiate the sedative effect of another drug or alcohol taken concomitantly. The expression of single or combined sedative drug effects in causing inadequate performance of an inherently dangerous task, such as car driving, is a matter of common concern. The present investigation was primarily undertaken to measure and compare the influence of loratadine and cetirizine on the actual driving performance, of the same subjects in a standardized, over-the-road test. The effects were determined with and without the co-administration of a moderate dose of alcohol. Further, supporting evidence was sought by assessing the psychometric testing of subjects before and after driving, and by analysing subj ective feelings, and E E G measurements made during driving.
Subj ects and methods
Subjects and design Sixteen healthy subjects 8 men and 8 women, aged 22-35 y, were selected. Inclusion criteria were the possession of a valid driver's licence for the previous three years, and driving experience of at least 8000 km per year. Exclusion criteria, applied followinga medi-
364 cal examination, were a history of severe mental or physical disorders, alcohol or drug abuse, excessive smoking or caffeine consumption, body weight 10% outside the population norm, requirement for chronic medication (except oral contraceptives) and known allergic reactions to antihistamine drugs. The study was conducted according to a 6-way, double-blind, cross-over design, in which single doses of loratadine 10 mg, cetirizine 10 mg and placebo were administered with and without alcohol, on separate occasions at least one week apart. Sixteen different treatment orders were constructed, so that a given condition occurred either 2 or 3 times at each ordinal position in the series. The treatments were randomly assigned to the respective subjects. The study protocol was approved by the institutional Ethics Committee.
Drug administration Subjects fasted for at least 3h before ingesting drugs and placebo, which were formulated in identical gelatine capsules. For half of the group ingestion was at 10.00 h and for the others, at 11.15 h. One hour later they drank orange juice containing a weight-calibrated dose of ethanol (99.8 % ), or the juice alone, within 15 min. The dose of ethanol was 0.72 g/kg-~ lean-body-mass [LBM, Froentjes, 1968]. A standard low-fat meal was consumed with the beverage to slow alcohol ab sorption. Blood alcohol concentrations (BAC) were estimated from expired alveolar air, using a Lion SD-3 "Breath Analyzer", before and after each period of continuous performance testing. Prior to the administration subjects were individually trained to stable performance criteria in each of four psychometric tests. They also undertook an entire "dress rehearsal" of the standard driving test. Psychometric testing began on treatment days with the first repetition of the battery 1.5-2.5 h after drug or placebo administration. It continued with the driving test after 3 4 h, and the second battery of tests after 4.5-5.5 h.
Driving test The driving task was operation of a vehicle over a 100 km circuit on a primary highway while attempting to maintain a constant speed (95 ka~.h -~) and steady lateral position between the delineated boundaries of the right (slower) traffic lane. Subjects were accompanied during all the tests by a licenced driving instructor, who couldintervene if necessary by using duplicate controls at his position in the front passenger seat. The test vehicle was a specially instrumented 1989 Volvo 240 GL station wagon. An electro-optical device was used to measure the lateral position of the vehicle relative to the paint-stripe delineation. This analogue signal, plus those for speed and steering wheel angle, were sampled at 4 Hz and were digitized. The resulting data were filed in an on-board microcomputer system. Later, they were edited to remove sections containing incomplete data due to signal loss, or which arose during relatively infrequent overtaking manoeuvres. Afterwards a program was applied which calculated the mean and standard deviations of all directly measured parameters for successive 5 km segments of the ride, and over the test as a whole. The primary measure of road tracking ability was the standard deviation of lateral position (SDLP). The method was standardized and has repeatedly been applied to measure the sedative effects of drugs [O'Hanlon et al., 1986]. An additional analytical procedure [Godthelp, 1988] was used to obtain another measure of road tracking ability. Simultaneous samples of speed, lateralposition, heading angle and steeringwheel angle were used to derive an integrated measure, Time to Line Crossing (TLC). The calculation predicted the interval before the left or right front wheel of the vehicle would cross the appropriate lane boundary line if the driver did not take any corrective action. A TLC value was derived at each data sampling time and the distribution of values over time in both directions was calculated. They range from short intervals when the angle subtended between the projected path of the re-
hicle and the boundary was most acute to the infinitely high value which occurred momentarily when the path was exactly parallel to the boundary lines. The 15 th percentile TLC value, averaged over both left and right distributions, was taken as the performance measure over successive 5 km segments and for the test as a whole.
EEG E E G recordings were taken throughout every test ride from bipolar leads, O2-Pz, referred to the right mastoid, according to the International 10-20 System [Jasper, 1958]. E O G recordings were taken from electrodes above and below the left eye, referred to the left mastoid, in order to detect eye- and head movement artifacts. Electrodes were attached by short cables to preamplifiers (system gain 2 x 10~) mounted on a headband. The latter was connected by shielded cable to an A/D converter and computer. The E E G system frequency response was essentially flat between 0.4 Hz and 130 Hz (-3 db points). Frequency attenuation beyond those points was 3 db per octave. The time constants of the E E G and E O G filters were 0.3 s and 3 s respectively. The two analogue signals passed through a low pass filter with a cut-off frequency of 20 Hz and were sampled at a rate of 50 Hz. The data were segregated into consecutive 2.5 s epochs. The data sets were then automatically screened to remove those containing head or eye movement artifacts. Those remaining were subjected to Fast Fourier Analysis with cosine tapering to yield corresponding energy spectra with 1 Hz resolution between 4 and 20 Hz. Energy spectra (50-65) in successive 3 min periods of the driving test, excluding those occurring during the mid-test turning manoeuvre, were averaged. For analytical purposes, the 10 average spectra measured before the turning manoeuvre, and the 10 subsequent spectra were themselves averaged to yield representations of E E G during the first and second halves of the test. Total log energies within each of the following contiguous frequency bands were than calculated as the parameters to show treatment effects: theta: 4--7 Hz; slow-alpha: 8-10 Hz; fast-alpha: 11-13 Hz; and beta: 14-20 Hz.
Psychometric tests The battery included the following tests administered in the order given: Critical Tracking [CTI', Jex et al., 1966], Divided Attention [DAT, Moskowitz, 1973], Choice Reaction Time [CRT, Sternberg, 1969] and Response Competition [RCT, Erikson and Erikson, 1974]. CTF measures the ability to control an inherently unstable error signal in a P*-order compensatory tracking task. The subject uses a joy-stick to control the direction and velocity of a cursor, which tends to diverge horizontally from the centre of a display with progressively increasing velocity. The compensatory response of the subject increasingly lags the error signal until the point comes where the two frequencies are 180 ° out of phase. At that response frequency, called the °'critical frequency" or "lambdac", control is lost. The average lambda~ obtained in five consecutive trials was the performance measure. Theoretically, the reciprocal of lambdac is a direct measure of the subject's minimum perceptual-motor delay-lag during closedloop operation. D A T measures the ability to divide attention between tracking and monitoring tasks performed simultaneously. The former subtask is similar to that described above, except that the error signal velocity was fixed at a constant 50 % of that which was just controllable by the particular subject. Tracking error was measured as the average absolute distance (mm) between the position of the cursor and display centre over the entire 12 min test. The latter subtask was to monitor 24 peripheral LED display fixed to both sides of the main display. The displays presented the numerals 0-9, which changed asynchronously every 5 s. The subject had to remove his foot from a pedal-switch as quickly as possible after detecting the target numeral "2". A target occurred twice at each location over the course of a
365 Possible adverse-effects were measured after the driving test on separate visual analogue scales between the endpoints "none" and "severe". The items included drowsiness, lack of concentration, dizziness, headache, stomach ache, nausea, perspiration and dry mouth. A final scale was added to score any affective reaction from "pleasurable" to "unpleasurable".
SDLP (crn) 26,
24-
No Alcohol
Statistical analysis
22
18
PLA
LOR
CET
PLA
LOR
CET
Fig. 1. Mean (SEM) Standard Deviation of Lateral Position (SDLP) after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
12-min test. Within this constraint, target locations were random. The interval between target occurrences varied randomly between 5 and 25 s. Average reaction time was the second response measure. The two responses were usually analyzed separately, but in this study they were combined after separate T-score transformation of each subtask measures, according to the formula, Q = (T2TR+ T2RT)~/2, where TT~ and TaT are the T-scores for the tracking and reaction times, and Q is a combined performance quality score. The Q measure is a vector in a circular coordinate system. The angle subtended by the vector measures the performance bias in favour of one or the other subtask. Tile y-axis corresponds to performance in the tracking subtask and the x-axis to that in the monitoring subtask, so angles below and above 45 ° indicate biases in favor of relatively better scores in the tracking and monitoring dimensions, respectively. The usual trigonometric formula for calculating angles was used - @ (Bias) = Arctan (T~/TRT) CRT was based on the Sternberg memory search paradigm and lasted for 10 rain. The subject was shown a set of letters ("memory set") and was told to memorize them. Then a series of 90 letters was presented at intervals of 2 s. After each one the subject had to decide whether or not the presented letter was contained in the memory set, and to respond as quickly and accurately as possible using corresponding push-buttons. The presented letters comprised equal numbers of members and non-members of the memory set, in random order. Memory sets of 1, 2 and 4 letters were given, each followed by its respective series. Average (RT) and standard deviation (SDRT)both of correct "yes" and "no" reaction times were measured for each memory set. RCT measures the ability to ignore distracting stimuli while responding to a target stimulus. Prior to this task, subjects were informed that the displayed target stimuli, "K" and "H", required a leftward joystick deflection and "S" and "C" the opposite movement. They were told that a target stimulus would always be present on a given presentation, either singly or flanked by two letters on each side (visual angle = 2.5 °). The flankers were either the same as the target (e. g. KKKKK), different but compatible (e. g. HHKHH) or different and incompatible (e. g. SSKSS). Finally, subjects were told to concentrate on responding to the target as quickly as possible and to ignore the flankers, as their influence could delay the response. During the task, the subject was shown a random sequence of 384 patterns, comprising equal numbers of all types, at a rate of one every 2 s. They were given in five blocks, with 30 s rest pauses in between (total time 15 min). Average reaction time (RT) and error frequency (i. e. "misses") normally depend upon the type of pattern presented, and are normally lowest after singleqetter presentations. They increase progressively with redundant, compatible and incompatible presentations. Treatment effects can cause similar or differential increases in RT and misses over all categories.
All variables were tested first in separate applications of repeatedmeasures multivariate analysis of variance (MANOVA). The gender of the subjects was included as a between-group factor in this analysis. Although this factor occasionally produced significant differences, it failed to do so as an interaction either with Drugs of Alcohol, i. e. males and females responded similarly to the treatments. The effects of gender have been ignored therefore. The factor is mentioned to explain why degrees of freedom appearing in the text are less than might have been expected. Driving parameters were tested according to a 3 x 2 factorial model for the main effects of Drugs (Ioratadine-cetirizine-placebo)and Alcohol (present-absent) and their interaction. EEG and psychometric parameters were analyzed in a 3 x 2 x 2 model for the same main effects and Time, and their interactions. The additional factors of Memory Set ( x 3) and Response Category ( x 4) were added to analyse data obtained from the CRT and RCT, respectively. The purpose in both cases was to determine whether treatment effects were the same or different depending upon the type of stimulus presentation in the tests. When MANOVA revealed a significant (P < 0.05) overall difference between drugs and placebo conditions, data obtained after cetirizine and loratadine were separately compared with those obtained after placebo using parallel repeated-measures analysis of variance (ANOVA). Such comparisons allow identification of the specific drug-placebo differences that contribute most to the overall effect. All analyses were conducted by microcomputer employing the SPSS PC + statistical program series [Norusis, 1986].
Results
Blood Alcohol Concentration (BA C) M e a n B A C did n o t differ significantly b e t w e e n c o n d i t i o n s i n v o l v i n g the a d m i n i s t r a t i o n of alcohol with drugs or placebo, n o r b e t w e e n m a l e a n d f e m a l e subjects. T h e g r o u p m e a n B A C s before a n d after the three c o n s e c u t i v e testing periods were 0 . 0 5 7 ~ . 5 3 , 0.37-0.20 (driving) and 0.12-0.2 rag. ml -~.
Drivingperformance T h r e e driving tests were s t o p p e d b y the instructor, who c o n s i d e r e d that the subjects were b e c o m i n g too drowsy to c o n t i n u e safely. T h e y o c c u r r e d twice after the c o m b i n a tion of p l a c e b o a n d alcohol a n d once after cetirizine a n d alcohol, w h e n the c o r r e s p o n d i n g j o u r n e y s had b e e n 80, 35 a n d 55 % c o m p l e t e d . M e a n ( S E M ) s t a n d a r d deviations of lateral p o s i t i o n ( S D L P ) a n d speed (SDSP) in every c o n d i t i o n are s h o w n in Figs. 1 a n d 2. M A N O V A i n d i c a t e d significant effects of D r u g s o n b o t h measures: S D L R F2,13 = 4.31; P < 0.04; and, SDSP, F2, t3 = 4.37; P < 0.04. A N O V A i d e n t i f i e d the separate effect of cetirizine as significant: S D L R F1, 14= 7.99; P < 0,02; and, SDSR F1,14 = 7.07; P < 0.02. T h e s e p a r a t e effects of l o r a t a d i n e were n o t significant; F1, 14= 0.65 a n d 0.02, respectively. B o t h m e a s u r e s were also significantly
366 SDSP(kin/h) 3.0-
Alcohol
No Alcohol
2.B-
2.6
2.4
2.2
2.0 PLA
LOR
CET
PLA
LOR
CET
Fig.l, Mean (SEN) Standard Deviation of Speed (SDSP) after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
affected by Alcohol: SDLP, F1. 14= 17,6; P < 0.001: and, SDSR F1, 14----6.73, P < 0.03. In neither case was the interaction of Drugs and Alcohol significant. TLCls was significantly affected by Alcohol (F1, 14----11.0; P < 0.005), although not by drugs or the interaction of the two factors.
EEG during driving Geometric mean difference spectra were obtained in the following manner. After all energy values recorded at i Hz frequency points were transformed into logarithms, those obtained at a given elapsed driving time in the placebo condition were subtracted from the corresponding values in each of the drug and/or alcohol conditions. The differences
were averaged across subjects per frequency, time and condition. The resulting values were transformed into antilogs (geometric means) for presentation in Fig. 3. Fig. 3 is divided into six parts, A - E The first shows the loratadine-alone difference spectra as a function (z-axis) of elapsed driving time. Those spectra were relatively flat and sometimes negative in the theta and alpha regions, indicating no drug-induced slow-wave activity. In contrast, Part B shows that cetirizine-alone produced considerably more slow-wave activity than placebo, which generally increased as a function of driving time. The effects of alcohol alone, shown in Part C, were similar to although larger, than those of cetirizine. The effects of loratadine and cetirizine, plus alcohol, are shown in Parts D and E, respectively. There was little to distinguish the effect of either on the difference spectra from that of alcohol alone, except perhaps for an earlier rise in slow-wave activity following the combination of cetirizine and alcohol. All energy spectra measured over driving time in each condition were averaged to provide a single spectrum per condition (Part F). It is apparent that loratadine-alone had the least effect on the average difference spectrum. Progressively greather effects were apparent after cetirizine-alone, alcohol-alone, loratadine plus alcohol and cetirizine plus alcohol. Statistical analysis generally confirmes the impressions given by the figure. The effects of Time measured by M A N O V A as the difference between the first and second halves of the test were significant for energies in every frequency band (F1,14 > 800). The effects of Alcohol were significant on energies in both the slow- and fast-alpha bands ( F I , 14 = 6.51 & 5.71, respectively; P < 0.05). The overall Drugs effect on slow-alpha energy was nearly significant (FI, 13--3.72; P = 0.053). Separate ANOVA's revealed a significant effect of cetirizine on slow-alpha (F1, 14= 5.31; P < 0.05) but not of loratadine (F1, z4= 2.32). There was
Fig.3. Geometric mean difference EEG energy spectra (drug and/or alcohol minus placebo) in separate time series ((~60 min) after each of the following; loratadine (A), cetirizine (B), alcohol (C), loratadine + alcohol (D) and cetirizine+ alcohol (E); and, the average mean difference spectra, collapsing across time, for each of those conditions (F). Colour coding is used to indicate EEG frequency bands; red = theta (4-7 Hz), yellow = slow-alpha (8-10 Hz), green - fast-alpha (11-13 Hz), blue = beta (14-20 Hz)
367 Table 1. Major results from MANOVA and ANOVA of the psychometric variables. Significant F-ratios are shown with the associated P-value (*, < 0.05 and **, < 0.01) CTT
DAT a
Lambda c TR
RT
Drugs ( d r = 2,13)
CRT b
RCT c
Q
Q
RT
SDRT R T
-
4.60*
-
4.35*
9.67**
C E T v. PLA
MISS
8.46**
L O R v. PLA (1,14) Alcohol
4.47*
5.85* -
5.60*
4.78*
6.21"
18.5"*
12.0" -
5.10"
11.0"*
5 39*
7.29*
-
6.46*
7.79* 6.68*
(l,t4) Time (1.14) DxA (2,13) DxT (2,13) AxT
ordinate system. Poorer combined subtask performance increases the vector length. Relatively better performance in the tracking subtask than the monitoring subtask rotates the vector counterclockwise from 45 ° (vertical in the figure). The opposite bias rotates the vector clockwise. The effect of alcohol is shown by an extension of the vector in every condition where it was given in combination with drug or placebo in comparison to conditions where the latter were given alone. Yet the length of the vector was not affected by either drug relative to placebo. Instead, both drugs at times caused the vector to rotate in the clockwise direction, particularly cetirizine during the second test replication. This suggests the occurrence of a bias in favor of relatively better performance in the monitoring subtask at the expense of tracking.
Subjective feelings
(1,14) DxAxT (2,13)
'~ Degrees of freedom associated with error variance for these variables is reduced by (1) owing to loss of one subject's data " Effects of memory-load on RT and SDR,rwere, as expected, highly significant (p < 0.001), but there was no significant interaction between memory-load and either drugs or alcohol c Effects of stimulus-type on RT and Misses were, as expected, highly significant (p < 0.001) but there was no significant interaction between stimulus-type and either drugs or alcohol
one significant interaction, an effect of Drugs x Alcohol x Time on fast alpha (F2. i,~= 4.27; P < 0.05). Judged from the data in Fig. 3, this was attributable to the unique rise in fast alpha after cetirizine plus alcohol. The components of the interaction were tested in separate ANOVA's; that involving cetirizine was almost significant (F~, 14= 4.01; P = 0.065), but that involving loratadine was not (F~, ~4= 0.00).
Psychometric performance Significant results in the psychometric tests are summarized in Table l. Alcohol affected most performance measures in the expected directions. The Alcohol x Time interaction was significant for lambdac as obtained in the CTT, and the general performance quality score (Q), obtained in theDAT. In both cases, the greatest impairment was measured in the first test replication. The overall effect of Drugs was significant in only two tests, CRT and DAT. In both cases, separate drug-placebo comparisons showed that cetirizine was primarily responsible for the overall effect. Cetirizine significantly increased the variability of the reaction time (SDRT) in the CRT, although not the mean reaction time (RT). Cetirizine also significantly affected performance in the D A T the way illustrated in Fig. 4, which presents the mean D A T performance quality and bias of the subjects by, respectively, vector length and angular rotation in a circular co-
Among the side effects rated by the subjects only "drowsiness" showed a significant treatment effect. This feeling was influenced by Drugs (F2, 13= 4.30; P < 0.04) as well as Alcohol ( F 1 , 14 = 5 . 1 1 ; P < 0 . 0 4 ) . Separate comparisons of drowsiness scores after cetirizine and loratadine versus those following placebo revealed an almost significant effect of the former (F1,14 = 4.40; P = 0.055), but none of the latter (F,. ~4= 0.17). As shown in Fig. 5, the greatest feelings of drowsiness occurred after the combination of cetirizine and alcohol, when the mean score was about midway between "none" and "severe".
Discussion and c o n d u s i o n
The results of the study consistently demonstrate that cetirizine 10 mg possesses acute sedative activity. It significantly impaired driving performance, altered E E G energy spectra in the direction of electrocortical deactivation and caused marked feelings of drowsiness during driving. On the other hand, loratadine 10 mg had no significant effect on any of the measured variables. The conclusion appears inescapable: after single recommended doses cetirizine is sedative and impairing whereas loratadine is not. The difference between the effects of the antihistamines on performance, E E G and subjective feelings during the driving test cannot easily be attributed to pharmacokinetic factors. According to the data cited above, the peak plasma concentrations of both drugs should have occurred well in advance of the driving test. The slightly faster absorption and elimination of cetirizine should have led to lower plasma concentrations as a proportion of its Cm~×than those of loratadine during the test. The apparently greater sedative activity of the former may instead be attributed to more rapid penetration of the blood-brain barrier, or greater affinity for central histamine receptors, or to both. The practical relevance of these results should not be exaggerated. The sedative activity of cetirizine might diminish due to tolerance developing during the course of therapy. Even if the observed degree of performance im-
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Fig.4. Mean performance quality (vector) and subtest bias (angle) in the Divided AttentionTest (DAT) for the first (left) and second (right) test repetitions after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
BIAS (o)
Subjective drowsiness (max=10) 8
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Fig. 5. Mean (SEM) reported drowsiness after driving after placebo (PLA), loratadine (LOR) and cetirizine (CET), with and without alcohol
pairment were to persist, it would not necessarily constitute an important safety hazard for patients engaged in potentially dangerous tasks, such as driving. The mean elevations in speed and lateral position variability after cetirizine alone were less than those following alcohol alone while the mean blood concentrations in the subjects declined from 0.37 to 0.20 mg. ml- 1. Alcohol but not cetirizine significantly reduced the time available for the subjects to correct the course of the vehicle before it would stray from the traffic lane (i. e. TLC). Even such low blood alcohol concentrations had a greather influence on driving performance than cetirizine 10 mg. The effects of cetirizine on driving in this study were not very different from those of other "nonsedating" antihistamines given in multiple, higher than normal doses to healthy volunteers [Riedel et al., 1990]. Loratadine 20 mg OD and terfenadine 120 mg b.d. significantly elevated SDLP in the standard test on the first and fourth day of separate treatments to almost the same extent as did cetirizine here. It appears as if every modern antihistamine penetrates the blood brain barrier. Whether its brain concentration exceeds a threshold causing sedation and per-
formance impairment depends on the administered dose and the pharmacokinetic factors responsible for accumulation of the drug. The only apparent difference between cetirizine and the other antihistamines is that the former has a lower ratio of the sedative to recommended therapeutic doses. This simply means that sedation is more likely to occur when patients take cetirizine, as it is ordinarily prescribed, than the other antihistamines. The present study appears to have been the first to demonstrate the capacity of cetirizine to impair performance after a single 10 mg dose. Ostensibly well conducted studies by Gengo et ai. (1987) and Seidel et al. (1987), among others, failed to show any significant effects in various short-term psychometric tests. Betts et al. (1989) were able to measure significant impairment in certain staged driving manoeuvres 2-3 h after a single 20 mg dose but none after a 10 mg dose. The question is why acute impairment by the drug was observed here but not previously. The answer may lie in the duration and monotonous nature of the highway driving test. It lasted 6-12 times longer than most conventional psychometric tests used to assess drug effects. It is not unreasonable to suppose that some sort of decrement in vigilance normally occurs in subjects performing the driving test and that it is accelerated by drug-induced sedation. It might have been difficult to discriminate between the effects of cetirizine and placebo in a driving test lasting only for 5-10 min, just as it was to measure significant differences between those conditions using the present test battery. All that was found after cetirizine was an increase of reaction time variability within individuals in the CRT and a change in how they chose to divide their attention between subtasks in the DAT. No overall impairment of performance occurred in either test. Without the diverse and mutually supportive results obtained during the driving test, we would have had to join previous investigators in concluding that cetirizine 10 mg had little or no effect on performance. Alcohol not only served as a challenging agent to evaluate antihistamine effects, it also served as the positive control. Changes in driving performance after alcohol alone were as expected on the basis of a previous dose-effect study by Louwerens et al. (1987). Those authors derived an empirical equation for predicting the change in
369 S D L P f r o m p l a c e b o levels with i n c r e a s i n g b l o o d a l c o h o l c o n c e n t r a t i o n s . T h e p r e d i c t e d effect at 0.40 m g - m l - ~ was a m e a n rise o f 2.1 cm, close to t h e significant m e a n eleva t i o n of 2.6 c m actually o b s e r v e d . E E G a l p h a activity was also significantly a f f e c t e d b y alcohol. E v e r y o n e of the p s y c h o m e t r i c tests a d m i n i s t e r e d while t h e B A C s of t h e subjects w e r e b e t w e e n 0.60 a n d 0,50 r a g - m l - 1 in the first r e p e t i t i o n , a n d a b o u t 0.10 m g . m l - 1in the s e c o n d , s h o w e d s o m e significant effect. N e i t h e r a n t i h i s t a m i n e p o t e n t i a t e d the effect of alcohol. H a d t h a t b e e n the case, a significant D r u g x A l c o h o l i n t e r a c t i o n w o u l d h a v e b e e n e x p e c t e d in the results. T h e lack of a n y such i n t e r a c t i o n i n d i c a t e s t h a t t h e two factors w e r e i n d e p e n d e n t . W h e n b o t h factors c a u s e d significant imp a i r m e n t in t h e s a m e test (e. g. driving), t h e i r effects w e r e additive.
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Dr. J. G. Ramaekers Institute for Drugs, Safety and Behavior Beeldsnijdersdreef 85 NL-6216 EA Maastricht The Netherlands
