Sedation, Cognition, and Antihistamines Julie C. Qidwai, BS, Ginger S.Watson, PhD, and John M. Weiler, MD
Address National Advanced Driving Simulator and Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52244, USA. Email:
[email protected] Current Allergy and Asthma Reports 2002, 2:216–222 Current Science Inc. ISSN 1529–7322 Copyright © 2002 by Current Science Inc.
First-generation antihistamines are well-known to cause subjective drowsiness. A myriad of studies has also been published that suggest a clear relationship between the use of these drugs and objective performance impairment. Although not all of the tests used in these studies have been validated, the data are fairly consistent, and suggest a difference between earlier (first-generation) sedating antihistamines and the newer (second-generation) nonsedating antihistamines.
Introduction In late 2001, the US National Transportation Board (NTSB) and the US Food and Drug Administration (FDA) held a joint hearing to consider the labeling of drugs that have the potential to impair performance. Witnesses at this hearing suggested the need for the development and use of standardized performance tests that can be used to define which drugs are impairing. In the end, it was agreed that it is important for practitioners and their patients to have a clear understanding of which drugs may cause impairment, how much they may cause, and whether this impairment can be appreciated by the affected individual. In this review, we consider the potential for antihistamines to cause impairment. Antihistamines have been used very widely for more than 50 years to treat allergic and dermatologic disorders, and it is important to understand how we have tested these drugs for impairment, and what their effects may be. More than 26 million American adults suffer from allergic rhinitis [1]. In 1997, doctors wrote more than 11.5 million new and refill prescriptions to treat allergies [1]. It is difficult to estimate total sales of over-the-counter antihistamines, but the numbers are likely to be even higher than those for prescription drugs. Consumers have an obvious need to know whether the medications they take have performance-impairing or sedating side effects. They need this knowledge to make intelligent choices about whether to perform complex tasks such as driving an automobile. Unfortunately for the consumer, the FDA, which requires extensive pharmacologic, safety, and
efficacy testing for all new drugs, has no requirements for performance testing to detect impairment with potentially sedating drugs. Sedation is recorded as an adverse event in efficacy and safety studies. In fact, very few clinical trials are released without at least one participant reporting an instance of drowsiness or fatigue. Therefore, drowsiness is listed as a possible side effect on the packaging information of most prescription drugs. Additionally, the standard warning regarding driving and operation of heavy equipment is often attached to drugs somewhat indiscriminately—according to drug class (eg, benzodiazepines, firstgeneration antihistamines) rather than based upon the unique nature of each agent. There is a sea of literature from hundreds of research laboratories regarding the sedating properties of first-generation antihistamines. Health-care professionals must digest all of this information (and many reports offer conflicting results) and attempt to provide patients with an informed opinion regarding whether or not safe drug usage entails restriction of daily activities. The confusion over antihistamines is so great, in fact, that some pharmacies place stickers on medication bottles warning patients about driving after taking any antihistamine, even fexofenadine and loratadine, which have almost never been observed to impair performance or cause drowsiness when taken as prescribed [2••,3]. Many over-thecounter medications for treatment of allergy symptoms have significant sedative side effects. Patients who rely on these drugs may have no contact with health-care professionals at all before self-medicating. The burden of warning the patient then falls to the package information, which the patient may or may not read or heed.
Sedation and Impairment It is well established that drug-induced sedation can be broken down into two components [4]. The first is objective performance impairment, which refers to a drug’s propensity to cause deficits in information processing and psychomotor performance. Researchers have devised many methods of testing for performance impairment, only some of which have sufficiently valid evidence for their use. The second characteristic of sedation is subjective drowsiness, which, by its nature, is a quality only noticeable to the patient. Subjective drowsiness is most commonly evaluated using visual analogue scales (VAS), or drowsiness measurement applications such as the Stanford Sleepiness Scale. Many patients rely on their own perceptions of their drowsiness to indicate when they are not fit to perform difficult or complex tasks.
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As a subjective phenomenon, drowsiness may be overcome, with patient tolerance commonly accruing after sedating drugs have been prescribed for long periods as part of acute-treatment protocols [5,6]. Performance impairment, on the other hand, is not thought to resolve over time, because the drugs continue to exert the same pharmacologic effects on the central nervous system regardless of how long they are taken [7•]. Unfortunately, the two aspects of sedation are essentially unrelated. A number of studies have shown that participants’ own ratings of their performance and alertness do not correlate with objective performance measures. We found that correlations between subjective drowsiness and simulated driving performance (for distance between cars, steering instability, and straying into the left lane) never rose above r = 0.21 even though P values were less than 0.001 [8••]. Similarly, Walsh et al. [9] noted that two subjects in their study of complex performance gave their best performances after rating themselves as high as possible on sleepiness after taking cetirizine. Similar findings have appeared in the literature on alcohol intake. It is useful to know whether or not patients feel drowsy after taking a drug, especially to categorize an adverse event, but this feeling may be completely unrelated to the ability to perform complex tasks. Many patients and even some healthcare providers are unaware of the lack of association between the two, and this fact must be more widely publicized, lest patients believe that they are fit to drive if they think they feel alert.
Performance Testing Each researcher has his or her own “pet” performance measures, resulting in the glut of conflicting research reports. Hindmarch et al. [2••] have reviewed many of these tests, and have reported the variability in results obtained with different measures. Table 1 displays many of these tests. The critical questions are: Which of these measures correlate best with actual driving performance, and how well do they correlate? Moreover, it is important to determine the correlation between subjective drowsiness and measured levels of impairment. It is for these reasons that a need exists for a standard set of tests that could be used to categorize agents and to determine those that should be classified as impairing. These standard tests would be invaluable to doctors and patients, and could revolutionize warning labels on drugs. Currently, almost none of the testing paradigms listed by Hindmarch [2••] are commercially available, and each group attempting to do research in this area must develop its own tests. Moskowitz [10] has suggested that the ideal test for drug effects on skills performance is a divided-attention task (with at least two subtasks). This task should be so difficult or attention-consuming that it causes a performance decrement in one or both of the component tasks. The component tasks must also be chosen to require time-sharing in
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performance; time-sharing between the two tasks must be a part of whole-task performance. Divided-attention tasks designed with these considerations in mind have discriminated between participants who had 0.02% and 0% blood alcohol concentrations (BACs) [10]. However, there is a wide variety of divided-attention tasks and subtasks that can be and have been studied. This variation often leads to different conclusions depending upon which test is selected. For example, there are three types of tracking tasks that are commonly used—continuous, adaptive, and critical. It is not clear which of these is the most diagnostic as part of a divided-attention test. Driving performance Driving an automobile has frequently been characterized as a divided-attention task. The two component tasks commonly identified in driving are vigilance (for other vehicles and traffic movement patterns) and tracking (maintaining lateral lane position). These component tasks are performed in parallel, and significant time-sharing is required. Consider what happens to speed maintenance and lane tracking when a driver is searching for an address somewhere along the driving route. Other component tasks (or distractors) may be added to the driving task as well, including activities such as maintaining distance between cars, tuning a radio, and using a cellular/digital phone. Standard Dutch test Dutch researchers [11,12] have led the charge for testing the performance effects of drugs on driving. O’Hanlon et al. [11] developed a “standard” on-the-road driving task. Their test involves navigation of a 100-km highway circuit while maintaining a constant speed and lane position. The main performance measure in this test is standard deviation of lateral position (SDLP). This is a measure of the variability of the driver’s path around his or her line of best fit within the lane. This Dutch test has detected the sedating effects of many firstgeneration antihistamines, and of anxiolytics, and a few second-generation antihistamines (notably cetirizine) as well. The standard Dutch test demonstrates information processing decrements associated with sedating drugs and is a long enough test to allow participants to begin to exhibit significant symptoms of drowsiness. When alertness is high, participants may perform well because of motivation and familiarity with the task [13]. However, after 30 minutes of uneventful driving (with or without drugs), drivers begin to lose interest in the task at hand. As mental stimulation is reduced with tiredness, the brain begins to depend on the environment for stimulation, and, not finding it, the driver begins to exhibit classic signs of extreme sleepiness with associated performance loss. These include lapses (microsleeps), decrements in vigilance, and response criterion shifts (such as increases in reaction time [14]). However, length of the drive is not the sole basis that determines whether these impairments will occur and be observed. The nature of the driving scenario should also be
Description
May help to study the neurologic bases of sedation/impairment
Analog of steering performance
Driving in traffic in a vehicle instrumented to collect data “Driving” in an environment and scenario designed by researchers while performance data are collected
Meaningful to real-world driving performance Meaningful to real-world driving performance, safe
9/9 6/6 High-fidelity simulation is expensive and complicated; low-fidelity simulation does not mimic real world
6/6
44/48
15/15
8/8
1/1 5/5
8/8
Potentially dangerous
Must be correlated with performance impairment; usually correlation is low
Must be correlated with performance impairment; usually correlation is low
Little agreement about whether to use adaptive, continuous or critical tracking tasks Low face validity, complicated and expensive to administer
Some of these tests may not be particularly important in relation to everyday behavior or psychomotor performance; needs standardization; depends upon baseline ability of subjects Elicits drowsiness responses Long administration time Divided attention is a good analog of Long tasks border on vigilance domain complex real-world performance
Depending upon the test, may be relevant to real-world behavior
9/9
13/15
18/20
Past Track Record*
*Based on Hindmarch [2••]—Number of tests reviewed showing impairment vs. total number of tests for antihistamines whose impairing and sedating qualities are well known (chlorpheniramine, clemastine, diphenhydramine, triprolidine and hydroxyzine).
Simulated driving
Stanford Sleepiness Scale Driving Performance On-the-road driving
Subjective Measures Visual analog
Limited generalizability to real-world performance Limited generalizability to real-world performance
Well-validated test Easy to administer
Simplistic—simple RT has not reliably shown performance decrements
Cons
Has some relevance to real-world behavior; well-validated test
Pros
Patient bisects 100-mm line with endpoints Very easy to administer labeled (eg, very sleepy vs. not at all sleepy) to indicate drowsiness Patient selects level of drowsiness on Very easy to administer 7-point scale
MSLT, P300
EEG measures
Tracking
Listen or watch for infrequent signals Many varieties—simple and divided— typically monitoring a stream of information for signals or to respond to later questioning Follow moving target with cursor
Vigilance Attention
Button press in response to frequent stimulus—or choose from a number of buttons corresponding to several stimuli Critical flicker fusion Identify the point at which a pair of light flashes merge into one (see above) Digit symbol substitution Paper and pencil--fill in a symbol for each digit presented according to a scheme given at the top of the page Memory Many tests have been based upon memory— list memory, recognition, recall
Reaction time (simple/choice)
Laboratory Tests
Table 1. Common testing paradigms for drowsiness and performance impairment
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essentially designed to impact on the subject’s alertness, eg, it should be boring. Rural and other low-traffic environments with few intersections and interactions with other vehicles are ideal for this sort of evaluation. Other performance criteria Other researchers have measured the driver’s ability to follow a lead vehicle as closely but also as safely as possible [8••,12]. Coherence, phase shift (phase angle), and root mean square (RMS) error are the endpoints in such an investigation. We used the Iowa Driving Simulator (IDS) at the University of Iowa to simulate a 50-mile drive after participants had been dosed with fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (to 0.1% BAC), or placebo [8••]. Participants exhibited poor lane tracking (more lane excursions) after diphenhydramine and alcohol consumption compared with placebo and fexofenadine. They also reacted more quickly to an emergency driving situation after taking fexofenadine than after receiving alcohol (although this difference was not significant). Additionally, coherence with a lead vehicle was significantly better after alcohol and placebo than after diphenhydramine. The lack of a coherence deficit associated with a 0.1% BAC may seem unusual, but is a recognized phenomenon in the alcohol literature [15]. Alcohol-impaired participants who must divide their attention between two tasks often concentrate on one, resulting in relatively good performance on that task (the primary endpoint, in our study), with considerable impairment in the performance of the other task(s). Participants who received alcohol in this study apparently concentrated their attention on maintaining following distance while neglecting to maintain lane position, as evidenced by large numbers of center-line crossings. Driving simulators Driving simulators offer considerable advantages over the use of on-the-road driving tests. Following distance illustrates one of these advantages. The lead car can vary its speed considerably without risking injury to the driver of either the lead car or the test car. Simulators also offer the chance to test standard driving behaviors (such as keeping an adequate distance between cars, and keeping to one’s lane) as well as sudden, potentially dangerous scenarios that could not be tested in on-the-road studies. An additional important advantage of simulators is the ability to reuse precisely the same driving scenario for each participant after receiving each study drug. This may allow for reduced within- and between-subject variability and relatively simple replication of studies. Driving simulators also allow researchers to program driving scenarios that are ideal to test for drug effects. Researchers have control over weather conditions, opposing traffic, sudden obstacles, and any other environmental element perceived to assist in the discrimination of drug effects. It is important to note that simulation studies vary considerably in technology as well as design. Some studies have used a desktop computer to present a driving
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scenario, whereas others, such as the studies that we have performed and reported, were performed in an immersive environment with complex scenarios, wide field-of-view graphics, and a real car sitting in a domed structure with a hexapod motion base tuned to create vehicle movement appropriate to the scenario. Similarly, some studies have used a challenging, game-like scenario, whereas others have relied upon a long, boring drive to enhance the opportunity for drowsiness and driving impairment. The Daimler-Benz study The technology and design of a study may have major impact on the results that are observed with a given agent. For example, diphenhydramine is generally considered to be sedating and impairing, and is frequently used as a positive control in driving studies. However, one simulator study using the Daimler-Benz driving simulator, a high-end design, failed to show any significant impact of diphenhydramine on driving performance (except that the diphenhydramine-treated subjects were so drowsy that they required assistance in exiting the simulator) [16]. In that open-label study, doses were based on participant weight, and averaged 46 and 70 mg for the low-dose and high-dose–treated groups, respectively, which were compared with a placebo-treated group. Driving performance was worse following the lower dose as compared with the higher dose of diphenhydramine. The study was designed to: 1) include between-subjects analysis; 2) enroll males only between the ages of 22 and 26 (because women’s driving is reported to be more impaired by a given dose of antihistamine than men’s driving [11]; 3) avoid strict control of the time between dosing and driving, even though the time allowed for drug absorption was variable among participants; and 4) allow participants to sleep while waiting to drive. The drive lasted about 20 minutes. It included a total of nine critical events such as driving through snow, merging into traffic, and reacting to another vehicle darting into the driving path. Thus, the overall driving scenario offered an emergency every 2 minutes, and can be viewed as excessively alerting and not consistent with the everyday experience of driving an automobile. Why were drivers who took the higher doses of diphenhydramine less impaired than those who received the lower doses? The authors of the study suggested that drivers who had ingested the high diphenhydramine doses realized that they were impaired (because they were drowsy or recognized their impairment, or knew that they should be drowsy and impaired because they had been told that they had received the high dose of diphenhydramine) and adjusted their driving responses to make up for this impairment. This implies that driving performance can be improved only if the subject knows that he or she may be impaired. Perhaps it is true that subjects had modified their behavior based upon actual knowledge of what treatment they had received; however, in our study [8••], there was very poor correlation between subjective reporting of drowsiness and objective impairment. We found that the
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best correlation was between drowsiness and left-lane excursions, and in that case, although the P value was 0.01, the r2 was only 0.044. The results of the Daimler-Benz driving simulator study are also in disagreement with the vast majority of studies that demonstrate that diphenhydramine is impairing. Only two out of the 57 studies that used diphenhydramine and were reviewed by Hindmarch [2••] showed lack of impairment, and one was the Daimler-Benz study. Another review by Hindmarch [3] suggested that diphenhydramine was only outranked in its impairment qualities by triprolidine. The Iowa study The design and results of our study differ considerably from the Daimler-Benz study [8••]. We compared diphenhydramine, fexofenadine, and placebo for their effects on driving performance. Diphenhydramine significantly increased the number of lane excursions observed, and also had significant negative effects on car-following performance. This study used a within-subjects design; included participants between the ages of 25 and 45, both men and women; utilized a double-blind, double-dummy dosing protocol; kept absorption time constant; and monitored participants to prevent them from falling asleep. Sufficient washout periods of other medications and alcohol were also observed in this study, whereas the Daimler-Benz researchers made no attempt to control this. The test drive was approximately 1 hour long. It began with a 15-minute car-following segment, followed by 45 minutes of monotonous driving on a rural two-lane road with minimal traffic in the opposing lane. The most difficult feature of the drive was negotiation of moderate curves, two in each direction. Only at the very end of each participant’s last (fourth) drive in the simulator did he or she encounter a single emergency situation of a car pulling out of a driveway across the driving path. Therefore, this study gave good evidence of the ability of drivers to maintain complex divided attention performance; drivers were subjected to a long drive in an environment that did not encourage alertness. Tests of driving performance have good face validity (eg, meaningful generalization to real-world driving conditions). Researchers and the lay general public both recognize the driving task as a potentially dangerous activity performed on a daily basis. Many laboratory tests for drowsiness and performance impairment are somewhat arcane and difficult to associate with real-world performance decrements (eg, critical flicker fusion, evoked potentials, letter cancellation). In contrast, driving measures are relatively simple to interpret. The consequences of frequent lane excursions and slowed reaction times to emergency situations are very apparent to researchers and the general public alike.
Relevance The face validity and relevance of driving tests offer an important opportunity to drug manufacturers and those
charged with creating warning labels for potentially sedating drugs. For example, in addition to efficacy testing, drugs could be subjected to a standardized driving test and given a rank according to their impact on driving performance. This would be useful in permitting comparison of drugs for their potentially impairing capacities. If such tests were to be accepted by regulatory authorities, then this could even become a part of drug labeling. O’Hanlon suggested using his SDLP measure and standard driving test for this purpose in 1984 [17], but in the United States, no action has been taken on his suggestion to date.
Critical Flicker Fusion Many tests with high criteria-related validity (high positive correlations with scores on similar/related abilities) simply do not have the same relevance or face validity as a driving performance task. Critical flicker fusion, for example, is a test in which participants view a series of pairs of flashing lights. The temporal separation between the two lights is gradually decreased, and the participant reports when he or she can no longer observe the separation (ie, each presentation appears as only one flash, rather than a pair). This test has proven quite reliable in distinguishing among first- and second-generation antihistamines [18]. Nevertheless, critical flicker fusion is a laboratory test. It seems unlikely that this test would convince most construction workers that a lack of ability to see the separation between blinking lights suggests impairment of the ability to operate a backhoe after taking chlorpheniramine.
Multiple Sleep Latency Test Likewise, the multiple sleep latency test (MSLT) is a sensitive measure. Participants in this test are connected to EEG equipment and asked to lie down and rest in a darkened room. Researchers then monitor their EEG patterns for characteristics of stage 1 sleep and wake participants up after stage 1 occurs, or 20 minutes pass. The test is administered repeatedly to assess mean sleep latency [19]. There is no doubt that this technology is valuable for use in research with sleep disorders and also with determining a drug’s potential for causing its users to fall asleep [20]. However, the situation in which the MSLT is administered is not analogous to the situations in which sedating drugs are dangerous. When people drive, they know that they must not fall asleep at the wheel, in the same way assembly line workers know they are not allowed to sleep on the job. In everyday situations, when one must stay awake, the continued effort to maintain wakefulness may even lead to reductions in alertness beyond what would be expected from drug effects alone. When the MSLT is administered, on the other hand, patients are asked to lie quietly on a bed in a darkened room. In the situation in which the MSLT is administered, it is obviously acceptable to fall asleep, and indeed, the ability to fall asleep is what the MSLT gauges.
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P300 Evoked Potential Test A somewhat related test reported to demonstrate the effects of sedating drugs such as first-generation antihistamines and anxiolytics is the P300 tonal oddball or evoked potential test [21,22]. The measure in this test is the appearance of a characteristic EEG pattern (the P300). Participants in such a test are connected to EEG equipment and presented with a series of regular auditory tones. The participant is instructed to respond to a different tone, presented infrequently and randomly, called the oddball. The primary measure in such a study is typically the latency to P300 following the tonal oddball. Using this type of test, Loring and Meador found that terfenadine produced significantly less slowing of the P300 evoked potential than chlorpheniramine. While this test may allow researchers to come closer to discovering precisely which neurologic functions are altered by sedating drugs, the P300 is another test with limited generalization to real-world tasks. It is difficult to draw a meaningful connection between a single EEG pattern and complex performance like driving.
Simulated Assembly-line Task One ingenious performance testing scenario has been introduced by Walsh et al. [9,13]. It is known as the simulated assembly line task (SALT), and functions as a complex divided attention task. The participant in a SALT study views images of electronic circuit boards as they pass before him or her on a simulated assembly line on a video screen. Participants are instructed to inspect each circuit board visually for manufacturing errors, to discard unrepairable boards, and to attempt to repair boards with certain kinds of errors. They are also required to respond to periodic “alarms,” giving the task an additional vigilance component. Signal detection parameters are measured for the assembly line task (such as correct rejections and false alarms), as well as response times and correct repair rates. The SALT is the kind of test whose results might be able to convince workers in dangerous manufacturing settings that some drugs really can cause safety risks. It has discriminated between 25 mg hydroxyzine and 10 mg cetirizine in an 8-hour testing period. When study participants took hydroxyzine, they made significantly fewer correct responses, correct discards and correct repairs than they did after taking cetirizine or placebo [9].
Conclusions Clearly, there is a myriad of tests available to assess impairment. Many of these are laboratory tests that have been performed by multiple groups to demonstrate impairment with drugs that cause drowsiness (as has been found for antihistamines). Unfortunately, the majority of these tests appear to lack generalizability to real-world performance decrements. Moreover, there is no requirement from the United States drug regulatory authorities requiring evaluation of the impairing capacities of drugs. Consequently, impairing
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drugs still remain on the market and are taken in situations in which their impairment may have negative consequences. It would be virtually impossible to subject every drug to testing in a sophisticated driving simulator to determine its risk of causing impairment. However, drugs that cause drowsiness should all be examined thoroughly to determine their capacities to impair, and to determine whether subjective drowsiness can be used to indicate impairment in patients taking this drug. And since impairment and drowsiness are not always associated (as has been explained above), even drugs causing limited drowsiness should at least be subjected to a standard battery of laboratory tests to assure that they are likely to be safe to take for people who drive a car, pilot a plane or boat, or operate machinery. Drug warning labels need to be improved. Labels are often ignored because they are applied indiscriminately to substances without regard to the likelihood or significance of their impairment capabilities. For example, it is inappropriate to label either fexofenadine or loratadine as sedating or impairing. Patients are left with the impression that all antihistamines cause drowsiness and impairment, and then may make poor decisions in their selection of medications. A new, more accurate and understandable labeling standard is long overdue, and would give patients (and health care providers) the ability to discriminate between drugs that necessitate activity restriction and those that do not.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Malone DC, Lawson KA, Smith,DH, et al.: A cost-of-illness study of allergic rhinitis in the United States. J Allergy Clin Immunol 1997, 99:22–27. 2.•• Hindmarch I, Shamsi Z: Antihistamines: Models to assess sedative properties, assessment of sedation, safety and other side effects. Clin Exp Allergy 1999, 29(S3):133–142. Excellent, useful review of the effects of many different antihistamines on performance in tasks from digit-symbol substitution to on-road driving. Gives a ratio of studies showing impairment to studies showing no impairment for each reviewed drug. 3. Hindmarch I: Psychometric aspects of antihistamines. Allergy 1995, 50:48–54. 4. Gengo FM, Dabronzo J, Yurchak A, et al.: The relative antihistaminic and psychomotor effects of hydroxyzine and cetirizine. Clin Pharmacol Ther 1987, 42:265–272. 5. Moskowitz H, Smiley A: Effects of chronically administered buspirone and diazepam on driving-related skills performance. J Clin Psychiatry 1982, 43:45–55. 6. Volkert ER, van Willigenburg AP, van Laar MW, Maes RA: Does cetirizine belong to the new generation of antihistamines? An investigation into its acute and subchronic effects on highway driving, psychometric test performance and daytime sleepiness. Hum Psychopharmacol 1992, 7:227–238. 7.• Hindmarch I: It's all in the mind: Measuring somnolence and CNS drug side effects. Hum Psychopharmacol 1998, 13:385–387. Discusses differences between the subjective and objective effects of drugs affecting the central nervous system (CNS). Also touches on building tolerance to performance impairment and the lack of correlation between alertness and performance impairment.
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8.•• Weiler JM, Bloomfield JR, Woodworth GG, et al.: Effects of fexofenadine, diphenhydramine and alcohol on driving performance: A randomized, placebo-controlled trial in the Iowa Driving Simulator. Ann Intern Med 2000, 132:354–363. Reports on a clinical trial comparing the effects of alcohol, diphenhydramine, and fexofenadine on driving performance in the Iowa Driving Simulator. Diphenhydramine and alcohol significantly impaired driving performance in a number of measures, but fexofenadine did not. Diphenhydramine was associated with high levels of subjective drowsiness; fexofenadine did not cause participants to feel drowsy. 9. Walsh JK, Muehlbach MJ, Schweitzer PK: Simulated assembly line performance following ingestion of cetirizine or hydroxyzine. Ann Allergy 1992, 69:195–200. 10. Moskowitz H: Attention tasks as skills performance measures of drug effects. Br J Clin Pharmacol 1984, 18:51S–61S. 11. O'Hanlon J, Ramaekers J: Antihistamine effects on actual driving performance in a standard test: A summary of Dutch experience, 1989–1994. Allergy 1995, 50:234–242. 12. Brookhuis KA, de Vries G: Repeated dose effects of two antihistamines upon actual driving performance. Paper presented at Proceedings of the 11th International Conference on Alcohol, Drugs and Traffic Safety, October 24–27, 1989, Chicago. 13. Schweitzer PK, Muehlbach MJ, Walsh JK: Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 1994, 94:716–724. 14. Dinges DF, Kribbs NB: Performing while sleepy: Effects of experimentally-induced sleepiness. In Sleep, Sleepiness and Performance. Edited by Monk, TH. Chichester: John Wiley and Sons; 1991:97–128.
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