Effects of Fexofenadine, Diphenhydramine, and Alcohol on Driving Performance

Allergic rhinitis afflicts more than 39 million persons in the United States (1). Only about 4.8 million persons (12%) take prescription drugs for this condition; most go without treatment or self-treat with over-the-counter medications, which generally contain a first-generation antihistamine. These medications may be effective but carry potential risks, including drowsiness and impairment in performing everyday tasks (2-6). These adverse events may be sufficient to dissuade some persons from treating their symptoms. Other patients take these sedating drugs, become impaired, and try nonetheless to perform complex tasks; as a result, they are more likely to be involved in collisions (2, 7, 8). Our goal was to examine automobile driving performance, a complex multiaspect task requiring mental alertness; visual, auditory, and kinesthetic information processing; eye-hand coordination; and manual dexterity. By using the Iowa Driving Simulator, a unique state-of-the-art facility, we evaluated driving performance measures and self-ratings of drowsiness to determine the effects of alcohol and first- and second-generation antihistamines on driving performance. No previous study has compared the effects of these drugs in the highly controlled environment of a driving simulator. Methods Study Design During ragweed season, we compared the effects of fexofenadine (60 mg), a second-generation antihistamine; diphenhydramine (50 mg) (Benadryl, Warner-Lambert Co., Morris Plains, New Jersey), a first-generation antihistamine; alcohol; and placebo on driving performance and self-reported drowsiness of persons who were allergic to ragweed. A randomized, double-blind, double-dummy, crossover design was used (9). The University of Iowa Institutional Review Board approved the study, and all participants signed a consent form before participation in the study. Inclusion and Exclusion Criteria Key inclusion criteria were ability to remain for 5 hours after the drives, history of alcohol use and willingness to consume alcohol, age 25 to 45 years, seasonal allergic rhinitis caused by ragweed pollen, previous successful use of antihistamine to treat seasonal allergic rhinitis, status as a currently licensed experienced driver who drove an average of at least three times a week for at least 3 years, and 20/20 corrected vision. Key exclusion criteria were medical conditions that might interfere with ability to perform the study, pregnancy or lactation, unusual sleep patterns (including those of third-shift workers), excessive alcohol consumption, use of tobacco in the past year or excessive caffeine consumption, previous experience in the Iowa Driving Simulator, and a positive result on a drug screening test. Procedures At visit 1, participants were selected on the basis of inclusion and exclusion criteria. Qualified participants drove in the Iowa Driving Simulator for 8 minutes; those with a tendency to develop simulator sickness were excluded. Visits 2, 3, 4, and 5 (treatment visits) occurred weekly on the same day at the same time. Participants avoided consuming food or beverages, except water, for 2 hours before these visits. Participants completed the baseline drowsiness visual analogue scale immediately before taking a capsule of fexofenadine, diphenhydramine, or placebo; the drive was scheduled to start 2.5 hours later to coincide with peak levels of antihistamine. Both researchers and participants were blinded to the treatment given. After treatment, participants were permitted to consume only fluids; caffeine, stimulants, and depressants were excluded. Vital signs were determined and participants completed the second drowsiness scale 1 hour after taking the capsule. The study beverage was dispensed 60 minutes before the scheduled drive and was consumed over 20 to 30 minutes with a light snack. The dose of alcohol (or placebo alcohol) was derived by using an algorithm that included the participant's sex and weight to reach an estimated blood alcohol concentration of 0.1% (21.7 mmol/L) (10). Male participants received the equivalent of 800 mg of absolute alcohol per kg of body weight, and female participants received 640 mg/kg. Ninety-five percent alcohol (or placebo alcohol) was added to a glass, which was filled with the participant's choice of noncaffeinated carbonated soda. Alcohol was swabbed on the rim of each glass to maintain blinding. Immediately before and after the drive, participants again completed drowsiness scales. After the drive, study staff determined vital signs. Participants were observed until they were sober. To maintain the double-blinding of the alcohol treatment, participants remained for 5 hours or until the blood alcohol level was less than 0.03% after alcohol and after one of the other treatments (selected randomly). An unblinded Clinical Research Center nurse with no other study role determined alcohol levels by using a breath analyzer (Alco-Sensor, Intoximeters, Inc., St. Louis, Missouri). Treatment Preparation and Randomization Capsules (fexofenadine, diphenhydramine, and placebo) were blinded and packaged by Hoechst Marion Roussel, Inc. (Kansas City, Missouri). The Division of Pharmaceutical Service, College of Pharmacy, University of Iowa, Iowa City, Iowa, prepared alcohol and placebo beverages. Driving Simulation The Iowa Driving Simulator allowed collection of data on driving performance measures in a manner not available with on-street driving (11, 12). Briefly, the simulator consists of a domed enclosure mounted on a hexapod motion platform. The inner walls of the dome act as a screen on which correlated images are projected. The experimental drive was conducted in dry weather conditions, with good visibility, on a two-lane rural highway that was 72.4 km (45 miles) long. The lane widths were standard (3.66 m [12 ft]) and the road surface was standard blacktop. The posted speed limit was 88.6 km/h (55 miles/h) for most of the course. Vehicles in the oncoming lane simulated low-density traffic. Participants practiced driving in the simulator for 8 to 10 minutes before each experimental drive. The experimental drive consisted of two phases driven consecutively without interruption. In phase 1 (30% of the total driving distance), the driver followed a Volkswagen Golf. Phase 2 began when this lead vehicle turned off the main road and participants continued to drive as you normally would along the designated route. In the first three sessions, the experimental drive ended uneventfully. At the end of the fourth and final session, participants encountered a vehicle that unexpectedly pulled out from a driveway into the lane of the experimental vehicle. A truck with trailer simultaneously occupied the oncoming lane. Outcome Measures During the first phase, participants were instructed to maintain a constant distance behind a lead car, which had realistic random velocity fluctuations. The primary end point was coherencethe correlation between the velocity of the participant's vehicle and the velocity of the lead vehicle. Participants with high coherence were able to maintain a relatively uniform distance from the lead vehicle, whereas those with low coherence had more variability in distance between their cars and the lead vehicle. In both phases of the drive, we evaluated steering instability, the root-mean-square deviation (in meters), of the participant's car around the participant's preferred position in the lane. Participants with high instability wandered left and right within (and sometimes out of) the lane. We measured deviations from the preferred position rather than the geometric center of the lane to avoid penalizing otherwise steady drivers who simply preferred to be closer to the center line or to the right shoulder line. We also evaluated left-lane excursionsthe total number of times the participant partially or totally crossed the center line during the second phase of the driving session. We measured participants' responses to the blocking vehicle (the last event on the final drive). Videotapes and a computer-generated aerial view of the driving course and vehicles (generated by using Scenario Authoring Tool software [National Advanced Driving Simulator, Iowa City, Iowa]) were reviewed by three blinded investigators who evaluated two aspects of the participants' responses to the blocking vehicle. Response time was the time from the moment the blocking vehicle began to move until the instant the participant started to respond. The blocking vehicle response category was based on whether the participant's car came into contact with the incoming car or approaching truck (collision), stopped completely in the lane before passing the plane of the incoming car (clear avoidance), or either passed the plane of the incoming car or was more than a tire's width out of lane before stopping (potentially unsafe avoidance). Finally, we evaluated drowsiness by using a visual analogue scale (3, 4, 13-15) that asked participants to rate drowsiness from I feel wide awake to I feel extremely sleepy. Data Capture, Reduction, and Management Simulator data were collected in real time at 30 Hz and were then reduced. During the data reduction stage, checks were performed to ensure that output was correct and meaningful. Data were visually inspected, sorted to identify extreme values, and plotted to ensure that all points were within naturally occurring boundaries. When extreme values were found, operator and experimenter source documents were consulted to determine an explanation. Videotape records were inspected to establish the origin of any anomalies in the data, and, if necessary, the raw data were fed into the Scenario Authoring Tool, which replayed the drive using animation. Statistical Analysis The experiment was run as a crossover design with four periods and four treatments so that each participant received all four treatments (alcohol, diphenhydramine, fexofenadine, and placebo) on four successive sessio