Edmund R. Volkerts

Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance

Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual impairment when used in the middle of the night.

Antihistamines and driving ability: evidence from on-the-road driving studies during normal traffic

BACKGROUND All antihistamines are capable of crossing the blood-brain barrier and thus may cause sedation. Most antihistamine users are ambulatory patients and therefore presumably drive a car. OBJECTIVE To summarize the effects of antihistamine drugs on driving ability. DATA SOURCES AND STUDY SELECTION A literature search (MEDLINE and cross-references) was performed using the keywords driving and antihistamine. Sixteen studies using the on-the-road driving test during normal traffic were included in the review. Studies were double-blind and placebo-controlled and included a positive control. RESULTS First-generation antihistamines (diphenhydramine, triprolidine, terfenadine, dexchlorpheniramine, clemastine) significantly impair driving performance after both one-time and repeated (daily) administration. Second-generation antihistamines (cetirizine, loratadine, ebastine, mizolastine, acrivastine, emedastine, mequitazine) may also impair driving performance, but the magnitude and extent of impairment depend on the administered dose, sex, and time between testing and treatment administration. Tolerance develops after 4 to 5 days of administration, but impairment is not absent. Third-generation antihistamines (fexofenadine and levocetirizine) have been shown to produce no driving impairment after both one-time and repeated administration. CONCLUSIONS First- and second-generation antihistamines may significantly impair driving performance. In the context of driving safety but also taking into account the cardiotoxic properties of some of the second-generation antihistamines, we advise treating patients with third-generation antihistamines such as fexofenadine and levocetirizine.

Effects of Alprazolam on Driving Ability, Memory Functioning and Psychomotor Performance: A Randomized, Placebo-controlled Study

Alprazolam is prescribed for the treatment of anxiety and panic disorder. Most users are presumably involved in daily activities such as driving. However, the effects of alprazolam on driving ability have never been investigated. This study was conducted to determine the effects of alprazolam (1 mg) on driving ability, memory and psychomotor performance. Twenty healthy volunteers participated in a randomized, double-blind, placebo-controlled crossover study. One hour after oral administration, subjects performed a standardized driving test on a primary highway during normal traffic. They were instructed to drive with a constant speed (90 km/h) while maintaining a steady lateral position within the right traffic lane. Primary performance measures were the Standard Deviation of Lateral Position (SDLP) and the Standard Deviation of Speed (SDS). After the driving test, subjective driving quality, mental effort, and mental activation during driving were assessed. A laboratory test battery was performed 2.5 h after treatment administration, comprising the Sternberg Memory Scanning Test, a Continuous Tracking Test, and a Divided Attention Test. Relative to placebo, alprazolam caused serious driving impairment, as expressed by a significantly increased SDLP (F1,19 = 97.3, p < .0001) and SDS (F1,19 = 30.4, p < .0001). This was confirmed by subjective assessments showing significantly impaired driving quality (F1,19 = 16.4, p < .001), decreased alertness (F1,19 = 43.4, p < .0001), decreased mental activation (F1,19 = 5.7, p < .03) and increased mental effort during driving (F1,19 = 26.4, p < .0001). Furthermore, alprazolam significantly impaired performance on the laboratory tests. In conclusion, alprazolam users must be warned not to drive an automobile or operate potentially dangerous machinery.

Therapeutic effects and effects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients

Two groups of 12 outpatients each (six men and six women) with generalized anxiety disorder, participated in this study. Each patient was treated single-blind with placebo during the first 7 days (baseline), followed by a double-blind drug treatment period of 4 consecutive weeks (active) and ending again with 7 days single-blind placebo treatment (washout). One group received buspirone 5 mg three times a day in the first week and continued with 10 mg in the morning, 5 mg in the afternoon, and 5 mg in the evening during the second, third, and fourth weeks. The other group received diazepam 5 mg three times a day in all 4 weeks. On the evening of the seventh day of each treatment week the Hamilton Rating Scale for Anxiety and the Symptom Check List (90 items) were applied to assess the therapeutic effects, followed by an on-the-road driving test that started 1.5 hours after the last drug or placebo intake. The test consisted of operating an instrumented vehicle over a 100 kilometer highway circuit while attempting to maintain a constant speed and a steady lateral position within the right traffic lane. Two patients in the diazepam group were unable to complete their test after the first and second treatment week, respectively, because of serious sedative reactions. Both buspirone and diazepam were equally effective in reducing overall anxiety symptoms. The specific profiles showed that buspirone also reduced concomitant depressive symptoms and symptoms of interpersonal sensitivity and anger-hostility. In contrast, diazepam was found to be slightly more effective in reducing somatic symptoms and to positively affect sleep disturbances. Moreover, abrupt discontinuation of diazepam resulted in a relapse of psychic anxiety symptoms comparable with the placebo-baseline level and a partial relapse of somatic anxiety symptoms. Chronic treatment with buspirone had no significant effects on lateral position and speed control. In contrast, diazepam significantly impaired control of lateral position in the first 3 weeks of treatment. There was no significant impairment in the fourth treatment week and the placebo-washout week. Speed control was significantly impaired only in the first week. The relevance of the trend toward decreasing performance impairment during chronic treatment remains to be established.

Acute and subchronic effects of nefazodone and imipramine on highway driving, cognitive functions, and daytime sleepiness in healthy adult and elderly subjects

The acute and subchronic effects of two dosages of a new serotonergic antidepressant, nefazodone, and those of the tricyclic imipramine were examined in a double-blind, crossover, placebo-controlled study. Twenty-four healthy subjects from two age groups (12 adults and 12 elderly from both sexes) received the four treatments (nefazodone, 100 and 200 mg twice daily; imipramine, 50 mg twice daily; and placebo) for 7 days with a 7-day washout period. Measurements were performed after the morning doses on day 1 and day 7. These included a standard over-the-road highway driving test, a psychomotor test battery, and sleep latency tests. Blood samples were taken on both days and analyzed to determine concentrations of parent drugs and their major metabolites. The main results showed that the reference drug, imipramine, had a detrimental effect after a single dose on lateral position control in the driving test, primarily in the adult group, that diminished after repeated dosing. Minor impairment on psychomotor test performance was found with both days. On the other hand, a single administration of both doses of nefazodone did not impair highway driving performance (even showed some improvement) and had no or only minor effects on psychomotor performance. After repeated dosing, nefazodone 200 mg twice daily (but not the 100-mg dose) produced slight impairment of lateral position control; dose-related impairment of cognitive and memory functions was found. The effects of nefazodone were generally in the same direction in both age groups. Significant correlations were found between steady-state concentrations of nefazodone in plasma (200-mg, twice-daily condition) as well as imipramine, and reaction time changes in a memory scanning task. Neither drug appeared to induce daytime sleepiness as measured by the sleep latency tests.

Hypnotics and driving safety: Meta-analyses of randomized controlled trials applying the on-the-road driving test

BACKGROUND Many people who use hypnotics are outpatients and are likely to drive a car the day after drug intake. The purpose of these meta-analyses was to determine whether or not this is safe. METHODS Placebo-controlled, randomized, double-blind trials were selected if using the on-the-road driving test to determine driving ability the day following one or two nights of treatment administration. Primary outcome measure of the driving test was the Standard Deviation of Lateral Position (SDLP); i.e., the weaving of the car. Fixed effects model meta-analyses were performed. Effect size (ES) was computed using mean standardized (weighted) difference scores between treatment and corresponding placebo SDLP values. RESULTS Ten studies, published from 1984 to 2002 (207 subjects), were included in the meta-analyses. The morning following bedtime administration, i.e. 10-11 hours after dosing, significant driving impairment was found for the recommended dose of various benzodiazepine hypnotics (ES=0.42; 95% Confidence Interval (CI)=0.14 to 0.71). Twice the recommended dose impaired driving both in the morning (ES=0.68; CI=0.39 to 0.97) and afternoon, i.e. 16-17 hours after dosing (ES=0.57; CI=0.26 to 0.88). Zopiclone 7.5 mg also impaired driving in the morning (ES=0.89; CI=0.54 to 1.23). Zaleplon (10 and 20 mg) and zolpidem (10 mg) did not affect driving performance the morning after dosing. Following middle-of-the-night administration, significantly impaired driving performance was found for zopiclone 7.5 mg (ES=1.51, CI=0.85 to 2.17), zolpidem 10 mg (ES=0.66, CI=0.13 to 1.19) and zolpidem 20 mg (ES=1.16, CI=0.60 to 1.72). Zaleplon (10 and 20 mg) did not affect driving performance. CONCLUSIONS The analyses show that driving a car the morning following nocturnal treatment with benzodiazepines and zopiclone is unsafe, whereas the recommended dose of zolpidem (10 mg) and zaleplon (10 mg) do not affect driving ability.

Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking.

The impairing effects on memory functioning after acute alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. A total of 48 healthy volunteers participated in a single-blind study comprising an evening (baseline) session, followed by a treatment administration (ethanol 1.4 g/kg or placebo), and a morning session. Memory was tested with a word-learning test (including immediate and delayed recall, and recognition). Further, a 45-min Mackworth clock test for measuring vigilance was included (parameters: number of hits and false alarms) and subjective alertness was assessed, to infer whether word-learning test findings reflect sedation or specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol group when compared to the placebo group (F1,42=6.0, p<0.02). In contrast, immediate recall and recognition were unimpaired in the alcohol group. In the morning session, relative to the placebo group, subjective alertness was significantly reduced in the alcohol group before and after the tests (F1,44=8.7, p<0.005; F1,44=13.3, p<0.001, respectively). However, in the Mackworth clock test, the alcohol group and placebo group did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. Vigilance performance was not significantly affected, indicating that this memory impairment does not reflect sedation.

Effect of chronic nonmalignant pain on highway driving performance

Abstract Most pain patients are treated in an outpatient setting and are engaged in daily activities including driving. Since several studies showed that cognitive functioning may be impaired in chronic nonmalignant pain, the question arises whether or not chronic nonmalignant pain affects driving performance. Therefore, the objective of the present study was to determine the effects of chronic nonmalignant pain on actual highway driving performance during normal traffic. Fourteen patients with chronic nonmalignant pain and 14 healthy controls, matched on age, educational level, and driving experience, participated in the study. Participants performed a standardized on‐the‐road driving test during normal traffic, on a primary highway. The primary parameter of the driving test is the Standard Deviation of Lateral Position (SDLP). In addition, driving‐related skills (tracking, divided attention, and memory) were examined in the laboratory. Subjective assessments, such as pain intensity, and subjective driving quality, were rated on visual analogue scales. The results demonstrated that a subset of chronic nonmalignant pain patients had SDLPs that were higher than the matched healthy controls, indicating worse highway driving performance. Overall, there was a statistically significant difference in highway driving performance between the groups. Further, chronic nonmalignant pain patients rated their subjective driving quality to be normal, although their ratings were significantly lower than those of the healthy controls. No significant effects were found on the laboratory tests.

Effects of an opioid (Oxycodone/Paracetamol) and an NSAID (Bromfenac) on driving ability, memory functioning, psychomotor performance, pupil size, and mood

ObjectiveIt has been suggested that driving a car is relatively safe when the driver is treated with nonsteroid anti-inflammatory drugs than when he or she is treated with opioid analgesics. However, the evidence for this statement is scarce. The objective of this study was to determine the effects of a nonsteroid anti-inflammatory drug (bromfenac 25 mg and 50 mg) and an opioid (oxycodone/paracetamol 5/325 mg and 10/650 mg), and placebo on driving ability, memory functioning, psychomotor performance, pupil size, and mood. MethodsOut of 30 healthy volunteers, 18 completed this randomized, double-blind, placebo-controlled crossover study, before the study had to be stopped due to bromfenac being pulled out from the market. One hour after administration of the drugs, the participants performed a standardized driving test during normal traffic. Thereafter, driving quality, mental effort and mental activation during driving were assessed. A laboratory test battery was performed 2.5 hours after administration of the drug. Visual analog scales assessing mood and pupil measurements were performed on several occasions during each test day. ResultsBoth analgesics did not significantly affect performance in any test. However, volunteers reported that significantly more effort was needed to perform the driving test when treated with oxycodone/paracetamol, and that they experienced increased sedation and reduced alertness. Also, the pupil size was significantly decreased. In contrast, subjective assessments after both doses of bromfenac matched that of placebo. DiscussionNo significant impairment in behavior was found in the volunteers for both bromfenac and oxycodone/paracetamol. The lack of impairment from oxycodone/paracetamol may have been related to the participants reporting increased effort during driving while under the influence of this drug.

Next-Day Effects of Ramelteon (8 mg), Zopiclone (7.5 mg), and Placebo on Highway Driving Performance, Memory Functioning, Psychomotor Performance, and Mood in Healthy Adult Subjects

STUDY OBJECTIVES To evaluate the next-morning residual effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on driving performance, memory functioning, psychomotor performance, and mood in healthy adult subjects following bedtime dosing and a middle of the night awakening. DESIGN Single-center, randomized, double-blind, double-dummy, placebo-controlled, crossover study. SETTING Utrecht University, The Netherlands. PARTICIPANTS 30 healthy volunteers (15 males and 15 females). INTERVENTIONS a single dose of ramelteon (8 mg), zopiclone (7.5 mg), and placebo, administered at bedtime. MEASUREMENTS A balance test was performed at night. Other tests were performed the following morning, 8.5 h after administration. Subjects performed a 100-km highway driving test in normal traffic. Primary outcome measure was the standard deviation of the lateral position (SDLP), i.e., the weaving of the car. After driving, cognitive, memory, and psychomotor tests were performed and mood was assessed. RESULTS SDLP was significantly increased after the intake of ramelteon (+2.2 cm) and zopiclone (+2.9 cm). Ramelteon and zopiclone produced significant impairment on reaction time (P<0.024) in the Sternberg Memory Scanning Test, slow (P<0.007) and fast (P<0.010) tracking, reaction speed (P<0.015) and tracking (P<0.001) in the Divided Attention Test, and delayed recall (P<0.032) in the Word Learning Test. In contrast to ramelteon, zopiclone additionally impaired performance on the Digit Symbol Substitution Test (P<0.001) and the balance test (P<0.001). CONCLUSIONS Ramelteon (8 mg) and zopiclone (7.5 mg) significantly impaired driving performance, cognitive, memory, and psychomotor performance the morning following bedtime administration. In contrast to zopiclone, ramelteon produced no balance impairments. CLINICAL TRIAL IDENTIFIER: NCT00319215 (www.clinicaltrials.gov).