Annemiek Vermeeren

Residual effects of hypnotics: epidemiology and clinical implications

The risk of ‘hangover’ effects, e.g. residual daytime sleepiness and impairment of psychomotor and cognitive functioning the day after bedtime administration, is one of the main problems associated with the use of hypnotics. However, the severity and duration of these effects varies considerably between hypnotics and is strongly dependent on the dose administered.This article reviews epidemiological evidence on the effect of hypnotics on patients’ risk for accidents such as traffic accidents, falls and hip fractures (i.e. end-points for residual effects). Information on the duration and severity of residual effects of 11 hypnotics (flunitrazepam, flurazepam, loprazolam, lormetazepam, midazolam, nitrazepam, temazepam, triazolam, zaleplon, zolpidem and zopiclone) was derived from expert ratings, a meta-analysis and actual driving studies. Epidemiological studies show that the risks of an accident increase with increasing half-life of the hypnotic, but that the use of hypnotics with a short half-life, such as triazolam, zopiclone and zolpidem, can also be associated with increased risks. A summary of results from experimental studies should enable prescribing clinicians to compare residual effects of the various hypnotics at different doses and select the one considered most favourable in this respect for the individual patient. This information should also enable them to inform patients more adequately about the likelihood and duration of residual effects of a specific hypnotic dose.

Fexofenadine's effects, alone and with alcohol, on actual driving and psychomotor performance

BACKGROUND Fexofenadine is the hydrochloride salt of terfenadines active metabolite. OBJECTIVE Fexofenadines effects on performance were assessed in this study for the purpose of determining its safety of use by patients who engage in potentially dangerous activities, especially car driving. METHODS Fexofenadine was administered in daily doses of 120 or 240 mg, each in single and divided units given over 5 days. Two milligrams of clemastine given twice daily and placebo were given in similar series. Twenty-four healthy volunteers (12 men, 12 women; age range, 21 to 45 years) participated in a double-blind six-way crossover study. Psychomotor tests (critical tracking, choice reaction time, and sustained attention) and a standardized actual driving test were undertaken between 1.5 to 4 hours after administration of the morning dose on days 1, 4, and 5 of each series. On day 5, subjects were challenged with a moderate alcohol dose before testing. RESULTS Fexofenadine did not impair driving performance. On the contrary, driving performance was consistently better during twice daily treatment with 120 mg fexofenadine than during treatment with placebo, significantly so on day 4. Both of the 240 mg/day regimens significantly attenuated alcohols adverse effect on driving on day 5. Effects in psychomotor tests were not significant, with the exception of the critical tracking test in which the first single doses of fexofenadine, 120 and 240 mg, had significantly impairing effects. CONCLUSION It was concluded that fexofenadine has no effect on performance after being taken in the recommended dosage of 60 mg twice daily.

Residual effects of evening and middle-of-the-night administration of zaleplon 10 and 20 mg on memory and actual driving performance

Zaleplon, a new pyrazolopyrimidine hypnotic, possesses an unusually short elimination half‐life (ca 1 h). This study was conducted to determine whether middle‐of‐the‐night administration of zaleplon affects memory or driving performance the following morning. Twenty‐eight healthy volunteers participated in a double‐blind, 7‐way, crossover study. They ingested capsules twice on each treatment night; once before initiating sleep and again after being briefly awakened 5 h later. Treatments were: placebo at both times, zaleplon 10 or 20 mg, or zopiclone 7·5 mg followed by placebo, or the same in reverse order. Subjects arose 3 h after the second dose. One hour later, sleep quality and mood were assessed by questionnaires and balance and memory in a test battery. A standardized actual driving test was undertaken between 5 and 6 h after the second dose. All drugs similarly improved sleep quality, but only zopiclone hindered awakening. Evening zaleplon doses were without significant effects. Late‐night zaleplon had minor effects in one memory test. Evening zopiclone shared these effects and also significantly impaired driving performance. Late‐night zopiclones effects were significant in every test. Its effects on driving were severe. The results suggest that zaleplon 10 mg certainly, and 20 mg probably, can be taken at bedtime or later in the night, up to 5 h before driving with little risk of serious impairment.

Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem

Gaboxadol is a selective extrasynaptic GABAA receptor agonist previously in development for the treatment of insomnia. Due to its short half‐life (1.5–2 h) it is expected to be free from residual effects the next morning. The present study assessed the residual effects of evening and middle‐of‐the‐night administration of 15 mg of gaboxadol on cognitive, psychomotor and driving performance. Twenty‐eight healthy volunteers entered the study with 25 (12 women; mean age 31.4 years) completing a double‐blind, placebo‐controlled, active‐referenced five‐way cross‐over study. Each treatment night subjects ingested one capsule at 23:00 hours and one at 04:00 hours. Treatments were placebo at both times, 15 mg gaboxadol or 7.5 mg zopiclone followed by placebo, and placebo followed by 15 mg gaboxadol or 10 mg zolpidem. Effects on cognition and psychomotor performance were assessed between 07:30 and 08:30 hours and on driving between 09:00 and 10:00 hours. Driving, as measured by standard deviation of lateral position in an on‐the‐road driving test, was almost significantly (P < 0.07) impaired after evening administration of gaboxadol for the all‐subjects‐completed set (n = 25) but significantly (P < 0.05) in the full analysis set (n = 28). Effects of all other active treatments on driving were significant. Evening administration of gaboxadol had minor effects on divided attention only, whereas middle‐of‐the‐night administration impaired performance significantly in all tests except memory. Zolpidem and zopiclone impaired performance significantly in every test except tracking after zopiclone; 15 mg of gaboxadol can produce minor residual effects on driving after evening administration. Administration later at night is associated with moderately impairing residual effects on driving and psychomotor performance but not on memory.

Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females

Emedastine is registered in its country of origin (Japan) as an antihistamine for the indication of seasonal allergic rhinitis. Further research on the drugs sedating properties was needed to secure its registration elsewhere. The present study was designed to compare the effects of emedastine 2 mg and 4 mg twice daily after single and repeated doses, on actual driving performance versus those of cetirizine 10 mg once daily and placebo; and to determine how repeated doses of each drug interact with alcohol to affect driving. Each treatment was administered for 5 days to 19 healthy volunteers (nine men and ten women, aged 21–45 years) according to a four-period double-blind cross-over design. Driving performance was measured in a standardized test between 3 and 4 h after administration of the morning dose on days 1, 4 and 5. Alcohol, sufficient for achieving a blood alcohol concentration of 0.05 g/dl was given before driving on day 5 of each period. Both emedastine doses similarly and significantly impaired driving in every test. The effects of cetirizine were less. They were significant over days 1, 4 and 5 combined, although not separately. Women were more impaired by both drugs. Alcohol increased driving impairment similarly in every condition. Subjects were only able to discriminate the sedating and impairing effects of the first dose of emedastine 4 mg from placebo. Emedastine, in oral doses of 2mg and 4 mg twice daily, is sedating and impairs driving. The drug could therefore constitute a traffic hazard and its users should be warned accordingly.

A dose‐ranging study of the effects of mequitazine on actual driving, memory and psychomotor performance as compared to dexchlorpheniramine, cetirizine and placebo

Background Mequitazine is a so‐called ‘non‐sedative’ second‐generation antihistamine even though it has never been firmly established that this drugs sedative potential actually differs from that of the ‘sedative’ first‐generation antihistamines.

Highway driving in the elderly the morning after bedtime use of hypnotics: a comparison between temazepam 20 mg, zopiclone 7.5 mg, and placebo

Abstract A major problem related to hypnotic drug use is residual sedation the morning after bedtime administration. This constitutes a particular safety hazard for patients who have to drive a car the next morning. Information on the severity of residual effects is mainly derived from studies conducted with young healthy volunteers. However, most users of hypnotics are older people who may be more sensitive to drug effects. The aim of this study was to evaluate the residual effects the morning after evening doses of temazepam 20 mg and zopiclone 7.5 mg on driving performance in healthy elderly drivers. Eighteen healthy elderly drivers (10 females and 8 males; mean age, 64.3 years) participated in a double-blind, 3-way crossover study. Treatments were single oral doses of temazepam 20 mg, zopiclone 7.5 mg, and placebo administered at bedtime. Subjects performed a standardized highway driving test between 10 and 11 hours after hypnotic intake. Before and after the driving test, cognitive performance was assessed. Driving performance did not differ between temazepam and placebo but was significantly impaired after zopiclone 7.5 mg (P < 0.002). The results of the laboratory tests were in line with the effects on driving of both hypnotics. Temazepam 20 mg is unlikely to impair driving 10 hours or more after bedtime administration in healthy elderly aged 75 years or younger. Zopiclone 7.5 mg moderately impairs driving in the elderly at least until 11 hours after administration. The magnitude of impairing effects in the elderly was comparable with those found previously in younger volunteers.

A Randomized Trial on the Acute and Steady-State Effects of a New Antidepressant, Vortioxetine (Lu AA21004), on Actual Driving and Cognition

The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double‐blind, placebo‐controlled, three‐way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on‐the‐road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.

Histamine H1-receptor blockade in humans affects psychomotor performance but not memory

Results from recent animal studies suggest an important role for histamine in memory functioning. Histaminergic drugs might prove beneficial for people suffering from memory impairment. To determine if histamine is involved in memory functioning this study evaluates the effects of histaminergic dysfunction on memory performance by administrating a H1-antagonist to humans. The study was conducted according to a 4-way, double-blind, crossover design in 20 healthy female volunteers, aged 18—45 years. On each test day subjects completed three test sessions: before and around 2 and 4 h after administration of single oral doses of dexchlorpheniramine 2 mg or 4 mg, scopolamine 1 mg or placebo. Drug effects were assessed using tests of memory, psychomotor and attention performance, and subjective alertness. Results showed that dexchlorpheniramine impaired performance in tests of spatial learning, reaction time, tracking and divided attention but showed no effects on working memory, visual memory, word learning or memory scanning. Scopolamine induced a similar pattern of effects. In addition, both drugs decreased subjective alertness. In conclusion results show that dexchlorpheniramine and scopolamine clearly impaired performance on psychomotor and attention tasks but do not suggest a specific role of the histaminergic system in learning and memory in humans.

Effects of the use of hypnotics on cognition

Hypnotic drugs are intended to induce sedation and promote sleep. As a result, they have deteriorating effects on cognitive performance following intake. Most hypnotics are benzodiazepine receptor agonists which can have effects on memory in addition to their sedative effects. Other sedating drugs, such as histamine H1 antagonists or melatonin agonists, may have less effect on memory and learning. Hypnotics with other mechanisms of action are currently being investigated for efficacy and safety. For patients using hypnotic drugs, the effects on cognition are relevant to the extent that a drug dose affects daytime performance. Use of benzodiazepine hypnotics is associated with increased risk of car accidents and falling. Therefore, most hypnotics are studied to determine whether they produce residual sedation and impairing effects on performance the morning after bedtime use. Experimental studies using a standardized driving test clearly show that some drugs and doses produce severe residual effects, whereas others seem to have no or only minor impairing effects on next-day performance. No hypnotic has been found yet to improve daytime performance. Studies on long-term use of benzodiazepine hypnotics suggest that effects on daytime performance may diminish over time due to tolerance. However, there are also studies showing that performance may improve after discontinuation of chronic benzodiazepine use, which suggests that tolerance may not be complete.