Effects of the use of hypnotics on cognition

H. P. A. Van Dongen and G. A. Kerkhof (Eds.) Progress in Brain Research, Vol. 190 ISSN: 0079-6123 Copyright Ó 2011 Elsevier B.V. All rights reserved.

CHAPTER 5

Effects of the use of hypnotics on cognition Annemiek Vermeeren{,* and Anton M. L. Coenen{ {

Department of Neuropsychology and Psychopharmacology, Maastricht University, Maastricht, The Netherlands { Donders Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands

Abstract: 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. Keywords: hypnotics; benzodiazepines; zolpidem; (es)zopiclone; zaleplon; cognition; memory; driving; acute effects; residual effects; long-term use.

*Corresponding author. Tel.: þ31 43 3881952; Fax: þ31 43 3884560 E-mail: [email protected] DOI: 10.1016/B978-0-444-53817-8.00005-0

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Introduction Population surveys show that between 0.7% and 7% of all adults report current use of sleepenhancing medication, while approximately 20–30% of the adults complaining of poor sleep (mostly females and elderly) report using some form of sleep-enhancing medication (for a review, see Vermeeren, 2004). Although sleep-enhancing medication includes not only prescribed hypnotics but also anxiolytics, antidepressants, and nonprescription (over the counter, OTC) drugs, the most frequently mentioned drugs for the treatment of insomnia are still the benzodiazepines or benzodiazepine-like drugs, that is, GABA agonists. In spite of the recommendation and consensus among clinicians that hypnotics should be used at their lowest possible doses and for limited durations only, the majority of hypnotic users report using the drug for more than a year. A major problem associated with the use of hypnotics may be the residual daytime sleepiness and associated impairment of psychomotor and cognitive functioning during the day after bedtime administration, sometimes called “hangover” effects. Already in 1982, an extensive critical review of 52 placebo-controlled studies assessing residual effects of benzodiazepine hypnotics on performance concluded that although these drugs generally improved sleep, they did not improve the quality of daytime performance, as expected when adverse effects of poor sleep would be normalized by the use of hypnotics (Johnson and Chernik, 1982). In particular, at higher dose levels, all hypnotics available at that time were likely to be associated with residual effects. Tasks showing the largest decrements were those involving speeded performance and memory for information presented during the night, indicating that the drugs mainly produced psychomotor slowing and anterograde amnesia. Newer hypnotics with shorter half-lives generally have a more favorable safety profile with respect to patients’ daytime functioning, although there is still little evidence that their use has significant positive effects on patients’ performance.

The high prevalence of hypnotic use in the population constitutes a public health problem. It can worsen the clinical expression of early dementia, and the effects on motor functions and attention have been shown to constitute risk factors for falls and accidents at home, at work, or on the road. A number of epidemiological studies have shown that the use of benzodiazepines is associated with increased risk of injurious car accidents (e.g., Barbone et al., 1998; Neutel, 1995, 1998) and falling and hip or femur fractures (c.f., Vermeeren, 2004). In the elderly, in particular, ataxia and impaired motor coordination may increase risk of falling and hip fractures, which is of concern, since hip fractures constitute a major cause for referrals to nursing homes.

Hypnotics The majority of available prescription hypnotics are benzodiazepine receptor agonists (BzRAs) that act by enhancing the effectiveness of sleeppromoting GABAergic pathways. They act on the GABA-A receptor complex that regulates the chloride channels of the cell membrane. GABA-A receptors consist of five subunits of which the subunits are three principal families that are designated alpha (a), beta (b), and gamma (g). Whereas GABA binds at the interface between a and b subunits, most hypnotics act via the so-called benzodiazepine-binding site, located at the interface between a and g subunits (c.f., Winsky-Sommerer, 2009). The binding of GABA to its receptor induces a conformational change that opens the chloride ion channel, whereupon chloride ions can enter the cell producing a slight, short lasting hyperpolarization causing reduced excitability of the neuron. BzRA hypnotics increase the affinity of the receptors for GABA and enhance the effects of GABA on the neuron. Since 1987, many different subtypes of a, b, and g subunits have been identified, which has significantly improved insights into the mechanism of

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action of hypnotics (c.f., Winsky-Sommerer 2009). Each of the subunits display several isoforms (a1–a6, b1–b3, g1–g3), but only certain combinations of subtypes seem to occur, and these appear to be localized in specific cell types and at different locations of the neurons. The most common receptor subtypes are a1b2g2, a2b3g2, and a3b3g2 (Nutt and Stahl, 2010). The majority of GABA-A receptors containing a1, a2, and a3 subunits are localized synaptically, while receptors containing a5 and d subunits combined with a4 and a6 appear to be predominantly peri- and/or extrasynaptic. Benzodiazepines act at GABA-A receptors containing a1, a2, a3, and a5 subunits (in combination with a g2 subunit), but not on receptors containing a4 or a6 subunits. The newer BzRAs (zopiclone, zolpidem, zaleplon, and eszopiclone) are structurally different from benzodiazepines and show differential-binding affinities and potencies for a1, a2, a3, and a5 subunits. They all bind to GABAA receptors containing a1, a2, and a3 subunits, but their affinity for a1 subunits seems relatively higher than for a2 and a3 subunits. In addition, zopiclone and eszopiclone act on a5-containing receptors, whereas zolpidem and zaleplon do not (Nutt and Stahl, 2010). BzRAs have multiple actions. The most prominent central effects are sedation, sleep induction, anxiety reduction, muscle relaxation, anterograde amnesia, and anticonvulsant activity. The sedative effects seem to be linked to the a1 subunit, which is the most common of the GABA-A subunits and present throughout the brain, particularly on hippocampal and cortical interneurons. This subunit does not seem to mediate changes in sleep EEG. GABA-A receptors containing a2 and a3 subunits located in the thalamus, hypothalamus, and cortex seem to be mediating EEG delta and theta activity, and thalamo-cortical oscillations during sleep. Receptors in the limbic system are assumed to mediate the anxiolytic effects. GABA-A receptors containing a5 subunits are highly expressed in the hippocampus suggesting a role for this subunit in effects of

benzodiazepine on learning and memory (Nutt and Stahl, 2010). Benzodiazepines mainly shorten sleep latency and diminish the number and duration of awakenings during sleep, thus increasing the total time spent asleep during the night. Yet, the extra time asleep is mostly spent in stage 2 or light sleep. Compared to normal sleep, the percentage of time spent in the (putatively) most restorative stages of sleep, that is, deep sleep (stages 3 and 4) and REM sleep, is decreased following administration of a benzodiazepine. With continued use of benzodiazepines, tolerance seems to develop to their effects on sleep stages, although rebound occurs when such use is discontinued. During the first nights after discontinuation, the increase in REM sleep may be especially prominent. Nonbenzodiazepine BzRAs show overall similar actions on sleep as benzodiazepines, including a dose-dependent reduction in REM sleep and the spectral EEG signature of benzodiazepines (i.e., reduction of EEG components below 10 Hz, and an increase in EEG power in the spindle frequency range during NREM sleep; WinskySommerer, 2009). All hypnotics have a rapid onset of action (between 30 and 90 min), whereas the duration of their action differs considerably. Both characteristics are dose dependent. Onset of action is largely determined by the pharmaceutical formulation and the rate of absorption of the drug from the gastrointestinal tract after oral administration. For rapidly absorbed benzodiazepines, such as diazepam and flurazepam, time to peak plasma concentration (tmax) is often taken to indicate the onset of action. In case of the slowly absorbed loprazolam, however, tmax is delayed with respect to the onset of action. The pharmaceutical preparation (formulation) can influence the rate of absorption; for example, temazepam is much more slowly absorbed from hard gelatin capsules than from soft capsules. Once reaching the blood, all benzodiazepines quickly reach their site of action, since all are lipophilic substances that easily traverse the blood–brain barrier.

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BzRA hypnotics are often divided into categories based on their elimination half-life (t½), as short-acting (t½ less than 6 h), intermediate-acting (t½ between 6 and 24 h), or long-acting (t½ more than 24 h) drugs. As these categories imply, duration of action is often equated to elimination half-life. However, a drug's action may be terminated by at least three mechanisms: disappearance from the receptor site by redistribution from the brain to peripheral tissue, biotransformation by the liver to inactive metabolites, and acute tolerance of the receptors. In addition, dose is considered one of the most important determinants of a drug's duration of action. It will take longer for drug concentrations to drop below effective levels after administration of twice the recommended dose, and shorter after only half the recommended dose. The relation between half-life and duration of action is therefore not straightforward.

Acute effects Most studies of the cognitive effects of hypnotics have focused on the acute adverse effects of benzodiazepines. Best known and detrimental are the effects on memory, in particular, on explicit (declarative, episodic) memory, whereas the other types of memory (implicit, procedural) are relatively unaffected (Curran, 1999). Several studies in human subjects have provided evidence that benzodiazepines have detrimental effects on memory processing, that is, benzodiazepines induce severe anterograde amnesia (Coenen et al., 1989; Curran and Birch, 1991; Lister, 1985). The administration of benzodiazepines before learning of a list of words such as the classic 15-words list impairs the recall of these words in a delayed recall test. In a series of experiments, Gorissen et al. (1995, 1997, 1998) and Gorissen and Eling (1998) tried to specify the benzodiazepineinduced amnesia more precisely. Effects of diazepam on the chain of encoding operations were investigated, such as on activation of memory

processes, on spreading of activation, on semantic encoding, on organizational processes, as well as on retrieval processes. The main conclusion from these studies was that diazepam impairs memory processing by slowing down and reducing cognitive processes. Under the influence of diazepam, subjects do not seem to benefit optimally from opportunities to organize the learning material adequately in an early stage of the acquisition of information. The adequate organization of the material in relevant memory chains appears affected, and this forms the basis for the observed anterograde amnesia. In a recent review paper, Beracochea (2006) extends this conclusion to the benzodiazepines in general and states that benzodiazepine-induced anterograde amnesia can be explained by an impairment of acquisition processes, due to a disruption of the ability to build new associations between pieces of information. A number of studies investigated whether the effects of benzodiazepine on memory and learning are due to a direct effect on memory processes or a by-product of their sedative effects. Results show that these effects can be dissociated and can act independently. For example, Curran and Birch (1991) found that the benzodiazepine antagonist flumazenil was able to reverse the midazolam-induced sedation effects, but could not counteract the amnesic effects of this benzodiazepine. Also, Gorissen et al. (1997) found that 24 h of sleep deprivation, as a form of nonpharmacological sedation, reduced subjective alertness and slowed reaction times more than diazepam 15 mg, but only diazepam, and not sleep deprivation, impaired the delayed recall of a word list task. This shows that the reduction in alertness could not account for the benzodiazepine-induced memory impairments. The different effects of benzodiazepines are supported by findings that GABA-A receptor subtypes demonstrate distinct regional distribution patterns in the brain. As described above, the amnestic effects of benzodiazepines are thought to be mediated by GABA-A receptors containing a5 subunits which are highly expressed in the

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hippocampus and related regions (Nutt and Stahl, 2010), regions known to contribute to performance on episodic memory tests (Squire, 1992). Alertness-reducing effects, however, seem to be mediated by GABA-A receptors containing a1, a2, and a3 subunits in regions of the brain regulating and controlling wakefulness, such as the hypothalamic nuclei and areas of the brainstem. In contrast to the general finding that benzodiazepines impair memory, Hinrichs et al. (1984) first presented evidence for a remarkable, facilitating effect of benzodiazepines on memory. They showed that information provided just before the intake of benzodiazepines was recalled better than without the administration of benzodiazepines. Coenen and van Luijtelaar (1997) also demonstrated this retrograde facilitation effect on word recall for diazepam and flunitrazepam in healthy volunteers. These authors argued that the positive effect of the benzodiazepines on memory might be analogous to the positive effect of sleep on memory. Compared to wakefulness, sleep is associated with less interference during consolidation of previously learned information. Benzodiazepines induce sedation with alertness-reducing effects, which might imply that, in analogy to sleep, the encoding of new information is reduced. Hence, interference with the consolidation of previously obtained material is weaker, resulting in better recall of previously learned information. Thus, retrograde facilitation seems to be caused by reduced interference, due to the sedating effects of benzodiazepines. Benzodiazepine-induced sedation and effects on psychomotor performance have been found to differ from those of alcohol, which also acts as a modulator of the GABA-A receptor. Tiplady et al. (2003) found comparable impairing effects of temazepam and ethanol on information processing capacity and on long-term memory formation, but a dissociation between the effects on speed and accuracy of psychomotor performance. Temazepam caused a reduction in psychomotor speed with few changes in accuracy, while ethanol

was associated with a substantial increase in errors and only little effect on speed. Perhaps the differential action of these drugs could be explained by the broader effects of alcohol on other neurotransmitters, both on excitatory and inhibitory ones. Benzodiazepines have also been found to affect oculomotor behavior. In particular, they slow down saccadic eye movements, which may be related to effects on attention (Fafrowicz et al., 1995; Van Leeuwen et al., 1994). Performance in vigilance tasks was found to be very sensitive to the deleterious effects of benzodiazepines. For example, Van Leeuwen et al. (1992) evaluated the effects of the benzodiazepines bromazepam and oxazepam on performance in a long-duration visual vigilance test. The expected decrement in performance was found as a reduction in accuracy. In the case of bromazepam, however, this was associated with improved speed, suggesting that subjects were less cautious with bromazepam (van Leeuwen et al., 1992). The effects of benzodiazepines on eventrelated potentials in the EEG have also been studied to unravel to their effects on cognitive processes. Event-related potentials are useful as a means to gain more insight into the covert processes underlying changes in performance and in executive functions. Results from these studies suggest that effects of benzodiazepines are already manifest in an early stage of information processing, as reflected by effects on the N1 amplitude (Abduljawad et al., 2001; Van Leeuwen et al., 1992). Effects on N1 indicate a deterioration of stimulus detection ability (attention–detection), which is thought to be responsible for the slowing down and adverse effects on later information processing. Subjects under the influence of benzodiazepines probably gather less signal information for further processing due to dampening of the input signal. Thus, administration of benzodiazepines deteriorates the ability of a subject to detect relevant information in an early stage of acquisition (van Leeuwen et al., 1992). In line with this,

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benzodiazepines have also been found to reduce the amplitude of P3 in an oddball task (Unrug et al., 1997a,b). Generally, the electrical positivity of P3 reflects cognitive processing of incoming information. The reduction of P3 by a benzodiazepine is therefore interpreted as a reduction of cognitive processing of relevant stimuli. This reduction was also found to be associated with more omissions in target detection and longer reaction times. The changes in electrical brain activity produced by benzodiazepines correspond well with their deteriorating effects on cognitive functions. All in all, anterograde amnesia associated with benzodiazepine use most likely results primarily from less thorough cognitive processing of relevant information. In addition to their effects on evoked potentials, benzodiazepines also have nonspecific effects on the EEG, in particular, on the background EEG. Since benzodiazepines have sedative properties, an increase in low frequencies is expected. In contrast, however, benzodiazepines have been found to increase high frequency beta activity in the background EEG. This phenomenon is known as “pharmacological dissociation” because the effects on behavior are not in agreement with the effects on background EEG (Coenen and van Luijtelaar, 1991). So, whereas the effects of benzodiazepines on event-related potentials reflect their effects on behavior, their effects on background EEG do not reflect their effects on behavior. Although there may be some slight pharmacodynamic differences, the mechanism of action and the behavioral effects of nonbenzodiazpine BzRAs, such as (es)zopiclone, zolpidem, and zaleplon, are largely comparable to those of benzodiazepines. Similar to benzodiazepines, they produce sedation and associated impairment of attention and psychomotor performance. They also impair memory functions (e.g., Leufkens et al., 2009a,b; Leufkens and Vermeeren 2009; Vermeeren et al., 1998). In line with this, flumazenil, a benzodiazepine receptor antagonist which is used for antagonizing a benzodiazepine

overdose, was found to be able to reverse the zolpidem's sedative and memory impairing effects (Quaglio et al., 2005). It might be argued that the effects of nonbenzodiazepine BzRAs are less severe and of shorter duration than those of most benzodiazepines, but that can also be explained by pharmacokinetic differences. Still, not all GABA agonists seem to have similar effects on cognitive performance. For example, gaboxadol, a hypnotic that has been withdrawn from development in 2007, was found to have residual effects on car driving and psychomotor performance, but not on memory (Leufkens et al., 2009a). In contrast to BzRAs, gaboxadol does not interact with synaptically located GABA-A receptors, but exerts its effects via extrasynaptic GABA-A receptors containing a4 and a6 subunits. These receptors have been found to mediate persistent tonic inhibition, which is assumed to have a different functional role compared to phasic postsynaptic responses (WinskySommerer 2009).

Residual effects Hypnotics all have largely comparable pharmacodynamic effects, but they differ substantially in their pharmacokinetic profiles. As a consequence, the cognitive problems associated with their use in clinical practice differ mainly in quantity (i.e., magnitude and duration), not in quality. Hypnotics are intended to be taken at bedtime and rapidly induce sleepiness and sedation. Ideally, these effects should continue throughout the sleep period but should no longer be present after awakening in the morning. Unfortunately, that is not the case for many drugs (for a review, see Vermeeren, 2004). Results from experimental performance studies show that hypnotics can have deteriorating effects on psychomotor performance, attention, and memory the day after bedtime use. Epidemiological studies confirm that these effects reduce patients’ quality of life and increase the risk of becoming involved in

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accidents, such as falling, hip fractures, and traffic accidents. Both experimental and epidemiological studies show that increased risk varies with treatment-related factors, such as drug, dose, time after dosing, and frequency of dosing, and with patient-related factors such as age and gender. Several hypnotics are available in doses that have no or minimal next-day residual effects. So, the most effective way of minimizing the accident risks associated with use of hypnotics is to prescribe a safe alternative. However, if use of a hypnotic without clinically relevant residual effects is not possible, patients should at least be adequately informed about the duration and severity of the residual effects in order to be able to adjust their behavior appropriately. Information on the duration and severity of residual effects is best derived from experimental studies using objective performance tests that validly measure druginduced changes in daytime functioning. Many studies have been conducted to determine whether a particular drug dose has effects on performance that differ from placebo. The differences in methodologies used make comparison between studies very difficult, however. A few performance tests have been applied consistently for several years, providing comparable data on the effects of a variety of drugs and doses. One such test is a highway driving test, which was standardized in the early 1980s (O'Hanlon, 1984) and subsequently used in over 75 studies. The test evolved from studies on driver fatigue conducted in the United States during the early 1970s. It involves subjects driving a specially instrumented car over a 100-km (61 mile) primary highway circuit while maintaining a constant speed and a steady lateral position between the boundaries of the slower traffic lane (Fig. 1). Subjects are supervised by a licensed driving instructor, having access to dual controls. Speed and lateral position relative to the lane delineation are continuously recorded during the 1-h drive by apparatus aboard the vehicle. After completion of the test, several parameters are derived from the data, including the primary performance

parameter, standard deviation of lateral position (SDLP, in centimeters). SDLP can be interpreted as an index of weaving or road tracking error. It is a reliable index of individual driving performance (the test–retest correlation ranges from 0.7 to 0.9) and has proven sensitive to many sedating drugs (c.f., Ramaekers, 2003; Theunissen et al., 2009; Vermeeren 2004, Vermeeren et al., 2009). The test calibrated for the effects of alcohol in a closed circuit study wherein 24 social drinkers were tested sober and after controlled drinking, raising blood alcohol concentrations (BACs) in steps of 0.3 mg/ml to a maximum of 1.2 mg/ml (Louwerens et al., 1987). In line with the established relation between BAC and accident risk, the relation between BAC and SDLP was shown to be an exponential function. Based on this relation, BACs of 0.5, 0.8, and 1.0 mg/ml were associated with mean changes in SDLP of 2.4, 4.2, and 5.1 cm. Mean changes in driving performance under the influence of hypnotic drugs can thus be compared to those associated with BACs at various limits considered legal in different countries. Figure 2 shows the results from 12 studies employing comparable procedures for assessing the residual effects of hypnotic drugs on driving performance the next morning. Five studies assessed residual effects after two nights of treatment with hypnotics in women complaining of insomnia and who previously used hypnotics. In the other studies, testing occurred with subjects who were healthy and included both genders, or after a single night of treatment. In all studies, driving tests were undertaken in the morning between 10 and 11 h after intake. In six studies, a second driving test was performed in the afternoon, between 16 and 17 h after bedtime administration. The effects of zolpidem, zopiclone, and zaleplon were also assessed after administration of these drugs in the middle of the night, that is, 4 or 5 h before testing. The most severe residual effects were found for flurazepam 30 mg and loprazolam 2 mg. The average degrees of impairment were worse than

96 (a)

(b)

Lateral position8 (c) Placebo e.g. SDLP = 18 cm

Sedating drug e.g. SDLP = 35 cm Fig. 1. Highway driving test used in experimental studies for assessing residual effects of hypnotics on driving performance. (a) Subjects drive a specially instrumented vehicle over a 100-km primary highway in normal traffic, accompanied by a driving instructor having access to dual controls. They are instructed to drive as straight as possible in the middle of the slower (right) traffic lane with a constant speed of 95 km/h. (b) A camera on top of the car continuously registers the lateral position of the car on the road with respect to the left lane delineation. (c) The standard deviation of lateral position (SDLP in centimeters) is an index of road tracking error or “weaving.” It is a highly reliable variable of individual driving performance (mean test–retest correlation is 0.85) and it has proven sensitive to the effects of many sedating drugs including low doses of alcohol.

those associated with a BAC of 1.0 mg/ml in the morning and equivalent to 0.8 mg/ml in the afternoon. Drugs that had residual effects in the morning equivalent to BACs between 0.5 and 0.8 mg/ ml were nitrazepam 10 mg, flunitrazepam 2 mg, zopiclone 7.5 mg, oxazepam 50 mg, and lormetazepam 2 mg (capsules). The residual effects dissipated rapidly over time for hypnotics with short and intermediate half-lives (zopiclone 7.5 mg, lormetazepam 2 mg, and oxazepam 50 mg) but remained significant or even increased for hypnotics with long half-lives (flunitrazepam 2 mg and nitrazepam 10 mg, respectively). Drugs that had no significant residual effects in the morning and afternoon were zaleplon 10 and 20 mg, zolpidem 10 mg, lormetazepam 1 mg (capsules), temazepam 20 mg (soft gelatin capsules), and nitrazepam 5 mg. Table 1 summarizes the effects of hypnotics doses at different times after administration, categorized as unlikely, minor (comparable to BACs < 0.5 mg/ml), moderate (comparable

to BACs between 0.5 and 0.8 mg/ml), and severe (comparable to BACs > 0.8 mg/ml). For more details, see Vermeeren (2004). Not shown in the figure are the results of a study comparing the residual effects of triazolam 0.5 mg, midazolam 15 mg, and temazepam 20 mg (in soft gelatin capsules) after daytime sleep in shift workers. Results are not comparable to those of the other studies because the procedures differed: the driving test was performed in the afternoon, between 7.5 and 8.5 h after morning ingestion of drugs or placebo. Nonetheless, results confirmed previous findings suggesting that temazepam 20 mg is unlikely to produce residual effects on driving. In contrast, triazolam 0.5 mg produced residual impairment equivalent to a BAC over 1.0 mg/ml after the first treatment and equivalent to a BAC of 0.8 mg/ml after the fifth consecutive treatment. Midazolam 15 mg had minor effects on the fifth day of treatment, but none on the first day.

Equivalent effects of alcohol while BAC is

*

*

*

FLU 30

8

LOP 2

97

6 1.0 mg/ml

*

0.8 mg/ml

ZOP 7.5

SEC 200

* *

FLU 15

FLN 2

LMT 2 (caps)

OXA 50

* * *

ZOP 7.5

NIT 10

LMT 1 (tabs)

GBX 15

TEM 20

NIT 5

ZPD 10

LMT 1 (caps)

–2

ZAL 10

0

*

*

ZOP 7.5

2

*

LOP 1

0.5 mg/ml

* *

ZOP 7.5

4

Fig. 2. Residual effects of hypnotics on performance in a standardized highway driving test between 10 and 11 h after bedtime administration. Effects on SDLP (in centimeters) are presented as mean changes from placebo. Indicated are the hypnotic doses (in milligrams) and formulation (caps, capsules; tabs, tablets) for flunitrazepam (FLN), flurazepam (FLU), gaboxadol (GBX), lormetazepam (LMT), loprazolam (LOP), nitrazepam (NIT), oxazepam (OXA), secobarbital (SEC), temazepam (TEM), zaleplon (ZAL), zolpidem (ZPD), and zopiclone (ZOP). Asterisks indicate significant (p < 0.05) differences from placebo. The dotted lines indicate the equivalent effects of alcohol on SDLP while blood alcohol concentrations are 0.5, 0.8, and 1.0 mg/ml, as measured by Louwerens et al. (1987).

Effects in elderly and insomnia patients have recently been studied by (Leufkens et al., 2009b,c; Leufkens and Vermeeren, 2009). Using the same test and methods, they found that the severity of residual effects in middle-aged and older-age groups (up to 75 years) is comparable to those found in young adults. Temazepam 20 mg was found to have no residual effects on driving in the elderly, whereas the effects of zopiclone 7.5 mg in the same group were comparable to those found in young volunteers (Leufkens and Vermeeren, 2009). In addition, these investigators found that zopiclone 7.5 mg had moderately severe residual effects on driving of insomnia patients who did not use hypnotics on a regular basis (Leufkens et al., 2009b). Effects in insomniacs chronically using hypnotics were found to be slightly reduced, but still significant. This suggests that the residual effects of hypnotics are not compensated by therapeutic

effects on sleep in patients, and that tolerance to these effects is not complete in chronic users.

Long-term effects In spite of recommendations to limit the use of hypnotics to a few weeks, a large number of patients use them chronically. This raises the question whether the adverse effects on cognition diminish with prolonged use or even disappear, due to the development of tolerance. To answer this, a number of studies have compared cognitive performance of long-term benzodiazepine users to that of controls using cross-sectional designs. According to a metaanalytic evaluation of 13 studies published between 1980 and 2000, long-term benzodiazepine users show impairment over a wide range of cognitive functions (Barker et al., 2004a). The authors

98 Table 1. Categorization of the residual effects of hypnotics Drug

Dose (mg)

Time after bedtime administration 4-8 h (2nd half of the night)

8-12 h (morning)

12-16 h (afternoon)

16-22 h (evening)

zaleplon zaleplon

10 20

Unlikely Unlikely

Unlikely Unlikely

Unlikely Unlikely

Unlikely Unlikely

zolpidem midazolam temazepam SGC triazolam lormetazepam capsules

10 7.5 20 0.125 1

Moderate Moderate Moderate Moderate Moderate

Unlikely Unlikely Unlikely Unlikely Unlikely

Unlikely Unlikely Unlikely Unlikely Unlikely

Unlikely Unlikely Unlikely Unlikely Unlikely

lormetazepam tablets midazolam temazepam HGC triazolam zolpidem

1 15 30 0.25 20

Severe Severe Severe Severe Severe

Minor Minor Minor Minor Minor

Unlikely Unlikely Unlikely Unlikely Unlikely

Unlikely Unlikely Unlikely Unlikely Unlikely

lormetazepam capsules loprazolam flunitrazepam triazolam zopiclone

2 1 1 0.5 7.5

Severe Severe Severe Severe Severe

Moderate Moderate Moderate Moderate Moderate

Unlikely Unlikely Unlikely Unlikely Unlikely

Unlikely Unlikely Unlikely Unlikely Unlikely

nitrazepam

5

Severe

Minor

Minor

Unlikely or minor

flunitrazepam

2

Severe

Moderate

Minor to moderate

Minor

nitrazepam flurazepam

10 15

Severe Severe

Moderate Moderate

Moderate Moderate

Moderate Moderate

flurazepam loprazolam

30 2

Severe Severe

Severe Severe

Severe Severe

Moderate Moderate

Source: Vermeeren (2004).

categorized the neuropsychological tests used in these studies into 12 cognitive domains and calculated effect sizes for differences found in each domain. Results showed that long-term benzodiazepine users were consistently more impaired than controls across all cognitive categories examined, with weighted effect sizes ranging between  1.30 for sensory processing and  0.42 for verbal reasoning. The most frequently used test in these studies was the digit symbol substitution test (DSST, category psychomotor speed, effect size  0.99), and the most frequently measured category was verbal memory (effect size  0.58). This clearly shows that the negative effects of benzodiazepines on cognition

do not disappear due to development of tolerance. This is of particular concern for elderly patients, many of whom use these drugs chronically and show age-related memory decline. Additional druginduced cognitive dysfunction may induce a state of clinical dementia. It should be noted that most studies included in the meta-analysis did not differentiate between benzodiazepines used as hypnotics and benzodiazepines used as anxiolytics. This may be relevant, however, because hypnotics should be effective during the night with minimal residual effects during the day, whereas anxiolytics should be effective at daytime. Van Steveninck et al.

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(1997) showed that development of tolerance to the effects of a hypnotic (temazepam) was less than to the effects of an anxiolytic (lorazepam). Chronic users of lorazepam showed no objective impairment compared to controls, despite high plasma concentrations. In addition, their response to a subsequent acute dose of lorazepam was much smaller than in controls. In contrast, chronic users of temazepam and controls responded similarly to an acute dose of temazepam. Chronic users of lorazepam had higher baseline drug concentrations than users of temazepam, which suggests that exposure to lorazepam was more prolonged than to temazepam. This may have led to a difference in the development of tolerance. It could be argued that there is development of tolerance, but that there are premorbid differences in cognitive functioning between benzodiazepine users and controls that explain the differences between the groups. Longitudinal studies are therefore needed to reveal differential changes in cognition of users and nonusers over time. A longitudinal populationbased study by Paterniti et al. (2002) examined cognitive performance of 1176 elderly (aged 60–70 years) at 2-year intervals over a 4-year period. Results showed that those reporting to take benzodiazepines on all of these examinations did not differ significantly from nonusers at the start, but did show an accelerated decline of cognitive performance compared with nonusers. This indicates that long-term use of benzodiazepines is a risk factor for cognitive decline in elderly. The development of new hypnotics and increasing awareness of the risks associated with use of older benzodiazepines has changed the drugs prescribed. The majority of prescriptions nowadays are for relatively low doses of short half-life hypnotics, which have minor residual effects on daytime performance. In line with this, a recent study by Puustinen et al. (2007) found no difference in cognitive functioning between a group of elderly chronic users of zopiclone, temazepam, and oxazepam, and a group of nonusers. The authors examined 164 elderly patients admitted to acute hospital wards in Finland, using

interviews, the Mini Mental State Examination (MMSE), and analyses of serum concentrations of hypnotics. Only temazepam serum concentrations correlated negatively with decreases in MMSE scores, which was probably due to the relatively high doses used in this frail population. Similarly, Leufkens et al. (2009b,c) recently failed to find differences in cognitive performance and car driving ability between chronic users of hypnotics and a group of controls, which may have been due to the fact that the majority of patients in this study used hypnotics in doses that were not expected to have residual effects on performance. The same subjects participated in a subsequent double-blind placebo-controlled crossover study assessing the residual effects of a hypnotic known to produce nextday impairment (zopiclone 7.5 mg). Results of this study showed that chronic users were still sensitive to the adverse residual effects on driving and cognitive performance of zopiclone. It was also found that the drug–placebo differences in performance were smaller in chronic users than in controls, suggesting that chronic users were partially tolerant. However, performance after use of placebo was also worsened compared to baseline in chronic users, suggesting that their relatively small drug–placebo difference may in part be due to the adverse effects of withdrawal. Although discontinuation of hypnotics may initially be associated with withdrawal symptoms, it may result in a reversal of drug-induced impairment after some time. Two further metaanalyses of studies before 2000 by Barker et al. (2004b) focused on the changes after discontinuation and impairment at long-term follow-up. The authors concluded that while some recovery of function was observed after discontinuation, previous users displayed impairment in many areas some years after discontinuation. Some studies examined recovery in older adults. One of them was conducted by McAndrews et al. (2003), who examined a sample of outpatients (aged 50 years and older) presenting to a sleep clinic with

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complaints of sleep problems. Twenty-five patients completed a cognitive test battery before discontinuation and at 1 month postdiscontinuation. The battery comprised measures in three cognitive domains: attention/speed of processing, psychomotor speed, and learning/ memory. Results showed that the performance of benzodiazepine users at baseline showed modest reductions in attention and psychomotor speed compared to controls. Importantly, however, benzodiazepine users improved more from baseline to postrecovery reassessment than controls. So, recovery from benzodiazepine use was associated with subtle and reversible effects on cognition. Another study was conducted by Curran et al. (2003). They examined 192 long-term users of benzodiazepine hypnotics aged 65 years or older. Of these, 104 who wished to withdraw from benzodiazepines were randomly allocated to one of two groups under double-blind, placebo-controlled conditions. In group 1, the benzodiazepine dose was tapered from week 1 of the trial. Group 2 were administered their usual dose for 12 weeks, which was then tapered thereafter. An additional group of 35 patients who did not wish to withdraw from benzodiazepines participated as controls. All patients were assessed at 0, 12, and 24 weeks, and one-half of these patients were reassessed at 52 weeks. Sixty percent of the patients had been taking the drug continuously for > 10 years, while 27% of the patients had been taking the drug continuously for > 20 years. Of all the patients beginning the trial, 80% had withdrawn successfully 6 months later. There was little difference between groups 1 and 2, but both groups differed from the controls in that the performance of the withdrawers on several cognitive and psychomotor tasks showed improvements at 24 and 52 weeks relative to baseline. Withdrawers and controls did not differ in sleep (as measured by subjective ratings of problems sleeping or intensity of dreaming) or benzodiazepine withdrawal symptoms. The results of this study imply that withdrawal from benzodiazepines produces some

subtle cognitive advantages for elderly people, yet little in the way of withdrawal symptoms or emergent sleep difficulties.

Novel hypnotics Most currently available prescription hypnotics enhance the effects of the sleep-promoting neurotransmitter GABA, whereas many OTC treatments induce sedation by blocking the wake promoting neurotransmitter histamine. These drugs contain antihistamines, such as diphenhydramine and hydroxyzine, which are antagonists for histamine H1 receptors and can penetrate the central nervous system. Several antidepressant and antipsychotic drugs have similar effects on H1 receptors and can induce pronounced sedation. In fact, some are antidepressants that are currently in development for the treatment of insomnia, for example, low doses of doxepin (Krystal et al., 2010). The effects of H1 antagonism on cognition have been extensively studied and were recently reviewed by van Ruitenbeek et al. (2010). They conclude that H1 antagonism primarily affects psychomotor functions and attention and have little effect on memory. Melatonin is involved in the circadian regulation of sleep and is therefore also a target for the treatment of sleep problems. Administration of exogenous melatonin or analogs such as ramelteon, which is licensed in the United States, can promote sleep onset (Wilson et al., 2010). Effects on cognitive functions have not been studied as extensively as those of benzodiazepines and antihistamines. Most studies assessed residual effects on performance using a DSST and no significant residual effects of ramelteon on this test have been reported. Mayer et al. (2009) evaluated the residual effects of ramelteon in adults with chronic insomnia using the DSST and a word recall test. Although these authors report a consistently reduced sleep onset, with no next-morning residual effects, it is, however, still too early to draw final conclusions about its efficacy and adverse effects.

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Nevertheless, drugs binding to the melatonin receptors seem to be interesting as potential hypnotics, given the main role of melatonin in the sleep–wake cycle. Other targets for the treatment of insomnia are antagonists for serotonin 5HT-2 receptors and orexin/hypocretin receptors (c.f., Wafford and Ebert, 2008). As these compounds are very new and mostly still under development, little information is published yet on the effects on cognition.

Summary and conclusion To summarize, hypnotic drugs can have deteriorating effects on cognitive performance, which is expected from all drugs when taken in doses that induce sedation and promote sleep. BzRAs can have effects on memory that are at least partially independent of their sedative effects. Other sedating drugs, with different mechanisms of action such as histamine H1 antagonists or melatonin agonists, may have less effect on memory and learning. For patients using hypnotic drugs, the effects on cognition are relevant to the extent that a drug dose affects daytime performance. Therefore, most hypnotics are studied to determine whether they produce residual sedation and impairing effects on performance the morning after bedtime use. 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, either directly or by improving sleep. 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. Selection of a drug that has minimal residual sedating effects

the next day is therefore important, whatever its mechanism of action. More studies are needed to determine whether use of a hypnotic drug can actually improve cognitive functions in patients complaining of insomnia. References Abduljawad, K. A., Langley, R. W., Bradshaw, C. M., & Szabadi, E. (2001). Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man. Journal of Psychopharmacology, 15, 237–242. Barbone, F., McMahon, A. D., Davey, P. G., Morris, A. D., Reid, I. C., McDevitt, D. G., et al. (1998). Association of road-traffic accidents with benzodiazepine use. Lancet, 352, 1331–1336. Barker, M. J., Greenwood, K. M., Jackson, M., & Crowe, S. F. (2004a). The cognitive effects of long-term benzodiazepine use: A meta-analysis. CNS Drugs, 18, 37–48. Barker, M. J., Greenwood, K. M., Jackson, M., & Crowe, S. F. (2004b). Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: A meta-analysis. Archives of Clinical Neuropsychology, 19, 437–454. Beracochea, D. (2006). Anterograde and retrograde effects of benzodiazepines on memory. The Scientific World, 6, 1460–1465. Coenen, A. M. L., & van Luijtelaar, E. L. J. M. (1997). Effects of benzodiazepines, sleep and sleep deprivation on vigilance and memory. Acta Neurologica Belgica, 97, 123–129. Coenen, A. M. L., van Poppel, H. C. A. J. M., Gribnau, F. W. J., Vossen, J. M. H., & van Luijtelaar, E. L. J. M. (1989). Benzodiazepines and cognition: Effects on intentional and incidental learning. In J. Horne (Ed.), Sleep ‘88 (pp. 201–204). Stuttgart, New York: Gustav Fischer Verlag. Coenen, A. M. L., & Van Luijtelaar E. L. J. M. (1991). Pharmacological dissociation of EEG and behavior: a basic problem in sleep-wake classification. Sleep 14, 464–465. Curran, H. V. (1999). Effects of anxiolytics on memory. Human Psychopharmacology: Clinical and Experimental, 14(S1), S72–S79. Curran, H. V., & Birch, B. (1991). Differentiating the sedative, psychomotor and amnestic effects of the benzodiazepines: A study with midazolam and the antagonist, flumazenil. Psychopharmacology, 103, 519–523. Curran, H. V., Collins, R., Fletcher, S., Kee, S. C., Woods, B., & Iliffe, S. (2003). Older adults and withdrawal from benzodiazepine hypnotics in general practice: Effects on cognitive function, sleep, mood and quality of life. Psychological Medicine, 33, 1223–1237. Fafrowicz, M., Unrug, A., Marek, T., van Luijtelaar, G., Noworol, C., & Coenen, A. (1995). Effects of diazepam

102 and buspirone on reaction times of saccadic eye movements. Neuropsychobiology, 32, 156–160. Gorissen, M. E. E., Curran, H. V., & Eling, P. A. T. M. (1998). Proactive interference and temporal context encoding after diazepam intake. Psychopharmacology (Berlin), 138, 334–343. Gorissen, M. E. E., & Eling, P. A. T. M. (1998). Dual task performance after diazepam intake: Can resource depletion explain the benzodiazepine-induced amnesia? Psychopharmacology (Berlin), 138, 354–361. Gorissen, M., Eling, P., van Luijtelaar, G., & Coenen, A. (1995). Effects of diazepam on encoding processes. Journal of Psychophysiology, 9, 113–121. Gorissen, M., Tielemans, M., & Coenen, A. (1997). Alertness and memory after sleep deprivation and diazepam intake. Journal of Psychopharmacology, 11, 233–239. Hinrichs, J. V., Ghoneim, M. M., & Mewaldt, S. P. (1984). Diazepam and memory: Retrograde facilitation produced by interference reduction. Psychopharmacology, 84, 158–162. Johnson, L. C., & Chernik, D. A. (1982). Sedative-hypnotics and human performance. Psychopharmacology, 76, 101–113. Krystal, A. D., Durrence, H. H., Scharf, M., Jochelson, P., Rogowski, R., Ludington, E., et al. (2010). Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep, 33, 1553–1561. Leufkens, T. R. M., Lund, J. S., & Vermeeren, A. (2009a). Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. Journal of Sleep Research, 18, 387–396. Leufkens, T. R. M., Ramaekers, J. G., de Weerd, A. W., Riedel, W. J., & Vermeeren, A. (2009b). Residual effects of zopiclone 7.5 mg on highway driving in elderly insomnia patients: A placebo controlled study. In T. R. M. Leufkens (Ed.), Hypnotics and anxiolytics: Field and laboratory measures of drug safety in driving performance and cognitive functions. Thesis, Maastricht University. Leufkens, T. R. M., Ramaekers, J. G., de Weerd, A. W., Riedel, W. J., & Vermeeren, A. (2009c). On the road driving performance and driving related skills in untreated insomnia patients and chronic users of hypnotics. In T. R. M. Leufkens (Ed.), Hypnotics and anxiolytics: Field and laboratory measures of drug safety in driving performance and cognitive functions. Thesis, Maastricht University. Leufkens, T. R. M., & Vermeeren, A. (2009). Highway driving in the elderly the morning after bedtime use of hypnotics: A comparison between temazepam 20 mg, zopiclone 7.5 mg, and placebo. Journal of Clinical Psychopharmacology, 29, 432–438. Lister, R. G. (1985). The amnestic action of benzodiazepines in man. Neuroscience Biobehavioural Reviews, 9, 87–94.

Louwerens, J. W., Gloerich, A. B. M., De Vries, G., Brookhuis, K. A., & O'Hanlon, J. F. (1987). The relationship between drivers’ blood alcohol concentration (BAC) and actual driving performance during high speed travel. In P. C. Noordzij & R. Roszbach (Eds.), International congress on alcohol, drugs and traffic safety, T86 (pp. 183–186). Amsterdam: Excerpta Medica. Mayer, G., Wang-Weigand, S., Roth-Schechter, B., Lehmann, R., Staner, C., & Partinen, M. (2009). Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep, 32, 351–360. McAndrews, M. P., Weiss, R. T., Sandor, P., Taylor, A., Carlen, P. L., & Shapiro, C. M. (2003). Cognitive effects of long-term benzodiazepine use in older adults. Human Psychopharmacology, 18, 51–57. Neutel, C. I. (1995). Risk of traffic accident injury after a prescription for a benzodiazepine. Annals of Epidemiology, 5, 239–244. Neutel, C. I. (1998). Benzodiazepine-related traffic accidents in young and elderly drivers. Human Psychopharmacology: Clinical and Experimental, 13, 115s–123s. Nutt, D. J., & Stahl, S. M. (2010). Searching for perfect sleep: The continuing evolution of GABAA receptor modulators as hypnotics. Journal of Psychopharmacology, 24, 1601–1612. O'Hanlon, J. F. (1984). Driving performance under the influence of drugs: Rationale for, and application of, a new test. British Journal of Clinical Pharmacology, 18, 121s–129s. Paterniti, S., Dufouil, C., & Alpérovitch, A. (2002). Long-term benzodiazepine use and cognitive decline in the elderly: The epidemiology of vascular aging study. Journal of Clinical Psychopharmacology, 22(3), 285–293. Puustinen, J., Nurminen, J., Kukola, M., Vahlberg, T., Laine, K., & Kivelä, S. L. (2007). Associations between use of benzodiazepines or related drugs and health, physical abilities and cognitive function: A non-randomised clinical study in the elderly. Drugs & Aging, 24(12), 1045–1059. Quaglio, G., Lugoboni, F., Fornasiero, A., Lechi, A., Gerra, G., & Mezzelani, P. (2005). Dependence on zolpidem: Two case reports on detoxification with flumazenil infusion. International Clinical Psychopharmacology, 20, 285–287. Ramaekers, J. G. (2003). Antidepressants and driver impairment: Empirical evidence from a standard on-theroad test. The Journal of Clinical Psychiatry, 64, 20–29. Squire, L. R. (1992). Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychological Review, 99, 195–231. Theunissen, E. L., Vermeeren, A., Vuurman, E. F. P. M., & Ramaekers, J. G. (2009). Drugs, driving and traffic safety in allergic rhinitis. In J. C. Verster, S. R. PandiPemural, J. G. Ramaekers & J. J. De Gier (Eds.), Drugs, driving and traffic safety. (pp. 371–382). Basel: Birkhäuser.

103 Tiplady, B., Hiroz, J., Holmes, L., & Drummond, G. (2003). Errors in performance testing: A comparison of ethanol and temazepam. Journal of Psychopharmacology, 17, 41–49. Unrug, A., Coenen, A. M. L., & van Luijtelaar, E. L. J. M. (1997a). Effects of the tranquillizer diazepam and the stimulant methylphenidate on vigilance and memory. Neuropsychobiology, 36, 42–48. Unrug, A., van Luitelaar, E. L. J. M., Coles, M. G. H., & Coenen, A. M. L. (1997b). Event related potentials in a passive and active auditory condition: Effects of diazepam and buspirone in slow wave positivity. Biological Psychology, 46, 101–111. Van Leeuwen, T. H., Verbaten, M. H., Koelega, H. S., Camfferman, G., van der Gugten, J., & Slangen, J. L. (1994). Effects of oxazepam on eye movements and performance in vigilance tasks with static and dynamic stimuli. Psychopharmacology, 116, 499–507. Van Leeuwen, T. H., Verbaten, M. N., Koelega, H. S., Kenemans, J. L., & Slangen, J. L. (1992). Effects of bromazepam on single-trial event-related potentials in a visual vigilance test. Psychopharmacology, 106, 555–564. Van Ruitenbeek, P., Vermeeren, A., & Riedel, W. J. (2010). Cognitive domains affected by histamine H1-antgonism in humans: A literature review. Brain Research Reviews, 64, 263–282. Van Steveninck, A. L., Wallnöfer, A. E., Schoemaker, R. C., Pieters, M. S., Danhof, M., van Gerven, J. M., et al.

(1997). A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population. British Journal of Clinical Pharmacology, 44(3), 267–275. Vermeeren, A. (2004). Residual effects of hypnotics: Epidemiology and clinical implications. CNS Drugs, 18, 297–328. Vermeeren, A., Danjou, P. E., & O'Hanlon, J. F. (1998). Effects of evening and middle of the night doses of zaleplon 10 and 20 mg on memory and actual driving performance. Human Psychopharmacology, 13, S98–S107. Vermeeren, A., Leufkens, T. R. M., & Verster, J. C. (2009). Effects of anxiolytics on driving. In J. C. Verster, S. R. PandiPemural, J. G. Ramaekers & J. J. De Gier (Eds.), Drugs, driving and traffic safety. (pp. 289–306). Basel: Birkhäuser. Wafford, K. A., & Ebert, B. (2008). Emerging anti-insomnia drugs: Tackling sleeplessness and the quality of wake time. Nature Reviews. Drug Discovery, 7, 530–540. Wilson, S. J., Nutt, D. J., Alford, C., Argyropoulos, S. V., Baldwin, D. S., Bateson, A. N., et al. (2010). British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. Journal of Psychopharmacology, 24, 1577–1601. Winsky-Sommerer, R. (2009). Role of GABAA receptors in the physiology and pharmacology of sleep. The European Journal of Neuroscience, 29, 1779–1794.