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16 With the exception of RozeremTM, all other prescription of obtaining a good night sleep. In reviewing the impairing medications indicated for insomnia are classified as Sched- effects of benzodiazepines on human performance, Wittenborn ule IV controlled substances by the DEA. It is recommended (1979) documented that the effects vary among the different that ramelteon not be mixed with alcohol and that users avoid types of benzodiazepines. When impairment was found, it operating heavy machinery until they are sure how they react was generally with higher doses, and within 2 to 6 h of drug to the medication. administration. The effects were drug-specific, but there were observable impairments in the speed for accomplishment Johnson et al. (2006) did an experiment to compare of simple repetitive acts, as well as impaired learning and ramelteon with triazolam and to placebo. Compared with immediate memory; however, overall, there was relatively placebo, ramelteon at 16, 80, and 160 mg (about 20 times the little indication that well-established higher mental faculties recommended dose) showed no significant effect on any of are adversely involved. After that period the drug effects on the subjective measures collected, including those related behavior tended to dissipate (Wittenborn 1979). Koelega to potential for abuse. In the study, 79% of participants (1991) found that with young volunteers, vigilance is relatively (11 of 14) identified the highest dose of ramelteon as placebo sensitive to benzodiazepine impairment, causing individuals (meaning they could not differentiate). Similarly, compared to miss more signals and respond more slowly to signals they with the placebo, ramelteon at any dose had no effect on any did see. Kunsman et al. (1992) found that benzodiazepines at observer-rated or motor and cognitive performance measure. therapeutic doses when measured within 1 to 3 h of ingestion In contrast, triazolam showed dose-related effects on a wide slowed simple and choice reaction time. However, continued range of subject-rated, observer-rated, and motor and cog- repeated administrations eventually caused resistance (adap- nitive performance measures, consistent with its profile as a tation) to the impairing effects. Johnson and Chernik (1982) sedative drug with abuse liability. Johnson et al. (2006) con- concurred with Wittenborn's findings, but also reported that cluded that ramelteon may represent a useful alternative to high-dose levels of all benzodiazepines, taken at night, impair existing insomnia medications. next-day performance, and the impairment is greater for long- life hypnotics. Because of its action on melatonin receptors, which help control the body's circadian phase, ramelteon has been used An array of laboratory tests that relate to driving skills to facilitate phase advance in circadian rhythm disorders such sensitive to sedation have been developed in various labo- as jet lag and shift work (see section on melatonin). Circadian ratories; however, the predictive validity of many of the lab factors are recognized as an important factor in road accidents tests tends to be unreliable. The most useful example of such (Gertler et al. 2002; Richardson et al. 2008). test protocols is that of James O'Hanlon and colleagues in the Netherlands. In a decade-long series of driving studies, Assessment of ramelteon. No studies of human perfor- O'Hanlon developed an over-the-road driving test in which mance as affected by ramelteon were located for this literature participants operate an instrumented vehicle over a 100 km review. More research is needed with this new, potentially primary highway circuit in normal traffic (O'Hanlon and promising hypnotic compound. DeGier 1986). Driver performance measures of speed and lateral position are recorded, and the standard deviation of SLEEP-PROMOTING COMPOUNDS the lateral position (SDLP) is most often cited as the primary AND DRIVING PERFORMANCE outcome variable: the "weaving index" (O'Hanlon and Volkerts 1986; DeGier 2005). Although many benzodiazepines are generally well-tolerated, with higher doses they impair concentration and produce O'Hanlon and his research team published more than sedative effects even after their drug effects might be 75 major studies about the effects of drugs on driving perfor- expected to have worn off (O'Hanlon 1985). The active mance. In many of O'Hanlon et al.'s experiments, hypnotic effects of benzodiazepines may include sedation, depression, drugs were taken by subjects for several nights before they disorientation, daytime drowsiness, impaired balance, and were tested in actual driving tasks (O'Hanlon 1985; O'Hanlon with increased dosage they produce associated increased side et al. 1995). Almost all of the experiments employed the basic effects. Although the margin of safety associated with these paradigm using an actual road driving course and reported drugs is considerable overdose can occur, and continuous SDLP as the principal indicator of driving performance. use for several months can result in psychological or physical dependence--that is, they can be addictive (Davis 1996). The All of the mean performance changes (degradations) effects of benzodiazepines are enhanced if accompanied by occurring after two nights of drug treatment with benzodi- alcohol, and mixing some benzodiazepines with alcohol can azepines were significant in morning or afternoon tests, or both, have toxic effects (Carskadon 1993). except those following nitrazepam (5 mg) and temazepam (20 mg). The magnitudes of some changes were relatively Medical providers who prescribe hypnotic medication for small for lorazepam (1 mg), nitrazepam (10 mg), zoplicone drivers must carefully weigh the potential risks of daytime (7.5 mg), and flunitrazepam (2 mg). These were the equivalent impairment from a hypnotic medication against the benefit to the amount of impairment attributable to blood alcohol

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17 concentrations in a range from just under 0.5 mg/mL to about ing health care providers and dispensing pharmacists in their 0.6 mg/mL. Slightly greater impairment was measured with decision making, making it possible for them to offer relatively 15 mg of flurazepam in the morning test. However, a serious safer alternative sleep-inducers to patients who drive and need degree of impairment, greater than the equivalent of a BAC of hypnotic medications (DeGier 2005). 1 mg/mL, was attributable to the residual effects of secobar- bital (200 mg), flurazepam (30 mg), and loprazolam (2 mg) DeGier and Volkert's figure indicates that 6 of 11 hypnotics (O'Hanlon 1985). After a week of taking diazepam (5 mg, (mostly shown on the left in the figure) appear to impair driving 3 times per day) and lorazepam (2 mg, twice per day) driv- performance less, in both the morning and the afternoon of ing performance was impaired more than it was by a BAC the next day (after dosing) than do the other 5 hypnotic drugs of 1 mg/mL (O'Hanlon et al. 1995). Some of these results are (mostly depicted on the right side of the figure). The six drugs depicted in Figure 1, along with results from subsequent presenting lower sleep inertia were zaleplon, zolpidem, nitra- studies undertaken by O'Hanlon and his colleagues. zepam, lormetazepam, temazepam, and loprazolam, whereas the five hypnotics that produced higher sleep inertia scores Extracting the findings of many of those studies for a meta- the next day were flunitrazepam, zopiclone, secobarbital, analysis of the work, DeGier (2005) provided an informative oxazepam, and flurazepam (see also O'Hanlon 1985). figure summarizing the results in terms of residual sedation after sleep at measurement times ranging from 5 to 17 h post- In another review, Berghaus and Grass (1997) summarized dosing with various hypnotic drugs (mostly benzodiazepines more than 500 experimental studies describing performance and the so-called nonbenzodiazepines). DeGier's figure impairment on driving-related psychomotor and perceptual (Figure 1) is attributed to E. R. Volkerts (DeGier 2005). tasks as attributed to benzodiazepines. They reported a near- linear relationship between serum concentration and the The difference in SDLP relative to placebo is presented percent of studies that obtained a significant effect, for both with an indication for comparison with calibrated BAC levels the short-acting triazolam and for the long-acting nitrazepam. of 0.5, 0.8, and 1.0 (the horizontal lines across the figure). Similar relationships were assessed for other benzodiazepines DeGier cites the comparison figure to illustrate two things: such as temazepam, flunitrazepam, flurazepam, alprazolam, (1) that many prescribed hypnotics have a detrimental effect bromazepam, diazepam, oxazepam, and lorazepam. When on driving (sleepinertia hangover effects) even in the after- measured during the absorption phase (>3 h after adminis- noon of the day following administration of the sleep-inducing tration), the impairment was about 30% higher than when it dosing the night before; and (2) that some other hypnotics was measured during the elimination phase (>5 h). This effect apparently do not have such effects, or at least they are sub- is similar to that obtained for alcohol, but it is much stronger stantially less. DeGier suggests that performance data such as for benzodiazepines. Despite significant differences among those in his report (depicted in the figure) can assist prescrib- individual benzodiazepines, as a class these drugs generally FIGURE 1 Residual effects of various hypnotics on Standard Deviation of Lateral Position (SDLP) while driving. Attributed to E. R. Volkerts, cited by DeGier (2005).