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INTRODUCTION TO SLEEP-PROMOTING CHEMICALS The best approach to fostering driver alertness and manag- ing driver fatigue on the roadway is to establish for oneself a suitable workârest schedule, and especially to adhere to a sleep management plan during extended or sustained work- ing hours, such as might be encountered during over-the-road operations (OâNeill et al. 1996; Orris et al. 2005). Obtaining adequate quantity and quality sleep is crucial for a commercial driver to maintain alertness on the job. Drivers preferably should obtain 7 to 8 h of sleep each 24-h day, which includes a contiguous stretch of at least 4 to 5 h of uninterrupted sleep (Krueger 1997, 2003; National Sleep Foundation 2010). The FMCSAâs current hours of service (HOS) rules for commercial drivers took effect in January 2004 (www.fmcsa. dot.gov). Specifically, the new HOS rules permit a 14-h work day (duty shift) of which 11 h can be driving, but require that on-duty periods be followed by 10 h off duty (the so-called 14â10 schedule). Under these HOS rules, drivers are expected to have more influence than they did previously for matching their working hours with known periodicities in circadian rhythm physiology, and thus make it more likely that drivers have the time during their weekly work schedules to obtain close to the desired 7 to 8 or more hours of restorative sleep per day. If commercial drivers cannot obtain 7 to 8 h of continuous sleep, they then need to augment the sleep they obtain by taking supplemental naps each day (OâNeill et al. 1996; Krueger 1989, 1997, 2003). However, work schedules for many commercial drivers do not always permit enough time for them to take additional naps, nor are delivery schedules always conducive to drivers obtaining adequate sleep at the right physiological times on the 24-h clock (e.g., it is often difficult to sleep during daylight after driving through the dark hours of night). Applying what is known about sleep needs and circadian physiology is a key to maintaining driving alertness. The topic also raises issues of whether as a part of their sleep management plan drivers might judiciously enact pro- tocols employing hypnotic or sleep-promoting medications to induce and maintain sleep, and upon awakening to resume and maintain safe driving practices. This literature review covers performance effects regarding: (1) classes of depressant medications such as benzodiazepines and other closely allied 12 prescription hypnotics, (2) prescription nonbenzodiazepine medications and others, (3) the synthetic sleep-inducing hor- mone melatonin, (4) first- and second-generation antihista- mines, and (5) alcohol when used as a sleep-promoting chemical. After each separate compound is described, some literature reporting on performance effects is cited, and then a short assessment of its pertinence to the issues facing the commercial driving community is presented. Performance after sleeping. The goal of many labo- ratory studies in the literature appeared to illustrate what performance detriments hypnotics produce when a person attempts to perform (e.g., to drive a vehicle) in the immediate period after taking a sleep-promoting drug, when sleep would be a naturally expected con- sequence. Such studies generally report decreased performance owing to effects of benzodiazepines, benzodiazepine-like drugs, first-generation antihista- mines, tricyclic antidepressants, narcotic analgesics, and antipsychotics (OâHanlon and DeGier 1986; Ramaekers 2003; Vermeeren 2004; DeGier 2005). Other studies addressed population-based driving risks following pre- scription use of both benzodiazepine and nonbenzo- diazepine hypnotics. This synthesis literature review is less concerned with the âeffects of hypnotics on driver performance soon after ingesting the medicationâ (under the influence), particularly if the driverâs inten- tion is to take a hypnotic to sleep. Rather, the goal here is to identify sleep-promoting compounds that can be used safely by commercial drivers to assist them to fall asleep; to help them obtain restful, restorative quantity and quality of sleep; and then to ensure that there are no important sleep inertia aftereffects soon after awakening and upon resuming driving (concern is for safe driving after awakening from drug-assisted sleep periods). Sleep disorders. Some commercial drivers experience insomnia and other sleep maladies whether they have been medically diagnosed for them or not (e.g., Pack et al. 2002, 2006). Any sleep initiation or maintenance disorder that reduces sleep efficiency has the potential to affect transportation safety. Discussion of prescribing hypnotic medications for treatment of sleep disorders [e.g., insomnia, shiftwork sleep disorder (SWSD), sleep apnea, and restless legs syndrome] is beyond the scope of this report. For an outline of treatment pro- tocols involving recommended drug doses for sleep disturbed patients who continue to drive, see DeGier (2005) and OâHanlon and Volkerts (1986) whose work, done in conjunction with the activities of the ICADTS Working Group, was formulated as a guidance document, âPrescribing and Dispensing Guidelines for Medicinal Drugs affecting Driving Performanceâ (ICADTS 2001). CHAPTER THREE HYPNOTICS AND SLEEP-PROMOTING COMPOUNDS
13 PRESCRIPTION BENZODIAZEPINES AS SLEEP-PROMOTING COMPOUNDS Benzodiazepines are a family of depressant drugs in the class of anxiolytic agents. Because they produce CNS depression, benzodiazepines commonly have been prescribed for treat- ing insomnia and anxiety. These hypnotics can be very effec- tive in helping a person fall asleep more quickly, reduce the number of awakenings, and increase the total sleep time (Mendelson 2005). Benzodiazepines are classified as Schedule IV depressants under the Controlled Substances Act (U.S. DEA 2009). NIDA cites the five most frequently prescribed drugs in the benzodiazepine class as: lorazepam (Ativan), diazepam (ValiumÂ®), alprazolam (Xanax), tema- zepam (RestorilÂ®), and clonazepam (Klonopin). Others include triazolam (HalcionÂ®), chlordiazepoxide (LibriumÂ®), Dalmane, Doral, and ProSom. Flunitrazepam is unique among the benzodiazepines for being placed in Schedule IV, but having Schedule I penalties. The five most prescribed benzo- diazepines are also some of the most frequently encountered drugs on the illicit drug market. NIDA lists the following as street names for benzodiazepines: candy, benzos, downers, nerve pills, sleeping pills, and tranks. Benzodiazepines are marketed as mild or minor tranquil- izers, sedatives, hypnotics, or anticonvulsants based to some extent on differences in their time-of-action, which ranges from less than 6 h to more than 24 h. Lorazepam (Ativan), alprazolam (Xanax), and oxazepam each have short half-lives. Some benzodiazepines have active metabolites that prolong their effects; therefore, for example, the half-life of diazepam is much longer, lasting up to 4 days. A drugâs âhalf-lifeâ refers to the period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half. The elimination half-lives of benzodiazepines vary widely, from the relatively short-acting triazolam, to intermediate agents such as temazepam, to long-acting substances such as flurazepam, to clonazepam, the longest acting of the benzodi- azepines (for details see Mendelson 2005). [See also the report of the FMCSA expert medical panel-psychiatric (Metzner et al. 2009), which presents a list of half-lives and a recom- mendation for blanket prohibition on commercial driving after use of benzodiazepines and nonbenzodiazepine hypnotics (within 7 half-lives)]. Application of low doses of the âshorter half-lifeâ drugs may be useful as sleep aids for those doing shift work or for use in helping to induce sleep during long overseas flights, where the body has to adjust to a different time zone in a relatively short time (Reiter and Robinson 1995; Technical Cooperation Program 2001). The literature on performance effects under the influence of benzodiazepines is covered later in this section following a description of a few of the newer sleep medications currently available. NONBENZODIAZEPINE SLEEP-PROMOTING MEDICATIONS Several other newer medications, essentially developed as alternatives to benzodiazepines, are currently being prescribed as sleep-promoting compounds. Some of the more common ones, often identified as nonbenzodiazepines, are described here: zolpidem, zaleplon, eszopiclone, ramelteon, and indiplon. Zolpidem Zolpidem produces sleep-inducing effects similar to those of benzodiazepines. In April 2007, the FDA approved 13 generic versions of zolpidem tartrate, a Schedule IV controlled substance. Zolpidem is available (as AmbienÂ®, StilnoxÂ®, MysleeÂ®, and others) for oral administration in 5 mg and 10 mg tablets. Zolpidem has been prescribed for short-term treatment of sleep problems such as insomnia, because it acts on the brain to produce a calming effect (Scharf et al. 1994; Roth et al. 1995). Zolpidem may help a person fall asleep faster, stay asleep longer, and reduce the number of times that a person awakens during the night (Elie et al. 1999). As a practical matter, with its relatively short half-life of 2.5 h, zolpidem is especially useful for promoting short- to moderate-length sleep durations (of 4 to 7 h) when shorter sleep opportunities occur at times that are not normally conducive to sleep, such as for taking daytime naps. Day- time naps are sometimes difficult to maintain, especially in individuals who are not sleep-deprived. The short half-life of zolpidem can provide short sleeps while minimizing the pos- sibility of post-nap sleep inertia hangovers. Thus, zolpidem can make it feasible to take advantage of a nap without sig- nificantly lengthening the post-nap time needed to ensure that any drug effects have dissipated before being expected to resume performance of oneâs job. Some research results are a bit conflicting. Zolpidem of 10 mg at bedtime was reported to be free of cognitive performance impairment within 6.5 h (Nicholson and Pascoe 1988; Langtry and Benfield 1990; Balkin et al. 1992; Caldwell and Caldwell 1998). However, Vermeeren (2004) reported residual hangover effects such as sleepiness, and he reported that impaired psychomotor and cognitive performance after nighttime administration may persist into the next day, possibly impairing the ability of users to drive safely. Gustavsen et al. (2008) indicated that use of zolpidem may impair driving skills with a resultant risk of road traffic accidents, and called for cautious use by drivers. In the military setting, Caldwell et al. (2009) suggested that zolpidem may be the optimal choice for sleep periods of less than 8 h and, if there were a possibility that the hypnotic- induced sleep period is likely to be unexpectedly shortened, zolpidem would be a better choice than temazepam. The U.S. Air Force has approved the use of zolpidem as one of the hypnotics referred to as âno-go pillsâ; however, prior
documented experience during ground testing with the drug is required before controlled administration. Even prior testing with such drugs however is no guarantee that they will work well in operations. Recently, when zolpidem successfully induced sleep in pilots before they controlled unmanned aerial vehicles in surge operations, side effects were reported in some crewmembers even though they had previously tested with the drug without side effects (Van Camp 2009). For results of military research employing zolpidem and other nonbenzodiazepines during lengthy operations and for use in transmeridian flight, see Caldwell et al. (2009). Although zolpidem under the trade name AmbienÂ® is one of the most widely prescribed sleeping pills in the United States, it is important to note that some users experi- ence troublesome side effects. AmbienÂ® users have reported instances of sleepwalking, as well as instances of eating or driving while not fully awakeâwith no memory of the events. Reports include AmbienÂ® users âsleepwalkingâ into awkward circumstances and then not knowing how they got there. AmbienÂ® use has shown up with some regularity as a factor in traffic arrests, and anecdotal stories relate how drivers later say they were sleep-driving and have no memory of taking the wheel after taking the drug. In 2007, the FDA cited reports of individuals getting out of bed after taking AmbienÂ® and then driving their cars while not fully awake, often with no memory of the eventâa phenomenon Shinar refers to as the âAmbien driverâ (Shinar 2007b). The FDA stated that this behavior is more likely to occur when AmbienCRÂ® (an extended release formulation) is taken with alcohol or other CNS depressants. The FDA warned that if a patient experiences such an episode, it should be reported to a physi- cian immediately, because âsleep-drivingâ can be dangerous (www.fda.gov). After similar reports of adverse events involving zolpidem marketed as StilnoxÂ® occurred in Australia in 2007 and 2008, the Australian Therapeutic Goods Administration attached a Black Box warning to zolpidem, stating that âZolpidem may be associated with potentially dangerous complex sleep- related behaviours which may include sleepwalking and other bizarre behaviours. Zolpidem is not to be taken with alcoholâ (www.tga.gov.au). An additive effect of alcohol with zolpidem was demonstrated on memory and psychomotor performance (Isawa et al. 2000; Uchiumi et al. 2000). More recently, in April 2010, reports surfaced that some Royal Australian Air Force pilots were becoming addicted to StilnoxÂ® because of repeated use of the drug over months-long deploy- ments to Afghanistan (Parnel and Callinan 2010). Assessment of zolpidem. The scientific literature does not currently provide sufficient explication of the potential of zolpidem-based products such as AmbienÂ® and AmbienCRÂ® for operational use with commercial driving. In particular there is a need to delineate any residual inertia hangover effects or effects on worker performance upon awakening from zolpidem-induced sleep periods, and to more fully 14 explore the reported potential for adverse events such as sleepwalking, sleep-driving, and tendencies toward addiction following repeated use. Zaleplon Zaleplon, available as SonataÂ® or StarnocÂ®, is a sedative/ hypnotic (pyrazolopyrimidine) that binds selectively to the benzodiazepine-l receptor. Zaleplon is rapidly absorbed after oral administration, with peak concentration being reached in about 1 h. The mean elimination half-life is around 1 h as well (Moore 2000). The claimed benefits are that zaleplon is effec- tive in initiating sleep; it is mainly used to treat insomnia. Clin- ical trials of the hypnotic efficacy of zaleplon showed improve- ment in sleep initiation, particularly with a 20-mg dose (Elie et al. 1999; Fry et al. 2000), and it produced no hangover effects as early as 6 to 7 h later (Chagan and Cicero 1999). Zaleplon speeds sleep onset, reduces awakenings, and also is effective in sustaining sleep, thus increasing the total sleep time. For times when one has difficulty falling asleep, it is recom- mended that zaleplon (usually 10 mg) be taken immediately before bedtime or even after a person has gone to bed. After zaleplon exerts its initial effects, the drug is subsequently and quickly eliminated in time for more natural physiological mechanisms to take over and maintain the remainder of the sleep period. Whitmore et al. (2004) found that when com- pared with a placebo, 10 mg of zaleplon effectively promoted sleep during the daytime even in well-rested individuals. Zaleplon allowed participants to obtain significantly more slow-wave sleep, as well as more sleep overall than under placebo. Performance was not adversely affected following a 3.5 h daytime sleep under zaleplon, nor were any undesirable symptoms determined (Whitmore et al. 2004). Although some studies (Paul et al. 2003) found that 10 mg of zaleplon impaired psychomotor performance for up to 2.25 h after ingestion, Hurst and Nobel (1999) reported 10 mg of zaleplon was without effect on cognitive performance measured 4 h after ingestion. To avoid any possible memory difficulties, zaleplon can be taken up to 4 h before planned time of arising and returning to work (Paul et al. 2004). Caldwell et al. (2009) indicated that in the military setting, zaleplon (5â10 mg) may be the best choice for initiating very short naps (1 to 2 h) or for promoting slightly longer naps (2 to 4 h), which would otherwise be difficult to initiate and maintain during a period of sustained wakefulness. They also indicated that zaleplon (10 mg) may help hasten early-to-bed sleep onsets in personnel who are trying to ensure sufficient sleep before a very early start time the next morning (i.e., at 0400â0500 h). With regard to facilitating early report times, zaleplon is perhaps a preferred option to zolpidem; however, both compounds are important for the same reasons. With its ultra-short 1-h half-life, zaleplon is less likely to pose hazards in terms of residual drug effects that can exacerbate the drowsiness associated with the predawn awakening dictated by an early start time.
15 Assessment of zaleplon. Owing to its ultra-short 1-h half-life, zaleplon (e.g., SonataÂ®) offers potential in select commercial driving applications for initiating naps of from 1 to 4 h, especially at times when it is otherwise difficult to fall asleep. Research specific to the commercial driving needs must confirm that there are no residual inertia effects that could interfere with safe applications meeting the needs of the commercial driving sector. Eszopiclone Eszopiclone (LunestaÂ®) is an FDA-approved prescription drug used for treatment of insomnia. It is another new nonbenzo- diazepine hypnotic agent, a derivative of the class of drugs known as cyclopyrrolones. Eszopiclone acts as an agonist on benzodiazepine receptors (Jufe 2007). It is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 h. The elimination half-life of eszopiclone is approx- imately 6 h, and it is extensively metabolized by oxidation and demethylation (Halas 2006). In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is roughly equivalent to 10 mg of diazepam. LunestaÂ® tablets contain 1 mg, 2 mg, or 3 mg of eszopiclone along with a variety of inactive ingredients. LunestaÂ® helps one to fall asleep quickly, so it is recommended that it be taken right before bedtime to be sure of having at least 8 h of sleep before becoming active. LunestaÂ® has a half-life of 5 to 6 h, making it a potential choice over temazepam, which has a longer half-life (Caldwell et al. 2009). LunestaÂ® demon- strated minimal residual drug effects after as little as 10 h post-dose (Leese et al. 2002). Lettieri et al. (2008) administered 3 mg of eszopiclone to 113 adults undergoing polysomnog- raphy for suspected sleep disorder breathing, and found that eszopiclone pre-medication significantly reduced sleep latency, improved sleep efficiency, reduced wake after sleep onset, and prolonged sleep time. Eszopiclone (LunestaÂ®), along with zolpidem (AmbienÂ®) and zaleplon (SonataÂ®), are the three most commonly pre- scribed sedative hypnotics in the United States. Pharma- ceutical information includes advising users that until they know how they will react to Lunesta, Ambien, or Sonata, they should not drive or operate machinery. It is recommended that none of these three hypnotics be taken with alcohol, as it might increase the likelihood of adverse behavioral side effects such as sleep-driving. Assessment of eszopiclone. For times when longer sleep opportunities are available; for example, during a driverâs mandatory 34-h time off duty for a restart period, the new hypnotic compound eszopiclone (LunestaÂ®) might offer assis- tance in helping a driver to fall asleep. Even with its estimated half-life of from 5 to 6 h, some research findings identified minimal residual drug effects at 10 h post-dose. Subsequent additional research could confirm how long after drug dosing a commercial driver taking eszopiclone should refrain from driving. Remaining research issues include identifying any residual sleep inertia effects on performance from acute use and determining whether or not noteworthy effects occur with repeated use over a longer period of time (e.g., weeks or months). Indiplon Indiplon is a nonbenzodiazepine sedative/hypnotic that is relatively new to the marketplace. It is currently undergoing clinical trials and has been under consideration by the FDA. Caldwell et al. (2009) indicated that indiplon is chemically similar in structure to zaleplon and has a half-life of approx- imately 1.5 h. Indiplon, which is said to work by enhancing the action of the inhibitory neurotransmitter, Î³-Aminobutyric acid (GABA), is like most other nonbenzodiazepine sedatives. It is being produced in a modified release formula that will extend its half-life to aid in sleep maintenance (Ebert et al. 2006). An indiplon immediate-release version targets sleep onset insomnia, whereas a modified-release form addresses sleep maintenance insomnia. Both forms of indiplon have shown improvement compared with a placebo in patients with primary insomnia in various areas of subjective and objective sleep measurements (Lankford and Ancoli-Israel 2007; Marrs 2008). Specifically, improvements in total sleep time, latency to persistent sleep, latency to sleep onset, wake after sleep onset, and sleep quality have been noted in clinical trials. So far, trials evaluating both indiplon immediate-release and modified-release have not identified any major serious adverse effects (Marrs 2008). Assessment of indiplon. No research relating human operator performance and indiplon was located for this liter- ature review. With its apparent ultra-short-half-life charac- teristics, indiplon may have potential for use in inducing sleep in some commercial driving scenarios. When the drug is available, conducting performance-oriented research on indiplon would be helpful to determine its effects. Ramelteon Ramelteon (Rozeremâ¢), a novel oral hypnotic drug, is a nonscheduled prescription insomnia medication that can be prescribed for long-term use. Ramelteon promotes falling asleep and is used for treating insomnia. As opposed to tar- geting the GABA-A receptor, ramelteon acts by stimulating receptors for melatonin in the brain, by binding to the MT-1 and MT-2 receptors found in the suprachiasmatic nucleus (SCN), and thus helps to regulate the bodyâs sleepwake cycle (Johnson et al. 2006; Owen 2006). Ramelteon therefore does not promote sleep by CNS depression. Research indicates that ramelteon is efficacious for sleep onset, but not for sleep maintenance (Lieberman 2007; Zammitt et al. 2007). Unlike many compounds used for treating insomnia, ramelteon is not addictive and is not a controlled substance. Ramelteon does not cause withdrawal symptoms or rebound insomnia when its use is stopped. Ramelteon was approved by the FDA in July 1995, and is available as Rozeremâ¢ in 8 mg tablets.
With the exception of Rozeremâ¢, all other prescription medications indicated for insomnia are classified as Sched- ule IV controlled substances by the DEA. It is recommended that ramelteon not be mixed with alcohol and that users avoid operating heavy machinery until they are sure how they react to the medication. Johnson et al. (2006) did an experiment to compare ramelteon with triazolam and to placebo. Compared with placebo, ramelteon at 16, 80, and 160 mg (about 20 times the recommended dose) showed no significant effect on any of the subjective measures collected, including those related to potential for abuse. In the study, 79% of participants (11 of 14) identified the highest dose of ramelteon as placebo (meaning they could not differentiate). Similarly, compared with the placebo, ramelteon at any dose had no effect on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cog- nitive performance measures, consistent with its profile as a sedative drug with abuse liability. Johnson et al. (2006) con- cluded that ramelteon may represent a useful alternative to existing insomnia medications. Because of its action on melatonin receptors, which help control the bodyâs circadian phase, ramelteon has been used to facilitate phase advance in circadian rhythm disorders such as jet lag and shift work (see section on melatonin). Circadian factors are recognized as an important factor in road accidents (Gertler et al. 2002; Richardson et al. 2008). Assessment of ramelteon. No studies of human perfor- mance as affected by ramelteon were located for this literature review. More research is needed with this new, potentially promising hypnotic compound. SLEEP-PROMOTING COMPOUNDS AND DRIVING PERFORMANCE Although many benzodiazepines are generally well-tolerated, with higher doses they impair concentration and produce sedative effects even after their drug effects might be expected to have worn off (OâHanlon 1985). The active effects of benzodiazepines may include sedation, depression, disorientation, daytime drowsiness, impaired balance, and with increased dosage they produce associated increased side effects. Although the margin of safety associated with these drugs is considerable overdose can occur, and continuous use for several months can result in psychological or physical dependenceâthat is, they can be addictive (Davis 1996). The effects of benzodiazepines are enhanced if accompanied by alcohol, and mixing some benzodiazepines with alcohol can have toxic effects (Carskadon 1993). Medical providers who prescribe hypnotic medication for drivers must carefully weigh the potential risks of daytime impairment from a hypnotic medication against the benefit 16 of obtaining a good night sleep. In reviewing the impairing effects of benzodiazepines on human performance, Wittenborn (1979) documented that the effects vary among the different types of benzodiazepines. When impairment was found, it was generally with higher doses, and within 2 to 6 h of drug administration. The effects were drug-specific, but there were observable impairments in the speed for accomplishment of simple repetitive acts, as well as impaired learning and immediate memory; however, overall, there was relatively little indication that well-established higher mental faculties are adversely involved. After that period the drug effects on behavior tended to dissipate (Wittenborn 1979). Koelega (1991) found that with young volunteers, vigilance is relatively sensitive to benzodiazepine impairment, causing individuals to miss more signals and respond more slowly to signals they did see. Kunsman et al. (1992) found that benzodiazepines at therapeutic doses when measured within 1 to 3 h of ingestion slowed simple and choice reaction time. However, continued repeated administrations eventually caused resistance (adap- tation) to the impairing effects. Johnson and Chernik (1982) concurred with Wittenbornâs findings, but also reported that high-dose levels of all benzodiazepines, taken at night, impair next-day performance, and the impairment is greater for long- life hypnotics. An array of laboratory tests that relate to driving skills sensitive to sedation have been developed in various labo- ratories; however, the predictive validity of many of the lab tests tends to be unreliable. The most useful example of such test protocols is that of James OâHanlon and colleagues in the Netherlands. In a decade-long series of driving studies, OâHanlon developed an over-the-road driving test in which participants operate an instrumented vehicle over a 100 km primary highway circuit in normal traffic (OâHanlon and DeGier 1986). Driver performance measures of speed and lateral position are recorded, and the standard deviation of the lateral position (SDLP) is most often cited as the primary outcome variable: the âweaving indexâ (OâHanlon and Volkerts 1986; DeGier 2005). OâHanlon and his research team published more than 75 major studies about the effects of drugs on driving perfor- mance. In many of OâHanlon et al.âs experiments, hypnotic drugs were taken by subjects for several nights before they were tested in actual driving tasks (OâHanlon 1985; OâHanlon et al. 1995). Almost all of the experiments employed the basic paradigm using an actual road driving course and reported SDLP as the principal indicator of driving performance. All of the mean performance changes (degradations) occurring after two nights of drug treatment with benzodi- azepines were significant in morning or afternoon tests, or both, except those following nitrazepam (5 mg) and temazepam (20 mg). The magnitudes of some changes were relatively small for lorazepam (1 mg), nitrazepam (10 mg), zoplicone (7.5 mg), and flunitrazepam (2 mg). These were the equivalent to the amount of impairment attributable to blood alcohol
17 concentrations in a range from just under 0.5 mg/mL to about 0.6 mg/mL. Slightly greater impairment was measured with 15 mg of flurazepam in the morning test. However, a serious degree of impairment, greater than the equivalent of a BAC of 1 mg/mL, was attributable to the residual effects of secobar- bital (200 mg), flurazepam (30 mg), and loprazolam (2 mg) (OâHanlon 1985). After a week of taking diazepam (5 mg, 3 times per day) and lorazepam (2 mg, twice per day) driv- ing performance was impaired more than it was by a BAC of 1 mg/mL (OâHanlon et al. 1995). Some of these results are depicted in Figure 1, along with results from subsequent studies undertaken by OâHanlon and his colleagues. Extracting the findings of many of those studies for a meta- analysis of the work, DeGier (2005) provided an informative figure summarizing the results in terms of residual sedation after sleep at measurement times ranging from 5 to 17 h post- dosing with various hypnotic drugs (mostly benzodiazepines and the so-called nonbenzodiazepines). DeGierâs figure (Figure 1) is attributed to E. R. Volkerts (DeGier 2005). The difference in SDLP relative to placebo is presented with an indication for comparison with calibrated BAC levels of 0.5, 0.8, and 1.0 (the horizontal lines across the figure). DeGier cites the comparison figure to illustrate two things: (1) that many prescribed hypnotics have a detrimental effect on driving (sleepâinertia hangover effects) even in the after- noon of the day following administration of the sleep-inducing dosing the night before; and (2) that some other hypnotics apparently do not have such effects, or at least they are sub- stantially less. DeGier suggests that performance data such as those in his report (depicted in the figure) can assist prescrib- ing health care providers and dispensing pharmacists in their decision making, making it possible for them to offer relatively safer alternative sleep-inducers to patients who drive and need hypnotic medications (DeGier 2005). DeGier and Volkertâs figure indicates that 6 of 11 hypnotics (mostly shown on the left in the figure) appear to impair driving performance less, in both the morning and the afternoon of the next day (after dosing) than do the other 5 hypnotic drugs (mostly depicted on the right side of the figure). The six drugs presenting lower sleep inertia were zaleplon, zolpidem, nitra- zepam, lormetazepam, temazepam, and loprazolam, whereas the five hypnotics that produced higher sleep inertia scores the next day were flunitrazepam, zopiclone, secobarbital, oxazepam, and flurazepam (see also OâHanlon 1985). In another review, Berghaus and Grass (1997) summarized more than 500 experimental studies describing performance impairment on driving-related psychomotor and perceptual tasks as attributed to benzodiazepines. They reported a near- linear relationship between serum concentration and the percent of studies that obtained a significant effect, for both the short-acting triazolam and for the long-acting nitrazepam. Similar relationships were assessed for other benzodiazepines such as temazepam, flunitrazepam, flurazepam, alprazolam, bromazepam, diazepam, oxazepam, and lorazepam. When measured during the absorption phase (>3 h after adminis- tration), the impairment was about 30% higher than when it was measured during the elimination phase (>5 h). This effect is similar to that obtained for alcohol, but it is much stronger for benzodiazepines. Despite significant differences among 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).
impair performance on most performance tasksâin particular, benzodiazepines impair performance on tasks that entail visual encoding of information (such as attention, vigilance, visual search, peak saccadic velocity, and critical flicker fusion) and on a variety of short-term memory tasks. One study of drivers of commercial vehicles identified increased self-reported crash risk. Self-reported crash data were analyzed for Australian truck drivers who regularly or occasionally reported use of a variety of medications, including benzodiazepines. Drivers reporting the use of benzodiazepines were deemed to be 1.91 times more likely to have had a crash in the previous three years. This is compared with those who used antihistamines, who were 3.44 times more likely to have crashed; those who used narcotic analgesics, who were 2.4 times more likely to have crashed; and those with regular consumption of alcohol drinks, who were 1.09 times more likely to crash. Those who consumed mild stimulant drugs such as caffeine were no more or less likely to have crashed (Howard et al. 2004). [See also the assessment of various sleep-inducing drugs and the incidence of accident crashes by Gustavsen et al. (2008).] In terms of practical operational use, military forces in several westernized countries have used fast-acting ben- zodiazepines [e.g., triazolam (HalcionÂ®) or temazapam (RestorilÂ®)] as hypnotics or as sedative sleep aids to help âput one to sleep quicklyâ (Nicholson et al. 1980, 1985; Penetar et al. 1989; Nicholson 1990, 1998, 2009; Wesensten et al. 1996; Caldwell et al. 2003). In such applications there is less concern over the immediate effects of the drugs on other forms of performance, because the person in a nap-induced state is âsupposed to be sleeping.â However, even though the U.S. Army continues to authorize limited use of triazolam for pre-deployment rest or for gaining sleep during continuous operations, it is now rarely prescribed (Caldwell et al. 2009). The U.S. military had concerns about individuals who upon awakening from benzodiazepine-induced sleep experienced hangover effects of antegrade short-term memory loss for events/information occurring before going to sleep (Penetar et al. 1989; IOM 1997). Consequently, the U.S. military has mostly moved on from employing the quick-acting benzodi- azepines, switching instead to the use of less risky compounds such as administering synthetic forms of the hormone mela- tonin for use as sleep aids (Caldwell and Caldwell 2003, 2005; Caldwell et al. 2009). More recently, U.S. military forces also have been employing several newer sleep-promoting non- benzodiazepine compounds such as zolpidem (AmbienÂ®) and zaleplon (SonataÂ®) for quick acting sleep initiation (Cald- well et al. 2009; Gore et al. 2010). As DeGier (2005) and the ICADTS Working Group pointed out, some of the new short-acting hypnotics could possibly serve as viable treatments for insomnia with commercial drivers. The FMCSA has published medical guidance regard- ing use of hypnotics in drivers of commercial vehicles since publication of the Psychiatry Medical Conference report in 18 1991 (FHWA 1991). This was reinforced in the most recent Psychiatry Evidence Report (Tragear et al. 2008), and the Medical Expert Panel recommendations (Metzner et al. 2009). These documents are advisory in nature, and recommended against commercial driver medical certification in drivers tak- ing both benzodiazepine and nonbenzodiazepine hypnotics and anxiolytics. The bases of these recommendations are the multiple studies indicating impairment of cognitive function and driving ability for up to three weeks (DeGier et al. 1981; OâHanlon et al. 1995; van Laar and Volkerts 1998; van Laar et al. 1992), and the increased odds of crash of 1.3 to 2.2 times greater than those individuals who did not use benzodiazepines. Crash risk was particularly increased in individuals of more than 40 years of age, and in the first week after prescription. The FMCSA noted that it âconsiders evidence, expert recommendations and other data, however all proposed changes to current standards and guidance will be subject to public notice-and-commentâ (FMCSA Medical Expert Panel reports web page, accessed May 16, 2010). Assessment of benzodiazepines. Use of benzodiazepines for induction of sleep, even for treatment of insomnia, has become less common with the recent entry of the alternative nonbenzodiazepines into the pharmaceutical marketplace. The several research studies examined and cited earlier provide sufficient indication that there would be some value in conducting additional, controlled, medical, and perfor- mance research to examine the potential of applications of some of the newer short-acting, and short-half-life hypnotics. Just as they might provide assistance in aviation operations (Caldwell et al. 2009; Caldwell 2011), potentially some of these newer hypnotics could be prescribed in safe sleeping environments when it is anticipated that commercial drivers have plenty of sleep time and recovery time before returning to their driving chores. ALTERNATIVE SLEEP-INDUCING COMPOUNDS There are a few additional chemical compounds that are being used or could be used to help induce sleep, but that do not fit conveniently into the two categories described previously. These are outlined here. Alterialâ¢ Alterial is an OTC, all-natural sleep inducer, which claims to help people fall asleep fast, stay asleep longer, and improve the quality of sleep all night long. Advertising claims report that Alterial contains natural ingredients (including melatonin, L-tryptophan, and valerian, along with additional ingredients) that help calm, relax, and prepare one for a good nightâs sleep. The claims are that Alterial does not leave a person feeling groggy and irritable the next morning, but rather energized, refreshed, and ready to perform. The manufacturerâs claim is that the mix of ingredients helps a person achieve deep, restful sleep without dependency or side effects.
19 Assessment of Alterial. No research on Alterialâ¢ and human performance measurement was located for this review; therefore, it is too early to make any predictive statements about this developmental compound. Melatonin Melatonin, a hormone secreted by the pineal gland in response to the onset of darkness, is believed to play a role in making us sleepy. Consequently, melatonin frequently has been referred to as our bodyâs natural sleeping pill (Reiter and Robinson 1995). The benefits of both natural secretions of melatonin and applications of synthetic melatonin (available in pill or tablet form in health food stores) elicit interest in this synthesis because of the role melatonin plays in offering good potential to help people to feel drowsy, fall asleep, deal with insomnia, sleep better, and assist in re-setting an individualâs circadian clocks during work shift changes (i.e., coping with work shift lag). For more than a decade synthetic melatonin has commonly been used for that purpose by some commercial drivers (Krueger 1996â2006). It has also been widely used in other transportation applications to help travelers to combat jet lag when making transmeridian flights (Petrie et al. 1989; Lieberman and Mays 1994). Accordingly, the coverage of this compound is more extensive here than that provided for other sleep promotion compounds. The ways in which melatonin might alter sleep still are not well-understood, and medical researchers do not agree on exactly how melatonin helps people sleep. The internal core body temperature of humans has a distinct circadian rhythm, rising during the day and falling at night (a swing of only about a degree Fahrenheit) and having a strong influence on sleep. In general, it is easier to fall asleep when body temperature is falling, and it is easier to wake up or maintain wakefulness when body temperature is on the rise. Melatoninâs effect on body temperature is one of the keys to its ability to enhance sleep. Melatonin is naturally synthesized in the pineal gland (a pea-size structure in the center of the brain) during the dark phase of the daily light/dark cycle and thus it is intimately tied into our circadian rhythm physiology (Comperatore and Krueger 1990). As the sun sets each day and darkness begins, our internal core temperature starts to drop and the pineal gland produces a surge of a small quantity of melatonin (maintained at about a 0.3 mg level) that goes to all parts of the body. The nightly fall in body temperature happens to coincide with the steep- est rise in nightly melatonin levels, which for adults takes place somewhere between 9 p.m. and midnight, depending on oneâs unique circadian rhythm (Campbell and Broughton 1994; Reiter and Robinson 1995). Melatonin levels are main- tained in the human body during nighttime sleep (i.e., during darkness). The next morning, when sunlight hits the retina of the eyes, neural impulses signal the pineal gland to slow, and eventually cease melatonin production and, in daylight, the nighttime levels of melatonin already in the body quickly dissipate. As the foregoing indicates, it is important to take melatonin at the correct hour on the circadian physiological clock and to limit the amount of ambient light in the sleeping environment. Melatonin users are encouraged to give proper consideration to the timing of the onset of drowsiness and a strong urge to sleep. It has been hypothesized by Mendelson (2005) that mela- tonin and its agonists might act to affect circadian systems through effects on melatonin receptors in the SCN (the site of the so-called circadian timing system). From his studies on animals, Mendelson speculated that one possibility is that the effects in humans are GABAergic, and the site of melatonin action may be similar to that of benzodiazepines, barbiturates, adenosine, and ethanol (Mendelson 2005). [For a review of early research on melatonin and sleep see Dawson and Encel (1993), and Cramer et al. (1974), who more than 35 years ago concluded that âmelatonin induced sleep, behaviorally as well as by its polygraphic pattern, strikingly resembles natural sleep.â] Subsequent studies repeatedly support this finding. Exogenously administered synthetic melatonin has been shown to induce a slowing of the electroencephalogram (EEG) to bring about sleep (Anton-Fay 1971, 1974; Cramer 1980). Sack et al. (2003a, b) labeled synthetic melatonin as one of a new class of medicinal chemicals called chronobiotics because they are useful in adjusting the timing of circadian rhythms, capable of âresetting the biological clock,â and therefore useful for dealing with jet lag, advanced and delayed sleep-phase patterns, and for treatment of other forms of insomnia. Sack and colleagues (Sack et al. 2003a), as well as others (Santhi et al. 2008), declared melatonin use to be safe, and, as a naturally occurring hormone, its administration causes fewer problems than many other âsynthetic hypnotics.â Taking synthetic melatonin seemingly has none of the negative side effects associated with traditional sleep medications. It does not significantly disrupt the sleep architecture. Individuals who take melatonin report sound nighttime sleep and no resultant grogginess the next day, nor does melatonin interfere with a personâs memory or performance the next day as some other sleep aids do (Sack et al. 2003a; Santhi et al. 2008). Researchers studying melatonin have searched for classical problems normally associated with traditional sleeping pills (e.g., suppression of REM sleep, losing the hypnotic impact over time with repeated use, and chance for addiction). Melatonin exhibited no substantial concerns on these topics. After numerous studies administering high doses of synthetic melatonin (10 to 100 mg) Wurtman and colleagues at the Massachusetts Institute of Technology demonstrated that 1.0 mg, 0.3 mg, and even as little as 0.1 mg of melatonin can hasten the onset of sleep, whatever the time of day (Lieberman et al. 1984; Zhdanova et al. 1995). Hughes and Badia (1997) conducted a study examining the ability of melatonin in doses ranging from 1 to 40 mg to
induce naps, followed shortly after awakening 4-h post-dose, by administering tests of performance, memory, and fatigue. They found no carry-over fatigue and no negative effects on memory or performance. Even high doses of synthetic melatonin (50 mg) showed no interference with elderly adults (average age 84.5 years, who likely have no naturally occurring melatonin owing to old age) on memory, concentration, or motor control (Singer et al. 1994). This is quite different from what would happen with most, if not all, benzodiazepines. Today, researchers generally induce sleep in their lab studies with considerably lower doses of from 0.1 to 0.3 mg of melatonin. It is important to note this because most syn- thetic preparations of melatonin sold in health food stores provide tablets ranging from 1 to 5 mg each, without specifying how much melatonin is actually in the tablets (quantity and quality assurance in such formulations is unspecified). Benzodiazepines can become less effective after only two or three nights of use. By contrast, melatonin does not lose its effectiveness over time, and may even become more effective with chronic use as a sleep aid. In a study described by Reiter and Robinson (1995) 2-mg doses of melatonin were given to elderly volunteers for two months, and at the end of the treat- ment period, the participants fell asleep even more quickly than they did after the first week of treatment. At the Walter Reed Army Institute of Research, Wesensten et al. (2005a) set out to determine whether combining mela- tonin with low-dose zolpidem might promote daytime sleep without exacerbating performance impairments seen with high- dose zolpidem alone. This research was initiated out of concern that at effective (higher) doses zolpidem not only induces sleep, but also impairs performance. They found no advantages to administering melatonin plus zolpidem âcocktails.â Unlike zolpidem, melatonin alone (5 mg) improved daytime sleep without impairing memory and vigilance (Wesensten et al. 2005a). Driver Applications of Melatonin Experiments show that bright lights can trigger the response to cease a personâs melatonin production even at nightâan intervention that has been successfully tried to keep individuals alert in night-shift factory work (Santhi et al. 2008). Research findings are less clear about our bodyâs ability to initiate pro- duction of melatonin simply by going into a darkened envi- ronment during daytime. However, a low dose of synthetic melatonin can be used to âtrickâ the body into thinking that dusk (darkness) has arrived earlier, especially if one enters a darkened room to attempt to sleep (Santhi et al. 2008). This has obvious implications for commercial drivers whose work and rest schedules are subject to frequent time-of-day changes (shift workers). Climbing into a darkened truck sleeper berth after taking synthetic melatonin is a napping strategy commonly advocated and used by commercial drivers 20 (G. P. Krueger, personal communications with CMV drivers while teaching a decade of driver fatigue management classes, 1996 through 2006). Military medical research illustrated that using synthetic melatonin as a sleep aid can be an important contributor to the repertoire of soldier fatigue countermeasures during mil- itary training and operations. OâNeill et al. (1996) addressed similar applications for use of melatonin, suggesting that it can be of assistance to commercial drivers attempting to combat fatigue. They suggested that melatonin would provide advantages both in terms of assisting drivers to obtain needed sleep during arduous work weeks and for use in adjusting to work schedule changes to combat work shift lag when their weekly schedules change (from night shifts to day shifts and vice versa). Practical applications taught to commercial drivers included ingesting synthetic melatonin and then attempting to obtain daytime sleep by using completely blacked-out sleeper berths in Class 8 trucks or in completely blacked-out hotel rooms during the day (Krueger and Brewster 2005). Availability of Synthetic Melatonin Synthesized into tablet forms, melatonin has been touted as one of the past decadeâs natural supplement âmiracle compoundsâ and is sold in health food and grocery stores throughout the United States. Because melatonin is a synthesized hormone, in the United States at least, it is identified as a health food or dietary supplement and not as a drug. Therefore, synthetically produced melatonin is not subject to FDA approval. The FDA (www.fda.gov) merely states that melatonin is not a regulated compound, and that no FDA-sponsored evaluation and testing for safety, effectiveness, or purity has occurred. In some European countries, synthetic melatonin is classified as a neurohormone and it cannot be sold over the counter. In the United States, synthetic melatonin is readily avail- able in pill form and is inexpensive (a monthâs supply costs $12 to $20 at many health food stores). Because synthetic melatonin sold over the counter as a health food supplement is not governed by the FDA, its production is not required to adhere to âgood manufacturing practices.â Consumers are expected to trust what is on the label of the containers of melatonin sold in stores. Independent laboratory tests of popular synthetic melatonin products have on occasion found inconsistency regarding the amount of melatonin actually found in commercially sold products and what appeared as the contents on the containerâs labeling. Ongoing medical research on melatonin continues to explore such questions as: What dosage and use regimen is safe for administration of synthetic melatonin for specific purposes? Most sleep research is done with doses of 0.1 and 0.3 mg of melatonin, and it would appear that less than a 1-mg dose is probably recommended for most operational applications. However, most readily available melatonin pills
21 or tablets may contain higher doses than the levels of mela- tonin normally secreted into the body by the pineal gland (0.3 mg at a semi-continuous level until daybreak). Many health food stores sell synthetic melatonin in 1 to 5 mg tabletsâ if those tablets were all melatonin, that would amount to a dose more than a 10 times higher than is seemingly required to induce sleep naturally, which may raise concerns about the advisability of repeatedly treating our bodies to this synthetic overdose of a hormone that is so intimately linked to many of our important biological processes. Although to date no signi- ficant hazardous concerns have arisen, in actuality not enough scientific data have been collected to identify supplier quality assurance issues and any potential long-term effects derived from chronically taking synthetic melatonin supplements. Assessment of melatonin. Synthetic melatonin has been demonstrated to be beneficial to some individuals some of the time in assisting them to fall asleep, especially at times of day that are not normally conducive to sleeping (e.g., daytime cir- cadian high points). It is essential that with its use additional steps are taken to ensure a darkened sleeping environment. Melatonin offers promise as a sleep-inducing aid for commer- cial drivers, especially for their use as an aid to induce naps during the daytime. Importantly, this topic suggests that some additional research may be needed to work out âsleep and alert- ness management protocols and fatigue countermeasuresâ for proper and appropriate use of synthetic melatonin in the particular work settings of commercial drivers. What is needed is to determine âtreatment protocols,â to develop âguidanceâ for how and when to use melatonin for help in inducing sleep; for example, for naps. Such protocols might be developed in conjunction with additional guidance about the use of other sleep-promoting compounds that may be suitable for truck, bus, and motorcoach drivers to use both at home and during operations on the road. Researchers could be asked to provide such guidance, perhaps ultimately promulgating it in the form of a user-friendly handbook. Additionally, because synthetic melatonin marketed in health food stores and elsewhere is not governed by the good manufacturing practices act, some way must be determined to ensure that those who produce or supply the product provide sufficient quality assurance and indicate appropriate dose levels for the intended purposes of the commercial driver. Alcohol Used as a Sleep-Inducing Aid Perhaps the most commonly used technique for inducing sleep or for resolving insomnia is to drink modest amounts of alcohol (ethanol); perhaps a glass of wine or one or two beers before bedtime at night to relax and prepare to fall asleep. Reiter and Robinson (1995) estimated that 20% of insomniacs rely on alcohol to relax their muscles, ease their anxiety, and help them fall asleep. A telephone survey of approximately 1,000 representative adults in the general population reported that 10% had âself-medicatedâ with alcohol in the previous year (National Sleep Foundation 1998). A survey in Detroit, Michigan, reported that in the previous year, 13% had used alcohol to aid sleep, 18% used medication (either prescription or over the counter), and 5% had taken both (Johnson et al. 1998). Although drinking alcohol has some sleep-inducing prop- erties, using it to help one to fall asleep often promotes sleep disturbance as the night progresses (Mendelson 1987, 2005). Although a ânightcapâ drink may help a person fall asleep more quickly, several hours later, as the alcohol oxidizes in the body, the sedative effect of the alcohol wears off and the alcohol may cause a rebound effect, making the person rest- less and agitated. In the second half of the night alcohol may disrupt dreaming (REM) sleep, thus making the period of sleep less restful and restorative of alertness. In that sense, alcohol is not a very effective sleep sedative. Drinking a larger amount of alcohol before bedtime may also result in âhangover effectsâ the next morning, presenting symptoms of headache, grogginess, sleep inertia, and decreased alertness. Frequent consumption of alcohol is known to expose individuals to the risk of ethanol dependence or addiction. Alcohol has also been demonstrated to interact significantly in individuals with obstructive sleep apnea, making the condition worse by increasing the number of apneic episodes and causing deeper (worse) oxygen deprivation during sleep (Mendelson 2005). Standard restrictions for commercial driving are that BAC cannot exceed 0.04%. Since 1995, the FAA also set the lim- its for pilots in the U.S. aviation industry at BAC of less than 0.04%, whereas the NTSB requires reporting any ethanol value exceeding a BAC equal to 0.02%. Assessment of alcohol as a sleep aid. Although much information about the effects of alcohol on performance and health is known, consuming alcohol as a sleep inducer may result in disrupted and less restorative sleep, as the alcohol oxidizes over the several hours a person may be sleeping and therefore is not widely promulgated as a tenet of sleep main- tenance guidance. The commercial driving community would benefit from development of user-friendly information and guidance documents on numerous chemical substances, including the use of alcohol as a sleep aid. First-Generation Antihistamines Used as Sleep Aids Millions of Americans experience problems with seasonal allergies, including sneezing and runny nose associated with the common cold, as well as allergic rhinitis; itchy, watery eyes; and itchy throat (i.e., bodily response to pollens in the air). For decades, the most common, effective treatment for such allergies has been to take so-called first-generation antihistamines of the diphenhydramineâhydrochloride type (which contain active ingredients of either diphenhydramine
or doxylamine) to block H1 receptors and therefore counter the actions of histamine, a naturally occurring chemical in the body (Kay et al. 1997; Kay 2000). Diphenhydramine is often used to treat the common cold, suppress coughs, and treat motion sickness (e.g., in DramamineÂ®), and for reactions to insect bites, hives, and rashes. First-generation antihistamines also produce mild to moderate sedative effects that cause drowsiness and sedation. A large segment of the sleep-deprived population occasionally turns to such first-generation anti- histamines (with diphenhydramine) for assistance in falling asleep, and it is this feature that is of principal interest in this synthesis report. The concern for transportation safety is two-fold: (1) that drivers who regularly take first-generation antihistamines for allergy relief may encounter performance impairments while driving a vehicle, owing to the drowsiness effects of maintenance levels of diphenhydramine in the body; and (2) occasionally taking first-generation antihistamines expressly for its sleep-promoting characteristics may leave one with next-day sleep inertia hangover effects on performance, and these may impact driving safety. The FMCSA has provided advisory guidance on use of first-generation antihistamines in the Neurology Medical Conference Report (FHWA 1988), and the Pulmonary Med- ical Conference report (Turino et al. 1991), where use of first- generation antihistamines is not recommended. A more recent Pulmonary Evidence review and Medical Expert Panel report had not been published at the time of this writing. The most widely known, first-generation antihistamine is BenadrylÂ®âan OTC medication containing diphenhydramine, and that offers allergy relief. Allergy sufferers also commonly take chlorpheniramine, hydroxyzine, brompheniramine, prome- thazine, or doxylamine, along with other first-generation anti- histamines under such trade names as UnisomÂ®, SleepgelsÂ®, DytussÂ®, and DramamineÂ®. All of them cross the bloodâ brain barrier to block cortical histamine receptors. Antihista- mine products containing diphenhydramine are accompanied by caution warnings that they not be used when driving, oper- ating machinery, or performing other hazardous activities, as they may cause dizziness or drowsiness. Users also are warned that consuming alcohol while taking diphenhydramine may increase drowsiness and dizziness. BenadrylÂ®, in several capsule forms, usually contains 25 mg of diphenhydramine. Recommended doses of diphen- hydramine (e.g., BenadrylÂ®) for treatment of allergies in adults is 25 to 50 mg every 6 to 8 h, not to exceed 50 to 100 mg every 4 to 6 h. If the intended purpose is sedation; that is, for treatment of occasional insomnia, then the first-generation antihistamines such as diphenhydramine may help a person to induce sleep. For example, when it is being used as a sleep aid, 50 mg diphenhydramine should be taken approximately 30 min before bedtime. Taking diphenhydramine while also taking other sleep medicines or alcohol is not recommended, as 22 these drugs interact in the body. First generation antihistamines are not recommended for chronic use, especially for those individuals with glaucoma, peptic ulcer, bronchial asthma, seizures, or prostate enlargement (Reiter and Robinson 1995). Many other commercially available OTC sleep aids (e.g., Compoz, Nytol, Sleep-Exe, and Somnitabs) contain antihistamine as the active ingredientâmost often as diphen- hydramine. However, to be truly effective as sleep aids, many such antihistamine products would have to contain a higher dosage of diphenhydramine than what is normally inserted in each antihistamine pill or tablet by the manufacturers. SomnitabsÂ®, for example, contain 25 mg of diphenhydramine per tablet. Some individuals in search of a suitable sleep aid take Dramamine, normally used for prevention and treatment of nausea, vomiting, or dizziness associated with motion sick- ness, because it contains 50 mg of diphenhydramine, which may relax them somewhat and help them to fall asleep. The research literature on the use of antihistamines to induce sleep reports on several aspects related to operator perfor- mance. Kay et al. (1997) conducted a number of laboratory experiments demonstrating that first-generation histamine-1 receptor antagonists used to treat allergic disorders frequently cause sedation. Most sleep-inducing applications recommend that a person take first-generation antihistamine tablets at least 30 min to 1 h before the desired sleep period. Generally, these cause drowsiness and bring about reduced sleep onset latencies (versus placebo) anywhere from 1 to 8 h post-administration (Kay et al. 1997). However, some findings also indicate that first-generation antihistamines often can leave next-day drowsiness as a side effect (Mendelson 2005). For example, doxylamine has a half-life of 9 h, which means that if a person takes a doxylamine tablet at 2300 hours there will still be a sig- nificant amount in the bloodstream at 8 a.m. the next morning (Carskadon 1993). Tolerance to daytime sleepiness appears to develop rapidly, in approximately 4 days (Richardson et al. 2002). First-generation antihistamine preparations often are not potent enough to resolve serious sleep difficulties or night- time anxiety. The major concern for using antihistamines for sleep management is over their potential for leaving after- effects such as sleep inertia upon awakening. If a person is using first-generation antihistamines for allergy relief (that is, he or she uses them not with intentions to aid in falling asleep per se, but rather to lessen allergic discomforts), it is critically important to note that bodily maintenance levels of all first-generation antihistamines, espe- cially those containing diphenhydramine, have been demon- strated to diminish cognitive and psychomotor performance in healthy volunteers (Gengo and Gabos 1987; Gengo et al. 1989; Gengo and Manning 1990; Rice and Snyder 1993; Kay et al. 1997). Performance impairment may be of greater significance in patients when the allergic disorder per se adversely affects CNS function, as suggested in studies in which a reduction in cognitive functioning in patients was exacerbated by diphenhydramine (Gengo 1996). Laboratory
23 studies have shown diphenhydramine to decrease alertness, decrease reaction time, induce somnolence, impair concentra- tion, impair time estimation, impair tracking, decrease learning ability, and impair attention and memory within the first 2 to 3 h post-dose (Moskowitz and Burns 1988; Gengo et al. 1989; Gengo and Manning 1990; Kay et al. 1997). Signifi- cant adverse effects on vigilance, divided attention, working memory, and psychomotor performance have been demon- strated. Impairment has been shown even in the absence of self-reported sleepiness or sedation. Sedative effects are dose-dependent. Interactions with alcohol can exacerbate performance decrements. Diphenhydramine has repeatedly been shown to severely impair tracking and reaction time performance in actual on-the-road driving tests. Single doses of 50 mg have been shown to cause significant impairment during a 90 km highway test (measuring vehicle following constant speed and lateral position). In contrast, single 25- to 100-mg doses caused no significant driving effects during a short 15-min driving test. Using the Iowa Driving Simulator (passenger car), Weiler et al. (2000) compared the effects demonstrated by test participants who took only a single oral dose of 50 mg diphenhydramine with the effects corresponding to a blood alcohol concentration of 0.1 g/100 ml. Diphenhydramine caused significantly less coherence (ability to maintain a constant distance) and impaired lane keeping (steering instability and crossing the centerline) compared with alcohol. Overall driving performance was poorest after taking diphenhydramine, and participants were most drowsy after taking diphenhydramine (measured both before and after test driving). The authors concluded that diphenhydramine clearly impairs driving performance and may have an even greater impact than alcohol on the com- plex task of operating a motor vehicle (Weiler et al. 2000) [see also Betts et al. (1984)]. No reports were located documenting involvement of first-generation antihistamines in commercial driving studies, or as they might be implicated in actual crash fatalities. How- ever, examination of more than ten years of pilot fatalities in U.S. general aviation crashes determined that approximately 5% were involved with antihistamines (Soper et al. 2000; Chaturvedi et al. 2005). Assessment of first-generation antihistamines. Although first-generation antihistamines often provide effective treat- ment for allergy sufferers, such compounds frequently pro- duce side effects such as drowsiness, sedation, fatigue, and an inability to concentrate (Gengo 1996). First-generation antihistamines (such as those containing diphenhydramine) were described with a particular focus on the notion that for some users such antihistamines also can bring about sedation when used for sleep promotion. However, the use of first- generation antihistamines is discouraged under task and work conditions that require the worker to maintain vigilance or to put forth sustained mental effort. Such cautions are issued because maintenance levels of all first-generation antihis- tamines have been demonstrated to have antagonist effects on cognitive performance and because in using them as sleep aids most have been demonstrated to leave a person with hangover inertia effects long after the sleep period has ended. Commercial drivers must be properly informed of the haz- ards and risks of using antihistamines both for allergy relief and for use as a sleep aid. Guidance information on this topic should be provided in materials prepared for overall infor- mation dissemination on chemical substances. SUMMARY OF OPERATIONAL CONSEQUENCES OF SLEEP-PROMOTING COMPOUNDS Table 2 summarizes the previous information regarding some key points of employing various sleep-promoting compounds in an operational setting, whether for commercial transportation purposes or some other work environment. The literature conveying U.S. military medical research findings and oper- ational procedures being followed during training and military deployment activities is presented in Appendix B to this report. SECOND-GENERATION NONSEDATING ANTIHISTAMINES FOR ALLERGIES Second-generation antihistamines are described here to ensure that descriptions of both antihistamine types remain in close proximity in this synthesis report. Acute, seasonal allergic reactions may inhibit a workerâs operational capability, which is of special concern during attention-demanding work; that is, commercial driving. A class of second-generation antihistamines (e.g., loratadine, fexofenadine, cetirizine, and astemizole)âthe so-called nonsedating antihistaminesâ are touted to offer effective symptomatic relief for treating seasonal allergies. Allegedly, because they are said not to cross the bloodâbrain barrier, they should not bring about worker drowsiness and, therefore, should be more suitable to meet some CMV driversâ needs for allergy relief. Second-generation antihistamines have improved safety profiles compared with the older first-generation anti- histamines. This is because these second-generation agents have increased specificity for the H-1 receptor and bulky side chains that hinder their ability to cross the bloodâbrain barrier. As a result, second-generation antihistamines are more hydrophilic, having a higher affinity for peripheral histamine receptors than for cortical sites. Their active agents enter the CNS less readily, produce less sedation, and result in far less CNS impairment than do the first-generation antihistamines. Although second-generation antihistamines provide allergy relief, in principle they should not affect cognitive perfor- mance, making them a preferred treatment choice for many allergy sufferers (Kay et al. 1997; Timmerman 1999; Van Cauwenberge et al. 2000). The FMCSA has provided guidance on âNon-sedatingâ or second-generation antihistamines in the Pulmonary Medical
Conference report (Turino et al. 1991), where use of these substances is allowed. Gary Kay and his colleagues conducted laboratory exper- iments comparing the effects of first- with second-generation antihistamines. In a comprehensive review, Kay and colleagues reported impairments to cognitive performance attributable to second-generation nonsedating antihistamines that ranged from none to mild (Kay et al. 1997a, b; Kay 2000; Kay and Quig 2001). Although several comparison studies confirm the hypnotic effects of diphenhydramine, basically they showed no significant differences in sedation with some of the non- sedating second-generation antihistamines such as astemizole or loratadine (Roth et al. 1987; Schweitzer et al. 1994; Gengo and Gabos 1987). In a comparison of effects of three different antihistamine drugs on driving, Ramaekers and OâHanlon (1994) exam- 24 ined the effects of diphenhydramine, terfenadine (second- generation: Seldane), and acrivastine on driving performance as a function of dose and time after dosing. Lateral deviations (lane weaving and crossings) during driving were found to vary with both the particular drug chosen and with the dose administered. This prompted additional studies evaluating performance of subjects driving while using either first- or second-generation antihistamines (OâHanlon and Ramaekers 1995; Ramaekers et al. 1995). Single doses of diphenhydramine (50 mg), clemastine (2 mg), and multiple doses of triprolidine (5 and 10 mg) produced changes equivalent to those produced by BACs of 0.5 to 1 mg/ml. However, terfenadine (second-generation) was taken in single doses of up to 180 mg and multiple doses over 4 days of up to 120 mg twice per day. The single dose and multiple doses of 60 mg taken two times per day, and a 120-mg dose four times per day never produced a significant Benzodiazepines Rx Trade Name Average Half-Life Recommended Use Comments/ Cautions Temazepam RestorilÂ® 8.0â12.0 hr Daytime sleep; sleep maintenance Need 8-hr sleep period post dose Triazolam HalcionÂ® 2.0â4.0 hr Diazepam ValiumÂ® Lorazepam AtivanÂ® Alprazolam XanaxÂ® Chlordiazeproxide LibriumÂ® Clonazepam KlonopinÂ® Newer Hypnotics (Rx) (non- Benzodiazepines) Sleep initiation; napping strategy Zolpidem AmbienÂ®, StilnoxÂ®, MysleeÂ® 2.0â2.5 hr 1.0 hr Sleep initiation; intermediate length naps Promotes sleep of 4â7 hr Zaleplon SonataÂ®, StarnocÂ® Short naps; 20 mg for sleep initiation w/20 mg, no hangover effects at 6+ hr Eszopiclone LunestaÂ® 5.0â6.0 hr Sleep initiation, & maintenance Minimal residual effects at 10 hr Indiplon & Indiplon modified release ~ 1.5 hr Sleep initiation & maintenance Undergoing clinical trials Ramelteon RozeremÂ® Sleep initiation, but not for sleep maintenance Long-term treatment of insomnia Alternative Sleep Inducers Alterial Includes melatonin, L-tryptophan, valerian All natural sleep inducer Claims restful sleep with no residual effects Melatonin Synthetic hormone in health stores Dissipates in blood stream in daylight Effective daytime sleep inducer in darkened room Works for some people; no side effects or hangover First Generation Antihistamines BenadrylÂ®, UnisomÂ®, SleepgelsÂ®, DytussÂ®, DramamineÂ® Maintains in body for allergy relief 25â50 mg diphenhydramine induces sleepiness Maintenance level may produce hangover sleepiness TABLE 2 OPERATIONAL CONSEQUENCES OF SLEEP-PROMOTING COMPOUNDS
25 rise in lateral position tracking (SDLP). On the contrary, there was a tendency for 60 and 120 mg to produce a slight fall in SDLP, suggesting a mild stimulating activity (or perhaps a performance settling effect) of the drug. When subjects took doses of 120 mg twice per day for 4 days, impairment was equivalent of up to that of 0.05% BAC (OâHanlon and Ramaekers 1995). Only a few studies have reported some degradation of cognitive and psychomotor performance with second-generation antihistamines; see for example the study by Rice and Snyder (1993) on terfenadine: Seldaneâwhich is no longer on the market; and see also studies here reporting on the performance effects of cetirizine (Zyrtec). Several of the newer second-generation antihistamines are briefly described here. Cetirizine Although second-generation antihistamines are claimed by their pharmaceutical manufacturers to be nonsedating, research reports some second-generation antihistamines [e.g., cetirizine (Zyrtec)] do produce some level of cognitive impairment (Vacchiano et al. 2008). Cetirizine, which is demonstrated to be more sedating than the other nonsedating antihistamines, has been reported to impair cognitive performance in a number of studies (Ramaekers et al. 1992; Lockey et al. 1996; Meltzer et al. 1996; Nicholson and Turner 1998; Howarth et al. 1999). After investigating the effects of cetirizine on tasks such as tracking and vigilance as they relate to aviation personnel, Nicholson and Turner (1998) suggested that cetirizine should not be used by aviation personnel. Cetirizineâs effects on SDLP in driving studies are a matter of contention between different groups of investigators (OâHanlon and Ramaekers 1995). One showed a single-dose of cetirizine (10 mg) impaired, whereas another found no effect with that dose on either the first or fourth day. Cetirizine may be slightly sedating even at normally recommended doses. In 2007, the FDA approved nonprescription use of Zyrtec-D (combining cetirizine with a nasal decongestant) for use in obtaining relief from hay fever or other upper respiratory allergies. Fexofenadine In a similar study, Nicholson et al. (2000) demonstrated that fexofenadine (AllegraÂ®) had no impairing effects on tracking, vigilance, and other tasks related to aviation. Bower et al. (2003) and Vacchiano et al. (2008) demonstrated no signifi- cant effects of fexofenadine on a variety of cognitive perfor- mance tasks, concluding that fexofenadine is comparable to placebo in its effect on cognitive skills involving accuracy, speed, and attentiveness; each important for piloting an aircraft. The results were comparable to those involving fexofenadine in assessments of the types of cognitive performance expected in driving (Ramaekers et al. 1992; Hindmarch and Shamsi 1999; Hindmarch et al. 2002). Further evidence for the lack of cognitive decrements by fexofenadine was demonstrated in a study in the Iowa Driving Simulator that showed that fexofenadine subjects had better coherence (ability to maintain a constant distance from a lead car with randomly changing speed) compared with subjects with diphenhydramine. In addition, the ability to stay in the lane, measured by steering instability and crossing the centerline, was impaired in alcohol- and diphenhydramine-affected subjects, as com- pared with those with only fexofenadine (Weiler et al. 2000). Of the three most popular second-generation antihistamines, fexofenadine (AllegraÂ®) appears to be the least sedating, even in higher doses. Loratadine and Desloratadine Loratadine and desloratadine (ClaritinÂ®, Claritin-RediTabsÂ®, Alavert, and others) is a piperidine histamine H-1 receptor antagonist with anti-allergic properties and without sedative effects. In April 1993, the FDA approved loratadine as a second-generation antihistamine for use without a prescription. Loratadine is a longer-acting antihistamine that blocks the actions of histamine; it does not enter the brain through the blood, and it does not cause CNS effects. Loratadine is generally used for the relief of nasal and nonnasal symptoms of seasonal allergic rhinitis and to treat patients with chronic urticaria, a type of allergic skin rash. The distributor has indi- cated that there may be occasional side effects with loratadine, including headache, drowsiness, fatigue, and dry mouth. Claritin-DÂ® is a combination of loratadine and the decongestant pseudoephedrine (Geha and Meltzer 2001). Although potentially effective in providing relief of runny nose, sneezing, and nasal stuffiness from the common cold, it is also used for relief of nasal and nonnasal symptoms of various allergic conditions such as seasonal allergic rhinitis. Side effects of Claritin-D may include stimulation of the nervous system leading to nervousness, restlessness, excitabil- ity, dizziness, and headache. Loratadine (ClaritinÂ®) does bring about some sedation at higher doses and is less potent than fexofenadine (Allegra) and cetirizine (Zyrtec). Pseudo- ephedrine used as a decongestant can be associated with cardiac arrhythmia, hypertension, or other adverse effects in susceptible individuals. A review by Kay and Harris (1999) revealed minimal effects of loratadine on sedation, cognition, mood, and psychomotor performance. Satish et al. (2004) suggested seasonal allergic rhinitis (SAR) by itself diminishes task performance and decreases quality of life. These experimenters administered desloratadine to a group of subjects who were experiencing SAR, and gave a placebo to another group. Their performance was measured on simulated real-world information processing scenarios, which ranged through several levels of difficulty from easy to difficult decision-making tasks. Desloratadine
either completely restored performance to the level of the asymptomatic placebo control or improved performance in six of nine performance categories, which previously had been diminished by the presence of SAR. Their findings suggested that treatment with desloratadine has beneficial effects on workplace performance when individuals suffer from SAR (Satish et al. 2004). In the car driving experiment reported by OâHanlon and Ramaekers (1995) and briefly described earlier, loratadine in single doses of 10 and 20 mg produced no significant rise in SDLP (lane weaving). When given in 20-mg doses four times per day for 4 days, the impairment attributable to loratadine was similar to that of terfenadine. Building on that study, Vuuman et al. (2004) compared the acute effects of desloratadine with diphenhydramine (active control) and placebo on performance of healthy subjects evaluated with standard over-the-road driving tests, and also on a battery of conventional performance tests. The subjects were given either a single dose of 5 mg of desloratadine, 50 mg of diphen- hydramine, or placebo during each period of a randomized, double-blind, three-way crossover study. Two hours post- dosing subjects operated a specially instrumented vehicle in a 90-min test designed to measure their ability to (1) main- tain constant speed and lateral position while following another vehicle at a constant distance, and (2) respond to brake signals. Additional test batteries were administered. No significant differences were noted between desloratadine and placebo on SDLP, whereas diphenhydramine significantly increased SDLP. Brake reaction time was significantly faster following treatment with desloratadine than diphenhydramine. No differences were seen among treatments in deviation of speed or distance to the lead car. The majority of performance tests showed no significant differences among groups. Vuuman et al. (2004) concluded that desloratadine at a therapeutic dose does not impair driving performance. 26 In a study combining alcohol and desloratadine (7.5 mg daily), Scharf and Berkowitz (2007) demonstrated that a single dose of desloratadine does not potentiate alcohol- mediated CNS impairment, and desloratadine alone or in com- bination with alcohol was safe and well-tolerated. Nicholson et al. (2003) did a study examining effects of desloratadine on performance and sleepiness and concluded that 5 mg of desloratadine appears to be free of adverse effects on psycho- motor performance, daytime sleep latencies, and subjective sleepiness, and could prove to be suitable for those working in skilled activity including transportation. Assessment of antihistamines. It is the intent here to cull through the results of available research studies and to report on those that depict the effects of various chemical com- pounds. It is not within the scope of this synthesis to propose âtreatment protocolsâ regarding whether antihistamines could or should be used by commercial drivers, nor to be specific about when one should consider taking a particular anti- histamine. Because so many commercial drivers experience seasonal discomfort attributable to allergies, rhinitis, and other ailments treatable with antihistamines, more performance- oriented research should be done with second-generation, and eventually third-generation antihistamines to determine their potential efficacy for allergy treatment (relief), without producing degrading sedation effects on driving alertness, fatigue, and performance. Based on subsequent research results, what is needed is to (1) provide summary information to commercial drivers and their employers about what these new second-generation antihistamines are about, (2) spell out their advantages and disadvantages, and (3) begin to propose such guidance in an easy-to-relate-to format that describes their probable safe appli- cation for drivers who require seasonal allergy relief several times per year.