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13 PRESCRIPTION BENZODIAZEPINES NONBENZODIAZEPINE SLEEP-PROMOTING AS SLEEP-PROMOTING COMPOUNDS MEDICATIONS Benzodiazepines are a family of depressant drugs in the class Several other newer medications, essentially developed as of anxiolytic agents. Because they produce CNS depression, alternatives to benzodiazepines, are currently being prescribed benzodiazepines commonly have been prescribed for treat- as sleep-promoting compounds. Some of the more common ing insomnia and anxiety. These hypnotics can be very effec- ones, often identified as nonbenzodiazepines, are described tive in helping a person fall asleep more quickly, reduce here: zolpidem, zaleplon, eszopiclone, ramelteon, and indiplon. the number of awakenings, and increase the total sleep time (Mendelson 2005). Benzodiazepines are classified as Zolpidem Schedule IV depressants under the Controlled Substances Act (U.S. DEA 2009). NIDA cites the five most frequently Zolpidem produces sleep-inducing effects similar to those prescribed drugs in the benzodiazepine class as: lorazepam of benzodiazepines. In April 2007, the FDA approved (Ativan), diazepam (Valium), alprazolam (Xanax), tema- 13 generic versions of zolpidem tartrate, a Schedule IV zepam (Restoril), and clonazepam (Klonopin). Others controlled substance. Zolpidem is available (as Ambien, include triazolam (Halcion), chlordiazepoxide (Librium), Stilnox, Myslee, and others) for oral administration in Dalmane, Doral, and ProSom. Flunitrazepam is unique among 5 mg and 10 mg tablets. Zolpidem has been prescribed for the benzodiazepines for being placed in Schedule IV, but short-term treatment of sleep problems such as insomnia, having Schedule I penalties. The five most prescribed benzo- because it acts on the brain to produce a calming effect diazepines are also some of the most frequently encountered (Scharf et al. 1994; Roth et al. 1995). Zolpidem may help drugs on the illicit drug market. NIDA lists the following as a person fall asleep faster, stay asleep longer, and reduce street names for benzodiazepines: candy, benzos, downers, the number of times that a person awakens during the night nerve pills, sleeping pills, and tranks. (Elie et al. 1999). Benzodiazepines are marketed as mild or minor tranquil- As a practical matter, with its relatively short half-life of izers, sedatives, hypnotics, or anticonvulsants based to some 2.5 h, zolpidem is especially useful for promoting short- to extent on differences in their time-of-action, which ranges moderate-length sleep durations (of 4 to 7 h) when shorter from less than 6 h to more than 24 h. Lorazepam (Ativan), sleep opportunities occur at times that are not normally alprazolam (Xanax), and oxazepam each have short half-lives. conducive to sleep, such as for taking daytime naps. Day- Some benzodiazepines have active metabolites that prolong time naps are sometimes difficult to maintain, especially in their effects; therefore, for example, the half-life of diazepam individuals who are not sleep-deprived. The short half-life of is much longer, lasting up to 4 days. A drug's "half-life" zolpidem can provide short sleeps while minimizing the pos- refers to the period of time required for the concentration or sibility of post-nap sleep inertia hangovers. Thus, zolpidem amount of drug in the body to be reduced to exactly one-half. can make it feasible to take advantage of a nap without sig- The elimination half-lives of benzodiazepines vary widely, nificantly lengthening the post-nap time needed to ensure from the relatively short-acting triazolam, to intermediate that any drug effects have dissipated before being expected agents such as temazepam, to long-acting substances such as to resume performance of one's job. Some research results are a bit conflicting. Zolpidem of 10 mg at bedtime was reported flurazepam, to clonazepam, the longest acting of the benzodi- to be free of cognitive performance impairment within 6.5 h azepines (for details see Mendelson 2005). [See also the report (Nicholson and Pascoe 1988; Langtry and Benfield 1990; of the FMCSA expert medical panel-psychiatric (Metzner Balkin et al. 1992; Caldwell and Caldwell 1998). However, et al. 2009), which presents a list of half-lives and a recom- Vermeeren (2004) reported residual hangover effects such as mendation for blanket prohibition on commercial driving after sleepiness, and he reported that impaired psychomotor and use of benzodiazepines and nonbenzodiazepine hypnotics cognitive performance after nighttime administration may (within 7 half-lives)]. persist into the next day, possibly impairing the ability of users to drive safely. Gustavsen et al. (2008) indicated that Application of low doses of the "shorter half-life" drugs use of zolpidem may impair driving skills with a resultant may be useful as sleep aids for those doing shift work or for risk of road traffic accidents, and called for cautious use use in helping to induce sleep during long overseas flights, by drivers. where the body has to adjust to a different time zone in a relatively short time (Reiter and Robinson 1995; Technical In the military setting, Caldwell et al. (2009) suggested Cooperation Program 2001). that zolpidem may be the optimal choice for sleep periods of less than 8 h and, if there were a possibility that the hypnotic- The literature on performance effects under the influence induced sleep period is likely to be unexpectedly shortened, of benzodiazepines is covered later in this section following a zolpidem would be a better choice than temazepam. The description of a few of the newer sleep medications currently U.S. Air Force has approved the use of zolpidem as one available. of the hypnotics referred to as "no-go pills"; however, prior

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14 documented experience during ground testing with the drug explore the reported potential for adverse events such as is required before controlled administration. Even prior testing sleepwalking, sleep-driving, and tendencies toward addiction with such drugs however is no guarantee that they will work following repeated use. well in operations. Recently, when zolpidem successfully induced sleep in pilots before they controlled unmanned aerial Zaleplon vehicles in surge operations, side effects were reported in some crewmembers even though they had previously tested Zaleplon, available as Sonata or Starnoc, is a sedative/ with the drug without side effects (Van Camp 2009). For hypnotic (pyrazolopyrimidine) that binds selectively to the results of military research employing zolpidem and other benzodiazepine-l receptor. Zaleplon is rapidly absorbed after nonbenzodiazepines during lengthy operations and for use in oral administration, with peak concentration being reached in transmeridian flight, see Caldwell et al. (2009). about 1 h. The mean elimination half-life is around 1 h as well (Moore 2000). The claimed benefits are that zaleplon is effec- Although zolpidem under the trade name Ambien is tive in initiating sleep; it is mainly used to treat insomnia. Clin- one of the most widely prescribed sleeping pills in the ical trials of the hypnotic efficacy of zaleplon showed improve- United States, it is important to note that some users experi- ment in sleep initiation, particularly with a 20-mg dose (Elie ence troublesome side effects. Ambien users have reported et al. 1999; Fry et al. 2000), and it produced no hangover effects instances of sleepwalking, as well as instances of eating or as early as 6 to 7 h later (Chagan and Cicero 1999). Zaleplon driving while not fully awake--with no memory of the speeds sleep onset, reduces awakenings, and also is effective in events. Reports include Ambien users "sleepwalking" into sustaining sleep, thus increasing the total sleep time. awkward circumstances and then not knowing how they got there. Ambien use has shown up with some regularity as a For times when one has difficulty falling asleep, it is recom- factor in traffic arrests, and anecdotal stories relate how drivers mended that zaleplon (usually 10 mg) be taken immediately later say they were sleep-driving and have no memory of before bedtime or even after a person has gone to bed. After taking the wheel after taking the drug. In 2007, the FDA cited zaleplon exerts its initial effects, the drug is subsequently and reports of individuals getting out of bed after taking Ambien quickly eliminated in time for more natural physiological and then driving their cars while not fully awake, often with mechanisms to take over and maintain the remainder of the no memory of the event--a phenomenon Shinar refers to as sleep period. Whitmore et al. (2004) found that when com- the "Ambien driver" (Shinar 2007b). The FDA stated that pared with a placebo, 10 mg of zaleplon effectively promoted this behavior is more likely to occur when AmbienCR sleep during the daytime even in well-rested individuals. (an extended release formulation) is taken with alcohol or Zaleplon allowed participants to obtain significantly more other CNS depressants. The FDA warned that if a patient slow-wave sleep, as well as more sleep overall than under experiences such an episode, it should be reported to a physi- placebo. Performance was not adversely affected following a cian immediately, because "sleep-driving" can be dangerous 3.5 h daytime sleep under zaleplon, nor were any undesirable (www.fda.gov). symptoms determined (Whitmore et al. 2004). Although some studies (Paul et al. 2003) found that 10 mg of zaleplon impaired After similar reports of adverse events involving zolpidem psychomotor performance for up to 2.25 h after ingestion, marketed as Stilnox occurred in Australia in 2007 and 2008, Hurst and Nobel (1999) reported 10 mg of zaleplon was the Australian Therapeutic Goods Administration attached a without effect on cognitive performance measured 4 h after Black Box warning to zolpidem, stating that "Zolpidem may ingestion. To avoid any possible memory difficulties, zaleplon be associated with potentially dangerous complex sleep- can be taken up to 4 h before planned time of arising and related behaviours which may include sleepwalking and returning to work (Paul et al. 2004). other bizarre behaviours. Zolpidem is not to be taken with alcohol" (www.tga.gov.au). An additive effect of alcohol with Caldwell et al. (2009) indicated that in the military setting, zolpidem was demonstrated on memory and psychomotor zaleplon (510 mg) may be the best choice for initiating very performance (Isawa et al. 2000; Uchiumi et al. 2000). More short naps (1 to 2 h) or for promoting slightly longer naps recently, in April 2010, reports surfaced that some Royal (2 to 4 h), which would otherwise be difficult to initiate and Australian Air Force pilots were becoming addicted to Stilnox maintain during a period of sustained wakefulness. They also because of repeated use of the drug over months-long deploy- indicated that zaleplon (10 mg) may help hasten early-to-bed ments to Afghanistan (Parnel and Callinan 2010). sleep onsets in personnel who are trying to ensure sufficient sleep before a very early start time the next morning (i.e., at Assessment of zolpidem. The scientific literature does not 04000500 h). With regard to facilitating early report times, currently provide sufficient explication of the potential of zaleplon is perhaps a preferred option to zolpidem; however, zolpidem-based products such as Ambien and AmbienCR both compounds are important for the same reasons. With for operational use with commercial driving. In particular its ultra-short 1-h half-life, zaleplon is less likely to pose there is a need to delineate any residual inertia hangover hazards in terms of residual drug effects that can exacerbate effects or effects on worker performance upon awakening the drowsiness associated with the predawn awakening from zolpidem-induced sleep periods, and to more fully dictated by an early start time.

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15 Assessment of zaleplon. Owing to its ultra-short 1-h residual sleep inertia effects on performance from acute use half-life, zaleplon (e.g., Sonata) offers potential in select and determining whether or not noteworthy effects occur commercial driving applications for initiating naps of from with repeated use over a longer period of time (e.g., weeks 1 to 4 h, especially at times when it is otherwise difficult to or months). fall asleep. Research specific to the commercial driving needs must confirm that there are no residual inertia effects that Indiplon could interfere with safe applications meeting the needs of the commercial driving sector. Indiplon is a nonbenzodiazepine sedative/hypnotic that is relatively new to the marketplace. It is currently undergoing Eszopiclone clinical trials and has been under consideration by the FDA. Caldwell et al. (2009) indicated that indiplon is chemically Eszopiclone (Lunesta) is an FDA-approved prescription drug similar in structure to zaleplon and has a half-life of approx- used for treatment of insomnia. It is another new nonbenzo- imately 1.5 h. Indiplon, which is said to work by enhancing diazepine hypnotic agent, a derivative of the class of drugs the action of the inhibitory neurotransmitter, -Aminobutyric known as cyclopyrrolones. Eszopiclone acts as an agonist on acid (GABA), is like most other nonbenzodiazepine sedatives. benzodiazepine receptors (Jufe 2007). It is rapidly absorbed It is being produced in a modified release formula that will after oral administration, with serum levels peaking between extend its half-life to aid in sleep maintenance (Ebert et al. 1 and 1.3 h. The elimination half-life of eszopiclone is approx- 2006). An indiplon immediate-release version targets sleep imately 6 h, and it is extensively metabolized by oxidation onset insomnia, whereas a modified-release form addresses and demethylation (Halas 2006). In terms of benzodiazepine sleep maintenance insomnia. Both forms of indiplon have receptor binding and relevant potency, 3 mg of eszopiclone shown improvement compared with a placebo in patients with is roughly equivalent to 10 mg of diazepam. primary insomnia in various areas of subjective and objective sleep measurements (Lankford and Ancoli-Israel 2007; Marrs Lunesta tablets contain 1 mg, 2 mg, or 3 mg of eszopiclone 2008). Specifically, improvements in total sleep time, latency along with a variety of inactive ingredients. Lunesta helps to persistent sleep, latency to sleep onset, wake after sleep one to fall asleep quickly, so it is recommended that it be onset, and sleep quality have been noted in clinical trials. taken right before bedtime to be sure of having at least 8 h of So far, trials evaluating both indiplon immediate-release and sleep before becoming active. Lunesta has a half-life of modified-release have not identified any major serious adverse 5 to 6 h, making it a potential choice over temazepam, which effects (Marrs 2008). has a longer half-life (Caldwell et al. 2009). Lunesta demon- strated minimal residual drug effects after as little as 10 h Assessment of indiplon. No research relating human post-dose (Leese et al. 2002). Lettieri et al. (2008) administered operator performance and indiplon was located for this liter- 3 mg of eszopiclone to 113 adults undergoing polysomnog- ature review. With its apparent ultra-short-half-life charac- raphy for suspected sleep disorder breathing, and found that teristics, indiplon may have potential for use in inducing eszopiclone pre-medication significantly reduced sleep latency, sleep in some commercial driving scenarios. When the drug improved sleep efficiency, reduced wake after sleep onset, is available, conducting performance-oriented research on and prolonged sleep time. indiplon would be helpful to determine its effects. Eszopiclone (Lunesta), along with zolpidem (Ambien) and zaleplon (Sonata), are the three most commonly pre- Ramelteon scribed sedative hypnotics in the United States. Pharma- ceutical information includes advising users that until they Ramelteon (RozeremTM), a novel oral hypnotic drug, is a know how they will react to Lunesta, Ambien, or Sonata, they nonscheduled prescription insomnia medication that can be should not drive or operate machinery. It is recommended prescribed for long-term use. Ramelteon promotes falling that none of these three hypnotics be taken with alcohol, as it asleep and is used for treating insomnia. As opposed to tar- might increase the likelihood of adverse behavioral side effects geting the GABA-A receptor, ramelteon acts by stimulating such as sleep-driving. receptors for melatonin in the brain, by binding to the MT-1 and MT-2 receptors found in the suprachiasmatic nucleus Assessment of eszopiclone. For times when longer sleep (SCN), and thus helps to regulate the body's sleepwake cycle opportunities are available; for example, during a driver's (Johnson et al. 2006; Owen 2006). Ramelteon therefore does mandatory 34-h time off duty for a restart period, the new not promote sleep by CNS depression. Research indicates hypnotic compound eszopiclone (Lunesta) might offer assis- that ramelteon is efficacious for sleep onset, but not for sleep tance in helping a driver to fall asleep. Even with its estimated maintenance (Lieberman 2007; Zammitt et al. 2007). Unlike half-life of from 5 to 6 h, some research findings identified many compounds used for treating insomnia, ramelteon is not minimal residual drug effects at 10 h post-dose. Subsequent addictive and is not a controlled substance. Ramelteon does additional research could confirm how long after drug dosing not cause withdrawal symptoms or rebound insomnia when a commercial driver taking eszopiclone should refrain from its use is stopped. Ramelteon was approved by the FDA in driving. Remaining research issues include identifying any July 1995, and is available as RozeremTM in 8 mg tablets.