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79 APPENDIX B U.S. Military Policies Regarding Use of Hypnotics and Stimulants INTRODUCTION length of the sleep period, and the probability of an earlier- then-expected awakening, which may increase the risk of sleep In January 2009, a team of six prominent members of the inertia effects. Table B1 lists the categories of hypnotics and Aerospace Medical Association (AsMA) published a position their conditions of use as outlined by Caldwell et al. (2009). paper regarding the use of fatigue countermeasures in aviation. Each of the U.S. military services has its own policy con- The position paper (Caldwell et al. 2009) espouses numerous cerning the use of hypnotics. Table B2 summarizes the U.S. operator fatigue mitigation strategies and countermeasures military policies for hypnotic use (predominately specified highlighting the need for sleep management, work-rest sched- for military aviation operations). Just as is followed with the uling, copious use of nap-taking, and so on. Because of the military use of stimulants, a ground test with hypnotics under implications of that position paper for all transportation modes, controlled conditions is necessary prior to use during opera- it is of particular importance in this synthesis to reference their tions. The U.S. Navy guidance explicitly forbids administration comprehensive coverage of research and recommendations of more than one dose of a hypnotic per 24-h period, with no concerning the use of pharmacological agents (both hypnotics more than two doses of consecutive use of temazepam. There and stimulants) as countermeasures to sleep-deprivation, is also guidance for planning and briefing in the grounding fatigue, and associated problems in aviation operations (both restriction (U.S. Navy OPNAV Instruction 3710.7S 2001). military and civilian aviation situations are addressed). Their As with other medications, the use of hypnotics is voluntary. work also has implications for the commercial driving com- The reader is referred to the review of military pharmacological munity (truck and bus/motorcoach operators). The treatise policies by Caldwell et al. (2009) for details on the specific here is largely extracted from that position paper (Caldwell et al. 2009). "treatment protocols" for use of temazepam, zolpidem, and zaleplon in military aviation settings. Although differences exist between civil and military operations, it is clear similar factors and conditions lead to fatigue in both Caldwell et al. (2009) also look toward the potential civilian and military aviation environments and fatigue mitiga- military aviation application of some of the newer hypnotics tion strategies for both contexts should be scientifically based. available to help with sleep maintenance because they Understandably however, different regulations and operational considerations have resulted in fatigue countermeasure approaches offer a shorter half-life than the extended longer half-life that differ in important ways. For example, a variety of pharmaco- of temazepam. For example, the extended-release zolpidem logical countermeasures have been approved for use in certain (Ambien-CR) improves sleep maintenance beyond that of circumstances by U.S. military aviators but not by civilian aviators. The current prohibition regarding use of pharmacological counter- zolpidem (Greenblatt et al. 2005). Eszopiclone (Lunesta) measures by civilian pilots can be attributed to safety concerns has a half-life of 5 to 6 h with minimal residual drug effects and issues of adequate policies for oversight. The military ser- after as little as 10 h post-dose (Leese et al. 2002). Ramelteon vices have addressed these issues through targeted research, (Rozerem) is a novel hypnotic in that it targets the melatonin explicit policies on medical oversight, and recognition of the sometimes overriding importance of operational considerations receptors in the brain in order to regulate the body's sleepwake (e.g., US NAVMED P-6410 2000). cycle, and research indicates this drug is efficacious for sleep onset, but not for sleep maintenance (Lieberman 2007). The use of pharmacological countermeasures to fatigue in civilian Caldwell et al. also mention the new hypnotic indiplon, which (but not military) pilots is addressed by Caldwell et al. (2009). should be on the market in the near future. Indiplon is similar in structure to zaleplon and has a half-life of approximately HYPNOTICS AND AVIATION 1.5 h and is being formulated with a modified release that will extend its half-life to aid in sleep maintenance (Ebert For circumstances where sleep is difficult to obtain in et al. 2006). There also are new compounds that are rapidly operational contexts, pharmaceutical strategies (espoused by absorbed and that have a short half-life, and several have Caldwell et al. 2009) include U.S. Air Force and U.S. Army the ability to increase both slow-wave sleep and slow-wave approval of limited use of temazepam, zolpidem, and zaleplon. activity, which improves sleep efficiency. These compounds [Only the U.S. Army continues to authorize limited use of may improve sleep efficiency to the point that effective wake- triazolam (Halcion) for pre-deployment rest or sustained fulness can be sustained on fewer than the 8 h of daily sleep operations--although in actuality it is rarely prescribed]. These now required (Caldwell et al. 2009). These developments three hypnotics Caldwell et al. (2009) state can optimize the should be carefully watched to determine their potential quality of crew rest in circumstances where sleep is possible, applicability to the commercial driving community. but difficult to obtain. The choice of which compound is best for each circumstance they say must take several factors As for current civilian aviation policy, the FAA only allows into account, including time of day, half-life of the compound, limited use of zolpidem (Ambien) and at that no more

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80 TABLE B1 LIST OF HYPNOTICS AND THEIR USES Generic Average Name Brand Name Dosage Half-Life Recommended Use Cautions Temazepam Restoril 1530 mg 9h Sleep maintenance; Need 8 h sleep Euhypnos daytime sleep period; not Normison recommended if Remestox on-call Norkotral Zolpidem Ambien 510 mg 2.5 h Sleep initiation; Stilnox intermediate-length naps; Myslee assisting early sleep onset due to early bedtimes from shift or time zone change Zaleplon Sonata 510 mg 1h Sleep initiation; short naps; Not recommended Starnoc assisting early sleep onset if on-call due to early bedtimes from shift or time zone change Source: Aviation, Space and Environmental Medicine (Caldwell et al. 2009). than twice per week, stating it cannot be used for circadian with varying length of action that policy would encourage adjustment. In addition, there is a 24-h grounding policy for selection of the appropriate drug for the specific time of use. any pilot who uses zolpidem. Caldwell et al. (2009) suggest These authors offer recommendations for permitting use of that the FAA's policy that hypnotics not be used for circadian additional hypnotics in civilian aviation. Interested readers disruption is overly restrictive because it is precisely for this are referred to Caldwell et al. 2009 for details. reason that hypnotics would be useful for pilots crossing multiple time zones or flying early morning flights. They Caldwell et al. (2009) suggest that sleep-promoting suggest that rather than permitting a choice of only one compounds can be useful in operational contexts where there hypnotic, if they allowed a choice of a variety of hypnotics are problems with sleep initiation or sleep maintenance. TABLE B2 U.S. MILITARY POLICIES FOR USE OF HYPNOTICS Medication Dose Half-Life Grounding U.S. Army Rest Agent Policy Temazepam (Restoril) 15 or 30 mg 8.012.0 h 24 h Triazolam (Halcion ) 0.125 or 0.25 mg 2.04.0 h 9h Zolpidem (Ambien) 5 or 10 mg 2.02.5 h 8h Zaleplon (Sonata) 5 or 10 mg 1.0 h 8h U.S. Air Force No-Go Pill Policy Temazepam (Restoril) 15 or 30 mg 8.012.0 h 12 h Triazolam (Halcion) Not authorized N/A N/A Zolpidem (Ambien ) 10 mg 2.02.5 h 6h Zaleplon (Sonata) 10 mg 1.0 h 4h U.S. Navy Sleep Initiator Policy Temazepam (Restoril) 15 mg 8.012.0 h 7h Triazolam (Halcion) Not authorized N/A N/A Zolpidem (Ambien) 5 or 10 mg 2.02.5 h 6h Zaleplon (Sonata) Not authorized N/A N/A Source: Aviation, Space and Environmental Medicine (Caldwell et al. 2009). N/A = not available.

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81 However, they state that as with all medications there are that in sustained aviation operations the occasional use of the both benefits and risks associated with the use of hypnotic alertness-enhancing medications such as dextroamphetamine compounds. The risks should be considered by the prescribing (authorized by all three U.S. military services) and modafinil physician (flight surgeon) and the individual pilot before (authorized for use in the U.S. Air Force) can often signifi- the decision to use hypnotic therapy is finalized. If the crew- cantly enhance the safety and effectiveness of sleep-deprived member is likely to be called back to duty earlier than antici- personnel. pated, then a hypnotic of any type probably should not be used because this would put the pilot at risk of performing flight duties before the medication has been fully metabolized. Modafinil (ProVigil) Particular research studies on modafinil were described in this Although temazepam, zolpidem, and zaleplon are widely synthesis in chapter four. Caldwell et al. (2009) suggested recognized as being both safe and effective, operational that modafinil is gaining popularity as a way to enhance the personnel should be cautioned about potential side effects alertness of sleepy personnel, largely because it is considered and instructed to bring these to the attention of their physician safer and less addictive than compounds such as the amphet- should they occur (Caldwell et al. 2009). For reasons related to anticipated side effects, military personnel are required to amines. Modafinil also produces less cardiovascular stimulation receive a test dose of the hypnotic of interest under medical than amphetamine and, despite its half-life of approximately supervision before using the medication during actual oper- 12 to 15 h (Robertson and Hillriegel 2003), the drug's impact on ational situations. Further, even after the test dose yields sleep architecture is minimal. Caldwell et al. (2009) reminded favorable results and it is clear that operationally important side readers that modafinil has not been as thoroughly tested as effects are absent, hypnotics should be used with particular dextroamphetamine in real-world operational environments caution when the aim is to aid in advancing or delaying cir- and some data suggest modafinil is less effective than amphet- cadian rhythms in response to time zone shifts. Reviews by amine (Mitler and Aldrich 2000). Caldwell et al. (2009) Nicholson (1990), Stone and Turner (1997), and Waterhouse indicated that the U.S. Air Force has approved the use of et al. (1997) offer detailed information on this rather complex modafinil in certain long-range combat aviation missions, and issue (Caldwell et al. 2009). it is likely the U.S. Army and the U.S. Navy soon will approve of use of modafinil as well. STIMULANTS DURING MILITARY OPERATIONS Amphetamine (Dexedrine, Dextrostat) There is a sizeable literature base describing U.S. military research, mostly by medical research laboratories, on the Dextroamphetamine (5 to 10 mg) has been authorized for use application of a select number of stimulant drugs by military by all three U.S. military services for certain types of lengthy personnel, to demonstrate possible protocols for usage dur- flight missions (i.e., 12 or more hours of flight). Some of the ing training or actual military operations. In particular, work research described in chapter four supported policy decisions with aviators has examined dextroamphetamine stimulants concerning use of amphetamines in the three U.S. military (e.g., predominately dexedrine) with helicopter pilots (e.g., services (for details, see Caldwell et al. 2009). Caldwell et al. Caldwell et al. 1995, 1997, 2000a, b; Caldwell and Caldwell (2009) recommend the use of dextroamphetamine in doses of 1997, 2000a, b), with fighter jet pilots (e.g., in simulators by 10 to 20 mg (not to exceed 60 mg per day) for situations in Caldwell et al. 2004), and in actual combat operations reported which heavily fatigued military pilots simply must complete by Schultz and Miller (2004a, b) and Gore et al. (2010), in the mission despite dangerous levels of sleep deprivation. The bomber aircraft operations (Kenagy et al. 2004); and exem- following stimulant use protocol guidance, which Caldwell plified in the United Kingdom's Royal Air Force use of pemo- et al. (2009) attributed to the U.S. Air Force, is extracted from line in air operations (e.g., Nicholson and Turner 1998). It is their report. beyond the scope of this synthesis to detail the numerous studies and their findings here. U.S. Air Force Combat Aviation Operations Guidance for Use of Stimulants The same team of AsMA scientists mentioned earlier Prior to the operational use of dextroamphetamine regarding hypnotics also detailed research that informed U.S. or modafinil, an informed consent agreement must military policies regarding the use of stimulants in military be obtained to ensure that crews are fully aware of both the positive and the potential negative effects aviation (Caldwell et al. 2009). These authors stated that of these compounds. one option for sustaining wakefulness of flight crews during The decision to authorize the use of alertness- extended missions wherein adequate crew rest is not feasible enhancing compounds should be made by the Wing is to employ alertness-enhancing medications (stimulants). Commander in conjunction with the Senior Flight Caldwell et al. (2009) prefaced their treatise by stating that Surgeon. All distribution of alertness-enhancing medications these compounds should not be considered a replacement for must be closely monitored and documented. adequate crew rest planning and they should never be con- Ground testing (during non-flight periods) is required sidered a substitute for restorative sleep. However, they state prior to operational use.

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82 The currently authorized dose of dextroamphetamine authorized for use in any type of civil aviation operation. is 5 to 10 mg, and although the dosing interval is not Caldwell et al. (2009) suggested that because civil aviation explicitly stated, a 4-hour interval is often recom- operations generally are more predictable than military oper- mended. No more than 60 mg should be administered in any 24-hr period, and often, no more than 30 mg ations, and since prolonged periods of sleep deprivation are are administered. not the norm in civil operations (but are almost unavoidable in The currently authorized dose of modafinil is 200 mg the military), meaning in civil aviation that other allowances every 8 hours, not to exceed 400 mg in any 24-hour can be planned on, it would seem prudent to withhold wide- period; however, recent F-117 research has indicated spread authorization of prescription alertness enhancers in that 100 mg doses also are efficacious (and this lower dose is authorized as well). the civilian aviation sector. The use of alertness-enhancing compounds normally can be authorized in fighter missions longer than Intense military operations are generally time limited, in 8 hours or bomber missions longer than 12 hours that they expose military pilots to only relatively brief periods (although exceptions can be made). in which intense sleep deprivation necessitates administration Caffeine generally is not considered to be a suitable alternative for modafinil or dextroamphetamine; how- of appropriate counter-fatigue medications (Caldwell et al. ever, caffeine in the form of foods or beverages may 2009). Because the continuous combat conditions in Iraq be consumed without restriction. Caffeine in the form and Afghanistan have now been extended over several years, of tablets or capsules can only be used after flight many military pilots have been exposed to pharmaceutical surgeon approval. intervention on what comes closer to chronic rather than Source: Aviation, Space and Environmental Medicine acute circumstances. A concern in civil aviation operations (Caldwell et al. 2009). has always been that if such medications were authorized, commercial pilots might continue day-in and day-out for weeks, U.S. Army and U.S. Navy guidance is mostly consistent months, years, and even for the duration of a pilot's career, with that of the U.S. Air Force (listed earlier), with the most which in effect could potentially expose moderately fatigued notable exception being that modafinil is not currently autho- pilots to years of chronic medication use. Caldwell et al. (2009) rized in the Army or Navy. The U.S. Army guidance for use take the position that this difference between military and civil of dextroamphetamine endorses the administration of 5- or aviation operations argues against widespread authorization 10-mg doses and specifies that no more than 30 mg may be of alertness-enhancing drugs in civil operations. used in any 24-h period. The medication is not be used to sustain wakefulness for longer than 64 continuous hours. U.S. Navy guidance suggests dextroamphetamine be admin- ASSESSMENT OF MILITARY USE OF HYPNOTICS istered in 5-mg doses, which may be repeated every 2 to 3 h; AND STIMULANTS TO SUSTAIN ALERTNESS however, total dosage should not exceed 30 mg in any 24-h period. The Navy does not specify an upper level for the To the MaineWay synthesis team it would appear that the duration of any period of continuous wakefulness, but it is cautions mentioned previously for treating differences in clear that extended periods without sleep should be avoided military versus commercial and civil aviation operations hold (Caldwell et al. 2009). After citing many research reports equally true, if not more so, for the commercial driving and related to the topic, Caldwell et al. recommended that all transport industries. Much of what takes place in operational three services sanction the use of modafinil under guidance employment of chemical countermeasures in select military consistent with that currently followed by the U.S. Air Force applications does not readily transfer one-for-one to potential (and described earlier). utilization of pharmaceutical countermeasures in commercial driving settings. This is particularly true when one considers Caffeine use is a relatively uncontrolled stimulant in the that the military's policies include ensuring tight controls over three U.S. military services, and Caldwell et al. (2009) recom- the use of psychoactive substances in training and during mended that aircrews should avoid habituation to caffeine military operations. This just would not be feasible or prac- and take advantage of its cortical stimulant properties when tical in commercial driving scenarios. it is needed to help ensure safe operations. More specifically, when aircrews are not suffering from the effects of fatigue, However, there are elements of the military medical research they should limit their total daily caffeine consumption from all findings that can benefit the commercial driving community, sources to 200 to 250 mg of caffeine per day. Additional doses such as the possibility of use of stimulating compounds such of caffeine should be used during situations in which fatigue as modafinil and caffeinated chewing gum. Under current elevates the risk of a mishap. In any 24-h period the total hours of service rules, which require daily ten-hour off-duty amount of caffeine consumed should not exceed 1000 mg. rest periods and include such facets as 34-h weekly restart rest Aircrew members are to be reminded of the 4 to 6 h half-life periods, the military protocols used with ultra-short hypnotics of circulating caffeine and preplan its use such that post-duty to induce sleep might make some sense in selected applica- day sleep is not disturbed by the caffeine consumed. tions in the commercial driving industries. Continuing new developments in military medical research and applications With the exception of caffeine and various nutritional sup- should be carefully monitored for their potential applications plements, no alertness-enhancing medications are currently for safe transportation operations.