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79 INTRODUCTION In January 2009, a team of six prominent members of the Aerospace Medical Association (AsMA) published a position paper regarding the use of fatigue countermeasures in aviation. The position paper (Caldwell et al. 2009) espouses numerous operator fatigue mitigation strategies and countermeasures highlighting the need for sleep management, work-rest sched- uling, copious use of nap-taking, and so on. Because of the implications of that position paper for all transportation modes, it is of particular importance in this synthesis to reference their comprehensive coverage of research and recommendations concerning the use of pharmacological agents (both hypnotics and stimulants) as countermeasures to sleep-deprivation, fatigue, and associated problems in aviation operations (both military and civilian aviation situations are addressed). Their work also has implications for the commercial driving com- munity (truck and bus/motorcoach operators). The treatise here is largely extracted from that position paper (Caldwell et al. 2009). Although differences exist between civil and military operations, it is clear similar factors and conditions lead to fatigue in both civilian and military aviation environments and fatigue mitiga- tion strategies for both contexts should be scientifically based. Understandably however, different regulations and operational considerations have resulted in fatigue countermeasure approaches that differ in important ways. For example, a variety of pharmaco- logical countermeasures have been approved for use in certain circumstances by U.S. military aviators but not by civilian aviators. The current prohibition regarding use of pharmacological counter- measures by civilian pilots can be attributed to safety concerns and issues of adequate policies for oversight. The military ser- vices have addressed these issues through targeted research, explicit policies on medical oversight, and recognition of the sometimes overriding importance of operational considerations (e.g., US NAVMED P-6410 2000). The use of pharmacological countermeasures to fatigue in civilian (but not military) pilots is addressed by Caldwell et al. (2009). HYPNOTICS AND AVIATION For circumstances where sleep is difficult to obtain in operational contexts, pharmaceutical strategies (espoused by Caldwell et al. 2009) include U.S. Air Force and U.S. Army approval of limited use of temazepam, zolpidem, and zaleplon. [Only the U.S. Army continues to authorize limited use of triazolam (HalcionÂ®) for pre-deployment rest or sustained operationsâalthough in actuality it is rarely prescribed]. These three hypnotics Caldwell et al. (2009) state can optimize the quality of crew rest in circumstances where sleep is possible, but difficult to obtain. The choice of which compound is best for each circumstance they say must take several factors into account, including time of day, half-life of the compound, length of the sleep period, and the probability of an earlier- then-expected awakening, which may increase the risk of sleep inertia effects. Table B1 lists the categories of hypnotics and their conditions of use as outlined by Caldwell et al. (2009). Each of the U.S. military services has its own policy con- cerning the use of hypnotics. Table B2 summarizes the U.S. military policies for hypnotic use (predominately specified for military aviation operations). Just as is followed with the military use of stimulants, a ground test with hypnotics under controlled conditions is necessary prior to use during opera- tions. The U.S. Navy guidance explicitly forbids administration of more than one dose of a hypnotic per 24-h period, with no more than two doses of consecutive use of temazepam. There is also guidance for planning and briefing in the grounding restriction (U.S. Navy OPNAV Instruction 3710.7S 2001). As with other medications, the use of hypnotics is voluntary. The reader is referred to the review of military pharmacological policies by Caldwell et al. (2009) for details on the specific âtreatment protocolsâ for use of temazepam, zolpidem, and zaleplon in military aviation settings. Caldwell et al. (2009) also look toward the potential military aviation application of some of the newer hypnotics available to help with sleep maintenance because they offer a shorter half-life than the extended longer half-life of temazepam. For example, the extended-release zolpidem (Ambien-CRÂ®) improves sleep maintenance beyond that of zolpidem (Greenblatt et al. 2005). Eszopiclone (LunestaÂ®) has a half-life of 5 to 6 h with minimal residual drug effects after as little as 10 h post-dose (Leese et al. 2002). Ramelteon (RozeremÂ®) is a novel hypnotic in that it targets the melatonin receptors in the brain in order to regulate the bodyâs sleepâwake cycle, and research indicates this drug is efficacious for sleep onset, but not for sleep maintenance (Lieberman 2007). Caldwell et al. also mention the new hypnotic indiplon, which should be on the market in the near future. Indiplon is similar in structure to zaleplon and has a half-life of approximately 1.5 h and is being formulated with a modified release that will extend its half-life to aid in sleep maintenance (Ebert et al. 2006). There also are new compounds that are rapidly absorbed and that have a short half-life, and several have the ability to increase both slow-wave sleep and slow-wave activity, which improves sleep efficiency. These compounds may improve sleep efficiency to the point that effective wake- fulness can be sustained on fewer than the 8 h of daily sleep now required (Caldwell et al. 2009). These developments should be carefully watched to determine their potential applicability to the commercial driving community. As for current civilian aviation policy, the FAA only allows limited use of zolpidem (AmbienÂ®) and at that no more APPENDIX B U.S. Military Policies Regarding Use of Hypnotics and Stimulants
80 than twice per week, stating it cannot be used for circadian adjustment. In addition, there is a 24-h grounding policy for any pilot who uses zolpidem. Caldwell et al. (2009) suggest that the FAAâs policy that hypnotics not be used for circadian disruption is overly restrictive because it is precisely for this reason that hypnotics would be useful for pilots crossing multiple time zones or flying early morning flights. They suggest that rather than permitting a choice of only one hypnotic, if they allowed a choice of a variety of hypnotics with varying length of action that policy would encourage selection of the appropriate drug for the specific time of use. These authors offer recommendations for permitting use of additional hypnotics in civilian aviation. Interested readers are referred to Caldwell et al. 2009 for details. Caldwell et al. (2009) suggest that sleep-promoting compounds can be useful in operational contexts where there are problems with sleep initiation or sleep maintenance. Generic Name Brand Name Dosage Average Half-Life Recommended Use Cautions Temazepam RestorilÂ® EuhypnosÂ® NormisonÂ® RemestoxÂ® NorkotralÂ® 15â30 mg 9 h Sleep maintenance; daytime sleep Need 8 h sleep period; not recommended if on-call Zolpidem AmbienÂ® StilnoxÂ® MysleeÂ® 5â10 mg 2.5 h Sleep initiation; intermediate-length naps; assisting early sleep onset due to early bedtimes from shift or time zone change Zaleplon SonataÂ® StarnocÂ® 5â10 mg 1 h Sleep initiation; short naps; assisting early sleep onset due to early bedtimes from shift or time zone change Not recommended if on-call Source: Aviation, Space and Environmental Medicine (Caldwell et al. 2009). TABLE B1 LIST OF HYPNOTICS AND THEIR USES Medication Dose Half-Life Grounding U.S. Army Rest Agent Policy Temazepam (RestorilÂ®) 15 or 30 mg 8.0â12.0 h 24 h Triazolam (HalcionÂ®) 0.125 or 0.25 mg 2.0â4.0 h 9 h Zolpidem (AmbienÂ®) 5 or 10 mg 2.0â2.5 h 8 h Zaleplon (SonataÂ®) 5 or 10 mg 1.0 h 8 h U.S. Air Force No-Go Pill Policy Temazepam (RestorilÂ®) 15 or 30 mg 8.0â12.0 h 12 h Triazolam (HalcionÂ®) Not authorized N/A N/A Zolpidem (AmbienÂ®) 10 mg 2.0â2.5 h 6 h Zaleplon (SonataÂ®) 10 mg 1.0 h 4 h U.S. Navy Sleep Initiator Policy Temazepam (RestorilÂ®) 15 mg 8.0â12.0 h 7 h Triazolam (HalcionÂ®) Not authorized N/A N/A Zolpidem (AmbienÂ®) 5 or 10 mg 2.0â2.5 h 6 h Zaleplon (SonataÂ®) Not authorized N/A N/A Source: Aviation, Space and Environmental Medicine (Caldwell et al. 2009). N/A = not available. TABLE B2 U.S. MILITARY POLICIES FOR USE OF HYPNOTICS
81 However, they state that as with all medications there are both benefits and risks associated with the use of hypnotic compounds. The risks should be considered by the prescribing physician (flight surgeon) and the individual pilot before the decision to use hypnotic therapy is finalized. If the crew- member is likely to be called back to duty earlier than antici- 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. Although temazepam, zolpidem, and zaleplon are widely recognized as being both safe and effective, operational personnel should be cautioned about potential side effects and instructed to bring these to the attention of their physician should they occur (Caldwell et al. 2009). For reasons related to anticipated side effects, military personnel are required to receive a test dose of the hypnotic of interest under medical supervision before using the medication during actual oper- ational situations. Further, even after the test dose yields favorable results and it is clear that operationally important side effects are absent, hypnotics should be used with particular caution when the aim is to aid in advancing or delaying cir- cadian rhythms in response to time zone shifts. Reviews by Nicholson (1990), Stone and Turner (1997), and Waterhouse et al. (1997) offer detailed information on this rather complex issue (Caldwell et al. 2009). STIMULANTS DURING MILITARY OPERATIONS There is a sizeable literature base describing U.S. military research, mostly by medical research laboratories, on the application of a select number of stimulant drugs by military personnel, to demonstrate possible protocols for usage dur- ing training or actual military operations. In particular, work with aviators has examined dextroamphetamine stimulants (e.g., predominately dexedrine) with helicopter pilots (e.g., Caldwell et al. 1995, 1997, 2000a, b; Caldwell and Caldwell 1997, 2000a, b), with fighter jet pilots (e.g., in simulators by Caldwell et al. 2004), and in actual combat operations reported by Schultz and Miller (2004a, b) and Gore et al. (2010), in bomber aircraft operations (Kenagy et al. 2004); and exem- plified in the United Kingdomâs Royal Air Force use of pemo- line in air operations (e.g., Nicholson and Turner 1998). It is beyond the scope of this synthesis to detail the numerous studies and their findings here. The same team of AsMA scientists mentioned earlier regarding hypnotics also detailed research that informed U.S. military policies regarding the use of stimulants in military aviation (Caldwell et al. 2009). These authors stated that one option for sustaining wakefulness of flight crews during extended missions wherein adequate crew rest is not feasible is to employ alertness-enhancing medications (stimulants). Caldwell et al. (2009) prefaced their treatise by stating that these compounds should not be considered a replacement for adequate crew rest planning and they should never be con- sidered a substitute for restorative sleep. However, they state that in sustained aviation operations the occasional use of the alertness-enhancing medications such as dextroamphetamine (authorized by all three U.S. military services) and modafinil (authorized for use in the U.S. Air Force) can often signifi- cantly enhance the safety and effectiveness of sleep-deprived personnel. Modafinil (ProVigilÂ®) Particular research studies on modafinil were described in this synthesis in chapter four. Caldwell et al. (2009) suggested that modafinil is gaining popularity as a way to enhance the alertness of sleepy personnel, largely because it is considered safer and less addictive than compounds such as the amphet- amines. Modafinil also produces less cardiovascular stimulation than amphetamine and, despite its half-life of approximately 12 to 15 h (Robertson and Hillriegel 2003), the drugâs impact on sleep architecture is minimal. Caldwell et al. (2009) reminded readers that modafinil has not been as thoroughly tested as dextroamphetamine in real-world operational environments and some data suggest modafinil is less effective than amphet- amine (Mitler and Aldrich 2000). Caldwell et al. (2009) indicated that the U.S. Air Force has approved the use of modafinil in certain long-range combat aviation missions, and it is likely the U.S. Army and the U.S. Navy soon will approve of use of modafinil as well. Amphetamine (DexedrineÂ®, DextrostatÂ®) Dextroamphetamine (5 to 10 mg) has been authorized for use by all three U.S. military services for certain types of lengthy flight missions (i.e., 12 or more hours of flight). Some of the research described in chapter four supported policy decisions concerning use of amphetamines in the three U.S. military services (for details, see Caldwell et al. 2009). Caldwell et al. (2009) recommend the use of dextroamphetamine in doses of 10 to 20 mg (not to exceed 60 mg per day) for situations in which heavily fatigued military pilots simply must complete the mission despite dangerous levels of sleep deprivation. The following stimulant use protocol guidance, which Caldwell et al. (2009) attributed to the U.S. Air Force, is extracted from their report. U.S. Air Force Combat Aviation Operations Guidance for Use of Stimulants â¢ Prior to the operational use of dextroamphetamine or modafinil, an informed consent agreement must be obtained to ensure that crews are fully aware of both the positive and the potential negative effects of these compounds. â¢ The decision to authorize the use of alertness- enhancing compounds should be made by the Wing Commander in conjunction with the Senior Flight Surgeon. â¢ All distribution of alertness-enhancing medications must be closely monitored and documented. â¢ Ground testing (during non-flight periods) is required prior to operational use.
82 â¢ The currently authorized dose of dextroamphetamine is 5 to 10 mg, and although the dosing interval is not explicitly stated, a 4-hour interval is often recom- mended. No more than 60 mg should be administered in any 24-hr period, and often, no more than 30 mg are administered. â¢ The currently authorized dose of modafinil is 200 mg every 8 hours, not to exceed 400 mg in any 24-hour period; however, recent F-117 research has indicated that 100 mg doses also are efficacious (and this lower dose is authorized as well). â¢ The use of alertness-enhancing compounds normally can be authorized in fighter missions longer than 8 hours or bomber missions longer than 12 hours (although exceptions can be made). â¢ Caffeine generally is not considered to be a suitable alternative for modafinil or dextroamphetamine; how- ever, caffeine in the form of foods or beverages may be consumed without restriction. Caffeine in the form of tablets or capsules can only be used after flight surgeon approval. Source: Aviation, Space and Environmental Medicine (Caldwell et al. 2009). U.S. Army and U.S. Navy guidance is mostly consistent with that of the U.S. Air Force (listed earlier), with the most notable exception being that modafinil is not currently autho- rized in the Army or Navy. The U.S. Army guidance for use of dextroamphetamine endorses the administration of 5- or 10-mg doses and specifies that no more than 30 mg may be 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- istered in 5-mg doses, which may be repeated every 2 to 3 h; however, total dosage should not exceed 30 mg in any 24-h period. The Navy does not specify an upper level for the duration of any period of continuous wakefulness, but it is clear that extended periods without sleep should be avoided (Caldwell et al. 2009). After citing many research reports related to the topic, Caldwell et al. recommended that all three services sanction the use of modafinil under guidance consistent with that currently followed by the U.S. Air Force (and described earlier). Caffeine use is a relatively uncontrolled stimulant in the three U.S. military services, and Caldwell et al. (2009) recom- mended that aircrews should avoid habituation to caffeine and take advantage of its cortical stimulant properties when it is needed to help ensure safe operations. More specifically, when aircrews are not suffering from the effects of fatigue, they should limit their total daily caffeine consumption from all sources to 200 to 250 mg of caffeine per day. Additional doses of caffeine should be used during situations in which fatigue elevates the risk of a mishap. In any 24-h period the total amount of caffeine consumed should not exceed 1000 mg. Aircrew members are to be reminded of the 4 to 6 h half-life of circulating caffeine and preplan its use such that post-duty day sleep is not disturbed by the caffeine consumed. With the exception of caffeine and various nutritional sup- plements, no alertness-enhancing medications are currently authorized for use in any type of civil aviation operation. Caldwell et al. (2009) suggested that because civil aviation operations generally are more predictable than military oper- ations, and since prolonged periods of sleep deprivation are not the norm in civil operations (but are almost unavoidable in the military), meaning in civil aviation that other allowances can be planned on, it would seem prudent to withhold wide- spread authorization of prescription alertness enhancers in the civilian aviation sector. Intense military operations are generally time limited, in that they expose military pilots to only relatively brief periods in which intense sleep deprivation necessitates administration of appropriate counter-fatigue medications (Caldwell et al. 2009). Because the continuous combat conditions in Iraq and Afghanistan have now been extended over several years, many military pilots have been exposed to pharmaceutical intervention on what comes closer to chronic rather than acute circumstances. A concern in civil aviation operations has always been that if such medications were authorized, commercial pilots might continue day-in and day-out for weeks, months, years, and even for the duration of a pilotâs career, which in effect could potentially expose moderately fatigued pilots to years of chronic medication use. Caldwell et al. (2009) take the position that this difference between military and civil aviation operations argues against widespread authorization of alertness-enhancing drugs in civil operations. ASSESSMENT OF MILITARY USE OF HYPNOTICS AND STIMULANTS TO SUSTAIN ALERTNESS To the MaineWay synthesis team it would appear that the cautions mentioned previously for treating differences in military versus commercial and civil aviation operations hold equally true, if not more so, for the commercial driving and transport industries. Much of what takes place in operational employment of chemical countermeasures in select military applications does not readily transfer one-for-one to potential utilization of pharmaceutical countermeasures in commercial driving settings. This is particularly true when one considers that the militaryâs policies include ensuring tight controls over the use of psychoactive substances in training and during military operations. This just would not be feasible or prac- tical in commercial driving scenarios. However, there are elements of the military medical research findings that can benefit the commercial driving community, such as the possibility of use of stimulating compounds such as modafinil and caffeinated chewing gum. Under current hours of service rules, which require daily ten-hour off-duty rest periods and include such facets as 34-h weekly restart rest periods, the military protocols used with ultra-short hypnotics to induce sleep might make some sense in selected applica- tions in the commercial driving industries. Continuing new developments in military medical research and applications should be carefully monitored for their potential applications for safe transportation operations.