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- Special Considerations In light of wide-ranging individual differences in caffeine sensitivity, dos- ing for optimal efficacy and minimal side effects should take into account qualitative conditions based on trait and state variations in individual sensitivity to caffeine. Trait variations are those based on the individual's genetic makeup and include such factors as stress reactivity, rate of metabolism of caffeine to paraxanthine, and kidney clearance rates. State variability factors include pre- existing caffeine intake from other sources (beverages, foods, supplements), other stimulant drug intake (ephedrine, over-the-counter, or prescription drugs), other drug or hormone use (e.g., oral contraceptives), smoking, stress (heat stress, exercise, other stress), sleep deprivation status, and relevant health condi- tions (e.g., hypertension, anxiety disorder). Ideally, a composite quantitative dosing scale (composite caffeine intake index) could be developed using parametric analysis to take into account differ- ences in state and trait variations in individual sensitivity to caffeine. Such a scale could be applied to determine more quantitatively the amount of caffeine that should be administered to individuals in specific contexts for improvements in cognitive function with minimal side effects based on individual differences in preexisting trait sensitivity as well as state variability factors. If the military adopts the use of caffeine to preserve cognitive performance and vigilance in special and sustained operations, consideration should be given to soldiers' information needs as well as to potential safety issues and ethical concerns. An order to use caffeine may be appropriate to ensure the safety of personnel and the success of a military operation. The committee endorses the 67 Am.

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68 CAFFEINE FOR MENTAL TASK PENANCE concept that the command structure at the lowest level should have the authority to require the consumption of caffeine if, in their judgment, the welfare of the war fighters or the success of a mission would otherwise be at risk. Neverthe- less, the dosage of caffeine should include some element of individual choice. That is, the individual should be permitted to control the intake of caffeine much like the civilian population does when consuming coffee or caffeine-containing soft drinks, on the basis of perceived need to sustain performance. EDUCATION AND TRAINING ISSUES An education or information component should be a crucial part of any pro- gram to provide military personnel with caffeine in order to facilitate an in- formed decision process. This information component should include potential benefits, methods of implementation including the timing and the dose that may be effective, potential dangers of misuse, physiological symptoms of excessive intake, and the potential dependence (and subsequent withdrawal symptoms) associated with continued moderate to high levels of use. This information com- ponent should also include opportunities for consumption of products that con- tain added caffeine in a controlled situation so that each individual will be aware of how a product impacts his or her own performance and mood prior to use in an operational situation. Training of command personnel is also essential to assist them in making decisions about when the products are appropriate to use, directions for their use, and any potential adverse effects resulting from misuse. LABELING Any nontraditional product that is used as a vehicle for providing caffeine to military personnel (particularly if it could possibly reach civilian hands) should be prominently labeled, including on the principal display panel, that the product contains added caffeine and is intended for use only during sustained or special operations. The label should also contain the amount of caffeine per recommended serving (e.g., stick of gum) and the total amount per package or container. Appropriate doses should be clearly labeled and the product (e.g., chewing gurn, food/energy bar, or tablet) should be scored or metered to facili- tate obtaining a certain dose (e.g., 100 mg). The Food and Drug Administration (FDA) has determined that there is no evidence to show a human health hazard arising from the use of caffeine and has approved its use as a food additive with a provisional listing status. Thus the committee believes that a warning statement is not necessary and could lead to unnecessary concern on the part of military personnel instructed to use the prod- uct. However, prominent information statements on the misuse of the product

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SPECIAL CONSIDERATIONS 69 are needed. For example, it is recommended that the label display instructions for use that provide the maximum single dose and the frequency of dosing. ETHICAL CONSIDERATIONS The committee has deliberated the potential ethical issues associated with the use of caffeine or other stimulants in military operations. In the committee's judgment, it is unethical to coerce any individual to consume caffeine, if for religious or health reasons that individual does not wish to consume stimulants. The committee is aware that it is the military custom for the individual and his or her superior to discuss concerns of this nature and secure consultation of the unit's surgeon if a waiver is necessary. There are also ethical concerns when caffeine, which is a legal and accept- able substance in American society, is denied in the course of a military opera- tion simply because of a logistical decision. In such situations heavy users are likely to undergo withdrawal symptoms and may put themselves and other war fighters at increased risk due to fatigue, sleepiness, loss of attentiveness, and other withdrawal symptoms. Although clinical studies do not provide evidence of acute side effects from caffeine consumption in the range under consideration, there seems to be an abundance of anecdotal information that some individuals have significant dis- comfort when consuming levels of caffeine equivalent to that found in 1 cup of coffee. It is recommended that research be done with volunteers who have been so identified to determine if there is a small segment of the population that may have an increased sensitivity to caffeine. ALTERNATIVES TO CAFFEINE FOR MAINTENANCE OF COGNITIVE PERFORMANCE There are a number of possible alternatives to caffeine for maintaining cog- nitive performance during sustained operations. These include naps and the use of various prescription drugs, which are discussed below. Naps Decrements in cognitive behavior due to sleep deprivation can best be re- versed by providing sleep. There is a dose effect for the restorative effects of sleep on cognitive performance (Bonnet, 1999; Bonnet and Arand, 1994a; Bon- net et al., 1995~. Any amount of sleep from as little as a 15-minute nap can re- store some degree of function, although the longer the sleep episode, the greater the amount of cognitive function restored (Bonnet et al., 1995~. Since the drive for sleep is governed both by a homeostatic drive and a circadian drive, which are interactive (Wyatt, 1999), these factors must be taken into consideration in

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70 CAFFEINE FOR MENTAL TASKPE~O~ANCE determining the timing of naps and their effectiveness in reconstituting mental functioning. Naps are effective both prior to (prophylactic naps) and during (restorative naps) a period of sleep deprivation (Bonnet, 1999; Bonnet and Arand, 1994b; Bonnet et al., 1995~. However, the quality of sleep differs be- tween prophylactic naps and naps taken during sleep deprivation. Despite the fact that prophylactic naps are associated with longer sleep latencies and less deep sleep than post-deprivation recovery sleep (Bonnet, 1999), studies by Dinges et al. (1987) demonstrated that prophylactic naps were more beneficial than restorative naps. They concluded that napping prior to a period of extended wakefulness was more important than circadian placement of the nap. A nega- tive side effect of naps during a period of sleep deprivation (restorative naps) is sleep inertia, a short period of mental confusion upon awakening which can last as long as 30 minutes. A combination of caffeine and naps is the most effective nonprescription drug alternative to caffeine administration alone when a normal sleep regimen is not possible. In a series of studies (Bonnet 1993; Bonnet et al., 1995; Horne and Reyner, 1996) the combination of a short nap and caffeine significantly de- creased driving impairment, subjective sleepiness, and drowsiness as measured by electroencephalogram (EEG) activity. The combination of a nap and caffeine also increased alertness during long periods of sleep deprivation compared to either caffeine or naps alone. Thus wherever possible commanders should in- corporate strategies that can provide short naps with the use of caffeine for maintaining vigilance, alertness, and other physiological and cognitive functions that are needed for sustained operations (SUSOPS). Placement of the nap as early as possible in the sleep deprivation period, followed by caffeine admini- stration during circadian troughs, would be most effective (Bonnet et al., 1995~. A number of potential alternatives to caffeine (other than sleep) for mainte- nance of cognitive performance were examined. The use of stimulants, other than caffeine, most frequently referred to in the scientific literature were the drugs pemoline, modafinil, and dextroamphetamine. Although methylphenidate, a drug very similar to amphetamine, is mentioned below, no studies were found in which it was used to enhance or maintain cognitive performance in normal, healthy individuals. Pemoline Pemoline is a central nervous system (CNS) stimulant structurally dissimi- lar from the amphetamines and methylphenidate. It is an oxizolidine compound with poor aqueous and lipid solubility. It is absorbed slowly from the gastroin- testinal tract and, in adults, reaches peak plasma concentrations within 2 to 4 hours of administration. The half-life is about 11 to 12 hours, and more than 90 percent of an oral dose is excreted in the urine, with 40 to 50 percent excreted as unchanged drug (Anonymous, 1992b; Sallee et al., 1992; Vermeulen et al.,

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SPECIAL CONSIDEMTIONS 71 1979~. Pemoline has a pharmacological activity similar to other CNS stimulants but with minimal sympathomimetic effects. Although the exact mechanism of action is not known, pemoline may act through dopaminergic mechanisms (Mo- lina and Orsinger, 1990; Nicholson and Pascoe, 1989~. Until around 1990 the prLmary indication for this drug was as a treatment for attention deficit disorder in children and adolescents. However, due to the consid- erable individual variation in onset and duration of action, its use was secondary to that of methylphenidate and d-amphetamine. Subsequently, it has also been evalu- ated for the treatment of narcolepsy and excessive daytime sleepiness (ED S). Since 1990 pemoline has been investigated, primarily by the British Royal Air Force, as a means of maintaining cognitive function during intensive and sustained military operations. Effects of pemoline on cognitive performance during 64 hours of sleep deprivation (Babkoffet al., 1992; Gomez et al., 1993) varied depending on the administration protocol. With single-dose administra- tion, pemoline improved performance on Matrix Pattern Recognition and a tapping test, but had no effect on the speed of reaction. However, on a mainte- nance protocol (pemoline administered every 12 hours during 64 hours of sleep deprivation), there was less effect on accuracy but a significant improvement in speed of response. Naitoh et al. (1992) compared the effects of prophylactic naps, no naps, pemoline (37.5 mg every 12 hours for a total dose of 200 lug), and placebo during a continuous 64-hour work period. Changes in performance were measured with a four-choice serial reaction time test. Significant benefits in counteracting fatigue and sleep loss were found both for naps and for pemo- line, with pemoline showing only a minimal loss in reaction time compared to the no-nap and placebo groups. Nicholson and Turner (1998) evaluated the effects of pemoline at doses of 10, 20, 30, and 40 mg on subjective alertness of volunteers during a 12-hour overnight work period, using a battery of cognitive function tests. A 6-hour prework sleep period and a 4-hour recovery sleep period were monitored. Pemoline significantly improved subject alertness and performance on all tasks except mental arithmetic and first basic reaction time compared with placebo. The first effects of pemoline were observed 4.5 hours after ingestion for the highest dose on digit symbol substitution and sustained attention reaction time. Positive effects of the lower doses were not seen until 6 hours postingestion, and maximal effects of the drug occurred 9 hours post-ingestion. Both the 30- and 40-mg doses impaired recovery sleep. Pemoline appears to have limited abuse or dependence potential. In animal studies, pemoline was not self-administered, either in naive or in cocaine- dependent animals (Larger et al., 1986~. However, an earlier study by Nicholson et al. (1980) found that 60 or 100 mg of pemoline significantly reduced sleep duration and percentage of rapid eye movement (REM) sleep, and increased the delay to the first REM period. Both doses shortened and fragmented sleep.

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72 CAFFEINE FOR MENTAL TASK PERFORMANCE Adverse effects that have been most frequently reported from the use of pemoline include hepatic dysfunction and dyskinetic movements of tongue, lips, face, and extremities. The onset of beneficial cognitive effects from pemoline is quite slow, ranging from 6 to 9 hours postingestion for 10-, 20-, and 30-mg doses. Higher doses have a more rapid onset but also interfere with recovery sleep. Plasma clearance rates are also relatively slow, with a half-life of 11-12 hours. In addi- tion, it is recommended that liver function tests be conducted prior to the use of pemoline because of potential side effects of the drug. Results published to date on aspects of cognitive performance improved by pemoline are confusing. Modafinil Modafinil is a benzhydrylsulfinylacetamide derivative first synthesized and produced in France in 1986 as a treatment for narcolepsy that would achieve alertness effects equivalent to those of amphetamine but without impairment of sleep. In the United States modafinil was designated as an orphan drug (for the treatment of EDS in patients with narcolepsy) in 1993. It was approved by FDA for this purpose in 1998, and is classified as a Schedule IV controlled substance (FDA, 1999~. Absorption of modafinil occurs at a rate similar to that of pemoline, with peak plasma concentrations occurring 2 - hours after oral administration and increasing linearly with doses from 200 to 600 ma. The extent of modafinil absorption was not significantly affected by the presence of food, but the rate of absorption was slightly reduced in fed versus fasted subjects (Moachon et al., 19969. Modafinil has low aqueous solubility and approximately 60 percent is bound to serum proteins, primarily albumin. It is metabolized extensively by the liver to inactive metabolites, modafinil acid (primary form), and modafinil sul- fone. The plasma half-life of modafinil after 7 days of dosing was 9-14 hours. Modafinil is excreted in the urine primarily as modafinil acid; only about 10 percent of the dose is excreted unchanged (Moachon et al., 1996~. The mechanism of action of modafinil has not been clearly established, but evidence suggests that it may indirectly increase wakefulness, at least in part, by decreasing gamma-aminobutyric acid-mediated neurotransmission (McClellan and Spencer, 1998), or increasing the secretion of the neuropeptide orexin (Che- melli et al., 1999~. Modafinil induces wakefulness and increases locomotor activ- ity in a variety of animal species without causing stereotyped behaviors (Herman" et al., 1991; Lin et al., 1992; Nicolaidis and De Saint Hilaire, 1993~. Evidence suggests that the site of action of modafinil differs from that of amphetamines and methylphenidate (tin et al., 1996), and studies in rats have indicated a po- tential mechanism of action for modafinil through Me stimulation of excitatory amino acids in the cerebral cortex (Pierard et al., 1995~. Edgar and Seidel (1997) compared the effects of equivalent doses of modafinil and amphetamine on

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SPECIAL CONSIDERATIONS 73 wakefulness and motor activity in rats and found that modafinil was equal to amphetamine in potently promoting wake time, but did not increase locomotor activity or produce rebound hypersorunolence. The authors concluded that the specificity of modafinil's wake-promoting effects further differentiated * from classical psychomotor stimulants such as amphetarn~ne and methylphenidate. In a study with cocaine stimulus-trained monkeys and rats, Gold and Balster (1996) evaluated the abuse potential of modafinil, using amphetamine and ephedrine as positive controls. In both rats and monkeys, modafinil did exhibit reinforcing and discriminative stimulus effects, but only at the highest doses tested (0.3 mg/kg). Modafinil was over 200 times less potent than amphetamine and was also less potent than ephedrine. Broughton and coworkers (1997) compared the effectiveness of placebo to 200 or 400 mg of modafinil in 75 patients meeting international diagnostic crite- ria for narcolepsy. Compared to placebo, modafinil significantly increased mean sleep latency, with no significant difference between the two doses. Modaf~nil also reduced the number of daytime sleep episodes and periods of severe sleepi- ness without interfering with nocturnal sleep initiation, maintenance, or archi- tecture. There were also no changes in blood pressure or heart rate in either norrnotensive or hypertensive patients. The 400-mg dose of modafinil was asso- ciated with increased reports of nausea and nervousness compared to placebo or the 200-mg dose. A number of studies have examined the effects of modafinil on cognitive performance and sleep recovery in sleep-deprived, but otherwise healthy, vol- unteers. Modafinil (300 ma) was as effective as 20 mg of dextroamphetamine in maintaining both subjective estimates of mood and fatigue and objective meas- ures of reaction time, logical reasoning, and short-term memory when adminis- tered three times during 64 hours of sleep deprivation (Pigeau et al., 19959. Effects on recovery sleep were also monitored in this study, and results indi- cated that the effects of amphetamine on recovery sleep were similar to those reported previously, with increased sleep latency, decreased total sleep time, decreased REM sleep, and reduced sleep efficiency. Results from the modafinil group exhibited decreased time in bed and sleep period time, with fewer sleep disturbances during the first night of recovery sleep compared to the ampheta- mine group. There was no effect of modafinil on REM sleep during the first night of recovery sleep, and the second night of recovery sleep did not differ from placebo. Thus, modafinil allowed sleep to occur, displayed sleep patterns close to placebo, and decreased the need for a long recovery sleep to compensate for total sleep deprivation (Buguet et al., 1995~. Stivalet et al. (1998) compared the effects of 300 mg of modafinil every 24 hours to placebo in healthy indi- viduals during 60 hours of sleep deprivation. This experiment used the visual search paradigm for assessing speed and accuracy in target detection. Rapid search rates remained unchanged for placebo and modafinil; however, slow search rates increased linearly in the placebo condition with increasing time

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74 CAFFEINE FOR MENTAL TASK PERFORMANCE without sleep, but remained the same as rested controls with modafinil. The number of errors also increased with placebo but remained the same for mo- dafinil. Batejat and Lagarde (1999) examined the effects of 200 mg of modafinil in conjunction with naps on performance during two 27-hour periods of sleep deprivation. The effects of modafinil on cognitive performance during sleep deprivation suggested the compound may act at two levels. First, modafinil maintains an efficient level of CNS general activation close to awakening, and second, it seems also to have a more specific action on neurophysiological mechanisms underlying short-term memory. As in previous studies, modafinil did not prevent sleep if sleep opportunities were available. Caldwell and coworkers (1999) recently reported on the use of modafinil in a helicopter simulator study with pilots exposed to two 40-hour periods of sleep deprivation. Three 200-mg doses of modafinil or placebo were administered dur- ing the 40-hour period. Modaf~nil significantly attenuated the effects of sleep deprivation on four of six flight maneuvers: straight and levels, straight descent, left standard-rate turns, and left descending sums, maintaining them at baseline levels. Modafinil also reduced the amount of slow-wave EEG activity (indicative of reduced CNS activation), lessened self-reported problems with mood and alert- ness, and curtailed the performance decrements that were found with placebo. According to these researchers, the most noticeable benefit of the drug was seen when the combined impact of sleep loss and circadian trough was most severe. As in other studies, no disruptions in recovery sleep architecture were observed. Compared with other well-known stimulatory substances such as caffeine and amphetamine, modafinil appears to have the advantage of combining wakening and stimulating properties, with an appreciable absence of unwanted side effects. Modafinil does appear to have some abuse potential at high doses, but it was 200 times less potent than amphetamines in this regard. Modafinil has been used as long as 3 years in the treatment of narcolepsy without signs of drug depend- ence. No toxic effects of high levels of modafinil have been observed in animals. A dose of 200 mg appears to be quite effective as a single dose for short pe- riods (24 hours) of no sleep or repeated at 12-hour intervals during long periods of sleep deprivation. Maximum effectiveness occurs about 4 hours postingestion and is most beneficial when modafinil is administered during circadian troughs. Amphetamine Amphetamines are sympathomimetic amines with CNS stimulant activity. CNS effects are mediated by release of norepinephrine from central noradrener- gic neurons. At higher doses, dopamine may be released in the mesolimbic sys- tem. Peripheral alpha- and beta-adrenergic activity includes elevation of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant activity.

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SPECIAL CONSIDERATIONS 75 Following oral administration, amphetamines are completely absorbed within 3 hours and widely distributed throughout the body with high concentra- tions in the brain. Peak plasma levels may occur within 2-3 hours, and maxi- mum effects are reported in the second hour (Angrist et al., 1987~. Amphetamine is metabolized in the liver by aromatic hydroxylation, N- dealkylation, and deamination. Urinary excretion of the unchanged drug is pH- dependent. Urinary acidification to pH below 5.6 yields a plasma half-life of 7-8 hours; alkalinization increases half-life (18-34 hours). For every one unit in- crease in urinary pH, there is an average 7-hour increase in plasma half-life (Anonymous, 1992a). Although the elimination half-life of amphetamines nor- mally exceeds 10 hours, its behavioral and subjective effects show a clear de- cline after 4 hours (Angrist et al., 1987~. Studies of the effects of amphetamines on human performance began over 60 years ago. Reviews of the effects of amphetamines on daytime alertness of well-rested subjects show conflicting results. Overall, well-rested individuals appear to benefit little from amphetamines (Spiegel, 1979~. In situations of reduced alertness (e.g., sleep deprivation, night work, sus- tained-attention tasks), amphetamines have proven to be potent in reversing or preventing performance decrements (Akerstedt and Ficca, 1997~. Newhouse et al. (1989) evaluated the effects of placebo, 5, 10, or 20 mg of d-amphetamine during 60 hours of sleep deprivation. The drug was administered 48 hours into the deprivation period, after which sleep latency, behavioral parameters, and cognitive performance were measured. The 20-mg dose returned sleep latency to baseline for 7 hours postadm~nistration. It also improved accuracy on attentional arithmetic tests and improved performance on verbal reasoning tasks. The lower doses were less effective. In extensive helicopter simulator and in-flight testing, 10 mg of d- amphetamine was observed by investigators (Caldwell and Caldwell, 1997; Caldwell et al., 1995, 2000) to "improve subjective feelings of fatigue, confu- sion, and depression while increasing feelings of vigor" compared to placebo during 40 hours of sleep deprivation. Amphetamine improved performance of flight maneuvers both in a flight simulator and in actual test flights. Performance was most noticeably improved in the early morning hours following 24 hours of sleep deprivation. Both EEG data and mood ratings showed that alertness was significantly maintained with amphetamine. In a comprehensive follow-up study, Caldwell et al. (2000) administered 10 mg d-amphetamine or placebo three times on each of two sleep-deprivation days (a total of 64 hours of sleep deprivation). Amphetamine sustained flight performance, physiological arousal, and mood throughout the 64-hour period. There were no clinically significant side effects attributable to amphetamine. Some of the aviators complained of palpitations and "jitteriness" with amphetamine, but this did not detract from their flight performance.

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76 CAFFEINE FOR MENTAL TASK PERFORMANCE In another study of 64 hours of sleep deprivation with 40 subjects in a con- tinuous work environment, 20 mg of d-amphetamine, administered on three occasions during the period, significantly improved objective measures of reac- tion time, logical reasoning, and short-term memory (Pigeau et al., 1995~. All of these studies have demonstrated serious impacts of amphetamine on recovery sleep. At least two uninterrupted 8-hour nights of recovery sleep were needed (Buguet et al., 1995; Caldwell et al., 2000~. Amphetamine reduces the amount of REM sleep and reduces sleep efficiency. Because of the powerful effects of low doses of amphetamine against sleep loss, the military has had considerable interest in the use of amphetamines in sustained operations. This interest is not new, however. Stimulants were used by both British and German aviators during World War II. Senechal (1988) reported on the use of amphetamine by British Royal Air Force pilots in connection with the Libyan air strike. Emonson and Vanderbeek (1995) reported on the incidence and effective- ness of amphetamine use by U.S. Air Force pilots during operations Desert Shield and Desert Storm. Both the U.S. Air Force (2001) and the U.S. Navy (2000) cur- rently have official memoranda and protocols in place that provide detailed guid- ance on the use of amphetamines by aviators during continuous operations. Amphetamine is a controlled substance and thus requires an individual medical evaluation to determine risk factors and health status before a prescrip- tion can be issued. Nevertheless, it is possible with appropriate supervision and control that amphetamine could show promise of providing benefits to individu- als with unique skills whose performance is critical to the safety of military personnel and complex military hardware. Amphetamines are very effective in maintaining alertness, cognitive per- formance, and mood during extended periods of sleep deprivation. These effects can be achieved at low doses (5-10 ma) where adverse side effects are minimal or nonexistent. The military has considerable experience in the use of this stimulant in combat operations, and both the Navy and the Air Force have pro- tocols for use already in place. To date, this use has been restricted to aviators during sustained flight operations. Amphetamine has a pronounced detrimental effect on recovery sleep that can last two or more nights. In contrast to caffeine in food, beverages, chewing gum, and pill or tablet form, most military personnel have little experience with amphetamine pill self-dosing and the hazards and adverse effects of self-dosing might therefore be expected to be greater. For all the armed services it would be preferable if maintenance of cognitive performance can be achieved without such substances. The potential for abuse of amphetamines is considerable, and appropriately monitoring its dispensing and use may add unnecessary burdens to personnel in the intense and demanding tasks that are directly involved in guar- anteeing the success of SUSOPS. Although amphetamine (10 or 20 ma) was more effective in reversing the negative effects of sleep deprivation on alertness

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SPECIAL CONSIDERATIONS 77 than caffeine at doses of 300 ma, it had deleterious effects on recovery sleep, which may also be important in the ultimate success of demanding and con- stantly changing SUSOPS (Bray et al., 1999~. Amphetamine should not be con- sidered a substitute for sleep, and more nights of recovery sleep are needed after its administration (Caldwell, 1999~. Therefore, considerable caution is war- ranted, and use of this stimulant should be restricted to only those extreme cir- cumstances when such measures are considered essential to the success of highly sensitive operations. The use of modafinil in place of amphetamines under these special circum- stances should be explored thoroughly. Research to date indicates that the po- tential for abuse of modafinil is considerably less than for amphetamines (about 200 times less), and modafinil does not affect initiation of recovery sleep. The committee recommends that modafinil receive more evaluation in simulated military operations before operational testing of the drug. Prescription drugs in the United States can be prescribed for off-label uses by physicians. In the case of modafinil, which is approved as a wakefulness- promoting drug, its use in healthy individuals as opposed to narcoleptics would be an off-label use. However, there is ample precedence for off-label use of drugs by military medical personnel, as in the limited prescription of dextroam- phetamine to pilots on long-range missions and the use of pyridostigmine bro- mide as a pretreatment to protect troops from the harmful effects of nerve agents during the Gulf War. SUMMARY Any program designed to provide caffeine to military personnel should al- low individual control of dosage and include an education and training compo- nent. Personnel should have the opportunity to experience the dose to be used in a nonoperational situation. Commanders should be advised of when caffeine use is appropriate as well as signs of adverse effects due to excessive dosing. Caf- feine-supplemented products should be clearly labeled as such, along with in- structions for use. Ethical considerations would include the question of forcing caffeine use when an individual has strong religious or health reasons for not doing so. Con- versely, denying access to caffeine for habituated users either for logistical rea- sons or in expectation of a subsequent need for a caffeine supplement could risk decrements in performance due to caffeine withdrawal. Alternatives to caffeine for maintaining cognitive performance include use of naps or prescription drugs. The prescription drugs that have been evaluated for use in healthy adults undergoing sleep deprivation are pemoline, ampheta- mine, and modafinil. Of these three compounds, modafinil and amphetamine have been shown to be superior to pemoline. Modafinil is as effective as am-

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78 CAFFEINE FOR MENTAL TASK PERFORMANCE phetamine, but does not interfere with recovery sleep and has significantly less potential for abuse.