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Modafinil as a Stimulant for Military Aviators

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Modafinil as a Stimulant for Military Aviators

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INTRODUCTION: Modafinil is a wakefulness-promoting stimulant that has been approved by the Republic of Singapore Air Force (RSAF) as a fatigue countermeasure medication since 2011. Each RSAF aircrew member must undergo a ground test to exclude operationally relevant adverse drug effects prior to consuming the medication for operational reasons. This study describes the RSAF's modafinil ground testing outcomes over a 7-yr period.METHODS: This is a retrospective case series of 243 RSAF aircrew members who underwent modafinil 100-mg test dosing over the 7-yr period from September 2011 to September 2018.RESULTS: The median age was 31 yr (range, 21-53 yr) and mean age was 31.7 yr ± 6.19 yr. Of the aircrew members, 234 (96.3%) were men and all were of Asian ethnicity. Of the subjects, 237 (97.5%) were medically cleared for the operational use of modafinil. Among the six (2.47%) who failed modafinil ground testing, headache (cumulative incidence, 1.65%), anxiety (cumulative incidence, 0.41%), diarrhea (cumulative incidence, 0.41%), and insomnia (cumulative incidence, 0.41%) were reported as the side effects experienced. None of the aircrew members experienced major adverse drug events.DISCUSSION: Our findings suggest a low occurrence of adverse drug effects among military aircrew members who undergo modafinil test dosing prior to using the drug operationally. To our knowledge, this is the single largest published case series of modafinil ground testing outcomes among Asian military aviators.Ooi T, Wong SH, See B. Modafinil as a stimulant for military aviators. Aerosp Med Hum Perform. 2019; 90(5):480-483.

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... Nine studies evaluated prevalence of use, perceptions about use, or reported side effects of at least one stimulant in military aviation (Belland & Bissell, 1994;Emonson & Vanderbeek, 1995;Gore et al., 2010;Kelley et al., 2018;Kenagy et al., 2004;Miller & Melfi, 2006;Ooi et al., 2019;Rosenberg & Caine, 2001;Schultz & Miller, 2004). One of these studies collected data from flight surgeon evaluations of pilots after flights (Kenagy et al., 2004). ...
... Retrospective questionnaires were used in seven studies (Belland & Bissell, 1994;Emonson & Vanderbeek, 1995;Gore et al., 2010;Kelley et al., 2018;Miller & Melfi, 2006;Rosenberg & Caine, 2001;Schultz & Miller, 2004), while Gore et al. (2010) also utilized pre-and post-flight questionnaires and data from postoperation evaluations. The final study reported results from mandatory ground testing of modafinil to determine if pilots were cleared for in-flight use (Ooi et al., 2019). ...
... Most participants were active-duty or reserve aviators from the U.S. military (Belland & Bissell, 1994;Emonson & Vanderbeek, 1995;Gore et al., 2010;Kelley et al., 2018;Kenagy et al., 2004;Miller & Melfi, 2006;Schultz & Miller, 2004). However, one study sent questionnaires to Israeli Air Force line commanders (Rosenberg & Caine, 2001) and another reported results from modafinil ground testing in Republic of Singapore Air Force pilots (Ooi et al., 2019). Five studies collected data from aircrew that were deployed or had recently been deployed (Belland & Bissell, 1994;Emonson & Vanderbeek, 1995;Gore et al., 2010;Kenagy et al., 2004;Schultz & Miller, 2004), while participants in the remaining studies were active-duty or reserve aviators not currently conducting combat operations (Kelley et al., 2018;Miller & Melfi, 2006;Ooi et al., 2019;Rosenberg & Caine, 2001). ...
Article
Objective: To synthesize the observational data on stimulant use in civilian and military aviation. Background: Pilot fatigue is a major safety concern and effective countermeasures are crucial for sustaining flight performance. Stimulants are not recommended for routine use but can help sustain alertness and flight performance when the risk of fatigue is high. However, they may also elicit side effects. It is important to fully understand the contexts in which stimulants are used, including factors that contribute to their use and how aviators perceive them. Methods: A systematic literature search was conducted to identify observational studies on stimulant use specific to aviation tasks. Results: Caffeine was frequently used in civilian aviation, though prevalence of use and perceptions about efficacy depend on task demands and individual caffeine responses. Stimulant use in military aviation was dependent on several operational factors, including the duration and timing of operations, recent hypnotic medication use, and whether other fatigue countermeasures could be utilized. Military aviators generally viewed stimulants as beneficial and side effects were sparse and mild-moderate with a few exceptions. Notably, most studies identified were published over 10 years ago. Conclusion: Stimulant use is relatively common in aviation and many (but not all) aviators perceive them as beneficial, though more studies should be conducted in the modern aviation environment. Major side effects were rare, with a few exceptions.
... However, military reports on modafinil applications remain rather rare. For instance, except a recent study by Ooi et al. 23 no study on modafinil in a military context has been published for the last 10 years certainly not outside a context of sleep deprivation. 24 Nevertheless, besides sleep deprivation 25 and an overall increased operational tempo, 26,27 mental fatigue among military personnel is becoming a pressing aspect of sustained operationality as well. ...
... 81 Hence, anxiety occurs-certainly in higher doses 82 -and the negative effects of modafinil may outweigh the cognitive benefit. 70 On a somatic level, the largest part of the reviewed studies did not investigate side effects, 42,[68][69][70][71][72][73][74]77,79,80,83,84 except for Ooi et al., 23 who examined side effects of 100 mg in military aviators. Ooi et al. followed 243 aircrew members (Republic of Singapore Air Force) for 7 years from 2011 to 2018 but only reported short-term effects. ...
... Ooi et al. followed 243 aircrew members (Republic of Singapore Air Force) for 7 years from 2011 to 2018 but only reported short-term effects. 23 In their study, only 2.5% of the exposed population reported side effects during ground testing (headache, anxiety, diarrhea, and insomnia), which was considered a counterindication for operational use. In other studies, side effects were reported to be absent 66,76,78 (100/200 mg) or minimal. ...
Article
Introduction: Modafinil is an eugeroic drug that has been examined to maintain or recover wakefulness, alertness, and cognitive performance when sleep deprived. In a nonmilitary context, the use of modafinil as a nootropic or smart drug, i.e., to improve cognitive performance without being sleep deprived, increases. Although cognitive performance is receiving more explicit attention in a military context, research into the impact of modafinil as a smart drug in function of operationality is lacking. Therefore, the current review aimed at presenting a current state-of-the-art and research agenda on modafinil as a smart drug. Beside the question whether modafinil has an effect or not on cognitive performance, we examined four research questions based on the knowledge on modafinil in sleep-deprived subjects: (1) Is there a difference between the effect of modafinil as a smart drug when administered in repeated doses versus one single dose?; (2) Is the effect of modafinil as a smart drug dose-dependent?; (3) Are there individual-related and/or task-related impact factors?; and (4) What are the reported mental and/or somatic side effects of modafinil as a smart drug? Method: We conducted a systematic search of the literature in the databases PubMed, Web of Science, and Scopus, using the search terms "Modafinil" and "Cognitive enhance*" in combination with specific terms related to the research questions. The inclusion criteria were studies on healthy human subjects with quantifiable cognitive outcome based on cognitive tasks. Results: We found no literature on the impact of a repeated intake of modafinil as a smart drug, although, in users, intake occurs on a regular basis. Moreover, although modafinil was initially said to comprise no risk for abuse, there are now indications that modafinil works on the same neurobiological mechanisms as other addictive stimulants. There is also no thorough research into a potential risk for overconfidence, whereas this risk was identified in sleep-deprived subjects. Furthermore, eventual enhancing effects were beneficial only in persons with an initial lower performance level and/or performing more difficult tasks and modafinil has an adverse effect when used under time pressure and may negatively impact physical performance. Finally, time-on-task may interact with the dose taken. Discussion: The use of modafinil as a smart drug should be examined in function of different military profiles considering their individual performance level and the task characteristics in terms of cognitive demands, physical demands, and sleep availability. It is not yet clear to what extent an improvement in one component (e.g., cognitive performance) may negatively affect another component (e.g., physical performance). Moreover, potential risks for abuse and overconfidence in both regular and occasional intake should be thoroughly investigated to depict the trade-off between user benefits and unwanted side effects. We identified that there is a current risk to the field, as this trade-off has been deemed acceptable for sleep-deprived subjects (considering the risk of sleep deprivation to performance) but this reasoning cannot and should not be readily transposed to non-sleep-deprived individuals. We thus conclude against the use of modafinil as a cognitive enhancer in military contexts that do not involve sleep deprivation.
... The adverse effects of modafinil seen in aviation studies seem to be very limited (Wesensten et al., 2002(Wesensten et al., , 2005Klopping et al., 2005;Killgore et al., 2008;Leduc et al., 2009). Ground testing of 100 mg modafinil in pilots of the Republic of Singapore Air Force found that 97.5% had no side effects, with the reported side effects being headache, anxiety, diarrhoea and insomnia (Ooi et al., 2019). However, the side effects of modafinil may be dose-related, as vertigo, nausea and dizziness were reported by most subjects after three doses of 200 mg modafinil (Caldwell et al., 2000a). ...
... Modafinil has been approved as an agent to counter fatigue by the air forces of Singapore, the United States, India and France (Ooi et al., 2019). A recent observational, retrospective analysis of flight records from tactical aircraft landings on a US Navy aircraft carrier showed that pilots took modafinil during 386 (33%) of the 1,154 sorties. ...
Article
Full-text available
Fatigue poses an important safety risk to civil and military aviation. In addition to decreasing performance in-flight (chronic) fatigue has negative long-term health effects. Possible causes of fatigue include sleep loss, extended time awake, circadian phase irregularities and work load. Despite regulations limiting flight time and enabling optimal rostering, fatigue cannot be prevented completely. Especially in military operations, where limits may be extended due to operational necessities, it is impossible to rely solely on regulations to prevent fatigue. Fatigue management, consisting of preventive strategies and operational countermeasures, such as pre-flight naps and pharmaceuticals that either promote adequate sleep (hypnotics or chronobiotics) or enhance performance (stimulants), may be required to mitigate fatigue in challenging (military) aviation operations. This review describes the pathophysiology, epidemiology and effects of fatigue and its impact on aviation, as well as several aspects of fatigue management and recommendations for future research in this field.
... On distingue deux catégories de substances: celles maintenant la vigilance : les psychostimulants. Les forces aériennes anglo-saxonnes ont fait le choix des « Go-pills » à base d'amphétamines, malgré les effets secondaires cardiovasculaires graves rapportées (24)(25)(26)(27). En France, le choix s'est porté sur la caféine à libération prolongée pour tout type de mission susceptible de générer une fatigue importante et le modafinil pour les situations de survie du PN. ...
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L’aviation militaire a connu une nette modification de ses missions avec l’extension des durées de vol et de leur élongation. La combinaison de l’amélioration des technologies et des performances de l’aéronef a engendré de nouvelles tactiques de combat et une fatigue opérationnelle du personnel navigant. Les substances modifiant la vigilance (caféine à libération prolongée et zolpidem) ont été utilisées lors des opérations aériennes continues « Harmattan » et « Serval ». Elles ont été à nouveau proposées aux PN lors de l’opération « Chammal ». Cet article est un retour d’expérience de la gestion de la fatigue opérationnelle et de l’utilisation de la caféine LP et du zolpidem.191 visites médicales ont permis d’étudier la gestion de la fatigue des PN (activité, sommeil, contre-mesures, aides pharmacologiques). Les résultats retrouvent un réel bénéfice de la caféine LP sur la vigilance, le maintien des performances et une très bonne tolérance
Article
A novel computationally designed-spectrofluorimetric method for the determination of a unique antinarcoleptic drug; modafinil (MDF) in tablets and human plasma was theoretically and experimentally established. Firstly, a density functional theory (DFT) computations were performed to investigate MDF-Tb3+ complex formation and to study the affinity of Tb3+ to MDF in aqueous solution. The computed formation energy of [Tb (MDF)4]3+ (ΔG= −246.0 kcal/mol) assured the ability of Tb3+ to recognize MDF in water and proved the strong nature of the Tb3+–O coordination bonds in addition to some contribution from inter-ligand hydrophobic interactions. Hence, a spectrofluorimetric method was optimized and validated depending on MDF quenching effect on Tb3+ fluorescence via fluorescence resonance energy transfer from Tb3+ to MDF. The formed [Tb (MDF)4]3+ complex was measured at λex. 222 nm/λem. 497 nm against a reagent blank. The Tb3+ fluorescence was significantly reduced upon addition of MDF (linearity range= 0.5–20.0 μg/mL). Detection and quantification limits were 0.129 and 0.391 μg/mL, respectively. Good recoveries (97.47–101.92%) were obtained upon application of the proposed method for the assessment of the target drug in bulk powder, tablets and plasma. According ICH guidelines, the results of the established method were statistically analyzed and validated.
Article
BACKGROUND: Modafinil, as a wake-promoting agent, is commonly used to relieve fatigue during military operations. However, there is a lack of clarity regarding the effects of modafinil on the equilibrium and vestibular organs, especially when prescribing this drug to flight crewmembers. The objective of this study was to evaluate the equilibrium- and vestibular-related safety effects of modafinil.METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 10 healthy male volunteers received a single 200-mg oral dose of modafinil or placebo. Equilibrium and vestibular functions were assessed 2 h after oral administration by the sensory organization test (SOT), adaptation test (ADT), and video head impulse test (v-HIT).RESULTS: There was no change in the equilibrium scores of the six SOT conditions or the composite scores between the modafinil and placebo groups. Statistically significant differences were not observed for the sway energy score (SES) in the toe-down test. In the toe-up test, the SES decreased by 16.7% in the modafinil group relative to the placebo group in trial 2, while the differences in other trials were not statistically significant. In the v-HIT, there was no significant difference in the gain of each semicircular canal between the two groups.DISCUSSION: A single 200-mg dose of modafinil did not cause any impairment to vestibular function, equilibrium ability, or adaptive balance response; in fact, modafinil might have a positive effect on adaptation function in healthy volunteers. These findings preliminarily suggest that there is no hidden risk of vestibular dysfunction among aviation employees using modafinil.Liu F, Zhang M, Chen T, Zhai L, Zhang Z, Xue J. Equilibrium and vestibular safety of modafinil in healthy volunteers. Aerosp Med Hum Perform. 2022; 93(6):487-492.
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Purpose: To optimize the usage of modafinil as a cognitive enhancer and increase safety and effectiveness, we sought to assess the trait-characteristic of modafinil-sensitivity. Methods: 11 healthy participants (age = 21 ± 2 yr) were tested on 2 separate occasions during which they were sleep deprived for one night. During one trial they received 2 × 200 mg modafinil (i.e. EXP); during the other they received 2 × a placebo-capsule (i.e. CON). Physiological (e.g. heart rate and blood pressure), subjective (e.g. sleepiness and mood state) and behavioral (e.g. psychomotor vigilance task) measures of sleep-wake regulation were followed up. Results: Both PVT performance and perceived sleepiness were significantly improved in EXP at 2AM and 4AM during the sleep deprivation-night, compared to in CON. Additionally, an ICC of 0.90 for the delta (CON – EXP) in non-adjusted reaction time was observed. Conclusion: Stable and robust interindividual differences in modafinil-sensitivity are clearly present across day and night.
Article
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