Ready for takeoff? A critical review of armodafinil and modafinil for the treatment of sleepiness associated with jet lag

Figures & data

Box 1 Factors contributing to sleep deprivation in transmeridian travelers

Disrupted/shortened sleep on travel days

Early rise time on day of journey

“Red eye” flights

Late arrival time at destination

Disrupted or shortened nocturnal sleep at destination

Unfamiliar or uncomfortable accommodations

Physical symptoms (eg, pain, nocturnal defecation)

Social or work responsibilities

Table 1 Treatment strategies for management of jet lag syndrome (JLS)

Strategy	Desired outcomes	Interventions used	Summary of evidence	Selected references
Enable better quality nocturnal sleep to prevent symptoms of sleep deprivation	Improve quality of nocturnal sleep; improve quality of daytime alertness	Benzodiazepines, benzodiazepine receptor agonists, melatonin	May improve sleep quality and duration. No convincing data to suggest improved daytime functioning. Potential benefits must be balanced with potential for harm	Paul^Citation27 Suhner^Citation28
Shift circadian phase	Speed transition to destination circadian cycle; improve quality of nocturnal sleep; improve quality of daytime alertness	Chronobiotic agents (eg, melatonin); light therapy; pre-travel chronotherapy	Melatonin improves sleep quality and may help accelerate phase-shifting in both eastward and westward travel. Optimum dose not known, but 0.5–5 mg has been used and immediate-release likely better than slow release; risk of treatment low. Care must be taken in timing of the dose, as phase advance or phase delay may result. Gradual pre-travel adjustment of the sleep–wake cycle using a combination of bright light exposure and gradual advancement of bedtime may be of benefit for phase shifting and may decrease daytime JLS symptoms in eastbound travelers	Petrie^Citation29 Petrie^Citation30 Suhner^Citation31 Burgess^Citation7 Boulos^Citation32 Paul^Citation33
Maintain circadian phase to point of origin	Allow continuation of innate rhythms to avoid discomfort of rhythm changes	Maintain schedule and sleeping habits on “home clock”	Keeping home based hours may decrease sleepiness and daytime JLS symptoms. Recommended trips lasting ≤2 days	Lowden^Citation17
Alerting agents	Improve quality of daytime alertness, preventing daytime naps may allow better nocturnal sleep consolidation	Over the counter stimulants (caffeine); traditional prescription stimulants: (methylphenidate, dextroamphetamine, others); non-traditional prescription stimulants (modafinil, armodafinil)	Caffeine 300 mg taken as a slow-release formulation may decrease daytime sleepiness, but nocturnal sleep may suffer. No peer-reviewed data are available for other alerting agents in managing daytime sleepiness in JLS	Beaumont^Citation18 Pierard^Citation19
Supportive measures and behavioral counseling	Decrease physical discomfort, thus improving nighttime sleep and daytime functioning	Avoid excessive alcohol or nocturnal caffeine, avoid large high-fat meals during atypical eating times, drink plenty of water, wear comfortable traveling clothes, avoid nocturnal travel if possible	No rigorous controlled studies. Because these elements may play a role in JLS symptoms, all patients should be counseled appropriately	Arendt^Citation34

Table 2 Comparison of efficacy of modafinil vs armodafinil for treatment of excessive daytime sleepiness associated with narcolepsy

Trial	Intervention	Mean MWT	Δ from Placebo	Notes
US Modafinil in narcolepsy multicenter group^Citation56	Placebo	5.1 min	n/a	20 minute MWT test done. Data reported are from 9 week follow-up testing
	Modafinil 200 mg	8.1 min	+3 min
	Modafinil 400 mg	8.9 min	+3.8 min
Broughton et al^Citation57	Placebo	11.2 min	n/a	40 minute MWT test done. Data reported are following 2 weeks on medication
	Modafinil 200 mg	15.7 min	+4.5 min
	Modafinil 400 mg	17.2 min	+6 min
Harsh et al^Citation58	Placebo	10.6 min	n/a	20 minute MWT test done. Data reported are from 12-week follow up testing
	Armodafinil 150 mg	13.4 min	+2.8 min
	Armodafinil 250 mg	12.1 min	+1.5 min

Abbreviation: MWT, maintenance of wakefulness test.

Table 3 Comparison of efficacy of modafinil vs armodafinil for the treatment of residual excessive daytime somnolence in continuous positive airway pressure-compliant patients with obstructive sleep apnea

Trial	Intervention	Mean MWT	Δ from Placebo	Notes
Black et al^Citation62	Placebo	12.65 min^a	n/a	20 minute MWT test done. Data reported are from 12 week follow up testing
	Modafinil 200 mg	14.85 min^a	+2.2 min
	Modafinil 400 mg	15.1 min^a	+2.45 min
Hirshkowitz et al^Citation38	Placebo	21.7 min^a	n/a	40 minute MWT test done. Data reported are from 12 week follow up testing
	Armodafinil 150 mg	26.4 min^a	+4.7 min

Abbreviation: MWT, maintenance of wakefulness test.

a Calculated from values estimated from graphic.

PaulMAGrayGSardanaTMPigeauRAMelatonin and zopiclone as facilitators of early circadian sleep in operational air transport crewsAviat Space Environ Med20047543944315152897

 PubMed Web of Science ®Google Scholar

SuhnerASchlagenhaufPHoferIJohnsonRTschoppASteffenREffectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lagAviat Space Environ Med20017263864611471907

 PubMedGoogle Scholar

PetrieKConaglenJVThompsonLChamberlainKEffect of melatonin on jet lag after long haul flightsBMJ19892987057072496815

 PubMed Web of Science ®Google Scholar

PetrieKDawsonAGThompsonLBrookRA double-blind trial of melatonin as a treatment for jet lag in international cabin crewBiol Psychiatry1993335265308513037

 PubMed Web of Science ®Google Scholar

SuhnerASchlagenhaufPJohnsonRTschoppASteffenRComparative study to determine the optimal melatonin dosage form for the alleviation of jet lagChronobiol Int1998156556669844753

 PubMed Web of Science ®Google Scholar

BurgessHJCrowleySJGazdaCJFoggLFEastmanCIPreflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright lightJ Biol Rhythms20031831832812932084

 PubMed Web of Science ®Google Scholar

BoulosZMacchiMMSturchlerMPLight visor treatment for jet lag after westward travel across six time zonesAviat Space Environ Med20027395396312398256

 PubMedGoogle Scholar

PaulMAMillerJCLoveRJTiming light treatment for eastward and westward travel preparationChronobiol Int20092686789019637048

 PubMed Web of Science ®Google Scholar

LowdenAAkerstedtTRetaining home-base sleep hours to prevent jet lag in connection with a westward flight across nine time zonesChronobiol Int1998153653769706413

 PubMed Web of Science ®Google Scholar

BeaumontMBatejatDPierardCCaffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travelJ Appl Physiol200496505812959951

 PubMed Web of Science ®Google Scholar

PierardCBeaumontMEnslenMResynchronization of hormonal rhythms after an eastbound flight in humans: effects of slow-release caffeine and melatoninEur J Appl Physiol20018514415011513308

 PubMed Web of Science ®Google Scholar

ArendtJSBSkeneDJSleep disruption in jet lag and other circadian rhythm-related disordersThomasKryger MHRDementWilliam CPrinciples and Practice of Sleep MedicinePhiladelphia, PAElsevier2005659672

 Google Scholar

US Modafinil in Narcolepsy Multicenter Study GroupRandomized trial of modafinil for the treatment of pathological somnolence in narcolepsyAnn Neurol19984388979450772

 PubMed Web of Science ®Google Scholar

BroughtonRJFlemingJAGeorgeCFRandomized, doubleblind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsyNeurology1997494444519270575

 PubMed Web of Science ®Google Scholar

HarshJRHaydukRRosenbergRThe efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsyCurr Med Res Opin20062276177416684437

 PubMed Web of Science ®Google Scholar

BlackJEHirshkowitzMModafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndromeSleep20052846447116171291

 PubMed Web of Science ®Google Scholar

HirshkowitzMBlackJEWesnesKNieblerGAroraSRothTAdjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndromeRespir Med200710161662716908126

 PubMed Web of Science ®Google Scholar