The Assessment of ‘Sleepiness’ in Human Drug Trials: A New Perspective

Author(s): Murray Johns* .

Journal Name: Current Psychopharmacology

Volume 8 , Issue 1 , 2019

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Abstract:

The investigation of the efficacy and safety of drugs requires assessments of their effects on alertness/sleepiness. Unfortunately, there is confusion about the nature of ‘sleepiness’, the factors which influence it, and how it can be measured under different circumstances. This review aims to clarify these matters and to offer some suggestions about how current difficulties might be overcome. Different meanings of the word ‘sleepiness’ are examined initially. Methods that purport to measure ‘sleepiness’ are then examined, including their testretest reliability and the relationship between the results of different measurements within the same subjects. Some objective methods are found not to be as reliable as was initially reported. Information about the reliability of several other methods is either inadequate or nonexistent. One assumption which underlies two frequently used objective methods for measuring ‘sleepiness’ (the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test) is that the ‘sleepier’ a person is, the quicker they will fall asleep. While this assumption has face validity, other assumptions about these tests are re-examined and are found wanting, at least sometimes. The difficulty arises in part because it is not always clear when the sleep onset process begins and ends. ‘Sleepiness’ is found to be influenced much more by short-term factors, such as the subject’s posture at the time and during the preceding few minutes, than has been acknowledged previously. Some possible solutions to these difficulties are suggested, including a new conceptual model of sleep-wake control, with implications for the design of drug trials.

Keywords: Sleepiness, alertness, drowsiness, sleep propensity, sleep-wake models, drug trials.

[1]
Broughton RJ, Fleming JAE, Genge CFP, et al. Morehouse. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurol 1997; 49: 444-51.
[2]
Ruoff C, Swick TJ, Doekel R, et al. Effect of oral JZP-110 (ADX-NO5) on wakefulness and sleepiness in adults with narcolepsy: A phase 2b study. Sleep 2016; 39: 1379-87.
[3]
Bogan RK, Feldman N, Emsellem HA, et al. Effect of oral JZP0110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med 2015; 16: 1102-8.
[4]
Roth T, Roehrs T, Koshorek G, Sicklesteel G, Zorick F. Sedative effects of antihistamines. J Allergy Clin Immunol 1987; 80: 94-8.
[5]
Tashiro M, Sakurada Y, Iwabuchi K, et al. Central effects of fexofenadine and cetirizine: Measurement of Psychomotor performance, subjective sleepiness, and brain histamine H1-recptor occupancy using 11 C-doxepin positron emission tomography. J Clin Pharmacol 2004; 33: 890-900.
[6]
Bliwise DL, Carskadon MA, Seidel WF, Nekich JC, Dement WC. MSLT-defined sleepiness and neuropsychological test performance do not correlate in the elderly. Neurobiol Age 1991; 12: 463-8.
[7]
Johns MW. A new perspective on sleepiness. Sleep Biol Rhythms 2010; 8: 170-9.
[8]
Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolspsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9: 789-95.
[9]
Plante DT, Finn LA, Hagen EW, Mignot E, Peppard PE. Subjective and objective measures of hypersomnolence demonstrate divergent associations with depression among participants in the Wisconsin Sleep Cohort study. J Clin Sleep Med 2016; 12: 571-8.
[10]
Carskadon MA, Dement WC. Daytime sleepiness: Quantification of a behavioral state. Neurosci Biobehav Rev 1987; 11: 307-17.
[11]
Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005; 28: 113-21.
[12]
Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the Epworth sleepiness scale: Failure of the MSLT as a gold standard. J Sleep Res 2000; 9: 5-11.
[13]
Thorpy MJ, Westbrook P, Ferber R, Fredrickson P. The clinical use of the Multiple Sleep Latency Test. Sleep 1992; 15: 268-76.
[14]
Mitler MM, Gujavarty KS, Browman CP. Maintenenace of wakefulness test: A polysomnographic technique for evaluation of treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 1982; 53: 659-61.
[15]
Arzi L, Shreter R, El-Ad B, Peled R, Pillar G. Forty- versus 20-minte trials of the Maintenance of Wakefulness test regimen for licensing of drivers. J Clin Sleep Med 2009; 5: 57-62.
[16]
Luce RD. Response times. New York: Oxford University Press 1986.
[17]
Dinges DF, Kribbs NB. Performing while sleepy: Effects of experimentally induced sleepiness. In: Timothy H Monk, Ed. Sleep, Sleepiness and Performance. New Jersey: Wiley 1991; pp. 97-128.
[18]
Dorrian J, Rogers NL, Dinges DF. Psychomotor vigilance performance: Neurocognitive assay sensitive to sleep loss. In: C.A. Kushida, Marcel Dekker, Ed. Sleep Deprivation. Clinical Issues, Pharmacology, and Sleep Loss Effects. New York: Taylor & Francis 2005; pp. 39-70.
[19]
Mackworth NH. The breakdown of vigilance during prolonged visual search. Q J Exp Psychol 1948; 1: 6-21.
[20]
Shattuck NL, Matsangas P. Psychomotor vigilance performance predicted by Epworth Sleepiness Scale scores in an operational setting with the United States Navy. J Sleep Res 2015; 24: 174-80.
[21]
Williamson AM, Feyer A-M. Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication. Occup Environ Med 2000; 57: 649-55.
[22]
Sauter C, Danker-Hopfe H, Loretz E, Zeitlhofer J, Geisler P, Popp R. The assessment of vigilance: Normative data on the Siesta sustained attention test. Sleep Med 2013; 14: 542-8.
[23]
Lichstein KL, Tiedel BW, Richman SL. The Mackworth Clock Test: A computerized version. J Psychol 2000; 134: 153-61.
[24]
Michael N, Johns M, Owen C, Patterson J. Effects of caffeine on alertness as measured by infrared reflectance oculography. Psychopharmacol 2008; 200: 255-60.
[25]
Johns MW, Crowley K, Chapman R, Tucker A, Hocking C. The effects of blinks and saccadic eye movements on visual reaction-times. Atten Percept Psychophys 2008; 71: 783-8.
[26]
Wilkinson RT, Houghton D. Field test of arousal: A portable reaction timer with data storage. Hum Factors 1982; 24: 487-93.
[27]
Dinges DF, Powell JW. Miscrocomputer analysis of performance on a portable, visual RT task during sustained operations. Behav Res Methods Instrum Comput 1985; 17: 652-5.
[28]
Wilkinson RT. Interaction of lack of sleep with knowledge of results, repeated testing, and individual differences. J Exp Psychol 1961; 26: 263-71.
[29]
Balkin TJ, Bliese PD, Belenky G, et al. Comparative utility of instruments for monitoring sleep-related performance decrements in the operational environment. J Sleep Res 2004; 13: 219-27.
[30]
Wilkinson RT, Houghton D. Portable four-choice reaction time test with magnetic tape memory. Behav Res Meth Instrum 1975; 7: 441-6.
[31]
Lim J, Dinges DF. A meta-analysis of the impact of short-term sleep deprivation on cognitive variables. Psychol Bull 2010; 136: 375-89.
[32]
Jongen S, Vuurman E, Ramaekers J, Vermeeren A. Alcohol calibration of tests measuring skills related to car driving. Psychopharmacol 2014; 231: 2435-47.
[33]
Jongen S, Perrier J, Vuurman EF, Raemaekers JG. Sensitivity and validity of psychometric tests for assessing driving impairment: Effects of sleep deprivation. PLoS One 2015; 10(2): e0117045.
[34]
Zoethout RWM, Delgado WL, Ippel AE, Dahan A, van Gerven JMA. Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers. Br J Clin Pharmacol 2011; 73: 331-50.
[35]
Verster JC, Roth T. Predicting psychopharmacological drug effects on actual driving performance (SDLP) from psychometric tests measuring driving-related skills. Psychopharmacol 2012; 220: 293-301.
[36]
Louca M, Short MA. The effect of one night’s sleep deprivation on adolescent neurobehavioral performance. Sleep 2014; 37: 1799-807.
[37]
Peiris MTR, Jones RD, Daivson PR, Carroll GJ, Bones PJ. Frequent lapses of responsiveness during an extended visuomotor tracking task in non-sleep-deprived subjects. J Sleep Res 2006; 15: 291-300.
[38]
Jackson ML, Kennedy GA, Clarke C, et al. The utility of automated measures of ocular metrics for detecting driver drowsiness during extended wakefulness. Accid Anal Prev 2016; 87: 127-33.
[39]
Anund AA, Kecklund G, Peters B, Forsman A, Lowden A, Akerstedt T. Driver impairment at night and its relation to physiological sleepiness. Scand J Work Environ Health 2008; 34: 142-50.
[40]
Alvaro PK, Jackson ML, Berlowitz DJ, Swann P, Howard ME. Prolonged eyelid closure episodes during sleep deprivation in professional drivers. J Clin Sleep Med 2016; 12: 1099-103.
[41]
Bentivoglio AR, Bressman SB, Cassetta E, Carretta D, Tonali P, Albenese A. Analysis of blink rate patterns in normal subjects. Mov Disord 1997; 12: 1028-34.
[42]
Monster AW, Chan HC, O’Connor D. Long-term trends in human eye blink rate. Biotelem Patient Monit 1975; 5: 206-22.
[43]
Evinger C, Manning KA, Sibony PA. Eyelid movements. mechanisms and normal data. Invest Ophthalmol Vis Sci 1991; 32: 387-400.
[44]
Bour LJ, Aramideh M, Ongerboer de Visser BW. Neurophysiological aspects of eye and eyelid movements during blinks in humans. J Neurophysiol 2000; 83: 166-76.
[45]
Van der Werf F, Brassinga P, Reits D, Aramideh M. Ongerboer de Visser B. Eyelid movements: bahavioral studies of blinking under different stimulus conditions. J Neurophysiol 2003; 89: 2784-96.
[46]
Caffier PP, Erdmann U, Ullsperger P. Experimental evaluation of eye-blink parameters as a drowsiness measure. Eur J Appl Physiol 2003; 89: 319-25.
[47]
Johns MW, Tucker A, Chapman R, Crowley K, Michael NJ. Monitoring eye and eyelid movements by infrared reflectance oculography to measure drowsiness in drivers. Somnologie 2007; 11: 234-42.
[48]
Anderson C, Chang A-M, Sullivan JP, Ronda JM, Czeisler CA. Assessment of drowsiness based on ocular parameters detected by infrared reflectance oculography. J Clin Sleep Med 2013; 9: 907-20.
[49]
Ftouni S, Sletten TL, Howard M, et al. Objective and subjective measures of sleepiness, and their associations with on-road driving events in shift workers. J Sleep Res 2013; 22: 58-69.
[50]
Bahill AT, Clark MR, Stark L. The main sequence. A tool for studying human eye movements. Math Biosci 1975; 24: 191-204.
[51]
Johns MW. The amplitude-velocity ratio of blinks: A new method for monitoring drowsiness. Sleep 2003; 26(Suppl.): A51-2.
[52]
Ingre M, Åkerstedt T, Peters B, Anund A, Kecklund G, Pickles A. Subjective sleepiness and accident risk avoiding the ecological fallacy. J Sleep Res 2006; 15: 142-8.
[53]
Wierwille WW, Ellsworth LA. Evaluation of driver drowsiness by trained raters. Accid Anal Prev 1994; 26: 571-81.
[54]
Dinges DF, Mallis MM, Maslin G, Powell JW. Evaluation of techniques for ocular measurement as an index of fatigue and the basis for alertness management DOT HS 808 762. US Department of Transportation, National Highway Safety Administration Washington, DC 1998.
[55]
Johns MW, Chapman R, Crowley K, Tucker A. A new method for assessing the risks of drowsiness while driving. Somnol 2008; 12: 66-74.
[56]
Wilkinson VE, Jackson ML, Westlake J, et al. The accuracy of eyelid movement parameters for drowsiness detection. J Clin Sleep Med 2013; 9: 1315-24.
[57]
Lee ML, Howard ME, Horrey WJ, et al. High risk of near-crash driving events following night-shift work. Proc Nat Acad Sci 2016; 113: 176-81.
[58]
Aidman E, Johnson K, Paech GM, et al. Caffeine reduces the impact of drowsiness on driving errors. Tansp Res Pt F 2018; 54: 236-67.
[59]
Akerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J Neurosci 1990; 52: 29-37.
[60]
Kaida K, Takahashi M, Akerstedt T, et al. Validation of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol 2006; 117: 1574-81.
[61]
Jung T, Makeig S, Stensmo M, Sejnowski T. Estimating alertness from the EEG power spectrum. IEEE Trans Biomed Eng 1997; 44: 60-9.
[62]
Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep 1991; 14: 540-5.
[63]
Parkes JD, Chen SY, Clift SJ, Dahlitz MT, Dunn G. The clinical diagnosis of the narcoleptic syndrome. J Sleep Res 1998; 7: 41-52.
[64]
Whitney CW, Enright PL, Newman AB, Bonekat W, Quan SF. Correlates of daytime sleepiness in 4578 elderly persons: the cardiovascular health study. Sleep 1998; 21: 27-36.
[65]
Killgore WDS, Vanuk JR, Knight SA, et al. Daytime sleepiness is associated with altered resting thalamocortical connectivity. Neurorep 2015; 26: 779-84.
[66]
Johns MW, Hocking B. Daytime sleepiness and sleep habits of Australian workers. Sleep 1997; 20: 844-9.
[67]
Scrima L, Emsellem HA, Becker PM, et al. Identifying clinically important differences on the Epworth Sleepiness Scale: Results from a narcolepsy clinical trial of JZP-110. Sleep Med 2017; 38: 108-12.
[68]
Erman M, Emsellm H, Black J, Mori F, Mayer G. Correlation between the Epworth Sleepiness Scale and the maintenance of Wakefulness Test in patients with narcolepsy participating in two clinical trials of sodium oxybate. Sleep Med 2017; 38: 92-5.
[69]
Reyner LA, Horne JA. Falling asleep whilst driving: Are drivers aware of prior sleepiness? Int J Legal Med 1998; 111: 120-3.
[70]
Hoddes E, Dement WC, Zarcone V. The development and use of the Stanford Sleepiness Scale (SSS). Psychophysiol 1973; 10: 431-6.
[71]
Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep 2001; 25: 268-76.
[72]
Pilcher JJ, Pury CL, Muth ER. Assessing subjective daytime sleepiness: an internal state versus behaviour approach. Behav Med 2003; 29: 60-7.
[73]
Zwyghuizen-Doorenbos A, Roehrs T, Schafer M, Roth T. Test-retest reliability of the MSLT. Sleep 1998; 16: 562-5.
[74]
Goldbart A, Peppard P, Finn L, et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. Sleep 2014; 37: 1043-51.
[75]
Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992; 15: 376-81.
[76]
Knutson KL, Rathouz PJ, Jan LL, Liu K, Lauderdale DS. Stability of the Pittsburgh sleep quality index and the Epworth sleepiness questionnaires over 1 year in early middle-aged adults: the CARDIA study. Sleep 2006; 29: 1503-6.
[77]
Nguyen ATD, Baltzan MA, Small D, Wolkove N, Guillon S, Palayew M. Clinical reproducibility of the Epworth Sleepiness Scale. J Clin Sleep Med 2006; 2: 170-4.
[78]
Sangal RB, Thomas L, Mitler MM. Maintenance of wakefulness test and multiple sleep latency test. Measurement of different abilities in patients with sleep disorders. Chest 1992; 101: 898-902.
[79]
Harrison Y, Horne JA. High sleepability without sleepiness. The ability to fall asleep rapidly without other signs of sleepiness. Neurophysiol Clin 1996; 26: 15-20.
[80]
Trotti LM. Another strike against sleepability. J Clin Sleep Med 2016; 12: 467-8.
[81]
Johns MW. Sleep propensity varies with behaviour and the situation in which it is measured: the concept of somnificity. J Sleep Res 2002; 11: 61-7.
[82]
Kleitman N. Sleep and Wakefulness. Chicago: University of Chicago Press 1963; pp. 220-1.
[83]
Caldwell JA, Prazinko B, Caldwell JL. Body posture affects electroencephalographic activity and psychomotor vigilance task performance in sleep-deprived subjects. Clin Neurophysiol 2003; 14: 23-31.
[84]
Bonnet MH, Arand DL. Sleepiness as measured by the MSLT varies as a function of preceding activity. Sleep 1998; 21: 477-83.
[85]
Wuyts J, De Valck E, Vandekerckhove M, et al. The influence of pre-sleep cognitive arousal on sleep onset processes. Int J Psychophysiol 2012; 83: 8-15.
[86]
Agnew HW Jr, Webb WB, Williams RL. The first-night effect: An EEG study of sleep. Phychophysiology 1966; 2: 263-6.
[87]
Bonnet MH, Arand DL. Impact of motivation on Multiple Sleep Latency Test and Maintenance of Wakefulness Test measurements. J Clin Sleep Med 2005; 1: 386-90.
[88]
Raichle ME. The brain’s default mode network. Annu Rev Neurosci 2015; 38: 433-47.
[89]
Weissman DH, Roberts KC, Visscher KM, Woldorff MG. The neural basis of momentary lapses in attention. Nat Neurosci 2006; 9: 971-8.
[90]
Grier RA, Warm JS, Dember WN, Matthews G, Galinsky TL, Parasuraman R. The vigilance decrement reflects limitations in effortful attention, not mindlessness. Hum Factors 2003; 45: 349-59.
[91]
De Havas JA, Parimal S, Soon CS, Chee MWL. Sleep deprivation reduces default mode network connectivity and anti-correlation during rest and task performance. Neuroimage 2012; 59: 1745-51.
[92]
Ward AM, McLaren DG, Schulz AP, et al. Daytime sleepiness is associated with decreased default mode network connectivity in both young and cognitively intact elderly subjects. Sleep 2013; 36: 1609-15.
[93]
Doran SM, Van Dongen HP, Dinges DF. Sustained attention performance during sleep deprivation: Evidence of state instability. Arch Ital Biol 2001; 139: 253-67.
[94]
Tirunahan VL, Zaidi SA, Sharma R, Skumick J, Ashtyan H. Microsleep and sleepiness: A comparison of multiple sleep latency test and scoring of microsleep as a diagnostic test of excessive daytime sleepiness. Sleep Med 2003; 4: 63-7.
[95]
Pizza F, Vandi S, Detto S, et al. Different sleep onset criteria at the multiple sleep latency test (MSLT): An additional marker to differentiate Central Nervous (CNS) hypersomnias. J Sleep Res 2011; 20: 250-6.
[96]
Achermann P, Borbély AA. Mathematical models of sleep regulation. Front Biosci 2003; 8: 683-93.
[97]
Borbély AA. A two-process model of sleep regulation. Hum Neurobiol 1982; 1: 195-204.
[98]
Saper CB, Chou TC, Scammell TE. The sleep switch: Hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24: 726-31.
[99]
Cajochen C. Alerting effects of light. Sleep Med Rev 2007; 11: 453-64.
[100]
Zeitzer JM, Dijk DJ, Kronauer RE, Brown EN, Czeisler CA. Sensitivity of the human circadian pacemaker to nocturnal light: Melatonin phase resetting and suppression. J Physiol 2000; 526: 695-702.
[101]
Siegal JM, Boehmer LN. Narcolepsy and the hypocretin system - where motion meets emotion. Nat Rev Neurol 2006; 2: 548-56.
[102]
Saper CB, Cano G, Scammell TE. Homeostatic, circadian, and emotional regulation of sleep. J Comp Neurol 2005; 493: 92-8.
[103]
George PT. The psycho-sensory wakedrive - a power source for power naps and other common sleep-wake phenomena: A hypothesis. Sleep Breath 2018; 22(1): 41-8.
[104]
Vallbo Å. Basic patterns of muscle spindle discharge in man In: Taylor A, Prochazka A, Eds Muscle Receptors and Movement London: Palgrave Macmillan 1981; pp 263-75
[105]
Jones BE. From waking to sleeping: neuronal and chemical substrates. Trends Pharmacol Sci 2005; 26: 578-86.
[106]
Cole RJ. Postural baroreflex stimuli may affect EEG arousal and sleep in humans. J Appl Physiol 1989; 67: 2369-75.
[107]
Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-wake cycle. J Neurosci 2005; 25: 6716-20.
[108]
Davranche K, Audiffren M, Denjean A. A distributional analysis of the effect of physical exercise on a choice reaction time task. J Sports Sci 2006; 24: 323-9.
[109]
Eggermann E, Serafin M, Bayer L, et al. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neurosci 2001; 108: 77-181.
[110]
Kennard DW, Smyth GL. Reflex regulation of the upper eyelids, with observations on the onset of sleep. J Physiol 1963; 166: 168-77.
[111]
Cantero JL, Atienza M, Stickgold R, Hobson JA. Nightcap: A reliable system for determining sleep onset latency. Sleep 2002; 25: 238-45.


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VOLUME: 8
ISSUE: 1
Year: 2019
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DOI: 10.2174/2211556007666180503170231
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