The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation

Abstract

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation.VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28–47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2–24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11–30%), saccadic eye movements decreased by 9–10 percent (95% CI, 5–13%/6–15%) and body sway increased by 37 percent (95% CI, 5–79%). In contrast, EEG b₂-amplitudes declined significantly at night by 18 percent (95% CI, 6–29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These resultsemphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may notreflect sedation in a stricter sense. The motivation and alertnessnecessary for DSST may overcome mild sedation.

Keywords

electroencephalogram healthy volunteers psychomotor performance sedation sleep deprivation subjective effects

References

Bond A , Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47: 211–218

Borland R G , Nicholson A N (1974) Immediate effects on human performance ofa 1, 5-benzodiazepine (clobazam) compared with the 1, 4-benzodiazepines, chloraldiazepoxide hydrochloride and diazepam. Br J Clin Pharmac 2: 215–221

Buttner U , Boyle R , Markert G (1986) Cerebellar control of eye movements. Progr Brain Res 64: 225–233

Cohen A F , Posner J , Ashby L , Smith R , Peck AW (1984) A comparison of methods for assessing the sedative effects of diphenhydramine on skills related to car driving. Eur J Clin Pharmac 27: 477–482

Cohen A F , Ashby L , Crowley D , Land G , Peck AW (1985) Lamotrigine (BW 430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmac 20: 619–629

Cohen A F , Hamilton M J , Peck AW (1987) The effects of acrivastine(BW 825C), diphenhydramine and terfenadine in combination with alcohol onhuman CNS performance. Eur J Clin Pharmac 32: 279–288

Dietrich B (1997) Polysomnography in drug development. J Clin Pharmac 37: 70S–78S

Dingemanse J , Van Gerven J M A , Schoemaker R C , Roncari G , Oberyé J J L , Van Oostenbruggen M F , Massarella J , Segala P , Zell M , Cohen A F (1997) Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects. Br J Clin Pharmac 44: 477–486

Eckmiller R , Bauswein E . (1986) Smooth pursuit eye movements Progr Brain Res 64: 313–323

10.

Folkard S (1990) Circadian performance rhythms–some practical and theoretical implications. Phil Trans R Soc Lond, Biol Sci 327: 543–553

11.

Glenville M , Broughton R , Wing A M , Wilkinson R T (1978) Effects of sleep deprivation on short duration performance measures compared to the Wilkinson auditory vigilance task. Sleep 1: 169–176.

12.

Hamilton M J , Cohen A F , Yuen AWC , Harkin N , Land G , Weatherley B C et al.(1993) Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia 34: 166–173

13.

Herrmann W M , Abt K , Coppola R , Etevenon ET , Ferber G , Fink G et al. International Pharmaco-EEG Group (IPEG) (1989) Recommendations for EEG and evokedpotential mapping. Neuropsychobiology 22: 170–176

14.

Hommer DW , Matsuo V , Wolkowitz O , Chrousos G , Greenblatt D J , Weingarter H et al. (1986) Benzodiazepine sensitivity in normal human subjects. Archs Gen Psychiat 43: 542–551

15.

Horne JA (1978) A review of the biological effects of total sleep deprivation in man. Biol Psychol 7: 55–102

16.

Jasper HH (1958) Report of the Committee on Methods of Clinical Examinationin Electroencephalography. Electroencephalogr Clin Neurophysiol 10: 370–375

17.

Johnson L C , Chernik DA (1982) Sedative-hypnotics and human performance. Psychopharmacology 76: 101–113

18.

Kerkhof GA (1985) Inter-individual differences in the human circadian system: a review. Biol Psychol 20: 83–112

19.

Koelega H S (1989) Benzodiazepines and vigilance performance: a review. Psychopharmacology (Berlin) 98: 145–156

20.

Koslowsky M , Babkoff H (1992) Meta-analysis of the relationship between total sleep deprivation and performance. Chronobiol Int 9: 132–136

21.

Kramer M S (1981) Diffculties in assessing the adverse effects of drugs. Br J Clin Pharmac 11: 105S–110S

22.

Kunsman GW , Manno J E , Manno B R , Kunsman C M , Przekop M A (1992) The use of microcomputer-based psychomotor tests for the evaluation of benzodiazepine effects on human performance: a review with emphasis on temazepam. Br J Clin Pharmac 34: 289–301

23.

Monk T H (1989)Circadian rhythms in subjective activation, mood, and performance effciency. In Kryger M H , Roth T , Dement WC (eds), Principles and practice of sleep medicine. Saunders, Philadelphia, pp.163–172

24.

Norris H (1971) The action of sedatives on brain stem oculomotor systems inman. Neuropharmacology 10: 181–191

25.

O'Hanlon J F (1984) Driving performance under the influence of drugs: rationale for, and application of, a new test. Br J Clin Pharm 18: 121S–129S

26.

Oster G , Huse DM , Adams S F , Imbimbo J , Russell M W (1990)Benzodiazepine tranquilizers and the risk of accidental injury. Am J Pub Hlth 80: 1467–1470

27.

Ramaekers J G , Muntjewerff N D , O'Hanlon J F (1995) A comparative study of the acute and subchronic effects of dothiepin, fluoxetine and placebo on psychomotor and actual driving performance. Br J Clin Pharmac 39: 397–404

28.

Ray WA , Griffn M R , Schaffner W , Baugh DK , Melton L J (1987) Psychotropic drug use and the risk of hip fracture. N Engl J Med 316: 363–369

29.

Roehrs T , Roth T (1992) Multiple sleep latency test: technical aspects and normal values. J Clin Neurophysiol 9: 63–67

30.

Roth T , Roehrs T , Carskadon M , Dement W (1989) Daytime sleepiness and alertness. In Kryger M H , Roth T , Dement WC (eds), Principles and practice of sleep medicine. Saunders, Philadelphia, PA, pp.14–23

31.

SantamariaJ , Chiappa K H (1987) The EEG of drowsiness in normal adults. J Clin Neurophysiol 4: 327–382

32.

Schoemaker R C , Van Houwelingen HC (1994) Repeated measures for two within-subject factors; analysis and missing data solutions. J Biopharm Stat 4: 173–188

33.

Sellers E M , Busto U (1982) Benzodiazepines and ethanol: assessment of the effects and consequences of psychotropic drug interactions. J Clin Psychopharmac 2: 249–262

34.

Skegg D C , Richards S M , Doll R (1979) Minor tranquillisers and road accidents. Br Med J 1: 917–919

35.

Sorock G S , Shimkin E E (1988) Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. ArchsIntern Med 148: 2441–2444

36.

van Steveninck A L , Kroon J M , Schoemaker HC , Pieters M S M , Breimer D D , Cohen A F (1991) A study comparing the sensitivities of adaptive tracking, eye movement analysis and visual analogue lines to the effects of incremental doses of temazepam in healthy volunteers. Clin Pharmac Ther 50:172–180

37.

van Steveninck A L , Verver S , Schoemaker HC , Pieters M S M , Kroon J M , Breimer D D et al. (1992) Effects of temazepam on saccadic eye movements; concentration–effect relationships in individual volunteers. Clin Pharmac Ther 52: 402–408

38.

van Steveninck A L , Gieschke R , Schoemaker HC , Pieters M S M , Kroon J M , Breimer D D et al. (1993) Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state. Psychopharmacology 110: 471–478

39.

Wechsler D (1972) Wechsler's measurement and appraisal of adult intelligence, 5th edn. Oxford University Press, New York.

40.

Wittenborn J R (1979) Effects of benzodiazepines on psychomotor performance. Br J Clin Pharmac 7: 61S–67S

41.

Wright B M (1971) A simple mechanical ataxiameter. J Physiol 218: 27P–28P