Eur J Clin Pharmacol (1991) 41:217 223 European J ..... I of (~[~[]~(~@~

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© Springer-Verlag 1991

Effect of dexmedetomidine and midazolam on human performance and mood M. J. Mattila t' 2, M. E. Mattila 1, K. T. O l k k o l a 2, and H. Scheinin 3

1 Departments of Pharmacology and Toxicology 2 Department of Clinical Pharmacology, University of Helsinki, Helsinki and 3 Farmos Research Centre, Turku, Finland Received: October 16, 1990/Accepted in revised form: January 29, 1991

Summary. The effects of dexmedetomidine (DXM), a novel cz2-adrenoceptor agonist, on human performance and mood were studied in a double-blind randomized crossover study in 12 healthy student volunteers. Single IM doses of dexmedetomidine, 0.6 gg/kg (DXM1) and 1.2~tg/kg (DXM2), 80 gg/kg midazolam (MID) and saline placebo, were given at one-week intervals. Performance was measured objectively and mood was assessed subjectively with visual analogue scales (VAS) at baseline and 40 rain, 2 h, 4 h and 6 h after each injection. Blood pressure and heart rate in the sitting position were measured and venous blood was sampled during each testing round. DXM1 did not significantly impair cognitive (digit symbol substitution), coordinative (tracking) or reactive skills, and at 6 h it shortened reaction time and reduced errors in complex tracking. It produced exophoria, increased body sway with the eyes open and impaired subjective performance on VAS. The higher dose dexmedetomidine also caused impaired cognitive, coordinative and reactive skills (although a trend towards improved coordination was found at 6 h), reduced attention, produced exophoria, increased body sway with the eyes open and caused drowsiness, clumsiness, passiveness and mental slowness on the appropriate VAS scales. MID resembled DXM2 in impaired objective and subjective measures of skilled performance, although the objective effects of MID were of speedier onset and shorter duration. In contrast to MID, D X M caused a significant and dose-dependent decrease in systolic and diastolic blood pressure still detectable 6 h after injection. It is concluded that IM D X M produces dose related impairment of skilled performance and produces subjective sedation, the effects of 1.2 pg/kg being comparable to those produced by 80 gg/kg MID, although the latter lasted for a shorter period and were not associated with haemodynamic changes. Since the effect of D X M on performance waned earlier than its haemodynamic actions, D X M may constitute a suitable preanaesthetic medication, particularly in hypertension.

K e y words: Dexmedetomidine, Midazolam; H u m a n performance, o~2-adrenoceptor agonist

Medetomidine and its dextro isomer dexmedetomidine (DXM), are novel, specific and selective ~a-adrenoceptor agonists. Compared to clonidine, they are about 10-fold more selective and they are several times more potent in most pharmacological test models [Scheinin et al. 1987, 1989; Kallio et al. 1989]. They exhibit full c~;-agonist characteristics in the fish melanocyte test model [Karlsson 1988]. Clonidine has been well recognized as an antihypertensive agent, but several recent studies have documented its beneficial effect as a premedication for anaesthesia and surgery [Flacke et al. 1987; Ghignone et al. 1987]. The rapid and fairly short-lasting sedative effect of D X M renders it a candidate as a premedication suitable for daysurgery patients, but inadequate information is available about its post-injection psychomotor effects. The aim of the present trial was to investigate the psychomotor and cognitive effects of IM DXM in a set of laboratory tests well recognized to reveal the impairment of those skills [Mattila 1989]. Midazolam (MID) was selected as the positive control, since this benzodiazepine is widely used for anaesthetic premedication.

Material and m e t h o d s

Subjects Twelve student volunteers, 8 f and 4 m, aged 20-26 y and weighing 53-82 kg, were trained in the tests before entering the trial. They gave their written informed consent and were paid for their time. On examination they were physically healthy and mentally stable. They were non-smokers and did not regularly use drugs or medicines, or alcohol in excess. Clinical laboratory tests (haematology, electrolytes, renal and hepatic function, electroradiography) before and after the trial revealed no clinically significant change from the normal range. The trial protocol was approved by the Ethics Committee

218

M. J. Mattila et al.: Effects of dexmedetomidine and midazolam

Table 1. Effects of two doses of dexmedetomidine (DXM1 and DXM2) and midazolam (MID) on performance in certain objective tests. TESI refers to tracking error severity index Mean values of performances eatment

BL

40'

2h

4h

6h

Objective tests

Digit substituted~3 rain Placebo DXM 1 DXM 2 MID

149 145 146 146

77.39

10.63

146 141 1332 140 Ns

26.0 26.9 26.8 26.1

25.0 26.2 25.8 22.6 c~ 2.46

25.5 24.3 b 23.4 bx 24.6 ~ 2.96

25.5 24.8" 24.5 b 25.1 a Ns

24,8 25.4 25.4 a 25.5 Ns

32 27 30 27

27 35 69 cy 87__~y 16.53

30 35 56 by 3__3b~ 3.33

25 35 31 28 Ns

32 23 25 27 Ns

53.8 57.5 56.2 54.3

53.6 57.5 62.7 ~y 67.7 cya 18.61

54.1 57.5 62.6 "x 59.1 "~ 4.43

54.6 57.5 58.82 55.6 Ns

55,0 54,3 y 57,7 a 54,8 5.81

F drug

148 144 130 c~ 72 cy~

149 135" 112 ~y 116 by

146 147 148 148 Ns

Flicker fusion (Hz) Placebo DXM 1 DXM 2 MID F drug

TESI Placebo DXM 1 DXM 2 MID F drug

Reaction time (s) Placebo DXM 1 DXM 2 MID F drug

tion. The subjects were told to avoid and report the use of any medicine between the sessions, and not to drink alcohol on the day before the session. The absence of alcohol in the breath was confirmed at the beginning of each session with an Alcolmeter.

a.b and c refer to differences from baseline at 5%, 1% and 0.1% levels (paired t-test); x and y refer to differences from placebo, and c~ and 13to differences from DXM2 at the 5% and 1% levels, respectively (three-way A N O V A and Duncan's test)

of the Department of Pharmacology and Toxicology, University of Helsinki, Finland.

Trial design and drugs In this placebo-controlled, randomized, double-blind crossover study, single intramuscular injections (volume 2.0 ml) of 0.6 ~tg/kg (DXM1) and 1.2 gg/kg (DXM2) dexmedetomidine (Farmos Group Ltd, Finland), 80 gg/kg midazolam (MID) (Hoffmann-La Roche, Basel), and saline placebo were given into the lateral vastus muscle, in a balanced (Latin square) order, always by the same doctor. The doses of D X M were selected on results of another Phase I study in which 1.5 gg/kg induced profound sedation in healthy subjects (Farmos Group Ltd; data on file).

Testing procedure The test sessions were held on Sundays, at one-week intervals, beginning at 08.30 h with the baseline tests. All subjects were in the same group, and they started the test runs at 6 rain intervals. After the baseline tests the subject received the coded injections. Then the tests were repeated in the same order, starting 40 min, 2 h, 4 h and 6 h post injection. Each test run lasted for 25 min. Venous blood was sampled in heparinized vacuum tubes after each test run, and plasma was stored at - 20°C for the subsequent assay of midazolam and dexmedetomidine. In the first session, the baseline run was done twice, only the latter being recorded for the data analysis. A light standard lunch (two slices of bread and fruit juice) was served 3 h after injec-

Digit symbol substitution refers to the number of digits substituted by coded simple symbols in 3 rain; it includes both cognitive and manual components [Stone 1984]. Matched new charts were provided for each consecutive test run. The Maddox wing test [HanningtonKiff 1970] measures heterophoria (exophoria or esophoria) in dioptres. It measures the tone and coordination of extraocular muscles; a drug-induced change towards exophoria reveals relaxation of those muscles. Critical flicker fusion frequency refers to the sensitivity of visual cortex, and drug-induced changes reflect altered arousal states. It was done with the Leeds equipment using red light [Hindmarch 1982], and the mean value (Hz) of the fusion points recorded from the upwards and downwards measurements was taken to represent the critical flicker fusion frequency threshold. Body balance was measured on an electronic platform [Savolainen and Linnavuo 1979] connected to an Osborne AT microcomputer. Body sway was measured both with the eyes open and closed, each for 20 s. The movement of the centre of gravity was recorded as representing body sway and was used for data analysis. In the simulated driving test [Linnavuo et al. 1987] a computergenerated road is shown on a colour TV screen and the subject had to keep an alignment mark ("car") on the road by turning the steering-wheel. The test lasted for 5 rain. Its first half comprised simple tracking, and the second half comprised a choice reaction task with 60 balanced light and/or sound stimuli to be answered while tracking. The numbers of tracking errors and the error percentages (relative length of the track driven off the road) were recorded separately for both halves of the track. A tracking error severity index was computed to cover the entire track. The number of reaction errors and the cumulative reaction time were recorded for the second half of the track. Two different matched versions of the test program were used in alternate weeks. Divided attention test provided a supramaximal amount of information for handling while the response itself was simple. Briefly, there were four microcomputer screens, the lateral ones in the 120 ° view angle, each showing a ball moving along a circular obstacle course at different rates [Mattila et al. 1988]. Each time the ball entered an obstacle on any screen, the subject had to respond by pressing the corresponding button. Each screen had one obstacle of deviating shape, which had to be preferred in responding if more than one ball were entering obstacles of different shape. The obstacles changed their positions on screens at random every 10 s. The numbers and percentages of correct responses were recorded for 5 rain, separately for each screen, as well as for the two medial (2 + 3) and two lateral (1 + 4) screens together. Subjective tests Visual analogue scales (VAS) [Bond and Lader 1974] were used to assess drug effect on mood; the subject marked his position between the extremes on 100 mm horizontal lines. The pairs, written in Finnish and English, were: alert/drowsy; calm/excited; happy/sad; skilful clumsy; quick-witted/mentally slow; contented/discontented; active/passive; and good-bad performance. Other measurements The subjects reported side-effects in a 10-item questionnaire after each test run, each item being scored from 0 to 5. Systolic and diastolic blood pressure (BP) and heart rate (by palpation) were measured in the sitting position before blood sampling, at the end of each test run.

M. J. Mattila et al.: Effects of dexmedetomidine and midazolam

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Fig.la,b. Effects (mean values) of two doses (DXM1 "- -* and DXM2 ~---O) of dexmedetomidine, midazolam (-- ") and placebo (x--x) on extraocular muscle balance in the Maddox wing test (a); and on body balance with the eyes open (b). Increase of dioptres in the Maddox wing test (exophoria) refer to muscle relaxation. a (P < 0.05), b (P < 0.01) and c (P < 0.001) refer to changes from the baseline; x (P < 0.05) and y (P < 0.01) to differences from respective placebo; and * (P