British Journal of Anaesthesia 1991; 67: 579-584
ALCOHOL AFTER SEDATION WITH I.V.
MIDAZOLAM-FENTANYL: EFFECTS ON PSYCHOMOTOR
FUNCTIONING!
J. L. LICHTOR, J. ZACNY, J. L. APFELBAUM, B. S. LANE, G. RUPANI,
R. A. THISTED, C. DOHRN AND K. KORTTILA
SUMMARY
Patients who arrive home several hours after
outpatient surgery may drink alcohol. The extent
to which residual drugs used in outpatient
surgery interact with alcohol is not known. The
purpose of this study was to determine if two i. v.
drugs commonly used together in outpatient
surgery, midazolam and fentanyf. have residual
effects which would interact with alcohol drunk
4 h after injection. Twelve healthy male volun-
teers participated in a double-blind, randomized,
placebo-controlled and cross-over study. Sub-
jects were studied four times successively with a
period of 1 week between trials. On each day of
testing, the subjects received randomly, by slow
i.v. injection (30 s), either saline followed im-
mediately by saline, or midazolam 0.1 mg kg~'
followed immediately by fentanyl 2 fig kg'1. Four
hours after the injection, the subjects consumed
a beverage which either did or did not contain
alcohol 0.7g kg-'. Before and 1, 3, 5 and 7 h
after injection (and before and 1 and 3 h after
consumption of beverage), psychomotor perfor-
mance and mood were assessed. While both the
combination midazolam-fentanyl and alcohol
had independent effects on the dependent
measures in this study, there was no interaction
between midazolam-fentanyl and alcohol (no
potentiating of effects of alcohol by i.v.
sedation). We conclude that the effects ofbenzo-
diazepines and opioids that are short-acting and
used in outpatient surgery have probably dis-
sipated by the time a patient arrives home, and
that effects from alcohol ingested at home will
probably not be affected by recent administration
of these drugs.
KEY WORDS
Alcohol: psychomotor function. Anaesthesia: day care.
Analgesics: fentanyl. Hypnotics, benzodiazepines: midazo-
lam.
The number of outpatient operations is increasing
[1,2]. In order to be ready for discharge, patients
must be able to dress and walk without assistance.
This does not imply that they can safely drive,
cook, or care for small children. Despite being
told not to, some patients drive or even drink
alcohol [3]. It is important, therefore, to under-
stand the residual effects of drugs used commonly
in outpatient surgery or endoscopy and the extent
to which these residual effects interact with
alcohol. Many of the drugs used in outpatient
surgery for analgesia or sedation are known to
impair various psychomotor functions well after
the patient is discharged from hospital [4].
There are many studies demonstrating that the
psychomotor impairing effects of alcohol are
potentiated by benzodiazepines when the two
substances are given in combination [5-10].
However, there is only one study to date which
has examined any interactions when alcohol was
given several hours after i.v. sedation [11]. In our
study, we sought to determine if fentanyl given in
combination with midazolam would potentiate
J. LANCE LICHTOR, M.D., JEFFREY L. APFELBAUM, M.D.,
BRADFORD S. LANE, B.A., GITA RUPANI, M.D., CATHLEEN
DOHRN, M.A., KARI KORTTILA, M.D., PH.D. (Department of
Anesthesia and Critical Care); JAMES ZACNY, PH.D. (Dep-
artment of Psychiatry); RONALD A. THISTED, PH.D. (Dep-
artment of Statistics); Box 428, University of Chicago,
5841 S. Maryland Avenue, Chicago, Illinois 60637, U.S.A.
Accepted for Publication: April 29, 1991.
Correspondence to J.L.L.
t Presented in part at the American Society of Anesthes-
iologists Annual Meeting, Las Vegas, U.S.A. 1990.
580 BRITISH JOURNAL OF ANAESTHESIA
the effects of psychomotor and cognitive func- 3, 5 and 7 h after i.v. sedation. Blood concentra-
tioning of alcohol consumed several hours later. tions of alcohol were measured before and 5 and
7 h after i.v. sedation (1 and 3 h after consumption
of beverage). A snack was served approximately
SUBJECTS AND METHODS
2 h after injection of drug, and lunch was served to
We studied 12 healthy males (mean age 23.0 yr subjects approximately 6h after injection (1.5 h
(range 21-30 yr); weights 78.5 (SD 11.9) kg; after alcohol ingestion).
heights 181.2 (7.5) cm) with a history of rec- Psychomotor effects, mood and blood concen-
reational use of alcohol. The study was approved trations of alcohol were the dependent measures
by our Board of Institutional Review and informed in this study. These measures took approximately
written consent was obtained from subjects before 25 min to complete and were performed always in
the first session. An anaesthetist performed a the same order. The Maddox wing test was used
history and physical examination. Subjects were to measure eso- and exophoria (motor function of
excluded if they had an adverse experience with the eyes) [12]. An action judgement tester, similar
general or i.v. anaesthesia, or sedation/analgesia, to a test of driving, was used: with a steering
or had any systemic disease. Persons eligible for wheel, subjects attempted to keep two pointers on
the study were not permitted to take medication a moving track without striking objects; number
that was prescription or over-the-counter during of mistakes (when pointers struck objects) was
the 3 weeks of the study. Subjects fasted before recorded. Body sway was measured using a strain
the testing sessions and did not drink alcohol for gauge that was computerized: subjects stood on a
24 h before sessions. Abstinence from alcohol was force plate for 60 s with their eyes closed and
verified by measuring the concentration of blood variations in movement in the antero-posterior
alcohol when the subject arrived for each session. and lateral direction were recorded. A critical
Subjects were paid £196 ($350 U.S.) for their flicker fusion test (CFFT) was used to measure
participation upon completion of the study. changes in overall integrative activity of the CNS
The study was double-blind, randomized and (the CFFT has been shown to be sensitive to the
cross-over. Each subject was tested on four effects of fentanyl [13]). Subjects first performed
different test sessions at intervals of 1 week. three ascending series of trials (from flicker to
Subjects received i.v. injections of either midazo- fusion) and then three descending series of trials
lam 0.1 mg kg"1 followed immediately by fentanyl (fusion to flicker).
2 (ig kg"1, or saline followed by saline, using the Subjects performed four psychomotor tests on
same volumes of saline as active drug. The time a computer. Simple auditory and visual reaction
for injection for each drug was 30 s. Four hours times were determined by measuring the time it
later the subjects consumed a beverage that either took the subject to press a button after hearing a
did or did not contain alcohol 0.7 g kg"1. The sound or seeing a letter on the computer screen.
doses of midazolam and fentanyl used are those Divided attention reaction time was determined
given usually during outpatient procedures for in a test in which several stimuli were presented
this age group. The dose of alcohol used is simultaneously in different sectors of the com-
approximately equivalent to 1.4 litre of beer, puter screen. The subject had to press the
950 ml of wine or 180 ml of spirits and would appropriate key when a certain target stimulus
be expected to increase the blood concentration appeared in a background of false stimuli; the test
of alcohol to approximately 0.6 ml dl"1 in a fasted, was run at supramaximal speed so it was im-
70-kg male. The lemonade-and-lime flavoured possible to react to all stimuli presented. Number
beverages that contained alcohol had 10% ethyl of responses that were correct and incorrect were
alcohol by volume in a volume of 450 ml (per recorded also in this test. Eye—hand co-ordination
70 kg). Beverages were served cold in cups. was measured by the subject tracking a moving
Subjects had 20 min to consume the beverage. circle on a computer screen with a cross controlled
Before the first session of the experiment, by a "mouse". Mistakes of co-ordination were
subjects were trained (three practice sessions) to measured by counting the number of times that
use the apparatus in order to prevent further the cross exceeded a certain distance (1 cm) from
learning of the tasks during actual testing. Evalu- the target circle. The duration (in seconds) that
ation of psychomotor performance and subjective the cross exceeded 1 cm from the circle was also
effects (see below) were performed before and 1, recorded. Accuracy of co-ordination was deter-
MIDAZOLAM, FENTANYL AND ALCOHOL 581
mined by measuring the mean distance (in pixels) saline injection-alcohol beverage have been
between the cross and the target during the test. averaged; and results for the groups of midazo-
Subjective effects were measured at baseline, lam—fentanyl injection-placebo beverage and
and 1,3,5 and 7 h after injection of drugs with the midazolam-fentanyl injection—alcohol beverage
Profile of Mood States (POMS). The POMS, have been averaged. Tests in which drug effects of
chosen because it is sensitive to momentary mood significance (or near signigicance) were obtained
states, consists of 72 adjectives used commonly to are presented. The injection of midazolam-
describe momentary mood states [14]. There is fentanyl caused significant changes in eso/exo-
concordance as measured by the POMS scale of phoria (P < 0.05) and increases in the number of
anxiety and two other standardized measures of mistakes made on the action judgement tester (P
"state" anxiety (Taylor Manifest Anxiety Scale, < 0.05). Body sway (antero-posterior) was in-
Spielberger State-Trait Anxiety Inventory) [15]. creased significantly (P < 0.05) by the drug com-
The POMS is the test used most often to quantify bination. Fusion—flicker threshold was also in-
moods [16]. Subjects indicate how they feel at the creased significantly by the drug combination (P
moment in relation to each of these adjectives, < 0.001). Auditory reaction time (P < 0.05), div-
from "not at all" (0) to "extremely" (4). Eight ided attention (P < 0.01), and eye-hand co-
clusters of items have been derived using factor ordination (P < 0.005) were impaired by midazo-
analysis and have been given names that best lam-fentanyl. Scores of confusion from the POMS
describe the clustered adjectives (anxiety, de- increased significantly after midazolam-fentanyl
pression, anger, vigour, fatigue, confusion, friend- (P < 0.05). The effects of midazolam-fentanyl on
liness and elation). In addition, two unvalidated fatigue (P<0.10) and arousal (P < 0.06) ap-
scales (arousal and positive mood), shown pre- proached significance. In general, the effects of
viously to be sensitive to drug effects, were scored. impairing and sedating of midazolam-fentanyl
Blood concentration of alcohol was measured had reached a peak 1 h after injection and
from breath air using an Alco-sensor 3-breath approached baseline values 3 h after injection.
analyser (Intoximetrics Instruments, St Louis, Mean (SD) blood concentration of alcohol 1 h
MO, U.S.A.). after ingestion of alcohol (5 h after injection of
For each test, two repeated measures multi- drug or saline) was 0.65 (0.16) mg dl"1 (frequently,
variate analyses of variance [17] were used. The a motorist with a blood concentration of alcohol of
first MANOVA studied the effects of drug 1.0 mg dl~' is considered to be driving under the
(present or absent), using all five timepoints influence of alcohol). Table II presents psycho-
(hours 0, 1, 3, 5 and 7) in the analysis. The second motor performance and measures of subjective
MANOVA studied the effects of alcohol (present effects obtained at baseline (0 h) and 1 and 3 h
or absent), and the interaction of midazolam- after ingestion of beverage comprising either
fentanyl and alcohol, if any, using the hours 0, 5 placebo or alcohol. In the table, the four groups of
and 7 after injection as timepoints (5 and 7 h after study have been reduced to two: results from the
injection were equivalent to 1 and 3 h after two groups receiving placebo (saline injection-
ingestion). P ^ 0.05 was considered significant. placebo beverage and midazolam—fentanyl injec-
Post hoc tests were used, when effects of signifi- tion—placebo beverage) were averaged and the two
cance of drug or alcohol were obtained, to groups receiving alcohol (placebo injection-
determine the duration that psychomotor per- alcohol beverage and midazolam-fentanyl injec-
formance was impaired. We performed additional tion-alcohol beverage) were averaged; tests are
ANOVAs to determine if significant effects of presented in which effects of significance (or near
learning were present by using week of testing as significance) of alcohol were noted. Alcohol
a factor. caused significant impairment in visual reaction
time (P < 0.05), eso/exophoria (P < 0.01), and
RESULTS eye-hand co-ordination (P < 0.05). These effects
Table I presents measures of psychomotor per- of alcohol reached a peak 1 h after ingestion and
formance and subjective effects obtained before returned to baseline 2 h later. Alcohol tended to
and 1 and 3 h after i.v. injection of either saline or increase fatigue (0.07), elation (0.09) and positive
midazolam-fentanyl. In the table, the four groups mood (0.14), and decrease anger (0.07) and arousal
of study have been reduced to two: results for the (0.10). No significant learning took place during
groups of saline injection—placebo beverage and the study. There were no significant interactions
582 BRITISH JOURNAL OF ANAESTHESIA
TABLE I. Psychomotor performance and measures of mood (mean (SD)) at baseline (0 h) and 1 and 3 h
after injections of either saline or midazolam—fentanyl. $ Significance (P value) is based on repeated meas-
ures multivariate analysis of variance comparing midazolam—fentanyl with saline, using hours 0, 1, 3, 5
and 7 as timepoints. Difference score (1 h — Oh) in mid-fentanyl injection condition significantly different
from difference score (1 h-0 h) in saline injection condition: * P < 0.05; ** P < 0.01; *** P < 0.001.
•f Difference score from baseline (3 h — 0 h) in mid-fentanyl injection condition significantly different (P <
0.05) from difference score from baseline (3 h — 0 h) in saline injection condition. RT = Reaction time;
CFFT = critical flicker fusion test; MDT = mean distance from target; POMS = profile of mood states

Time after injection

Oh lh 3h PS
Saline injection
Eso/exophoria 1.85(5.84) 1.96 (6.44) 2.17(6.5)
(diopters)
Action judgement 22.6(14.4) 185(12.4) 17.5(10.7)
(mistakes)
Body sway
Antcro-posterior 692.5(218.3) 764.1 (375.4) 831.4(478.2)
Lateral 651.2(231.4) 681.7(286.1) 706.0 (358.5)
CFFT descend (Hz) 39.4(6.1) 37.9(7.1) 37.6 (7.6)
Auditory RT (s) 0.285 (0.045) 0.295 (0.048) 0.284 (0.039)
Divided attention RT 0.546 (0.084) 0533 (0.078) 0531 (0.076)
(s)
No. correct 90.0 (8.6) 91.9(4.9) 91.5 (6.7)
No. incorrect 10.7 (6.9) 10.1 (7.2) 10.1 (7.6)
Eye-hand co-ord.
No. mistakes 16.0 (5.7) 15.9(5.6) 17.3 (6.0)
Time off target (s) 4.08(1.79) 3.98 (1.2) 5.09 (4.88)
MDT (pixels) 10.8(1.5) 10.7(1.1) 12.0 (5.6)
POMS (score)
Fatigue 05 (0.568) 0357 (0.509) 0.577 (0.725)
Confusion 0.083 (0.41) 0.042 (0.443) 0.0 (0.326)
Arousal 0.788 (0.972) 0.818(1.07) 0.405 (1.23)
Midazolam-fentanyl
injection
Eso/exophoria 2.13(6.01) 4.29 (6.83)* 3.71 (6.24) 0.05
(diopters)
Action judgement 16.5(12.1) 40.0 (46.8)** 19.1 (14.4)t 0.05
(mistakes)
Body sway
Antero-posterior 647.7(146.1) 1093.3 (453.7)*** 759.4 (382.0) 0.05
Lateral 5933(167.4) 831.7(359.1)* 5873 (236.0) 0.08
CFFT descend (Hz) 38.4(7.1) 333 (6.9)** 35.6 (7.6) 0.001
Auditory RT (s) 0.276 (0.041) 0317 (0.05)** 0.291 (0.042) 0.05
Divided attention RT 0.541 (0.071) 0.57 (0.085)** 0535 (0.068) 0.01
(s)
No. correct 923(4.1) 84.5(10.7)*** 89.4(10.0) 0.01
No. incorrect 8.5 (4.7) 15.4(10.9)** 12.4 (9.2)t 0.05
Eye-hand co-ord.
No. mistakes 143 (4.9) 25.1 (13.5)*** 17.7(10.2) 0.001
Time off target (s) 3.46 (0.98) 8.69 (7.85)*** 452 (2.9) 0.005
MDT (pixels) 10.7(1.2) 14.4(3.1)*** 11.6(2.0) 0.001
POMS (score)
Fatigue 0.476 (0.531) 0.827 (0.739)** 0.708 (0.759) 0.10
Confusion 0.048 (0.392) 0.286 (0.374)** 0.131 (0.415) 0.05
Arousal 0504(0.991) -0.127(1.33)** 0.153(1.28) 0.06
MIDAZOLAM, FENTANYL AND ALCOHOL 583
30 i
i n —> tn in « r- r~ o» o •**•
pp pop p p p -•« ~*
dd ooo oddod

—• o
2,2,26°
<noo w w <o
f* Ov O< CJ t--
d d o o o

FIG. 1. Number of mistakes made on the eye-hand co-

ordination task at 0, 1, 3, 5 and 7 h after injection of
midazolam-fentanyl. Five and 7 h after injection of midazo-
lam—fentanyl correspond with 1 and 3 h after ingestion of
alcohol. • = Placebo injection, placebo beverage; • =
midazolam-fentanyl injection, placebo beverage; • = placebo
•n t-: i
m in <s
injection, alcohol beverage; 0 = midazolam-fentanyl injec-
tion, alcohol beverage.

between injection of midazolam-fentanyl and

subsequent ingestion of alcohol for eye-hand co-
oq _; >o 2-2."^ S 2. ordination (fig. 1); number of mistakes made in
d 00 ' -"" 00 the test increased after both injection of midazo-
— 2 -* —> oo - < lam-fentanyl and ingestion of alcohol, but the
d do ddd injection of i.v. drug did not potentiate the effects
of alcohol.
DISCUSSION
IS? 2.2.52-2. We have demonstrated that short-acting sedatives
'd ijin^oifi
i
> o
^ r^ oo <^i i n
oo oo o
used commonly in outpatient surgery impaired
psychomotor performance and affected mood, but
did not potentiate the effects of alcohol when this
drug was ingested several hours after i.v. sedation.
nco * jo
The acute impairment of performance by midazo-
3
CM ^ 0 0 O> VO

? 2-2-2 2-2- lam [18-21] and fentanyl [13, 22, 23] is consistent
Q O
in
O* 00 ^O ^"^ o l 00 00 ^O
with other studies. Benzodiazepines have also
o -* inco'd doddd been shown to increase sedation and confusion
[19,21,24,25]. There is some evidence that
fentanyl may have effects on the CNS for several
—i t~ Q t- hours after administration [23]. However, im-
Mmoo o t^ pairment induced by drug in the present study,
2.2-262. for the most part, did not last long and returned to
S in op
OO ^ ^ ^ ^ I^»

baseline by 3 h after injection.

Alcohol had only modest effects in the present
study. Interestingly, body sway, which is usually
affected by this drug [26], was not affected. While
large doses of alcohol appear to have impairing
effects on a variety of measures of psychomotor
I? 1 w Sc a >
performance [26], more inconsistent data are
73 8 o J SP's s P a
reported when small to moderate doses of alcohol
i W ' are studied [10, 27, 28].
•0'
No interactions between midazolam-fentanyl
584 BRITISH JOURNAL OF ANAESTHESIA
and alcohol were noted, although other studies adinazolam and diazepam, alone and in combination with
have shown opposite results [5, 7-10]. However, ethanol, on psychomotor and cognitive performance and
on autonomic nervous system reactivity in healthy volun-
differences in results between our study and those teers. European Journal of Clinical Pharmacology 1990;
of other investigators may probably be accounted 38: 371-377.
for by differences in interdrug interval: in other 12. Hannington-Kiff JG. Measurement of recovery from
studies, benzodiazepines and alcohol were given outpatient genera] anaesthesia with simple ocular test.
together, whereas in our study the interval British Medical Journal 1970; 3: 132-135.
13. Manner T, Kanto J, Salonen M. Simple devices in
between i.v. sedation and ingestion of alcohol was differentiating the effects of buprenorphine and fentanyl
set at 4 h. We attempted to use times and doses in healthy volunteers. European Journal of Clinical
which mimicked the clinical situation. The results Pharmacology 1987; 31: 673-676.
of the present study suggest that sedation with 14. McNair DM, Lorr M, Droppleman LF. Profile of Mood
midazolam and fentanyl for outpatient surgery States (Manual). San Diego: Educational and Industrial
Testing Service, 1971.
probably dissipates by the time the patient arrives 15. de Wit H, Uhlenhuth EH, Hedeker D, McCracken SG,
home, and that effects from alcohol ingested at Johanson CE. Lack of preference for diazepam in anxious
home will probably not be influenced by the volunteers. Archives of General Psychiatry 1986; 43:
recent use of midazolam and fentanyl. 533-541.
16. Little K, Penman E. Measuring subacute mood changes
using the Profile of Mood States and visual analogue
scales. Psychopathology 1989; 22: 42^19.
17. Wilkinson L. SYSTAT: The System for Statistics.
Evanston, IL: SYSTAT, Inc., 1986.
REFERENCES 18. Hindmarch I, Subhan Z. The effects of midazolam in
conjunction with alcohol on sleep, psychomotor per-
1. Larkin H. Less money, more players in outpatient market. formance and car driving ability. International Journal of
Hospitals 1989; 63: 26. Clinical Pharmacology Research 1983; 3: 323-329.
2. Shannon K. Outpatient surgery up 77 percent: data. 19. Gudgeon AC, Hindmarch I. Midazolam: Effects on
Hospitals 1985; 59: 54. psychomotor performance and subjective aspects of sleep
3. Ogg TW. An assessment of postoperative outpatient and sedation in normal volunteers. British Journal of
cases. British Medical Journal 1972; 4: 573-576. Clinical Pharmacology 1983; 16: 121S-126S.
4. Korttila K. Postanesthetic cognitive and psychomotor 20. Schaffler K, Klausnitzer W. Acute effects of two dosages
impairment. International Anesthcsiology Climes 1986; 24: of orally administered midazolam on psychomotor per-
59-74. formance in healthy volunteers. Arzneimittel-Forschung
5. Linnoila M, HSkkinen S. Effects of diazepam and codeine, 1989; 39: 395-398.
alone and in combination with alcohol, on simulated 21. Nightingale JJ, Norman J. A comparison of midazolam
driving. Clinical Pharmacology and Therapeutics 1974; 15: and temazepam for premedication of day case patients.
368-373. Anaesthesia 1988; 43: 111-113.
6. Aranko K, Seppala T, Pellinen J, Manila MJ. Interaction 22. Scamman FL, Ghoneim MM, Korttila K. Ventilatory
of diazepam or lorazepam with alcohol. Psychomotor and mental effects of alfentanil and fentanyl. Ada
effects and bioassayed serum levels after single and Anaesthesiologica Scandinavica 1984; 28: 63-67.
repeated doses. European Journal of Clinical Pharmacology 23. Ghoneim MM, Mewaldt SP, Thatcher JW. The effect of
1985; 28: 559-565. diazepam and fentanyl on mental, psychomotor and
7. Hindmarch I, Subhan Z. The effects of midazolam in electroencephalographic functions and their rate of re-
conjunction with alcohol on sleep, psychomotor per- covery. Psychopharmacology 1975; 44: 61—66.
formance and car driving ability. International Journal of 24. Hargrcaves J. Benzodiazepine premedication in minor
Clinical Pharmacology Research 1983; 3: 323-329. day-case surgery: Comparison of oral midazolam and
8. Willumeit HP, Ott H, Neubert W, Hemmerling KG, temazepam with placebo. British Journal of Anaesthesia
Schratzer M, Fichte K. Alcohol interaction of lormeta- 1988; 61: 611-616.
zepam, mepindolol sulphate and diazepam measured by 25. Johanson CE, Uhlenhuth EH. Drug preference and mood
performance on the driving simulator. Pharmacopsychiatry in humans: diazepam. Psychopharmacology 1980; 71:
1984; 17: 36-43. 269-273.
9. Morland J, Setekleiv J, Haffner JF, Stromsacther CE, 26. Linnoila M. Effects of drugs and alcohol on psychomotor
Danielsen A, Wethe GH. Combined effects of diazepam skills related to driving. Annals of Clinical Research 1974;
and ethanol on mental and psychomotor functions. Acta 6: 7-18.
Pharmacohgica el Toxicologica 1974; 34: 5-15. 27. Fagan D, Tiplady B, Scon DB. Effects of ethanol on
10. Palva ES, Linnoila M, Saario I, Manila MJ. Acute and psychomotor performance. British Journal of Anaesthesia
subacute effects of diazepam on psychomotor skills: 1987; 59: 961-965.
interaction with alcohol. Acta Pharmacologica et Toxi- 28. McManus IC, Ankier SI, Norfolk J, Phillips M, Priest
cologica 1979; 45: 257-264. RG. Effects on psychological performance of the benzo-
diazepine, loprazolam, alone and with alcohol. British
11. Linnoila M, Stapleton JM, Lister R, Moss H, Lane E, Journal of Clinical Pharmacology 1983; 16: 291-300.
Granger A, Greenblatt DJ, Eckardt MJ. Effects of