between midazolam-fentanyl and alcohol (no potentiating of effects of alcohol by i.v. sedation). We conclude that the effects ofbenzo- diazepines and opioids ...
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 volunteers participated in a double-blind, randomized, placebo-controlled and cross-over study. Subjects 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 immediately 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 performance 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 ofbenzodiazepines and opioids that are short-acting and used in outpatient surgery have probably dissipated 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: midazolam.
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 understand 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. (Department 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 Anesthesiologists Annual Meeting, Las Vegas, U.S.A. 1990.
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the effects of psychomotor and cognitive functioning of alcohol consumed several hours later.
BRITISH JOURNAL OF ANAESTHESIA
3, 5 and 7 h after i.v. sedation. Blood concentrations 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 recPsychomotor effects, mood and blood concenreational 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 comapproximately 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 im70-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 mined by measuring the mean distance (in pixels) between the cross and the target during the test. Subjective effects were measured at baseline, and 1,3,5 and 7 h after injection of drugs with the Profile of Mood States (POMS). The POMS, chosen because it is sensitive to momentary mood states, consists of 72 adjectives used commonly to describe momentary mood states [14]. There is concordance as measured by the POMS scale of anxiety and two other standardized measures of "state" anxiety (Taylor Manifest Anxiety Scale, Spielberger State-Trait Anxiety Inventory) [15]. The POMS is the test used most often to quantify moods [16]. Subjects indicate how they feel at the moment in relation to each of these adjectives, from "not at all" (0) to "extremely" (4). Eight clusters of items have been derived using factor analysis and have been given names that best describe the clustered adjectives (anxiety, depression, anger, vigour, fatigue, confusion, friendliness and elation). In addition, two unvalidated scales (arousal and positive mood), shown previously to be sensitive to drug effects, were scored. Blood concentration of alcohol was measured from breath air using an Alco-sensor 3-breath analyser (Intoximetrics Instruments, St Louis, MO, U.S.A.). For each test, two repeated measures multivariate analyses of variance [17] were used. The first MANOVA studied the effects of drug (present or absent), using all five timepoints (hours 0, 1, 3, 5 and 7) in the analysis. The second MANOVA studied the effects of alcohol (present or absent), and the interaction of midazolamfentanyl and alcohol, if any, using the hours 0, 5 and 7 after injection as timepoints (5 and 7 h after injection were equivalent to 1 and 3 h after ingestion). P ^ 0.05 was considered significant. Post hoc tests were used, when effects of significance of drug or alcohol were obtained, to determine the duration that psychomotor performance was impaired. We performed additional ANOVAs to determine if significant effects of learning were present by using week of testing as a factor.
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saline injection-alcohol beverage have been averaged; and results for the groups of midazolam—fentanyl injection-placebo beverage and midazolam-fentanyl injection—alcohol beverage have been averaged. Tests in which drug effects of significance (or near signigicance) were obtained are presented. The injection of midazolamfentanyl caused significant changes in eso/exophoria (P < 0.05) and increases in the number of mistakes made on the action judgement tester (P < 0.05). Body sway (antero-posterior) was increased significantly (P < 0.05) by the drug combination. Fusion—flicker threshold was also increased significantly by the drug combination (P < 0.001). Auditory reaction time (P < 0.05), divided attention (P < 0.01), and eye-hand coordination (P < 0.005) were impaired by midazolam-fentanyl. Scores of confusion from the POMS increased significantly after midazolam-fentanyl (P < 0.05). The effects of midazolam-fentanyl on fatigue (P VO
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We have demonstrated that short-acting sedatives 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. The acute impairment of performance by midazolam [18-21] and fentanyl [13, 22, 23] is consistent with other studies. Benzodiazepines have also 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 hours after administration [23]. However, impairment induced by drug in the present study, for the most part, did not last long and returned to 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 performance [26], more inconsistent data are reported when small to moderate doses of alcohol are studied [10, 27, 28]. No interactions between midazolam-fentanyl
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adinazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers. European Journal of Clinical Pharmacology 1990; 38: 371-377. 12. Hannington-Kiff JG. Measurement of recovery from outpatient genera] anaesthesia with simple ocular test. British Medical Journal 1970; 3: 132-135. 13. Manner T, Kanto J, Salonen M. Simple devices in differentiating the effects of buprenorphine and fentanyl in healthy volunteers. European Journal of Clinical Pharmacology 1987; 31: 673-676. 14. McNair DM, Lorr M, Droppleman LF. Profile of Mood States (Manual). San Diego: Educational and Industrial Testing Service, 1971. 15. de Wit H, Uhlenhuth EH, Hedeker D, McCracken SG, Johanson CE. Lack of preference for diazepam in anxious volunteers. Archives of General Psychiatry 1986; 43: 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. 18. Hindmarch I, Subhan Z. The effects of midazolam in REFERENCES conjunction with alcohol on sleep, psychomotor perLarkin 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. 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 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. 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 per59-74. formance in healthy volunteers. Arzneimittel-Forschung 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. 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 Anaesthesiologica Scandinavica 1984; 28: 63-67. effects and bioassayed serum levels after single and 23. Ghoneim MM, Mewaldt SP, Thatcher JW. The effect of repeated doses. European Journal of Clinical Pharmacology diazepam and fentanyl on mental, psychomotor and 1985; 28: 559-565. electroencephalographic functions and their rate of reHindmarch I, Subhan Z. The effects of midazolam in covery. Psychopharmacology 1975; 44: 61—66. conjunction with alcohol on sleep, psychomotor performance and car driving ability. International Journal of 24. Hargrcaves J. Benzodiazepine premedication in minor day-case surgery: Comparison of oral midazolam and Clinical Pharmacology Research 1983; 3: 323-329. temazepam with placebo. British Journal of Anaesthesia Willumeit HP, Ott H, Neubert W, Hemmerling KG, 1988; 61: 611-616. Schratzer M, Fichte K. Alcohol interaction of lormetazepam, mepindolol sulphate and diazepam measured by 25. Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology 1980; 71: performance on the driving simulator. Pharmacopsychiatry 269-273. 1984; 17: 36-43. Morland J, Setekleiv J, Haffner JF, Stromsacther CE, 26. Linnoila M. Effects of drugs and alcohol on psychomotor skills related to driving. Annals of Clinical Research 1974; Danielsen A, Wethe GH. Combined effects of diazepam 6: 7-18. and ethanol on mental and psychomotor functions. Acta 27. Fagan D, Tiplady B, Scon DB. Effects of ethanol on Pharmacohgica el Toxicologica 1974; 34: 5-15. psychomotor performance. British Journal of Anaesthesia Palva ES, Linnoila M, Saario I, Manila MJ. Acute and 1987; 59: 961-965. subacute effects of diazepam on psychomotor skills: interaction with alcohol. Acta Pharmacologica et Toxi- 28. McManus IC, Ankier SI, Norfolk J, Phillips M, Priest RG. Effects on psychological performance of the benzocologica 1979; 45: 257-264. diazepine, loprazolam, alone and with alcohol. British 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
and alcohol were noted, although other studies have shown opposite results [5, 7-10]. However, differences in results between our study and those of other investigators may probably be accounted for by differences in interdrug interval: in other studies, benzodiazepines and alcohol were given together, whereas in our study the interval between i.v. sedation and ingestion of alcohol was set at 4 h. We attempted to use times and doses which mimicked the clinical situation. The results of the present study suggest that sedation with midazolam and fentanyl for outpatient surgery probably dissipates by the time the patient arrives home, and that effects from alcohol ingested at home will probably not be influenced by the recent use of midazolam and fentanyl.
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