COMPARISON OF THREE BENZODIAZEPINES FOR ORAL PREMEDICATION IN MINOR GYNAECOLOGICAL SURGERY

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1 Br.J. Anaesth. (9),, 9 COMPARISON OF THREE BENZODIAZEPINES FOR ORAL PREMEDICATION IN MINOR GYNAECOLOGICAL SURGERY C. G. MALE, Y. T. LIM, M. MALE, J. M. STEWART AND J. M. GIBBS SUMMARY Diazcpam and, lorazepam. and., flunitrazepam and, and a placebo, were compared in a randomized double-blind controlled trial as oral premedication for patients undergoing minor gynaecological surgery. and lorazepam. were superior to placebo (P< and P< respectively) in relieving patient anxiety when assessed by a trained observer min after premedication. also produced more drowsiness (P< ) than the placebo. Comparisons of other low-dose benzodiazepine groups with the placebo, and of the large dose with the small dose of each drug revealed no significant changes in anxiorysis or drowsiness. Dizziness and prolonged drowsiness were not apparent with low-dose flunitrazepam. The data suggests that flunitrazepam offers advantages over placebo, diazcpam and lorazepam. for routine oral premedication in minor gynaecological surgery. Reduction of fear and anxiety before anaesthesia and operation remains the prime reason for patient premedication (Atkinson, Rushman and Lee, 977). Although a preoperative visit by the anaesthetist has been shown to lessen anxiety in surgical patients (Leigh, Walker and Janaganathan, 977), medication before operation is widely used to allay patient fears over which the anaesthetist has less influence (Norris and Baird, 97). The benzodiazepine drugs diazepam, lorazepam and flunitrazepam are recognized anxiolytics. Oral preparations have have been compared for relative amnesic action (McKay, Dundee and George, 97) and the first two have been investigated for night sedation and the relief of anxiety before operation (Paymaster, 97; Wilson, 97). Our double-blind controlled trial was designed to identify the relative potency of oral flunitrazepam and to compare its suitability for premedication with diazepam and lorazepam in patients undergoing minor gynaecological surgery. CHRISTOPHER G. MALE,* M.B., CH.B., F.F.A.R.CS., F.F.AJLA.C.S.; YONG, T. LlM, M.B., B.S.J MARION MALE,* S.R.N.; JOANNA M. STEWART, M.SC.; JOHN M. GIBBS, M.D., F.F.AJLC.S., F.F.A-R.AX.S. ; Department of Anaesthesia, Christchurch Clinical School of Medicine, University of Otago, New Zealand. Reprint requests and correspondence to C. G. M. (present address): Department of Postgraduate Medicine, University of Keele, North Staffordshire Medical Institute, Hartshill Road, Hartshill, Stoke-on-Trent ST 7NY. 7-9//9- $. METHODS Female Caucasian patients admitted to four gynaecological wards for dilatation and curettage, and not in pain, were studied. The age range was - yr; weight kg inclusive, ASA class I or II and the haemoglobin concentration greater than g dl -. The Ethics Committee of the hospital approved the study and an anaesthetist sought informed verbal consent from the patient. Patient height and body weight were recorded with current medication including overnight sedation, smoking habits and the state of any pregnancy (for example incomplete or therapeutic abortion). The patient was assessed by a trained observer who gave scores for drowsiness (-), apprehension (-) and excitement (-) after Dundee, Moore and Nicholl (9). Dizziness (-), emesis (-) and headache (-) were graded by questioning the patient. Rather than produce a single figure for all desired or undesired effects, we scored each aspect in an attempt to improve the discrimination between the effects of individual drugs. As a self-rating score of anxiety, we asked the patient to choose from anxiety-present and anxiety-absent words, those adjectives which best described how the patient was feeling at that moment (Wassenaar et al., 977). These were displayed in large print on cards (9 x 7 mm). An Eysenck personality inventory (Form A) was completed by the patient to evaluate aspects of personality that might influence the success of drug Marmillan Journals Ltd 9

2 BRITISH JOURNAL OF ANAESTHESIA therapy. This provided scores for "neuroticism", "extroversion" and "lie" tendency (Eysenck and Eysenck, 9). Thirty doses each of diazepam and, lorazepam. and. and minitrazepam and were prepared in paired identical capsules, using lactose as the placebo. This provided oral premedication for patients in seven groups. Randomization was achieved by removing numbered cards from a bag. The contents of the two capsules in each numbered envelope were unknown to the trained observer, the anaesthetist and the patient The code identifying the drug and dose with the patient remained unbroken until the end of the -month trial. All patients were starved of food and fluid for at least h before operation. Approximately 9min before operation, the resting heart rate and the arterial pressure were recorded with the patient reclining at in bed. Following the initial interview and questioning, the two capsules were dispensed by the trained observer, a registered nurse, for the patient to swallow whole in ml of water. The patient was then left undisturbed in bed. About min after premedication, patient drowsiness, apprehension and excitement were again assessed by the observer, and then the patient selected from the anxiety-related words as previously. The exact time of the assessment was noted with the resting heart rate and the arterial pressure. Dizziness, emesis, headache and heart rate change were recorded after questioning and observation. Five picture cards ( x 7 mm) of common objects from a series of were shown to the patient and named by the observer for reinforcement. These were changed in cycle to prevent inter-patient contact distorting analysis of recall. The patient was transported to the anaesthetic room on a trolley. Before induction, the anaesthetist recorded the effect of premedication as satisfactory or not by his own criteria. The nature of the surgical procedure, the anaesthetic technique employed and its duration were recorded. Although participating anaesthetists approved the double-blind controlled trial of benzodiazepine premedication, a standardized anaesthetic technique could not be formulated to cover both pregnant and non-pregnant patients. On the morning following operation, the patient was assessed by the observer in respect of drowsiness, apprehension and excitement, and a self-rating score of anxiety obtained from the patient by adjective selection. An alternative form of the Eysenck personality inventory (Form B) was completed after operation by all patients except the first studied, to whom it was unavailable. A score for amnesia was created by noting the recall of picture cards previously shown h after premedication. The statistical methods used were one-way analysis of variance, Kruskal-Wallis one-way analysis of variance followed by Dunn's test for multiple comparisons where appropriate (Dunn, 9), Mann- Whitney U test, Chi-squared test, Wilcoxon matchedpairs signed-ranks test, Spearman's correlation coefficients and Fisher's discriminant analysis. A rank analysis of covariance (Quade, 97) was applied to those variables recorded both before and after premedication when investigating differences across the treatment groups. This has the effect of eliminating those differences across the treatment groups which might exist for the variable of interest before premedication, when looking at the differences after premedication. This was followed by Scheffe's method of multiple comparisons where appropriate. RESULTS The seven groups of patients were comparable with respect to age, height, weight, ASA physical status, haemoglobin concentrations and state of pregnancy (table I). Similarly, the Eysenck personality inventories before operation (table II), patient self-rating scores for anxiety before premedication (table III) and tie observer rating scores for drowsiness and apprehension before premedication (table IV) showed no significant differences across the seven groups. However, the observer rating score for excitement before premedication indicated that patients in the placebo group were more restless than those in the drug groups (table IV). The first two trained observers withdrew after the first and next patients and the remaining studies were completed by the third observer. This led to observer differences in the scoring across the groups of drowsiness (P<) and excitement (P< ), but not apprehension. Such differences reduce the validity of drowsiness in assessing drug effect, and because of the placebo difference, excitement was excluded from further consideration. Rank analysis of covariance of observer rating scores after premedication showed a significant difference for both drowsiness and apprehension amongst the seven treatment groups. Multiple comparison tests of placebo v. small doses and small doses v. large doses of each drug produced the

3 ORAL BENZODIAZEPINE PREMEDICATION TABLE I. Patient details.. Mean age (yr) ±SD Mean height (cm) ±SD Mean weight (kg) ±SD Mean haemoglobin (g dl~ l ) ±SD ASA physical status I/II Non-pregnant Spontaneous abortion Therapeutic abortion ±9 ±. ±..9 ±. 7/ 7 ± ± ±9.. ±.9 7/ ± ±7. ±.9. ±.9 / ± ±7 9.9 ±9.7. ±. / ± ± 9. ±9.. ±.79 / ±9 ±. ±.. ±.9 9/ ± ±. ±7.. ±. /7 7 TABLB II. Median Eysenck personality inventory scores.. completed Form A Before premedication Neuroticism Extroversion Lie completed Form B After operation Neuroticism Extroversion Lie i TABLB III. Patient self-rating median scores for anxiety, f max., score if selected; * max., score if not selected.. Before premedication Anxiety-present words')" Anxiety-absent words* After premedication Anxiety-present words t Anxiety-absent words* J.... Z.... After operation Anxiety-present words f Anxiety-absent words*.....

4 BRITISH JOURNAL OF ANAESTHESIA TABLB IV. Observer rating median scores. Scoring system: drowsiness good =, fair =, slight =, none = ; apprehension absent =, slight =, moderate = I, marked - ; excitement nil =, slight =, marked = Before premedication Drowsiness Apprehension Excitement After premedication ( min) Drowsiness Apprehension Excitement After operation ( h) Drowsiness Apprehension Excitement following results. and lorazepam. induced significantly greater drowsiness than the placebo (P< and P< respectively), but doubling the dose of all three benzodiazepine failed to increase the drowsiness significantly. Only flunitrazepam achieved significant relief of apprehension (P<) when compared with the placebo. Again, doubling the dose of diazepam, lorazepam and flunitrazepam failed to relieve apprehension further. For the self-rating scores of anxiety, a rank analysis of covariance was performed This showed no significant difference between the treatments for the number of anxiety-present words chosen, but the difference was significant (P<) for the number of anxiety-absent words. The correlation coefficient between the observer rating score of apprehension and the patient self-rating score of anxiety (formed by the addition of the number of anxiety-absent and anxiety-present words chosen) before premedication was. and after premedication.. Although highly significantly different from zero the coefficients are not very great. An attempt was made to explain why some patients received little relief of apprehension or failed to become drowsy after receiving the active drug. A Fisher's discriminant analysis of the data for age, weight, haemoglobin, smoking habits, personality, patients anxiety assessment, preoperative apprehension and time of assessment after premedication showed a tendency for those not gaining relief from apprehension to have been assessed earlier after premedication, and to have been slightly more apprehensive before premedication than others. However, these two factors did not explain the failure to relieve anxiety satisfactorily, therefore other unknown factors were operating. None of the above variables could account for the failure to become drowsy. The anaesthetists distinguished a significant difference (P<) in the drug response across the groups. This was mainly caused by describing the premedication as satisfactory in more cases receiving lorazepam and flunitrazepam and fewer cases given the placebo (table V). TABLE V. 77K anaesthetist's comment on the premedication Satisfactory Unsatisfactory Total no. of patients Analysis of covariance on the toxic effects of dizziness and emesis after premedication revealed no significant differences. There was also no difference m heart rate change among the treatment groups (table VI). The dizziness was unrelated to decreases in systolic aterial pressure which were never unacceptably large. Patients in the placebo group were shown to have a greater severity of headache compared with those receiving the benzodiazepines (P<).

5 ORAL BENZODIAZEPINE PREMEDICATION TABLE VI. Median rating scores for undesired effects. Scoring system: dizziness marked =, slight =, none = ; emesis vomiting =, marked nausea =, slight nausea =, none =; headache severe =, slight =, none = ; heart rate change mcrease^ beat mm' =, increase - beat nrin' =, no change =, decrease = Diflzepam.. Before premedication Dizziness Emesis Headache.... After premedication Dizziness Emesis Headache Heart rate increase Postoperative assessment h after premedication confirmed significantly different recall of the picture cards shown h after premedication between the seven groups (P< ) (table VII). A comparison of the alternative form (B) with the original form (A) of the Eysenck personality inventory showed significant (P< ) increases in "neurosis" and "extroversion" scores and a decrease (P< ) in the "lie" score after operation. TABLE VII. Patient recall of picture cards shown mm after premedication No. of cards recalled Group total The observer rating score for drowsiness after operation using the rank analysis of covariance produced a significant difference (P<) across the groups, but surprisingly the apprehension score was not significantly different (table IV). Although the frequency and nature of complications after operation was influenced by the anaesthetic technique, most patients expressed a preference for oral rather than parenteral premedication. All patients had recovered sufficiently for discharge home from hospital the day after surgery but some remained for surgical reasons. DISCUSSION Our study supports the view that oral benzodiazepines offer useful sedation and anxiolysis as premedication for minor gynaecological surgery. failed to produce significantly greater drowsiness than placebo when given h before assessment. and flunitrazepam gave a significant increase in drowsiness compared with the placebo. These observations match the clinical use of diazepam for daytime anxiolysis without drowsiness and that of nitrazepam for night sedation. is the ortho-chloro-phenyl derivative of the main metabolite of diazepam, desmethyldiazepam. Like diazepam, its use for daytime relief of apprehension has been more popular than as a night hypnotic. All will induce sleep at greater doses, although doubling the small dose in our study did not increase drowsiness significantly within each drug grouping. Unfortunately, a drowsy state does not necessarily mean that apprehension has been abolished (Egbert et al, 9; Morrison, Clarke and Dundee, 97). Relief of apprehension must be sought from premedication to reduce excessive hormonal and circulatory response which might antagonize the safe induction with the minimal effective dose of anaesthetic agent We attempted to assess patient anxiety before premedication by two different measures. The patient self-rating score of anxiety was derived from the Multiple Affect Adjective Check List (MAACL)

6 BRITISH JOURNAL OF ANAESTHESIA described by Zuckerman (9) but only anxietyrelated words out of the original list bearing words were used, and appropriate key words previously used for the assessment of depression and hostility (Wassenaar et al., 977) were omitted. Patient illiteracy and the short time available for assessment necessitated these modifications. Assessment of apprehension was also gained through use of a four-point observer rating scale. Correlation between the patient self-rating score and the observer rating score for anxiety in our study was poor unlike the findings of others (Wassenaar et al., 977). This was probably because the sensitivity of the former was reduced by extracting the anxiety-related words out of the word list Also, fewer of the anxietypresent words were selected than those of the anxiety-present words omitted by the patient (table III). An analogue line scoring system (Wilson, 99) might have been a more sensitive subjective method of assessing apprehension. The observer four-point rating score of anxiety was used for statistical analysis of data because of its widespread application previously (Morrison, Hill and Dundee, 9). We were unable to explain why some patients received little relief of their apprehension from the active drugs although assessment of the premedication before the -min interval had elapsed and increased apprehension before premedication were factors more frequently found in this group. Surprisingly, those who requested night sedation with nitrazepam before operation failed to get much relief from the benzodiazepine premedication, implying tolerance or minimal residual effect which is contrary to previous experience (Malpas et al., 97). Amnesia for unpleasant aspects of the perioperative period is a useful ingredient of premedication and the benzodiazepine group of drugs share this effect Lack of recall of picture cards does not necessarily mean that the patient will not remember events such as the journey to the operating theatre, and induction of anaesthesia, but recall of the long time spent lying on an uncomfortable theatre trolley may be obtunded. We demonstrated a differing amount of recall of five cards shown h after premedication across the one placebo and six drug groups (table VH). The relative amnesic actions and duration of effect have been described for i.v. diazepam, lorazepam and flunitrazepam (George and Dundee, 977). The frequency of observed toxic effects from benzodiazepine premedication is small (table VI) and there was no significant difference across the drug groups except for headache (P<). When examining the difference in median values after and before premedication, the placebo group recorded a higher score for headache whereas none of the drug groups showed an increase. Whether precipitated by fluid deprivation or emotional tension, benzodiazepine premedication seems to reduce the frequency and severity of headache, although these drugs have no analgesic properties. Dizziness is a recognized side-effect of larger doses of all benzodiazepine drugs, but as there was no significant difference amongst the treatment groups this was not shown in our study. Blurred vision occasionally accompanied dizziness when moderate or severe. Despite the number of anaesthetists judging the premedication immediately before induction, by various personal criteria, there was a significant difference in satisfactory comments across the drug groups (table V). This implied that benzodiazepine premedication probably did not interact adversely with the chosen anaesthetic techniques. It is interesting that the placebo was approved as a satisfactory premedication in 7% of those who received it. The influence of different trained observers on the rating score of drowsiness and excitement was quite marked. This observation contrasts with the findings of a previous study using the same observer assessment scheme (Morrison, Hill and Dundee, 9). However, in that study a single score of efficacy or desired effect was generated from combined assessment of sedation, freedom from apprehension and restlessness. We sought to distinguish each aspect and this discrimination led to differences in observer rating scores for excitement particularly, and somewhat less for drowsiness. has an elimination half-life of h, but has no active metabolites (Elliott, 97). and its major active metabolite, desmethyldiazepam, have elimination half-lives of more than h. Changes in serum flunitrazepam concentrations after i.v. injection of doses comparable to those in our study follow the same pattern as diazepam, but with 7-aminoflunitrazepam as the main metabolite (Korttila and Linnoila, 97). Drowsiness and tiredness with deterioration of co-ordinating skills were demonstrable for up to h after i.v. flunitrazepam and behavioural tests were impaired for h after oral flunitrazepam (Bond and Lader, 97). The fact that it was a young female patient population which we studied may explain the disparity between these findings and our observations. A detailed study of the postoperative recovery period after flunitrazepam

7 ORAL BENZODIAZEPDSTE PREMEDICATION premedication and standardized anaesthetic technique seems to be indicated. The significant changes in "neuroticism", "extroversion" and "lie" scores from before to after operation might be the result of the difference in content of alternative forms A and B, or the developing relationship of the observer and patient. It was disappointing to find that personality characteristics could not predict who might not gain relief of apprehension from standard benzodiazepine premedication. A strong positive correlation has been noted between the neuroticism score and vital capacity impairment with chest complications in female patients undergoing elective cholecystectomy (Dalrymple, Parbrook and Steel, 97). The lie score showed a significant correlation with the patient's subjective pain assessment in the same study, but not with the response of male patients to i.v. methadone or inhaled nitrous oxide for analgesia after gastric surgery (Dalrymple and Parbrook, 97). The development of the benzodiazepine group of drugs has given the anaesthetists a variety of interesting agents with different characteristics. If relief of apprehension and drowsiness within h of oral premedication are desirable for patients undergoing minor gynaecological procedures, flunitrazepam offers advantages over the placebo, diazepam and lorazepam. However, the improved efficacy is not accompanied by a significant increase in undesired effects. ACKNOWLEDGEMENTS The authors would like to record their gratitude for the kind co-operation of the nursing staff, surgeons and anaesthetists at Christchurch Women's Hospital, for the financial support of Roche Products (New Zealand) Ltd and the excellent secretarial assistance of Miss Joan Larsen. REFERENCES Atkinson, R. S., Rushman, G. B., and Lee, J. A. (977). A Synopsis of Anaesthesia, th edn, p.. Bristol: John Wright. Bond, A. J., and Lader, M. H. (97). Residual effects of flunitrazepam. Br. J. Clin. Pharmacol.,,. Dalrymple, D. G., and Parbrook, G. D. (97). Personality assessment and postoperative analgesia. A study in male patients undergoing elective gastric surgery. Br. J. Anaesth.,, 9. Steel, D. F. (97). Factors predisposing to postoperative pain and pulmonary complications. A study of female patients undergoing elective cholecystectomy. Br. J. Anaesth.,, 9. Dundee, J. W., Moore, J., and Nicholl, R. M. (9). Studies of drugs given before anaesthesia. I: A method of preoperative assessment. Br. J. Anaesth.,,. Dunn, O. J. (9). Multiple comparisons using rank sums. Technometrics,,. Egbert, L. D., Battit, G. E., Turndorf, H., and Beecher, H. K. (9). The value of the preoperative visit by an anaesthetist. J.A.M.A.,,. Elliott, H. W. (97). Metabolism of lorazepam. Br. J. Anaesth.,, 7. Eysenck, H. J., and Eysenck, S. B. G. (9). The Eysenck Personality Inventory. London: University of London Press. George, K. A., and Dundee, J. W. (977). Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man, Br. J. Clin. Pharmacol,,. Korttila, K., and Linnoila, M. (97). Skills related to driving after intravenous diazepam, flunitrazepam or droperidol. Br. J. Anaesth.,, 9. Leigh, J. M., Walker, J., and Janaganathan, J. (977). Effect of preoperative anaesthetic visit on anxiety. Br. Med. J.,, 97. McKay, A. C, Dundee, J. W., and George, K. A. (97). The amnesic effects of orally administered benzodiazepines. Br. J. Anaesth.,, P. Malpas, A., Rowan, A. J., Joyce, C. R. B., and Scott, D. F. (97). Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitne sodium. Br. Med. J.,, 7. Morrison, J. D., Clarke, R. S. J., and Dundee, J. W. (97). Studies of drugs given before anaesthesia. XXI: droperidol. Br.J. Anaesth.,, 7. Hill, G. B., and Dundee, J. W. (9). Studies of drugs given before anaesthesia. XV: Evaluation of the method of study after observations. Br.J. Anaesth.,,9. Norris, W., and Baird, W. L. M. (97). Preoperative anxiety: a study of the incidence and aetiology. Br. J. Anaesth., 9,. Paymaster, N. J. (97). (WY ) as a preoperative medication. Anaesthesia,,. Quade, D. (97). Rank analysis of covariance.j'. Am. Stat. Assoc.,, 7. Wassenaar, W., Lancee, W. J., Galloon, S., and Gale, G. D. (977). The measurement of anxiety in the presurgical patient. Br. J. Anaesth., 9,. Wilson, J. (99). A preliminary evaluation of analogue scoring in sedation. Br. J. Anaesth.,, 79. (97). as a premedicant for general anaesthesia. Curr. Med. Res. Opin.,,. Zuckerman, M. (9). The development of an affect adjective check list for the measurement of anxiety. J. Consult. Clin. Psycho!.,, 7. COMPARAISON DE TROIS BENZODIAZEPINES POUR ADMINISTRATION PAR VOIE BUCCALE EN TANT QUE PREMEDICATION POUR LES INTERVENTIONS GYNECOLOGIQUES MENEURES. RESUME On a compart, au cours d'une itude controlee a double inconnue effectuee au hasard, les effets de diazepam, a raison de et, du lorazepam, a raison de, et, du flunitrazepam a raison de et de, ainsi que d'un

8 BRITISH JOURNAL OF ANAESTHESIA placebo, administre par voie buccale en tant que premedication a femmes devant subir des interventions chirurgicales gynecologiques mineures. Le flunitrazepam a raison de et le lorazepam a raison de, ont et meilleurs que le placebo (P<, et P<, respectivement) pour soulager l'anxiete de la malade, lorsque cette anxiete a ete evaluee par un observateur entraine mn apres radministration de la premedication. Le flunitrazepam a raison de a aussi produit davantage de somnolence diurne que le placebo (P <,). Les comparaisons des autres groupes de benzodiazepine a faible dose avec le placebo, et de la forte dose avec la faible dose de chaque produit n'ont indique aucun changement significatif dans l'anxiolyse ou la somnolence diume. On n'a remarque aucun malaise ou aucune somnolence avec le flunitrazepam administre a faible dose. Les donnees laissent penser que le flunitrazepam a raison de presente des avantages par rapport au placebo, au diazepam a raison de ou au lorazepam a raison de, pour radministration routiniere par voie buccale, lore des interventions chirurgicales gynecologiques mineures. VERGLEICH DREIER BENZODIAZEPINE FtJR ORALE VORBEHANDLUNG FUR KLEINERE GYNAKOLOGISCHE EINGRIFFE ZUSAMMENFASSUNG und,, und,, und sowie ein Plazebo wurden in einem wfllkilrlichen, doppelblind-kontrolliertem Versuch als orales Vorbehandlungsmittel bei Patientinnen getestet, die sich kleineren gynakologischen Eingriffen unterzogen. und ^ waren dem Plazebo uberlegen (P<, bezw. P<,), was den Beruhigungseffekt betraf, der von einem geschulten Boebachter Minuten nach Verabreichung beurteilt wurde. bewirkte auch mehr Schlifrigkeit als das Plazebo. Vergleiche anderer Benzodiazepine in niedrigen Dosen mit dem Plazebo, und Vergleiche zwischen grossen und kleinen Dosen der jeweiligen Droge zeigten keine wesentlichen Anderungen bei Arotiolyse oder Sclafrigkeit. Schwindel uod verlfingerte Schlafrigkeit zeigten sich bei niedrig dnsiertem nicht. Diese Daten zeigen, dass, vorteilhaft ist gegenuber Plazebo, und, wenn es urn routinemissige orale Vorbehandlung fur kleinere gynskologische Eingriffe geht. COMPARACION DE TRES BENZODIAZEPINAS PARA PREMEDICACION ORAL EN CIRUJIA GINECOLOGICA MENOR SUMARIO Se procedio a una comparacion de y de diazepam,, y, de lorazepam, y de flunitrazepam y de un placebo en una prueba doble-ciega controlada al azar, como premedicacion oral de pacientea sometidas a operaciones quirurgicas ginecolgicas menores. Se comprob que de flunitrazepam y, de lorazepam daban mejores resultados que el placebo (P<, y P<,, respectivamente) en aliviar la ansieded de las padentes cuando los evaluaba un observador capacitado min despues de la premedicacion. Con de flunitrazepam se producfa tambien mayor somnolencia que con el placebo (P<,). No se registraron cambios significativos de la ansidlisis o de la somnolencia al realizar comparaciones de otros grupos de benzodiazepinas en dosis menores con el placebo, y de dosis mayores con dosis menores de cada substanda. No se manifestaron vertigos ni somnolencia prolongada con el flunitrazepam en dosis bajas. Estos datos hacen pensar que de flunitrazepam es mis ventajoso que el placebo, de diazepam, y, de lorazepam para la premedicacion oral corriente en operaciones quirurgicas ginecolgicas menores.