STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA X: TWO NON-PHENOTHIAZINE ANTI-EMETICS CYCLIZINE AND TRIMETHOBENZAMIDE

Transcription

1 Brit. f. Anaesth. (9),, STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA X: TWO NON-PHENOTHIAZINE ANTI-EMETICSCYCLIZINE AND TRIMETHOBENZAMIDE BY JOHN W. DUNDEE, FREDERICK HALLIDAY, ROBERT M. NICHOLL AND JAMES MOORE Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY Two non-phenothiazine anti-emetics, cydizine mg and trimethobcnzamide mg were studied after being given by injection with atropine. mg or pethidine mg (without atropine) as premedication before a standard gynaecological operation, performed under methohexitone, nitrous oxide and oxygen anaesthesia. was a poor preoperative sedative but trimethobenzamide was weakly effective. increased the incidence of excitatory phenomena following induction of methohexitone anaesthesia. Both drugs enhanced the soporific effect of pethidine and reduced pre-operative emetic effects. was more effective in reducing sickness in the postoperative period and was worthy of further study. In a recent paper from this department the effects of fourteen phenothiazines and two phenothiazine-like drugs when given in premedication under standard conditions were reported (Dundee ct al, 9a). The least toxic of these were chosen for further study in combination with pethidine mg (Dundee et al., 9b) and although some proved to be very effective anti-emetics, in most instances their value was outweighed by an increased incidence of side effects such as drowsiness, hypotension and restlessness. It was considered desirable to continue the study using nonphenothiazine anti-emetics and this paper reports the results of the investigation of two such drugs, cyclizine and trimethobenzamide, the structural formulae of which are shown in figure. CH } CHjCHi CHN NCH CH CH (Marzine, Valoid).OCH hydrochloride (Marzine, Valoid, Marezine), is an antihistamine which has been used widely in the prevention and treatment of travel sickness (Chinn et al., 9; Conner and Moyer, 9), and more recently for irradiation sickness (Stoll, 9). Its use in anaesthetic practice is based solely on its anti-emetic effects (Dent, Ramachandra and Stephen, 9; Moore et al., 9; Davys and Gallagher, 9), and it is particularly recommended for the postoperative control of nausea and vomiting following cataract surgery (Lorhan and Holman, 9). Opinions differ as to its efficacy, especially in comparison with the phenothiazine derivatives, but all workers report that, in the usual adult therapeutic dose of mg, it is a safe, non-toxic preparation. Trimethobenzamide (Tigan; Ro-9) differs chemically from both the phenothiazines and antihistamines, and in animals Schallek and his associates (99), Brandman (I9), and Wyant (9) reported that it is an almost specific antiemetic. It has definite therapeutic effect in man (Kolodny, 9; Nathan, 9) and, like cyclizine, all workers are agreed on its lack of toxicity (Sobel 9; Coppolino and Wallace, 9). CH Trimethobenzamide (Tigan) FIG. Formulae of drugs studied. METHOD This has been reported in detail in previous publications, and the main features are summarized here.

2 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIAX Subjects. Observations were carried out on fit patients from one hospital unit, who were scheduled for minor gynaecological operations. Almost all operations were carried out before noon, thus standardizing the ward activity before and after anaesthesia. Observers. Although this study was spread over a period of four years, all pre-operative and postoperative observations were carried out by the authors, who either personally administered the anaesthetics or supervised their administration. Pre-operative assessment (Dundee, Moore and Nichol, 9a; Dundee, Moore and Clarke, 9). Drugs were given by intramuscular injection and patients were "screened off" in the ward and visited between and 9 minutes later. The presence and degree of drowsiness, apprehension, and restlessness or excitement was noted at this time as were all side effects occurring up to then. These latter included persistent pain at injection site, dizziness, emetic effects, tachycardia and hypotension. The overall desired effects of the premedication were graded from (good sedation, no apprehension, etc.) to (no sedation, marked apprehension or restlessness), while the side effects were graded from (nil) to (severe). These are referred to as the "efficacy" and "toxic^ scores. The "net" score (efficacy minus toxic), which can vary from + to, is a means of expressing the relative effects of different drugs. Effect on course of anaesthesia (Dundee, Moore and Nicholl, 9b). Patients were anaesthetized with methohexitone (. mg/kg), nitrous oxide ( l./min), and oxygen ( l./min) for these minor operations and the frequency and severity of complications during anaesthesia noted. Each administration was graded as (uneventful), a (slight upset not interfering with the course of anaesthesia), b (moderate upset interfering with anaesthesia), or (patient unmanageable or other severe side effects). Postoperative sequelae. All patients were seen at approximately and hours after operation, and the nature and incidence of emetic sequelae recorded. This was analyzed according to the scheme described by Dundee, Nicholl and Moore (9). In order to validate the comparison between different groups it was necessary to arrange the series so that in half of the patients a cervical dilatation was performed prior to curettage, because this manoeuvre is known to have an effect on postoperative vomiting. Drugs studied. In the first part of the investigation atropine. mg was used alone, with cyclizine mg or with trimethobenzamide mg. Atropine was omitted in the second part of the study in which pethidine mg was used alone, with cyclizine mg or with trimethobenzamide mg. With the exception of pethidine and cyclizine (which are not miscible in the commercially available forms and required two separate injections at different sites) the "double blind" technique was used for most of the study which wts carried out concurrently with investigation* of the phenothiazines or different opiates. Presentation and analysis of data. For brevity only the percentage incidence of findings will be presented although statistical analysis was carried out on absolute numbers. With subjective findings which arc graded according to severity (such as the degrees of pre-operative drowsiness and apprehension) analysis was carried out on the distribution of the grades (using the x method with pooling of two or more groups if required). Small numbers necessitated the pooling of all degrees of restlessness, dizziness and emetic effects, and these were also analyzed by the X a method. Objective findings presented no problems in analysis and it was possible to compare the frequency of severe and mild hypotension with different premedicants, before, during and after anaesthesia. The ridit method of analysis (Belville, Bross and Howland, 99; Bross, 9) was employed when a scoring scheme was adopted in order to give an overall picture of the action of a drug. This included the pre-operative efficacy and toxicity score, the grades of anaesthesia and the postoperative emetic scores. Subjects. Table I shows that all groups are broadly comparable as regards the average age and weight of the patients. There was no significant difference in the average duration of anaesthesia in the three series when pethidine mg was used. Premedication TABLE I Details of subjects and average duration of No. of cases Atropine. mg plus Nil mg Trimethobenzamide mg Pethidine mg plus Nil mg Trimethobenzamide mg Average age (yr) operation. Average weight (kg) Average duration of anaesthesia (min). ±.. ±. ±.. ±.. ±.. ±

3 BRITISH JOURNAL OF ANAESTHESIA TABLE II Observations before anaesthesia, after pre-anaesthetic medication had been given. Atropine or pethidine were given alone or in combination with cyclizine mg and trimethobenzamide (tjn.b.) mg as indicated. Results expressed as percentage. Drowsiness Good Fair Slight Apprehension Slight Moderate Marked Restlessness or excitement Pain at injection site Dizziness Emetic effects Tachycardia (beats /min) Hypotension Efficacy score Mean Toxic score Mean Mean net score 9 Atropine. mg plus mg.. +. tm.b. mf? Pethidine mg plus mg t.m.b. mr RESULTS A summary of the prc-operative observations made with the different drugs is given in table II. The addition of cyclizine or trimethobenzamide to atropine or pethidine increased the frequency and degree of pre-operative drowsiness to a significant degree (P<.). However, ridit analysis of the distribution of efficacy scores shows that, according to the criteria telected by the authors, the addition of cyclizine or trimethobenzamide to atropine did not result in a significant increase in desired pre-operative effects as compared with those of atropine alone. By the same criteria cyclizine-pethidine was found to be markedly better than pethidine alone, but the improvement when trimethobenzamide was added to pethidine just failed to achieve the accepted per cent level of significance as compared with pethidine alone. Dizziness, a frequent complication with cyclizine, was always mild and transitory, as also was the pain at the injection site complained of after trimethobenzamide premedication. After the addition of the anti-emetic drugs to atropine the distribution of toxicity scores did not differ significantly from that following atropine alone. Both anti-emetics decreased the toxicity of pethidine to a significant degree. The data relating to the overall pre-operative effects of all drugs are summarized in table HI.

4 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIAX Table IV gives the dosage of methohexitone required for anaesthesia and the incidence of complications during operation. Cydizine increased the frequency of excitatory phenomena to a significant (P<.) degree when pethidine was not given, but no such increase was found when it was combined with pethidine. This tendency for cydizine to provoke muscle movements when given with atropine as premedication is reflected in the larger dose of methohexitone required in an endeavour to maintain anaesthesia and the high inddence of unsatisfactory (grade b and ) anaesthesia. Taking dosage differences into consideration, table IV does not show any evidence TABLE III Percentage incidence of overall pre-operative effects as assessed by net scores. Overall pre-operative effect (Net scores) Atropine. mg plus Nil mg Trimethobenzamide mg Pethidine mg plus Nil mg Trimethobenzamide mg that the addition of one or other anti-emetic delayed recovery from anaesthesia The percentage inddence of postoperative nausea and vomiting is shown graphically in figure. In the three pethidine series (table V) there was a highly significant reduction (P<.) in the proportion of patients vomiting, but not in those who complained of nausea, with both anti-emetics during the first hour after operation. During the - hour period, cydizine reduced both symptoms to a significant (P<.) degree, while trimethobenzamide only reduced the frequency of vomiting, and even this reduction did not reach the accepted per cent level of signi- Undesir- Good ( +, +) Fair ( +, +) Poor (, -) able (- + ) 9 TABLE IV Course of anaesthesia as shown by average dost of drugs, frequency of complications, and state of consciousness minutes after discontinuation of nitrous oxide-oxygen anaesthesia. Average dose of methohexitone (mg/kg) Induction. Total. ±. Course of anaesthesia % excitatory phenomena % respiratory upset % hypotension (fall mm Hg +) Grade of anaesthesia % (uneventful) % a (slight upset) % b (moderate upset) % (very troublesome) Condition min after end % awake % safe % unsafe Atropine. mg plus mg..9 ±. un.b. mg..±. Pethidine mg plus.. ±. 9 mg.9. ±. un.b. mg.. ±. 9

5 BRITISH JOURNAL OF ANAESTHESIA PREMEDICATION ATROPINE O- mg plus OI HOURS HOURS O- HOURS *o O io io S izo CYCLIZINE T.M.B. SO mg OOmq PETHIDINE IOO mg CYCLIZINE J.MB O mg OOmg FIG. Percentage incidence of emetic sequelae following different premedications. Solid column=vomiting, including retching. Hatched column=nausea. (T.M.B. = trimethobenzamide.) TABLE V Overall survey of per cent emetic sequelae with pethidine alone or in combination with cyclizine mg or trimethobenzamide (t.m.b.) mg. Pre-operative Postoperative - hour - hours - hours Nil Average emetic score (all patients) Average emetic score (sick patients) Total incidence Nil Average ridit of scores (relative to pethidine alone).. 9. ±. Pethidine mg plus mg ±. Lrn.b. mr... ±. includes retching, and when nausea and vomiting both occur, this is shown as vomiting.

6 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIAX ficance. The difference in the efficacy of the two anti-emetics can be judged from the fact that the significance in the reduction of vomiting and nausea during the first hours after operation (as compared with the series receiving pethidine alone) is. (df=; y = 9.) when cyclizine was given and only. (df=; -/ =.) when trimethobenzamide was used. DISCUSSION Considering first the pre-operative use of the two anti-emetics when given with atropine, it can be seen from table II that both led to an increase in the proportion of patients who showed evidence of sedation (increased drowsiness and decreased apprehension), but in the case of cyclizine this benefit is more than outweighed by the greater frequency of restlessness, dizziness and tachycardia. From the results shown in table HI it can be seen that the combination of cyclizine mg and atropine. mg cannot be recommended as pre-anaesthetic medication. The increased incidence of excitatory phenomena and the high average total dose of methohexitone following the use of cyclizine can be attributed to its moderate antanalgesic action as described by Nicholl, Moore and Dundee (9). This may be correlated with the frequency with which poor conditions of anaesthesia followed the use of this premedicant; a further reason is thus provided for advising against its pre-operative use without analgesics. The soporific effects of both anti-emetics are again evident when they were combined with pethidine (table II). In the case of cyclizine this has been noted by Bonica and associates (9) and Blatchford (9) whilst Moore and associates (9) recommended that, for this reason, doses of routine premedication drugs should be reduced when it is intended to combine them with cyclizine. Most of the publications on trimethobenzamide (Belville, Bross and Howland, 9; Nathan, 9; Wolfson, Torres-Kay and Foldes, 9) do not refer to a hypnotic action, but Ouellette (9) stated that it has a slight sedative effect and possibly potentiates other pre-operative drugs. An alternative explanation for the increased drowsiness noted with the pethidine-anti-emetic combinations, is the lower incidence of pre-operative nausea and vomiting as a result of which patients were less disturbed by sickness than after pethidine alone. It has been suggested (Dundee, Moore and Clarke, 9) that the reason why pethidine is a better pre-operative sedation when combined with atropine than when given alone lies in the capacity of atropine to exert an anti-emetic action. While cyclizine mg and trimethobenzamide mg both reduced the frequency of preoperative dizziness noted following pethidine, this symptom is still complained of by one-third of all patients; this is an unacceptably high incidence. Persistent pain at the injection site was an unexpected complication of the use of trimethobenzamide, and was complained of particularly by patients who had not been given an analgesic drug. This side-effect does not appear to have been noted by other workers. and trimethobenzamide were both effective in reducing significantly the pre-operative emetic effects, particularly vomiting, noted after pethidine (P<.). The significance of this will be discussed later. Taking all factors into consideration (table DI) the combination of pethidine mg with cyclizine mg or trimethobenzamide mg proved to be vastly superior to pethidine alone as a pre-operative medication. with atropine was the only combination of drugs that seriously interfered with the course of anaesthesia with methohexitone, nitrous oxide and oxygen. This was due to the high incidence of excitatory phenomena resulting from the antanalgesic effect of the cyclizine (Nicholl, Moore and Dundee, 9). It can be assumed that this study eliminates variables affecting postoperative nausea and vomiting to as great a degree as is possible in a clinical investigation, and that the differences in the constituents of premedication are responsible for the differences found in figure and table V. The control (atropine) incidence of emetic effects was so low that it was not to be expected that these doses of cyclizine or trimethobenzamide could reduce this to a significant extent. The most important clinical aspect of this study relates to the postoperative emetic sequelae when the two drugs are given with pethidine. As can be seen from figure, both are effective anti-emetics, cyclizine mg being more potent than trimethobenzamide mg. These data are amplified in table V, in which it is shown that the effect of trimethobenzamide mg is limited almost

7 BRITISH JOURNAL OF ANAESTHESIA entirely to a reduction in the incidence of vomiting following pethidine and that it is much less effective than cyclizine mg in lowering the frequency of nausea. The data in table V indicated that, in the doses used in this study, trimethobenzamide is somewhat shorter-acting than cyclizine. The greater anti-emetic potency of cyclizine is in agreement with the findings of Belville, Bross and Howland (I9), and of Blatchford (9). The reduction in vomiting by trimethobenzamide may be the reason why it has been termed a "specific" anti-emetic by Schallek et al. (99), but the findings of their animal experiments have not been shown to apply to man. In fact, Blatchford (9) thought it should be given in mg doses, while Wolfson, Torres-Kay and Foldes (9) found it to be only moderately effective in the prevention of nausea and vomiting, its usefulness being proportional to the strength of the stimulus. The only real advantage of trimethobenzamide over cyclizine was its miscibility with pethidine; doses of pethidine mg and trimethobenzamide mg were prepared premixed in -ml ampoules, whereas, as stated previously, pethidine and cyclizine required two syringes and two injection sites. This was unpleasant for the patients and inconvenient to the nursing staff, and could lead to a delay when large numbers of patients were requiring medication. The findings of the present investigation together with other accumulated data suggest that there is a need for research into the possibility of mixing these drugs. ACKNOWLEDGEMENTS Thanks are due to the gynaecologists at Musgrave Park Hospital, Balmoral, for their continuing forbearance with these studies. Generous supplies of Tigan brand trimethobenzamide were provided by Roche Products Limited, while Burroughs Wellcome similarly supplied the Valoid brand cyclizine. REFERENCES BeUville, J. W., Bross, I. D. J., and Howland, W. S. (99). A method for the clinical evaluation of antiemetic agents. Anesthesiology,,. (9). Post-operative nausea and vomiting. V: Antiemetic efficacy of trimethobenzamide and perphenazine. Clin. Pharmacol. Ther.,, 9. Blatchford, E. (9). Studies of antiemetic drugs: a comparative study of cyclizine (Marzine), pipamazine (Mornidine), trimethobenzamide (Tigan) and hyoscine. Canad. Anaesth. Soc. J.,, 9. Bonica, J., Cripps, W., Monk, B., and Bennett, B. (9). Post-anesthetic nausea, retching, and vomiting: evaluation of cyclizine (Marezine) suppositories for treatment. Anesthesiology, 9,. Brandman, O. (9). Clinical evaluation of the effectiveness and safety of trimethobenzamide. Gastroenterology,,. Bross, I. D. J. (9). How to use ridit analysis. Biometrics,,. Chinn, H I., Handford, S. W., Smith, P. K., Cone, T. E., Redmond, R. F., Maloney, J. V., and Smythe, C McC. (9). Evaluation of some drugs in sea sickness. J. Pharmacol, exp. Ther.,, 9. Conner, P. K., and Mover, J. H. (9). A therapeutic appraisal of antiemetic agents. GP,, No.. Coppolino, C A., and Wallace, G. (9). Trimethobenzamide antiemetic in the immediate postoperative period: double blind study in, cases. J. Amer. med. Ass.,,. Davys, R., and Gallagher, E. (9). Post-anaesthetic vomiting: a trial of cyclizine tartrate. J. Irish med. Ass.,,. Dent, S. J., Ramachandra, y., and Stephen, C R. (9). Postoperative vomiting: incidence, analysis and therapeutic measures in, patients. Anesthesiology,,. Dundee, J. W., Moore, J., and Clarke, R. S. J. (9). Studies of drugs given before anaesthesia. V: Pethidine mg alone and with atropine or hyoscine. Brit. J. Anaesth.,,. Love, W. J., Nicholl, R. M., and Clarke, R. S. J. (9a). Studies of drugs given before anaesthesia. VI: The phenothiazine derivatives. Brit. J. Anaesth.,,. Nicholl, R. M. (9a). Studies of drugs given before anaesthesia. I: A method of preoperative assessment. Brit. J. Anaesth.,,. (9b). Studies of drugs given before anaesthesia. II: A method for assessing their influence on the course of anaesthesia. Brit. J. Anaesth.,,. Nicboll, R. M., Clarke, R. S. J., Moore, J., and Love, W. J. (9b). Studies of drugs given before anaesthesia. VII: Pethidine-phenothiazine combinations. Brit. J. Anaesth.,,. Moore, J. (9). Studies of drugs given before anaesthesia. Ill: A method for the studying of their effects on post-operative vomiting and nausea. Brit. J. Anaesth.,,. Kolodny, A. L. (9). A controlled study of trimethobenzamide (Tigan), a specific antiemetic. Amer. J. med. Sci., 9,. Lorhan, P. H., and Holman, M. V. (9). hydrochloride (Marezine) for the postoperative control of nausea and vomiting following cataract surgery. Amer. J. Ophthal.,, No.. Moore, D. C, Bridenbaugh, L. D., Piccioni, V. F., Adams, P. A., and Lindstrom, C. A. (9). Control of postoperative vomiting with Marezine: a double blind study. Anesthesiology,, 9. Nathan, L. A. (9). Pediatric use of trimethobenzamide, a specific antiemetic. Curr. ther. Res.,,.

8 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIAX Nicholl, R. M., Moore, J., and Dundee, J. W. (9). Alterations in response to somatic pain associated with anaesthesia. XI: Two non-phenothiazine antiemetics: cyclizinc and trimethobenzamide. Brit. J. Anaesth.,,. Ouellette, R. D. (9). Control of postoperative nausea and vomiting with trimethobenzamide. Anesth. Analg. Curr. Res.,,. Schallek, W., Heise, G. A., Keith, E. F., and Bagdon, R- E. (99). Antiemetic activity of -(-dimethylaminoethoxy)-n-(,, trimethoxybenzoyl) benzylamine hydrochloride. J. Pharmacol, exp. Ther., <t,. Sobel, A. (9). Control of postanesthetic emesis with trimethobenzamide. Anesthesiology,, 9. Stoll, B. A. (9). New drugs for irradiation sickness. Radiology,,. Wolfson, B., Torres-Kay, M., and Foldes, F. F. (9). Investigation of the usefulness of trimethobenzamide (Tigan) for the prevention of postoperative nausea and vomiting. Anesth. Analg. Curr. Res.,,. Wyant, G. M. (9). Comparative study of antiemetic drugs. Canad. Anaesth. Soc. J., 9, 99. ETUDES SUR LES DROGUES ADMINISTREES AVANT L'ANESTHESIE X: DEUX ANTIEMETIQUES NON-PHENO- THIAZINIQUESLA CYLCLIZINE ET LA TRIMETHOBENZAMIDE SOMMAIRE Deux antiemitiques non-phenothiaziniques, a savoir mg de cyclizine et mg de trimethobenzamide ont it tudies apres administration parentlrale ensemble avec, mg d'atropine ou mg de pithidine (sans atropine) comme premedication avant une operation gynecologique standard effectuee sous m thohexitone, protoxyde d'azote et oxygene. La cyclizine itait un sedatif preopiratoire faible mais la trimfithobenzamide s'est montree legerement efficace. La cyclizine augments les phenomenes d'excitation apres 'induction de l'anesthesie par la methohexitone. Les deux drogues renforcerent l'effet soporifique de la pethidine et diminuirent les effets emitiques piioperatoires. La cyclizine etait plus efficace pour combatue les nausees apres l'operation et devrait faire l'objet de nouvelles Etudes. UNTERSUCHUNGEN t)ber DROGEN FUR DIE NARKOSEPRAMEDIKATION X: ZWEI ANTIEMETIKA AUSSERHALB DER PHENOTHIAZIN-REIHE: CYCLIZINE UND TRIMETHOBENZAMIDE ZUSAMMENFASSUNG Es wurden zwei Antiemetika auflerhalb der Phenothiazin-Reihe, mg und Trimethobenzamide mg, untersucht, die zusammen mit, mg Atropin oder mg Pethidine (ohne Atropin) als Pramcdikation fur ubliche gynakologische Operationen, durchgefuhrt in Methohexitone-Lachgas-Sauerstoff- Narkose, intravenos verabfolgt wurden. war ein schlechtes pra-operatives Sedativum, wahrend Trimethobenzamide sich als schwach wirksam envies. Nach kam es gehauft zu Erregungszustanden nach Einleitung der Methohexitone-Narkosen. Beidc Drogen steigerten die einschlafernde Wirkung des Pethidine und verringerten die praoperativc Brechreizneigung. envies sich als wirksamer in der Dampfung des Brechreizes in der post-operativen Phase und sollte weiter uberpruft werden. NOTICE REFRESHER COURSE IN ANAESTHESIA for General Practitioners and part-time Anaesthetists MAY TO MAY, 9 Numbers limited to. Particulars from Dr. R. A. FISHER, Postgraduate Medical Centre, Royal Victoria Hospital, Bournemouth, Hampshire.