TH,'E ACTION OFf THIETHYLPERAZI!~Ei: ~ITO!~ECANr A NE'~( ANTI''-- EMETIC, COMPARED,' WITH:". PER[P:NHE' i ' q[AZINE ' ( TRILAFON|:'1 L TR~METHOBENZAMIDE (TIGAN| AND[A PI.ACE~O IN THE" suPPRESSION OF POSTANAESTHETI~NAIUSEN AND V()MITING IAN E. PtrnICIS, M.B., B.S., ~.F.A..I~.C.S.O POSTa_Na_ESTH~TIC VOMITING has been ~shown ~0 b(l" i~ffffeneed ]~y a varie]ty of factors, and it is therefore unlikely that any a~i-ergetie drug will be completely effective and without side-effects in all patients. In[the absence of any ele~r-eut superiority of one drug over another,-the physi4ian naust exercise a choicK selecting a drug with minimum side-effects but maximum anti-emetic effect. This choice can only be made on the basis of ieontrolled studies of effectir and side-effects, since clinical impressions can be nlost misleading.~ Malay ~igents can be shown to have an anti-emetic effect wl~n e0mpared I with a placebo (e.g., atropine) 1 but they may not be clinically us,~fuI as anfi-erneties. If new drug can be shown to have an effect equal to ~or better than a drug whi, .a has proven highly effective against a strong clinica,l challenge, then it is likeb that the new agent will be clinically useful. Thiethylperazine (Toreean| is a phenothiazin Which possesses to a very marked degree the anti-emetic activity common to all drugs, of this group, while the other group activities of lowering bk od pressure,~=.potentiatign of narcotics and barbil~urates, and extrapyramidal et feets, are minimized. 2 There have been a numberl of reports of its anti-emetic ef ?ect compared with a plgcebo in man, ~.4,~ and there is experimental evidence :o suggest that its medullary action is not confined to the Chemoreceptor Trig ger Zone (CTZ) but elacom- passes the vomiting centre as welI2 Perphenazine (Trilafon| was c~sen as a comparative standard, since this drug had ranked as the most effective agent of four in ra/~revious comparative triald ~4z the same time the opportunity was taken l to corhpare these two ~,tgents with tnmethobenzamlde:;. (Tlgan (~ ) m........ high, dosage, since chmcally this latterI drug appeared to have minimal anti-emetic'~activlty.8 METHOD A previous triaF had shown that the highest incidence of emetic symlptoms followed the operations of abdominal hystereqtomy, vaginal hystereqtomy, and cholecystectomy, and that symptoms werejmore than twice as common in female patients as in ~ale. Accordingly, female patients undergoing hysterectomy and cholycystectomy were selected for this survey in order to provide ~ high *Department of Anaesthesia, Victoria General Hospital and Dalhousie University, Halifax, Nova Scotia. This study was supported by a grant-in-aid from Sandoz Pharmae~uticals (Canada) Ltd., whose assistance in statistical analysis and preparation of figures is gratefully acknowledged. 595 Can. Anaes. Soc. J., vol. 12, no. 6, November, 1965 I CANADIAN ANA]~STHETIS~" S~ ]OUBNAL! clialienge for the test drugs. All patients rec~@ed a standardpremedication of meperidine (Demerol) and atropm~,~:a~d a standard anaesthetic sequence of thiopentone' J ~' " induction with maint~nanl;~" "b '"~!n nitrous-oxide-ox)~gen-halotha~o~," " ' :~ I succinylcholiiie being used for relaxatio, as '.required. The,. test druust_J were coded m batchesI /in ~dentieal'i wals, and' :he aor)roonatej.s, J. ! dose of the selected drug was given by ntramuscular injecti6n :o each patient mcluded" m the" trial as she arrived i~a ti b recovery: room. The sr] lection ~ of drugI was dictated by reference to a randc)m llocatmn sheet for each operation, and the amount of drug was made prop(~rti( ml to body weight, by ~iving 0.04 ic.c. of test solution per pound of body We ,ht Peruhenazine was diluted to i.25 mg./e.c., ttimethobenzamide to 100 mg./'c:.c, and thiethylperazin~ to 5 mg./c.c. usin~ sterile 5 uer cent dextrose water, /which was also used f,)r the placebo. The'~l~10-pound ~patient, for example~ thus received~-7 mg. of perphenazine, !560 mg. of trimethobenzamide, or 28 mg. of thiethyl, perazine. All patients were Observed for two ho~rs m the recovery room, and incidents of nausea and vomiting were charted at 15-minute intervals using[ a score system. A complaint of nausea was scored as onc observed retchin~ ' or~gagging without lkluid emesis was scored as two, while each e uisodFe of liauid emesis scored three. Patients were visited betwee n 24 and 48 hours after operation, and t e me, dents cOl nausea and vomatmg recorde on the patient s chart were ~correlated wi~ thd/patiefit's observations, and" scored in the same way. Scores rlaade in ,. /. r the fir~t~15~,7~-: minutes were disreKarded,~ since it was felt thatY., the|test_ aKent had not b~6gun to act during this period. RESULTS On conclusion of the survey, the obs,~rvations, together with the identityof the test agents, were translated into a numerical code and placed on punch cards The data was subjected to a 3 X 3 X 4 factorial design analysi: which demon- stratbd that there was no significant difference in scores among he three chosen operative sites, that all sites had equal Lqfluence~on the emetic scores at different TAB.EL I , 3 X 3 X 4 FACTORIAL DESIGN ANALYSIS SHOWING SIGNIFICANT DIFFERENCES I3ETWEEN .TEST DRUGS AND TIME PERIODS, BUT N~D~ SIGNIFICANT. EFFECT. OF OPERATIVE..... SITE. ,ON'~.... DRU'GS./oR ~TIME2_. _ , , , , Source df Sum of squares Mean square F" ,, p Between Patients 331 2,980,. 6.55 Between drugs 3 I 118,.869 39.623 4.466 -<0.005 Between operations 2; 4:.798 2.399 2~0 n.s. Drug X operation interaction 6 17.816 2.969 335 n.s. Residual 320 2,839.172 8.872 Within Patients 664 2,793~333 Between periods 2 269. 774 134. 887 36.056 <0.00(1( Drug X period interaction 6 58. 661 9. 777 2. 613 <0.02,5 ~ Operation X period interactioia 4 18. 520 4. 630 1 238 n.s. Drug X Operation X period interacti0h ~ i2 511904 4.325 1. 156' 13, S. Residual fi40 2,394.474 3.741 Total 995 5,773. 988 J,, r , i , ' I. PUmKIS: THE ACTION OF TRIEq~-IYLI I~RAZINE 597 time periods, and that there was no interaction bet:ween the test drugs and the operative site (Table L). The data from all operations could thus be colnbi~ed, and was analysed with reference to incidence and ~severity of emetic sympt(~ms , and to the side effects of hypotension in the recovery room, potentiation of Inareotics~ and prolongation of postoperative sleep. Incidence of Emetic Symptoms Table II shows the increase in emetic syrnpfoms / in each group of patients with the passage of time. Thiethylperazine was given Io 86 patients, of whom 33.7 per cent showed sypm toms in the first two h~urs.~No more patients vomited during the next four hours, but by twenty-four hour~, 54..7 per cent had shown symptoms. Of the 79 patients receiving perphenaz [ne, 24.1 per cent showed symptoms after two hours, and 27.8 per cent after sk: hours, butday wenty-four hours, 48.1 per cent had shown emetic symFgoma These figures compared favourably with the placebo group of 83 patients, where 44.6 per cent were affected in the first two hours, the figure rising to 5( ~.6 per cent after six hoUrs, and reaching 66.3 per cent over the twenty-four ho ar p,e/iod. In contrast, 40.5 per cent of the 84 patients receiving trimethobenza: hide had symptoms in the first two hours, and the percentage increased to 52 .4 per cent after six hours and 82.1 per cent after twenty-four hours. The perc entage of patients showing symptoms in t~ese last two periods was thus grea',Lter than that seen in the placebo group. Statistical analysis of these figures (Table III) shows perphenazine to be significantly more effective (p < 0.05) than the other agents at two hours, but over the six-l~our period, perphenazine loses some of its effectiveness, wihile thiethylperazine does not, and thiethylperazine emerges as significantly more effect'iw~ than/placebo or trimethobenzamide over the six-hour period. Trimetho- benzamidemo~ w ranks as less effective than the plac,ebo~a"t this period, and ,this difference becomes significant over the twenty-four-hour period. Both perphenazine and triethylperazine are significantly superior to both placebo and trimetho- benzamide over the twenty-four-hour period, with perphenazine ranking as the most effective. The differences between perphenazine and triethylperazine are not significant on the basis of these incidence comparisons. The f es ul ts are shown graphically in FigUre J:. Severity of Emetic Symptoms: The average score for emetic symptoms (includ:l[ng ,;cores of Zero.) for all patients is shown in Table IV. VVith thiethylperazine, the average was' 1..035 over the first two hours, rising, to 1.326 over the six,hour period, and reaeMng 2~ for the full twenty-four',hour period. Perphenaizine was slightly less efFec- tive, the scores for the three(iperiods being 1.127, 1.747, and 3.266. Trimetho- benzamide was less effective than the other drugs, !with average scores of 1.381, 2.083, and 4.560 over the three time periods, but !t was still more effective than placebo, which showed average scores of 2.325, ~,]120, and 5,241 at these thnes. N-" Ir.-'-~ - . .,u---~---4 O qt T . G m ~ ~--o 4 rT') "5 A m O O O q 0 I.