The Action of Thiethylperazihe Torecan®), a New Anti-Emetic, Compared

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"r scored in the same way. Scores rlaade in 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 trimethobenzamide 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

T .

~ ~--o

4 rT')

"5 A m

0 I. PUIIKIS : THE ACTION OF TRIE~'~YI_3[?EBAT.I~CE 599

TABLE III ', ANALYSIS OF VARIAN~EA

Source of variation Sum of squares .. df Mean sq[uare F , ,,, , 1 15 rain.-2' hours Betv~een drugs 1.951 3 650 2.867 <0.05 ]Residual 74. 395 328 227 15 min.-6 hours Between drugs 3. 6732 3 t. 224i 5. 2302 <0 005 Residual 76.7937 328 i 234!1

15 min.-24 hours I Between drugs 5. 5196 3 t. 8399 8. 392 <0. 001 Residual 71.9111 328 ! .219,2

STUDENT NEwMAN-KEULS '~I~EST 15 mm.-2" c hours Perphenazine Triethylperazine Trimeflhob~i;nzamide Placebo

15 mim-6 hours Perphenazine Triethylperazine Placebo Trimethobenzamide

15 min.-24 hours Perphenazine Trlethylperazine Pla~cebo Trimethobenzamide

The test ranks driags in order of effectiveness, from the most effective on the left, to the l[east effective on the right Drugs underscored with the same line are Inot significantly different. Tlaose n O t underscored by the same line are significantly different at the 0.0.5 level

SIGNIFICANCE 2 HRS. 6 HRS. 24 HRS.

.05 LEVEL 4 2 3 5 4 2 5 3 42 5 3 ~ LEVEL 4 2 3 5 4 2 5 3 4 2 5 3

I00%~

80 PERPHENAZ INE (4) ~IE~YLPE~tN~ (2)

60 0

N z 40 u

2r~l I/4 - 2 2ml I/4 - 6 2nd I/4 - 24 Tt~ tNT~aw, ts ~N HOURS

FIGURE 1. Percentage of patients having no e~etic symptoms at two, six, and twenty-fo m" fours after administration of perphenazine, thiethylperazine, trimethobenzamide, or a placebo. 600 CANADIAN" ANAESTI~Tlslrs' SOCIETY JOUI~AL

. TABLF IV AVERAGE POSTOPERATIVE SYMPTOM SCORES OVER ]~HREEITIME PERIODS IN rA:~IENTS RE,:ElViNG 1PI-IIETHYLPERAZINE, PERPHENAZINE, TRIMETHOBENZAMIDE, OR A PL~kCEBO

Total Average symPtom scpre number of -~-~;' i " Drug patients .--2 hrs. 15 min!--6 hrs. 15 rain.-24 hrs. i ThiethyLperazine 86 i 1.1035 ,1. 326 2.628 Perphenazine 79 i 1 .!127 1.747 3.266 Trimethobenzamide 84 1. 381 2.083 4.560 Placebo 83 , 2. 325 3. 120 5.241

TABLE V ANALYSIS OFI VARIANCE + Source Sum of squares df :Mean square F P i 15 rain.-2 hours Between drugs 86. 980 3 28. 993 ~3.914 <0.01 Residual 2429.656 328 7.407 15 min.-6 hours Between drugs 147. 5099 3 49. 1700 3. (i023 <0.05 Residual 4477. 0323 328 13. 6495 15 min.-24 hours Between drugs 356.5701 3 118. 8567 4.5409 <0. 005 Residual 8585. 3938 328 26. 1750

S'~UDENT NE'~fMAN-KEULS' TEST 15 min.-2 hours Thiethylperazlne Perphena~ine:, Trimeth0benzamide Placebo

15 rain.-6 hours Thiethylperazine Perphena;i!ine ~ir~methobenzamide Placebo

15 rain.-24 hours Thiethylperazine Perphena~tine Trimethobenzamide Placebo / See legend following Table III.

Table V shows that statistically, thiel!hylperazine ranks as most effective in reducing emetic symptoms, and together with perphenazine is significantly more effective than placebo. Trim~thobenzamide does not show any significant differ- enee from placebo at the two-, six-, of twenty-four-hour periods. While it is difficult to demonstrate any sigmfieant] diffierence between the test drugs at the two- and six-hour peri6ds, thiethylpejrazine is significantly suiperior to trimethobenzamide at the twenty-four-hour period, while perphenazi~e is not. The results are shown graphically in Figure 2.

Rid it Analysis Using the criteria of Bellevflle et al2 the symptoms observed in the first two hours were ranked in order of increasing severity, and subiected to Riclit analysis, using the placebo group as the identified distribution. This form of analysis allows the comparison of dissimilar categories and serves to compare incidence and severity combined. The lresults shown graphically in Figure 3 L PunamS: THE A oN OF Tr m -XYUI EBAZ! B01

SIGNIFIcaNCE 2 HRS. 6 HRS. 24] I-[RGo

0.5 LEVEL 2 4 3 ,,5 2 4 3 5 2 V~[ 3'3 5 0.I LEVEL 2 4 ~ 2 4 3---5 9"~-~"--~ ~

,[/ PLACEBO (5)

, i/ TRINgTHOBENZAMIDE (3)

TH IETHYLPERAZINE, (2 }

O 2 nd I/4 - 2 2rid 1/4- 6 2nd ]L/4, - 24 TIHE INTERVALS IN HOURS FIatm~. 2. Average score of emetic symptom9 at two, six, and twenty-four hours after administration os perp]:llenazine, thiethylperazine, trimethobenzamide, or a placebo. /

.550

.500

./~50 I PL^CZBC l ot*O0 "1~ I ~ "[ILOBENZAM I D]!~

TII I ETHYLPEEAZ INE

.350 PEIIPHEHAZ IHE FIcuRE 3. Ridit analysis of the incidence and severity of emetic syanptoms Over the first two hours following injection of perphenazine thiethylperazine and t~dmetho- benzamide, using a placebo group, as the identified distribution. Bars indicate mean Ridit for group, blocks indicate 'the 95%- confidence ]~imits. Where these confidence limits do not overlap, the differences are signi~cant at the .05 level. 602 CANADIAN _ANAEST!-LETtSTS'iSOCIETY ]OUP~AL d o not differ ' greatly from the incidence| * comparisons I i * at the two-~mur period~ i already presented. Only perphenazine ~s statistically superior to aJ placebo at this time, while trimethobenzamide !ies[clos,ler to the placebo and thiethylpera- zinc lies closer to perphenazine in effe~tive~aess. Side-Effects I The blood pressure was recorded at 15-minute intervals in the recovery room, and the lowest observed systolic blood pres,mre was expressed as a percentage fall, compared to the pressure recorded immediately before inLduCtion of anaesthesia. The 15-minute interval in whicl the; patient awoke, as :determined by her ability to respond to her name, was recorded as the waking time. The time of the. first analgesic injection required by a patient was recorded, as was the number of injections that each receivec in the 24-hour perio& The need for a further injection of an anti-emetic dn g was also recorded. H~tpotension. The effects of the drugs on postoperative blood pressure are shown graphically in Figure 4. Perphenazine was associated with significantly

FmvRE 4. Postoperative hypotension following perphenazine, :thiethylperazine, trimethobenzamide, and a placebo. I. PUtlKIS" THE ACTION OF TRIETHYL~EmkZINE 603 more hypotension (p < 0.05) than the other arjtive a~ents, which did not drifter significantly from placebo. Postoperative sleep. There were ,no significant difference's among the test drugs in the duration of postoperative sleep, I altt toug]h 10.1 per cent of the patients receiving perphenazine slept longer than one hour, as compare to 2.3 per cent of patients receiving triethylperazine md ;3,6 per cent of pat tents ~ receiving trimethobenzamide. The observations are shown graphicall' ,, in Figure 5. Postoperative narcotics. Patients receiving perph,]~nazfme required fewer Inar- cotic injections postoperatively, averaging 2.063 in lections as ~ompared tc~ the number required with thiethylperazine (2.61B), "trimethobenzamide (2.667), and the placebo (2.651). This difference was si~nLfieant (p < 0.001 ), as]was the difference in the time of giving the first p0stopierative injection. The d~er- ences between the other drugs and the placebo were not significant. Additional anti-emetic. Additional anti-emetics \ cere required in 109 ol ttof 332 patients at some time during the 24-hour period of observation. ~he ave ,,rage symptom scores of those receiving additional a~ati-emetics ranged from 62 for those receiving thiethylperazine and trimethogen zamide initially, to 8.~ for

Fictra~. 5. Duration of postoperative sleep following perphenazme, thmthyplleraz he, trimethobenzamide and a plaeebo. 604 CANADIAN XNXESTtlETIST~' SOC'IETY JOURNAL those treated with perphenazine, ant 8.6 for those in the placebo group. :T_~is is substantially higher than the ave :age symptom score range~of 2.6-5.2 for all patients at l~he same 24-hour peri Dd, The number of patients in each tru~l ~rouo who reamred ddditlonal anti- u I ~ J. .L ! ' emetics is shown in Table VI. In :he 9hi-square analysis, per[~henazine and trimethobe .nzamide contributed most Io 9h~ square, perphenazine contributing less than the expected number, and trimethobenzamide more than exPected. These differerlces are significant (p < 0.0 I), indicating that significantly' fewer perphenazine patients required additior~al a::iati-emetics, whereas significantly more r patients required them.

TABLE VI NUMBER OF PATIENTS REQUIRING AN ADDITIONAL A,wrI-E~IETIC 'IN THE 2- TO! 24-Hour PERIOD POSTOPEI~ATIVELY

Patients Total No aftditional Additional needing . Drug patients anti-]emetic,~. _anti-e~etic I more (%) Thiethylperazine 86 66 ~20 23.3 Perphenazine 79 62 17 21.5 Trimethobenzamide 84 47 37 44.0 Placebo 83 48 35 42.0 Totals 332 '.i~23 109 32.7 !

DISCU:I~SlON Thg:.' comparisons of incidence and sev,~rity of postoperative emetic symptoms indicate a close similarity in clinical effectiveness between thietiaylperazine and perphenazine. Perphenazine secures a greater reduction in the incidence of nausea and vomiting, while triethylperazine is superior to perphenazine in reducing the severity of sy~aptoms exl:llerienced. Perphenazine appears to be more effective in the first" twb hours after administration, after which its action steadily declines, though it is still evi]dent over the whole twenty-four-hour period. Thiethylperazine appears to exerJt a steady effect over the first six hours a f ter administration,. r " but becomes much less effective, during:. the later part of the twenty-four-hour period. A subsec~uenti anti-emetic injection%vas[ ", necessary after discharge from the recovery roo m in almost a third of all patients, but the placebo and trimethobenzamide p~Itients required additional anti-emetics, almost twice as often as those in the thiethy]Lperazine and perphenazine groups. Although no extrapyramidal effects w~re seen with the limited dose schedules of perphenazine used, such effects ha~e been noted with quite low dosages repeated tlaree or four times daily, an~ with single doses as low as 10 rag. TM It is apparent that any attempt to susta~ ~the anti-emetic activity ~of perphenazine by repeating the doses used i.n. this survelT three or four times in !the first twenty- four hours would result in extrapyramidhl symptoms occurring in some patients. Thiethylperazine has been shown to lposs;ess little or no ability to produce extrapyramidal symptoms, 2 and could therefore be given at six hourly intervals to maintain maximum effect. Trirfiethobenzamide appears to possess very limited anti-emetic activity and I. PUI:IKIS: THE ACTION OF TI~I~THYLPEI~AZINE 605 it is difficult to distinguish it from the placebo, except o'~er the 24-hour incidence seoresa where it is signitleantly worse than a place~bo. Such an~-emetie activity as is shown by this~drug appears 40 be followed l~y a :rebound ~phase in which there is increased ineidence of emetic symptoms. Consideration of the side-effects shown by the two most active agents is helpful in comparing their clinical effectiveness. Th{ increased incidence of prolonged postoperative sleep noted with perphenazine has been reported in a previous study7 The criteria used to determine whether the patient was respond- ing or not may not be sufficiently sensitive to det~!,ct the patient who responds when roused by voice, but immediately lapses into sleep wl~en left alone. Clinically, many patients receiving perphenazine~s~ ;emed to follow th~s patetern, and yet did not far into the slow waking group iI the: survey. It is likely that this relapsing sleep is one factor which contribute:i to the much lower require- ment for postoperative narcotics in the perphenaz ne group, since it has been shown: that there is little potentiation of analgesia by this drug. u Hypotension in the immediate postoperative eriod is always a cause of anxiety, since the hypotension due to drug action has to be differentiated from that due to hypovolaemia or cardiac causes, among others. The increased fre- quency of hypotension seen in the perphenazine group tends to limit its useful- ness in the elderly and hypertensive patient; thietlhylperazine is not associated with a significant increase in hypotension.

CONCLUSIONS Thiethylperazine produces a marked reduction in the incidence and severity of postoperative vomiting. Its action, which appears tofl~a(st about six hours, is indistinguishable from that of perphenazine, a powerful anti-emetic drug. It does not potentiate narcotics or prolong postanaesthetic sleep, and, unlike',, perphenazine, does not produce a significant increase in the incidence of postoperative hypotension. Thiethylperazine is significantly' superior to a placebo and to trimethobenzamide as an anti-emetic. Trimethobenamide, even in high dosage, has little anti-emetic activity, and its use appears to be followed by a rebound increase in the incidence of emetic symptoms.

SUMMABY A comparative trial of thiethylperazine (Toreean| perphenazine (Trilafon| and trimethobenzamide (Tigan| has been carried out in a selected popuhatloI'1 " 71 of female patients anaesthetised with a standard anaesthetic technique for three operations associated with a high risk of postoperative nausea and vomiting. Compared with a placebo, both thiethylperazine and perphenazine were effective in reducing the incidence and severity of erotic :symptoms, whereas trimethobenzamide showed a tendency to increase these symptoms after an initial mild anti-emetic action. Postoperative hypotension occurred more frequently after perphenazine, but this drug reduced the need for postoperative analgesic drugs. It is suggested that increased drowsiness in patients receiving perphenazine may contribute to this apparent potentiation of narcotics. Thiethylperazine did not produce significantly more hypotension than the placebo, and did not potentiate 606 CANADIAN ANAESTHETIS'Irs' SOCIETY IOUt!NAG narcotics or prolong postoperative ~leep. No, extrap})ramidal signs were seen in any patients in this trial. tesu: 5 double iin- ~' Che~ un groupe choisi de malade , n0us avons fair une 6tud, I connu de trois m6dicaments et du placebo. Toutes les malad ~s 6talent desI femmes qu ! avaient regu, comme pr6n "didation,,.[~ de la m6p 6ridine ,t de l'atrop{ne; I'anesth6sie consistait en rune dose mnaire de thi~pentone et du protoxyde- oxyg6ne-halothane; elles ont subi une des; trms operations. Nous a vons ehoisi ices trois operatmns' " ( cholecystectomm,' " t Lyste[reetomie,I a b~t omina Ie et hyst6rectomie vaginale comme un d6fi aux m6dicationg ianti-6m6tiques puisque, au tours d'une 6tude ant6rieure, elles ont 6t6 suivies du taux le plus 6Iev6 de sympt6mes 6m6tiques. Les m6dieaments codifi& ont 6t6 admin [str6s au hasard, selon le poids corporel, l'arriv6e & la salle de r6veil; durant ]e~Jr s6jour & la,salt~(de ~6veil et 5 leur retour dans les salles, les malades ont 61:6 6tiquet6s selon les s~mpt6mes 6m6- tiques de naus6es ( 1 ), d'efforts (2) et:de v omissements (8). Nous avons analys~ les r6sultats selon 1~ frequence~' et la gravlteides r i symptomes,A chacune des trois p&iodes suivantes: e second quart d'heure apr6s 2 hres, le 26me quart d'heure apr6s (3 heures ! et [e 26me quart d'heure apr6s 24 heures. Dans chaque cas, nous n'avons pas tenu :ompte du premier quart d~neure parce que nous avons l'impression que le m6d: ~'ament n'avait pas en une action com- pl6te durant ce d61ai aprbs une injection h ltramusculaire. La perph6nazine a 6t6 le m6dicament le plus efficace pour diminuer la fr6- quence des sympt6mes, alors que la thigthy]pdrazine a 6% pluis effleaee pour diminuer la gravit6 des sy~rnpthmes. Ces deux m6dieaments !sei sont av6r6s sup6rieurs au placebo 5. phtsieurs points de vue. Le trim6thobemzamide a 6t6 diNcilement diff6renci~ du placebo, exce ~t6 ~ la p6riode de 24 l~eures, off il est devenu pire que le p]acebo, c'est&-dire ]u'il a sembl6 augment6r la fr6quence des vomissements. Dans la salle de r6ve I, la perph6nazine a prbduit beaucoup plus d'hypotension que la thi6thylp&az ine mais Ies malades recevant de la perph4nazine ont re~;u beaucoup moins d'i: ~jeetions de narcotiques. Nous en venons '~ la conclusion que 1~ thi(thylpdrazine est un anti-dm6tiqu~ dont l'e~cacit4 est ~gale ~ celle de la pe eph6nazine. L?~ off il devient importan} d'6viter route hypotension postop&atoire. la thmthylperazme I f * possedei X des avan- tages mar quest sur la perph~nazine; 1~ off [1 est important d'6viter ou de diminuer l'usage des narcotiques au tours des;sJites" ! operatoires,' ]a perphenaztne' ' est superieure. L'activitd anti-dm6tique du @mdthobenzamide n'est pas beaucoup plus grande que celle du placebo et ce ~m.dlcament peut accrmtre les symptomes 6m6tiques durant la premi6re journ6e pdstop&atoire.

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