Blecher, J

Lithgow, D.M.

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-20 Februarie 1971 S.-A. MEDIESE TYDSKRIF 203A CONTROLLED TRIAL OF GLIFANAN AND OMNOPON IN POSTOPERATIVE PAIN*D. M. LITHGOW, B.Sc., M.B., B.CH. (RAND), F.R.C.S. (EDIN.) AND J. BLECHER, B.Sc., M.D. (RAND), M.R.C.O.G.,F.e.o.G. (S.A.), Department oj Obstetrics and Gynaecology, University oj the Witwatersrand, Johannesburg*These operations included 34 salpingectomies, 3 salpingo-oophorectomies.4 ovarian cystectomies, 1 oophorectomy. 6 myomectomies, 1 hysterotomy,8 laparotomies, 6 vaginal repairs and 1 ventrisuspension.RESULTSOne hundred and eighty-one patients were admitted tothe trial. They were suffering from moderate pain followingthe operations shown in Table I. The results are presentedin two sections corresponding to the two phases of thetrial:Phase 1: Glijanan in Suppository Form vs. OmnoponInjectionA total of 609 dosage records was suitable for analysis,the principal reason for 'drop-out' being insufficient severityof pain. Table 11 shows the analysis of mean pain reliefscores following the administration of each trial drug.Significantly higher pain relief scores were obtained follow-ing Omnopon injection than following Glifanan suppositoryfor doses 1, 2, and 3. For dose 4 no significant differenceemerged.Table III shows the number of extra analgesics requiredfollowing the administration of each trial analgesic. Over-all, 64 doses of extra analgesics were administered follow-ing Glifanan suppository and 23 such doses following theIn order to preserve the double-blind character of thestudy, each active suppository was given with a placeboinjection and each active injection was given with a placebosuppository. In the second phase each active capsule wasgiven with a placebo injection, and each active injectionwith a placebo capsule. The Glifanan in phase 2 wasprepared in capsule form in order to facilitate the pro-duction of double-blind material.In the trial, provision was made for the use of a 'back-up' analgesic if analgesia was not produced within onehour, and all such administrations were recorded. Various'back-up' drugs were used, but pethidine 100 mg was usedfor the majority of patients. Effects other than the relief ofpain were also monitored over the 6-hour period followingeach dose.No. of patiellts60332464181TABLE I. SURGICAL PROCEDURESTotalOperationAbdominal hysterectomyCaesarean sectionVaginal hysterectomyOthers""Daie re<:eived: 2 OClOber 1970.Although Glifanan has been available in South Africa fortwo years, no well-controlled clinical evaluations have beenreported in this country. It was therefore decided to con-duct an investigation into the efficacy of Glifanan usingOmnopon 20 mg as the comparative drug. Chemically,Glifanan is 7-cWor-4-(0-(2,3-dihydroxy-propoxy-carbonyl)anilino) quinoline, a synthetic compound related to thequinoline group of antimalarial drugs. In animal tests itwas found to have an analgesic potency 5 - 10 times greaterthan that of aspirin.' Anti-inflammatory and antipyreticproperties were also demonstrated, but these were not asmarked as the analgesic property. Initial clinical evalua-tions have also demonstrated marked analgesic potency.'·"TRIAL DESIGNPathological pain is acknowledged to be the best yardstickfor the measurement of analgesic effect.'" In particular,postoperative pain, subjectively assessed, has given accurateand reproducible results. Excellent patient discernmentbetween differing degrees of analgesia was obtained.""·"The investigation reported here involved postoperativepain in gynaecological and obstetric patients. The trial wasa double-blind cross-over study. The trial medicationswere administered 6-hourly and the order of administrationwas randomized throughout. The study consisted essen-tially of two consecutive phases:Phase 1. During the first 24 hours postoperativelyGlifanan 500 mg in suppository form was compared withOmnopon 20 mg by injection.Phase 2. During the subsequent 12 hours Glifanan200 mg in capsule form was compared with Omnopon20 mg by injection. Subjective pain assessment was madeat the time of each drug administration and at hourlyintervals for the next 5 hours.In order to permit statistical evaluation of the results,pain was classified and scored according to principlessuggested by Keele." The classification and scores were asfollows:Severe pain . 3Moderate pain 2Mild pain INo~n 0The score at each hourly assessment was subtracted fromthe score at the time of administration. The 5 such valuesobtained were added to give a pain relief score for eachdose.TABLE H. A.N"ALYSIS OF MEAN PAIN RELIEF SCORES FOR OMNOPON INJECTIO' AND GllFANAN SUPPOSITORYMean pain relief scoreDifferenceGlifanan Omnopoll betweensUpposiTOry injection means t d·f· SignificanceDose I 3-39 5·86 2·57 4·108 168 s (p<O·OOI)Dose 2 4·67 5·98 I· 31 2·127 152 s (O·025<p<O·05)Dose 3 4·52 5·70 I-18 2·638 156 s (O·OO5<p<0{)l)Dose 4 3-56 4-89 I· 33 1·891 125 nos. (O·05<p<0·1)204 S.A. MEDICAL JOURNAL 20 February 197143291310848TotalOmnoponinjeceiononlyGlifanancapsuleonlyTABLE VID. SIDE-EFFECTS-PHASE 2Glifanancapsule andOmnopollinjeccionTABLE VII. EXTR.... A-NALGESlCS-PHASE 2Oral OmnoponGlifanan injection7 6127 109No. of patientsreportingside-effects ID 14 5Side-effects_Tausea 3 9 1Dizziness 2 7 1Vomiting 2 4 2Headache 2 2Others 3* 3t 2tTotal 12 25 6Table VII shows the number of extra analgesics requiredfollowing the administration of each trial analgesic. Thedifference is not statistically significant.'These side-effeclS included itchiness (I), prickly rash (1), sore throat (I)(probably intubation difficulty).tThese side-effects included itchiness (2). rash (I).tThese side-effeclS included sweating (I), mild hypotension (I).The mean pain relief scores following Omnopon in-jection and oral Glifanan showed no statistically significantdifference (Table VI).Trial doses followed by extra analgesicsTrial doses not followed by extra analgesicsTotalOmnoponinjecTiononlyG/ifanansUpposiTOryonlyTABLE IV. SIDE-EFFECTS-PHASEGlifananSlIppositoryandOmnoponinjecTionTABLE Ill. EXTRA ANALGESICS-PHASE 1Glifanan Omnoponsuppository injeqion64 23237 285No. of patientsreportingside-effects 17 25 26 68Side-effectsNausea 14 9 16 39Vomiting 13 9 7 29Dizziness 7 10 5 22Headache 3 2 2 7Sweating 1 2 2 5Others 3* 6, 5t 14Total 41 38 37 116administration of Omnopon. This difference is statisticallysignificant (x' = 26'7, 1 dJ., p<O·OOI).Table IV shows the incidence, type and distribution ofside-effects during phase 1.'These side-effects included palpitations in 1 patient, rash on arm (1),abdominal cramps (1).tThese side-effects included mild hypotension (3), iaundice (1), rash atinjection site (1), pain at injection site (l).;These side-effects included mild hypotension (1), light-headedness (I),hiccough (1), rash (1), shivering (1).Trial doses followed by extra analgesicsTrial doses not followed by extra analgesicsTABLE V. DISTRIBUTION OF ANALYSABLE RECORDS-PHASE 2Phase 2: Glifanan in Capsule Form vs. Omnopon InjectionOne hundred and sixty-two patients were given both trialdrugs. Of these, 85 patients received Glifanan followed byOmnopon and the remaining 77 Omnopon followed byGlifanan. A further 3 patients received Glifanan only and9 Omnopon only.A total of 246 dosage records was available for analysis(Table V). Again the principal reason for 'drop-out' wasinsufficient severity of pain. There was no significantdifference in the mean initial pain scores of the two treat-ment groups.Drugs receivedGlifanan followed by OmnoponOmnopon followed by GlifananGlifanan onlyOmnopon onlyNoneTotalNo. ofpatients8577397181No. of analysabledosage records12711423246Table VIII shows the incidence, type and distributionof side-effects during phase 2.DISCUSSIONThe main object of this investigation was the comparativeevaluation of oral Glifanan and Omnopon injection inorder to determine the place of Glifanan in the analgesicspectrum.The results obtained indicate that a high level of anal-gesia is possible with 200 mg of Glifanan by mouth. Thepain relief was found to be comparable to that obtainedfrom Omnopon injection 20 mg. On the evidence presentedit would appear that Glifanan could be a useful means ofminimizing the therapeutic gap between analgesics of theaspirin type and the narcotic analgesics.As postoperative patients were the subject of the studyit was necessary to wait until they could tolerate oralmedication. Glifanan was, however, made available in theform of suppositories and it was therefore decided to usethe first 24 hours in a second experiment comparingGlifanan suppositories with Omnopon. Glifanan in thisform was found to be less effective than Omnopon, butTABLE VI. ANALYSIS OF MEAN PAIN RELIEF SCORES FOR ·OMNOPON INJECTION AND ORAL GLIFANANMean pain relief scoreDifferenceOmnopon Glifanan betweeninjection capsules means d·f. SignificanceDose 1 5-80 4·&7 0·93 1·402 132 D.S. (0'1<p<0-2)Dose 2 5·55 5·07 0-48 0·777 113 D.S. ({)-4<p<6'5)-_0 Februarie 1971 S.-A. MEDIESE TYDSKRIF 205a considerable degree of analgesia was nevertheless ob-rained.In a subsequent investigation elsewhere" the blood levelsobtained following rectal GIifanan were found to be lowerhan those obtained following oral GIifanan, and thiscould aGcount for the therapeutic difference observed.It was gratifying to find that the method used was suffi-ciently sensitive to establish these differences and thismust endorse the findings in the main phase of the trial.Side-elIects noted throughout were of a minor natureand it is difficult to draw any conclusions regarding thesesince they all occurred within 36 hours of a major opera-tion.SUMMARYA double-blind cross-over technique was used to evaluate thepain dief obtained postoperatively. i!1 gxnaecological andobste:ric patIents followlDg the admlillstratlOn of Omnoponinjection, Glifanan suppositories. and Glifanan c.apsules. Painwas classified hourly by the patient and paID relief scores foreach test administration were calculated and statisticallyanalysed. Thesc shO\~e<:l n.o statistically signi~cant differencefollowing Omnopon IllJectlOn 20 mg and Ghfanan capsules200 mg. Pain relief scores following Omnopon injection 20 mgwere significantly higher than those following Glifanan sup-positories 500 mg.We should like to thank Dr M. Salmon, Medical Superin-tendent of Johannesburg Hospital, for permission to conductthe trial and for allowing publication of this paper; Prof. R.Charlton. of the Department of Pharmacology and Thera-peutics, for advice; Drs J. Young and L. Hughes, of RousselLaboratories, London, for assistance; Mr J. R. Sendak, forstatistical analvses; and the Roussel Library for making avail-able full Engiish translations of all for.eign publications re-ferred to in - the bibliography. We also wish to thank theregistrars and residents working within the Department ofObstetrics and Gynaecology, without whose co-operation thistrial would not have been possible.REFERENCES1. Peterfalvi. M., Branceni, D., Azadian-Boulanger, G., Chifflot, L. andJequier, R. (1966): Med. expo (Easel), 15, 254.2. AllaJi, P. (1965): Guide Prat.. 80, suppI. 1.3. Benoit, P., Michelet, X. and Gironet, J. (1966): Rev. franc. Odonto-stomaL, 24, 205.4. Bouche, J. and Bruker, J. (1965): Feuillers Medicaux, 107, 8.5. Catastini, M. (1969): Riv. Ostet. Ginec. prat., 51, 178.6. Couinaud, C. (1966): Vie med., 47, 1397.7. Couinaud, C. and Malamud, S. (1966): Bulletin d'Organomerapie etde Gerontologie, I, 18.8. Cuppini, A., Capuzzi, P. and Rossi, A. (1967/68): Mondo odonto-stomat., I, 115.9. Goguel, S., VaJognes, B. and Lecacheux, B. (1966): Ouest med., 21,1171.10. Ischia, S. and Terranova, O. (1967): Recenria med. (Roma), 6, 1665.11. Do Lego, G. R. (1967): Hospital (Rio de J.), 71, 503.12. Martinez, L. G. and Ovando, J. S. (1968): Sem. med. Mex., 55, 53.13. Massias. P. (1966): Vie med., 47, 557.14. Mazzuccato, P. (1968): Clin. ter., 45, 249.15. Menkes, P., Husson, J. F., Poitout, P. and Sureau, C. (1967): Viemed .. 48, 807.16. Le Menn, G. (1967): Ouest med., 9, 678.17. De la Moureyre, P. (1966): Mouvement Therapeutique. 1, 31.18. eumann, M. (1965): Concours med., 87, 7427.19. PaTaf, A. and Hafsia, M. (1965): Clinique (Paris). 60. 690.20. Pellegrini, Y., Prudhon, C. I. and Derrien, P. (1965): Chirurgien-Dentiste de France, 35, 61.21. Petit. M. and Tibi, G. (1967): Clinique (Paris), 62, 457.22. Peyron, J. (1965): H6pital (Paris). 53. 833.23. Porin, J. and Loyan, G. (1965): Ouest med .. 18, 1203.24. Rouchon. C. and Abravenel, J. (1965): Inform. dent. (Paris). 47, 3863.25. Schrub, J. C. and Laurent, D. (1965): Revue Medicale de 'ormandes.7. 71.26. De $oze, M. (1965): L'Information Therapeutique, 3, 21.27. Soubiran, J. M. (1966): Rev. fran9. Odonto-stomat., 8, 239.28. Turon, R. (1966): Rev. med. Toulouse, 2. 335.29. Keates, A. S., Beecher, H. K. and Moste!ler, F. C. (1950): J. AppI.PhysioI., 1, 35.30. Lasagna, L. and Beecher, H. K. (1954): J. Amer. Med. Assoc., 1;6,230.31. Modell, W. and Hou,e, R. W. (1958): Ibid., 167. 2190.32. Beecher, H. K. (1959): Measurement of Subjective Responses. London:Oxford University Press.33. Keele. K. D. (l948\: Lancet. 2, 6.34. Ronde!e!, J. (1964): Roussel Laboratories Internal Report. ReI. 247.THE ELECTROCARDIOGRAM IN CHRONIC BRONCmTIS AND EMPHYSEMA*S. ZWI, B.sc., M.B., B.CH. (RAND), M.R.C.P. (LOND.), D. J. KANAREK, M.B., B.CH. (RAND), D.C.H. (R.C.P. & S.),F.c.P. (SA), A. 1. CROSLEY, M.B., B.CH., (RAND), F.C.P. (SA) AND H. I. GOLDMAN, B.sc. HONS. (RAND),Respiratory Unit, Department of Medicine, University of the WitlVatersrand and Johannesburg HospitalThere have been a considerable number of reports on thesubject of the electrocardiogram in chronic lung disease.Generally, the authors have included a variety of lungdiseases, including bronchiectasis and pneumoconiosis,though the majority of cases have been diagnosed aschronic bronchitis and emphysema. Some articles includedvarious lung function tests, but these usually providedevidence of airway obstruction and we could find nopaper in which the degree of hyperinflation (as deter-mined by the measurement of lung volumes) was takeninto account. The purpose of this communication wasto study the electrocardiograms of patients suffering fromchronic obstructive airways disease and to relate theelectrocardiogram to the degree of obstruction and ofhyperinflation of the lung. A review of relevant findingsin the literature is included.l\1ATERIAL AND METHODSFifty cases were selected from the file.> of the pulmonaryfunction laboratory. They all had detailed clinical data,chest radiographs, a 12- or 13-lead scalar electrocardio-gram, measurement of the forced expiratory volume in 1'"'Date received: 3 November 1970.second (FEV,) and the forced vital capacity (FVC), andin 34 of these there were also measurements of the sub-divisions of lung volume. All were White subjects overthe age of 30 years. Most of the cases were outpatients,but some were convalescing in the wards. Patients wereexcluded who had a definite history of paroxysmal attacksof dyspnoea which could be due to asthma, if there wasany evidence of ischacmic heart disease, pneumoconiosis,rheumatic heart disease or hypertension, or if any othermajor disease was present. The patients, therefore, werea selected group with chronic obstructive airways diseasedue to bronchitis and emphysema.The forced vital capacity was performed on a GodartPulmotest and a Collins spirometer was used for theclosed-circuit helium dilution method for the measure-ment of lung volumes. The 50 cases in the series withmeasurements of FEV,/FVC% and 34 with measurementsof residual volume (RV) were subdivided into the cate-gories mild, moderate and severe obstruction and hyper-inflation as indicated in Table I. The predicted valuefor residual volume is based on normal subjects studiedin this laboratory.'The electrocardiograms were analysed for the following

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A controlled trial of Glifanan and Omnopon in postoperative pain

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A controlled trial of Glifanan and Omnopon in postoperative pain

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