A COMBINATION OF ANALGESIC AND IN POSTOPERATIVE PAIN

Transcription

1 Brit. J. Aaesth. (1960), 32, 481 A COMBINATION OF ANALGESIC AND IN OSTOERATIVE AIN BY ANTAGONIST G. HOSSLI AND G. BERGMANN The Departmet of Aaesthesia, Umversitdtskliik, Zurich, Switzerlad Cliicias ofte hesitate to give adequate doses of arcotic aalgesics such as morphie ad pethidie because these compouds are kow to have a marked respiratory depressat effect. As a result there has bee cosiderable iterest i the possibility of combiig a dose of oe of these aalgesics with a small quatity of oe of the specific arcotic atagoists. The latter substaces are kow to exert a much greater atagoism to the respiratory depressat effect tha to the aalgesic actio of the arcotics. Whe decidig o such a combiatio the first prerequisite is that the atagoist should have few udesirable effects of its ow ad the secod is that the atagoist ad the aalgesic should have approximately the same legth of actio. Although the arcotic atagoists alorphie ad levallorpha themselves possess slight respiratory depressat activity, this is isigificat i the doses i which they are used cliically. Levallorpha was chose for cliical trial because, eve i large doses such as are rarely used i therapy, it is tolerated without udesirable side effects by both coscious ad ucoscious patiets (Swerdlow, 1958). ethidie was selected as the aalgesic most likely to have a suitable legth of actio for combiatio with levallorpha. Havig decided o the combiatio of drugs we set out to establish whether, usig the two drugs together i suitable proportios, the presece of the atagoist iflueces the followig: the respiratory depressat effect of pethidie; the aalgesic activity; the icidece of side effects. Accordigly, the followig studies were carried out. Ifluece o Respiratory Depressio I order to study the ifluece of levallorpha o the respiratory depressat effect of pethidie, it was ecessary first to establish the optimal proportios of the two drugs. Accordigly prelimiary tests were carried out i 25 idividuals who were about to udergo surgical operatios. The patiets were premedicated with a barbiturate ad atropie ( ig), pethidielike drugs beig deliberately avoided. Aaesthesia was iduced with thiopetoe. The patiet was itubated after relaxatio had bee achieved with suxamethoium ad aaesthesia was maitaied with itrous oxide ad oxyge. Whe breathig had become regular ad traquil, a itraveous dose of pethidie 1-2 mg/kg was give, accompaied by, or followed by, a dose of levallorpha. Various ratios betwee 80:1 ad 35:1 were studied. After this the respiratory rate ad miute volume were measured at itervals. It was foud that the ratio of pethidie to levallorpha of 80:1 had o greater respiratory depressat effect tha the ratio of 35:1 ad as a result the 80:1 ratio was chose for the mai test. For this test two groups, each of 15 patiets, were studied uder accurately stadardized coditios ad the results have bee reported i detail elsewhere (Hossli ad Bergma, 1959). I brief, the patiets were aaesthetized as described above ad, whe breathig had become regular, each patiet was give a itraveous ijectio of pethidie 1 mg/kg aloe or combied with levallorpha i the ratio of 80:1. The respiratory rate ad miute volume were measured every miute for 20 miutes, ad figure 1 shows our fidigs. Statistical aalysis of the figures for the respiratory rate, miute volume ad alveolar vetilatio at 2, 3, 6, 12 ad 20 miutes after givig the pethidie or pethidie plus levallorpba showed that, compared with the iitial readigs, all these figures were reduced more by pethidie tha by pethidie with levallorpha. The differece was statistically sigificat o all occasios except for 481

2 482 BRITISH JOURNAL OF ANAESTHESIA 100 so o 100 I- 8 O t RESIRATORY RATE MINUTE VOLUME ALVEOLAR VENTILATION MINUTES ETHIDINE + ETHIDINE FIG. 1 LEVALLORHAN readigs for miute volume ad alveolar vetilatio at 12 miutes. It was thus show that pethidie with levallorpha i the proportio of 80:1 causes sigificatly less respiratory depressio tha does pethidie aloe. Effect o the Aalgesic Activity I order to compare the aalgesic activity of pethidie with that of pethidie plus levallorpha a double blid cotrol study was carried out i 96 idividuals who eeded a arcotic aalgesic for the relief of postoperative pai. Sixty-four of these patiets had udergoe major thoracic or abdomial operatios, 4 had had mior abdomial operatios (appedicectomy or laparotomy) ad the rrmaiig 28 had udergoe operatio for heria, sympathectomy, mastectomy or operatios o the limbs. A dose cotaiig 50, 75 or 100 mg of pethidie, aloe or with levallorpha (ratio 80:1), was give accordig to the patiet's eed. Ampoules were labelled with code umbers i order that the trial should be blid to all cocered i it. Before the admiistratio of ay aalgesic the severity of the pai was recorded, based o the patiet's ow statemet ad also o the impressio of the observer, usig the followig scheme: o pai 0; mild pai 1; moderate pai 2; severe pai 3; itolerable pai 4. After the ijectio the severity of the pai was recorded by the same method at 30-miute itervals for a period of 4 hours. A calculatio was made at each half-hourly period of the differece betwee the score for pai at that momet ad the score for the iitial pai. The sum-total of these differeces was take to be the figure represetig the "total aalgesic activity" of a sigle dose of the drug cocered. If it was ecessary to give additioal doses to the same patiet, the ampoules with the same code umber were used throughout. The sizes of additioal doses were adjusted, if ecessary, to the patiet's respose ad a repeat dose of aalgesic was give oly if the effect of the previous dose had wor off. It would have bee desirable to have had all the observatios carried out by the same idividual. However, as this was ot possible, care was take to esure that the same observer made all the observatios i a give patiet over the whole 4-hour period. Results. I total, 219 doses of aalgesic were give. O breakig the code, it was foud that 49 patiets had bee give a total of 154 ijectios of pethidie plus levallorpha. The cotet of pethidie was 50 mg o 65 occasios, 75 mg o 43 occasios ad 100 mg o 46 occasios. The other group, give pethidie aloe, comprised 47 patiets who had bee give a total of 137 ijectios; the dose was 50 mg o 51 occasios, 75 mg o 52 occasios ad 100 mg o 34 occasios. The umber of doses give to sigle idividuals varied from oe to seve, the average beig 3.1 i the pethidie with levallorpha group ad 2.9 i the pethidie group. I the pethidie with levallorpha group the patiet's ages varied betwee 19 ad 73 years (average 47). Their weight varied betwee 40 ad

3 A COMBINATION OF ANALGESIC AND ANTAGONIST kg (average 65.2). I the pethidie group, the figures were: age betwee 20 ad 79 years (average 49) ad weight betwee 45 ad 97 kg (average 68.8). As regards the types of operatio, the distributio was similar i the two groups. I occasioal patiets it was ecessary to iterrupt the observatios before the ed of the 4-hour period for reasos ucoected with the trial I these patiets the pai had ot retured to its iitial severity at the time whe the readigs were iterrupted. I order ot to reduce too much the umbers i each group by omittig these icomplete observatios we have also icluded i the average figures for "aalgesic activity" readigs take at 3^- ad 3 hours. I additio, o the very few occasios i which a half-hourly readig was omitted we took for the calculatio the lower of the two figures o each side of the missed readig. Tahle I shows the fidigs i the three subgroups, after 50-mg, 75-mg ad 100-mg doses of pethidie with or without levallorpha, as well as the umber of ijectios give at each dose level. As ca be see from this table, the figures show that there is extraordiarily good agreemet i all three groups as regards the average aalgesic activity of a sigle dose of pethidie or pethidie with levallorpha after 3, 3i ad 4 hours. It ca also be see that the average figures for the aalgesic effect of a dose icreased with the time (that is with the umber of observatios), ad that i geeral larger doses gave better aalgesia tha smaller doses. Statistical aalysis of these figures, usig the t-test, showed that at the three dose levels there was o sigificat differece betwee the average aalgesic activity of pethidie ad that of pethidie with levallorpha. O the basis of these fidigs it ca be cocluded that the additio of the arcotic atagoist levallorpha to pethidie i the above proportio does ot iterfere with the aalgesic activity of the pethidie. Ifluece o the Icidece of Side Effects As regards the geeral cliical use of the combiatio of pethidie with levallorpha a importat questio is raised. Does the atagoist prevet ot ethidie TABLE I Mea figures for the "aalgesic activity" of a sigle dose of pethidie or pethidie with levallorpha. ethidie + levallorpha Observatio period (hours) 50 mg pethidie A=average aalgesic activity of a sigle dose. = umber of ijectios. 75 rag pethidie mg pethidie TABLE Icidece of side effects after pethidie ad pethidie with levallorpha. ethidie ethidie + levallorpha TotaJ o. of patiets Total o. of ijectios atiets with sideeffects 15 16» Nausea (* Some patiets experieced more tha oe side effect.) =umber of patiets. =umber of ijectios Nature of side effects Vomitig Sweatig

4 484 BRITISH JOURNAL OF ANAESTHESIA oly respiratory depressio but also other udesirable effects of pethidie, especially ausea ad vomitig? I our study i postoperative patiets we recorded the presece or absece of ausea ad vomitig ad, as far as possible, other side effects that might have bee associated with medicatio. Some additioal patiets were icluded who could ot be used for assessmet of the aalgesic effect. Table II shows the icidece of ausea, vomitig ad excessive sweatig i the two groups. A breakdow ito three dose levels is omitted, as it was ot possible to show that there was a relatioship betwee the presece of such side effects ad the size of the dose. It was foud that the icidece of ausea was the same i the two groups. Vomitig was somewhat less commo i the pethidie with levallorpha group, whilst excessive sweatig was rather more frequet. However, these differeces were ot statistically sigificat. No other sigificat side effects were observed. I the pethidie with levallorpha group each of the followig were observed o oe occasio: restlessess, tachycardia, arrhythmia, vertigo, palpitatios ad flushig. I two patiets i the pethidie series there was a cosiderable rise of blood pressure (possibly a result of hypovetilatio). DISCUSSION The results of our previous ivestigatio cofirmed the protective effect of levallorpha agaist the respiratory depressat effect of pethidie. The study i postoperative pai showed that, i the dose ratio of 80:1, the aalgesic effect of pethidie o postoperative pai is ot reduced by levallorpha. As regards the icidece of side effects other tha respiratory depressio, this was similar i the two groups. Although we foud that the icidece of vomitig after pethidie with levallorpha was somewhat reduced ad excessive sweatig was slightly icreased, the differeces were ot statistically sigificat. Whe usig pethidie the additio of a small dose of levallorpha provides a greater margi of safety ad permits the admiistratio of adequate doses without the fear of iducig serious respiratory depressio. The followig two cases which occurred fairly recetly i our cliic illustrate the fact that severe respiratory depressio may occur eve whe usig pethidie i the usual therapeutic doses. A woma, aged 39 years, had bee admitted to hospital for a operatio. Some hours after the operatio she was foud to be ucoscious, cyaosed ad with dilated pupils; spotaeous respiratio was abset. Oxyge was applied immediately ad a edotracheal tube was passed. Te miutes later, regular spotaeous respiratio had retured ad after 4 hours the patiet had recovered completely. Later it was discovered that because of postoperative pai she had bee give a itramuscular ijectio of pethidie 100 mg about 30 miutes before the above icidet occurred. A ma, aged 73 years, with emphysema had bee subjected to prostatectomy. Durig the ight the patiet was erroeously give pethidie 100 mg itraveously istead of Novalgi. The physicia, who was called immediately, observed that the patiet had slow, gaspig respiratio, was ucoscious ad had costricted pupils (the cliical appearaces see i morphie poisoig). Oxyge was admiistered ad a edotracheal tube was passed. However, it was ecessary to admiister levallorpha 2 mg before spotaeous respiratio improved ad the reflexes retured. Oe hour later the patiet was agai coscious. These two experieces cofirm the fact that there is variatio i idividual sesitivity to respiratory depressat substaces ad that eve therapeutic doses ca cause serious complicatios. Without rapid medical assistace the apoea might well have resulted i death, or at least i severe hypoxic damage. SUMMARY The authors describe a series of studies desiged to establish whether the additio of a small quatity of the arcotic atagoist levallorpha reduces the respiratory depressat actio of pethidie. They also ivestigated the effect o aalgesic activity ad o the icidece of side effects. The study of respiratory depressio was carried out i two groups of aaesthetized patiets. Whe aaesthesia was established each patiet was give a dose of pethidie 1 mg/kg aloe or mixed with levallorpha i the proportio of 80:1. The results showed that there was a statistically sigificatly smaller reductio of the respiratory rate, miute volume ad alveolar vetilatio i the pethidie plus levallorpha group. To ivestigate the aalgesic activity two groups of patiets with postoperative pai were treated i a blid cotrol study with either pethidie or

5 A COMBINATION OF ANALGESIC AND ANTAGONIST 485 pethidie with levallorpha i the above proportio. It was foud that the average aalgesic activity was almost the same with the two types of treatmet. The icidece of side effects betwee the two groups was isigificatly differet. The authors coclude that the additio of levallorpha i the above proportio gives almost complete protectio agaist the respiratory depressat effect of pethidie without dimiishig the aalgesic effect ad without icreasig the icidece of side effects. REFERENCES Hossli, G., ad Bergma, G. (1959). Schweiz. mcd. Wschr., 89, 863. Swerdlow, M. (1958). Levallorpha: effects of large doses. Aaesthesia, 13, 318. This film is excellet ot oly from the teachig poit of view but also i its presetatio ad productio It is dramatic ad holds the iterest of the viewers throughout. There is a tedecy to react agaist the presetatio of medical techiques which picture teachig accompaied by all the trappigs commoly employed by the commercial film idustry. For example, music ad the employmet of over-dramatic situatios sometimes detract from useful teachig films. Nevertheless these are so skilfully employed i the productio uder review that they positively add to the teachig value of the film. The film shows the experieces of a ewspaper reporter who visits the Uiversity of Saskatchewa Hospital with the itetio of writig up moder methods of artificial respiratio. He sees a demostratio of mouth-to-mouth resuscitatio carried out o a paralyzed subject ad its efficacy cotrasted with that of the more usual methods available to the first-aid workers. He sees a class beig istructed i the techique with the aid of a woode "air passage demostrator" ad a FILM REVIEW "THAT THEY MAY LIVE" excellet "maiki". The direct mouth-to-mouth method is show ad also the more hygieic use of the Brook Airway. The reporter is the show a film demostratig "actio shots" of a variety of accidets: a car collisio; a drowig icidet; a child trapped i a abadoed icebox; a ifat suffocated by a plastic bag; a electrocutio occurrig at the top of a pylo; a chokig scee i a restaurat; all of these beig dealt with by members of the geeral public by mouth-tomouth resuscitatio. Fially, the reporter himself o leavig the hospital visits a fu-fair ad is called upo to use the techique i the resuscitatio of a case of electrocutio. This is quite the best film of its type that the reviewer has see ad should be i wide demad for showig to udergraduates, urses, ambulace persoel ad first-aid workers. This film is available from Messrs. Smith ad Nephew Ltd., Bessemer Road, Welwy Garde City, Herts, who also supply the airway passage demostrator ad the Brook Airway. Cecil Gray