BERGMANN, G.

HOSSLI, G.

RERO DOC Digital Library

Brit. J. Anaesth. (1960), 32, 481A COMBINATION OF ANALGESIC AND ANTAGONISTIN POSTOPERATIVE PAINBYG. HOSSLI AND G. BERGMANNThe Department of Anaesthesia, Umversitdtsklinik, Zurich, SwitzerlandClinicians often hesitate to give adequate doses ofnarcotic analgesics such as morphine and pethi-dine because these compounds are known to havea marked respiratory depressant effect. As a resultthere has been considerable interest in the possi-bility of combining a dose of one of these anal-gesics with a small quantity of one of the specificnarcotic antagonists. The latter substances areknown to exert a much greater antagonism to therespiratory depressant effect than to the analgesicaction of the narcotics.When deciding on such a combination the firstprerequisite is that the antagonist should havefew undesirable effects of its own and the secondis that the antagonist and the analgesic shouldhave approximately the same length of action.Although the narcotic antagonists nalorphineand levallorphan themselves possess slight respi-ratory depressant activity, this is insignificant inthe doses in which they are used clinically.Levallorphan was chosen for clinical trial because,even in large doses such as are rarely used intherapy, it is tolerated without undesirable sideeffects by both conscious and unconscious patients(Swerdlow, 1958). Pethidine was selected as theanalgesic most likely to have a suitable length ofaction for combination with levallorphan.Having decided on the combination of drugswe set out to establish whether, using the twodrugs together in suitable proportions, thepresence of the antagonist influences thefollowing:the respiratory depressant effect of pethidine;the analgesic activity;the incidence of side effects.Accordingly, the following studies were carriedout.Influence on Respiratory DepressionIn order to study the influence of levallorphan onthe respiratory depressant effect of pethidine, it481was necessary first to establish the optimal pro-portions of the two drugs. Accordingly preli-minary tests were carried out in 25 individualswho were about to undergo surgical operations.The patients were premedicated with a barbi-turate and atropine (0.25-0.5 ing), pethidine-like drugs being deliberately avoided. Anaesthesiawas induced with thiopentone. The patient wasintubated after relaxation had been achieved withsuxamethonium and anaesthesia was maintainedwith nitrous oxide and oxygen. When breathinghad become regular and tranquil, an intravenousdose of pethidine 1-2 mg/kg was given, accom-panied by, or followed by, a dose of levallorphan.Various ratios between 80:1 and 35:1 werestudied. After this the respiratory rate and minutevolume were measured at intervals. It was foundthat the ratio of pethidine to levallorphan of 80:1had no greater respiratory depressant effect thanthe ratio of 35:1 and as a result the 80:1 ratiowas chosen for the main test.For this test two groups, each of 15 patients,were studied under accurately standardized con-ditions and the results have been reported indetail elsewhere (Hossli and Bergmann, 1959). Inbrief, the patients were anaesthetized as describedabove and, when breathing had become regular,each patient was given an intravenous injection ofpethidine 1 mg/kg alone or combined with leval-lorphan in the ratio of 80:1. The respiratory rateand minute volume were measured every minutefor 20 minutes, and figure 1 shows our findings.Statistical analysis of the figures for the respira-tory rate, minute volume and alveolar ventilationat 2, 3, 6, 12 and 20 minutes after giving thepethidine or pethidine plus levallorpban showedthat, compared with the initial readings, all thesefigures were reduced more by pethidine than bypethidine with levallorphan. The difference wasstatistically significant on all occasions except for482 BRITISH JOURNAL OF ANAESTHESIA100soo 1 0 0I-8O 5010050tRESPIRATORY RATEMINUTE VOLUMEALVEOLAR VENTILATIONMINUTES 2 •4 6 8 10 12 14 16 18 20 22PETHIDINE + LEVALLORPHANPETHIDINEFIG. 1readings for minute volume and alveolar ventila-tion at 12 minutes.It was thus shown that pethidine with levallor-phan in the proportion of 80:1 causes signi-ficantly less respiratory depression than doespethidine alone.Effect on the Analgesic ActivityIn order to compare the analgesic activity ofpethidine with that of pethidine plus levallorphana double blind control study was carried out in 96individuals who needed a narcotic analgesic forthe relief of postoperative pain. Sixty-four ofthese patients had undergone major thoracic orabdominal operations, 4 had had minor abdom-inal operations (appendicectomy or laparotomy)and the rrmaining 28 had undergone operationfor hernia, sympathectomy, mastectomy or opera-tions on the limbs. A dose containing 50, 75 or100 mg of pethidine, alone or with levallorphan(ratio 80:1), was given according to the patient'sneed. Ampoules were labelled with code numbersin order that the trial should be blind to allconcerned in it.Before the administration of any analgesic theseverity of the pain was recorded, based on thepatient's own statement and also on the impres-sion of the observer, using the following scheme:no pain 0; mild pain 1; moderate pain 2; severepain 3; intolerable pain 4.After the injection the severity of the pain wasrecorded by the same method at 30-minute inter-vals for a period of 4 hours. A calculation wasmade at each half-hourly period of the differencebetween the score for pain at that moment andthe score for the initial pain. The sum-total ofthese differences was taken to be the figure repre-senting the "total analgesic activity" of a singledose of the drug concerned.If it was necessary to give additional doses tothe same patient, then ampoules with the samecode number were used throughout. The sizes ofadditional doses were adjusted, if necessary, to thepatient's response and a repeat dose of analgesicwas given only if the effect of the previous dosehad worn off.It would have been desirable to have had allthe observations carried out by the same indiv-idual. However, as this was not possible, care wastaken to ensure that the same observer made allthe observations in a given patient over the whole4-hour period.Results.In total, 219 doses of analgesic were given. Onbreaking the code, it was found that 49 patientshad been given a total of 154 injections of pethi-dine plus levallorphan. The content of pethidinewas 50 mg on 65 occasions, 75 mg on 43 occa-sions and 100 mg on 46 occasions. The othergroup, given pethidine alone, comprised 47patients who had been given a total of 137 injec-tions; the dose was 50 mg on 51 occasions, 75 mgon 52 occasions and 100 mg on 34 occasions. Thenumber of doses given to single individuals variedfrom one to seven, the average being 3.1 in thepethidine with levallorphan group and 2.9 in thepethidine group.In the pethidine with levallorphan group thepatient's ages varied between 19 and 73 years(average 47). Their weight varied between 40 andA COMBINATION OF ANALGESIC AND ANTAGONIST 48392 kg (average 65.2). In the pethidine group, thefigures were: age between 20 and 79 years (aver-age 49) and weight between 45 and 97 kg (average68.8). As regards the types of operation, the dis-tribution was similar in the two groups.In occasional patients it was necessary to inter-rupt the observations before the end of the 4-hourperiod for reasons unconnected with the triaL Inthese patients the pain had not returned to itsinitial severity at the time when the readings wereinterrupted. In order not to reduce too much thenumbers in each group by omitting these incom-plete observations we have also included in theaverage figures for "analgesic activity" readingstaken at 3^ - and 3 hours.In addition, on the very few occasions in whicha half-hourly reading was omitted we took for thecalculation the lower of the two figures on eachside of the missed reading.Tahle I shows the findings in the three sub-groups, after 50-mg, 75-mg and 100-mg doses ofpethidine with or without levallorphan, as well asthe number of injections given at each dose level.As can be seen from this table, the figures showthat there is extraordinarily good agreement in allthree groups as regards the average analgesicactivity of a single dose of pethidine or pethidinewith levallorphan after 3, 3i and 4 hours. It canalso be seen that the average figures for the anal-gesic effect of a dose increased with the time(that is with the number of observations), andthat in general larger doses gave better analgesiathan smaller doses.Statistical analysis of these figures, using thet-test, showed that at the three dose levels therewas no significant difference between the averageanalgesic activity of pethidine and that of pethi-dine with levallorphan.On the basis of these findings it can be con-cluded that the addition of the narcotic antagonistlevallorphan to pethidine in the above proportiondoes not interfere with the analgesic activity ofthe pethidine.Influence on the Incidence of Side EffectsAs regards the general clinical use of the combin-ation of pethidine with levallorphan an importantquestion is raised. Does the antagonist prevent notTABLE IMean figures for the "analgesic activity" of a single dose of pethidineor pethidine with levallorphan.Observa-tionperiod(hours)50 mgpethidine75 ragpethidine100 mgpethidinenPethidinePethidine +levallorphan13.3 5114.6 4714.8 3713.5 6515.0 6116.4 4913.0 5214.7 4916.1 4113.214.615.843414015.1 3417.1 3318.5 2914.4 4616.0 4417.6 38A=average analgesic activity of a single dose.n = number of injections.TABLEIncidence of side effects after pethidine and pethidine with levallorphan.PethidinePethidine +levallorphanTotaJno. ofpatients5153Total no.of injec-tions162171•Patientswith side-effects15°16»Nature ofNauseaP1110n1215sideVomitingP94n114effectsSweatingP26n38(* Some patients experienced more than one side effect.)P=number of patients.n=number of injections.484 BRITISH JOURNAL OF ANAESTHESIAonly respiratory depression but also other undes-irable effects of pethidine, especially nausea andvomiting? In our study in postoperative patientswe recorded the presence or absence of nauseaand vomiting and, as far as possible, other sideeffects that might have been associated withmedication. Some additional patients wereincluded who could not be used for assessment ofthe analgesic effect.Table II shows the incidence of nausea, vomit-ing and excessive sweating in the two groups. Abreakdown into three dose levels is omitted, as itwas not possible to show that there was a relation-ship between the presence of such side effects andthe size of the dose. It was found that the incid-ence of nausea was the same in the two groups.Vomiting was somewhat less common in thepethidine with levallorphan group, whilst exces-sive sweating was rather more frequent. However,these differences were not statistically significant.No other significant side effects were observed.In the pethidine with levallorphan group each ofthe following were observed on one occasion:restlessness, tachycardia, arrhythmia, vertigo, pal-pitations and flushing. In two patients in thepethidine series there was a considerable rise ofblood pressure (possibly a result of hypoventila-tion).DISCUSSIONThe results of our previous investigation confirmedthe protective effect of levallorphan against therespiratory depressant effect of pethidine.The study in postoperative pain showed that,in the dose ratio of 80:1, the analgesic effect ofpethidine on postoperative pain is not reduced bylevallorphan. As regards the incidence of sideeffects other than respiratory depression, this wassimilar in the two groups. Although we foundthat the incidence of vomiting after pethidinewith levallorphan was somewhat reduced andexcessive sweating was slightly increased, the dif-ferences were not statistically significant.When using pethidine the addition of a smalldose of levallorphan provides a greater margin ofsafety and permits the administration of adequatedoses without the fear of inducing serious respira-tory depression. The following two cases whichoccurred fairly recently in our clinic illustrate thefact that severe respiratory depression may occureven when using pethidine in the usualtherapeutic doses.A woman, aged 39 years, had been admitted to hos-pital for an operation. Some hours after the operationshe was found to be unconscious, cyanosed and withdilated pupils; spontaneous respiration was absent.Oxygen was applied immediately and an endotrachealtube was passed. Ten minutes later, regular spon-taneous respiration had returned and after 4 hoursthe patient had recovered completely. Later it was dis-covered that because of postoperative pain she hadbeen given an intramuscular injection of pethidine 100mg about 30 minutes before the above incidentoccurred.A man, aged 73 years, with emphysema had beensubjected to prostatectomy. During the night thepatient was erroneously given pethidine 100 mg intra-venously instead of Novalgin. The physician, who wascalled immediately, observed that the patient hadslow, gasping respiration, was unconscious and hadconstricted pupils (the clinical appearances seen inmorphine poisoning). Oxygen was administered andan endotracheal tube was passed. However, it wasnecessary to administer levallorphan 2 mg beforespontaneous respiration improved and the reflexesreturned. One hour later the patient was againconscious.These two experiences confirm the fact thatthere is variation in individual sensitivity to res-piratory depressant substances and that eventherapeutic doses can cause serious complications.Without rapid medical assistance the apnoeamight well have resulted in death, or at least insevere hypoxic damage.SUMMARYThe authors describe a series of studies designedto establish whether the addition of a small quan-tity of the narcotic antagonist levallorphanreduces the respiratory depressant action of pethi-dine. They also investigated the effect onanalgesic activity and on the incidence of sideeffects.The study of respiratory depression was carriedout in two groups of anaesthetized patients. Whenanaesthesia was established each patient was givena dose of pethidine 1 mg/kg alone or mixed withlevallorphan in the proportion of 80:1. Theresults showed that there was a statistically signi-ficantly smaller reduction of the respiratory rate,minute volume and alveolar ventilation in thepethidine plus levallorphan group.To investigate the analgesic activity two groupsof patients with postoperative pain were treatedin a blind control study with either pethidine orA COMBINATION OF ANALGESIC AND ANTAGONIST 485pethidine with levallorphan in the above propor-tion. It was found that the average analgesic acti-vity was almost the same with the two types oftreatment. The incidence of side effects betweenthe two groups was insignificantly different.The authors conclude that the addition of leval-lorphan in the above proportion gives almostcomplete protection against the respiratorydepressant effect of pethidine without diminishingthe analgesic effect and without increasing theincidence of side effects.REFERENCESHossli, G., and Bergmann, G. (1959). Schweiz. mcd.Wschr., 89, 863.Swerdlow, M. (1958). Levallorphan: effects of largedoses. Anaesthesia, 13, 318.FILM REVIEW"THAT THEY MAY LIVE"This film is excellent not only from the teachingpoint of view but also in its presentation and pro-duction It is dramatic and holds the interest ofthe viewers throughout. There is a tendency toreact against the presentation of medical tech-niques which picture teaching accompanied by allthe trappings commonly employed by the com-mercial film industry. For example, music and theemployment of over-dramatic situations some-times detract from useful teaching films. Never-theless these are so skilfully employed in theproduction under review that they positively addto the teaching value of the film.The film shows the experiences of a newspaperreporter who visits the University of Saskat-chewan Hospital with the intention of writing upmodern methods of artificial respiration. He seesa demonstration of mouth-to-mouth resuscitationcarried out on a paralyzed subject and its efficacycontrasted with that of the more usual methodsavailable to the first-aid workers. He sees a classbeing instructed in the technique with the aid ofa wooden "air passage demonstrator" and anexcellent "manikin". The direct mouth-to-mouthmethod is shown and also the more hygienic useof the Brook Airway. The reporter is then showna film demonstrating "action shots" of a varietyof accidents: a car collision; a drowning incident;a child trapped in an abandoned icebox; an infantsuffocated by a plastic bag; an electrocutionoccurring at the top of a pylon; a choking scenein a restaurant; all of these being dealt with bymembers of the general public by mouth-to-mouth resuscitation. Finally, the reporter himselfon leaving the hospital visits a fun-fair and iscalled upon to use the technique in the resuscita-tion of a case of electrocution.This is quite the best film of its type that thereviewer has seen and should be in wide demandfor showing to undergraduates, nurses, ambulancepersonnel and first-aid workers.This film is available from Messrs. Smith andNephew Ltd., Bessemer Road, Welwyn GardenCity, Herts, who also supply the airway passagedemonstrator and the Brook Airway.Cecil Gray

A COMBINATION OF ANALGESIC AND ANTAGONIST IN POSTOPERATIVE PAIN

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library