A COMPARISON OF PENTAZOCINE AND PETHIDINE IN PATIENTS WITH PAIN FOLLOWING CHOLECYSTECTOMY

Brit. J. Anaesth. (1971), 43, 58

A COMPARISON OF PENTAZOCINE AND PETHIDINE EN PATIENTS WITH PAIN FOLLOWING CHOLECYSTECTOMY BY

T. TAMMISTO AND S. TAKKI SUMMARY

The finding that an intravenous injection of pentazocine may cause an increase in blood pressure has been reported previously (Keats and Telford, 1964; Brown, 1969). Two further studies have suggested that this increase is beneficial when treating pain in patients following myocardial infarction (Lai, Savidge and Chhabra, 1969; Scott and Orr, 1969). The haemodynamic changes following intravenous pentazocine and pethidine have been studied in patients lightly anaesthetized with halothane (Stephen, Davie and Scott, 1970) and in patients anaesthetized with nitrous oxide, oxygen and tubocurarine (Tammisto, Takki and Toikka, 1970). The changes produced under these circumstances differ from those seen in conscious volunteers, but none of the patients involved in these previous studies were in pain at the time of the investigation. The present investigation was carried out to compare the analgesic efficacy of the two drugs in patients who were complaining of pain in the immediate postoperative period following cholecystectomy and to compare the haemodynamic changes with those which occurred in the other studies. T. TAMMISTO, M.D.; S. TAKKI, M.D,; Department of

Anaesthetics, Meilahti Hospital, Helsinki 29, Finland

PATIENTS

Forty-nine patients were included in this doubleblind, between-patient study, twenty-four of whom received pentazocine and twenty-five of whom received pethidine. There were nine male and forty female patients in the age range 20 to 69 years, with almost half the patients aged between 30 and 49 years. In an attempt to make the two groups as homogeneous as possible, patients were matched for age ( ± 10 years), sex, weight ( ± 1 0 kg) and, as far as possible, preoperative blood pressure. In each case the anaesthetics were administered by the authors. METHOD

All patients received the same pre-anaesthetic medication of atropine 0.01 mg/kg, promethazine 50 mg and pethidine 1 mg/kg, by intramuscular injection. Anaesthesia was induced with thiopentone 3-5 mg/kg and suxamethonium, and maintained, after intubation, with tubocurarine 0.5 mg/kg and mechanical positive pressure ventilation, using a mixture of nitrous oxide and oxygen (25 per cent). When required, further doses of tubocurarine 3-5 mg were given, and in some cases the anaesthetic had to be supplemented with 0.5 per cent halothane. No analgesic drugs

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Forty-nine patients who had undergone cholecystectomy were investigated in a doubleblind, between-patient single-dose comparison of pentazocine and pethidine. Patients were matched for age, sex, weight and pre-operative blood pressure, and received pentazocine 0.3 mg/kg body weight or pethidine 0.5 mg/kg by intravenous injection. All measurements were made by the same observers in the first 3 hours after the operation. Systolic and diastolic pressures remained unchanged in the pentazocine group, but there was a significant fall of about 10 per cent in both systolic and diastolic pressures 90 minutes after the injection of pethidine. Although pethidine gave slightly better analgesia, the degree of sedation was significantly greater, and side effects occurred more frequently. It is concluded that pentazocine may have advantages over pethidine especially in the immediate postoperative period when the cardiovascular system is unstable.

59

PENTAZOCINE AND PETHIDINE FOLLOWING CHOLECYSTECTOMY

pulse rate and side effects in any one patient were made by the same observer. RESULTS

Tables I and II show the distribution of patients with regard to age, sex and total body weight. The doses of each drug were small, and no patient received more than 36 mg of pentazocine or 55 mg of pethidine. The average doses were 19 mg of pentazocine and 33 mg of pethidine. It can be seen from these tables that the matching of patients succeeded in producing two homogeneous groups for comparison. All patients in the study spontaneously complained of pain within 30 minutes of the end of anaesthesia. Cardiovascular changes. Only results from those patients who completed the 2-hour investigation are included. The results for the five patients who did not complete the study have been excluded (see below). (a) Systolic blood pressure. Figure 1 shows the mean changes in systolic blood pressure following injection of the trial drugs. After injection of pentazocine the mean systolic blood pressure fluctuated between 130 mm Hg and 133 mm Hg; these changes were of no clinical or statistical significance. In the pethidine-treated group there was a fall in the mean systolic pressure from

TABLE I

Distribution of patients by age and sex. Age (yrs) Treatment Pentazocine Pithidine

20-29

30-39

40-49

50-59

60-69

M F M F

Total

Total 4 20

5 20 10

13

11

8

7

49

TABLE II

Distribution of patients by weight. Weight (kg) 70-79 60-69

Treatment

<49

80-89

90 +

Total

Pentazocine Pethidine

3 3

7 8

5 4

7 6

3

2 1

24 25

Total

6

15

9

13

3

3

49

50-59

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were administered during the period of general anaesthesia, and at the end of the operation the muscular relaxation was reversed by neostigmine 2 mg given with atropine 1 mg and the patients allowed to regain consciousness. In every case this occurred within a quarter of an hour. All the patients were nursed in the supine position and remained in the recovery room under observation for the period of the study. When the patient first complained of pain he was asked to assess the severity as "slight" (1), "moderate" (2) or "severe" (3), and at this time the observer made his own assessment of the severity, using the same scale. Blood pressure and pulse rate were also recorded at this time. One of the two test drugs from a randomized coded supply was then given by intravenous injection, 0.1 ml/10 kg body weight, so that each patient received either pentazocine 0.3 mg/kg or pethidine 0.5 mg/kg. Following the injection, further assessments of pain intensity were made by both patient and observer at 15-minute intervals until 2 hours after the injection, while blood pressure and pulse rate were recorded at 5-minute intervals for 30 minutes and thereafter at 15-minute intervals: patients who fell asleep were awakened for the assessments. Blood pressure was measured to the nearest 5 mm Hg, using auscultation on the same arm for each patient. Records of blood pressure,

BRITISH JOURNAL OF ANAESTHESIA

60

beats/min

3 O B 20 25 X

mm Hg

*5

60

75

90

KB

DO

Time after injection (min)

uo Mean systolic B.P.

FIG. 2 Heart rate (mean±l SE). Pentazocine; n=21 Pethidine; n=23

no

Assessments of pain intensity. During the 2 hours of the investigation five patients had no relief of pain and so they were no removed from the trial and given another analgesic injection. Three of these were in the pentazocine-treated group and two in the pethidine group. Pain severity was assessed independently by both the observer and the patient, using the same scale as before, "none" (0), "slight" (1), "moderate" (2), "severe" (3), and a pain-relief 0 5 » B»3 X 43 40 73 90 KB no score was calculated for each post-injection Time after injection (mln) assessment by subtracting the pain intensity value FIG. 1 from the original pre-injection figure. Using this method it is possible to obtain a negative score Blood pressure readings (mean ± 1 SE). if a patient who has only slight or moderate pain Pentazocine; n=21 Pethidine; n=23 initially fails to obtain adequate relief and the pain intensity becomes severe at some time after (c) Heart rate. The changes in mean heart rate the injection. This occurred on only eight occaare shown in figure 2. Following injection of sions altogether (an incidence of less than 1 per pentazocine there was an initial fall in rate, cent of the assessments made) and these assessments were scored as zero for no relief. The five which returned to the pre-injection level at 20 patients who were removed from the trial because minutes, and thereafter was slightly increased. of inadequate analgesia would obviously not have Patients in the pethidine group also showed a achieved any degree of pain relief during the slight increase in mean pulse rate. These increases remainder of the investigation, and their results are statistically significant (pentazocine, P<0.05; were therefore scored zero. Table HI shows the pethidine, P<0.02). in

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134 mm Hg at the time of injection to 123 mm Hg 90 minutes later. This change in blood pressure is statistically significant (P<0.002), and the difference between the two drug groups at this time is also significant (P<0.05). (b) Diastolic blood pressure. After injection, the mean diastolic blood pressure in the pentazocine-treated group varied between 84-88 mm Hg, but these changes were not significantly different from the initial level of 86 mm Hg (fig. 1). In the pethidine group the mean diastolic pressure was initially 90 mm Hg, and this fell steadily to 80 mm Hg an hour and a hah7 after injection. This fall is statistically significant (P<0.001) and also differs significantly from the pentazocine group at this time (P<0.02).

PENTAZOONE AND PETHIDINE FOLLOWING CHOLECYSTECTOMY TABLE

III

Observer's assessment of inixial pain

severity.

Initial pain Treatment

Slight

Moderate

Severe

Pentazocine Pethidine

12 7

9 16

3 2

24 25

Total

19

25

5

49

Total

Sedation. Seven patients in the pentazocine-treated group were recorded as "sleepy" before the injection and, of the remaining seventeen, nine (53 per

13

30

45

60

7S

90

103

Time after injection (min) FIG. 3 Pain relief scores—observer's assessments ( m e a n ± l SE). Pentazocine; n = 2 4 Pethidine; n = 2 5

cent) were recorded as being "drowsy" at some time during the next 30 minutes. In the pethidine group, ten patients were recorded as being "sleepy" before injection, but fourteen of the remaining fifteen patients (93 per cent) were recorded as being "drowsy" at some time during the next 30 minutes. This post-injection difference between the two drug groups is statistically significant (Fisher's Exact Test, P=0.018). TABLE

IV

Patient's assessment of initial pain severity. Initial pain Treatment

Slight

Moderate

Severe

Total

Pentazocine Pethidine

1

12 13

11 12

24 25

Total

1

25

23

49

Side effects. Thirteen patients in the pentazocine group and sixteen patients in the pethidine group complained of side effects during the study, and the details are shown in table V. Some patients reported more than one side effect but the differences between the two treatment groups are not statistically significant

15

»

43

60

73

90

103

Time after injection (min) FIG. 4 Pain relief scores—patient's assessments (mean±l SE). Pentazocine; n = 2 4 Pethidine; n = 25

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observer's assessment of the initial pain severity, and figure 3 the pain relief scores as assessed by the observer throughout the investigation. In each drug group on every occasion the mean pain relief scores differ significantly from the preinjection level (P<0.001) in all cases. The differences between these scores in the two groups, however, are not significant at the 5 per cent level. Table IV shows the severity of the initial pain, and figure 4 the pain relief scores as assessed by the patients themselves. Again, for each drug group the mean pain relief scores differ significantly from the pre-injection level (P<0.001), but at 30 and 45 minutes after the injection the differences between the two drug groups are significant at the 5 per cent level.

61

62

BRITISH JOURNAL OF ANAESTHESIA V of side effects.

TABLE

Distribution

Number of complaints Pentazocine

Pethidine

Total

Nausea Vomiting Sweating Itching Difficult breathing

10 2 4 1

13 3 4

23 5 8 1

1

1

Total

17

21

38

DISCUSSION

The patients in this study were all investigated immediately following cholecystectomy and were therefore in a labile general condition; thus the analgesia achieved, together with the cardiovascular changes which occurred during the period of assessment, may not have been entirely due to the test drugs administered. However, as pentazocine and pethidine have previously been compared by us in patients who were not in pain (Tammisto, Takki and Toikka, 1970) it seemed worthwhile to assess the two drugs in patients who were in pain under the conditions in which they will be commonly used, and an attempt was made to standardize as far as possible the two patient groups. By standardizing the anaesthetic technique and taking care not to give analgesic drugs during the period of surgery, a fairly constant time interval was achieved between the end of the operation and the moment that the patients first complained of pain. This was considered important, because it has been shown that the longer the rime between the operation and the injection the longer-lasting is the relief obtained from that injection (Swerdlow, Murray and Daw, 1963). In a previous study we have shown that pentazocine administered intravenously to conscious volunteers produces a sustained rise in blood pressure, whereas the injection of pethidine produces a rise which lasts for only 10 minutes (Tammisto, Takki and Toikka, 1970). With the small doses used in this study, in the immediate recovery period, these hypertensive responses were not seen. On the contrary, following the injection of pethidine, a fall in systolic blood pressure was observed which reached its maxi-

The disadvantages of asking patients to make a retrospective comparison of initial pain and the degree of relief at any one time are well known, and it would seem better to compare pain intensity both before and after injection. However, when, because of insufficient pain relief, patients have to be excluded at different times during the assessment, a further problem is created. Either one excludes these patients entirely, which reduces the total number of patients in the group and provides a bias in the results, or one includes them up to the moment they are removed from the study. This alternative produces a further bias in the between-group comparison because only those patients who obtained no relief are excluded. To avoid these difficulties we have used the technique of calculating pain relief scores from the pain intensity scores, as described by Houde, Wallenstein and Rogers (1960). This enables us to retain those patients who would otherwise have been excluded because of inadequate relief by giving them scores of zero for all the assessments that would have been made had they remained in the trial. The difficulties produced by negative

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Side effect

mum surprisingly late. The fall in diastolic blood pressure following the injection of petnidine reached its maximum at the same time, so that although this fall of 8 per cent was not of major clinical importance in our patients, it would seem that the use of pentazocine would be preferable in patients with a labile blood pressure, especially if higher doses of analgesic drugs are required. Changes in pulse rate were similar for both drug groups and were of no clinical importance. Previous comparisons of the analgesic efficacy of pentazocine and pethidine in postoperative pain have been described elsewhere. Scott, Abernethy and Livingston (1966) showed that pentazocine 20 mg produced the same degree of analgesia as pethidine 50 mg, while O'Connell and associates (1968) supported these findings with pentazocine 40 mg and of pethidine 100 mg. In a recent study, using both observer and patient assessments of pain, Guldmann and Sestoft (1969) showed that pentazocine 40 mg produced significantly better analgesia than pethidine 100 mg, pethidine 50 mg or pentazocine 20 mg, and these workers were unable to demonstrate any difference between the analgesia produced by the two doses of pethidine.

PENTAZOONE AND PETHIDINE FOLLOWING CHOLECYSTECTOMY

A significant difference was also seen in the degree of sedation produced by the two drugs, with a larger number of patients in the pediidine group being "drowsy" after die injection. Approximately diree-quarters of all the patients were reported as being "drowsy", and diis degree of sedation may explain why die observers consistendy rated die pain intensity below that of die patients themselves. Under the conditions of this investigation, pentazocine 30 mg would seem to be about as effective as pethidine 50 mg, and this is roughly in agreement with our previous comparison of diese two drugs (Tammisto, Lahdensuu and Fock, 1967). The different results seen when comparing analgesic potency might be explained by the fact diat the analgesic activity of pediidine in the present study may reflect its stronger sedative action radier dian a true analgesic potency. The postanaesthetic residual sedation may explain the adequate analgesia obtained by die majority of patients despite die relatively low doses of analgesic drug used. On die other hand, it has been shown by Slaughter, Parsons and Munal (1940) that neostigmine potentiates the analgesic action of morphine, and Christensen and Gross (1948) showed diat the duration and intensity of pediidine analgesia could be increased by neostigmine.

It may be diat die neostigmine used to reverse the neuromuscular action of tubocurarine was helping to potentiate die analgesic effect produced by the trial drugs. Side effects, particularly nausea and vomiting, occurred more frequendy in die pediidine group, but diis difference was not statistically significant. (P>0.05). Under the conditions of diis investigation we concluded that pentazocine is as an effective analgesic as pediidine, with die advantage diat it produces less change in blood pressure, less sedation and probably less nausea and vomiting. For these reasons it would seem diat pentazocine is preferable to pethidine for postoperative analgesia when the patients are in a labile cardiovascular state, especially if higher doses of die analgesic drugs are required. ACKNOWLEDGEMENTS

We wish to thank our surgical and nursing colleagues for their assistance with this study, and also M. K. Palmer, B.SC, who performed the statistical analysis. REFERENCES

Brown, A. S. (1969). Pentazocine, a potent analgesic: evaluation for anaesthetic use. Proc. roy. Soc. Med., 62, 805. Christensen, E. M., and Gross, E. G. (1948). Analgesic effects in human subjects of morphine, mepiridine and methadon. J. Amer. med. Ass., 137, 594. Guldmann, N., and Sestoft, K. H. (1969). A comparison of the analgesic efficacy of two dose levels of pintazocine and pcthidine. Clm. Trials J., 6, 173. Houde, R. W., Wallenstein, M. S., and Rogers, A. (1960). Clinical pharmacology of analgesics: • method of assaying analgesic effect Clm, Pharmacol. Ther., 1, 163. Keats, A. S., and Telford, J. (1964). Studies of analgesic drugs. VIII: A narcotic antagonist analgesic without psychotomimetic effects. J. Pharmacol exp. Ther., 143, 157. Lai, S., Savidge, R. S., and Chhabra, G. P. (1969). Cardiovascular and respiratory effects of morphine and pentazocine in patients with myocardial infarction. Lancet, 1, 379. O'Connell, T. C J., Heffernan, S. J., Lane, D. A. A., McMullin, J. P. O., CGrady, J. F., and Delaney, P. V. (1968). A comparison of the effects of pentazocine and pethidine injections in postoperative pain. J. Irish, med. Ass., 61, 357. Parkhouse, J., and Hallinon, P. (1967). A comparison of aspirin and paracetamol. Brit. J. Anacsth., 39, 146. Scott, M. E., and Orr, R. (1969). Effects of diamorphine, methadone, morphine and pentazocine in patients with suspected acute myocardial infraction. Lancet, 1, 1065.

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relief scores only occur when a large number of patients are in moderate or severe pain initially but, as these scores made up less than 1 per cent of the total assessments, we felt justified in following the example of Houde, Wallenstein and Rogers, and scored these patients as zero relief for the relevant assessment. The disadvantages of this scoring technique have been explained by Parkhouse and Hallinon (1967), but as these artificial scores represent such a small percentage of the total assessments made, we felt that the method was valid. In general, die observers assessed the degree of initial pain as less severe than did the patients diemselves. Both drugs produced a significant decrease in this pain intensity within 15 minutes of die injection, and diis improvement was maintained for the 2 hours of the study. There were no significant differences between die two drug groups except in the patients' assessments at die 30- and 45-minute assessments when the pethidine score was significandy higher dian that for the pentazocine group.

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BRITISH JOURNAL OF ANAESTHESIA

64

U N E COMPARAISON D E PENTAZOCINE ET PETHIDINE CHEZ DES PATIENTS AVEC DOULEUR APRES CHOLECYSTECTOMIE SOMMAIRE

Quarante-neuf patients, ayant subi une cholecystectomie, ont participe' a une comparaison a double-insu, entre patients d'une dose unique de pentazocine et pethidine. Les malades ont 6t6 grouped pour 1'Sge, le sexe, le poids et la pression sanguine preopiratoire, et recurent pentazocine 0 3 mg/kg de poids corporel ou pethidine 0,5 mg/kg par voie intraveineuse. Toutes les mesures furent faites par les memes observateurs dans les trois premieres heures apres l'ope'ration. La pression sanguine systolique et diastolique demeure inchangee dans le groupe pentazocine, mais il y cut une chute significative d'environ 10 pourcent, aussi bien dans la pression systolique quc diastolique, 90 minutes apres 1'injection de pethidini. Pethidine procure une anallgesie tegerement meilleure mais le degre" de sedation fut significativement plus grand et des effets secondaires se produisirent plus frequemment. On en conclue que pentazocine peut avoir des avantages en comparaison a la pethidine, surtout dans la periode postope'ratoire immediate, lorsque le systeme cardiovasculaire est ins table.

VERGLEICHENDE U N T E R S U C H U N G ZWISCHEN PENTAZOCINUM U N D PETHIDIN BEI PATIENTEN M I T SCHMERZEN NACH EINER CHOLEZYSTEKTOMIE ZUSAMMENFASSUNG

Bei neunundvierzig Patienten, die einmalig Pentazocinum und Pethidin im Anschlufi an eine Cholezystektomie erhalten hatten, wurde in einem Dopp:lbljidversuch zwischen den einzelnen Patienten eine vergbichende Untersuchung beziiglich der Wifkung der beiden Medikamente durchgefuhrt. Die Patienten wurden hinsichtlich Alter, Geschlecht, Gewicht und Blutdruck vor der Operation in entsprechende Gruppm unterteilt und erhielten 0,3 mg/kg K6rpergewicht Pentazocinum oder 0,5 mg/kg Pethidin intravenos. Samtliche Messungen wurden von den gleichen Untersuchem in den ersten 3 Stunden nach der Operation durchgefuhrt. In der Pentazocinum-Gruppi blieb der systolische und diastolische Blutdruck unver§ndert; es trat jedoch 90 Min. nach der Pethidin-Injektion ein signifikanter Abfall des systolischen und diastolischen Blutdrucks urn ca. 10% ein. Obwohl Pethidin eine etwas bessere analgetische Wirkung hatte, war das AusmaO der Sedierung wesenliich grofier und die Nebenwirkungen waren haufiger. Es wird gefolgert, dafi Pentazocinum gegeniiber Pethidin yor allem unmittelbar postoperativ, wenn das kardiovaskulfire Sytem instabil ist, bestimmte Vorziige aufweist. COMPARAQON DE LA P E N T A Z O d N A Y PETIDINA EN PACIENTES CON DOLOR DESPUES DE COLECISTECTOMIA RESUMEN

Curenta y nueve pacientes que habian sido sometidos a colecistectomia fueron investigados en una comparaci6n doble ciega, entre pacientes, dosis unica de pentazocina y petidina. Los pacientes fueron emparejados segiin edad, sexo, peso y presion arterial preoperatoria, y recibieron 0 3 mg/kg peso corporal de pentazocina 6 0,5 mg/kg de petidina en inyeccidn intravenosa. Todas las med£iones fueron efectadas por los mismos observadores durante las primeras tres boras despues de la operaci6n. La presi6n arterial ststoUca y diast61ka permanecieron inalteradas en el grupo de la pentazocina, pero hubo una reducci6n significativa de aproximadamente el 10 por ciento en las presiones tanto sist61icas como diast61ocas 90 minutos despues de la inyeccion de petidina. A pesar de que la petidina dk) una analgesia ligeramente mejor, el grado de sedacidn fue significativamente mayor y los efectos secundarios ocurrieron con mas frecuencia. Se concluye qiie la pentazocina pudiera tener ventajas sobre la petidina especialmente en el periodo posoperatorio inmediato cuando el sistema cardiovascular es inestable.

ERRATUM In the article entitled "The effect of repairs on the performance of the Wright respirometer" by J. N. Lunn and E. K. Hillard in the December 1970 issue (Brit. J. Anaesth., 42, 1127), line 10 of the first paragraph should read: "meters could be supplied. Repairs could then be"

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Scott, R., Abemethy, R. J., and Livingston, H. S. (1966). Pethidine and pintazocine in postoperative pain. Clm. Trials J,, 3, 305. Slaughter, D., Parsons, J. C , and Munal, H. D. (1940). New rliniral aspects of the analgesic action of morphine. J. Anter. med- Ass., 115, 2058. Stephen, G. W. t Davie, I., and Scott, D. B. (1970). Circulatory effects of pentazocine and pethidine during general anaesthesia with nitrous oxide, oxygen and halothane. Brit. J. Anaesth., 42, 311. Swerdlow, M., Murray, A., and Daw, R. H. (1963). A study of post-operative pain. Acta. anaesth. scand., 7, 1. Tammisto, T., Lahdensuu, M., and Fock, G. (1967). Pentazocine as a supplement in anaesthesia: a clinical comparison of pethidine, fentanyl and pentazocine in nitrous oxide-oxygen relaxant anaesthesia. Ann. OUT. Gynaec. Fenn., 56, 319. Takki, S., and Toikka, P. (1970). A comparison of the circulatory effects in man of the analgesics fentanyl, pentazocine and pethidine. Brit. J. Anaesth, 42, 317.