THE SEDATIVE PROPERTIES OF PENTAZOCINE (FORTRAL)

Transcription

1 Brit. J. Anaesth. (1968), 40, 341 THE SEDATIVE PROPERTIES OF PENTAZOCINE (FORTRAL) BY WALTER NORMS AND A. B. M TELFER SUMMARY In 100 healthy gynaecological patients the sedative properties of pentazocine (Fortral) 20 mg were studied, using a standard scoring system, and compared with morphine 10 mg. No significant difference was noted and this result was confirmed by measuring the changes in forearm blood flow in 30 of the cases. A significantly smaller fall in systolic blood pressure and significantly lower incidence of postoperative emetic sequelae were found after the administration of pentazocine in comparison with the results obtained with morphine in the dosage studied. Since its discovery and introduction into clinical practice morphine has been widely used as the standard potent analgesic against which all similar drugs have had to bear comparison. While its analgesic properties have been of unquestioned value, its use has been limited because of undesirable side effects such as nausea, vomiting, respiratory depression and liability to addiction. Many drugs have been investigated in an effort to separate the desirable from the undesirable effects but few have more than marginal advantages over morphine and addiction liability remains a major problem. The synthesis of nalorphine (N-allylnormorphine) in 1941 led to the discovery that this drug had analgesic properties without addiction liability but the unpleasant psychotomimetic properties of this drug made it unacceptable as an analgesic. Since then many other potent analgesics have been synthesized including a group of compounds based on the benzomorphan molecule. One of this group is pentazocine (Fortral). The formula of the drug is shown in figure 1, and chemically it is 2- hydroxy-5, 9-dimethyl-2-(3, 3-dimethylallyl)-6, 7- benzomorphan. The dimethylallyl group gives it a narcotic antagonist property which distinguishes it from phenazocine. After considering animal studies and the results of extensive clinical trials of pentazocine the W.H.O. Expert Committee on Dependence Producing Drugs considered that there was no need for narcotics control of pentazocine internationally or nationally (W.H.O. Technical Report, 1966) and the drug has now been released for clinical use under the trade name of Fortral outwith the restrictions of the Dangerous Drugs Acts. Many reports have been published on the use of pentazocine as an analgesic (Gold, Cartel and Wang, 1963; Keats and Telford, 1964; Lasagna, 1964) and these authors claimed that pentazocine 20 mg was equi-analgesic to and as powerful a respiratory depressant as morphine 10 mg. While there remains some controversy as to the equianalgesic dose of pentazodne, more recent papers (Swerdlow and Dalai, 1966; Hill, Loan and Dundee, 1967) have led us to regard pentazocine 20 mg as equal in analgesic potency and respiratory depression to morphine 10 mg. N.CH,.CH=C FIG. 1 The formula of pentazocine (Fortral). The usefulness of an analgesic depends on the incidence of its side effects as well as its analgesic potency. Such a drug may find particular application in some fields of practice if the degree of sedation or relief of anxiety which it produces is greater or less than that produced by morphine

2 342 BRITISH JOURNAL OF ANAESTHESIA in equi-analgesic dosage. This study of the sedative properties of pentazocine was therefore undertaken. It has previously been reported that the application of a facepiece to a resting subject results in an increase in the forearm blood flow (Bird and Telfer, 1966). The forearm blood flow was therefore measured in 30 of the patients as a pilot study, thus continuing the assessment of various objective tests in the measurement of sedation. The full results of this and subsequent investigations will be reported later. METHOD Assessment of sedation. The method of study in all patients was that previously described by Nisbet and Norris (1963). All measurements were made on otherwise healthy patients who were due to undergo minor gynaecological operations. The patients were aged from 20 to 50 years, and came from one unit. A total of 100 patients were studied, 50 receiving morphine 10 mg and 50 pentazocine 20 mg by intramuscular injection 1 hour pre-operatively. The study was double blind, the drugs being allocated in a random fashion. Assessment of sedative activity was by means of the scoring system (Nisbet and Norris, 1963) combining subjective assessments and objective measures. Scoring system. The patients are classified by the observer as "anxious", "drowsy" or, when neither state is readily apparent, as "fully awake". It is assumed that it is possible to detect drowsiness and anxiety but not that it is possible to grade them. By definition it is not possible for a sedated patient to be anxious and, therefore, when anxiety and drowsiness co-exist such patients are graded as "anxious". The heart rate and systemic arterial pressure are measured. The patients are first seen in bed in the ward on the day before operation, and an assessment and measurements made. Atropine is omitted at this stage. The patient is next seen in the anaesthetic room and the assessment and measurements are repeated. Thereafter a stimulus is applied by asking her to breathe into an anaesthetic facepiece and the measurements are again repeated. There are thus three sets of measurements which allow a comparison of the findings after premedication with those at rest in the ward and enable a scoring system to be evolved. Points were awarded thus: Subjective. A. Subjective state in anaesthetic room. (1) Apprehensive 0 (2) Fully awake 1 (3) Drowsy 2 B. Change in state from ward to anaesthetic room. (1) Apparent improvement, change in state 1-2, or (2) (3) Apparent deterioration, change in state Objective. A. Change from ward to anaesthetic room. Fall in blood pressure >10 mm Hg 2 Rise in blood pressure >10 mm Hg 0 Fall in heart rate >10 beats/min 2 Rise in heart rate >10 beats/min 0 B. After stimulation. Rise in blood pressure >10 mm Hg 0 Rise in heart rate >10 beats/min 0 This gives a possible maximum score of 10, only 4 points of which are dependent on subjective observations. The degree of change in heart rate and blood pressure which is considered significant was arbitrarily decided after consideration of the range of observer error and day-to-day fluctuation in normal patients. Thus greater allowance is made for differences between the readings made on consecutive days than for readings before and after stimulus. Measurement of forearm blood flow. In 30 of the patients the forearm blood flow was measured using strain-gauge plethysmography (Whitney, 1953). The modification of the equipment described by Bird and Telfer (1966) was

3 THE SEDATIVE PROPERTIES OF PENTAZOCINE (FORTRAL) 343 employed and the assessment of changes in forearm blood flow as an objective measure of sedation will be reported subsequently. The technique of venous occlusion plethysmography involves the intermittent compression of a cuff placed on the upper arm; the cuff is inflated to a pressure less than the diastolic blood pressure and this results in a swelling or increase in volume of the limb distal to the cuff. The assumption is made that the swelling is entirely due to blood flowing into the part, and the rate of swelling therefore represents the rate of blood flow, at least for the first few seconds following occlusion. It is usual to compress the cuff for about 5 seconds, then deflate it for 3 to 5 seconds, thus giving a reading approximately every 10 seconds. The rate of swelling may be detected and displayed either using the conventional water displacement plethysmograph or the mercury-inrubber strain gauge; this latter is much more convenient for clinical work and has been shown to correlate well with the conventional volume plethysmograph (Clarke and Hellon, 1957); these authors found that the strain gauge gave results which were 6.6 per cent lower than the conventional water plethysmograph used with a water temperature of C. In the present study no arterial occlusion cuff was placed around the wrist This was partly for convenience, since the procedure is less complicated and quicker without it, but also because a cuff inflated to 230 mm Hg is definitely unpleasant and in itself acts as a stimulus to a sedated patient whereas the gentle, regular inflation of the upper arm cuff has no such effect. The flow which is measured may therefore be defined as total forearm blood flow, including both forearm and hand components. Comparison of the scores of the patients who had their blood flow measured with those for the whole series showed that the additional investigation had no significant effect on the score obtained. The mean score for the 15 patients who received morphine and had their blood flow measured was 6.26 ±2.18 and for the 50 morphine patients in the series was 6.2 ±2.08. The corresponding figures for pentazocine were 5.46 ±2.16 and 5.82 ±2.07. In this series measurements of total forearm blood flow were made at rest in the ward before and 1 hour after administration of the drug under test, and again in the anaesthetic room before and during the application of the stimulus. When the subject is in a steady state it is usual to take the mean of 10 consecutive readings as the mean value, e.g. for resting flow, but in rapidly changing states (e.g. immediately following the application of a stimulus), readings obtained at 10-second intervals may be considered individually. In this work the stimulus was applied following 10 consecutive readings in the resting state and the readings continued for another 100 seconds, Le. another 10 measurements. The peak value of these last 10 results was taken as the peak post-stimulus value and the mean of the 10 pre-stdmulus results as the mean pre-stimulus value. It was found that in many patients the flow rose quickly to a peak value following the application of the stimulus, then fell away. In others the rise was more sustained. The changes in flow from mean prestimulus value to peak post-stimulus value have been calculated and expressed as a percentage of the mean pre-stimulus value. Only the changes in flow produced by application of the stimulus are considered in this paper. Side effects. The incidence of nausea and vomiting in the first hour after administration of the drug was noted and the incidence of nausea and vomiting up till 9 p.m. (when the nursing staff changed), a period of 9-12 hours, was also recorded. The occurrence of postoperative restlessness was also noted. RESULTS Sedation. The results of the trial are shown in the histogram (fig. 2). In table I the distribution of the scores is again shown, scores of 0-4 being considered "poor", 5, 6 "fair", and 7-10 "good". The mean score for pentazocine 20 mg (5.82 ±2.07) is slightly less than that obtained with morphine 10 mg (6.20 ± 2.08) although in the numbers tested the difference is not statistically significant Similarly, when the drugs are compared in respect of the number of patients considered to show "good", "fair", or "poor" sedation, there is no significant difference. Other studies have shown results similar to those obtained with pentazocine (20 mg) in this trial after administration of morphine

4 344 BRITISH JOURNAL OF ANAESTHESIA (10 mg) and M183 (0.06 /*g) (CampbeU et al., 1966), and after administration of pethidine and Pcthilorfan each in 100-mg doses (Campbell, Masson and Norris, 1965). J MOIfHIMI 10 MO JPENTAZOCINIJOMO TABLE II The mean percentage increase in blood flow after stimulation in the 30 cases studied. Morphine 10 mg Pentazocine 20 mg Mean* SE of mean * Mean percentage increase in total forearm blood flow from mean pre-stimulus to maximum post-stimulus; f=0.09 (NS). Pwtantag* Increas* in Wood flow SEDATION SCOIE FIG. 2 Histogram showing the distribution of scores after administration of morphine 10 mg and pentazocine 20 mg. Mean scores: morphine 10 mg 6.20±2.08 pentazocine 20 mg 5.82 ±2.07 t = 1.31; P>0.25. TABLE I The classification of the patients into groups "good", "fair" and "poor". There is no significant difference between the two drugs. Drug Morphine 10 mg Pentazocine 20 mg Poor (0-4) 9 12 Number of cases Fair (5,6) Good (7-10) Forearm blood flow. Only the changes in total forearm blood flow resulting from the application of the stimulus are presented. All patients showed a rise in total forearm blood flow on application of the stimulus. The mean percentage increase in flow after the application of the stimulus was similar for each drug. The results are presented in table n. The scatter of the values for the blood flow changes reflects the variations in sedation scores obtained. Figure 3 shows the mean percentage increase in blood flow plotted against that part of the score which was derived from the application of the stimulus. With the small number of patients involved the differences are not statistically significant. M«cn pr«- itimulut to maximum poit timulug FIG. 3 The mean percentage increase in forearm blood flow is here shown plotted against the score obtained on application of the specific stimulus. It can be seen that the mean increase in flow is greatest where there is a poor score obtained on stimulation, that is, where the patient reacted by showing a rise in blood pressure and/or heart rate. With the small number of patients involved the results are not at this stage statistically significant. Blood pressure and heart rate. The changes in blood pressure and heart rate from the levels obtained in the ward on the day before operation to the levels in the anaesthetic room before stimulation are shown in table HI. TABLE III The changes in blood pressure and heart rate from the resting level in the ward on the day before operation to those obtaining in the anaesthetic room 1 hour after administration of the drug and before application of the stimulus. The t test results obtained by comparing the means are shown. Morphine Pentazocine Systolic blood pressure (mm '. Diastolic blood pressure (mm Hg) Heart rate (beats/min) 10 mg 14.9 ±19.8 «= ±14.1 r= mg -6.6 ±20.0 P<0.05 NS +0.12± ± =0.61 NS

5 THE SEDATIVE PROPERTIES OF PENTAZOCINE (FORTRAL) 345 The fall in systolic blood pressure after pentazocine is less than after morphine, but otherwise the results are not significantly different between the two drugs. Nausea and vomiting. The incidence of nausea and vomiting after administration of the two drugs is shown in table IV. When the combined incidence of nausea and/ or vomiting postoperatively is examined it can be seen that this is significantly less with'pentazocine than morphine (x 2 = 6.121, P<0.02). TABLE IV The incidence of postoperative nausea and vomiting within 9-12 hours after operation. The total emetic sequelae after morphine were significantly greater than after pentazocine, x' =6-121, P<0.02. Only four patients were nauseated in the anaesthetic room, three after morphine and one after pentazocine. Nausea Vomiting Nausea and vomiting Total emetic sequelae Number of cases Morphine 10 mg Pentazocine 20 mg Postoperative restlessness. The incidence of postoperative restlessness is shown in table V. In view of the possibility of psychotomimetic sequelae, a close watch was kept on all incidents, such as weeping postoperatively. Although there is a higher incidence of restlessness with pentazocine, this is not statistically significant (); 2 =2.44, P>0.1). Most of the "weepy" patients were in the morphine group. TABLE V The incidence of postoperative restlessness after the two drugs. There is no significant difference, x'=2.44, P>0.1. Morphine Pentazocine 10 mg 20 mg Restless 12 DISCUSSION The results obtained suggest that the sedation or relief of anxiety obtained after administration of pentazocine 20 mg is comparable to that obtained E after administration of morphine 10 mg. The results obtained with the scoring system were confirmed by the blood flow studies. The lower incidence of nausea and vomiting after pentazocine is in agreement with the findings of other workers (Stoelting, 1965; Hamilton, 1967). The smaller fall in systolic blood pressure after pentazocine was a surprise finding. Changes in blood pressure from the resting level in the ward to that found in the anaesthetic room reflect not only drug effect but also the degree of relief of anxiety produced. In this study, however, the sedative effect was only marginally less with pentazocine and it is therefore difficult to attribute the difference entirely to this cause. It may be relevant to observe that Sadove, Balagot and Pecora (1964) in testing pentazocine found little effect of the drug on blood pressure but what change there was, was in the form of a rise in pressure. In conclusion it appears that the relief of anxiety or sedation obtained with pentazocine 20 mg is approximately equal to that produced by morphine 10 mg. Nausea and vomiting are less common and changes in heart rate and blood flow through the forearm are comparable with the two drugs. There appears to be a less pronounced fall in systolic blood pressure when the drug is used as premedication. It would seem therefore that, since the drug has been found by others to be equi-analgesic in the dose tested and to be non-addicting, it could with advantage be substituted for morphine without loss of sedative properties and with the gain that accrues from the lower incidence of emetic sequelae. REFERENCES Bird, A. D., and Telfer, A. B. M. (1966). The effect of oxygen at one and two atmospheres on resting forearm blood flow. Surg. Gynec. Obstet., 123, 260. Campbell, D., Masson, A. H. B., and Norris, W. (1965). The clinical evaluation of narcotic and sedative drugs. II: A re-evaluation of pethidine and Pethilorfan. Brit. J. Anaesth., 37, 199. Reid, J. M. (1966). The clinical evaluation of narcotic and sedative drugs. Ill: An evaluation of M183. Brit. J. Anaesth., 38, 603. Clarke, R. S. J., and Hellon, R. F. (1957). Venous collection in forearm and hand measured by the strain gauge and volume plethysmograph. Clm. Sci., 16, 103. Gold, H., Cartel, McK., and Wang, R. I. H. (1963). Control of pain. Amer. J. med. Sci., 246, 590.

6 346 BRITISH JOURNAL OF ANAESTHESIA Hamilton, R. C (1968). Side effects of pentazocine and other narcotic analgesics. Clinical Trials Journal (in press). Hill, G. B., Loan, W., and Dundee, J. W. (1967). The use of a discriminant function in the assessment of analgesic drugs. Clin. Pharmacol. Ther., 8, 543. Keats, A. S., and Tclford, J. (1964). Studies of analgesic drugs. VI: A narcotic antagonist without psychotomimetic effects. J. Pharmacol, exp. Ther., 143, 157. Lasagna, L. (1964). Pentazocine (Win 20228). Pharmacol. Rev., 16, 66. Nisbet, H. I. A., and Norris, W. (1963). Objective measurement of sedation. II: A simple scoring system. Brit. J. Anaeslh., 35, 618. Sadove, M., Balagot, R. C, and Pecora, F. N. (1964). Pentazocine: a new non-addicting analgesic. J. Amer. med. Ass., 189, 199. Stocking, U. K. (1965). Analgesic action of pentazocine compared with morphine in post-operative pain. Anesth. Analg. Curr. Res., 44, 769. Swerdlow, M., and Dalai, A. (1966). A trial of pentazocine in post-operative pain: an interim report. Anaesthesist, 15, 43. Whitney, R. J. (1953). Measurement of volume changes in human limbs. J. Physiol. (Lond.), 121, 1. W.H.O. Expert Committee on Dependence Producing Drugs: Fifteenth Report (1966). Wld. Hlth. Org. techn. Rep., Ser LES PROPRIETES SEDATIVES DE LA PENTAZOCINE (FORTRAL) SOMMAKB Chez 100 patiences gynecologiques en bonne same, les proprietes sedatives de la pentazocine (Fortral) a 20 mg ont etc etudiees grice a un systeme compteur standard et comparers avec la morphine a 10 mg. On ne nota pas de difference significative et ce resultat fut confinne par la mesure des cchanges dans le flux sanguin de l'avant-bras chez trente des cas. Une chute notablement plus basse de la presskm WE"'"* systolique et une incidence notablement plus faible des scquelles emetiques post-operatoires furent decouvertes apres 1'administration de la pentazocine en comparaison avec les resultats obtenus par la morphine a la posologic etudiee. DIE SEDIERENDEN EIGENSCHAFTEN VON PENTAZOCIN (FORTRAL) ZUSAMMENFASSTJKG Bei hundert gesunden gynskologischen Patientinnen wuiden unter Verwendung eines Standardregistriersystems die sedierenden Eigenschaften von 20 mg Pentazocin (Fortral) untersucht und mit denen von 10 mg Morphin verglichen. Es wurden keine signifikanten Unterschiede festgestellt. Die Messung der DurchblutungsSnderungen im Unterarm bei 30 Patientinnen beststigte dieses Ergebnis. Im Vergleich zu den Ergebnissen, die mit Morphin in der untersuchten Dosierung erhalten wurden, fanden sich nach der Verwendung von Pentazocin ein signifikant geringerer Abfall des systolischen Blutdrucks und cin signifikant weniger hsufiges Auftreten postoperativer emetischer Folgeerscheinungen. MATHEMATICS FOR MEDICINE A one-week course will be held in Cambridge from September 21 to 28 inclusive. It is intended mainly for anaesthetists working for the March 1969 Primary FFARCS examination, and will provide an introduction to the mathematics needed for physics, statistics, biochemistry and clinical measurement. Application forms and further details from: THE SECRETARY, CAMBRIDGE UNIVERSITY, BOARD OF EXTRA-MURAL STUDIES, STUART HOUSE, MILL LANE, CAMBRIDGE.