THE DURATION OF ACTION OF BUPIVACAINE, PRILOCAINE AND LIGNOCAINE

Transcription

1 Brit. J. Anaesth. (970), 4, 335 THE DURATION OF ACTION OF BUPIVACAINE, PRILOCAINE AND LIGNOCAINE BY M. SWERDLOW AND RUTH JONES SUMMARY The duration and of hypoaesthesia produced by a variety of solutions has been examined by skin weal testing; each separate study was carried out in twenty female volunteers under double-blind conditions. First, bupivacaine, lignocaine and prilocaine were compared with and without in 0,000 adrenaline. was found to give significantly longer analgesia than prilocaine and significantly longer hypoaesthesia than both the other agents. Adrenaline significantly lengthened the action of all three drugs, this prolongation being greatest with lignocaine. The second part of the trial compared the duration of action of hospital-prepared and commercially prepared solutions of the three local analgesics plus adrenaline. The commercial ampoule preparations provided significandy longer action than the corresponding drugs in hospitalprepared multidose vials. The third group of experiments studied the effect of doubling the concentrations of the solutions; there was no great increase in duration but die duration of hypoaesthesia was lengdiened, significandy so with bupivacaine. Throughout all die above studies die individual results with bupivacaine showed a greater range of variation dian diose widi the odier agents. Finally die analgesic effect of saline (with and widiout adrenaline) was investigated; it was found diat both agents generally produced a similar brief period of hypoaesdiesia. The findings and dieir practical implications are discussed. There have recendy been a number of publications on die use of bupivacaine (Marcaine) for regional analgesia (Ekblom and Widman, 966; Fortuna, 966; Watt, Ross and Atkinson, 968). The present trial was carried out in order to compare die duration of skin analgesia produced by this agent widi diat produced by lignocaine (Xylocaine) and prilocaine (Citanest). METHOD The tests were carried out on volunteer subjects (female nursing staff) by a mediod similar to diat reported by Foldes and Macnall (95). Skin weals were made in the ventral aspect of the left forearm by intradermal injection of 0.5 ml of local anaesthetic from a ml polyediylene tuberculin sringe with a 7 s.w.g. needle. Each weal was "labelled" widi the code letter of the corresponding "blind" ampoule. Measurement was made of the time when some sensation returned in die weal and of the time when analgesia completely disappeared ("regression time"). Testing of sensation was carried out at 5-0 minute intervals by touching each weal widi die fingertip and if analgesia or hypoaesdiesia appeared to have terminated this was confirmed by dropping the needle-loaded (empty) ml syringe from a height of 0.5 cm on to the weal. Three different comparisons of die agents were carried out. TRIAL. Duration of action of agents with and without adrenaline. Twenty volunteers received from "blind" coded ampoules the following: () bupivacaine HC 0.5 per cent; () bupivacaine HC 0.5 per cent widi adrenaline in 0,000; (3) lignocaine (HQ) per cent; (4) Jignocaine HQ per cent with adrenaline in 0,000; (5) prilocaine per cent; (6) prilocaine per cent widi adrenaline in 0,000. M. SWERDLOW, MX)., M.SC., F.F.A.R C.S.; RUTH JONES,* MJ., CH.B., D.R.C.O.G., D.A.; Department of Anaesthesia, Salford Hospital Group. * Present address: Princess Alexandra Hospital, Harlow, Essex.,

2 336 BRITISH JOURNAL OF ANAESTHESIA The allocation of the code letters to each of the six injections was determined by using a random code. Each volunteer received all six preparations (i.e. six weals). Table I shows the mean duration (and standard errors) and of hypoaesthesia produced by the various preparations. TABLE I Duration of effect of solutions with (*) and without adrenaline (mean and SE). used (%) 0.5 Prilocaine * 0.5 * Prilocaine* No. of cases Duration 99.5 ± ± ± ± ± ± 0. Duration of hypoaesthesia ±30.. ± ± ± ± ±3. Table II shows the significance of the differences between the effects of the three local anaesthetics used without adrenaline. It will be seen that bupivacaine gave significantly longer analgesia than prilocaine and significantly longer hypoaesthesia than both the other local anaesthetics. s compared v. prilocaine v. lignocaine v. prilocaine TABLE II Significance of differences. Difference in mean duration 0.0<P<0.05 P>0. P>0. Difference in mean duration of hypoaesthesia P< <P<0.05 P>0. The effect of adding adrenaline to the three drugs is very marked; the increased duration is highly significant for each of the three drugs, both in duration and hypoaesthesia (P<0.00 in each instance). On further analysis it is found that the increase in duration produced by adrenaline is not the same for each drug. Adrenaline resulted in a significantly longer prolongation of both analgesia and hypoaesthesia with lignocaine rhan with the other two agents. TRIAL. Comparison of hospital v. commercially prepared agents. Multiple-dose code-labelled vials were prepared by the hospital pharmacist containing bupivacaine 0.5 per cent plus in 0,000 adrenaline, lignocaine per cent plus in 0,000 adrenaline, and prilocaine per cent plus in 0,000 adrenaline. Twenty volunteers received an injection of each of the three preparations. The results were compared with those obtained with the commercially prepared (Trial ) preparations of the same three agents. Table HI shows that in every case injection of the commercially prepared drug resulted in a longer duration of both analgesia and hypoaesthesia than did the corresponding drug prepared in the hospital pharmacy. Statistical analysis shows that the comparisons are all significant at the level of either P<0.00 or 0.0<P<0.05. In an endeavour to explain the difference in duration of the two preparations of the same drugs, samples of both hospital-prepared and commercially prepared agents were sent for analysis. It was found that the identity and concentration of each coded container was as intended and that the results of ph measurements were: (with adrenaline) 0.5% % Prilocaine % Hospital preparation ph Commercial preparation ph TABLE III Comparison of hospital and commercial preparations (values are mean and SE). Duration Hospital Commercial Hospital 0.5% +adrenaline % + adrenaline Prilocaine % +adrenaline 65.8 ± ± ± ± ± 0. Duration of hypoaesthesia ± ±3.7 Commercial ±3.

3 ACTION OF BUPIVACAINE, PRILOCAINE AND LIGNOCAINE 337 To determine whether ionic dissociation differences were responsible for the differences in the duration of action of the two preparations acidbase titration analysis was carried out over the entire ph range, using glass electrodes. The results showed no appreciable difference in ionic dissociation between the two preparations. (Analyses were undertaken by Dr. E. Power, Department of Chemistry, Salford University.) TRIAL 3. Effect of concentration of analgesic solution. In order to study the influence of an increase in concentration of the agents on the duration of action, twenty volunteers received an injection of each of the following commercially prepared solutions : bupivacaine 0.5 per cent; lignocaine per cent; prilocaine per cent. Table IV shows the mean duration and table V of hypoaesthesia produced by these concentrations of the anaesthetics. The comparison shows that doubling the strength of the solution does not significantly increase the mean duration for any of the three drugs used. (For lignocaine the mean duration is actually less with the per cent concentration, though not significantly so.) TABLE IV Effect of concentration on duration {mean and SE). Prilocaine Concentiation «'» Mean duration ± ± ± ± Significance of difference PX).05 TABLE V Effect of concentration on duration of hypoaesthesia (mean and SE). Concen- Mean duration Significance trauon of hypoaesthesia of (%) difference Prilocaine ± ± ± <P<0.05 PX).05 It will be noted that the magnitude of the standard error differs with the results for the three drugs, and reference to the results of the other trials above shows a similar pattern for the standard errors. Variance-ratio tests were therefore carried out on the data in table IV and these showed that the variance when bupivacaine is used is very significantly greater than with either prilocaine or lignocaine (P<0.00 and 0.00<P<0.0 respectively) and the comparison of variances for prilocaine and lignocaine was just significant (i.e. PiO:0.05), that for prilocaine being the larger. This is an agreement with the findings in Trials and. With regard to the duration of hypoaesthesia, table V shows that, with each agent, the doublestrength solutions gave a greater duration than the single-strength. The increases were not significant with prilocaine or lignocaine, but the increase for bupivacaine was significant. No allergic effects were seen in any of the volunteers in the series, but slight irritation over the injected areas occurred in one subject who received doublestrength solutions without adrenaline. TRIAL 4. Effect of intradermal injection of saline with and without adrenaline. It is of interest to know what part, if any, is being played in these results by distension of the tissues by the injected solutions. Accordingly normal saline and normal saline plus in 0,000 adrenaline were prepared in "blind" containers and twenty nurses received intradermal weals of both preparations under the experimental conditions described above. It was found that, in nineteen of the twenty subjects, both preparations produced a period of hypoaesthesia. The mean duration of hypoaesthesia was 35.4 ±7. min with saline including adrenaline and 36. ±5.4 min with normal saline; the difference is not significant. These times are significantly shorter (P<0.00) than those obtained with any of the local analgesic solutions tested. With regard to analgesia, saline including adrenaline produced analgesia in only two subjects ( min; 9 min) and saline alone produced analgesia in three subjects ( min; 8 min; 6 min). Finally, a number of the volunteers stated that saline with adrenaline caused more pain during injection than did saline alone.

4 338 BRITISH JOURNAL OF ANAESTHESIA DISCUSSION The results of these trials provide some information on the duration of action of bupivacaine as compared with lignocaine and prilocaine. The results are not strictly comparable with the clinical situation in which the local analgesic is applied to nerve fibres within the body mass. However, skin weal testing in volunteers does allow the comparison of the effects of a number of preparations in the same subject and facilitates frequent testing of the state and hypoaesthesia. The "overloading" which may result from injection of 0.5 ml solution intradermally may to some extent hinder the clearance of the local analgesic by blood flow. Furthermore the skin has a somewhat limited blood supply so that blood clearance will be slower than in deeper tissues and in addition the effects of adrenaline will be exaggerated. Dhuner and Lewis (966) showed that both lignocaine and bupivacaine cause an increase in regional blood flow when injected intramuscularly but not when given subcutaneously. They found also that addition of adrenaline to the injected solutions significantly prolonged the duration of action of subcutaneous injections of local anaesthetic but not that of intramuscularly injected solutions. With regard to the different results produced by the hospital and commercial preparations of the same analgesics, it must be noted that the commercially prepared ampoules were gassed with nitrogen before sealing, whereas the hospital pharmacy prepared vials of the three agents by direct transfer from the manufacturer's ampoule. The vials were not filled with nitrogen and these solutions would undergo oxidation more readily, resulting in a lower ph which may partly account for the disparity in duration of action. It seems likely, however, that the main reason was a deactivation of the adrenaline in the solutions. Sodium metabisulphite is added to local anaesthetic solutions to prevent oxygenation of adrenaline, but in the hospital-prepared vials some oxygen would be let into the vial during preparation and every time it was used. It will be of interest to anaesthetists and others using local analgesics to realize that bottles and vials of local analgesic (particularly multidose ones) prepared in the hospital pharmacy and perhaps kept on the shelf for long periods will not provide as long a duration of action as intact ampoules. The marked prolongation of effect produced by adrenaline is well known (Braun, 94; Gray and Geddes, 954), absorption of the local anaesthetic from the site of injection being markedly slowed down. The finding that adrenaline prolonged the effect of lignocaine more than the other two agents confirms the work of Astrom (965) who postulates an anti-adrenaline action for prilocaine. Albert and Lofstrom (965) carried out bilateral ulnar nerve blocks in volunteers and tested by pinch-test for analgesia and hypoaesthesia. They found that adrenaline prolonged the duration of action of lignocaine four times and that of prilocaine twice. They also found that "the time from reappearance of pain sensation until complete recovery of pain perception" (regression time) were similar with prilocaine and lignocaine; the regression times were lengthened by adrenaline especially for lignocaine. This was not found in the present study. Widman (964), who performed digital nerve block in volunteers and tested analgesia by pinprick, found that 05 per cent bupivacaine with in 50,000 adrenaline gave a duration of anaesthesia of 445 ± 48 min a very similar duration to that found in the present trial with the same solution. Hollmen (966) also reported similar durations and hypoaesthesia when 0.5 per cent bupivacaine was used for axillary plexus block. Comparison of the duration produced by double-strength solutions with that of single-strength solutions plus adrenaline shows that adrenaline gives significantly longer analgesia, suggesting that maintenance of the solution at the injection site is important in prolonged action. The duration of hypoaesthesia is also significantly longer with single-strength solution plus adrenaline than with double-strength solution, except in the bupivacaine groups. Thus as far as intradermal injection is concerned the prolongation of action produced by adrenaline is of more importance than that resulting from increasing the concentration of local anaesthetic used. When the trial was planned it was hoped to include a study of times of onset of action. In practice this proved impossible because each skin weal was analgesic to pinprick immediately it was produced presumably due to the distension of the tissues produced by the solution. In this respect the findings of the present normal saline trial are of interest. No previous similar trial has been found

5 ACTION OF BUPIVACAINE, PRILOCAINE AND LIGNOCAINE 339 except that of Padfield (967) who also reported that saline produced a brief period after intradermal injection. It is chastening to discover that Halstead in 885 wrote: "The skin can be completely anaesthetised by cutaneous injections of water. The anaesthesia seldom oversteps the boundary of the original bloodlesss wheal, but does not always vanish just as hyperaemia supervenes." ACKNOWLEDGEMENTS Our thanks are due to the nursing staff of the Salford Group of Hospitals who volunteered to take part in the study. We are also grateful to Mr. B. A. Moore, M.SC., of the Department of Mathematics, Salford University, for carrying out the statistical analysis of the results. Finally we would like to thank Mr. A. Williams (Chief Pharmacist, Salford Hospital Group) and Mr. G. W. Williams of BDH Pharmaceuticals for preparing the "blind" preparations of the local analgesics. REFERENCES Albert, J., and Lofstrom, B. (965). Effects of epinephrine in solutions of local anaesthetic agents. Acta anaesth. scand., SuppL 6, 7. Astrom, A. (965). Factors affecting the action of Citanest in vivo. Acta anaesth. scand., SuppL 6, 3. Braun, H. fl94). Die Lokalanastesie, 4th ed., p. 63. Leipzig: Verlag von J. A. Barth. Dhuner, K. G., and Lewis, D. H. (966). Effects of local anaesthetics and vasoconstrictors upon regional bloodflow. Acta anaesth. scand., SuppL 3, 347. Ekblom, L., and Widman, B. (966). A comparison of the properties of LAC-43, prilocaine and mepivacaine in extradural anaesthesia. Acta anaesth. scand., SuppL, 0, 33. Foldes, F. F., and McNall, P. G. (95). Chloroprocaine a new local anesthetic agent. Anesthesiology, 3, 87. Fortuna, A. (966). Further experiences with LAC-43 in peridural block. Acta anaesth. scand., SuppL 3, 40. Gray, T. C, and Geddes, I. C (954). A review of local anaesthetics. 7. Pharm. Pharmacol, 6, 89. Halstead, W. S. (885). Water as a local anaesthetic. N.Y. med. J., 4, 37. Hollmin, A. (966). Axillary plexus block: a double blind study of 59 cases using mepivacaine and LAC-43. Acta anaesth. scand., SuppL, 0, 53. Padfield, A. (967). The intradennal local analgesic action of pnlocaine. Anaesthesia,, 556. Watt, M. ]., Ross, D. M., and Atkinson, R. S. (968). A rlintral trial of bupivacaine. Anaesthesia, 3,. Widman, B. (964). Clinical trial of a new local anaesthetic (LAC-43) with the aid of the pin-prick and ninhydrin methods in finger blocks. Acta anaesth. scand., 8, 9. LA DUREE D'ACTION DE BUPIVACAINE, PRILOCAINE ET LIGNOCAINE SOMMATRE La duree d'analgesie et d'hypoesthesie, produites par diverses solutions, a tti etudiee a l'aide du test de la papule cutanee; cheque essai sipazi a tti fait k double insu chez vingt volontaires feminines., lignocalne et prilocaine ont d'abord iti comparers avec et sans adrenaline, : causa une analgesic significativetnent plus longue que prilocaine, et une hypoth&ie significativement plus longue que les deux autres substances. Adrenaline prolongea significativement l'effet des trois medicaments, cette prolongation itant la plus grande pour lignocalne. Les auteurs ont compare au cours de la seconds partie de l'essai, la duree d'action de solutions, preparees a I'h6pital et d'origine commerciale, des trois analgesiques locaux + adrenaline. Les ampoules d'origine commerciale eurent une duree d'action significativement plus longue, que celle des flacons multidose prepares 4 l'hdpital. Le troisieme groupe d'experiments tudia l'effet d"un d&ioublement des concentrations des solutions; il n'y cut pas de prolongation importante de la duree d'analgesie mais l'hypoesth^sie se prolongea, merne significativement en ce qui concerne la bupivacaine. Les resultats individuels obtenus durant les diffirents essais varierent plus avec bupivacaine qu'avec les autres substances. Finalement on a e^udi^ l'effet analgesique d'une solution saline (avec et sans adrenaline); on observa que les deux solutions provoquerent en general une courte piriode similaire d'hypoesthesie. Les auteurs discutent les observations et leurs consequences pratiques. DIE WIRKUNGSDAUER VON BUPIVACAIN, PRILOCAIN UND LIGNOCAIN ZUSAMMENFASSUNG Die Analgesie- und Hypasthesie-Dauer, wie sie durch verschiedene Losnngen erzielt wird, ist mittels Intrakutantestung unrersucht worden: jede einzelne Studie wurde an wanzig freiwilligen weibliche Probandinnen unter Doppelbhndversuchs-Bedingungen durchgefuhrt Zuerst wiirden Bupivacain, Prilocain und Lignocain mit und ohne Zusatz von Adrenahn (:0 000) verguchen. Dabei wurde festgestellt, dafi die Analgesie mit Bupivacain wesentlich langer anhielt als mit Prilocain; die Hypasthesie-Dauer war nach Bupivacain wesentlich langer ab nach den beiden anderen Agenzien. AdrenaUn verlangerte die Wirkungsdauer aller drei Substanzen erhebh'ch; am starksten wird die Wirkung von Lignocain prolongiert. Im zweiten Teil der Priifung wurde die Wirkungsdauer von im Krankenhaus hergestellten Losungen der drei Lokalanalgerika, jeweib mit Adrenahn-Zusatz, mit den entsprechenden handebiiblichen Losungen verglichen. Die handelsublichen Ampullenpraparationen besaden eine erheblich langere Wirkungsdauer als die im Krankenhaus hergestellten Mulridosis-Flaschen. Im dritten Abschnitt der Prufung wurde die die Wirkung einer Konzentrationsverdopplung der Losungen untersucht: es kam zu keiner starken Verlangerung der Analgesiedauer, die Dauer der Hypasthesie jedoch wurde verlangert, nach Bupivacain sogar erheblich. Wahrend aller der oben beschriebenen Prflfungsabschnitte zeigten die individuelkn Ergebnisse fur Bupivacain eine groflere Schwankungsbreite als die der anderen Agenzien. Abschliefiend wurde der analgerische Effekt einer Salzlosung Cmit und ohne Zusatz von Adrenalin) untersucht: es wurde festgestellt, dafi beide Losungen gewohnlich eine Hypasthesie von gleich kurzer Dauer hervorriefen. Die Befunde und die sich ergebenden praktischen Folgerungen wurden diskutiert.