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CONTROLLED COMPARISON OF INTRATHECAL CINCHOCAINE WITH INTRATHECAL CINCHOCAINE AND MORPHINE
Br. J. Anaesth. (1984), 56, 837
CONTROLLED COMPARISON OF INTRATHECAL CINCHOCAINE WITH INTRATHECAL CINCHOCAINE AND MORPHINE Clinical effects and plasma morphine concentrations R. A. MOORE, G. M. C. PATERSON, R. E. S. BULLINGHAM, M. C. ALLEN, D. BALDWIN AND H. J. MCQUAY SUMMARY
Although extensive clinical use of extradural opiate drugs (Bullingham, McQuay and Moore, 1982) has followed the discovery of opiate receptors in the spinal cord (Yaksh and Rudy, 1976), the intrathecal route has received relatively little attention. Intrathecal injection is a more direct route of administration, since the drug is absorbed from the fluid bathing the spinal cord and opiate receptors. As the dose of drug administered intrathecally has tended to be less than that given into the extradural space (Bullingham, McQuay and Moore, 1982), it would seem likely that the effects from blood-borne drug at supraspinal or spinal levels can be neglected. Indeed, the plasma concentrations after intrathecal injection are much less than those following i.m. and extradural injections of the same dose (Chauvin et al., 1982). As a result, the analgesic, metabolic and ventilatory effects of these low (intrathecal) doses should be caused by the drug acting directly on the spinal opiate receptors. These effects, together with the plasma concentrations of morphine, were studied to compare the efficacy of intrathecal cinchocaine and morphine with that of intrathecal cinchocaine alone. M. C. ALLEN, B.SC; D . BALDWIN, A.I.MX.S., Nuffield Depart-
ment of flinimi Biochemistry, Raddiffe Infirmary, Oxford. R. A. MOORE, D.PHIL.; R. E. S. BULLINGHAM, F.F_A.R.CS.; H. J.
MCQUAY, FJ.AJLCS.; Pain Relief Research Unit, Oxford Regional Pain Relief Unit, Abingdon Hospital, Marcham Road, Abingdon, Oxon. G. M. C. PATERSON, F.FJLJLOS., Nuffield Department of Anaesthetics, Raddiffe Infirmary, Oxford. Correspondence toR. A. M.
PATIENTS AND METHODS
The approval of the ethics committee was obtained for this study of patients undergoing elective total hip replacement at the Nuffield Orthopaedic Centre, Oxford. Twenty patients were allocated alternately to one of two groups: one group received intrathecal cinchocaine and morphine, the other intrathecal cinchocaine alone. Patients were selected if their age was between 45 and 75yr and thenweight between 40 and 100 kg. Those with severe cardiac, hepatic, renal or neurological disease, or diabetes, were excluded; no patient had a history of regular narcotic medication and neither was any patient given corticosteroids before or during the study. Preservative-free morphine was made up in the Sterile Supplies Department at the Churchill Hospital, Oxford. Morphine hydrochloride trihydrate 5 ing was dissolved in Water-for-Injection B.P. 0.2 ml and filtered into a 5-ml glass ampoule. The gas space above the liquid was filled with filtered medical grade nitrogen, and the ampoule sealed and autoclaved at 115°C for 30 min. Ampoules were protected from light and stored for not more than 6 months. Before injection, 1/200 (Smgml"1) cinchocaine 3.0ml in hyperbaric 6% dextrose (Nupercaine, Ciba Laboratories, Horsham, West Sussex) was added to the morphine hydrochloride in the ampoule. The contents were mixed and the injection volume withdrawn. Patients were premedicated with lorazepam by mouth 2 h before operation. The intrathecal injec© The Macmillan Press Ltd 1984
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Twenty patients scheduled for elective total hip replacement were given either intrathecal cinchocaine with morphine hydrochloride 2.5 mg or intrathecal cinchocaine alone before general anaesthesia. Arterial plasma morphine concentrations were measured and analgesic, respiratory and biochemical effects compared. Plasma morphine concentrations increased to 19.3nmol litre"1 at 210 min. cozconcentrations increased p c significantly only in those patients who received morphine as well as cinchocaine. Patients receiving cinchocaine alone, but not those given cinchocaine and morphine, had significant ( P < 0 . 0 1 ) increases in plasma cortisol concentrations' in the period after operation. Median time to next nnalg«itK- in patients receiving cinchocaine with intrathecal morphine was 22 h, significantly (P<0.01) longer than in patients receiving intrathecal cinchocaine alone (7.8 h).
838
been reported previously (McQuay et al., 1980). Statistical analysis of differences between the groups was with Student f test or Mann - Whitney U test, and within the groups by paired t test. Statistical differences between the groups for sideeffects was assessed by Fisher's exact test. RESULTS There were no statistically significant differences between the groups as regards age, weight, height, sex distribution, blood loss and the intervals between the intrathecal injection and the start and termination of surgery (table I). Patients who received intrathecal cinchocaine plus morphine had a cinchocaine dose of 7.66±0.31mg/70kg (mean±SEM) and a morphine dose of 2.55±0.10mg (6.6nmol). The mean cinchocaine dose in patients receiving cinchocaine alone was 7.45±0.16mg/70kg. In the patients receiving intrathecal morphine the plasma morphine concentrations increased by 15 min after injection (table II), although the highest mean concentration (19.3 nmol litre"1) was achieved at the final 210-min sampling point. Data (not shown) from four of the patients indicated that plasma morphine concentrations continued to increase for at least 4 h after the intrathecal injection. Arterial Pcc^ values decreased in patients given intrathecal cinchocaine alone, and in the period after operation were significantly less than at 15 min after injection (table II). In contrast, P a c d values increased in the patients receiving intrathecal morphine, and had increased significantly ( P < 0 . 0 1 , paired t test) at 120 min. PacOj in patients given TABLE I. Demographic measures. Thtrt was no significant difftrence between the groups for any measure (Student t test). Values are mean±SEM ninrhfvflinf
and morphine n Age(yr) Weight (kg) Height (cm) Sex ratio (M/F) Time (min) Inj. to surgery Inj. toendsurg. Blood loss (ml) Cinchocaine dose (mg/70kg) Morphine dose (mg/70kg)
10
69.6 ±2.6 60.8 ±4.2 161.7±3.2
Cinchocaine alone 10
65.1±2.5 67.2±4.9 164.2 ±3.3
4/6
3/7
36±4 12O±5 460±81
35±5 131±8 588 ±63
7.66±0.31
7.4S±0.16
2.55±O.1O
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tion was performed using a 25-g spinal needle at the L3-4 space with the patient in the lateral position. Hyperbaric cinchocaine 1.0-1.5 ml with or without added morphine was administered. Doses were, approximately, cincnocaine 7.5 mg and morphine hydrochloride 2.5 mg per 70 kg. Anaesthesia was induced with thiopentone sodium 4 mg kg"' and maintained with nitrous oxide in oxygen (2:1) using a Bain coaxial breathing system with spontaneous ventilation through a mask and pharyngeal airway. Fresh gas flow was not less than ISOmlkg-'min- 1 . Halothane 0.5-2% was added until the conduction block was effective and a cannula was inserted to the radial artery to permit the monitoring of arterial pressure and blood sampling during and following surgery. Hartmann's solution and blood were administered according to a predetermined schedule. After operation, patients were transferred to a postoperative ward and breathed 28% oxygen through a Ventimask. Patients received additional analgesic drugs on request and the time was recorded. In the period immediately after operation they were looked after by a trained research sister who visited them again 24h after surgery. Any analgesic medication given following the operation was noted together with volunteered side-effects. Patients were also questioned directly as to evidence of itching, headache, backache or urinary problems. Arterial blood samples were collected at 15, 30, 60, 90, 120, 150, 180 and 210 min after the intrathecal injection for the estimation of blood-gas tensions and plasma concentrations of glucose, cortisol and morphine. A venous blood sample was taken before the intrathecal injection to obtain baseline values. Samples were collected into tubes containing lithium heparin or citrate-oxalate anticoagulants and stored in the cold until centrifuged, when plasma was frozen at — 20 °C until analysis. Plasma morphine was measured by radioimmunoassay using a 125I-morphine label prepared in the Nuffield Department of Clinical Biochemistry, a specific antiserum (Bioanalysis Ltd, Cardiff, Glamorgan) and a solid-phase second antibody (Saceel, Wellcome Diagnostics, Dartford, Kent). Crossreactivity to morphine-3-glucuronide and normorphine was less than 1%. The least amount measurable under these conditions was 0.8 nmol litre"1; coefficients of variation for control samples were less than 10% for values between 2 and 130 nmol litre"1. Methods for measuring the plasma concentrations of cortisol, glucose and the blood-gas tensions have
BRITISH JOURNAL OF ANAESTHESIA
INTRATHECAL CINCHOCAINE AND MORPfflNE
839
TABLE II. Changts in plasma morphint, Vacop and plasma cortisol concentrations during and afur optration. Vaiuts are mtan± SEM. Significant diffenncts from first sampling point for Paco? and plasma cortisol concentration wtrt asstssed by the paired t test (*P < 0.05; **P < 0.01). For Pacoj, significant difftrtncts between the groups (P < O.OSorUss) toere demonstrated by Studtntt Ust for values between 90and210min inclusive PiflHirifl morphine concn (nmol litre'1) Time (min)
(»-io)
Cinchocaine and morphine (»-10)
Cmrtwvflin^
alone (»=10)
0.0
5.2 ±1.0 6.7±0.8 9.6±1.0 12.2±1.3 16.0±1.5 16.2±1.6 18.411.5 19.311.9
6.2410.31 6.2510.30 6.5210.32 6.9510.38 6.7510.28** 6.8110.21* 6.8010.21** 6.7810.31**
6.1510.29 6.0110.27 5.7510.20 5.9710.24 5.8410.17 5.8710.16 5.5610.27** 5.71 ±0.25*
Cinchocaine and morphine (n-10) 406±50 406±55 365 ±63 344±57 530 ±103 633 ±112 636±87 672 ±81 586 ±105
rinrhomirv alone (n-10) 413±40 395 ±58 353 ±61 456±80 660 ±100* 796 ±100** 796 ±95** 761±104** 792 ±125**
cinchocaine plus morphine were significantly higher cinchocaine 7.5mg/70kg alone or in combination than those given cinchocaine alone between 90 and with morphine hydrochloride 2.5mg/70kg after 210 min. non-analgesic premedication. Patients receiving cinchocaine alone showed a Because of the small (6.6-fimol) intrathecal morsignificant increase in plasma cortisol concentra- phine dose used, the plasma morphine concentrations by 90 min (average about 400 nmol litre"1) tions were low. The maximum mean value obtained (table II). In those patients receiving cinchocaine was 19.3 nmol litre"1 210 min after injection. This and morphine the average increase was about was lower than the concentrations found 4-6 h after 200 nmol litre"1 (not significant) Mean values be- administration of 0.2mgkg"' i.m. (Chauvin et al., tween the groups were not significantly different at 1982). Thus, the effects which occur soon after any time. Plasma glucose values increased signific- intrathecal injection may be attributed to the direct antly (P<0.01, paired t test) in both groups by actions of the drug at the spinal opiate receptors 15 min- the extent of the increases was similar (max- rather than to any indirect actions following sysimum about 2.5 nmol litre"1), and at no time was temic absorption and redistribution. there any significant difference between the groups. After extradural injection, peak plasma concentPostoperative analgesia, as measured by the time rations usually occur within 15 min (Weddel and to the next analgesic, was of longer duration in Ritter, 1981; Chauvin et al., 1982; Gustaffsonetal., patients given intrathecal cinchocaine plus mor- 1982). Plasma morphine concentrations measured phine (median22 h, range 7.25->24) than those after the intrathecal injection of a large dose given cinchocaine alone (7.8h, 2.45-14.5). This (14mg/70kg) (Chauvin et al., 1982) showed great difference between the groups was significant variability in the time to peak concentration. The ( P < 0.01, Mann-Whitney [/test). The occurrence of side-effects during the 1st day after operation is shown in table III. There was a TABLE III. Number of patients with postoperative side-effects tendency for more facial itch and urinary difficulty Cinchocaine in patients who were given intrathecal morphine, and morphine alone but more nausea and vomiting in the patients who (n=10) (,,= 10) had cinchocaine alone. No untoward sedation was noted in either group. No side-effects DISCUSSION This study compared two similar groups of patients who were given an intrathecal injection of either
Itching (facial) Nausea and vomiting Micturition difficulty Headache
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0 15 30 60 90 120 150 180 210
Cinchocaine and morphine
Plasma cortisol concn (nmol litre"1)
Anerial PCOi (kPa)
840
BRITISH JOURNAL OF ANAESTHESIA
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dose-related peak plasma concentrations were about injection, is uncertain. 50% greater than in this study. It may be that large The increase in P&CO2 after morphine was consisintrathecal doses of opiates result in more rapid tent (as shown by the small standard errors of the systemic absorption. mean (table II)), and was about 1 kPa greater than The time to the administration of further the control group. Such values are not unusual in analgesia is a crude measure of analgesic efficacy, postoperative patients receiving parenteral opiates but in this trial the difference between the groups (McQuay et al., 1980). Substantial rostral flow of was considerable. The median value for patients spinal fluid with high morphine concentrations receiving morphine was three times that of patients would be expected to produce severe respiratory receiving cinchocaine alone and there was barely any depression, but no patient in this study had a reoverlap between the groups. Only one patient given spiratory rate less than 10 b.p.m. From this and the intrathecal morphine needed additional analgesia small and consistent change in Pbcch it can be within 12 h of injection, and seven did not need any concluded that high morphine concentrations did for at least 21 h. This represents consistent analgesia not occur in the cerebral ventricles. from a intrathecal dose of morphine 2.5 mg and The important features of the changes in .ftco? contrasts with the variable analgesia reported with were that they occurred late, and that they remained extradural opiates (Bullingham, McQuay and increased, although the duration of the change was Moore, 1982). not determined in this trial. This is in contrast to the Side effects were few: there was no incident of rapid onset of respiratory effects after parenteral late respiratory depression, and the occurrence of morphine. Whether spinal fluid- or blood-borne nausea and vomiting was low in both groups. Itch- morphine, alone or in combination, was the cause of ing and headache occurred in both groups, but were the change cannot be answered by the results presented. not particularly troublesome. Suppression of the glycoregulatory response to This study suggests that small intrathecal doses of surgical stimulation requires large doses of mor- opiate may be used to advantage in patients underphine i.v. ( > 1 mgkg"1) (George et al., 1974), al- going total hip replacement. Morphine may not be though the extradural administration of morphine the best opiate drug for intrathecal administration, or diamorphine has been shown to have suppressive and it may not have been given at the optimal dose, effects in therperiod after operation (Cowen et al., but it had beneficial effects without any unduly 1982). This report confirms the importance of spinal harmful side-effects. nociceptive pathways for the cortdsol response to surgery (Engquist et al., 1977). Failure to suppress ACKNOWLEDGEMENTS the glucose response simultaneously, probably re- We thank the patients at the Nuffield Orthopaedic Centre for flects the selective spinal component for this process their co-operation and the anaesthetic, surgical and postoperative staff for their help. Research Sisters Lesley Weir, Mamey (DeFronzo, Sherwin and Felig, 1980); removal of ward Rolfe and Tcena Sloane looked after the patients in the postoperathe cortdsol response alone is insufficient for effects tive period. MissZ. Ashraf made up the morphine hydrochkmde on plasma glucose concentrations. for intrathecal injection. MCA was supported by the Medical P&CO2 increased after intrathecal morphine. The Research Council and DB by the Oxford Regional Health Auincrease was significant within 120 min of injection, thority. but no further increase occurred. The late onset of REFERENCES this effect contrasts with the immediate occurrence Bullingham, R. E. S., McQuay, H. J., and Moore, R. A. (1982). of extremely high spinal fluid concentrations of Extradural and intrathecal narcotics; in Recent Advance in 1 Anaesthesia and Analgesia (eds R. S. Atkinson and C. Langton morphine of more than 100 000 nmol litre" after Hewer), vol. 14, p. 141. Edinburgh: Churchill Livingstone. intrathecal injection (Jorgensen, Andersen and EngM., Samii, K., Schermann, J. M., Sandouk, P., Bourquist, 1981; Moore et al., 1984). The changes in Chauvin, don, R., and Viars, P. (1982). Plasma pharmacokinetics of P&CO2 were more in keeping with the increase in the morphine after i.m., extradural and intrathecal administraplasma concentrations of morphine. Rigg (1978) tion. Br. J. Anaesth., 54, 843. demonstrated that morphine produced measurable Cowen, M. J., Bullingham, R. E. S., Paterson, G. M. C , McQuay, H. J., Turner, M., Allen, M. C , and Moore, R. A. ventilatory effects at plasma concentrations as low as 1 (1982). A controlled comparison of the effects of extradural 100 nmol litre" . Whether respiratory depression diamorphine and bupivacaine on plasma glucose and plasma can occur as a result of the much lower plasma cortisol in postoperative patients. Anesth. Analg., 61, IS. morphine concentrations associated with intrathecal DeFronzo, R. A., Sherwin, R. S., and Felig, P. (1980). Syncrgis-
INTRATHECAL CINCHOCAINE AND MORPHINE
COMPARAISON CONTROLEE DE LA CINCHOCAINE SEULE OU ASSOOEE A LA MORPHINE EN RACHIANESTHESIE Effea clmiqua et concentrations plasmatiques de morphine RESUME
Vingt patients qui devaient subir la pose d'une prothese totale de hanche en chirurgie reglee ont recu pour une rachianesthesie, de la cinnchocaine seule ou associee a 2,5 mg de chlorhydrate de morphine avant l'anestheiie generale. Les concentrations plasmatiques arterielles de morphine ont ete mesurees et les effets biochimiques respiratoires et analgesiques compares. Les concentrations plasmatiques de morphine atteignaient 19,3 mmol litre"1 a la 210c min. Les valeurs de la Pacoj n'augmentaicnt trignifimfivement que chez les patients qui recevaient de la morphine en mrnw temps que la cinchocaine. Les concentrations plasmatiques de cortisol dans la periode post-operatoire augmentaient de facon significative ( P < 0 , 0 1 ) chez les patients qui avaient recu de la cinchocaine seule, mais pas chez ceux qui avaient recu de la cinchocaine avec de la morphine. La duree moyenne avant une deuxieme injection d'analgesique etait de 22 h chez les patients qui avaient re£u de la cinchocaine avec de la morphine intrathecale, ce qui est significativenient ( P < 0 . 0 1 ) phis long que chez les patients qui n'avaient re^u que de la cinchocaine intrathecale seule (7-8 h).
EIN KONTROLLIERTER VERGLEICH ZWISCHEN INTRATHEKALEM CINCHOCAIN UND INTRATHEKALEM CINCHOCAIN MIT MORPHIUM Klmische Wirksamkeit und Ptasmamorphiumkonxentrationen ZUSAMMENFASSUNG
Zwanzig Patienten, die elektiv eine totale Huftendoprothese erhatten sollten, erhielten entweder 2,5 mg Cinchocain mit 2,5 mg Morphium hydrochlorid oder Cinchocain alleine intrathekal, bevor die Vollnarkose cingeleitet wurde. Es wurden die arteriellen Plasma-Morphiumkonzentrationeii gemessen und analgetische, respiratorische und biochemische Effektc verglichen. Die Morphhimkonzentrationen stiegen innerhalb von 210Minuten auf 19,3 nmol litre"1 an. Pacc>2 stiegen nur bei denen Patienten, die Cinchocain mit Morphium erhalten hatten. Signifikante Anstiege ( P < 0 , 0 1 ) von Plasmacortisolkonzentrationen in der postoperativen Phase traten nur bei Patienten auf, die Cinchocain alleine erhalten hatten, nicht bei denen mit Morphiumzusatz. Die mittlere Zeit bis zum nSchsten Analgetikabedarf war mit 22Stunden bei den Patienten mit Cinchocain und Morphium signifikant (P<0,01) langer als bei den Patienten mit Cinchocain alleine (7,8 Stunden).
COMPARACION CONTROLADA DE LA CINCOAINA INTRATECAL CON CINCOCAINA Y MORFINA INTRATECAL Efectos clinicos y conctntraciona de morftna en el plasma SUMARIO
Se administro a veinte pacientes previstos para un reemplazo total electivo de la cadera ya sea cincocaina con2,5 mgde hidrocloruro de morfina o cincocaina intratecal sola antes de la anestesia general. Se midieron las concentraciones de morfina en el plasma arterial y se compararon los efectos bioquimicos y respiratorios de la analgesia. Las concentrationes de morfina en el plasma aumentaron hasta 19,3 nmol litre"1 a los 210 min. Las concentraciones de Paco2 aumentaron de manera m'gnifirante unicamente'en los pacientes a los cuales se administro morfina asi como cincocaina. Los pacientes con cincocaina sola, pero no los con cincocaina y morfina, sufrieron aumentos signifkantes (P<0,01) de las concentraciones de cortisol en d plasma durante el periodo postoperatorio. El tiempo medio hasta la proxima administracidn de analgesico en los pacientes con cincocaina y morfina intratecal era de 22 h, o sea mucho mayor (i 7 <0,01) que en los pacientes con cincocaina intratecal sola (7,8 h).
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tic interactions of counterregulatory hormones: a for stress hyperfdycaemia. Ada Chir. Scand., (Suppl. 498), 33. Engquist, A., Brandt, M. R., Femandes, A., and Kehlet, H. (1977). The blocking effect of epidural analgesia on the adrenocortical and hypergrycaemic response to surgery. Acta Anaesthesia!. Scand., 21, 330. George, J. M., Reier, C. E., Larese, R. R., and Rower, J. M. (1974). Morphine anaesthesia blocks cortisol and growth hormone responses to surgical stress in humans. / . Ciin. Endocrinol. Mttab., 38,736. Gustafsson, L. L., Friberg-Nielsen, S., Garle, M., Mohall, A., Rane, A., Schildt,B.,and Symreng,T. (1982). Extraduraland parenteral morphine: kinetics and effects in postoperative pain. A controlled Hiniril study. Br. J. Anaath.,54,1167. Jorgensen, B. C , Andersen, H. B., and Engquist, A. (1981). CSF and pln*mn morphine after epidural and intrathccal application. Anesthaiology, 55, 714. McQuay, H. J., BuUingham, R. E. S., Paterson, G. M. C , and Moore, R. A. (1980). minimi effects of buprenorphine during and after operation. Br. J. Anaath., 52,1013. Moore, A., BuUingham, R., McQuay, H., Allen, M., Baldwin, D., and Cole, A. (1984). Spinal fluid kinetics of morphine and heroin in man. Clin. Pharmacol. Ther., 35,40. Rigg, J. R. A. (1978). Ventilatory effects and plasma concentration of morphine in man. Br. J. Anaath., 50, 759. Weddel, S. J., and Rirter, R. R. (1981). Serum levels following epidural administration of morphine and correlation with postsurgical pain. Anathaiology, 54,210. Yaksh, T. L., and Rudy, T. A. (1976). Analgesia mediated by a direct spinal action of narcotics. Science, 192,1357.
841
CONTROLLED COMPARISON OF INTRATHECAL CINCHOCAINE WITH INTRATHECAL CINCHOCAINE AND MORPHINE Clinical effects and plasma morphine concentrations R. A. MOORE, G. M. C. PATERSON, R. E. S. BULLINGHAM, M. C. ALLEN, D. BALDWIN AND H. J. MCQUAY SUMMARY
Although extensive clinical use of extradural opiate drugs (Bullingham, McQuay and Moore, 1982) has followed the discovery of opiate receptors in the spinal cord (Yaksh and Rudy, 1976), the intrathecal route has received relatively little attention. Intrathecal injection is a more direct route of administration, since the drug is absorbed from the fluid bathing the spinal cord and opiate receptors. As the dose of drug administered intrathecally has tended to be less than that given into the extradural space (Bullingham, McQuay and Moore, 1982), it would seem likely that the effects from blood-borne drug at supraspinal or spinal levels can be neglected. Indeed, the plasma concentrations after intrathecal injection are much less than those following i.m. and extradural injections of the same dose (Chauvin et al., 1982). As a result, the analgesic, metabolic and ventilatory effects of these low (intrathecal) doses should be caused by the drug acting directly on the spinal opiate receptors. These effects, together with the plasma concentrations of morphine, were studied to compare the efficacy of intrathecal cinchocaine and morphine with that of intrathecal cinchocaine alone. M. C. ALLEN, B.SC; D . BALDWIN, A.I.MX.S., Nuffield Depart-
ment of flinimi Biochemistry, Raddiffe Infirmary, Oxford. R. A. MOORE, D.PHIL.; R. E. S. BULLINGHAM, F.F_A.R.CS.; H. J.
MCQUAY, FJ.AJLCS.; Pain Relief Research Unit, Oxford Regional Pain Relief Unit, Abingdon Hospital, Marcham Road, Abingdon, Oxon. G. M. C. PATERSON, F.FJLJLOS., Nuffield Department of Anaesthetics, Raddiffe Infirmary, Oxford. Correspondence toR. A. M.
PATIENTS AND METHODS
The approval of the ethics committee was obtained for this study of patients undergoing elective total hip replacement at the Nuffield Orthopaedic Centre, Oxford. Twenty patients were allocated alternately to one of two groups: one group received intrathecal cinchocaine and morphine, the other intrathecal cinchocaine alone. Patients were selected if their age was between 45 and 75yr and thenweight between 40 and 100 kg. Those with severe cardiac, hepatic, renal or neurological disease, or diabetes, were excluded; no patient had a history of regular narcotic medication and neither was any patient given corticosteroids before or during the study. Preservative-free morphine was made up in the Sterile Supplies Department at the Churchill Hospital, Oxford. Morphine hydrochloride trihydrate 5 ing was dissolved in Water-for-Injection B.P. 0.2 ml and filtered into a 5-ml glass ampoule. The gas space above the liquid was filled with filtered medical grade nitrogen, and the ampoule sealed and autoclaved at 115°C for 30 min. Ampoules were protected from light and stored for not more than 6 months. Before injection, 1/200 (Smgml"1) cinchocaine 3.0ml in hyperbaric 6% dextrose (Nupercaine, Ciba Laboratories, Horsham, West Sussex) was added to the morphine hydrochloride in the ampoule. The contents were mixed and the injection volume withdrawn. Patients were premedicated with lorazepam by mouth 2 h before operation. The intrathecal injec© The Macmillan Press Ltd 1984
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Twenty patients scheduled for elective total hip replacement were given either intrathecal cinchocaine with morphine hydrochloride 2.5 mg or intrathecal cinchocaine alone before general anaesthesia. Arterial plasma morphine concentrations were measured and analgesic, respiratory and biochemical effects compared. Plasma morphine concentrations increased to 19.3nmol litre"1 at 210 min. cozconcentrations increased p c significantly only in those patients who received morphine as well as cinchocaine. Patients receiving cinchocaine alone, but not those given cinchocaine and morphine, had significant ( P < 0 . 0 1 ) increases in plasma cortisol concentrations' in the period after operation. Median time to next nnalg«itK- in patients receiving cinchocaine with intrathecal morphine was 22 h, significantly (P<0.01) longer than in patients receiving intrathecal cinchocaine alone (7.8 h).
838
been reported previously (McQuay et al., 1980). Statistical analysis of differences between the groups was with Student f test or Mann - Whitney U test, and within the groups by paired t test. Statistical differences between the groups for sideeffects was assessed by Fisher's exact test. RESULTS There were no statistically significant differences between the groups as regards age, weight, height, sex distribution, blood loss and the intervals between the intrathecal injection and the start and termination of surgery (table I). Patients who received intrathecal cinchocaine plus morphine had a cinchocaine dose of 7.66±0.31mg/70kg (mean±SEM) and a morphine dose of 2.55±0.10mg (6.6nmol). The mean cinchocaine dose in patients receiving cinchocaine alone was 7.45±0.16mg/70kg. In the patients receiving intrathecal morphine the plasma morphine concentrations increased by 15 min after injection (table II), although the highest mean concentration (19.3 nmol litre"1) was achieved at the final 210-min sampling point. Data (not shown) from four of the patients indicated that plasma morphine concentrations continued to increase for at least 4 h after the intrathecal injection. Arterial Pcc^ values decreased in patients given intrathecal cinchocaine alone, and in the period after operation were significantly less than at 15 min after injection (table II). In contrast, P a c d values increased in the patients receiving intrathecal morphine, and had increased significantly ( P < 0 . 0 1 , paired t test) at 120 min. PacOj in patients given TABLE I. Demographic measures. Thtrt was no significant difftrence between the groups for any measure (Student t test). Values are mean±SEM ninrhfvflinf
and morphine n Age(yr) Weight (kg) Height (cm) Sex ratio (M/F) Time (min) Inj. to surgery Inj. toendsurg. Blood loss (ml) Cinchocaine dose (mg/70kg) Morphine dose (mg/70kg)
10
69.6 ±2.6 60.8 ±4.2 161.7±3.2
Cinchocaine alone 10
65.1±2.5 67.2±4.9 164.2 ±3.3
4/6
3/7
36±4 12O±5 460±81
35±5 131±8 588 ±63
7.66±0.31
7.4S±0.16
2.55±O.1O
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tion was performed using a 25-g spinal needle at the L3-4 space with the patient in the lateral position. Hyperbaric cinchocaine 1.0-1.5 ml with or without added morphine was administered. Doses were, approximately, cincnocaine 7.5 mg and morphine hydrochloride 2.5 mg per 70 kg. Anaesthesia was induced with thiopentone sodium 4 mg kg"' and maintained with nitrous oxide in oxygen (2:1) using a Bain coaxial breathing system with spontaneous ventilation through a mask and pharyngeal airway. Fresh gas flow was not less than ISOmlkg-'min- 1 . Halothane 0.5-2% was added until the conduction block was effective and a cannula was inserted to the radial artery to permit the monitoring of arterial pressure and blood sampling during and following surgery. Hartmann's solution and blood were administered according to a predetermined schedule. After operation, patients were transferred to a postoperative ward and breathed 28% oxygen through a Ventimask. Patients received additional analgesic drugs on request and the time was recorded. In the period immediately after operation they were looked after by a trained research sister who visited them again 24h after surgery. Any analgesic medication given following the operation was noted together with volunteered side-effects. Patients were also questioned directly as to evidence of itching, headache, backache or urinary problems. Arterial blood samples were collected at 15, 30, 60, 90, 120, 150, 180 and 210 min after the intrathecal injection for the estimation of blood-gas tensions and plasma concentrations of glucose, cortisol and morphine. A venous blood sample was taken before the intrathecal injection to obtain baseline values. Samples were collected into tubes containing lithium heparin or citrate-oxalate anticoagulants and stored in the cold until centrifuged, when plasma was frozen at — 20 °C until analysis. Plasma morphine was measured by radioimmunoassay using a 125I-morphine label prepared in the Nuffield Department of Clinical Biochemistry, a specific antiserum (Bioanalysis Ltd, Cardiff, Glamorgan) and a solid-phase second antibody (Saceel, Wellcome Diagnostics, Dartford, Kent). Crossreactivity to morphine-3-glucuronide and normorphine was less than 1%. The least amount measurable under these conditions was 0.8 nmol litre"1; coefficients of variation for control samples were less than 10% for values between 2 and 130 nmol litre"1. Methods for measuring the plasma concentrations of cortisol, glucose and the blood-gas tensions have
BRITISH JOURNAL OF ANAESTHESIA
INTRATHECAL CINCHOCAINE AND MORPfflNE
839
TABLE II. Changts in plasma morphint, Vacop and plasma cortisol concentrations during and afur optration. Vaiuts are mtan± SEM. Significant diffenncts from first sampling point for Paco? and plasma cortisol concentration wtrt asstssed by the paired t test (*P < 0.05; **P < 0.01). For Pacoj, significant difftrtncts between the groups (P < O.OSorUss) toere demonstrated by Studtntt Ust for values between 90and210min inclusive PiflHirifl morphine concn (nmol litre'1) Time (min)
(»-io)
Cinchocaine and morphine (»-10)
Cmrtwvflin^
alone (»=10)
0.0
5.2 ±1.0 6.7±0.8 9.6±1.0 12.2±1.3 16.0±1.5 16.2±1.6 18.411.5 19.311.9
6.2410.31 6.2510.30 6.5210.32 6.9510.38 6.7510.28** 6.8110.21* 6.8010.21** 6.7810.31**
6.1510.29 6.0110.27 5.7510.20 5.9710.24 5.8410.17 5.8710.16 5.5610.27** 5.71 ±0.25*
Cinchocaine and morphine (n-10) 406±50 406±55 365 ±63 344±57 530 ±103 633 ±112 636±87 672 ±81 586 ±105
rinrhomirv alone (n-10) 413±40 395 ±58 353 ±61 456±80 660 ±100* 796 ±100** 796 ±95** 761±104** 792 ±125**
cinchocaine plus morphine were significantly higher cinchocaine 7.5mg/70kg alone or in combination than those given cinchocaine alone between 90 and with morphine hydrochloride 2.5mg/70kg after 210 min. non-analgesic premedication. Patients receiving cinchocaine alone showed a Because of the small (6.6-fimol) intrathecal morsignificant increase in plasma cortisol concentra- phine dose used, the plasma morphine concentrations by 90 min (average about 400 nmol litre"1) tions were low. The maximum mean value obtained (table II). In those patients receiving cinchocaine was 19.3 nmol litre"1 210 min after injection. This and morphine the average increase was about was lower than the concentrations found 4-6 h after 200 nmol litre"1 (not significant) Mean values be- administration of 0.2mgkg"' i.m. (Chauvin et al., tween the groups were not significantly different at 1982). Thus, the effects which occur soon after any time. Plasma glucose values increased signific- intrathecal injection may be attributed to the direct antly (P<0.01, paired t test) in both groups by actions of the drug at the spinal opiate receptors 15 min- the extent of the increases was similar (max- rather than to any indirect actions following sysimum about 2.5 nmol litre"1), and at no time was temic absorption and redistribution. there any significant difference between the groups. After extradural injection, peak plasma concentPostoperative analgesia, as measured by the time rations usually occur within 15 min (Weddel and to the next analgesic, was of longer duration in Ritter, 1981; Chauvin et al., 1982; Gustaffsonetal., patients given intrathecal cinchocaine plus mor- 1982). Plasma morphine concentrations measured phine (median22 h, range 7.25->24) than those after the intrathecal injection of a large dose given cinchocaine alone (7.8h, 2.45-14.5). This (14mg/70kg) (Chauvin et al., 1982) showed great difference between the groups was significant variability in the time to peak concentration. The ( P < 0.01, Mann-Whitney [/test). The occurrence of side-effects during the 1st day after operation is shown in table III. There was a TABLE III. Number of patients with postoperative side-effects tendency for more facial itch and urinary difficulty Cinchocaine in patients who were given intrathecal morphine, and morphine alone but more nausea and vomiting in the patients who (n=10) (,,= 10) had cinchocaine alone. No untoward sedation was noted in either group. No side-effects DISCUSSION This study compared two similar groups of patients who were given an intrathecal injection of either
Itching (facial) Nausea and vomiting Micturition difficulty Headache
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0 15 30 60 90 120 150 180 210
Cinchocaine and morphine
Plasma cortisol concn (nmol litre"1)
Anerial PCOi (kPa)
840
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dose-related peak plasma concentrations were about injection, is uncertain. 50% greater than in this study. It may be that large The increase in P&CO2 after morphine was consisintrathecal doses of opiates result in more rapid tent (as shown by the small standard errors of the systemic absorption. mean (table II)), and was about 1 kPa greater than The time to the administration of further the control group. Such values are not unusual in analgesia is a crude measure of analgesic efficacy, postoperative patients receiving parenteral opiates but in this trial the difference between the groups (McQuay et al., 1980). Substantial rostral flow of was considerable. The median value for patients spinal fluid with high morphine concentrations receiving morphine was three times that of patients would be expected to produce severe respiratory receiving cinchocaine alone and there was barely any depression, but no patient in this study had a reoverlap between the groups. Only one patient given spiratory rate less than 10 b.p.m. From this and the intrathecal morphine needed additional analgesia small and consistent change in Pbcch it can be within 12 h of injection, and seven did not need any concluded that high morphine concentrations did for at least 21 h. This represents consistent analgesia not occur in the cerebral ventricles. from a intrathecal dose of morphine 2.5 mg and The important features of the changes in .ftco? contrasts with the variable analgesia reported with were that they occurred late, and that they remained extradural opiates (Bullingham, McQuay and increased, although the duration of the change was Moore, 1982). not determined in this trial. This is in contrast to the Side effects were few: there was no incident of rapid onset of respiratory effects after parenteral late respiratory depression, and the occurrence of morphine. Whether spinal fluid- or blood-borne nausea and vomiting was low in both groups. Itch- morphine, alone or in combination, was the cause of ing and headache occurred in both groups, but were the change cannot be answered by the results presented. not particularly troublesome. Suppression of the glycoregulatory response to This study suggests that small intrathecal doses of surgical stimulation requires large doses of mor- opiate may be used to advantage in patients underphine i.v. ( > 1 mgkg"1) (George et al., 1974), al- going total hip replacement. Morphine may not be though the extradural administration of morphine the best opiate drug for intrathecal administration, or diamorphine has been shown to have suppressive and it may not have been given at the optimal dose, effects in therperiod after operation (Cowen et al., but it had beneficial effects without any unduly 1982). This report confirms the importance of spinal harmful side-effects. nociceptive pathways for the cortdsol response to surgery (Engquist et al., 1977). Failure to suppress ACKNOWLEDGEMENTS the glucose response simultaneously, probably re- We thank the patients at the Nuffield Orthopaedic Centre for flects the selective spinal component for this process their co-operation and the anaesthetic, surgical and postoperative staff for their help. Research Sisters Lesley Weir, Mamey (DeFronzo, Sherwin and Felig, 1980); removal of ward Rolfe and Tcena Sloane looked after the patients in the postoperathe cortdsol response alone is insufficient for effects tive period. MissZ. Ashraf made up the morphine hydrochkmde on plasma glucose concentrations. for intrathecal injection. MCA was supported by the Medical P&CO2 increased after intrathecal morphine. The Research Council and DB by the Oxford Regional Health Auincrease was significant within 120 min of injection, thority. but no further increase occurred. The late onset of REFERENCES this effect contrasts with the immediate occurrence Bullingham, R. E. S., McQuay, H. J., and Moore, R. A. (1982). of extremely high spinal fluid concentrations of Extradural and intrathecal narcotics; in Recent Advance in 1 Anaesthesia and Analgesia (eds R. S. Atkinson and C. Langton morphine of more than 100 000 nmol litre" after Hewer), vol. 14, p. 141. Edinburgh: Churchill Livingstone. intrathecal injection (Jorgensen, Andersen and EngM., Samii, K., Schermann, J. M., Sandouk, P., Bourquist, 1981; Moore et al., 1984). The changes in Chauvin, don, R., and Viars, P. (1982). Plasma pharmacokinetics of P&CO2 were more in keeping with the increase in the morphine after i.m., extradural and intrathecal administraplasma concentrations of morphine. Rigg (1978) tion. Br. J. Anaesth., 54, 843. demonstrated that morphine produced measurable Cowen, M. J., Bullingham, R. E. S., Paterson, G. M. C , McQuay, H. J., Turner, M., Allen, M. C , and Moore, R. A. ventilatory effects at plasma concentrations as low as 1 (1982). A controlled comparison of the effects of extradural 100 nmol litre" . Whether respiratory depression diamorphine and bupivacaine on plasma glucose and plasma can occur as a result of the much lower plasma cortisol in postoperative patients. Anesth. Analg., 61, IS. morphine concentrations associated with intrathecal DeFronzo, R. A., Sherwin, R. S., and Felig, P. (1980). Syncrgis-
INTRATHECAL CINCHOCAINE AND MORPHINE
COMPARAISON CONTROLEE DE LA CINCHOCAINE SEULE OU ASSOOEE A LA MORPHINE EN RACHIANESTHESIE Effea clmiqua et concentrations plasmatiques de morphine RESUME
Vingt patients qui devaient subir la pose d'une prothese totale de hanche en chirurgie reglee ont recu pour une rachianesthesie, de la cinnchocaine seule ou associee a 2,5 mg de chlorhydrate de morphine avant l'anestheiie generale. Les concentrations plasmatiques arterielles de morphine ont ete mesurees et les effets biochimiques respiratoires et analgesiques compares. Les concentrations plasmatiques de morphine atteignaient 19,3 mmol litre"1 a la 210c min. Les valeurs de la Pacoj n'augmentaicnt trignifimfivement que chez les patients qui recevaient de la morphine en mrnw temps que la cinchocaine. Les concentrations plasmatiques de cortisol dans la periode post-operatoire augmentaient de facon significative ( P < 0 , 0 1 ) chez les patients qui avaient recu de la cinchocaine seule, mais pas chez ceux qui avaient recu de la cinchocaine avec de la morphine. La duree moyenne avant une deuxieme injection d'analgesique etait de 22 h chez les patients qui avaient re£u de la cinchocaine avec de la morphine intrathecale, ce qui est significativenient ( P < 0 . 0 1 ) phis long que chez les patients qui n'avaient re^u que de la cinchocaine intrathecale seule (7-8 h).
EIN KONTROLLIERTER VERGLEICH ZWISCHEN INTRATHEKALEM CINCHOCAIN UND INTRATHEKALEM CINCHOCAIN MIT MORPHIUM Klmische Wirksamkeit und Ptasmamorphiumkonxentrationen ZUSAMMENFASSUNG
Zwanzig Patienten, die elektiv eine totale Huftendoprothese erhatten sollten, erhielten entweder 2,5 mg Cinchocain mit 2,5 mg Morphium hydrochlorid oder Cinchocain alleine intrathekal, bevor die Vollnarkose cingeleitet wurde. Es wurden die arteriellen Plasma-Morphiumkonzentrationeii gemessen und analgetische, respiratorische und biochemische Effektc verglichen. Die Morphhimkonzentrationen stiegen innerhalb von 210Minuten auf 19,3 nmol litre"1 an. Pacc>2 stiegen nur bei denen Patienten, die Cinchocain mit Morphium erhalten hatten. Signifikante Anstiege ( P < 0 , 0 1 ) von Plasmacortisolkonzentrationen in der postoperativen Phase traten nur bei Patienten auf, die Cinchocain alleine erhalten hatten, nicht bei denen mit Morphiumzusatz. Die mittlere Zeit bis zum nSchsten Analgetikabedarf war mit 22Stunden bei den Patienten mit Cinchocain und Morphium signifikant (P<0,01) langer als bei den Patienten mit Cinchocain alleine (7,8 Stunden).
COMPARACION CONTROLADA DE LA CINCOAINA INTRATECAL CON CINCOCAINA Y MORFINA INTRATECAL Efectos clinicos y conctntraciona de morftna en el plasma SUMARIO
Se administro a veinte pacientes previstos para un reemplazo total electivo de la cadera ya sea cincocaina con2,5 mgde hidrocloruro de morfina o cincocaina intratecal sola antes de la anestesia general. Se midieron las concentraciones de morfina en el plasma arterial y se compararon los efectos bioquimicos y respiratorios de la analgesia. Las concentrationes de morfina en el plasma aumentaron hasta 19,3 nmol litre"1 a los 210 min. Las concentraciones de Paco2 aumentaron de manera m'gnifirante unicamente'en los pacientes a los cuales se administro morfina asi como cincocaina. Los pacientes con cincocaina sola, pero no los con cincocaina y morfina, sufrieron aumentos signifkantes (P<0,01) de las concentraciones de cortisol en d plasma durante el periodo postoperatorio. El tiempo medio hasta la proxima administracidn de analgesico en los pacientes con cincocaina y morfina intratecal era de 22 h, o sea mucho mayor (i 7 <0,01) que en los pacientes con cincocaina intratecal sola (7,8 h).
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tic interactions of counterregulatory hormones: a for stress hyperfdycaemia. Ada Chir. Scand., (Suppl. 498), 33. Engquist, A., Brandt, M. R., Femandes, A., and Kehlet, H. (1977). The blocking effect of epidural analgesia on the adrenocortical and hypergrycaemic response to surgery. Acta Anaesthesia!. Scand., 21, 330. George, J. M., Reier, C. E., Larese, R. R., and Rower, J. M. (1974). Morphine anaesthesia blocks cortisol and growth hormone responses to surgical stress in humans. / . Ciin. Endocrinol. Mttab., 38,736. Gustafsson, L. L., Friberg-Nielsen, S., Garle, M., Mohall, A., Rane, A., Schildt,B.,and Symreng,T. (1982). Extraduraland parenteral morphine: kinetics and effects in postoperative pain. A controlled Hiniril study. Br. J. Anaath.,54,1167. Jorgensen, B. C , Andersen, H. B., and Engquist, A. (1981). CSF and pln*mn morphine after epidural and intrathccal application. Anesthaiology, 55, 714. McQuay, H. J., BuUingham, R. E. S., Paterson, G. M. C , and Moore, R. A. (1980). minimi effects of buprenorphine during and after operation. Br. J. Anaath., 52,1013. Moore, A., BuUingham, R., McQuay, H., Allen, M., Baldwin, D., and Cole, A. (1984). Spinal fluid kinetics of morphine and heroin in man. Clin. Pharmacol. Ther., 35,40. Rigg, J. R. A. (1978). Ventilatory effects and plasma concentration of morphine in man. Br. J. Anaath., 50, 759. Weddel, S. J., and Rirter, R. R. (1981). Serum levels following epidural administration of morphine and correlation with postsurgical pain. Anathaiology, 54,210. Yaksh, T. L., and Rudy, T. A. (1976). Analgesia mediated by a direct spinal action of narcotics. Science, 192,1357.
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