EXTRADURAL MORPHINE: INFLUENCE OF ADRENALINE ADMIXTURE

Transcription

1 Br. J. Anaesth. (1986), 58, EXTRADURAL ORPHINE: INFLUENCE OF ADRENALINE ADIXTURE G. NORDBERG, T. ELLSTRAND, L. BORG AND T. HEDNER Spinal opiate analgesia is now accepted widely in clinical practice (Gustafsson, Schildt and Jacobsen, 1982). A number of studies have shown that more prolonged and intense analgesia can be achieved with the regional administrtion of opiates compared with their systemic administration (Bromage, Camporesi and Chestnut, 1980; Gustafsson et al., 1982; Lanz et al., 1982). The effects of spinal opiate analgesia are thought to be related to the distribution of the drug to, and its binding at, the opiate receptors in the spinal cord (Kitahata and Collins, 1981; Yaksh, 1981). Pharmacokinetic studies of extradural morphine have shown that the vascular uptake of morphine accounts for the major portion of the morphine administered, while the cerebrospinal fluid (CSF) availability comprises only a small percentage of the total dose (Nordberg et al., 1984a); yet, very high CSF morphine concentrations are achieved as a result of a small volume of distribution for morphine in the CSF as compared with plasma (Nordberg et al., 1983, 1984a, b). Adrenaline is used widely to prolong the duration of local anaesthetics by delaying vascular absorption (Burfoot and Bromage, 1971). Logically, therefore, adrenaline should be beneficial in association with the extradural administration of opiates. A study on healthy volunteers suggested that adrenaline did decrease the vascular absorption of extradural morphine, and that its administration enhanced the clinical (and side effects) of morphine (Bromage et al., 1983). However, contradictory results have been found in studies in patients there being no benefit when the admixture of adrenaline and morphine (Bromage, Camporesi and Chestnut, 1980; Youngstrom et al., 1982) or pethidene (Skjoldebrand et al., 1982), was used extradurally. G. NORDBERG,.D. (Department of Anaesthesiology): T. ELLSTRAND, PHAR., L. BORG, FHAR., T. HEDNER,.D. (Department of Clinical Pharmacology); Sahlgrenska Hospital, S Goteborg, Sweden. SUARY The influence of the addition of adrenaline on extradural morphine analgesia and pharmacokinetics was investigated in a double-blind study. orphine 2 mg was administered to 14 patients undergoing thoracotomy. In addition, adrenaline 50 pg added to the extradural solution, was administered to half of the patients, selected randomly. orphine concentrations in serial plasma and cerebrospinal fluid (CSF) samples were measured. Postoperative analgesia was estimated by determining the requirement for additional analgesics. Following extradural administration of plain morphine, the peak morphine concentraions in CSF were 22 ±5 (SE) times those in plasma; during the elimination phase the CSF concentrations exceeded those in plasma by about 150 times. The area under the concentration v. time curve (AUC) was 162±27 (SE) times larger in CSF than in plasma. The admixture of adrenaline with the extradural morphine increased the individual variability in CSF and plasma concentrations. However, compared with the plain morphine group, adrenaline did not significantly increase the concentrations of morphine in CSF, nor were the morphine concentrations in plasma significantly decreased. The duration of analgesia was related to the amount of morphine in CSF, that is AUC (P < 0.05) and peak concentrations of morphine in CSF (P <0.05). Since it seems likely that extradural morphine has a spinal site of action, more information on the influence of adrenaline could be obained by investigating the kinetics of morphine in the CSF. Accordingly, the purpose of this investigation was to determine whether the combination of adrenaline and extradural morphine could delay the vascular absorption of morphine and, at the same time,

2 EXTRADURAL ORPHINE 599 increase morphine concentrations in the CSF. Furthermore, we wished to study whether the adrenaline admixture enhanced the duration of postoperative analgesia or the side effects, or both, of the extradural morphine, and whether these effects were related to any alteration in pharmacokinetic indices. PATIENTS AND ETHODS Fourteen patients undergoing elective thoracotomy were studied. Informed consent was obtained and the study had the approval of the local Ethics Committee. No patient was receiving narcotics at the time of the study. One patient had been troubled by upper back pain for many years, and in another patient spinal fusion at L3-5 had been performed in 1947 after trauma. Otherwise the patients were without disorders associated with the spine. They were premedicated with pethidine mg and dixyrazine mg, given i.m. The anaesthetic agents used included thiopentone, fentanyl and nitrous oxide in oxygen. Neuromuscular blockade was provided with pancuronium. Following the induction of anaesthesia the patients were placed on one side as determined by the surgical procedure. An extradural catheter was inserted at the L2-3 or L3-^ space and advanced cephalad by a few centimetres. The extradural space was identified using the loss of resistance technique. Potential CSF leakage through the dural membrane was controlled by aspiration via the catheter. The study was double-blind. Patients were randomly allocated to receive extradural morphine (preservative-free morphine 2 mg in saline 10 ml) either with or without adrenaline 50 ug before the start of the operation. The solutions were prepared by the hospital pharmacy according to the randomization list. From each patient 8-12 samples of CSF (1-2 ml) were collected in plastic tubes for the determination of morphine concentration. The CSF samples were collected from the space below the injection site through Antoni-Sise needles having an external diameter of 0.5 mm. Three to five samples of CSF were collected over min through an indwelling needle before the operation was started. After these samples were obtained, the subarachnoid needle was removed and the operation performed. Following the end of the operation (that is at about 3-4 h after the administration of the extradural morphine, and during the next h, another four or five samples were collected through separate punctures at the same space. Consecutive arterial blood samples of 10 ml were drawn into plastic tubes from a radial artery catheter over 5 h. The plasma was separated and, as with the CSF, frozen until analysed using gas chromatography with electron capture detection (Edlund, 1981), which has a variability of 4 % at a concentration of 10 ng ml" 1. The limit of detection for morphine is 0.5 ng ml" 1. oreover, the technique is specific for morphine and does not include the metabolites of morphine. In the postoperative period, the patients were nursed under close supervision for 24 h. Heart rate, arterial pressure and respiratory rate were monitored at regular intervals. Blood-gas tensions were analysed at 6, 10, 16 and 24 h after the administration of the morphine. The need for additional analgesia (pethidine i.m.) was noted during a 48-h period following the extradural morphine. Nurses were instructed to administer pethidine mg i.m. when the patients asked for analgesics or showed signs of discomfort from pain (restricted coughing, groaning or anxiously moving around in the bed). Side effects, such as itching, nausea, headache and vomiting were monitored by active questioning during the study period. If urinary retention was present 12 h after the end of the operation, carbacholine was administered and, if this was unsuccessful, the bladder was catheterized. Statistical analyses were carried out by means of Student's t test and linear regression analysis. Area under the curve (AUC) was calculated individually by the lin-lin trapezoid rule with the addition of the residual area. RESULTS Patients Each group consisted originally of seven patients. The data from two patients in the morphine-saline group were, however, invalidated and excluded from further comparison. Demographic data revealed very little variation between the groups (table I). The sex distribution (nine TABLE I. Demographic pattern {mean value±se) in 12 patients given extradural morphine-adrenaline or plain morphine n Sex (/F) Age (yr) Height (cm) Weight (kg) orphine- 7 4/3 66±3 170±l 75±4 adrenaline orphine-saline 5 5/0 67±3 170±2 63±4

3 600 BRITISH JOURNAL OF ANAESTHESIA 3OOO orphine-saline 3000 orphine - Adrenaline ^ 30 T E CSF o I c a. 3O 30 a 10 E <n 5 a Time (h) Time (h) FIG. 1. Individual CSF and plasma morphine concentrations after the extradural administration of morphine 2 mg (n = 5) or the combination of morphine 2 mg and adrenaline 50 ng (n = 7) male and three female) as well as the ages of the patients (range yr) reflected the nature of the disease. Operative and anaesthetic procedures All patients underwent a left or right thoracotomy for surgical management of pulmonary tumour. According to operability, a variable amount of parenchyma was resected. Following the extradural administration of morphine the mean durations of general anaesthesia were 4.7 ±0.4 h and 5.3 ± 0.3 h, and the amount of fentanyl administered during surgery was 0.79 ± 0.08 mg and 0.82 ± 0.07 mg, respectively, for the morphine-adrenaline and the plain morphine groups (mean±se). These differences were not statistically different. Pharmacokinetic parameters Plasma. A semilog plot of plasma morphine concentration indicated a rapid vascular uptake and a biphasic disposition reaching immeasurable values after 4-5 h (fig. 1). In the morphineadrenaline group the peak (C max ) was lower that is 12.7 ± 2.2 ng ml" 1 compared with 20.5 ±4.6 ng ml" 1 in the plain morphine group (mean±se) and was attained more slowly: 19 ± 5 min compared with 10 ± 2 min in the plain morphine group (mean ± SE). These differences were, however, not statistically significant. Between the groups no difference in AUC was found, indicating that the total vascular uptake was similar. CSF. The individual CSF concentration-time plots in general showed a common appearance, that is a rapid CSF uptake followed by a monophasic or biphasic elimination (fig. 1). The predominant appearance, revealed by the 12 patients included in the calculations, demonstrated a concentration v. time profile which was most likely representative of morphine turnover in CSF following extradural administration. Following absorption, peak values (C max ) were reached

4 EXTRADURAL ORPHINE 601 TABLE II. Pharmacokmetic data in CSF and plasma {mean values ±SE) Peak value (ng ml" 1 ) AUC (ug ml ' min ') Patient Sex CSF Plasma CSF Plasma orphine-saline S.B. I.S. B. K. R.W. L.T ean SE orphine-adrenaline I.L. B.R. W.E. G.L. A.K. R.S. S.A. F F F ean SE after 2.1 ± 0.9 h and 2.4 ±1.3 h (mean ± SE) in the adrenaline-morphine and plain morphine groups, respectively, and estimated to be estinongml- 1 and 390±62ngml- 1 in the morphine adrenaline and the plain morphine groups, respectively (mean ± SE) (table II). The differences were, however, not significant. oreover, the AUC for the adrenaline-morphine group seemed to be slightly increased compared with that found for the plain morphine group: 223±62ugml- 1 min~ l and 162±25ugml" 1 min" 1, respectively (mean± SE) (table II). However, a pronounced interindividual variation in CSF concentrations was found. This was more evident in the adrenaline-morphine group in which a 10-fold variation in AUC and peak values was found. In the plain morphine group a 3-fold variation was found. No inverse correlation between plasma and CSF concentrations was found. Analgesia The time between the end of the operation and the first dose of pethidine i.m., that is, the duration of postoperative analgesia, varied between 2.5 and 19.1 h for all 12 patients and was 10.4 ± 2.3 h in the morphine adrenaline group and 7.1 ±2.6 h in the plain morphine group. The differences were not significant (fig. 2). The o "s e I orphine /ine orphine/ adrenaline FIG. 2. Intervals between extradural administration of morphine (n = 5) or the combination morphine-adrenaline (n = 7) and the first i jn. administration of pethidine after compensation for duration of operation.

5 602 BRITISH JOURNAL OF ANAESTHESIA a AUC.CSFtngmT'min' 1 ) r P<005 FIG. 3. Correlation between CSF morphine concentrations over time, AUC, and duration of analgesia (measured as the time to the first i.m. pcthidine injection after operation) after extradural administration of morphine 2 mg ( ) or the combination morphine 2 mg - adrenaline 50 ng (#) (n = 12). average cumulative consumption of pethidine during 24 and 48 h, respectively, did not differ between the groups. The duration of analgesia was related to the amount of drug in CSF, that is AUC (P < 0.05, log-linear regression analysis) (fig. 3) and peak morphine concentrations in CSF (P < 0.05, loglinear regression analysis) (fig. 4). No correlation was found between peak plasma concentrations and the duration of analgesia. Side effects One to two hours after operation, that is, 6 h after the administrtion of the extradural morphine, some patients were acidotic (range ) mainly as a result of increases in Pco 2 (range = 8 S 4 P Peak CSFccncn (ngml" 1 ) r 0.67 FIG. 4. Correlation between peak CSF morphine concentrations and analgesic duration (measured as the time to the first i i.m. pethidine injection after operation) after extradural administration of morphine 2 mg ( ) or the combination morphine 2 mg - adrenaline 50 ng (#) (n = 12) kpa), but there was no difference between the groups. Blood-gas tensions obtained over the next 24 h indicated a gradual normalization. The ventilatory depression was, however, more pronounced in the three women participating in the study, that is Pco 2 ranged between 7.2 and 8.0 kpa, and all were treated with naloxone. Nausea bothered three patients in each group. All patients denied itching and headache. Urinary retention occurred in all but three patients and was equally frequent in both groups. DISCUSSION The typical concentration v. time curves in CSF and plasma for extradural morphine have been described previously (Nordberg et al., 1984a), and were further illustrated in the present study, which showed comparable profiles of the concentration curves in the majority of patients. Following the admixture of adrenaline and extradural morphine, a more pronounced interindividual variation in morphine concentrations was found in plasma as well as CSF. Although the adrenaline group exhibited peak morphine concentrations that were lower in plasma and higher in CSF compared with the plain morphine group, thesedifferenceswerenotsignificant. Furthermore, similar results were obtained by calculating the area under the concentration curves in CSF and plasma. Such differences may be found to be statistically significant by extending the study. However, the concentration data derived from CSF and plasma in the present study indicate that the influence of the admixture of adrenaline on the vascular and CSF uptake of extradural morphine was, at the most, small. This is consistent with the modest influence on postoperative extradural analgesia reported by others (Bromage, Camporesi and Chestnut, 1980; Youngstrom et al., 1982). The extent of the vascular uptake is reported to be a function of the lipophilicity of the opiates (Watson et al., 1984) and it may be that the more lipophilic opiates would benefit from the admixture of adrenaline (Welchew, 1983). Adrenaline is regarded as the preferable vasoconstrictor for admixture to local anaesthetics (Covino and Vassallo, 1976; Bromage, 1978). Logically, it was chosen for this study and administered in a dose that was considered adequate (Covino and Vassallo, 1976; Bromage, 1978). However, it is possible that other vasoconstrictors, for example more specific

6 EXTRADURAL ORPHINE 603 o^-stimulants, could be more beneficial as far as extradural opiate analgesia is concerned. Following vascular uptake, morphine will distribute in a volume estimated to be about 200-^WO litre (Dahlstrom et al., 1982). Thus it is likely that only a marked change in vascular uptake of morphine will be revealed by determining the plasma concentration curve. The volume of distribution in the CSF, on the other hand, is estimated to be times less, that is about 70 ml (Nordberg et al., 1984b). In such a small volume of distribution it is most probable that a slight improvement in CSF bioavailability caused by the admixture of adrenaline should be revealed by monitoring the CSF morphine concentrations rather than those in plasma. Furthermore, the plasma concentrations (peak concentration and AUC) did not correlate inversely with those in CSF. Thus, monitoring of plasma morphine concentrations seems to be not only an insensitive but also an unreliable predictor of pharmacokinetic events in the CSF. The lack of influence of adrenaline on the morphine availability in CSF and plasma was also reflected by the insignificant influence on the duration of postoperative analgesia as noted in the present as well as previous studies (Bromage, Camporesi and Chestnut, 1980; Skjoldebrand et al., 1982; Youngstrom et al., 1982). The time between the end of the operation and the time when the patients required additional analgesia varied greatly, but was not increased by the addition of adrenaline. The variable duration of analgesia was, however, related to the CSF concentration, that is, the peak CSF concentration and the AUC, irrespective of the presence of adrenaline. At present there is insufficient evidence to define the role of vasoconstrictors in association with extradural narcotics and, accordingly, these drugs should be omitted in clinical practice until further studies determine their proper place. An alternative mechanism of action may be that adrenaline itself interferes with spinal adrenergic receptors and blocks nociceptive pathways. It has been demonstrated that the spinal administration of adrenergic agonists is capable of producing behavioural analgesia in animals (Yaksh and Reddy, 1981) and of suppressing noxiously evoked activity of wide dynamic range neurones in the dorsal horn of the spinal cord (Collins et al., 1984). These neurones have been associated with central transmission of noxious information. The significance of this mechanism is, however, still to be demonstrated in man. A few hours after the end of operation, that is around 6 h after extradural administration of morphine, ventilation was depressed in both groups. Although it has been shown that ventilation is depressed also with low doses of extradural morphine {2-4 mg) (ccaughey and Graham, 1982; Rawal and Wattwil, 1984), it is most likely that the operation itself will have a primary effect on the blood-gas tensions. In this study the effects of the extradural morphine and the effects of the operation could not be separated. The ventilatory depression seemed to be more pronounced in the women participating in the study. Naloxone was required in three patients and all were women. The ventilatory response to carbon dioxide is considered to be highly variable in healthy subjects, but women are found to be less responsive than men (Rebuck and Slutsky, 1981) supporting the impression gained in this study. In conclusion, this study demonstrated that the duration of extradural morphine analgesia was related to morphine concentrations in the CSF. CSF and plasma pharmacokinetics as well as analgesia varied greatly between the individual patients. This variability was further increased by the addition of adrenaline which, however, seemed to enhance analgesia only marginally. ACKNOWLEDGEENTS This research was supported by grants from the edical Faculty, University of Goteborg, and "Gdteborgs Lakaresallskap". Technical assistance of the research nurses at the Department of Anaesthesiology and Intensive Care, and Gabriella Salen is gratefully acknowledged. REFERENCES Bromage, P. R. (1978). Epidural Analgesia, pp. 85, 285. Philadelphia: W. B. Saunders Company. Camporesi, E., and Chestnut, D. (1980). Epidural narcotics for postoperative analgesia. Anesth. Analg., 59, 473. Durant, P. A., and Nielsen, C. H. (1983). Influence of epinephrine as an adjuvant to epidural morphine. Anesthesiology, 58, 257. Burfoot,. F., and Bromage, P. R. (1971). The effects of epinephrine on mepivacaine absorption from the spinal epidural space. Anesthesiology, 35, 488. Collins, J. G., Kitahata, L.., atsumoto,., Homma, E., and Suzukawa,. (1984). Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Anesthesiology, 80, 269.

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