British Journal of Anaesthesia 1992; 69: 637-639
EFFECT OF INTERPLEURAL MORPHINE ON POSTOPERATIVE PAIN AND PULMONARY FUNCTION AFTER THORACOTOMY M. WELTE, E. HAIMERL, J. GROH, J. BRIEGEL, L. SUNDER-PLASSMANN, A. HERZ, K. PETER AND C. STEIN
SUMMARY
KEY WORDS Analgesics: morphine. Anaesthetic techniques: interpleural analgesia. Pain: postoperative.
Recently, we and others have demonstrated that opioid agonists may produce peripheral antinociceptive effects in inflamed tissue of rats [1]. These effects are mediated by opioid receptors located on peripheral terminals of primary afferent neurones [2]. In patients undergoing arthroscopic knee surgery, we showed that intra-articularly applied morphine 0.5—1 mg produced more profound postoperative analgesia^ than the same dose-given i.v. [-3]. In this study we hypothesized that, after thoracotomy, interpleurally (i.p.) injected morphine might occupy receptors on intercostal nerves and produce analgesia. We investigated the effect of morphine i.p. on postoperative pain and pulmonary
METHODS AND RESULTS
The study was approved by our Institutional Ethics Committee and written informed consent was obtained from each patient. We studied 20 patients undergoing anterolateral thoracotomy, allocated randomly to two groups. After premedication with fiunitrazepam 1 mg, anaesthesia was induced with thiopentone 3-5 mg kg"1 and fentanyl 1.5-3 ug kg"1, followed by suxamethonium 1 mg kg"1. Anaesthesia was maintained with 0.6-1.2 vol% isoflurane, fentanyl (maximal total dose 10 ug kg"1) and pancuronium. Incisions were made in the 5th anterolateral intercostal space. Chest tubes were positioned posteriorly and anteriorly in the pleural space. Before closure of the thoracotomy, an interpleural catheter (18-gauge extradural catheter, BraunMelsungen, Melsungen, Germany) was inserted percutaneously via a Tuohy needle in the anterior axillary line. The catheter tip was positioned cranial to the incision in the anterior midclavicular line. Before tracheal extubation, the following solutions were injected simultaneously i.p. and i.v.: group I received morphine hydrochloride 2.5 mg in normal saline 40 ml i.p. and normal saline i.v.; group II received normal saline 40 ml i.p. and morphine hydrochloride 2.5 mg i.v. The choice of doses of morphine was based on previous studies [1,3]. After their injection, chest tubes were clamped for 20 min. After arrival of the patient in the recovery room simultaneous i.v. and i.p. infusions were started and maintained for 24 h: group I received morphine hydrochloride 0.5 mg in normal saline 20 ml per hour i.p. and normal saline i.v.; group II received normal saline 20 ml h"1 i.p. and morphine hydroM. WELTE*, M.D., E. HAIMERL, B.S., J. GROH, M.D., J. BRIEGEL, M.D., C. STEIN, M.D. (Institute of Anaesthesiology); L. SUNDER-
PLASSMANN, M.D. (Department of Surgery); Ludwig-Maximilians- Universitft Muhchen, Klinilcum Grosshadern, Munchen. A. HERZ, M.D, Department of Neuropharmacology, Max-PlanckInstirut fur Psychiatric, Martinsried, Germany. Accepted for Publication: July 17, 1992. * Address for correspondence: Institute of Anaesthesiology, Klinikum Grosshadem, Marchioninistrasse 15, D-8000 Munchen 70, Germany.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
We have investigated the effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. At the end of surgery, an interpleural catheter was inserted in 17 patients and, in a double-blind and randomized manner, either a bolus of morphine 2.5 mg interpleura/ly (i.p.) and normal saline i.v. (group I) or, as a control for systemic absorption, morphine 2.5mg i.v. and i.p. saline (group II) was injected. After the initial bolus, a continuous infusion of morphine 0.5 mg h~' i.p. and saline i.v. (group I) or morphine 0.5 mg i.v. and saline i.p. (group II) was maintained for 24 h. Postoperative pain was assessed by a visual analogue scale, a numerical rating scale and the McGill Pain Questionnaire. Pulmonary function was assessed by spirometry. Supplementary analgesics, side effects, degree of sedation, vital signs and chest tube drainage were recorded. All variables were assessed on the day before surgery and 1, 2, 3, 4, 5, 6 and 24 h and 7 days after surgery. Supplementary morphine was given upon request. There was no significant difference in any pain measure or postoperative pulmonary function variable between the groups. We conclude that, after thoracotomy. • interpleural morphine does not provide superior analgesia or improve pulmonary function compared with systemic morphine. (Br. J. Anaesth. 1992; 69: 637-639)
function. To exclude the possibility that the effect of i.p. morphine was mediated by central opioid receptors, the same dose of morphine was given i.v. in a control group.
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FIG. 1 A: Pain scores as determined by visual analogue scale (VAS). B: Forced expiratory volume during the first 1 s (FEV,)—postoperative value (post) as a percentage of preoperative value (pre). O = I y - morphine; % = interpleural morphine. Mean values and SEM.
chloride 0.5 mg h"1 i.v. The codes were broken at the end of the observation period (7 days). The patients were positioned supine with the head 30° elevated. A suction of 15—20 cm H2O was applied to the chest tubes. During the first 24 h, the patients received supplementary morphine hydrochloride in increments of 2.5 mg i.v. upon request. Postoperative pain was assessed using a visual analogue scale ranging from no pain (0 cm) to unbearable pain (10 cm), a numerical rating scale (0-100), and a German adaptation of the McGill Pain Questionnaire [4]. All scores were taken by the same blinded investigator on the day before surgery and at 1,2, 3, 4, 5, 6, 22-24 h and 7 days after surgery. Pulmonary function was assessed at these intervals using a bedside spirometer (Microspiro H 1-298, Chest Corp., Tokyo, Japan) and arterial blood-gas analysis. Somnolence was assessed using a five-point scale from awake and oriented to not arousable. Side effects were monitored, including respiratory depression, nausea, pruritus, rash and urinary retention. To score the McGill Pain Questionnaire, the pain rating indices were calculated according to Melzack [4]. The total consumption of supplementary morphine during the first 24 h after surgery was recorded. Comparisons between groups were made using the Mann-Whitney U test. P < 0.05 (twotailed) was considered significant. Data are given as mean (SEM). Three patients in group I were excluded because of surgical revision or respiratory failure. Patient characteristics, vital signs, sedation score (grade I—II), and preoperative pain scores and pulmonary function did not differ significantly between groups. Surgical procedures included wedge resections (n = 7), lobectomies (n = 8) and the combination of both (n = 2). The duration of surgery was 132 (SEM 17) min in group I and 84 (11) min in group II (U test, ns). There were more lobectomies in group II (six of 10 patients) than in group I (two of seven patients). The total intraoperative dose of fentanyl did not
differ between groups (group I, 590 (110) |ig; group II, 580 (50) ug). There were no major side effects. After operation, there was no difference between groups in any pain score at any time (fig. 1). Supplementary analgesic requirements did not differ between groups (U test, data not shown). Pulmonary function variables (fig. 1) and blood-gas values did not differ significantly between groups. Total chest tube drainage after 24 h was 680 (138) ml in group I and 775 (120) ml in group II (ns). COMMENT
We have found no difference in postoperative pain scores, pulmonary function or supplementary analgesic requirements in patients given morphine i.p. or i.v. after thoracotomy. These results indicate that i.p. administered morphine in the doses used did not provide analgesia superior to that obtained with i.v. morphine. This finding is at variance with our results in patients after arthroscopic knee surgery, in which intra-articular morphine yielded analgesic effects superior to the same dose given i.v. [3]. A probable mechanism of action of opioids in the periphery is activation of opioid receptors on terminals of primary afferent neurones [2]. We hypothesized that morphine might occupy such receptors on intercostal nerves. Even though we have used a 2.5-fold greater concentration of morphine compared with our previous study [3], postoperative bleeding and secretion may lead to a dilution of the morphine solution and may thus reduce the concentration of morphine at the receptors. Unlike local anaesthesia, which interrupt action potential generation and propagation at both the axon and nerve terminal [5], opioids appear to exert their inhibitory effects predominantly at the nerve terminals [1]. Gravity-dependent pooling in dependent areas of the pleural space may preclude an action of morphine upon nerve terminals.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
Preop. 1 2 3 4 5 6 Time (h)
INTERPLEURAL MORPHINE AFTER THORACOTOMY In contrast with the knee joint after arthroscopic surgery, the interpleural cavity is not a closed space after thoracotomy. Any drug injected into the interpleural space may be lost partially through the chest drains. Thirty to forty percent of the total dose of bupivacaine injected into the pleural space may be recovered in the thoracostomy fluid [6]. Even though we did not measure morphine concentrations in the thoracostomy fluid, one may speculate that a similar amount of morphine was lost through the chest tubes. In conclusion, we found that low doses of interpleural morphine after thoracotomy did not improve analgesia or pulmonary function compared to the same dose given i.v.. ACKNOWLEDGEMENT
REFERENCES 1. Stein C. Opioid anagesia at peripheral sites. In: Almeida OTX, Shippenberg TS, eds. Neurobiology ofOpioids. Heidelberg: Springer, 1991; 273-285. 2. Stein C, Hassan AHS, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proceedings of the National Academy of Sciences U.S.A. 1990; 87: 5935-5939. 3. Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K. Analgesic effect of intraarticular morphine after artnroscopic knee surgery. Neto England Journal of Medicine 1991; 325: 1123-1126. 4. Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985; 22: 1-31. 5. Riegler FX, VadeBoncouer TR, Pelligrino DA. Interpleural anesthetics in the dog: differential somatic neural blockade. Anesthesiology 1989; 71: 744-750. 6. Ferrante FM, Chan VWS, Arthur GR, Rocco AG. Interplcural analgesia after thoracotomy. Anesthesia and Analgesia 1991; 72: 105-109.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
This study was supported by Deutsche Forschungsgemeinschaft (He 321/9-6).
639
EFFECT OF INTERPLEURAL MORPHINE ON POSTOPERATIVE PAIN AND PULMONARY FUNCTION AFTER THORACOTOMY M. WELTE, E. HAIMERL, J. GROH, J. BRIEGEL, L. SUNDER-PLASSMANN, A. HERZ, K. PETER AND C. STEIN
SUMMARY
KEY WORDS Analgesics: morphine. Anaesthetic techniques: interpleural analgesia. Pain: postoperative.
Recently, we and others have demonstrated that opioid agonists may produce peripheral antinociceptive effects in inflamed tissue of rats [1]. These effects are mediated by opioid receptors located on peripheral terminals of primary afferent neurones [2]. In patients undergoing arthroscopic knee surgery, we showed that intra-articularly applied morphine 0.5—1 mg produced more profound postoperative analgesia^ than the same dose-given i.v. [-3]. In this study we hypothesized that, after thoracotomy, interpleurally (i.p.) injected morphine might occupy receptors on intercostal nerves and produce analgesia. We investigated the effect of morphine i.p. on postoperative pain and pulmonary
METHODS AND RESULTS
The study was approved by our Institutional Ethics Committee and written informed consent was obtained from each patient. We studied 20 patients undergoing anterolateral thoracotomy, allocated randomly to two groups. After premedication with fiunitrazepam 1 mg, anaesthesia was induced with thiopentone 3-5 mg kg"1 and fentanyl 1.5-3 ug kg"1, followed by suxamethonium 1 mg kg"1. Anaesthesia was maintained with 0.6-1.2 vol% isoflurane, fentanyl (maximal total dose 10 ug kg"1) and pancuronium. Incisions were made in the 5th anterolateral intercostal space. Chest tubes were positioned posteriorly and anteriorly in the pleural space. Before closure of the thoracotomy, an interpleural catheter (18-gauge extradural catheter, BraunMelsungen, Melsungen, Germany) was inserted percutaneously via a Tuohy needle in the anterior axillary line. The catheter tip was positioned cranial to the incision in the anterior midclavicular line. Before tracheal extubation, the following solutions were injected simultaneously i.p. and i.v.: group I received morphine hydrochloride 2.5 mg in normal saline 40 ml i.p. and normal saline i.v.; group II received normal saline 40 ml i.p. and morphine hydrochloride 2.5 mg i.v. The choice of doses of morphine was based on previous studies [1,3]. After their injection, chest tubes were clamped for 20 min. After arrival of the patient in the recovery room simultaneous i.v. and i.p. infusions were started and maintained for 24 h: group I received morphine hydrochloride 0.5 mg in normal saline 20 ml per hour i.p. and normal saline i.v.; group II received normal saline 20 ml h"1 i.p. and morphine hydroM. WELTE*, M.D., E. HAIMERL, B.S., J. GROH, M.D., J. BRIEGEL, M.D., C. STEIN, M.D. (Institute of Anaesthesiology); L. SUNDER-
PLASSMANN, M.D. (Department of Surgery); Ludwig-Maximilians- Universitft Muhchen, Klinilcum Grosshadern, Munchen. A. HERZ, M.D, Department of Neuropharmacology, Max-PlanckInstirut fur Psychiatric, Martinsried, Germany. Accepted for Publication: July 17, 1992. * Address for correspondence: Institute of Anaesthesiology, Klinikum Grosshadem, Marchioninistrasse 15, D-8000 Munchen 70, Germany.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
We have investigated the effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. At the end of surgery, an interpleural catheter was inserted in 17 patients and, in a double-blind and randomized manner, either a bolus of morphine 2.5 mg interpleura/ly (i.p.) and normal saline i.v. (group I) or, as a control for systemic absorption, morphine 2.5mg i.v. and i.p. saline (group II) was injected. After the initial bolus, a continuous infusion of morphine 0.5 mg h~' i.p. and saline i.v. (group I) or morphine 0.5 mg i.v. and saline i.p. (group II) was maintained for 24 h. Postoperative pain was assessed by a visual analogue scale, a numerical rating scale and the McGill Pain Questionnaire. Pulmonary function was assessed by spirometry. Supplementary analgesics, side effects, degree of sedation, vital signs and chest tube drainage were recorded. All variables were assessed on the day before surgery and 1, 2, 3, 4, 5, 6 and 24 h and 7 days after surgery. Supplementary morphine was given upon request. There was no significant difference in any pain measure or postoperative pulmonary function variable between the groups. We conclude that, after thoracotomy. • interpleural morphine does not provide superior analgesia or improve pulmonary function compared with systemic morphine. (Br. J. Anaesth. 1992; 69: 637-639)
function. To exclude the possibility that the effect of i.p. morphine was mediated by central opioid receptors, the same dose of morphine was given i.v. in a control group.
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FIG. 1 A: Pain scores as determined by visual analogue scale (VAS). B: Forced expiratory volume during the first 1 s (FEV,)—postoperative value (post) as a percentage of preoperative value (pre). O = I y - morphine; % = interpleural morphine. Mean values and SEM.
chloride 0.5 mg h"1 i.v. The codes were broken at the end of the observation period (7 days). The patients were positioned supine with the head 30° elevated. A suction of 15—20 cm H2O was applied to the chest tubes. During the first 24 h, the patients received supplementary morphine hydrochloride in increments of 2.5 mg i.v. upon request. Postoperative pain was assessed using a visual analogue scale ranging from no pain (0 cm) to unbearable pain (10 cm), a numerical rating scale (0-100), and a German adaptation of the McGill Pain Questionnaire [4]. All scores were taken by the same blinded investigator on the day before surgery and at 1,2, 3, 4, 5, 6, 22-24 h and 7 days after surgery. Pulmonary function was assessed at these intervals using a bedside spirometer (Microspiro H 1-298, Chest Corp., Tokyo, Japan) and arterial blood-gas analysis. Somnolence was assessed using a five-point scale from awake and oriented to not arousable. Side effects were monitored, including respiratory depression, nausea, pruritus, rash and urinary retention. To score the McGill Pain Questionnaire, the pain rating indices were calculated according to Melzack [4]. The total consumption of supplementary morphine during the first 24 h after surgery was recorded. Comparisons between groups were made using the Mann-Whitney U test. P < 0.05 (twotailed) was considered significant. Data are given as mean (SEM). Three patients in group I were excluded because of surgical revision or respiratory failure. Patient characteristics, vital signs, sedation score (grade I—II), and preoperative pain scores and pulmonary function did not differ significantly between groups. Surgical procedures included wedge resections (n = 7), lobectomies (n = 8) and the combination of both (n = 2). The duration of surgery was 132 (SEM 17) min in group I and 84 (11) min in group II (U test, ns). There were more lobectomies in group II (six of 10 patients) than in group I (two of seven patients). The total intraoperative dose of fentanyl did not
differ between groups (group I, 590 (110) |ig; group II, 580 (50) ug). There were no major side effects. After operation, there was no difference between groups in any pain score at any time (fig. 1). Supplementary analgesic requirements did not differ between groups (U test, data not shown). Pulmonary function variables (fig. 1) and blood-gas values did not differ significantly between groups. Total chest tube drainage after 24 h was 680 (138) ml in group I and 775 (120) ml in group II (ns). COMMENT
We have found no difference in postoperative pain scores, pulmonary function or supplementary analgesic requirements in patients given morphine i.p. or i.v. after thoracotomy. These results indicate that i.p. administered morphine in the doses used did not provide analgesia superior to that obtained with i.v. morphine. This finding is at variance with our results in patients after arthroscopic knee surgery, in which intra-articular morphine yielded analgesic effects superior to the same dose given i.v. [3]. A probable mechanism of action of opioids in the periphery is activation of opioid receptors on terminals of primary afferent neurones [2]. We hypothesized that morphine might occupy such receptors on intercostal nerves. Even though we have used a 2.5-fold greater concentration of morphine compared with our previous study [3], postoperative bleeding and secretion may lead to a dilution of the morphine solution and may thus reduce the concentration of morphine at the receptors. Unlike local anaesthesia, which interrupt action potential generation and propagation at both the axon and nerve terminal [5], opioids appear to exert their inhibitory effects predominantly at the nerve terminals [1]. Gravity-dependent pooling in dependent areas of the pleural space may preclude an action of morphine upon nerve terminals.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
Preop. 1 2 3 4 5 6 Time (h)
INTERPLEURAL MORPHINE AFTER THORACOTOMY In contrast with the knee joint after arthroscopic surgery, the interpleural cavity is not a closed space after thoracotomy. Any drug injected into the interpleural space may be lost partially through the chest drains. Thirty to forty percent of the total dose of bupivacaine injected into the pleural space may be recovered in the thoracostomy fluid [6]. Even though we did not measure morphine concentrations in the thoracostomy fluid, one may speculate that a similar amount of morphine was lost through the chest tubes. In conclusion, we found that low doses of interpleural morphine after thoracotomy did not improve analgesia or pulmonary function compared to the same dose given i.v.. ACKNOWLEDGEMENT
REFERENCES 1. Stein C. Opioid anagesia at peripheral sites. In: Almeida OTX, Shippenberg TS, eds. Neurobiology ofOpioids. Heidelberg: Springer, 1991; 273-285. 2. Stein C, Hassan AHS, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proceedings of the National Academy of Sciences U.S.A. 1990; 87: 5935-5939. 3. Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K. Analgesic effect of intraarticular morphine after artnroscopic knee surgery. Neto England Journal of Medicine 1991; 325: 1123-1126. 4. Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985; 22: 1-31. 5. Riegler FX, VadeBoncouer TR, Pelligrino DA. Interpleural anesthetics in the dog: differential somatic neural blockade. Anesthesiology 1989; 71: 744-750. 6. Ferrante FM, Chan VWS, Arthur GR, Rocco AG. Interplcural analgesia after thoracotomy. Anesthesia and Analgesia 1991; 72: 105-109.
Downloaded from http://bja.oxfordjournals.org/ at Pennsylvania State University on March 13, 2015
This study was supported by Deutsche Forschungsgemeinschaft (He 321/9-6).
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