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Analgesia administration attenuates surgery-induced tumor promotion
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Analgesia Administration Attenuates Surgery-Induced Tumor Promotion Gayle G. Page, R.N., D.N.Sc., F.A.A.N.
T
he regulation of the immune system by neural input and circulating hormones is well documented, as are the neuroendocrine and immune perturbations resulting from undergoing and recovering from surgery. The immune system has been shown to play a key role in cancer resistance, and natural killer (NK) cells have been shown to be particularly important in controlling metastasis.1 In support of these relationships between NK activity and metastatic susceptibility, animal studies have shown surgery to result in decreases in both NK activity and resistance against metastasis,2 and lower NK activity levels in humans undergoing cancer surgery are associated with a greater incidence of metastatic sequelae.3 Surgery is often a first step in cancer treatment; therefore, limiting surgery-induced NK suppression might enhance host resistance against cancer recurrence. Given that acute pain has also been shown to suppress NK activity4 and to promote tumor development in animals,5 our studies have sought to address the possibility that relieving the pain associated with undergoing and recovering from surgery might improve host resistance against metastatic development. To explore this issue, we have used a mammary adenocarcinoma cell line, MADB106, which is syngeneic to the inbred Fischer 344 rats we study. Following intravenous injection, the seeding and colonization of MADB106 cells in the lungs is controlled by NK cells, but only during the first 24 hours after injection and in a timedependent and decremental manner. Therefore, the From the School of Nursing, Johns Hopkins University, Baltimore, Maryland. Accepted for publication September 3, 2001. Supported by National Institutes of Health (NIH) Grant No. NR03915. Reprint requests: Gayle G. Page, R.N., D.N.Sc., F.A.A.N., Associate Professor and Independence Foundation Chair in Nursing Education, 525 N Wolfe St, Baltimore, MD 21205. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2702-0028$35.00/0 doi:10.1053/rapm.2002.29730
lung retention of MADB106 cells reflects both host tumor resistance and in vivo levels of NK activity.6 Our studies testing possible benefits of analgesia administration have used a simple 2⫻2 experimental design such that animals undergo either abdominal laparotomy under halothane anesthesia or halothane alone and receive either the analgesic or the vehicle. In separate studies, pharmacologic approaches were used to attenuate or block 3 different pain transmission mechanisms, including the systemic -opioid agonists, morphine and fentanyl, the prototypical nonsteroidal anti-inflammatory drug, indomethacin, and intrathecal (IT) administration of bupivacaine plus morphine. MADB106 tumor cells were injected into the tail vein at 5 hours after surgery in an effort to reflect the postoperative experience of the animal rather than intraoperative events. All studies described herein were approved by the institutional animal care and use committee. Three different studies used -agonists. In our first study, morphine was administered in analgesic doses both before and after surgery, and animals were euthanized at 3 weeks after MADB106 cell injection to assess the impact of morphine administration on surgery-induced increases in tumor colonization. We found that morphine significantly attenuated the tumor-enhancing effects of surgery, but did not significantly affect the number of tumors that developed in the anesthesia-only animals. To suggest that the morphine relieved abdominal discomfort, we observed animals from the same 4 experimental groups for the incidence of rearing behavior, the lifting of both forepaws off of the cage floor, during the first 4 hours following surgery. That humans exhibit a hunching or slouching posture following abdominal surgery supports the suggestion that in rats, a reduction in a normal exploratory behavior that requires the stretching out of the abdominal wall might indicate abdominal discomfort. We found that whereas the unmedicated surgery animals exhibited few incidences of rearing, the rearing incidence of surgery animals receiving
Regional Anesthesia and Pain Medicine, Vol 27, No 2 (March–April), 2002: pp 197–199
197
198
Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002
morphine was similar to that of the unoperated rats.7 In a substantial replication, using radiolabeled MADB106 cells in a lung clearance assay to assess lung tumor cell retention at 18 hours after injection, we similarly showed that pre- and postoperative morphine administration provided significant protection against the tumor-enhancing effects of surgery. Specifically, surgery resulted in a more than 5-fold increase in tumor cell retention compared with the anesthesia-only group, and morphine treatment reduced this effect by more than 50%. Again, morphine exerted no significant effects in the unoperated animals.8 The pre- and postoperative administration of fentanyl was similarly beneficial in significantly attenuating surgery-induced increases in lung tumor cell retention. An important finding in this study was that both female and male rats derived similar tumor protection from fentanyl, a comparison that had not been previously tested. The behavioral benefits were less evident, although medicated surgery animals reared significantly more than the unmedicated surgery animals.9 To complete the systemic drug regimens, indomethacin administration at the completion of surgery also provided significant protection against surgery-induced decreased host resistance against lung tumor cell retention. Similar to the morphine studies, significant interactions between the effects of surgery and indomethacin treatment were observed in both the lung tumor cell retention assay and the rearing study. Specifically, whereas untreated surgery animals were compromised in resisting tumor retention and were inactive, surgery animals treated with indomethacin exhibited significantly greater resistance against tumor retention and rearing incidence equivalent to that of the unoperated animals. The immune and abdominal discomfort relieving effects of indomethacin were equally apparent in male and female rats.10 Finally, the IT administration of bupivacaine plus morphine has been shown to provide significant protection against the tumor-enhancing effects of surgery in 2 different laboratories.9,11 Both studies showed that IT bupivacaine plus morphine significantly attenuated the tumor-enhancing effects of surgery. Further, Bar-Yosef et al11 showed that the IT treatment resulted in better tumor outcomes than a single preoperative systemic administration of morphine. Taken together, these findings strongly support the suggestion that relieving pain improves tumor development outcomes following surgery. Two points support that it is the pain-relieving effects of these drugs that decreased the tumor-enhancing impact of surgery versus other possible interpreta-
tions, such as direct effects upon immunity, the tumor cells themselves, or other mechanisms that impact upon tumor development. First, the benefits of the analgesia regimens were observed only in the surgery animals; there were no treatment-related benefits observed in animals not experiencing pain. Indeed, the drug regimens slightly increased tumor susceptibility in the unoperated animals in the above-mentioned studies. Such an interaction of effects between the analgesia administration and the surgery suggests that there was some block of the impact of surgery, not an independent effect of the drug on tumor development. Second, that the very low doses used in the IT injections of morphine (10 to 20 g) plus bupivacaine (10 to 50 g) exerted significant benefits would argue against possible peripheral effects of these drugs. Several studies in humans provide corroborative evidence that effective analgesia regimens improve immune-related outcomes. Compared with general anesthesia, epidural anesthesia was associated with significantly fewer infectious sequelae in high-risk surgical patients12 and preservation of NK activity.13,14 Additionally, surgical patients receiving small dose fentanyl anesthesia exhibited a significantly faster recovery of surgery-induced suppression of NK activity than those receiving large dose fentanyl anesthesia.15 If similar relationships between surgery, NK activity, and metastatic susceptibility can be extended to humans, findings from our studies would suggest that the provision of adequate pain relief should become an important adjunct in cancer care.
References 1. McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM. The role of adrenocorticoids as modulators of immune function in health and disease: Neural, endocrine and immune interactions. Brain Res Brain Res Rev 1997;23:79-133. 2. Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 1999;80:880-888. 3. Koda K, Saito N, Takiguchi N, Oda K, Nunomura M, Nakajima N. Preoperative natural killer cell activity: Correlation with distant metastases in curative research colorectal carcinomas. Int Surg 1997;82:190193. 4. Shavit Y, Martin FC, Yirmiya R, Ben-Eliyahu S, Terman GW, Weiner H, Gale RP, Liebeskind JC. Effects of single administration of morphine or footshock stress on natural killer cell cytotoxicity. Brain Behav Immun 1987;1:318-328. 5. Lewis JW, Shavit Y, Terman GW, Gale RP, Liebeskind JC. Stress and morphine affect survival of rats
Analgesia and Surgery-Induced Tumor Promotion
6.
7.
8.
9.
10.
challenged with a mammary ascites tumor (MAT 13762B). Nat Immun 1983;3:43-50. Ben-Eliyahu S, Page GG. The in vivo assessment of natural killer cell activity in rats. Prog NeuroEndocrin Immunol 1992;5:199-214. Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 1993;54:2128. Page GG, Ben-Eliyahu S, Liebeskind JC. The roll of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain Behav Immun 1994;8:241-250. Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001;90:191199. Page GG, Blakely WP, Ben-Eliyahu S. Cyclooxygenase inhibition attenuates surgery-induced suppression of NK activity, tumor promotion and exploratory behavior [abstract]. Brain Behav Immun 2001; 15:174.
•
Gayle G. Page
199
11. Bar-Yosef S, Melamed R, Page GG, Shakhar G, David K, Ben-Eliyahu S. Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 2001;94:1066-1073. 12. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:729-736. 13. Koltun WA, Bloomer MM, Tilberg AF, Seaton JF, Ilahi O, Rung G, Gifford RM, Kauffman GL. Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and reduced stress response. Am J Surg 1996;171:68-73. 14. Tønnesen E, Wahlgreen C. Influence of extradural and general anaesthesia on natural killer cell activity and lymphocyte subpopulations in patients undergoing hysterectomy. Br J Anaesth 1988;60:500-507. 15. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, Bessler H. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 1996;82:492-497.
Analgesia Administration Attenuates Surgery-Induced Tumor Promotion Gayle G. Page, R.N., D.N.Sc., F.A.A.N.
T
he regulation of the immune system by neural input and circulating hormones is well documented, as are the neuroendocrine and immune perturbations resulting from undergoing and recovering from surgery. The immune system has been shown to play a key role in cancer resistance, and natural killer (NK) cells have been shown to be particularly important in controlling metastasis.1 In support of these relationships between NK activity and metastatic susceptibility, animal studies have shown surgery to result in decreases in both NK activity and resistance against metastasis,2 and lower NK activity levels in humans undergoing cancer surgery are associated with a greater incidence of metastatic sequelae.3 Surgery is often a first step in cancer treatment; therefore, limiting surgery-induced NK suppression might enhance host resistance against cancer recurrence. Given that acute pain has also been shown to suppress NK activity4 and to promote tumor development in animals,5 our studies have sought to address the possibility that relieving the pain associated with undergoing and recovering from surgery might improve host resistance against metastatic development. To explore this issue, we have used a mammary adenocarcinoma cell line, MADB106, which is syngeneic to the inbred Fischer 344 rats we study. Following intravenous injection, the seeding and colonization of MADB106 cells in the lungs is controlled by NK cells, but only during the first 24 hours after injection and in a timedependent and decremental manner. Therefore, the From the School of Nursing, Johns Hopkins University, Baltimore, Maryland. Accepted for publication September 3, 2001. Supported by National Institutes of Health (NIH) Grant No. NR03915. Reprint requests: Gayle G. Page, R.N., D.N.Sc., F.A.A.N., Associate Professor and Independence Foundation Chair in Nursing Education, 525 N Wolfe St, Baltimore, MD 21205. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2702-0028$35.00/0 doi:10.1053/rapm.2002.29730
lung retention of MADB106 cells reflects both host tumor resistance and in vivo levels of NK activity.6 Our studies testing possible benefits of analgesia administration have used a simple 2⫻2 experimental design such that animals undergo either abdominal laparotomy under halothane anesthesia or halothane alone and receive either the analgesic or the vehicle. In separate studies, pharmacologic approaches were used to attenuate or block 3 different pain transmission mechanisms, including the systemic -opioid agonists, morphine and fentanyl, the prototypical nonsteroidal anti-inflammatory drug, indomethacin, and intrathecal (IT) administration of bupivacaine plus morphine. MADB106 tumor cells were injected into the tail vein at 5 hours after surgery in an effort to reflect the postoperative experience of the animal rather than intraoperative events. All studies described herein were approved by the institutional animal care and use committee. Three different studies used -agonists. In our first study, morphine was administered in analgesic doses both before and after surgery, and animals were euthanized at 3 weeks after MADB106 cell injection to assess the impact of morphine administration on surgery-induced increases in tumor colonization. We found that morphine significantly attenuated the tumor-enhancing effects of surgery, but did not significantly affect the number of tumors that developed in the anesthesia-only animals. To suggest that the morphine relieved abdominal discomfort, we observed animals from the same 4 experimental groups for the incidence of rearing behavior, the lifting of both forepaws off of the cage floor, during the first 4 hours following surgery. That humans exhibit a hunching or slouching posture following abdominal surgery supports the suggestion that in rats, a reduction in a normal exploratory behavior that requires the stretching out of the abdominal wall might indicate abdominal discomfort. We found that whereas the unmedicated surgery animals exhibited few incidences of rearing, the rearing incidence of surgery animals receiving
Regional Anesthesia and Pain Medicine, Vol 27, No 2 (March–April), 2002: pp 197–199
197
198
Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002
morphine was similar to that of the unoperated rats.7 In a substantial replication, using radiolabeled MADB106 cells in a lung clearance assay to assess lung tumor cell retention at 18 hours after injection, we similarly showed that pre- and postoperative morphine administration provided significant protection against the tumor-enhancing effects of surgery. Specifically, surgery resulted in a more than 5-fold increase in tumor cell retention compared with the anesthesia-only group, and morphine treatment reduced this effect by more than 50%. Again, morphine exerted no significant effects in the unoperated animals.8 The pre- and postoperative administration of fentanyl was similarly beneficial in significantly attenuating surgery-induced increases in lung tumor cell retention. An important finding in this study was that both female and male rats derived similar tumor protection from fentanyl, a comparison that had not been previously tested. The behavioral benefits were less evident, although medicated surgery animals reared significantly more than the unmedicated surgery animals.9 To complete the systemic drug regimens, indomethacin administration at the completion of surgery also provided significant protection against surgery-induced decreased host resistance against lung tumor cell retention. Similar to the morphine studies, significant interactions between the effects of surgery and indomethacin treatment were observed in both the lung tumor cell retention assay and the rearing study. Specifically, whereas untreated surgery animals were compromised in resisting tumor retention and were inactive, surgery animals treated with indomethacin exhibited significantly greater resistance against tumor retention and rearing incidence equivalent to that of the unoperated animals. The immune and abdominal discomfort relieving effects of indomethacin were equally apparent in male and female rats.10 Finally, the IT administration of bupivacaine plus morphine has been shown to provide significant protection against the tumor-enhancing effects of surgery in 2 different laboratories.9,11 Both studies showed that IT bupivacaine plus morphine significantly attenuated the tumor-enhancing effects of surgery. Further, Bar-Yosef et al11 showed that the IT treatment resulted in better tumor outcomes than a single preoperative systemic administration of morphine. Taken together, these findings strongly support the suggestion that relieving pain improves tumor development outcomes following surgery. Two points support that it is the pain-relieving effects of these drugs that decreased the tumor-enhancing impact of surgery versus other possible interpreta-
tions, such as direct effects upon immunity, the tumor cells themselves, or other mechanisms that impact upon tumor development. First, the benefits of the analgesia regimens were observed only in the surgery animals; there were no treatment-related benefits observed in animals not experiencing pain. Indeed, the drug regimens slightly increased tumor susceptibility in the unoperated animals in the above-mentioned studies. Such an interaction of effects between the analgesia administration and the surgery suggests that there was some block of the impact of surgery, not an independent effect of the drug on tumor development. Second, that the very low doses used in the IT injections of morphine (10 to 20 g) plus bupivacaine (10 to 50 g) exerted significant benefits would argue against possible peripheral effects of these drugs. Several studies in humans provide corroborative evidence that effective analgesia regimens improve immune-related outcomes. Compared with general anesthesia, epidural anesthesia was associated with significantly fewer infectious sequelae in high-risk surgical patients12 and preservation of NK activity.13,14 Additionally, surgical patients receiving small dose fentanyl anesthesia exhibited a significantly faster recovery of surgery-induced suppression of NK activity than those receiving large dose fentanyl anesthesia.15 If similar relationships between surgery, NK activity, and metastatic susceptibility can be extended to humans, findings from our studies would suggest that the provision of adequate pain relief should become an important adjunct in cancer care.
References 1. McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM. The role of adrenocorticoids as modulators of immune function in health and disease: Neural, endocrine and immune interactions. Brain Res Brain Res Rev 1997;23:79-133. 2. Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 1999;80:880-888. 3. Koda K, Saito N, Takiguchi N, Oda K, Nunomura M, Nakajima N. Preoperative natural killer cell activity: Correlation with distant metastases in curative research colorectal carcinomas. Int Surg 1997;82:190193. 4. Shavit Y, Martin FC, Yirmiya R, Ben-Eliyahu S, Terman GW, Weiner H, Gale RP, Liebeskind JC. Effects of single administration of morphine or footshock stress on natural killer cell cytotoxicity. Brain Behav Immun 1987;1:318-328. 5. Lewis JW, Shavit Y, Terman GW, Gale RP, Liebeskind JC. Stress and morphine affect survival of rats
Analgesia and Surgery-Induced Tumor Promotion
6.
7.
8.
9.
10.
challenged with a mammary ascites tumor (MAT 13762B). Nat Immun 1983;3:43-50. Ben-Eliyahu S, Page GG. The in vivo assessment of natural killer cell activity in rats. Prog NeuroEndocrin Immunol 1992;5:199-214. Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 1993;54:2128. Page GG, Ben-Eliyahu S, Liebeskind JC. The roll of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain Behav Immun 1994;8:241-250. Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001;90:191199. Page GG, Blakely WP, Ben-Eliyahu S. Cyclooxygenase inhibition attenuates surgery-induced suppression of NK activity, tumor promotion and exploratory behavior [abstract]. Brain Behav Immun 2001; 15:174.
•
Gayle G. Page
199
11. Bar-Yosef S, Melamed R, Page GG, Shakhar G, David K, Ben-Eliyahu S. Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 2001;94:1066-1073. 12. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:729-736. 13. Koltun WA, Bloomer MM, Tilberg AF, Seaton JF, Ilahi O, Rung G, Gifford RM, Kauffman GL. Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and reduced stress response. Am J Surg 1996;171:68-73. 14. Tønnesen E, Wahlgreen C. Influence of extradural and general anaesthesia on natural killer cell activity and lymphocyte subpopulations in patients undergoing hysterectomy. Br J Anaesth 1988;60:500-507. 15. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, Bessler H. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 1996;82:492-497.