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From the Department of Anaesthesiology, Kanto Rohsai Hospital, 2035 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, Kanagawa 211, Japan. Phone: 81-44-411-3131; Fax: 81-44-433-3150
Address correspondence to: Dr. Tetsuya Yokota
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Abstract |
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Methods: Forty patients were divided into four groups of ten. The groups received intrathecal 0.5 mg morphine (Group IT0.5), intrathecal 0.1 mg morphine (Group IT0.1) or 10 mg morphine iv (Group IV). The remaining ten patients served as controls and received inhalation anesthesia alone (Group C). Blood samples were withdrawn before and two hours after surgery and on postoperative days one and two to determine the blood NK cell activity using a chromium release assay with K562 cells as targets, plasma catecholamines and cortisol levels. The postoperative pain score and side effects were studied in the four groups.
Results: In Group IT0.5, the NK cell activity was lower on postoperative day 1 (23.9 ± 8.4%) than the baseline level (45.7 ± 13%) before surgery, and recovered on postoperative day 2. In Groups IT0.1, C and IV, the NK cell activities showed no significant changes. In all four groups, neither plasma adrenaline nor noradrenaline concentrations changed. In all four groups, the plasma cortisol levels increased after surgery, on postoperative days 1 and 2. The pain score was lower two hours after surgery and on postoperative day 1 in Group IT0.5 than in the other groups.
Conclusion: These results suggest that long-lasting analgesic effects of intrathecal 0.5 mg morphine suppress the immune response following abdominal surgery.
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Introduction |
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Natural Killer cells, because of their unique ability to recognize and kill tumour cells without processing tumour specific antigen, are thought to form a primary immune defence mechanism against the development of tumours and have a secondary role in defence against tumour metastases. In order to evaluate the effects of intrathecal and intravenous doses of morphine on the immune process of surgery, we investigated NK cell activity, using an immunological tests, in patients undergoing hysterectomy for uterine myoma.
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Methods |
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General anesthesia was induced with 5 mg•kg–1 thiamylal followed by 0.12 mg•kg–1 vecuronium for muscle relaxation and, after tracheal intubation, anesthesia was maintained with isoflurane 0.6-1.5% and nitrous-oxide 66% in oxygen. Vecuronium was given as needed during surgery. None of the patients received blood transfusion.
Before surgery around 9 a.m. for a baseline value, two hours after surgery and on postoperative days 1 and 2, blood samples were withdrawn to determine blood NK cell activity, plasma noradrenaline, adrenaline and cortisol concentrations.
Natural Killer cell activity was measured against K-562 target cells in a chromium-51(51Cr) release assay. 51Chromium-labeled target cells, 5x103, of the human erythroleukemic cell line K-562 were mixed with different concentrations of mononuclear cells from blood samples of the patients, for use as effector cells, to obtain effector to target cell ratios 100:1, 50:1, 25:1 and 12:1. Cell suspensions were incubated for four hours at 37°C in humidified air and carbon dioxide 5%. After incubation, the radioactivity of 100 µl of cell-free supernatant was counted with an automatic well-type gamma scintillation counter. Percentage cytotoxicity was computed from the formula:
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Spontaneous 51Cr release was measured by incubating target cells with assay medium, and maximum release was measured by incubating target cells in water containing sodium sulphate 5%. The values of spontaneous release were in the range of 5%-10% of the maximal release in all experiments. Maximal release was always greater than 5.0x103 cpm•10–4 cells.
Plasma concentrations of adrenaline and noradrenaline were measured by high pressure liquid chromatography. Serum cortisol was measured by radioimmunoassay.
After recovery from general anesthesia, pain score and side effects were examined. Postoperative pain was assessed by one of three observers who was unaware of the dose of morphine used after questioning the patient and asking them to breathe deeply, cough, and move about. It was rated on a scale of 0 to 4 (0; pain free with movement or coughing, 1; minimal discomfort on movement or coughing, 2; comfortable at rest, moderate pain on movement or coughing, 3; discomfort at rest, considerable pain with movement or coughing, 4; severe pain, even at rest.) according to the pain rating. Supplemental analgesia was limited to non-steroidal antiinflammatory drugs such as diclofenac sodium and indomethacin: opioids were not used. The side effects were examined about respiratory depression, nausea, vomiting, pruritus and hypotension. Respiratory depression was defined as respiratory frequency of less than 10 bpm and hypotension was defined as decrease in systolic arterial pressure of at least 20 mmHg.
Statistical comparisons were made by non-parametric methods with Wilcoxon matched, pairs signed ranks test for paired data, and Mann-Whitney Test for unpaired data. P < 0.05 was considered statistically significant. Values are presented as the means ± SD.
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Side effects
Nausea occurred in one or two patients in each group without differences among groups. Itching occurred in one patient in each of the three groups receiving morphine. Neither respiratory depression nor hypotension occurred in any group. Postoperative infection did not occur in any group. (Table II)
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Discussion |
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Morphine has been reported to suppress NK cell activity3,4 and several mechanisms have been proposed for immune suppression caused by opioids.5 First, opioids have an indirect effect on immune function through alterations in effector cell populations. For example, morphine pellet implantation in mice resulted in thymic and splenic atrophy with an increased ratio of CD4+/CD8+ cells, but decreased total number of both cell populations.6 Second, opioids can also act to suppress directly some components of the immune response such as the antibody response of splenocytes7 and rosette formation by lymphocytes.8 Third, opioids interact with suppressor cell populations or endogenous immune mediators. Fourth, opioids affect immune function by suppression of endogenous, tonic enhancement of effector cell activity. For example, endogenous opioids such as ß-endorphin have been shown to stimulate immune effector cells in vitro.9 Finally, opioids can suppress immunity through effects on the central nervous system. For example, peripheral administration of N-methylmorphine, which does not cross the blood-brain barrier, did not suppress NK cell activity, whereas, microinjections of N-methylmorphine into the third ventricle of the brain suppressed NK cell activity.5 This effect was blocked by an opioid antagonist, naltrexone. After microinjection of 1 or 10 µg morphine into the third ventricle, lymphocyte proliferative responses were decreased by 50 and 75%, respectively, in rats. Similarly, a 50% decrease was observed after the microinjection of 1 µg morphine into the anterior hypothalamus in rats. Morphine has also been shown to inhibit splenic NK cell activity after central administration in mice. These data implicate opioid receptors in the brain in morphine-induced suppression of NK cell cytotoxicity. Morphine might suppress NK cell activity by inducing or modulating the release of hormones. Intracerebroventricular-administered morphine has been shown to elevate plasma cortisol and catecholamines concentrations in rats.5 These cortisol and catecholamines could suppress NK cell activity by stimulating central sympathetic outflow.
Despite these data implicating opioids as a cause of impaired immunity in vivo and in vitro, there are few data evaluating in vivo effects of opioids on human immunity.10 Our study evaluated the effects of morphine on NK cell activity in a clinical study, and indicated that intrathecal morphine suppress NK cell activity through effects on the central nervous system.
Surgical stress has been considered one of the causes that affect endocrine responses and suppress immune function, including NK cell activity.11 Endocrine responses caused by surgical stress, in particular a postoperative rise of cortisol, are reported to increase endogenous catecholamine reactions, leading to a decrease in NK cell activity.12 Pedersen et al., reported that both methylprednisolone and hydrocortisone produced dose-dependent suppression of NK cell activity.13 In the present study, cortisol was increased after surgery and on postoperative day 1 in all four groups, however, the NK cell activity was not decreased in Group C. With effects of catecholamine on the NK cell activity, it has been reported that catecholamines suppressed immune function.14 Anatomical data indicate that the spleen is inverted by sympathetic nerve fibres that have access to lymphocytes and can modulate lymphocyte function. In this study, neither plasma adrenaline nor noradrenaline concentrations changed in all four groups.
Anesthesia itself has been reported to affect NK cell activity.12 However, Griffith et al.,15 reported that neither halothane nor nitrous oxide affected NK cell activity at clinical concentrations. If inhalation anesthesia is used at high concentration or if the quantity of anesthetic used is increased as a result of operation, anesthetics alone may suppress NK cell activity. In order to maintain immunity at high levels, the doses or concentrations of anesthetics should be as low as possible. Intrathecal morphine allows the use of anesthetics at low concentrations to maintain anesthesia.16 In fact, the concentration of the anesthetics for maintenance was lower in Group IT0.5 and IT0.1 than in the other two groups. In all four groups, the duration of surgery was short, and the bleeding was low. There was no decrease in NK cell activity in Group C. Consequently, the effects of anesthetics and surgical stress on NK activity was only slight in the present study.
In clinical practice, intrathecal doses of morphine ranging from 0.02 to 10 mg have been used.17 From the present results, intrathecal morphine at a dose of 0.5 mg and 0.1 mg produced analgesia after surgery and at a dose of 0.5 mg produced improved analgesia over the period from immediately after surgery to postoperative day 1, compared with Group C.
In vitro, morphine inhibition of lymphocyte proliferative responses occurs at concentrations that are two orders of magnitude greater than the plasma concentrations resulting from systemic administration, which suppress lymphocyte proliferation and produce analgesia in vitro.18 The 0.5 mg and 0.1 mg intrathecal doses used in this study cannot be regarded as equivalent to the 10 mg intravenous dose for postoperative analgesia. The validity of a simple comparison of NK cell activity observed in Group IT0.5 and IT0.1 with that in Group IV is not certain. According to Hamra et al.,19 subcutaneous morphine inhibited lymphocyte proliferation and altered phenotypic expression of cell surface markers, whereas equianalgesic doses of intrathecal morphine did not. Nelson et al.,20 reported that morphine's immunologic and analgesic effects may be modulated by different mechanisms. Systemic morphine, which has potent supraspinal effects, but not intrathecal morphine, modulated lymphocyte function, providing further evidence that the immunomodulatory actions of morphine are centrally mediated. The lack of effect of spinally administered morphine suggests that spinal opioid receptors are not involved in morphine immunomodulation, and indicates a dose-response relation at supraspinal opioid receptors. According to Bromage et al.,21 morphine remains in the cerebrospinal fluid for a prolonged period because of its water-soluble property. Its prolonged retention in the central nervous system gives rise to its long-lasting effects. In our study, NK cell activity showed no changes in Groups C, IV and IT0.1, but NK cell activity was lower on postoperative day 1 in Group IT0.5. This suggests that the immunosuppressive effects of intrathecal morphine may be dose-dependent.
Morphine-induced side effects included nausea, pruritus and respiratory depression. Respiratory depression is a severe side effect, but none of the patients given intrathecal 0.5 mg or 0.1 mg morphine developed respiratory depression. Postoperative immune suppression may be a serious complication because patients who have undergone surgery are vulnerable to infection even in the absence of immune suppression. However, in the present study, postoperative infection did not occur in any group.
Intrathecal injection of 0.5 mg morphine was useful for postoperative pain relief, but NK cell activity was suppressed on postoperative day 1. The NK cell activity was not suppressed by intrathecal administration of 0.1 mg or intravenous injection of 10 mg morphine. These data suggest that intrathecal morphine is useful for the treatment of postoperative pain, but intrathecal morphine causes suppression of immunity in a dose-dependent manner. The mechanism of morphine suppression of NK cell activity may be through effects on the central nervous system.
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Acknowledgments |
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Accepted for publication December 20, 1999.
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References |
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2 Shvit Y, Depaulis A, Martin FC, et al. Involvement of brain opiate receptors in the immune-suppressive effect of morphine. Neurobiology 1986; 83: 7114–7.
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8
Wybran J, Appleboom T, Famaey J-P, Govaerts A. Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J Immunol 1979; 123: 1068–70.
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Walton B. Effect of anaesthesia and surgery on immune status. Br J Anaesth 1979; 51: 37–43.
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Griffith CDM, Kamath MB. Effect of halothane and nitrous oxide anaesthesia on natural killer lymphocytes from patients with benign and malignant breast disease. Br J Anaesth 1986; 58: 540–3.
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Samii K, Chauvin M, Viars P. Postoperative spinal analgesia with morphine. Br J Anaesth 1981; 53: 817–20.
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19 Hamra JG, Yaksh TL. Equianalgesic doses of subcutaneous but not intrathecal morphine alter phenotypic expression of cell surface markers and mitogen-induced proliferation in rat lymphocytes. Anesthesiology 1996; 85: 355–65.[Medline]
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Bromage PR, Camporesi EM, Durant PAC, Nielsen CH. Nonrespiratory side effects of epidural morphine. Anesth Analg 1982; 61: 490–4.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), Group ITO.1 (
) and Group ITO.5 (
).
: P < 0.05 compared with Groups C, IV and ITO.1.
) and Group ITO.5 (