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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer Patients

Paola Sacerdote, PhD^*, Mauro Bianchi, MD^*, Leda Gaspani, PhD^*, Barbara Manfredi, PhD^*, Antonio Maucione, MD, Giovanni Terno, MD, Mario Ammatuna, MD, and Alberto E. Panerai, MD^*

*Department of Pharmacology, University of Milano; and National Cancer Institute, Anesthesia and Intensive Care Unit, Milan, Italy

Address correspondence and reprint requests to Paola Sacerdote, PhD, Department of Pharmacology, University of Milano, via Vanvitelli 32, 20129 Milano, Italy. Address e-mail to paola.sacerdote{at}unimi.it

	Abstract

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There has been growing interest in determining the possible immune consequences of opioid administration for the management of postoperative pain. We studied the effects of morphine and tramadol on pain and immune function during the postoperative period in 30 patients undergoing abdominal surgery for uterine carcinoma. Phytohemoagglutinin-induced T lymphocyte proliferation and natural killer cell activity were evaluated immediately before and after surgery, and 2 h after the acute administration of either 10 mg of morphine IM or 100 mg tramadol IM for pain. In all patients, phytohemagglutinin-induced lymphoproliferation was significantly depressed by surgical stress. However, in the morphine-treated group, proliferative values remained lower than basal levels for 2 h after treatment, whereas in tramadol-administered patients proliferative values returned to basal levels. Natural killer cell activity was not significantly affected by surgery nor by morphine administration, whereas tramadol significantly enhanced the activity of natural killer cells. Both drugs produced a comparable reduction in postoperative pain. We conclude that, as previously observed in the experimental animal, tramadol and morphine, when administered in analgesic doses, induce different immune effects.

Implications: Recent studies suggest that opioids can have an adverse impact on the immune system. Because surgical stress also induces immune dysfunction, the search for analgesic drugs devoid of immunosuppressive effects is of import. This study compared the effects on immune responses of morphine and of the atypical opioid analgesic, tramadol, given for postoperative pain to gynecological cancer patients. Tramadol and morphine showed comparable analgesic activity; however, tramadol, in contrast to morphine, induced an improvement of postoperative immunosuppression and, therefore, may be preferred to morphine for the treatment of postoperative pain.

	Introduction

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Several studies conducted in animals and humans have shown that opioids can exert immunosuppressive effects (1–3). In particular, acute, as well as chronic administration of morphine decreases lymphoproliferation, natural killer (NK) activity, macrophage functions, and the production of interferon- and interleukin-2 in the rodent (2). Consistent with these observations, opioid administration has been associated with increased susceptibility of animals to bacterial and viral infections (4), and with decreased survival in tumor-bearing animals (5). Similar effects have been shown in humans, in which most studies have been performed in IV-opioid abusers (4) and relatively few in subjects exposed to opioids for therapeutic reasons (6,7).

It is well known that the activation of endocrine and sympathetic nervous systems during surgery leads to a transient period of immunosuppression (8–10). The therapeutic use of morphine might, therefore, be relatively contraindicated in the postoperative period, in which the functionality of the immune system is already compromised by stress exposure. Tramadol is a centrally acting, analgesic drug, with a double mechanism of action; it binds with low affinity to µ-opioid receptors, and activates central monoaminergic pathways inhibiting the neuronal uptake of serotonin and noradrenaline (11,12). We previously showed that, in mice, in contrast to morphine, tramadol did not suppress cellular immune functions, whereas it increased NK activity, lymphocyte proliferation, and interleukin-2 production (13).

For all of these reasons, we wanted to study, in humans, the effects on immune responses of tramadol and morphine administered for acute treatment of postoperative pain in cancer patients. We evaluated the impact of surgical stress and drug administration on two typical immune functions, proliferation of T lymphocyte and NK activity. Proliferation of T lymphocyte is a reliable index of the ability of these cells to undergo clonal expansion after antigen stimulation, and NK cells are a population of lymphocytes important in tumor surveillance and in defense against viral infections (14).

	Methods

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A total of 30 patients undergoing abdominal surgery for uterine carcinoma entered the study. These patients had never received radiotherapy, chemotherapy, nor immunosuppressive drugs. After informed consent, and approval of the ethical committee of the Department of Pharmacology, University of Milano, Italy, patients were randomized into one of the two study groups according to a computer-generated, randomized list.

In all patients, after the IV induction with fentanyl 1 µg/kg, thiopental 5 mg/kg, and succinylcholine 1 mg/kg, anesthesia was maintained with isoflurane 1.5–1.7 minimum alveolar anesthetic concentration (% inspiration 1.6:1.2 and % expiration 1.2:1.0), 66% nitrous oxide in oxygen and pancuronium 0.07 mg/kg. Immediately after the end of surgery, patients were given an IM injection of either 10 mg of morphine HCl or 100 mg of tramadol. At 2 h after the administration of morphine or tramadol, pain was assessed by using visual analog scale (VAS) (scores 0–100), and the degree of sedation was evaluated by clinicians with scores from 0 to 4, where 0 = awake, 1 = easily aroused, 2 = awakens after tactile stimulation, 3 = awakens after verbal stimulation, and 4 = not arousable. Both evaluations were performed by clinicians unaware of patient treatment group.

Blood was withdrawn before the beginning of surgery, before drug administration, and 2 h after drug administration. Blood was collected into tubes containing EDTA. Peripheral blood mononuclear cells were separated by gradient centrifugation over Ficoll-Paque (Amersham Pharmacia Biotech, Milano, Italy) as described by Manfredi et al. (15). Microcultures of fresh peripheral blood mononuclear cells were set up in triplicate for each sample (10⁶ cells/mL) in RPMI 1640, 10% fetal calf serum with or without Phytohemoagglutinin (4, 1, and 0.25 µg/mL) (15).

Background values, (<1000 cpm), i.e., thymidine incorporation by unstimulated cells, were subtracted from values of mitogen-induced proliferation. NK cell activity was evaluated by using a standard 4-h ⁵¹Cr-release assay, with K562 cells as target cells (16,17). ⁵¹Cr-labeled K562 (target cells) were incubated with splenocytes (effector cells) at effector/target cell ratios of 100:1.

Specific ⁵¹Cr release was calculated according to the formula:

All of the immunological analysis were performed in a blinded fashion by researchers unaware of patient treatments. A sample size of 15 patients in each group has 80% power to detect a difference of 1 SD between the means of Group 1 and Group 2, assuming that the common SD is 1 by using a two-tailed t-test with a 0.05 two-sided significance level. Demographic data of patients and VAS values were analyzed by using one-way analysis of variance and the degree of sedation measured by Mann-Whitney U-test. Lymphocyte proliferation and NK activity were analyzed by using mean of one-way analysis of variance for repeated measures.

	Results

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Patient characteristics were homogeneous in the two groups. Indeed, no statistical differences were observed considering age (50 ± 14 vs 51 ± 15 yr), weight (66 ± 13 vs 65 ± 13 kg), and the duration of surgery (126 ± 33 vs 122 ± 35 min). No patient needed blood transfusion during or after surgery.

The analgesic effects of acute tramadol and morphine were similar; in fact, the VAS values 2 h after the drug administration were not significantly different (tramadol 44 ± 19 mm; morphine 31 ± 20 mm). There was a comparable degree of sedation in the two treatment groups (scores, 1.3 ± 0.9 vs 1.6 ± 0.8).

As shown in Figure 1, immediately after the end of surgery, T lymphocyte proliferation was significantly lower than basal proliferative levels in all patients. At 2 h after the injection of the analgesic drugs, a different pattern of responses was observed in the two groups of patients. In the morphine-treated patients (Figure 1, left panel) lymphocyte proliferation was still significantly lower than in basal conditions. In contrast, the Phytohemoagglutinin-induced proliferation in the group of patients treated with tramadol was not significantly different from that observed before the beginning of surgery, whereas a significant difference was present in comparison with postsurgery values (Figure 1, right panel).

View larger version (14K): [in this window] [in a new window]   Figure 1. Phytohemoagglutinin (PHA) (0.25, 1.0, 4.0 µg/mL) induced proliferation of lymphocytes obtained from patients before the beginning of surgery (basal), immediately after surgery and predrug (postsurgery), and 2 h after treatment with 10 mg of morphine IM (left panel) or 100 mg of tramadol IM (right panel). Values are mean ± SD. *P < 0.01 versus basal. +P < 0.01 versus postsurgery.

View larger version (28K): [in this window] [in a new window]   Figure 2. Natural killer cells activity obtained from patients before the beginning of surgery (basal), immediately after surgery and predrug (postsurgery), and 2 h after treatment with 10 mg of morphine IM or 100 mg of tramadol IM. Values are mean ± SD. *P < 0.01 versus basal.

	Discussion

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The current study was undertaken to evaluate whether similar effects could be described in humans. The postoperative period represents an interesting opportunity to address this problem, because it is known that surgical stress results in activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, leading to an alteration of immune responses (8–10). Indeed, we observed a clear-cut decrease in T lymphocyte proliferation immediately after the end of surgery. Cancer patients enrolled in the study were not immunosuppressed, and before the surgical procedure, immune responses were comparable to those described in healthy people (16,17).

The impaired response of T lymphocytes persisted two hours after the administration of morphine, whereby after the administration of tramadol the lymphoproliferation was not different in comparison with presurgery values. Immunosuppression induced by surgical stress has generally been shown to last longer than two hours (18); however, from our study, it is difficult to hypothesize whether the lymphoproliferation levels would have returned to normal values in the absence of treatment with morphine.

We cannot say whether the apparently reestablished levels of lymphoproliferation observed after tramadol administration are caused by the immunostimulant properties of this drug, as was observed in mice (13), or the immune function was slowly returning to basal levels and no interference by tramadol was present. In any case, these findings indicate that tramadol does not exert immunosuppressive actions.

In contrast to what was observed with lymphocyte proliferation, surgery did not affect the cytotoxic activity of NK cells. These two immune variables seem, therefore, to show a different sensitivity to the stress induced by this type of surgical procedure. Although NK activity has generally been observed to be decreased after surgical stress (19,20), increased (21), as well as unchanged (22), NK activity in the perioperative period has also been reported. It is reasonable to suggest that different surgical procedures can produce different modifications of this variable. At two hours after morphine administration, no significant alteration of NK activity was present. Because it has been shown that the immunosuppressive effects of morphine are evident at doses larger than those needed for controlling pain (2), it is likely that doses larger than 10 mg of morphine are required to fully evidentiate the suppression of NK activity in humans. Whereas two hours after morphine administration there was no significant modification of NK activity in the group of patients treated with tramadol, a clear and significant increase of this immune variable was evident. These observations lead us to hypothesize a stimulatory effect of tramadol on NK activity. Taken together, these results confirm the pharmacological properties of tramadol observed in the experimental animal (13).

Morphine and tramadol share the opioid mechanism of action, although the affinity of tramadol for µ-opioid receptors is significantly lower than that of morphine. However, the antinociceptive effects of tramadol are mediated also via a separate, nonopioid mechanism, caused by the inhibition of neuronal uptake of noradrenaline and serotonin (11,12). These differences can account for the diverse pharmacodynamic profile of morphine and tramadol on immune functions.

The involvement of the noradrenergic and serotoninergic systems in neural-immune interactions has been studied by using different experimental models. Although both enhancement and reduction of immune responses have been related to the activation of the noradrenergic system (23), the increase of serotoninergic tone has usually been associated with stimulation of NK activity and lymphocyte pro- liferation (24,25). Consistent with these observations, drugs which increase serotoninergic tone, such as D-fenfluramine and fluoxetine, stimulate immune function in rodents (24) and our unpublished results. Moreover, in the mouse, we observed that the immune effects of tramadol on lymphoproliferation and NK activity were prevented by the administration of the nonspecific serotoninergic antagonist metergoline (25), indicating an involvement of the serotoninergic system in the immune effects of this drug. Interestingly, we have observed (our unpublished results) that tramadol, when added in vitro to splenocyte cultures, was not able to modulate either proliferation or NK activity, thus eliminating a direct effect of the drug on immune cells. Therefore, it can be suggested that activation of the serotoninergic system might be involved in the immune effects of tramadol in experimental and clinical conditions.

In conclusion, we have confirmed in humans that the immune function is differently affected by morphine and tramadol. Analgesic drugs devoid of immunosuppressive effects might offer a good alternative to morphine for the treatment of postoperative pain.

	References

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