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We previously showed, in mice, that morphine and tramadol exerted different effects on immune responses. Indeed, although morphine decreased lymphocyte proliferation and NK activity (2), the same variables were significantly enhanced by tramadol (13), ibuprofen and tramadol. 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, side effecs of tramadol, and before the surgical procedure, immune responses were comparable to those described in healthy people (16,17), side effecs of tramadol. 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, side effecs of tramadol. 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), side effecs of tramadol, or the immune function was slowly returning to basal levels and no interference by tramadol was present. In any case, side effecs of tramadol, 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, side effecs of tramadol. 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, pain relief shoes. 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), side effecs of tramadol. 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), side effecs of tramadol. Consistent with these observations, , drugs which increase serotoninergic tone, side effecs of tramadol, 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, side effecs of tramadol. 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.
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