Mauro Bianchi

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

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.

Cognitive function in young and adult IL (interleukin)-6 deficient mice

Interleukin-6 (IL-6) is a cytokine shown to affect brain function and to be involved in pathological neurodegenerative disorders such as Alzheimers disease (AD). In the present study we investigated the cognitive function in transgenic mice not expressing IL-6 (IL-6 KO) and in wild type (WT) genotype at 4 and 12 months of age, using a passive avoidance and an eight-arm radial maze tasks. Motor function was quantified using an Animex apparatus. Hippocampal choline acetyltransferase (ChAT) activity was evaluated in both genotypes. No difference was observed in both genotypes for spontaneous motor activity. The mean latency (s) to re-enter the shock box, was similar in both young mutant and WT mice. However, a decreased sensitivity (50%) to scopolamine (1 mg/kg) in mutant compared to WT mice, was obtained. IL-6 KO mice exhibited a facilitation of radial maze learning over 30 days, in terms of a lower number of working memory errors and a higher percentage of animals reaching the criterion as compared with WT genotype tested at both ages. Furthermore, mutant mice, at the age of 12 months, showed a faster acquisition (22 days versus 30 days to reach the criterion). The pattern of arm entry exhibited by IL-6 KO mice showed a robust tendency to enter an adjacent arm at both ages, while WT only at the age of 4 months. ChAT activity was inversely correlated with memory performance. These findings suggest a possible involvement of IL-6 on memory processes, even if the mechanism remains still unclear.

The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats

Surgery stress has been shown to be associated in rat with decreased natural killer (NK) cell activity and enhancement of tumor metastasis. We have previously shown that the analgesic drug tramadol stimulates NK activity both in the rodent and in the human. In the present study, we analyze, in the rat, tramadol ability to prevent the effect of experimental surgery on NK activity and on the enhancement of metastatic diffusion to the lung of the NK sensitive tumor model MADB106. The administration of tramadol (20 and 40 mg/kg) before and after laparatomy significantly blocked the enhancement of lung metastasis induced by surgery. In contrast, the administration of 10 mg/kg of morphine was not able to modify this enhancement. The modulation of NK activity seemed to play a central role in the effect of tramadol on MADB106 cells. In fact, both doses of tramadol were able to prevent surgery-induced NK activity suppression, while the drug significantly increased NK activity in normal non-operated animals. Morphine, that in normal rats significantly decreased NK cytotoxicity, did not prevent surgery-induced immunosuppression. The good analgesic efficacy of tramadol combined with its intrinsic immunostimulatory properties suggests that this analgesic drug can be particularly indicated in the control of peri-operative pain in cancer patients.

Evidence for an opioid inhibitory effect on T cell proliferation

The proliferative response of human or rat T lymphocytes to phytohemagglutinin (PHA) or concanavalin A (ConA) was measured after acute (30 min) or chronic (8 days) treatment with the opiate receptor antagonists naloxone or naltrexone. Both in the rat and in the human, proliferation was significantly enhanced by acute treatment with the opiate receptor antagonists. In contrast, after chronic treatment proliferation always decreased. The sudden removal of an opioid inhibitory tone might be the basis for the increased proliferative responses observed after acute treatment. The decrease after chronic treatment could be ascribed to the amplification of the inhibitory effect of endogenous opioids due to the up-regulation of opiate receptors that follows chronic antagonist administration. Receptor binding studies of beta-endorphin receptors on splenocytes of chronically naloxone treated rats confirmed this hypothesis: a higher number of beta-endorphin receptors were expressed on splenocytes of naloxone-treated rats compared to controls (Bmax = 9.8 x 10(-12) vs. 1.16 x 10(-12), respectively).

A randomized study on oral administration of morphine and methadone in the treatment of cancer pain

Abstract Over a period of 14 days, 54 patients with incurable chronic cancet pain were observed: 27 were randomized for treatment with morphine per os and 27 with methadone per os. Data regarding daily dosage, analgesic effects, hours of sleep, hours standing, performance status (PS) and side effects were collected during both treatments. The results show overlapping analgesic efficacy and side effects for both drugs, and confirm the hypothesis that lower doses of methadone are required than morphine. In the treatment with methadone, the initial average dose was 18 mg, and this dose was maintained throughout the entire period, whereas the initial average daily dose of morphine was 72.74 mg (±39.25), and the final average daily dose was 119.40 mg (±79.1). The findings in this study show that methadone is a valid alternative to morphine in cancer pain treatment even though, as a result of its pharmaceutical charcteristics, it requires a differnt titration for the patient.

Effects of tramadol on immune responses and nociceptive thresholds in mice

Abstract Tramadol is a centrally acting analgesic drug with a dual mechanism of action: binding to &mgr;‐opioid receptors and potentiation of the monoaminergic systems. In this study, we evaluated the effects of the acute and chronic administration of tramadol on nociceptive thresholds (by the hot‐plate test) and on immune responses (by measuring Concanavalin A‐induced splenocyte proliferation, IL‐2 production and natural killer activity) in the mouse. After acute subcutaneous administration, tramadol induced antinociception starting from a dose of 20 mg/kg, whereas it significantly enhanced natural killer activity and IL‐2 production at doses as low as 1 mg/kg and splenocyte proliferation starting from a dose of 10 mg/kg. After the chronic administration, the antinociceptive effect of the drug was still present, whereas the immune modifications disappeared. Thus, the pharmacological profile of tramadol is totally different from that of other drugs which bind &mgr;‐opioid receptors. Our results suggest that tramadol could be a good choice for the treatment of pain in patients where immunosuppression may be particularly contraindicated.

Central effects of tumor necrosis factor α and interleukin-1α on nociceptive thresholds and spontaneous locomotor activity

Abstract To extend the knowledge on the central effects of cytokines, we studied the effects of tumor necrosis factor α and interleukin-1α on nociceptive thresholds and spontaneous locomotor activity in rats. After central administration, both tumor necrosis factor α and interleukin-1α significantly ( P

Effects of chlomipramine and fluoxetine on subcutaneous carrageenin-induced inflammation in the rat.

We have previously shown that, after acute administration, antidepressant drugs exert anti-inflammatory actions in rats. In this study we evaluated the effects of 3 different doses of chlomipramine (10, 20, and 40 mg/kg i.p), and fluoxetine (5.0, 10, and 20 mg/kg i.p.) on subcutaneous carrageenin-induced inflammation. Both drugs dose-dependently reduced the inflammatory exudate, as well as the PGE2-like bio- and immuno-activity in the exudate. Chlomipramine dose-dependently reduced substance P concentrations in the exudate, whereas fluoxetine was effective only at the highest dose. Our results confirm that antidepressant drugs are able to reduce the development of inflammation in the rat and suggest that the inhibition of substance P production might play a role in mediating the anti-inflammatory effects of chlomipramine.

The use of methadone for cancer pain

Methadone is not a new analgesic drug [69]. Several studies have demonstrated that methadone is a valid alternative to morphine, hydromorphone, and fentanyl for the treatment of cancer-related pain, and extensive reviews on the subject have been published in recent years [10,23,25,64,70,71]. Most people involved in pain therapy, however, are not well informed about the properties of methadone. The authors believe that the low cost of methadone paradoxically contributes to the limited knowledge of its characteristics and to the restricted therapeutic use of this drug. The low cost of methadone means there is little financial incentive for pharmaceutical companies to invest in research or to disseminate scientific information. Unfortunately, the lack of scientific information from pharmaceutical companies frequently results in a lack of knowledge on the part of physicians. Unless the existing approach changes, both culturally and politically, ignorance about methadone will persist among medical experts. The low cost of methadone, rather than being an advantage, will result in the limited exploitation of an effective drug.

Increased tumor necrosis factor-alpha and prostaglandin E2 concentrations in the cerebrospinal fluid of rats with inflammatory hyperalgesia: the effects of analgesic drugs.

BACKGROUND:We examined the changes in cerebrospinal fluid (CSF) concentrations of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) after intraplantar administration of complete Freund’s adjuvant (CFA) in rats. In addition, we investigated whether different analgesic drugs orally administered at antihyperalgesic doses were able to prevent the changes in PGE2 and TNF-α spinal levels associated with hindpaw inflammation. METHODS:The Randall–Selitto paw-withdrawal test was used to measure inflammatory hyperalgesia. Tramadol (7.5 mg/kg), paracetamol (65 mg/kg), tramadol plus paracetamol and nimesulide (5 mg/kg) were administered orally twice a day, starting from the first day after the CFA injection. PGE2 in the CSF was measured by enzyme immunoassay, and TNF-α by ELISA. Behavioral and biochemical parameters were measured on Day 7 after intraplantar injection of CFA or saline. RESULTS:Withdrawal thresholds to mechanical stimuli decreased markedly in the CFA-treated paw. In these animals the quantification of proinflammatory mediators in the CSF revealed a significant increase in both PGE2 and TNF-α concentrations. All the pharmacological treatments prevented the development of the hyperalgesia as well as the PGE2 increase in the CSF. Conversely, a prevention of the increase in TNF-α levels was observed only in rats treated with nimesulide or tramadol and paracetamol in combination. CONCLUSIONS:Our results demonstrate that peripheral inflammatory hyperalgesia is associated with significant changes of proinflammatory mediators in the CSF. It is important to note, however, that spinal PGE2 and TNF-α proved to be differently affected by pharmacological treatments able to fully abolish the hyperalgesia.