Sydor R. I., Lisnyy I. I., Stakhovsky E. A., Khranovska N. M., Skivka L. M.

CLINICAL AND EXPERIMENTAL MEDICINE

Scentific article

Adequate recovery after surgical procedure requires normal functionality of the patient’s immune system. Experimental and clinical studies have brought evidence that surgical trauma and other perioperative stress factors markedly affect the immune system, inhibiting cell-mediated response in the first place. Opioid drugs are often used for perioperative analgesia and cancer pain relief. However, opioids can depress the immune system, thus contributing to the perioperative immune suppression and potentially promoting cancer recurrence and metastasis. On the other hand, novel cyclooxigenase-2 (COX-2) inhibitors can promise an alternative to opioid drugs for cancer surgery analgesia. Aim: To investigate the influence of perioperative analgesia with COX-2 inhibitor parecoxib and opioid drug omnopon on some indices of cell-mediated immune response in renal cancer patients after surgical procedure. Materials and methods: After informed consent had been obtained, 38 patients with stage I-II renal cell carcinoma undergoing partial nephrectomy were prospectively allocated into 2 groups. Patients of the first group received opioid drug omnopon for perioperative analgesia (1 ml of 2% solution intramuscularly: 2 times before surgery and 4 times a day during 3 days for postsurgical pain relief), while patients of the second group received cyclooxigenase-2 inhibitor parecoxib (40 mg intramuscularly: 2 times before surgery and 2 times a day during 3 days for postsurgical pain relief). Quantity of peripheral blood lymphocyte populations (CD3+, CD4+, CD8+, CD16+ cells), CD3+IFNγ+ cells and cytotoxic activity of natural killer (NK) cells were assessed a day before surgery, at the end of the surgical procedure and 3 days after the surgery using flow cytometry methods. Results: It is known from in vitro studies that opioids can directly affect T cells via opioid receptors. In our study, absolute number of peripheral blood T lymphocytes (CD3+ cells) was lowered after the surgery, though there was no difference between two study groups. On the other hand, postoperative changes in IFN-γ synthesis by T-cells showed opposite tendencies in omnopon and parecoxib groups. Quantity of CD3+IFNγ+ cells in the omnopon group slightly decreased after the surgery, while in the parecocxib group postoperative quantity of these cells had a tendency to increase. Thus, the number of CD3+IFNγ+ cells on day 3 after the surgery was 2,2 times higher in patients received parecoxib compared to those received omnopon (p < 0,05). Relative quantity of NK cells (CD16+ cells) in the peripheral blood of patients who received omnopon significantly decreased from (20,5 ± 1,8)% to (13,0 ± 1,2)% on day 3 after the surgery, whereas their cytotoxic activity against K 562 tumor cell line was lowered 2,9 times (p < 0,05) in comparison with the preoperative level. At the same time, only insignificant decrease of postoperative NK cells relative quantity was observed in parecoxib group, while NK cell cytotoxic activity was lowered 1,8 times (p < 0,05) as compared to preoperative values. Taking to account, that NK cells doesn’t express opioid receptors, we could presume that the effect of omnopon on NK cells was mediаted by the neuro-humoral response or by the influence on immune cells which express opioid receptors. Conclusion: Perioperative analgesia with cyclooxygenase-2 inhibitor parecoxib results in less severe immunosuppression after the surgery as compared to analgesia with opioid drug omnopon. Thus, parecoxib in perspective could be used as an alternative to opioid analgesia in cancer surgery.

omnopon, parecoxib, immune system, renal cell carcinoma

• 1. Гриневич Ю. А. Новообразовательный процесс и стрессовая патология / Ю. А. Гриневич, В. А. Барабой. – Киев: Логос, 2010. — 155 с.
• 2. Feng Y. Current Research on Opioid Receptor Function / Y. Feng, X. He, Y. Yang et al. // Curr Drug Targets. – 2012. – Vol. 13, № 2. – P. 230-246.
• 3. Gutkin D. Clinical evaluation of systemic and local immune responses in cancer: time for integration / D. Gutkin, M. Shurin // Cancer Immunol Immunother. – 2014. – Vol. 13, № 1. – P. 45-57.
• 4. Jiang J. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection / J. Jiang, R. Dingledine // Trends Pharmacol Sci. – 2013. – Vol. 34, № 7. – P. 413-423.
• 5. Jin-Chun S. Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia / S. Jin-Chun, S. He-Liang, Z. Ming-Qiang [et al.] // Int J Clin Pharmacol Ther. – 2014. – Vol. 52, № 8. – P. 669-675.
• 6. Kaye A. Effect of Opiates, Anesthetic Techniques, and Other Perioperative Factors on Surgical Cancer Patients / A. Kaye, N. Patel, F. Bueno [et al.] // The Ochsner Journal. – 2014. – Vol. 14, № 8. – Р. 216-228.
• 7. Mizota T. Dual modulation of the T-cell receptor-activated signal transduction pathway by morphine in human T lymphocytes / T. Mizota, H. Tsujikawa, T. Shoda [et al.] // J Anesth. – 2013. – Vol. 27, № 1. – P. 80-87.
• 8. Narahara H. Comparative effects of flurbiprofen and fentanyl on natural killer cell cytotoxicity, lymphocyte subsets and cytokine concentrations in post-surgical intensive care unit patients: prospective, randomized study / H. Narahara, Y. Kadoi, H. Hinohara [et al.] // J Anesth. – 2013. – Vol. 27, № 5. – P. 676-683.
• 9. Nikovic J. Role of the mu opioid receptor in opioid modulation of immune function / J. Nikovic, S. Roy // Amino Acids. – 2013. – Vol. 45, № 1. – P. 9-24.
• 10. Porta C. Immunological stress in kidney cancer patients undergoing either open nephrectomy or nephron-sparing surgery: an immunophenotypic study of lymphocyte subpopulations and circulating dendritic cells / C. Porta, L. Bonomi, B. Lillaz [et al.] // Oncology Reports. – 2008. – Vol. 20, № 6. – P. 1511-1519.
• 11. Sacerdote P. Opioid-induced immunosuppression / P. Sacerdote // Curr Opin Support Palliat Care. – 2008. – Vol. 2, № 1. – Р. 14-18.
• 12. Saurer T. Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation / T. Saurer, S. Ijames, K. Carrigan [et al.] // Brain Behav Immun. – 2008. – Vol. 22, № 1. – P. 89-97.
• 13. Snyder G. Effect of anaesthetic technique and other perioperative factors on cancer recurrence / G. Snyder, S. Greenberg // British Journal of Anaesthesia. – 2010. – Vol. 105, № 2. – P. 106-115.
• 14. Tabellini G. Effects of opioid therapy on human natural killer cells / G. Tabellini, E. Borsani, M. Benassi [et al.] // International Immunopharmacology. – 2014. – Vol. 18, № 1. – Р. 169-174.
• 15. Tsujikawa H. Morphine induces DNA damage and P53 activation in CD3+ T cells / H. Tsujikawa, T. Mizota, T. Shoda [et al.] // Biochimica et Biophysica Acta. – 2009. – Vol. 1790, № 8. – Р. 793-799.

«Bulletin of problems biology and medicine» Issue 1 part 1 (126), 2016 year, 204-208 pages, index UDK 616-006/08:57.04