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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 11, pp 1169–1178 | Cite as

Morphine as a treatment of cancer-induced pain—is it safe? A review of in vivo studies and mechanisms

  • David Brinkman
  • Jiang H. Wang
  • Henry P. Redmond
Review
  • 112 Downloads

Abstract

Morphine has been used in the treatment of pain for centuries. It is commonly used by oncology in terminal cancer cases and by surgery perioperatively for oncology surgery. Its extra-analgesic effects on cancer have been described extensively but conflicting results abound. It has been shown to have varying effects on tumour progression, cell proliferation, tumour invasion, angiogenesis, immune function, and metastatic potential. In vivo studies on the effects of morphine and the mu-opioid receptor on tumours are discussed below. Mechanisms involved are also discussed, drawn from a combination of both in vivo and in vitro methods. At present, no consensus can be drawn from data collected, and further studies are necessary to elicit the safest method and agent for analgesia in oncology patients.

Keywords

Morphine In vivo Cancer Mu-opioid receptor 

Notes

Author contribution

DB conceived, researched, and wrote the manuscript. All authors read and approved the manuscript.

References

  1. Afsharimani B, Baran J, Watanabe S, Lindner D, Cabot PJ, Parat MO (2014) Morphine and breast tumor metastasis: the role of matrix-degrading enzymes. Clin Exp Metastasis 31:149–158.  https://doi.org/10.1007/s10585-013-9616-3 CrossRefPubMedGoogle Scholar
  2. Balasubramanian S, Ramakrishnan S, Charboneau R, Wang J, Barke RA, Roy S (2001) Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. J Mol Cell Cardiol 33:2179–2187.  https://doi.org/10.1006/jmcc.2001.1480 CrossRefPubMedGoogle Scholar
  3. Belcheva MM, Szùcs M, Wang D, Sadee W, Coscia CJ (2001) μ-Opioid receptor-mediated ERK activation involves calmodulin-dependent epidermal growth factor receptor transactivation. J Biol Chem 276:33847–33853.  https://doi.org/10.1074/jbc.M101535200 CrossRefPubMedGoogle Scholar
  4. Bjelland TW, Klepstad P, Haugen BO, Nilsen T, Dale O (2013) Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Drug Metab Dispos 41:214–223.  https://doi.org/10.1124/dmd.112.045567 CrossRefPubMedGoogle Scholar
  5. Boehncke S, Hardt K, Schadendorf D, Henschler R, Boehncke W-H, Duthey B (2011) Endogenous μ-opioid peptides modulate immune response towards malignant melanoma. Exp Dermatol 20:24–28.  https://doi.org/10.1111/j.1600-0625.2010.01158.x CrossRefPubMedGoogle Scholar
  6. Buchanan FG, Wang D, Bargiacchi F, DuBois RN (2003) Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 278:35451–35457.  https://doi.org/10.1074/jbc.M302474200 CrossRefPubMedGoogle Scholar
  7. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257.  https://doi.org/10.1038/35025220 CrossRefPubMedGoogle Scholar
  8. Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T (2004) Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A 101:591–596.  https://doi.org/10.1073/pnas.2535911100 CrossRefPubMedGoogle Scholar
  9. Chen C, Farooqui M, Gupta K (2006) Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. Curr Neurovasc Res 3:171–180CrossRefGoogle Scholar
  10. Cheng W-F, Chen LK, Chen CA, Chang MC, Hsiao PN, Su YN, Lee CN, Jeng HJ, Hsieh CY, Sun WZ (2006) Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis. Mol Ther 13:203–210CrossRefGoogle Scholar
  11. Cronin-Fenton DP et al (2015) Opioids and breast cancer recurrence: a Danish population-based cohort study. Cancer 121:3507–3514.  https://doi.org/10.1002/cncr.29532 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605CrossRefGoogle Scholar
  13. Doornebal CW, Vrijland K, Hau CS, Coffelt SB, Ciampricotti M, Jonkers J, de Visser KE, Hollmann MW (2015) Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2(+) breast cancer. Pain 156:1424–1432.  https://doi.org/10.1097/j.pain.0000000000000136 CrossRefPubMedGoogle Scholar
  14. Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K (2007) COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer 97:1523–1531.  https://doi.org/10.1038/sj.bjc.6604057 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Fulton D et al (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601CrossRefGoogle Scholar
  16. Gach K, Szemraj J, Fichna J, Piestrzeniewicz M, Delbro DS, Janecka A (2009) The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line. Chem Biol Drug Des 74:390–396.  https://doi.org/10.1111/j.1747-0285.2009.00875.x CrossRefPubMedGoogle Scholar
  17. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62:4491–4498PubMedGoogle Scholar
  18. Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, Saiki I (2002) Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells. Cancer Lett 187:121–127CrossRefGoogle Scholar
  19. Hatsukari I, Hitosugi N, Matsumoto I, Nagasaka H, Sakagami H (2003) Induction of early apoptosis marker by morphine in human lung and breast carcinoma cell lines. Anticancer Res 23:2413–2417PubMedGoogle Scholar
  20. Hatsukari I, Hitosugi N, Ohno R, Hashimoto K, Nakamura S, Satoh K, Nagasaka H, Matsumoto I, Sakagami H (2007) Induction of apoptosis by morphine in human tumor cell lines in vitro. Anticancer Res 27:857–864PubMedGoogle Scholar
  21. Heaney Á, Buggy DJ (2012) Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? BJA: British J Anaesthesia 109:i17–i28CrossRefGoogle Scholar
  22. Hsiao PN, Chang MC, Cheng WF, Chen CA, Lin HW, Hsieh CY, Sun WZ (2009) Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology 256:83–91.  https://doi.org/10.1016/j.tox.2008.11.015 CrossRefPubMedGoogle Scholar
  23. Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR (2010) Evidence that opioids may have toll like receptor 4 and MD-2 effects. Brain Behav Immun 24:83–95.  https://doi.org/10.1016/j.bbi.2009.08.004 CrossRefPubMedGoogle Scholar
  24. Iglesias M, Segura MF, Comella JX, Olmos G (2003) Mu-opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. Neuropharmacology 44:482–492CrossRefGoogle Scholar
  25. Ishikawa M, Tanno K, Kamo A, Takayanagi Y, Sasaki K (1993) Enhancement of tumor growth by morphine and its possible mechanism in mice. Biol Pharm Bull 16:762–766CrossRefGoogle Scholar
  26. Iwamoto K, Klaassen CD (1977) First-pass effect of morphine in rats. J Pharmacol Exp Ther 200:236–244PubMedGoogle Scholar
  27. Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM (2007) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 323:346–355.  https://doi.org/10.1124/jpet.107.119560 CrossRefPubMedGoogle Scholar
  28. Kam AY, Chan AS, Wong YH (2004) Phosphatidylinositol-3 kinase is distinctively required for mu-, but not kappa-opioid receptor-induced activation of c-Jun N-terminal kinase. J Neurochem 89:391–402.  https://doi.org/10.1111/j.1471-4159.2004.02338.x CrossRefPubMedGoogle Scholar
  29. Khabbazi S, Goumon Y, Parat M-O (2015) Morphine modulates Interleukin-4- or breast cancer cell-induced pro-metastatic activation of macrophages. Sci Rep 5:11389.  https://doi.org/10.1038/srep11389 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kim MS et al (2001) Protective effects of morphine in peroxynitrite-induced apoptosis of primary rat neonatal astrocytes: potential involvement of G protein and phosphatidylinositol 3-kinase (PI3 kinase). Biochem Pharmacol 61:779–786CrossRefGoogle Scholar
  31. Koodie L, Ramakrishnan S, Roy S (2010) Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway. Am J Pathol 177:984–997.  https://doi.org/10.2353/ajpath.2010.090621 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Koodie L, Yuan H, Pumper JA, Yu H, Charboneau R, Ramkrishnan S, Roy S (2014) Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol 184:1073–1084.  https://doi.org/10.1016/j.ajpath.2013.12.019 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lam CF et al (2008) Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesth Analg 107:686–692.  https://doi.org/10.1213/ane.0b013e31817e6719 CrossRefPubMedGoogle Scholar
  34. Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA (2012) Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology 116:857–867.  https://doi.org/10.1097/ALN.0b013e31824babe2 CrossRefPubMedGoogle Scholar
  35. Lin X et al (2009) Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J 276:2022–2036.  https://doi.org/10.1111/j.1742-4658.2009.06938.x CrossRefPubMedGoogle Scholar
  36. Luk K, Boatman S, Johnson KN, Dudek OA, Ristau N, Vang D, Nguyen J, Gupta K (2012) Influence of morphine on pericyte-endothelial interaction: implications for antiangiogenic therapy. J Oncology 2012:1–10.  https://doi.org/10.1155/2012/458385 CrossRefGoogle Scholar
  37. Mathew B et al (2011) The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 112:558–567.  https://doi.org/10.1213/ANE.0b013e31820568af CrossRefPubMedGoogle Scholar
  38. Nguyen J, Luk K, Vang D, Soto W, Vincent L, Robiner S, Saavedra R, Li Y, Gupta P, Gupta K (2014) Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. BJA: British J Anaesthesia 113:i4–i13.  https://doi.org/10.1093/bja/aeu090 CrossRefGoogle Scholar
  39. Ovtcharov R, Mircheva Y, Yakimova K, Stoichkov Y (1987) Changes in the antitumour effect of some cytostatic agents applied under conditions of morphine-induced hyperthermia. Acta Physiol Pharmacol Bulg 13:55–59PubMedGoogle Scholar
  40. Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC (1993) Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 54:21–28CrossRefGoogle Scholar
  41. Polakiewicz RD, Schieferl SM, Gingras A-C, Sonenberg N, Comb MJ (1998) μ-Opioid receptor activates signaling pathways implicated in cell survival and translational control. J Biol Chem 273:23534–23541.  https://doi.org/10.1074/jbc.273.36.23534 CrossRefPubMedGoogle Scholar
  42. Poonawala T, Levay-Young BK, Hebbel RP, Gupta K (2005) Opioids heal ischemic wounds in the rat. Wound Repair Regen 13:165–174.  https://doi.org/10.1111/j.1067-1927.2005.130207.x CrossRefPubMedGoogle Scholar
  43. Salem A, Hope W (1997) Role of morphine glucuronide metabolites in morphine dependence in the rat. Pharmacol Biochem Behav 57:801–807CrossRefGoogle Scholar
  44. Sasamura T et al (2002) Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. Eur J Pharmacol 441:185–191CrossRefGoogle Scholar
  45. Schafer B, Gschwind A, Ullrich A (2004) Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. Oncogene 23:991–999.  https://doi.org/10.1038/sj.onc.1207278 CrossRefPubMedGoogle Scholar
  46. Shariftabrizi A et al (2006) Matrix metalloproteinase 2 secretion in WEHI 164 fibrosarcoma cells is nitric oxide-related and modified by morphine. Eur J Pharmacol 530:33–39.  https://doi.org/10.1016/j.ejphar.2005.11.043 CrossRefPubMedGoogle Scholar
  47. Shoda T, Fukuda K, Uga H, Mima H, Morikawa H (2001) Activation of mu-opioid receptor induces expression of c-fos and junB via mitogen-activated protein kinase cascade. Anesthesiology 95:983–989CrossRefGoogle Scholar
  48. Simon RH, Arbo TE (1986) Morphine increases metastatic tumor growth. Brain Res Bull 16:363–367 doi:0361-9230(86)90057-2CrossRefGoogle Scholar
  49. Singhal P, Kapasi A, Reddy K, Franki N (2001) Opiates promote T cell apoptosis through JNK and caspase pathway. Adv Exp Med Biol 493:127–135.  https://doi.org/10.1007/0-306-47611-8_15 CrossRefPubMedGoogle Scholar
  50. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J (2006) Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res 72:3–11.  https://doi.org/10.1016/j.mvr.2006.04.004 CrossRefPubMedGoogle Scholar
  51. Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG (2007) Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231.  https://doi.org/10.1165/rcmb.2006-0327OC CrossRefPubMedGoogle Scholar
  52. Sueoka E et al (1998) Anticancer activity of morphine and its synthetic derivative, KT-90, mediated through apoptosis and inhibition of NF-kappaB activation. Biochem Biophys Res Commun 252:566–570.  https://doi.org/10.1006/bbrc.1998.9695 CrossRefPubMedGoogle Scholar
  53. Tegeder I, Grösch S, Schmidtko A, Häussler A, Schmidt H, Niederberger E, Scholich K, Geisslinger G (2003) G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res 63:1846–1852PubMedGoogle Scholar
  54. Ustun F, Durmus-Altun G, Altaner S, Tuncbilek N, Uzal C, Berkarda S (2011) Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC. Med Oncol 28:1264–1272.  https://doi.org/10.1007/s12032-010-9573-5 CrossRefPubMedGoogle Scholar
  55. Wang CZ et al (2009) Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells. Anticancer Res 29:2927–2932PubMedGoogle Scholar
  56. Yeager MP, Colacchio TA (1991) Effect of morphine on growth of metastatic colon cancer in vivo. Arch Surg 126:454–456CrossRefGoogle Scholar
  57. Yin D, Mufson RA, Wang R, Shi Y (1999) Fas-mediated cell death promoted by opioids. Nature 397:218–218CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Academic SurgeryCork University HospitalCorkIreland
  2. 2.University College CorkCorkIreland

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