Clinical and Translational Oncology

, Volume 20, Issue 7, pp 808–814 | Cite as

Morphine: double-faced roles in the regulation of tumor development

  • XY. Zhang
  • YX. Liang
  • Y. Yan
  • Z. Dai
  • HC. Chu
Review Article


Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.


Morphine Tumor Apoptosis Metastasis Angiogenesis Immunosuppression 



The authors would like to thank to Professor Chu and Professor Liang for the instructions to this review.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Schmitz R. Friedrich Wilhelm Serturner and the discovery of morphine. Pharm Hist. 1985;27(2):61–74.PubMedGoogle Scholar
  2. 2.
    Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol. 1993;16(1):1–18.CrossRefPubMedGoogle Scholar
  3. 3.
    Sueoka N, Sueoka E, Okabe S, Fujiki H. Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression. Carcinogenesis. 1996;17(11):2337–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Maneckjee R, Minna JD. Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ. 1994;5(10):1033–40.PubMedGoogle Scholar
  5. 5.
    Pasi A, Qu BX, Steiner R, Senn HJ, Bar W, Messiha FS. Angiogenesis: modulation with opioids. Gen Pharmacol. 1991;22(6):1077–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Hatzoglou A, Bakogeorgou E, Papakonstanti E, Stournaras C, Emmanouel DS, Castanas E. Identification and characterization of opioid and somatostatin binding sites in the opossum kidney (OK) cell line and their effect on growth. J Cell Biochem. 1996;63(4):410–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Hatzoglou A, Ouafik L, Bakogeorgou E, Thermos K, Castanas E. Morphine cross-reacts with somatostatin receptor SSTR2 in the T47D human breast cancer cell line and decreases cell growth. Cancer Res. 1995;55(23):5632–6.PubMedGoogle Scholar
  8. 8.
    Maneckjee R, Biswas R, Vonderhaar BK. Binding of opioids to human MCF-7 breast cancer cells and their effects on growth. Cancer Res. 1990;50(8):2234–8.PubMedGoogle Scholar
  9. 9.
    Kampa M, Bakogeorgou E, Hatzoglou A, Damianaki A, Martin PM, Castanas E. Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors. Eur J Pharmacol. 1997;335(2–3):255–65.CrossRefPubMedGoogle Scholar
  10. 10.
    Tegeder I, Grosch S, Schmidtko A, Haussler A, Schmidt H, Niederberger E, et al. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res. 2003;63(8):1846–52.PubMedGoogle Scholar
  11. 11.
    Yeager MP, Colacchio TA. Effect of morphine on growth of metastatic colon cancer in vivo. Arch Surg (Chicago, Ill: 1960). 1991;126(4):454–6.CrossRefGoogle Scholar
  12. 12.
    Sasamura T, Nakamura S, Iida Y, Fujii H, Murata J, Saiki I, et al. Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. Eur J Pharmacol. 2002;441(3):185–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, Saiki I. Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells. Cancer Lett. 2002;187(1–2):121–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Hatzoglou A, Bakogeorgou E, Castanas E. The antiproliferative effect of opioid receptor agonists on the T47D human breast cancer cell line, is partially mediated through opioid receptors. Eur J Pharmacol. 1996;296(2):199–207.CrossRefPubMedGoogle Scholar
  15. 15.
    Mathew B, Lennon FE, Siegler J, Gerhold L, Mambetsariev N, Moreno-Vinasco L, et al. Abstract C78: The mu opioid receptor regulates Lewis lung carcinoma tumor growth and metastasis. Mol Cancer Ther. 2009;8(12 Supplement):C78.CrossRefGoogle Scholar
  16. 16.
    Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Zagon IS, McLaughlin PJ. Opioids and the apoptotic pathway in human cancer cells. Neuropeptides. 2003;37(2):79–88.CrossRefPubMedGoogle Scholar
  18. 18.
    Lin X, Wang YJ, Li Q, Hou YY, Hong MH, Cao YL, et al. Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J. 2009;276(7):2022–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Hatsukari I, Hitosugi N, Ohno R, Hashimoto K, Nakamura S, Satoh K, et al. Induction of apoptosis by morphine in human tumor cell lines in vitro. Anticancer Res. 2007;27(2):857–64.PubMedGoogle Scholar
  20. 20.
    Fernández-Checa JC, Garcia-Ruiz C. Apoptosis and mitochondria. Berlin: Springer; 2005.CrossRefGoogle Scholar
  21. 21.
    Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999;11(2):255–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Yin D, Woodruff M, Zhang Y, Whaley S, Miao J, Ferslew K, et al. Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways. J Neuroimmunol. 2006;174(1–2):101–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Zhao M, Zhou G, Zhang Y, Chen T, Sun X, Stuart C, et al. beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways. Neoplasma. 2009;56(2):108–13.CrossRefPubMedGoogle Scholar
  24. 24.
    Cadet P, Rasmussen M, Zhu W, Tonnesen E, Mantione KJ, Stefano GB. Endogenous morphinergic signaling and tumor growth. Front Biosci. 2004;9:3176–86.CrossRefPubMedGoogle Scholar
  25. 25.
    Crawford KW, Coop A, Bowen WD. Sigma(2) receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol. 2002;443(1–3):207–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Diao CT, Li L, Lau SY, Wong TM, Wong NS. kappa-opioid receptor potentiates apoptosis via a phospholipase C pathway in the CNE2 human epithelial tumor cell line. Biochem Biophys Acta. 2000;1499(1–2):49–62.CrossRefPubMedGoogle Scholar
  27. 27.
    Cao LH, Li HT, Lin WQ, Tan HY, Xie L, Zhong ZJ, et al. Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts. Sci Rep. 2016;6:18706.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Karaman H, Tufek A, Karaman E, Tokgoz O. Opioids inhibit angiogenesis in a chorioallantoic membrane model. Pain Physician. 2017;20(2s):Se11–21.PubMedGoogle Scholar
  29. 29.
    Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87(7):1153–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Brekken RA, Thorpe PE. Vascular endothelial growth factor and vascular targeting of solid tumors. Anticancer Res. 2001;21(6b):4221–9.PubMedGoogle Scholar
  31. 31.
    Balasubramanian S, Ramakrishnan S, Charboneau R, Wang J, Barke RA, Roy S. Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. J Mol Cell Cardiol. 2001;33(12):2179–87.CrossRefPubMedGoogle Scholar
  32. 32.
    Koodie L, Ramakrishnan S, Roy S. Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway. Am J Pathol. 2010;177(2):984–97.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Martin JL, Charboneau R, Barke RA, Roy S. Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing. Cell Immunol. 2010;265(2):139–45.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Duffy MJ, Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin Biochem. 2004;37(7):541–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Mignatti P, Rifkin DB. Nonenzymatic interactions between proteinases and the cell surface: novel roles in normal and malignant cell physiology. Adv Cancer Res. 2000;78:103–57.CrossRefPubMedGoogle Scholar
  36. 36.
    Jespersen C, Doller A, el Akool S, Bachmann M, Muller R, Gutwein P, et al. Molecular mechanisms of nitric oxide-dependent inhibition of TPA-induced matrix metalloproteinase-9 (MMP-9) in MCF-7 cells. J Cell Physiol. 2009;219(2):276–87.CrossRefPubMedGoogle Scholar
  37. 37.
    Lynch CC, Matrisian LM. Matrix metalloproteinases in tumor-host cell communication. Differentiation. 2002;70(9–10):561–73.CrossRefPubMedGoogle Scholar
  38. 38.
    Gach K, Szemraj J, Wyrebska A, Janecka A. The influence of opioids on matrix metalloproteinase-2 and -9 secretion and mRNA levels in MCF-7 breast cancer cell line. Mol Biol Rep. 2011;38(2):1231–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Min TJ, Park SH, Ji YH, Lee YS, Kim TW, Kim JH, et al. Morphine attenuates endothelial cell adhesion molecules induced by the supernatant of LPS-stimulated colon cancer cells. J Korean Med Sci. 2011;26(6):747–52.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Boettger MK, Weber K, Gajda M, Brauer R, Schaible HG. Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis. Brain Behav Immun. 2010;24(3):474–85.CrossRefPubMedGoogle Scholar
  42. 42.
    Hua S, Cabot PJ. Mechanisms of peripheral immune-cell-mediated analgesia in inflammation: clinical and therapeutic implications. Trends Pharmacol Sci. 2010;31(9):427–33.CrossRefPubMedGoogle Scholar
  43. 43.
    Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schafer M, Loeffler JP, et al. Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. J Clin Investig. 1997;100(1):142–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Finley MJ, Happel CM, Kaminsky DE, Rogers TJ. Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression. Cell Immunol. 2008;252(1–2):146–54.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Buga GM, Wei LH, Bauer PM, Fukuto JM, Ignarro LJ. NG-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms. Am J Physiol. 1998;275(4 Pt 2):R1256–64.PubMedGoogle Scholar
  46. 46.
    Mottaz H, Schonenberger R, Fischer S, Eggen RI, Schirmer K, Groh KJ. Dose-dependent effects of morphine on lipopolysaccharide (LPS)-induced inflammation, and involvement of multixenobiotic resistance (MXR) transporters in LPS efflux in teleost fish. Environ Pollut (Barking, Essex: 1987). 2017;221:105–15.CrossRefGoogle Scholar
  47. 47.
    Sergeeva MG, Grishina ZV, Varfolomeyev SD. Morphine effect on proliferation of normal and tumor cells of immune origin. Immunol Lett. 1993;36(2):215–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002;62(15):4491–8.PubMedGoogle Scholar
  49. 49.
    Lazarczyk M, Matyja E, Lipkowski AW. A comparative study of morphine stimulation and biphalin inhibition of human glioblastoma T98G cell proliferation in vitro. Peptides. 2010;31(8):1606–12.CrossRefPubMedGoogle Scholar
  50. 50.
    Zong J, Pollack GM. Morphine antinociception is enhanced in mdr1a gene-deficient mice. Pharm Res. 2000;17(6):749–53.CrossRefPubMedGoogle Scholar
  51. 51.
    Trapaidze N, Gomes I, Cvejic S, Bansinath M, Devi LA. Opioid receptor endocytosis and activation of MAP kinase pathway. Brain Res Mol Brain Res. 2000;76(2):220–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Lin X, Li Q, Wang YJ, Ju YW, Chi ZQ, Wang MW, et al. Morphine inhibits doxorubicin-induced reactive oxygen species generation and nuclear factor kappaB transcriptional activation in neuroblastoma SH-SY5Y cells. Biochem J. 2007;406(2):215–21.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Iglesias M, Segura MF, Comella JX, Olmos G. Mu-opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. Neuropharmacology. 2003;44(4):482–92.CrossRefPubMedGoogle Scholar
  54. 54.
    Ma Y, Ren Z, Ma S, Yan W, He M, Wang D, et al. Morphine enhances renal cell carcinoma aggressiveness through promotes survivin level. Ren Fail. 2017;39(1):258–64.CrossRefPubMedGoogle Scholar
  55. 55.
    Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007;97(11):1523–31.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Singleton PA, Moss J. Effect of perioperative opioids on cancer recurrence: a hypothesis. Future Oncol (London, England). 2010;6(8):1237–42.CrossRefGoogle Scholar
  57. 57.
    Radisavljevic Z, Avraham H, Avraham S. Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/Nitric oxide pathway and modulates migration of brain microvascular endothelial cells. J Biol Chem. 2000;275(27):20770–4.CrossRefPubMedGoogle Scholar
  58. 58.
    Kevil CG, Orr AW, Langston W, Mickett K, Murphy-Ullrich J, Patel RP, et al. Intercellular adhesion molecule-1 (ICAM-1) regulates endothelial cell motility through a nitric oxide-dependent pathway. J Biol Chem. 2004;279(18):19230–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Wu Y, Ip JE, Huang J, Zhang L, Matsushita K, Liew CC, et al. Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circ Res. 2006;99(3):315–22.CrossRefPubMedGoogle Scholar
  60. 60.
    Nair MPN, Mahajan SD, Reynolds JL. Opiates upregulate adhesion molecule expression in brain microvascular endothelial cells (BMVEC): implications for altered blood brain barrier (BBB) permeability. Am J Infect Dis. 2006;2(2):58–66.CrossRefGoogle Scholar
  61. 61.
    Leo S, Nuydens R, Meert TF. Opioid-induced proliferation of vascular endothelial cells. J Pain Res. 2009;2:59–66.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Shapiro RL, Duquette JG, Roses DF, Nunes I, Harris MN, Kamino H, et al. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res. 1996;56(15):3597–604.PubMedGoogle Scholar
  63. 63.
    Nylund G, Pettersson A, Bengtsson C, Khorram-Manesh A, Nordgren S, Delbro DS. Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci. 2008;53(2):461–6.CrossRefPubMedGoogle Scholar
  64. 64.
    Gach K, Szemraj J, Fichna J, Piestrzeniewicz M, Delbro DS, Janecka A. The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line. Chem Biol Drug Des. 2009;74(4):390–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Liu S, Qi L, Yu Q, Song Y, Han W, Zu X, et al. Survivin and HLA-I expression predicts survival of patients with clear cell renal cell carcinoma. Tumour Biol. 2014;35(8):8281–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Chen X, Chen XG, Hu X, Song T, Ou X, Zhang C, et al. MiR-34a and miR-203 inhibit survivin expression to control cell proliferation and survival in human osteosarcoma cells. J Cancer. 2016;7(9):1057–65.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7(5):651–8.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–11.CrossRefPubMedGoogle Scholar
  69. 69.
    Borner C, Stumm R, Hollt V, Kraus J. Comparative analysis of mu-opioid receptor expression in immune and neuronal cells. J Neuroimmunol. 2007;188(1–2):56–63.CrossRefPubMedGoogle Scholar
  70. 70.
    Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004;11(5):354–65.CrossRefPubMedGoogle Scholar
  71. 71.
    Wei G, Moss J, Yuan CS. Opioid-induced immunosuppression: is it centrally mediated or peripherally mediated? Biochem Pharmacol. 2003;65(11):1761–6.CrossRefPubMedGoogle Scholar
  72. 72.
    McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend. 2001;62(2):111–23.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Du JY, Liang Y, Fang JF, Jiang YL, Shao XM, He XF, et al. Effect of systemic injection of heterogenous and homogenous opioids on peripheral cellular immune response in rats with bone cancer pain: a comparative study. Exp Ther Med. 2016;12(4):2568–76.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Department of AnesthesiologyQingdao University Medical CollegeQingdaoChina
  2. 2.Department of AnesthesiologyAffiliated Hospital of Medical College Qingdao UniversityQingdaoChina

Personalised recommendations