Advertisement

Wiener Medizinische Wochenschrift

, Volume 168, Issue 7–8, pp 159–167 | Cite as

Methadone as anticancer treatment: hype, hope, or hazard?

A series of case reports and a short review of the current literature and recommendations of the societies
  • Gudrun KreyeEmail author
  • Eva-Katharina Masel
  • Klaus Hackner
  • Beate Stich
  • Friedemann Nauck
main topic

Summary

Recently, the use of methadone in cancer patients has increased due to in vitro studies indicating that methadone is capable of inducing cell death. However, thus far there are no relevant clinical studies indicating that the use of methadone can prolong survival in cancer patients. Based on low-quality evidence, methadone is a drug that has similar analgesic benefits to morphine and has a role in the management of cancer pain in adults. Other opioids such as morphine, hydromorphone, and fentanyl are easier to manage but may be more expensive than methadone in many economies. Methadone is an opioid that is only approved for replacement therapy in Austria. Methadone can be used as a second- or third-line agent for severe cancer-related pain, but its use should be restricted to experts. Here we report a series of cases of patients who developed problems when using methadone as an antitumor treatment, with a brief review on the role of methadone as a pain medication and the current lack of value as an anti-tumor therapy. Methadone is not approved or recommended as an anticancer treatment in Austria or Germany. The Austrian Association for Hemato-oncology (OeGHO), the Austrian Association for the Management of Pain (ÖSG), and the Austrian Association for Palliative Care (OPG) do not recommend the use of methadone as an anticancer treatment. Thus, from a medical and ethical point of view, the use of methadone as an antitumor therapy is to be rejected, based on the views of various Austrian (OeGHO, ÖSG, OPG) and German specialists. Unqualified use of methadone by nonexperienced pain therapists is dangerous and must also be rejected.

Keywords

Methadone Anticancer treatment Tumor therapy Palliative 

Methadon als Antitumortherapie: Schwindel, Hoffnung oder Risiko?

Eine Serie von Kasuistiken und kurzer Überblick über aktuelle Literatur sowie Empfehlungen der Fachgesellschaften

Zusammenfassung

In letzter Zeit hat die Verwendung von Methadon bei Krebspatienten zugenommen, weil Daten zeigten, dass Methadon in vitro in der Lage ist, den Zelltod zu induzieren. Bisher gibt es jedoch keine relevanten klinischen Studien, die darauf hinweisen, dass die Verwendung von Methadon das Überleben bei Krebspatienten verlängern kann oder das Tumorwachstum zurückdrängt. Gemäß Nachweisen von geringer Qualität ist Methadon eine Substanz, die einen ähnlichen analgetischen Nutzen wie Morphin hat und zur Linderung von Tumorschmerzen bei Erwachsenen eingesetzt wird. Andere Opioide wie Morphin, Hydromorphon und Fentanyl sind leichter zu handhaben, aber möglicherweise in vielen Wirtschaftssystemen teurer als Methadon. Methadon ist ein Opioid, welches in Österreich lediglich zur Substitutionstherapie zugelassen ist. Von sehr erfahrenen Schmerztherapeuten kann es als Schmerzmittel eingesetzt werden, wenn die Wirkung anderer Opioide nicht ausreicht. Anbei ergänzen die Autoren eine Reihe von Fallberichten von Patienten, die unter erheblichen Nebenwirkungen von Methadon, welches bei ihnen als Antitumormittel eingesetzt wurde, mit einem kurzen Review über den Stellenwert von Methadon als Schmerzmittel und den derzeit nicht vorhandenen Stellenwert als Antitumortherapie. Methadon ist in Österreich oder Deutschland nicht als Antitumortherapie zugelassen oder empfohlen. Die Österreichische Gesellschaft für Hämatoonkologie, die Österreichische Gesellschaft für Schmerzbehandlung und die Österreichische Gesellschaft für Palliative Care sprechen sich gegen die Anwendung von Methadon als Antitumortherapie aus. Aus medizinischer und ethischer Sicht ist daher die Anwendung von Methadon als Antitumortherapie nach Ansicht verschiedener österreichischer (OeGHO, ÖSG, OPG) und deutscher Spezialisten abzulehnen. Die unqualifizierte Verwendung von Methadon durch unerfahrene Ärzte ist gefährlich und muss ebenfalls abgelehnt werden.

Schlüsselwörter

Methadon Anti-Krebs-Behandlung Tumortherapie Palliativ 

Notes

Conflict of interest

G. Kreye, E.-K. Masel, K. Hackner, B. Stich, and F. Nauck declare that they have no competing interests.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

References

  1. 1.
    Foley KM. The treatment of cancer pain. N Engl J Med. 1985;313(2):84–95.CrossRefPubMedGoogle Scholar
  2. 2.
    Hanks GW, Conno F, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001;84(5):587–93.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Radbruch L, Nauck F. Morphin und andere Opioide in der Tumorschmerztherapie. Die Empfehlungen der EAPC. Schmerz. 2002;16:186–93.CrossRefPubMedGoogle Scholar
  4. 4.
    Cherny N, Ripamonti C, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19(9):2542–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Weschules DJ, et al. Pain Med. 2008;9(5):595–612.CrossRefPubMedGoogle Scholar
  6. 6.
    Cherny NJ, Chang V, et al. Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration. Cancer. 1995;76(7):1283–93.CrossRefPubMedGoogle Scholar
  7. 7.
    World Health Organization. WHO model list of essential medicines. 15th ed. 2007. http://www.who.int/medicines/publications/08_ENGLISH_indexFINAL_EML15.pdf.Google Scholar
  8. 8.
    Roth HJ. Arzneistoffe. Stuttgart: Deutscher Apotheker Verlag; 2000.Google Scholar
  9. 9.
    Kristensen K, Christensen CB, et al. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):PL45–PL50.CrossRefPubMedGoogle Scholar
  10. 10.
    Raynor K, Kong H, et al. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol. 1994;45(2):330–4.PubMedGoogle Scholar
  11. 11.
    Codd EE, Shank RP, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274(3):1263–70.PubMedGoogle Scholar
  12. 12.
    Rostami-Hodjegan A, Wolff K, et al. Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes. Br J Clin Pharmacol. 1999;48(1):43–52.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sawe J. High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet. 1986;11(2):87–106.CrossRefPubMedGoogle Scholar
  14. 14.
    Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613–24.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fainsinger R, Schoeller T, et al. Methadone in the management of cancer pain: a review. Pain. 1993;52(2):137–47.CrossRefPubMedGoogle Scholar
  16. 16.
    Weschules DJ, et al. Actual and potential drug interactions associated with methadone. Pain Med. 2008;9(3):315–44.CrossRefPubMedGoogle Scholar
  17. 17.
    Lotsch J, Skarke C, et al. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet. 2004;43(14):983–1013.CrossRefPubMedGoogle Scholar
  18. 18.
    Lotsch J, Skarke C, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther. 2006;79(1):72–89.CrossRefPubMedGoogle Scholar
  19. 19.
    Nicholson AB, et al. Methadone for cancer pain. Cochrane Database Syst Rev. 2017; 2.  https://doi.org/10.1002/14651858.CD003971.pub31.PubMedCrossRefGoogle Scholar
  20. 20.
    Weschules DJ, Bain KT. A systematic review of opioid conversion ratios used with methadone for the treatment of pain. Pain Med. 2008;9(5):595–612.CrossRefPubMedGoogle Scholar
  21. 21.
    Nauck F, Ostgathe C, et al. A German model for methadone conversion. Am J Hosp Palliat Care. 2001;18(3):200–2.CrossRefPubMedGoogle Scholar
  22. 22.
    Hofbauer H, Schenk M, et al. Schmerz. 2017;31:2–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Friesen C, Hormann I, et al. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle. 2014;13:1560–70.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Friesen C, Roscher M, et al. Cell death sensitization of leukemia cells by opioid receptor activation. Oncotarget. 2013;4(5):677–90.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bundscherer A, Malsy M, et al. Effects of ropivacaine, bupivacaine and sufentanil in colon and pancreatic cancer cells in vitro. Pharmacol Res. 2015;95–96:126–31.CrossRefPubMedGoogle Scholar
  26. 26.
    Harimaya Y, Koizumi K, et al. 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
  27. 27.
    Malsy M, Gebhardt K, et al. Effects of ketamine, s‑ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells. BMC Anesth. 2015;15:111.CrossRefGoogle Scholar
  28. 28.
    Sacerdote P, Bianchi M, et al. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg. 2000;90:1411–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Shavit Y, Ben-Eliyahu S, et al. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation. 2004;1:255–60.CrossRefGoogle Scholar
  30. 30.
    Tegeder I, Grosch S, et al. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res. 2003;63:1846–52.PubMedGoogle Scholar
  31. 31.
    Onken C, Friesen C, et al. Safety and tolerance of D.L-methadone in combination with chemotherapy in patients with glioma. Anticancer Res. 2017;37(3):1227–36.CrossRefPubMedGoogle Scholar
  32. 32.
    Salpeter SR, Buckley JS, et al. The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia. J Pall Med. 2013;16(6):616–22.CrossRefGoogle Scholar
  33. 33.
    Alinejad S, Kazemi T, et al. A systematic review of the cardiotoxicity of methadone. EXCLI J. 2015;14:577–600.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Anghelescu DL, Patel RM, et al. Methadone prolongs cardiac conduction in young patients with cancer-related pain. J Opioid Manag. 2016;12:131–8.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Minkowitz HS, Scranton R, et al. Development and validation of a risk score to identify patients at high risk for opioid-related adverse drug events. J Manag Care Spec Pharm. 2014;20:948–58.PubMedGoogle Scholar
  36. 36.
    Christian K. Off-label use” von Arzneimitteln. In: Ennöckl D, Raschauer N, et al., editors. Über Struktur und Vielfalt im öffentlichen Recht. Vienna: Springer; 2008.Google Scholar
  37. 37.
  38. 38.
  39. 39.
  40. 40.
    Ostgathe C, et al. Practicability, safety, and efficacy of a “German model” for opioid conversion to oral levo-methadone. Support Care Cancer. 2012;20(9):2105–10.  https://doi.org/10.1007/s00520-011-1320-8.CrossRefPubMedGoogle Scholar
  41. 41.
    McLean S, Tworney F. Methods of rotation from another strong opioid to methadone for the management of cancer pain: a systematic review of the available evidence. J Pain Symptom Manage. 2015;50(2):248–59.  https://doi.org/10.1016/j.jpainsymman.2015.02.029.CrossRefPubMedGoogle Scholar
  42. 42.
    Rennick A, et al. Variability in opioid equivalence calculations. Pain Med. 2015;  https://doi.org/10.1111/pme.12920.PubMedCrossRefGoogle Scholar
  43. 43.
    Fürst P, et al. Improved pain control in terminally ill cancer patients by introducing low-dose oral methadone in addition to ongoing opioid treatment. J Palliat Med. 2017;  https://doi.org/10.1089/jpm.2017.0157.CrossRefPubMedGoogle Scholar
  44. 44.
    Krebs EE, Becker WC, et al. Comparative mortality among department of veterans affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain. 2011;152:1789–95.CrossRefPubMedGoogle Scholar
  45. 45.
    Reddy A, et al. Overall survival among cancer patients undergoing opioid rotation to methadone compared to other opioids. J Palliat Med. 2017;20(6):656–61.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2018

Authors and Affiliations

  • Gudrun Kreye
    • 1
    Email author
  • Eva-Katharina Masel
    • 2
  • Klaus Hackner
    • 3
  • Beate Stich
    • 1
  • Friedemann Nauck
    • 4
  1. 1.Division of Palliative Care, Department of Internal Medicine 2, University HospitalKarl Landsteiner University of Health SciencesKrems an der DonauAustria
  2. 2.Division of Palliative Care, Department of Internal Medicine IMedical University of ViennaViennaAustria
  3. 3.Department of Pneumonology, Krems University Hospital, Krems, Austria.Karl Landsteiner University of Health SciencesKremsAustria
  4. 4.Abteilung PalliativmedizinUniversitätsmedizin GöttingenGöttingenGermany

Personalised recommendations