Safety aspects of opioid-naïve patients with high-grade glioma treated with D,L-Methadone: an observational case series

Abstract

It was suggested that D, L-Methadone might improve the clinical course of glioma patients. Owing to massive press coverage, patients demand the prescription of D, L-Methadone, but regarding its adjunctive use in glioma therapy there is no standard medication plan. Furthermore, it is not known which side effects the administration of D, L-Methadone might harbor, especially if the patients are opioid-naïve and if D, L-Methadone therapy was managed by the patients themselves or their general practitioners. Opioid-naïve patients with high-grade glioma (new diagnosis or recurrent) receiving D, L-Methadone were included in this retrospective observational analysis. Side effects were assigned if the condition deteriorated in conjunction with the initiation of D, L-Methadone and resolved/ ameliorated after cessation of the intake/reduction of the dosage. Side effects were categorized according to the common toxicity criteria (CTC). Twenty-four patients were included. All patients were opioid-naïve and received D, L-Methadone from their general practitioners. Sixteen patients experienced side effects. The median dosage when side effects began to occur was 15.8 mg/ 24 h. Fatigue and mood changes were reported most frequently (14 of 24 patients). Five patients had severe side effects related to relatively high doses. In all cases, symptoms resolved after cessation or dose reduction. Our results show that D/L M intake lead to frequent occurrence of side effects in opioid-naïve patients especially when not handled with caution and close supervision. Patients, their relatives, their GPs and neuro-oncologists need to be informed about the broad spectrum of side effects in order to thoroughly counsel glioma patients.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Abedalthagafi M, Barakeh D, Foshay KM (2018) Immunogenetics of glioblastoma: the future of personalized patient management. NPJ Precis Oncol 2:27. https://doi.org/10.1038/s41698-018-0070-1

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  3. 3.

    Rahman M, Abbatematteo J, De Leo EK, Kubilis PS, Vaziri S, Bova F, Sayour E, Mitchell D, Quinones-Hinojosa A (2017) The effects of new or worsened postoperative neurological deficits on survival of patients with glioblastoma. J Neurosurg 127:123–131. https://doi.org/10.3171/2016.7.JNS16396

    Article  PubMed  Google Scholar 

  4. 4.

    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen H-J, ALA-Glioma Study Group (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401. https://doi.org/10.1016/S1470-2045(06)70665-9

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu J-J, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma. JAMA 314:2535–2543. https://doi.org/10.1001/jama.2015.16669

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Applebaum AJ, Buda K, Kryza-Lacombe M, Buthorn JJ, Walker R, Shaffer KM, D’Agostino TA, Diamond EL (2018) Prognostic awareness and communication preferences among caregivers of patients with malignant glioma. Psychooncology 27:817–823. https://doi.org/10.1002/pon.4581

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Friesen C, Roscher M, Alt A, Miltner E (2008) Methadone, commonly used as maintenance medication for outpatient treatment of opioid dependence, kills leukemia cells and overcomes Chemoresistance. Cancer Res 68:6059–6064. https://doi.org/10.1158/0008-5472.CAN-08-1227

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Friesen C, Hormann I, Roscher M, Fichtner I, Alt A, Hilger R, Debatin K-M, Miltner E (2014) Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle 13:1560–1570. https://doi.org/10.4161/cc.28493

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Wick W (2015) Gliomtherapie mit Methadon

  10. 10.

    Onken J, Friesen C, Vajkoczy P, Misch M (2017) Safety and tolerance of D,L-methadone in combination with chemotherapy in patients with glioma. Anticancer Res 37:1227–1236. https://doi.org/10.21873/anticanres.11438

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Gesch CB, Prof V, Hallek M, Dgho V, Prof B, Prof V, Wei F, Alexanderplatz V, Tel B (2017) Stellungnahme der DGHO Methadon bei Krebspatienten: Zweifel an Wirksamkeit und Sicherheit. 1–3

  12. 12.

    Palliativmedizin DG f (2017) Stellungnahme der Deutschen Gesellschaft für Palliativmedizin zum Einsatz von D,L-Methadon zur Tumortherapie (Stand: 5.7.2017)

  13. 13.

    Cancer Institute N (2017) Common terminology criteria for adverse events (CTCAE) common terminology criteria for adverse events (CTCAE) v5.0

  14. 14.

    Oppermann H, Matusova M, Glasow A, Dietterle J, Baran-Schmidt R, Neumann K, Meixensberger J, Gaunitz F (2019) D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro. Cancer Chemother Pharmacol 83:1017–1024. https://doi.org/10.1007/s00280-019-03816-3

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Latzer P, Kessler T, Sahm F, Rübmann P, Hielscher T, Platten M (2018) P04.30 methadone does not increase toxicity of temozolomide in glioblastoma cells. Neuro Oncol 20:iii285–iii285. https://doi.org/10.1093/neuonc/noy139.264

    Article  PubMed Central  Google Scholar 

  16. 16.

    Brawanski K, Brockhoff G, Hau P, Vollmann-Zwerenz A, Freyschlag C, Lohmeier A, Riemenschneider MJ, Thomé C, Brawanski A, Proescholdt MA (2018) Efficacy of D,L-methadone in the treatment of glioblastoma in vitro. CNS Oncol 7:CNS18. https://doi.org/10.2217/cns-2018-0006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Hübner J, Muenstedt K, Muecke R, Micke O, Stoll C, Kleeberg UR, Buentzel J, Dennert G, Prott FJ, PRIO (Working group Prevention and Integrative Oncology of the German Cancer Society), AKTE (Working group Trace Elements of the German Society of Radiooncology (DEGRO)) (2013) Counseling cancer patients on complementary and alternative medicine. Strahlentherapie und Onkol 189:613–617. https://doi.org/10.1007/s00066-013-0392-4

    Article  Google Scholar 

  18. 18.

    Rudolph I, Seilacher E, Köster M-J, Stellamanns J, Liebl P, Zell J, Ludwig S, Beck V, Hübner J (2015) Der Informationsbedarf von Patienten mit Krebserkrankungen in Deutschland – eine Befragung von Patienten und Angehörigen. DMW - Dtsch Medizinische Wochenschrift 140:e43–e47. https://doi.org/10.1055/s-0041-100585

    Article  Google Scholar 

  19. 19.

    Piche T, Vanbiervliet G, Cherikh F, Antoun Z, Huet PM, Gelsi E, Demarquay JF, Caroli-Bosc FX, Benzaken S, Rigault MC, Renou C, Rampal P, Tran A (2005) Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut 54:1169–1173. https://doi.org/10.1136/gut.2004.055251

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Piedad J, Rickards H, Besag FMC, Cavanna AE (2012) Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations. CNS Drugs 26:319–335

    CAS  Article  Google Scholar 

  21. 21.

    Sacher M, Meixensberger J, Krupp W (2018) Interaction of quality of life, mood and depression of patients and their informal caregivers after surgical treatment of high-grade glioma: a prospective study. J Neuro-Oncol 140:367–375. https://doi.org/10.1007/s11060-018-2962-x

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Christian von der Brelie.

Ethics declarations

Conflict of interest

This study was not funded. The authors declare that they have no conflict of interest. This study was approved by the institutional review board, ethical approval was obtained. Informed consent was not achieved since this was a retrospective observational study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

von der Brelie, C., Schatlo, B., Bettag, C. et al. Safety aspects of opioid-naïve patients with high-grade glioma treated with D,L-Methadone: an observational case series. Neurosurg Rev 44, 579–586 (2021). https://doi.org/10.1007/s10143-020-01250-1

Download citation

Keywords

  • High-grade glioma
  • Methadone
  • Treatment