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First-line methadone for cancer pain: titration time analysis

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Abstract

Background

Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce.

Objective

To describe the titration phase of the treatment with low-dose first-line methadone and the use of methadone for breakthrough pain.

Methods

Prospective study with strong opioid–naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5–5 mg/day every 8, 12, or 24 h. Titration allowed daily dose increases from day 1, and prescription of oral methadone 2.5 mg every 2 h with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0–T7).

Results

Sixty-two patients were included. Initial median (IQR) methadone dose was 5 (2.5) mg/day. Pain intensity decreased from a median (IQR) of 8 (2.3) at T0 to 4 (2.3) at T1 and remained ≤ 4 until T7 (all p < 0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 h. Methadone daily doses at T2 and T7 were higher than that at T0: 7.5 (3) and 6.7 (5.5) versus 5 (2.5), respectively (all p < 0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose, and time for stabilization was 0 (1), 5(4.5) mg, and 3(2) days, respectively. Two patients were discontinued due to delirium. All other side effects were mild.

Conclusions

First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week.

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Availability of data and material

All data relevant to the study are included in the article.

Code availability

N/A.

References

  1. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ (2016) Update on prevalence of pain in patients with cancer: systematic review and Meta-analysis. J Pain Symptom Manag 51:1070–1090

    Article  Google Scholar 

  2. Salpeter SR, Buckley JS, Bruera E (2013) The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia. J Palliat Med 16(6):616–622

    Article  Google Scholar 

  3. Good P, Afsharimani B, Movva R, Haywood A, Khan S, Hardy J (2014) Therapeutic challenges in cancer pain management: a systematic review of methadone. J Pain Palliat Care Pharmacother 28:197–205

    Article  Google Scholar 

  4. Sunilkumar MM, Lockman K (2018) Practical pharmacology of methadone: a long-acting opioid. Indian J Palliat Care 24(Suppl 1):S10–S14

    Article  CAS  Google Scholar 

  5. McPherson ML, Costantino RC, McPherson AL (2018) Methadone. Maximizing safety and efficacy for pain control in patients with cancer. Hematol Oncol Clin N Am 32(3):405–415

    Article  Google Scholar 

  6. De Lima L, Pastrana T, Radbruch L, Wenk R (2014) Crosssectional pilot study to monitor the availability, dispensed prices, and affordability of opioids around the globe. J Pain Symptom Manage 48(4): 649-659.e1.

  7. McPherson MK, Walker KA, Davis MP, Bruera E et al (2019) Safe and appropriate use of methadone in hospice and palliative care: expert consensus white paper. J Pain Symptom Manag 57(3):635–645

    Article  Google Scholar 

  8. Mercadante S, Bruera E (2018) Methadone as a first-line opioid in cancer pain management: a systematic review. J Pain Symptom Manag 55(3):998–1003

    Article  Google Scholar 

  9. Madden K, Mills S, Dibaj S, Williams JL, Liu D, Bruera E (2018) Methadone as the initial long-acting opioid in children with advanced cancer. J Palliat Med 21(9):1317–1321

    Article  Google Scholar 

  10. Barahona E, Pinhao R, Galindo V, Noguera A (2018) The diagnostic sensitivity of the Memorial Delirium Assessment Scale-Spanish version. J Pain Symptom Manag 55(3):968–972

    Article  Google Scholar 

  11. Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Verna L, Villari P, Ficorella C, Gebbia V, Riina S, Casuccio A, Mangione S (2008) Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. Eur J Pain 12:1040–1046

    Article  CAS  Google Scholar 

  12. Fainsinger RL, Nekolaichuk C, Lawlor P, Hagen N, Bercovitch M, Fisch M, Galloway L, Kaye G, Landman W, Spruyt O, Zhukovsky D, Bruera E, Hanson J (2010) An international multicentre validation study of a pain classification system for cancer patients. Eur J Cancer 46(16):2896–2904

    Article  Google Scholar 

  13. Paul SM, Zelman DC, Smith M, Miaskowski C (2005) Categorizing the severity of cancer pain: further exploration of the establishment of cutpoints. Pain 113:37–44

    Article  Google Scholar 

  14. Farrar JT, Portenoy RK, Berlina JA, Kinman JL, Strom BL (2000) Defining the clinically important difference in pain outcome measures. Pain 88:287–294

    Article  Google Scholar 

  15. Parsons HA, de la Cruz M, El Osta B et al (2010) Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer 116:520–528

    Article  CAS  Google Scholar 

  16. Hui D, Bruera E (2014) A personalized approach to assessing and managing pain in patients with cancer. J Clin Oncol 32:1640–1646

    Article  Google Scholar 

  17. Mercadante S (2012) Switching methadone: a 10-year experience of 345 patients in an acute palliative care unit. Pain Med 13:399–404

    Article  Google Scholar 

  18. Lawlor PG, Nekolaichuk C, Gagnon B, Mancini IL, Pereira JL, Bruera ED (2000) Clinical utility, factor analysis, and further validation of the Memorial Delirium Assessment Scale in patients with advanced cancer: assessing delirium in advanced cancer. Cancer 88:2859–2867

    Article  CAS  Google Scholar 

  19. Carvajal Valcárcel A, Martínez García M, Centeno CC (2013) The Spanish version of the ESAS: a reference tool for evaluating the symptoms of the patient with advanced cancer. Medicina Paliativa 20(4):143–149. https://doi.org/10.1016/j.medipa.2013.02.001

    Article  Google Scholar 

  20. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655

    Article  CAS  Google Scholar 

  21. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, Strasser F, Willey J, Bertolino M, Mathias C, Spruyt O, Fisch MJ (2004) Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol 22(1):185–192

    Article  CAS  Google Scholar 

  22. Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De Conno F (1986) A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom Manag 1:203–207

    Article  CAS  Google Scholar 

  23. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, Inturrisi C, Knight JR, Otis-Green S, Marcus SM, Mehta D, Meyer MC, Portenoy R, Savage S, Strain E, Walsh S, Zeltzer L, American Pain Society, Heart Rhythm Society (2014) Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain 15:321–337

    Article  CAS  Google Scholar 

  24. Baxter LE, Campbell A, Deshields M et al (2013) Safe methadone induction and stabilization: report of an expert panel. J Addict Med 7:377–386

    Article  CAS  Google Scholar 

  25. Palat G, Chary S (2018) Practical guide for using methadone in pain and palliative care practice. Indian J Palliat Care 24(Suppl 1):S21–S29

    Article  Google Scholar 

  26. Mercadante S, Bianchi M, Villari P, Ferrera P, Casuccio A, Fulfaro F, Gebbia V (2003) Opioid plasma concentration during switching from morphine to methadone: preliminary data. Support Care Cancer 11(5):326–331

    Article  CAS  Google Scholar 

  27. Peraino GP, Mammana GP, Bertolino MS et al (2016) Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit. Support Care Cancer 24(8):3551–3556

    Article  Google Scholar 

  28. De Conno F, Groff L, Brunelli C, Zecca E, Ventafridda V, Ripamonti C (1996) Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 14:2836–2842

    Article  Google Scholar 

  29. Mercadante S, Sapio M, Serretta R, Caligara M (1996) Patient controlled analgesia with oral methadone in cancer pain: preliminary report. Ann Oncol 7:613–617

    Article  CAS  Google Scholar 

  30. Mercadante S, Casuccio A, Agnello A, Barresi L (1999) Methadone response in advanced cancer patients with pain followed at home. J Pain Symptom Manag 18:188–192

    Article  CAS  Google Scholar 

  31. Mercadante S, Casuccio A, Agnello A, Serretta R, Calderone L, Barresi L (1998) Morphine versus methadone in the pain treatment of advanced cancer patients followed up at home. J Clin Oncol 16:3656–3661

    Article  CAS  Google Scholar 

  32. Haumann J, Geurts JW, van Kuijk SM, Kremer B, Joosten EA, van den Beuken-van Everdingen MJ (2016) Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. Eur J Cancer 65:121–129

    Article  CAS  Google Scholar 

  33. Hui D, Glitza I, Chisholm G, Yennu S, Bruera E (2013) Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer 119:1098–1105

    Article  Google Scholar 

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Funding

“Subsidio para la investigación en cáncer de origen nacional 2016-2018”, Instituto Nacional del Cáncer, Argentina.

Author information

Author notes

  1. Mammana Guillermo and Bertolino Mariela contributed equally to this work.

Authors and Affiliations

  1. Unidad de Cuidados Paliativos - Fundación FEMEBA, Hospital de Agudos Dr. E. Tornú, Buenos Aires, Argentina

    Guillermo Mammana, Mariela Bertolino, Fernando Orellana, Fanny Vega, Gabriela Peirano & Sofía Bunge

  2. Department of Palliative, Rehabilitation, & Integrative Medicine, UT MD Anderson Cancer Center, Houston, TX, USA

    Eduardo Bruera

  3. Facultad de Ciencias de la Salud, UNICEN, Buenos Aires, Argentina

    Sofía Bunge

  4. Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Arnaldo Armesto

  5. Programa de Bioética, Facultad Latinoamericana de Ciencias Sociales (FLACSO), Buenos Aires, Argentina

    Graciela Dran

  6. Consejo Nacional de Investigación Científica y Tecnológica (CONICET), Buenos Aires, Argentina

    Graciela Dran

Authors
  1. Guillermo Mammana
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  2. Mariela Bertolino
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  3. Eduardo Bruera
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  4. Fernando Orellana
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  5. Fanny Vega
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  6. Gabriela Peirano
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  7. Sofía Bunge
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  8. Arnaldo Armesto
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  9. Graciela Dran
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Contributions

Drs. Dran, Bertolino, and Mammana have full access to all the data used in the study and take the responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Dran, Bertolino, and Mammana participated in the conception and design of the study, the data analysis, and the writing of the manuscript. Dr. Bruera has made substantial contributions to the conception of the study and has critically revised the final and previous versions of the manuscript. Drs. Orellana, Vega, Peirano, and Bunge have performed the material preparation and data collection, and contributed to the analysis and interpretation of data. Mr. Armesto has developed the statistical analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Graciela Dran.

Ethics declarations

Ethics approval

The study was approved by the Hospital Tornú Ethical Committee, Buenos Aires, Argentina (No. 022/2015).

Consent to participate

All patients gave their informed consent to participate.

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All authors consented for the submission and publication of the manuscript in Supportive Care in Cancer.

Conflict of interest

The authors declare no competing interests.

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Mammana, G., Bertolino, M., Bruera, E. et al. First-line methadone for cancer pain: titration time analysis. Support Care Cancer 29, 6335–6341 (2021). https://doi.org/10.1007/s00520-021-06211-y

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  • DOI: https://doi.org/10.1007/s00520-021-06211-y

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