First-line methadone for cancer pain: titration time analysis



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.


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


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).


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.


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

Author information




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.

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

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Mammana, G., Bertolino, M., Bruera, E. et al. First-line methadone for cancer pain: titration time analysis. Support Care Cancer (2021).

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  • Advanced cancer
  • Cancer pain
  • First-line methadone
  • Titration