Efficacy and Safety of Two Methadone Titration Methods for the Treatment of Cancer-Related Pain: The EQUIMETH2 Trial (Methadone for Cancer-Related Pain)

J Pain Symptom Manage. 2016 Nov;52(5):626-636.e1. doi: 10.1016/j.jpainsymman.2016.05.022. Epub 2016 Sep 30.


Context: In the European Association for Palliative Care recommendations for cancer pain management, there was no consensus regarding the indications, titration, or monitoring of methadone.

Objectives: This national, randomized, multicenter trial aimed to compare two methadone titration methods (stop-and-go vs. progressive) in patients with cancer-related pain who were inadequately relieved by or intolerant to Level 3 opioids.

Methods: The primary end point was the rate of success/failure at Day 4, defined as pain relief (reduction of at least two points on the visual scale and a pain score <5 for two consecutive days) and no overdose (Rudkin scale ≥3 and respiratory rate <8/minute). The patients were followed for two months after enrollment.

Results: The cancer-related pain characteristics of the 146 patients were as follows: 16% were nociceptive, 85% experienced breakthrough pain, and 84% had mixed types of pain. The reasons for switching to methadone were a lack of efficacy that was either isolated (56%) or associated with intolerance (38%). Adequate pain relief was obtained in 80% of the patients (median of three days in both groups [P = 0.12]) and lasted until D56. The rate of success/failure was approximately 40% at Day 4 in both groups, with overdoses in 13% of the patients throughout the study. The two methods were considered equally easy to perform by nearly 60% of the clinicians.

Conclusion: Methadone is an effective and sustainable second-line alternative opioid for the treatment of cancer-related pain. The methods of titration are comparable in terms of efficacy, safety, and ease of use.

Keywords: Cancer pain; methadone; opioid.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Breakthrough Pain
  • Cancer Pain / drug therapy*
  • Drug Overdose
  • Female
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Methadone / administration & dosage*
  • Methadone / adverse effects
  • Middle Aged
  • Pain Measurement
  • Retreatment
  • Treatment Outcome


  • Analgesics, Opioid
  • Methadone