Methadone versus Fentanyl in Patients with Radiation-Induced Nociceptive Pain with Head and Neck Cancer: A Randomized Controlled Noninferiority Trial

Background: Pain is still a burden for many patients with cancer. A recent trial showed the superiority of methadone over fentanyl in neuropathic pain, and we expect that this finding could influence the number of patients treated with methadone.

Methods: We performed a randomized controlled noninferiority trial in patients with nociceptive pain. Eighty-two strong-opioid-naïve patients with head and neck cancer with substantial pain (pain numeric rating scale [NRS] score ≥ 4) due to radiation therapy were included. Forty-two patients were treated with methadone, and 40 with fentanyl. Patients were evaluated at 1, 3, and 5 weeks. The primary outcomes were reduction in average pain and clinical success (50% pain decrease). We set the predefined noninferiority margin at 1 on the NRS and 10% clinical success. Secondary outcomes were pain interference, global perceived effect (GPE), side effects, and opioid escalation index.

Results: Noninferiority was shown for decrease in NRS for maximum and mean pain scores at 1 and 3 weeks. Noninferiority was shown for clinical success at 1 week only. The opioid escalation index was lower in the methadone group at 3 and 5 weeks as compared to fentanyl (1.44 vs. 1.99, P = 0.004; and 1.50 vs. 2.32, P = 0.013). The pain interference in the methadone group was significantly decreased at 3 weeks only. GPE and side effects were not different.

Conclusion: This is the first study to show noninferiority of methadone compared to fentanyl at 1 and 3 weeks in the treatment of radiation-induced nociceptive pain in patients with head and neck cancer.