Opioid therapy vs. Multimodal analgesia in head and neck cancer (OPTIMAL-HN): Results of a randomized clinical trial.

Background: Radiation-induced mucositis (RIM) pain confers substantial morbidity for head and neck cancer (HNC) patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT). With no well-established standard treatment, OPTIMAL-HN aimed to demonstrate the non-inferiority of multimodal analgesia (MMA; analgesic medications with different mechanisms of action) to opioid analgesia alone.

Methods: OPTIMAL-HN (ClinicalTrials.gov identifier: NCT04221165) was an open-label, non-inferiority, randomized clinical trial. We enrolled HNC patients receiving curative-intent RT/CRT and experiencing moderate ≥ 4/10 RIM pain. We randomized 1:1, stratified by RT vs. CRT, to opioids alone (standard arm) or MMA (pregabalin, acetaminophen, naproxen, and opioids if required). The primary endpoint was mean pain score (range: 0-10) during the last week of RT. Secondary endpoints included mean weekly opioid use, duration of opioid requirement, quality of life, weight loss, and toxicity. All analyses were pre-specified, including testing for superiority if non-inferiority was demonstrated.

Results: Forty-nine patients were enrolled, 25 in the opioid analgesia arm and 24 in the MMA arm. Median follow-up was 4.2 months. The primary endpoint, mean pain score during the last 7 days of RT, was 5.1 (95 % confidence interval [CI]: 4.1-6.1) in the opioid arm and 4.9 (95 % CI: 3.8-5.9) in the MMA arm (non-inferiority p = 0.039, superiority p = 0.72). Analyzing all pain scores from enrollment to 6-weeks post-RT, MMA demonstrated both non-inferiority and superiority compared to opioids alone (non-inferiority p = 0.0024, superiority p < 0.001). One patient in the MMA arm was admitted with acute kidney injury, possibly related to the analgesic regimen. Arms were similar for all other secondary endpoints.

Conclusions: MMA demonstrates non-inferiority to opioid analgesia alone in managing RIM pain during the last week of RT and superiority when analyzing the post-RT time period. MMA should, therefore, be considered an effective mode of analgesia for HNC patients receiving RT.