Opioid Therapy vs. Multimodal Analgesia in Head and Neck Cancer (OPTIMAL-HN): Results of a Randomized Clinical Trial

Purpose/Objective(s)

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

Materials/Methods

OPTIMAL-HN (NCT04221165) was an open label, single-institution, non-inferiority, randomized clinical trial. HNC patients receiving curative-intent RT/CRT and experiencing moderate 4 of 10 RIM pain were randomized 1:1, stratified by RT vs. CRT, to opioids alone per institutional standard 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, mean daily pain score, quality of life, hospitalizations for analgesic medication-related complications, time to feeding tube insertion, weight loss, toxicity, RT interruptions, and death. Assuming a non-inferiority margin of 1 point, a standard deviation of 1.5 in both arms (80% power, 1-sided alpha 0.05, dropout rate 6%), 62 patients were required. All analyses were pre-specified, including testing for superiority if non-inferiority was demonstrated, and intention-to-treat.

Results

Forty-nine patients were enrolled, 25 in the opioid analgesia alone arm and 24 in the MMA arm. The trial was prematurely closed due to slow accrual. Baseline characteristics were well-balanced between arms; median age was 61 (IQR = 53-70) years; 36 male (73.5%) and 13 female (26.5%); baseline median pain score was 5 (IQR = 4-6) in the opioid arm and 4 (IQR = 4-6) in the MMA arm (P = 0.161). Median follow-up was 4.24 (IQR = 3.75-4.73) months. The primary endpoint, mean pain score during the last 7 days of RT, was 5.10 (95% CI = 4.11-6.09) in the opioid arm and 4.85 (95% CI = 3.81-5.90) in the MMA arm (non-inferiority P = 0.039, superiority P = 0.724). Analyzing all pain scores from enrollment to 6 weeks post-RT using linear mixed models, MMA demonstrated significantly lower pain scores compared to opioids alone (non-inferiority P = 0.002, superiority P < 0.001). Median weekly opioid use was numerically higher in the opioid arm (99.2 mg oral morphine equivalent dose [OMED], IQR = 16.3-173.1) compared to the MMA arm (50.5 mg OMED; IQR = 8.4-126.3), although nonsignificant (P = 0.435). One patient in the MMA arm was admitted with grade 3 acute kidney injury, possibly related to the analgesic regimen. There was no grade ≥ 3 toxicity in the opioid arm. Arms were similar for all other secondary endpoints.

Conclusion

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 is therefore an effective analgesic regimen and should be considered for use in HNC patients.