Gabapentin plus tramadol versus tramadol alone for chemoradiotherapy-induced oral mucositis pain in head and neck cancer: Results of a randomized phase III trial.

LBA12001 Background: Oral mucositis-related pain during concurrent chemoradiation (CTRT) for head and neck squamous cell carcinoma (HNSCC) significantly impairs quality of life (QoL) and frequently necessitates opioid escalation. Despite tramadol-based analgesia, up to one-third of patients require stronger opioids. Gabapentin may improve pain control by targeting the neuropathic component of mucositis-related pain. We conducted a randomized phase III trial evaluating whether the addition of gabapentin to tramadol improves mucositis pain control during CTRT. Methods: In this single-center, open-label, randomized phase III superiority trial, 154 patients with HNSCC receiving radical or adjuvant CTRT who developed CTCAE v5.0 grade ≥1 mucositis with pain [Visual Analogue Scale (VAS) ≥1] were enrolled. Eligible patients were aged 18–70 years with ECOG performance status 0–2. Patients were randomized 1:1 to tramadol plus topical anaesthetic (Arm A) or gabapentin plus tramadol and topical anaesthetic (Arm B). Gabapentin was escalated from 300 mg/day to a maximum of 1,800 mg/day. The primary endpoint was pain control measured as the area under the curve (AUC) of VAS pain scores following the first dose of analgesic. Secondary endpoints included analgesic escalation at day 7, weight loss at the end of CTRT, QoL, treatment compliance, adverse events, and treatment delays. With 154 patients, the study had 80% power to detect an effect size of 0.5 at a two-sided α of 0.05. The study was registered with the Clinical Trials Registry-India (CTRI/2020/03/024269). Results: A total of 154 patients were randomized. Median age was 49 years (IQR 42–57), and most patients had locally advanced disease (T3–4 77.3%, N2–3 69.5%, stage IVA–B 83.1%). The primary endpoint, pain control measured by AUC of VAS scores following the first dose of analgesic, was similar between the two arms [median AUC 1170 (95% CI 727–1638) vs 1080 (95% CI 802–1800)]. However, analgesic escalation requiring morphine occurred significantly more frequently in the tramadol arm compared with the gabapentin arm (37.3% vs 12.0%, p < 0.001), corresponding to an absolute risk reduction of 25.3%. Grade ≥2 weight loss occurred in 33.8% vs 27.3% of patients (p = 0.382), and radiotherapy interruptions occurred in 6.5% vs 1.3% (p = 0.096), favoring the gabapentin arm. QoL scores were comparable between arms. Gabapentin-related toxicities were mostly grade 1–2 and manageable. Conclusion: Addition of gabapentin to tramadol during CTRT significantly reduced the need for opioid escalation for mucositis-related pain in patients with head and neck cancer. Although early pain scores were similar, gabapentin demonstrated a clinically meaningful opioid-sparing effect, suggesting it may be an effective strategy for managing CTRT-induced mucositis pain. Clinical trial information: CTRI/2020/03/024269.