<p>Head and neck cancer (HNC) is the sixth most common cancer globally. Chronic persistent post-surgical pain (CPPP) is a significant complication following HNC surgery, severely impacting patients' quality of life. This study aims to evaluate and compare the efficacy, acceptability and safety outcome of transdermal buprenorphine (TDB) and transdermal fentanyl (TDF) in prevention of chronic persistent post-surgical pain (CPPP) in patients of head and neck carcinoma (HNC) and to explore its association with the modulation of mRNA expression of IL-6 and mTORc1 genes in these patients. This randomized, double-blinded pilot study included 40 HNC patients with persistent pain (NRS ≥ 4/10) on post-operative day 6. Patients were randomized to receive TDB (10 µg/hr) or TDF (50 µg/hr) patches. Pain intensity, neuropathic pain components, quality of life, and gene expression of IL-6 and mTORc1 were assessed at baseline and at the 12th week. The incidence of CPPP was significantly lower in the TDB group (10%) compared to the TDF group (40%). Both groups showed significantly lower NRS pain scores (p &lt; 0.001) and better quality of life scores at 12 weeks. Both groups exhibited significant downregulation in mRNA expression of IL-6 and mTORc1 genes post-treatment, with no significant difference between the groups (p &gt; 0.05). TDB is more effective than TDF in preventing CPPP in HNC patients, with associated improvements in quality of life and significant modulation of IL-6 and mTORc1 gene expression. Further research with larger cohorts and longer follow-up is needed to validate these findings.</p>