Introduction The COMT gene is involved in modulating pain perception. The interplay between the COMT genotype and analgesic effects of Pregabalin, and Naproxen can suggest individualized pain management strategies. We hypothesize that patients undergoing thoracotomy mainly for empyema thoracis and receiving Pregabalin as pre-emptive analgesia would have better pain optimization than the group receiving Naproxen . Methodology: In this RCT, 78 adult patients undergoing thoracotomy were randomized in Group 1 received pregabalin (2.5 mg/kg) while Group II received naproxen (7mg/Kg) orally 2 hr before surgery along with multimodal general anesthesia. Post operatively pain was observed.After that, the Genotyping of COMT Gene polymorphism by PCR-RFLP was done. Two ml blood from patients was collected in EDTA vial. DNA was extracted using DNA extraction kit . In all patients' Single Nucleotide Polymorphism (SNPs) of COMT (rs4633) were screened by amplified DNA or PCR-restriction fragment length polymorphism. COMT primers were of rs4633: forward 5′-GCTGGAACGAGTTCATCCTG-3′ and reverse 5′GCTTCTCCTGTAAGGGCTTTG-3′. The COMT (rs4633) genotype was detected by PCR and digestion of PCR product, rs4633, by Eco72I. Results: In both the groups CC is common homozygous yet this difference was not found to be significant statistically. Conclusion: There was no notable disparity in pain scores between the two groups. This study revealed a highly intricate relationship between COMT genotypes and post-operative pain. Therefore, it can be inferred that both pregabalin and naproxen are equally efficacious in patients undergoing thoracotomy procedures.