Sciatica, a musculoskeletal condition is a common cause of disability and early deaths, affecting millions of people globally. The aim of the study was to evaluate efficacy of different drug combinations for treatment of acute sciatica. It is a single-center, clinical trial with three arms, registered at Clinicaltrials.gov; (NCT05626140). Adults from 18-70 years of age were enrolled (n=130). Patients were placed in three groups each i.e. 40 in diclofenac plus placebo group, 40 in codeine plus diclofenac group and 40 in lacosamide plus diclofenac group and followed up for 15 days for change in mean pain scores using Visual Analog Scale (VAS). Pairwise comparison assessed change from baseline in mean pain scores. The VAS mean pain scores with combination of lacosamide and diclofenac showed significant decrease from 7.785cm to 1.115cm. Codeine with diclofenac displayed a lesser decline of 7.43cm to 2.71cm while diclofenac monotherapy exhibited the least change from 7.50cm to 3.45cm. P value was significant (p < 0.001) for 10th and 15th day of follow up. Adequate analgesia was attained in all the three arms. In conclusion, combination of lacosamide with diclofenac showed clinical superiority in relieving symptoms of acute sciatica compared with diclofenac plus codeine or diclofenac monotherapy.