Background: There is a high incidence of moderate to severe postoperative pain in patients undergoing neurosurgery. Post-craniotomy headache (PCH) remains undertreated due to the cautious use of opioids in this surgical population. Various alternative analgesics such as acetaminophen and scalp blocks are widely utilized for the treatment of PCH, but this is often inadequate. Although a multimodal approach to the management of PCH may be effective in improved pain relief, only a limited number of randomized controlled trials have explored this. Aim: This study aims to investigate whether or not a multimodal analgesic regime, consisting of gabapentinoids and non-steroidal inflammatory drugs (NSAIDs) provides superior pain relief in patients undergoing elective craniotomy compared to the standard of care analgesia utilized at a local South African hospital. Methods: Twenty-seven patients, 18 years or older, scheduled for elective craniotomy for the management of their epilepsy were recruited into this clinical trial. Enrolled participants were randomized into one of two groups. The experimental group received oral 150mg pregabalin one hour before surgery, IV 40mg parecoxib at surgical closure, and oral 150mg pregabalin two hours after surgery. The control group received a matching placebo at these respective time points. Postoperatively, all patients received standard of care analgesia consisting of 24 hours IV paracetamol and additional analgesia as required (prn). Pain assessments using the numerical rating scale (NRS) and visual analogue scale (VAS) were performed at 1 hour, 8 hours, 24 hours, 48 hours and 72 hours postoperatively. Additional analgesia consumption, postoperative nausea and vomiting, as well as the incidence of any adverse events were captured. Results: Patients who received placebo showed an average trend of higher mean NRS pain scores compared to patients receiving pregabalin and parecoxib, although there was no significant difference (p = 0.218) in the maximum mean NRS pain scores between the experimental and control groups. However, patients who received pregabalin and parecoxib consumed significantly less dihydrocodeine than those who received placebo (p = 0.029). No significant differences were identified in use of other additional opioids and non-opioid analgesia during the first 24 postoperative hours. Conclusion: There is insufficient evidence to confirm that the perioperative use of pregabalin and parecoxib reduces PCH in patients undergoing elective craniotomy. The study medication did, however, result in a significant reduction in the use of postoperative dihydrocodeine, although it was also associated with higher rates of reported blurred vision and dizziness.