Background: Post-craniotomy pain can be severe and undermanaged. While opioids are the mainstay treatment, they have the potential to interfere with neurological monitoring. The objectives of this review are: 1) to identify measures to provide opioid-free analgesia 2) to compare the effectiveness of non-opioid to opioid analgesia in post-craniotomy pain. Methods: A comprehensive search of EMBASE, MEDLINE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) databases was conducted for RCTs evaluating the effect of opioid vs non-opioid pain control strategies in patients undergoing supratentorial craniotomy. Results: The literature search yielded 462 citations, 5 RCTs that met the inclusion criteria for a total of 250 patients. Scalp infiltration/block was found to provide equivalent analgesia to morphine1 and fentanyl.2 Morphine was associated with slightly higher postoperative nausea and vomiting. Paracetamol was less likely to induce nausea and vomiting,3,4 but provided inadequate pain relief compared to nalbuphine,3 tramadol,3 morphine4 and sufentanil.4 Dexmedetomidine5 provided similar analgesia to remifentanil but did delay the time to first dose of rescue analgesia with similar side effects. Conclusions: Based on the limited number of RCTs comparing opioid to non-opioid techniques, no definite recommendations can be made with regards to the optimal management of post-craniotomy pain. Considerations should be made for use of multimodal analgesia-including adjuvant analgesics.