BACKGROUND: Pain intensity after craniotomy is considered to be moderate to severe during the first 2 postoperative days. The ideal pain treatment to facilitate a rapid postoperative recovery and optimize outcome is unknown.OBJECTIVES: This systematic review aims to report current clinical evidence related to pharmacological and adjuvant analgesic modalities for postcraniotomy pain control.DESIGN: Systematic review of randomized controlled trials (RCTs).DATA SOURCES: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (January 2011 to April 2016).ELIGIBILITY CRITERIA: Original research involving the use of any analgesic drug, analgesic method, or nonpharmacological intervention for postcraniotomy pain relief, as assessed by pain scores up to 48 hours postoperatively, supplemental analgesic requirements, or occurence of adverse events.RESULTS: Nineteen RCTs enrolling a total of 1,805 patients were included. Most of the retrieved studies were of moderate-to-good methodological quality. Systemic pharmacological intervention was assessed in 14 RCTs. Opioids (5 RCTs) provided superior pain relief to other analgesics with no significant side effects, but the quality of studies was low. Diclofenac (3 RCTs) presented adequate craniotomy pain control without any adverse effects, while the use of parecoxib is not supported. Dexmedetomidine (3 RCTs) provided adequate transitional analgesia, but further research is needed. Data on the analgesic efficacy of gabapentin, pregabalin, and intravenous lidocaine are very limited (1 RCT for each). Scalp infiltration/block (3 RCTs) provided adequate analgesia in the early postoperative period, while more studies are needed to verify the analgesic benefit obtained from nonpharmacological interventions, such as multipoint electro-acupuncture, in craniotomy surgery (2 RCTs).CONCLUSIONS: No definite recommendations can be made based on this systematic review of pharamacological interventions following craniotomy due to significant divergence in the methodology of available studies. Limited evidence on scalp infiltration/block suggests an adequate analgesic effect in the early postoperative period. Analgesic efficacy of dexmedetomidine and multipoint electro-acupuncture needs further evaluation.