Adequate analgesia can be challenging, as pharmacological options are not necessarily effective for all types of pain and are associated with adverse effects. Methadone is increasingly being considered in the management of both cancer-related and non-cancer-related pain. The purpose of this article is to provide a narrative review of all available randomized controlled trials (RCT) investigating the effectiveness of methadone in the management of pain, in relation to a comparison drug. The primary outcome was analgesic effectiveness, and the secondary outcomes were side effects and cost. A search of PubMed, Medline, Embase, and Google Scholar databases was conducted to identify eligible RCTs and methodologic quality was assessed. A total of 40 RCTs were included in this review. The majority compared methadone to morphine or fentanyl. Analgesic effectiveness of methadone was demonstrated in different types of pain, including post-procedural, cancer-related, nociceptive, and neuropathic pain. The evidence demonstrates that the use of methadone in post-procedural pain and in cancer-related pain may be dependent on the procedure and cancer type, respectively. Side effects experienced were generally similar to the comparison drug, and lower cost was a benefit to using methadone. Methadone may also be useful as an adjunctive analgesic for adequate pain control, as well as in patients with renal impairment. Additional high quality large-scale RCT evidence is needed to establish its role as monotherapy or as an adjunctive medication. Future research should also aim to standardize reported outcomes for measuring analgesic effectiveness to permit for pooled analysis across studies. PERSPECTIVE: This article presents a systematic review, which includes a summary of published randomized controlled trials investigating the effectiveness of methadone in the management of pain. This is important for determining its analgesic utility and for identifying gaps in existing knowledge.