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To assess the efficacy of 10 mg intramuscular (IM) methadone in patients with opioid withdrawal syndrome (OWS).This was a prospective observational, convenience sample of patients presenting to the ED with mild to moderate OWS. Evaluations included the Clinical Opiate Withdrawal Scale (COWS), Withdrawal Symptoms Scale (WSS), Altered Mental Status Scale (AMSS) and a physician assessment of the patient's WSS (MDWSS). After enrollment, 10 mg of IM methadone was administered and patients were reassessed at 30 min post-methadone administration. The primary outcome was the change in COWS at baseline and after methadone administration. Secondary outcomes were the differences between AMSS, and WSS post-methadone.Fifty-seven patients had COWS scores recorded at baseline and 30 min. Fifty-six had mild to moderate OWS. The COWS improved a mean of 7.6 after methadone administration (P < 0.001). The improvement was greater among patients presenting with moderate versus mild withdrawal (mean decrease = −9.1 vs. −5.5, P < 0.001). Patients were more likely to self-score themselves as having withdrawal compared to MDs (93.6% vs. 76.6% respectively, P = 0.027). Of the 62 patients with baseline and follow-up WSS by self-assessments, 69% improved post-methadone administration. In addition, the AMSS score remained the same or improved among 86% of cases with measurements at baseline and follow-up.A single IM dose of 10 mg methadone in the ED reduces the severity of acute mild to moderate OWS by 30 min. Larger prospective, randomized controlled, and blinded studies would be needed to confirm these results.