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Background: Pain is one of the main reasons to present to emergency departments (EDs). Opioids are indispensable for acute pain management but are associated with side effects, misuse, and dependence. The aim of this study was to test whether a single dose of intravenous (IV) acetaminophen (paracetamol) can reduce the use of morphine for pain relief and/or morphine-related adverse events (AEs)., Methods: ED patients >18 years with acute pain (i.e., Numeric Rating Scale [NRS] > 4) were screened for eligibility. Patients with analgesia in the past 6 h, chronic pain, or clinical instability were excluded. Patients were randomized in a 1:1 ratio to receive either morphine 0.1 mg/kg and 1 g acetaminophen IV or morphine 0.1 mg/kg and placebo IV. The intervention was double-blinded. Additional morphine 0.05 mg/kg IV was administered every 15 minutes until pain relief (defined as NRS < 4) and whether the pain recurred. The primary outcome was the mean morphine dose for pain relief. Secondary outcomes were the total amount of morphine given, time to achieve pain relief, and AEs., Results: A total of 220 patients were randomized and 202 evaluated for the primary outcome. The mean morphine dose for pain relief was similar in both groups (acetaminophen 0.15 mg ± 0.07 mg/kg, placebo 0.16 ± 0.07 mg/kg). There were no differences in the total amount of morphine given (acetaminophen 0.19 ± 0.09 mg/kg, placebo 0.19 ± 0.1 mg/kg), the time to achieve pain relief (acetaminophen 30 min [95% CI 17-31 min], placebo 30 min [95% CI 30-35 min]), and the frequency of AEs (overall 27.4%). Time to pain recurrence did not differ significantly between the groups (hazard ratio 1.23 [0.76-1.98], p = 0.40)., Conclusions: In ED patients, acetaminophen had no additional effect on pain control or morphine-sparing effect at the time of first morphine administration. Titrated morphine with the algorithm used was highly effective, with 80% of all patients reporting pain relief within 60 min of starting therapy., (© 2022 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)