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BACKGROUND: Children undergoing palatoplasty may receive adequate pain control with opioid administration but are at risk for opioid-related adverse effects such as nausea and vomiting which can result in decreased oral intake and subsequently increased hospital length of stay. Multimodal analgesic therapy endeavors to provide satisfactory pain control while limiting opioid-related adverse effects. This study aimed to determine if intra-operative acetaminophen, via intravenous (IV) or per rectal (PR) routes, was able to decrease opioid consumption and improve pain scores, oral intake and length of stay. METHODS: Institutional review board approval was obtained to retrospectively review one hundred consecutive patients with cleft lip and palate who underwent a von Langenbeck or two-flap palatoplasty and intravelar veloplasty by the two senior authors from 2012 to 2015. Patients were excluded if they underwent concomitant procedures except for placement of myringotomy tubes. Three intra-operative treatment groups were analyzed; 15 mg/kg IV acetaminophen, 15 mg/kg PR acetaminophen and no acetaminophen. All patients received local anesthesia infiltration of the operative site with lidocaine, bupivacaine and epinephrine. Additionally, all patients were admitted over-night and given PO acetaminophen (15 mg/kg), PO oxycodone (0.5 mg/kg) and IV morphine (0.5 mg/kg) as needed by the discretion of the nursing staff. Opioids were converted to morphine equivalents (mg/kg) to allow for comparison. Primary outcomes measured were numeric FLACC pain scores and opioid intake. Secondary outcomes were oral intake and length of stay. RESULTS: The treatment groups were comprised of forty-six patients that received IV acetaminophen, 20 rectal acetaminophen and 22 no acetaminophen. There was no statistically significant difference in age, gender or weight between treatment groups. There was no statistically significant difference for opioid intake although both IV and PR acetaminophen groups had decreased pain scores (p=0.03). There was no difference in oral intake or length of stay between treatment groups. CONCLUSION: In the current study, intra-operative administration of acetaminophen was not associated with an opioid-sparing effect, albeit decreased pain scores when acetaminophen was given. This may be due to the long-acting effect of the local anesthetic infiltration, or differences in pain interpretation. As multiple studies in the pediatric anesthesia literature have shown the effectiveness of post-operative acetaminophen administration, we currently recommend withholding the intra-operative dose and beginning therapy in the post-operative period when a greater benefit may be derived.