BACKGROUND: Intravenous acetaminophen has been approved in Europe and elsewhere for the treatment of acute pain and fever, and was recently approved by the US Food and Drug Administration (FDA) for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. OBJECTIVE: The aim of this work was to evaluate the analgesic efficacy and safety of repeated doses of 2 dosing regimens of intravenous acetaminophen compared with placebo over 24 hours in subjects with moderate to severe pain after abdominal laparoscopic surgery. METHODS: This double-blind, placebo-controlled, parallel-group study was conducted at 17 sites in the United States and enrolled adult subjects (aged 18-80 years) who were randomized to 4 groups (IV acetaminophen 1000 mg [100 mL] q6h; IV acetaminophen 650 mg [65 mL] q4h; IV placebo 100 mL q6h; or IV placebo 65 mL q4h), each given as a 15-minute infusion after surgery for 24 hours. An open-label extension was offered to all subjects who remained in the hospital beyond the study period. Two subjects (1 in the placebo 100 mL q6h group and 1 in the IV acetaminophen 1000 mg q6h group) were enrolled in the open-label extension and were eligible to receive unblinded IV acetaminophen 1000 mg. Before randomization, the choice of opioid for patient-controlled analgesia (PCA) rescue was left to the investigator; however, acetaminophen-containing products, NSAIDs, and aspirin were not allowed. The morning after abdominal laparoscopic surgery procedure, subjects' PCA was withheld until pain intensity (PI) was moderate (2) or severe (3) on a categorical scale (range, 0-3) and between 40 and 70 mm, inclusive, on a 100-mm visual analog scale, at which point they were randomized. After the first dose of study medication, intravenous rescue was restricted to morphine or hydromorphone, and oral rescue was restricted to morphine or oxycodone immediate-release tablets. Efficacy analyses were performed using the modified intent-to-treat (mITT) population, defined as all randomized subjects who received ≥ 1 complete dose of study medication before requesting rescue medication, and who had ≥ 1 completed PI/pain relief (PR) assessment after baseline. The primary efficacy end point was the weighted sum of PI differences over 24 hours (SPID24) using an ANCOVA model. Time to meaningful PR was documented after the first dose of study medication using a double-stopwatch method: at T0, 2 stopwatches were started, and subjects were instructed to stop the first stopwatch when they felt perceptible PR and the second when it became meaningful. Safety was assessed via spontaneous adverse event (AE) reporting and laboratory tests. RESULTS: A total of 349 subjects were screened before elective surgery for eligibility. Of these, 244 subjects were randomized to a study arm (IV acetaminophen 1000 mg [n = 92]; IV acetaminophen 650 mg [n = 42]; IV placebo 100 mL [n = 43]; or IV placebo 65 mL [n = 67]) and included in the ITT population, of whom 81.1% (198/244) were women and 87.3% (213/244) were white; the mean (SD) age was 46.2 (12.51) years (range, 18-78 years), and the mean weight was 174.3 (35.7) lb (range, 103-284 lb). There was an allocation error in the contract research organization's program linking group assignment and kit randomization; therefore, the original randomization procedure was replaced with a modified randomization schedule created by an independent biostatistician under the supervision of the FDA. The mITT population included 241 subjects; of these, 227 completed 24 hours of treatment. Four subjects withdrew before completing treatment because of AEs (1 subject in the placebo group because of fever and 3 in the IV acetaminophen 1000 mg q6h group because of infusion-site pain [n = 1] or infiltration [n = 2]), 8 because of withdrawal of consent, 2 because of early discharge from the hospital, and 2 for other reasons. Only 2 subjects participated in the elective open-label extension. Both intravenous acetaminophen dosing regimens were associated with significantly reduced SPID24 compared with placebo (1000 mg q6h, P < 0.007; 650 mg q4h, P < 0.019). Among the mITT population, SPID24 (using nonimputed data after first rescue: 1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.020), sum of PR scores over 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.003) and 12 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.001), and subjects' global evaluations at 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.005) were statistically significant in favor of both acetaminophen dosing regimens compared with the combined placebo group. Time to meaningful PR (by double stopwatch method) after the first dose was significantly shorter among subjects who received IV acetaminophen 1000 mg compared with subjects in the placebo 100 mL group (median of 24.9 vs 53.9 minutes, respectively). The most common overall AEs (ie, those that occurred in >10% of any group) were constipation, flatulence, nausea, and headache. The frequency of treatment-emergent AEs (TEAEs) across the treatment groups was not statistically significant. Most TEAEs were deemed to be unrelated to study medication. There were 6 subjects with serious TEAEs (1 [0.9%] in the IV acetaminophen 1000 mg group, 3 [7.0%] in the IV acetaminophen 650 mg group, and 2 [1.8%] in the placebo group). There was 1 (2.3%) related hepatic TEAE (transaminase increased) in the placebo group. CONCLUSION: Both regimens of intravenous acetaminophen (1000 mg q6h and 650 mg q4h) were associated with statistically significant analgesic efficacy compared with placebo and were well tolerated in these adults after abdominal laparoscopic surgery. ClinicalTrials.gov identifier: NCT00564486.