IV acetaminophen: Efficacy of a single dose for postoperative pain after hip arthroplasty: subset data analysis of 2 unpublished randomized clinical trials.

Inadequate control of postoperative pain after orthopedic procedures may trigger complications that increase morbidity. Multimodal analgesia is used to manage pain effectively after surgical procedures and reduce the need for rescue analgesia. Intravenous (IV) acetaminophen (OFIRMEV; Cadence Pharmaceuticals, Inc.), an analgesic that has been studied and used in the multimodal management of acute pain after major orthopedic procedures, combines the safety seen with oral and rectal formulations with a preferred route of administration. Two double-blind, randomized, placebo-controlled clinical trials were conducted (total 130 patients) to determine the efficacy and safety of single-dose IV acetaminophen in patients following total hip arthroplasty. Although both studies were stopped prematurely, overlap in patient populations, study design, and methodologies in the single-dose phase of these studies allowed for analysis of their results to be presented concurrently. Both trials demonstrated IV acetaminophen having greater efficacy than placebo in terms of primary endpoints [pain intensity differences from T0.5 to T3 (P < 0.05 in both studies)]. The use of IV acetaminophen also reduced the need for rescue opioid consumption, with patients receiving IV acetaminophen consuming, on average, less than half the amount of rescue medication as those receiving placebo. IV acetaminophen was effective in treating moderate-to-severe pain after total hip arthroplasty and reduced the need for rescue opioid consumption.

Safety and efficacy of intravenous acetaminophen in the elderly after major orthopedic surgery: subset data analysis from 3, randomized, placebo-controlled trials.

As the number of patients aged 65 years and older increases, joint replacement has become a frequent procedure after progressive osteoarthritis or fractures. Although hip and knee arthroplasty has become a relatively commonplace procedure in this age-group, the advanced age in patients undergoing these procedures often is associated with comorbidities and potential complications that can present challenges and limit analgesic choices. This subset analysis is designed to determine the efficacy and safety of intravenous (IV) acetaminophen in the elderly subpopulation from 3 placebo-controlled studies conducted to document the safety and efficacy of IV acetaminophen. A total of 231 patients were enrolled in the 3 trials, and of these, a total of 107 patients (46%) were aged 65 years or older. Across the studies, safety and efficacy were well documented in the elderly subpopulation and were comparable with the subpopulation younger than 65 years. A review of the literature similarly demonstrates the efficacy and safety of IV acetaminophen used for postoperative analgesia after joint replacement.

Effect of i.v. acetaminophen on total hip or knee replacement surgery: a case-matched evaluation of a national patient database.

PURPOSE: The effects of i.v. acetaminophen on adverse events, hospital length of stay (LOS), and overall hospital costs for total hip or knee replacements were evaluated. METHODS: We conducted a matched-pairs analysis of adult inpatients who underwent elective total hip arthroplasty or total knee arthroplasty in hospitals participating in the Premier Healthcare Alliance from January 1, 2011, to November 30, 2012. Each case who received i.v. acetaminophen on the day of surgery was matched to a control who did not receive i.v. acetaminophen within the same hospital. Treatment groups were analyzed for differences in the rate of adverse effects, LOS, and hospital resource utilization. RESULTS: A total of 22,146 cases and controls were similar in terms of age, race, sex, marital status, insurance status, and preoperative comorbidities. Overall adverse events were significantly lower with i.v. acetaminophen (24.3%) than with controls (26.3%, p < 0.001), numerically less frequent in all subgroups, and significantly less frequent for renal, infectious, and miscellaneous adverse events (all p < 0.05). I.V. acetaminophen was also associated with a shorter LOS, with 1 out of 11 patients discharged one day earlier (p < 0.001) and lower average hospital costs: $16,381 for cases compared with $16,927 for controls (p < 0.001). Cost savings estimated by structural equation modeling of $547 per patient were due to $325 from direct effects and $222 from indirect effects, the latter mediated through adverse events and reduced LOS. CONCLUSION: In this retrospective cohort study of case-matched patients who underwent total hip or knee replacement surgery, multimodal analgesia with i.v. acetaminophen was associated with improved clinical outcomes in terms of fewer adverse events, shortened LOS, and reduced total hospital resources compared with patients who did not receive i.v. acetaminophen.

A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery.

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.