Anesthesiology 2005; 102:822–31 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery Raymond S. Sinatra, M.D., Ph.D.,* Jonathan S. Jahr, M.D.,† Lowell W. Reynolds, M.D.,‡ Eugene R. Viscusi, M.D.,§ Scott B. Groudine, M.D.,ʈ Catherine Payen-Champenois, M.D.#

Background: Intravenous acetaminophen injection (parac- patients treated with intravenous acetaminophen, propaceta- etamol) is marketed in Europe for the management of acute mol, and placebo, respectively. pain. A repeated-dose, randomized, double-blind, placebo-con- Conclusion: Intravenous acetaminophen, 1 g, administered Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 trolled, three–parallel group study was performed to evaluate over a 24-h period in patients with moderate to severe pain after the analgesic efficacy and safety of intravenous acetaminophen orthopedic surgery provided rapid and effective analgesia and as compared with its prodrug (propacetamol) and placebo. was well tolerated. Propacetamol has been available in many European countries for more than 20 yr. Methods: After orthopedic surgery, patients reporting mod- EFFECTIVE pain management is an important compo- erate to severe pain received either 1 g intravenous acetamino- nent of postsurgical care. Many patients, however, con- phen, 2 g propacetamol, or placebo at 6-h intervals over 24 h. tinue to experience inadequate pain relief.1 Despite im- Patients were allowed “rescue” intravenous patient-controlled provements in analgesic delivery, including patient- analgesia morphine. Pain intensity, pain relief, and morphine use were measured at selected intervals. Safety was monitored controlled analgesia (PCA) and sustained-release opioids, through adverse event reporting, clinical examination, and lab- several recent surveys have found that up to 80% of oratory testing. patients report moderate to severe pain after surgery.2–4 Results: One hundred fifty-one patients (intravenous acet- The ideal postoperative analgesic treatment should pro- aminophen: 49; propacetamol: 50; placebo: 52) received at least vide rapid and effective pain relief, have a low incidence one dose of study medication. The intravenous acetaminophen and propacetamol groups differed significantly from the pla- of adverse effects, and have minimal impact on major cebo group regarding pain relief from 15 min to6h(P < 0.05) organ systems or no significant interaction with other and median time to morphine rescue (intravenous acetamino- pharmacologic agents. phen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous Opioids remain the agents of choice for severe pain; acetaminophen and propacetamol significantly reduced mor- however, this class of analgesics is associated with dose- phine consumption over the 24-h period: The total morphine doses received over 24 h were 38.3 ؎ 35.1 mg for intravenous dependent adverse effects and negative postoperative 5,6 acetaminophen, 40.8 ؎ 30.2 mg for propacetamol, and 57. 4 ؎ outcomes. Nonopioid analgesics are commonly used mg for placebo, corresponding to decreases of ؊33% alone or as adjuncts to opioid-based analgesia to treat 52.3 ؊ (19 mg) and 29% (17 mg) for intravenous acetaminophen and moderate to severe pain. Perioperative administration of propacetamol, respectively. Drug-related adverse events were reported in 8.2%, 50% (most of them local), and 17.3% of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) has been advocated to provide “multimodal” or “balanced” analgesia that decreases opioid dose re- quirements and may reduce associated adverse events This article is featured in “This Month in Anesthesiology.” while reducing postsurgical pain intensity.5–9 ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. Acetaminophen has a well-established safety and anal- gesic profile. It has few contraindications and lacks sig-

* Professor of Anesthesiology, Department of Anesthesiology, Yale University nificant drug interactions. Hepatic toxicity is relatively School of Medicine. † Professor of Anesthesiology, David Geffen School of rare but can occur with acetaminophen overdose. Its Medicine, UCLA. Charles R. Drew University of Medicine and Science. ‡ Asso- ciate Professor of Anesthesiology, Loma Linda University School of Medicine. possible potentialization by chronic alcoholism remains § Associate Professor of Anesthesiology, Jefferson Medical College of Thomas controversial.10–12 Jefferson University. ʈ Associate Professor of Anesthesiology, Albany Medical College. # Project Leader, Medical Department, Bristol-Myers Squibb Company. Until recently, there has not been an intravenous acet- Received from the Department of Anesthesiology, Yale University School of aminophen solution available because it is poorly soluble Medicine, New Haven, Connecticut; Departments of Anesthesiology and Pain in water and not stable in solution. As a result, propac- Medicine, University of California-Davis, Sacramento, California; Loma Linda University School of Medicine, Loma Linda, California; Jefferson Medical College etamol, an intravenous, water-soluble prodrug of acet- of Thomas Jefferson University, Philadelphia, Pennsylvania; Albany Medical Col- aminophen with a well-established analgesic efficacy and lege, Albany, New York; and the Medical Department, Bristol-Myers Squibb Company, Rueil-Malmaison, France. Submitted for publication May 26, 2004. safety profile, has been widely prescribed in Europe for Accepted for publication October 22, 2004. Supported by Bristol-Myers Squibb the management of acute pain for the past 20 yr. It is not Company, Rueil-Malmaison, France. available in the United States. Address correspondence to Dr. Sinatra: Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, TMP-3 New Haven, Connecticut Propacetamol is rapidly hydrolyzed to acetaminophen 06520-8051. Address electronic mail to: [email protected]. Individual in the blood by the enzymatic action of esterases. Hy- article reprints may be purchased through the Journal Web site, www.anesthesiology.org. drolysis of 2 g propacetamol yields 1 g intravenous

Anesthesiology, V 102, No 4, Apr 2005 822 IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN 823 acetaminophen.13 In clinical trials conducted in patients cluded if they had received NSAIDs within 8 h, any with moderate to severe pain after orthopedic and gy- analgesic drug within 12 h, or corticosteroids within 7 necologic surgery, the analgesic efficacy of propaceta- days before administration of study medication. mol was similar to that of NSAID comparators.14–16 The study was conducted in accordance with Good While providing fast and significant pain relief as well as Clinical Practice and the Declaration of Helsinki and was a significant morphine-sparing effect,17–19 it is not asso- approved by an institutional review board for each clin- ciated with the increased incidence of nausea, vomiting, ical center. All participating patients provided written and respiratory depression observed with opioids or the informed consent. deleterious gastrointestinal, hematologic, and renal ef- fects associated with NSAIDs and cyclooxygenase Study Design (COX)-2 inhibitors.20 Lack of inhibition of COX-1 periph- This was a repeated-dose, randomized, double-blind, erally by paracetamol may explain its favorable safety placebo-controlled, three–parallel group study compar- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 effect.21 However, propacetamol has some drawbacks: It ing intravenous acetaminophen and propacetamol to must be reconstituted into a solution, and rare cases of placebo and was conducted in seven centers in the contact dermatitis have been reported in healthcare pro- United States (see appendix). Patients were enrolled fessionals handling the drug.22 In addition, propaceta- from September 1999 to June 2000. mol can be associated with pain at the intravenous in- Propacetamol was chosen as a comparator because it jection site or along the vein being infused. is the only injectable, prodrug form of acetaminophen A ready-to-use formulation of intravenous acetamino- commercially available and because, having been widely phen has recently been developed that does not require prescribed for many years in Europe, its analgesic effi- reconstitution and is not associated with contact derma- cacy and safety profile have been well characterized. titis or pain at the injection site. In the clinical develop- The dose of 2 g propacetamol was chosen because it ment program, 1 g intravenous acetaminophen has been releases 1 g intravenous acetaminophen. found to be bioequivalent to 2 g propacetamol.23 More- During the screening visit scheduled within 21 days over, clinical studies have shown that intravenous acet- before the administration of study drug, informed con- aminophen offers improved local safety at infusion sites, sent and medical history were obtained, physical exam- compared with propacetamol.23 ination and laboratory testing were performed, and train- The aim of this study was to evaluate the analgesic ing on the use of the intravenous PCA device and pain efficacy and safety of a single dose and repeated doses of scales was provided. 1 g intravenous acetaminophen in comparison with 2 g Patients received either general, spinal, or epidural propacetamol and placebo in patients experiencing anesthesia as judged appropriate by the attending anes- moderate to severe pain after total hip or knee replace- thesiologist on the day of surgery. They did not receive ment. These procedures were chosen because patients epidural or intrathecal opioids or local anesthetics for recovering from them consistently experience moderate postoperative pain control. Most patients received gen- to severe postoperative pain and require high doses of eral anesthesia, which included premedication with mi- opioid analgesics.24–26 dazolam, isoflurane–desflurane, fentanyl, and morphine for maintenance. In the postanesthesia care unit, when patients first requested analgesics, a PCA pump contain- Materials and Methods ing morphine (1 mg/ml) was connected to the intrave- Patients nous infusion. The PCA device was programmed to de- Patients aged at least 18 yr who were recovering from liver 1-ml boluses of morphine on demand, with a total hip or knee replacement performed during general lockout time interval of 6 min. If adequate pain relief was or regional anesthesia and had an American Society of not achieved with the intravenous PCA device alone, Anesthesiologists physical status of I–III were eligible for supplemental “rescue” boluses of 2 mg intravenous mor- the study. Other entry criteria included body weight phine were administered as needed. between 50 and 120 kg, ability to use the pain scales and On the morning of the first postoperative day, after to operate an intravenous PCA device, and reporting completion of routine nursing activities, the PCA device baseline pain of moderate to severe intensity on a cate- was temporarily discontinued, and the total amount of gorical rating scale. morphine administered to the patient was recorded. Exclusion criteria included known allergy or hypersen- A study observer closely monitored and recorded the sitivity or contraindication to opioids or acetaminophen, patients’ pain intensity. Patients reporting moderate to impaired liver function (transaminases Ͼ twice upper severe intensity on a four-point verbal pain intensity limit), renal dysfunction (creatinine Ͼ 2.0 mg/dl), un- categorical scale (0 ϭ none, 1 ϭ mild, 2 ϭ moderate, controlled chronic diseases, known or suspected history and 3 ϭ severe) were randomly assigned to one of the of alcohol or drug abuse. Patients who were pregnant or three treatment groups: 1 g intravenous acetaminophen, breast-feeding were excluded. Patients were also ex- 2 g propacetamol, or placebo. The study medications

Anesthesiology, V 102, No 4, Apr 2005 824 SINATRA ET AL. were prepared by an unblinded hospital pharmacist who ministered were analyzed with an analysis of covariance was not involved in the data collection. All of the study for overall difference among treatments and the Fisher medications were administered as a 100-ml solution in- protected least significant difference for multiple com- fused over 15 min at 6-h intervals for the next 24 h. To parison procedure. Time to peak effect and time to first properly evaluate the local tolerance of the study medi- rescue remedication were analyzed using the stratified cation at the infusion site, no other drug was adminis- Gehan-Wilcoxon test with center as the stratum variable tered through the cannula dedicated to infusion of the applied as the Fisher protected least significant differ- study solution. ence procedure and survival distribution using the Kaplan-Meier estimator. The Cochran-Mantel Haenszel Efficacy Measurements test stratified by center and applied as the Fisher pro- Pain intensity was measured immediately before the tected least significant difference procedure was used start of infusion of study medication. The start of the for analysis of patients requiring rescue medication and Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 study drug infusion was defined as time 0. Pain intensity patient global evaluation. Responders were defined as at rest was measured at selected intervals (15, 30, and 45 subjects who had a reduction in pain intensity of at least min and 1, 2, 3, 4, 5, 6, 18, 20, and 24 h after the first one unit. All efficacy analyses were performed on the dose) with a 100-mm visual analog scale (VAS; 0 ϭ no intent-to-treat population. pain to 100 ϭ worst possible pain) and on a four-point ϭ ϭ verbal scale (0 none to 3 severe). Pain relief (pri- Safety Analyses mary endpoint) was measured on a five-point verbal Adverse events were analyzed using the chi-square or ϭ ϭ scale (0 none to 4 complete) at the same selected Fisher exact test, and descriptive statistics were used for intervals up to 6 h. Time to rescue medication, quantity vital signs and laboratory evaluations. These analyses of morphine used, and patients’ global evaluations over were performed on the safety population (defined as the the 24-h study interval were recorded. set of all enrolled study subjects who received at least one dose of study treatment). Safety Assessments Adverse events (AEs) and serious AEs were monitored throughout the study period. Safety was also assessed by Results infusion site examination, vital signs measurements (sys- tolic and diastolic blood pressure, heart rate, and respi- Patients ratory rate on the first postoperative day just before the A total of 156 patients were randomized (intravenous first infusion, 2 h after infusion, and on the morning of acetaminophen: n ϭ 51; propacetamol: n ϭ 52; placebo: day 2), and routine laboratory testing (hematology and n ϭ 53), and 151 patients (intravenous acetaminophen: biochemistry before and 48 h after the surgery). n ϭ 49; propacetamol: n ϭ 50; placebo: n ϭ 52) re- ceived at least one dose of study medication. All of these Statistical Analysis 151 patients were included in the intent-to-treat popula- Sample Size. A sample size of 50 patients per group tion and analyzed for demographics, efficacy, and safety. was required to detect a difference of at least one point Most of the patients (137 of 151 [90.7%]) received four of pain relief (on the five-point categorical scale) for administrations of the study drug over 24 h. Fourteen active treatments versus placebo, with a 90% power and patients (9.3%) withdrew from the study after the first a type I error at 0.0167 (two-sided test adjusted for three study drug administration: 3 (6.1%) from the intravenous comparisons). acetaminophen group, 6 (12.0%) from the propacetamol All of the analyses were performed in the intent-to- group, and 5 (9.6%) from the placebo group. Six of these treat population.27 patients were withdrawn because of consent withdraw- Efficacy analyses included 6-h single-dose pain inten- al: 2 (4%) in the intravenous acetaminophen group, 2 sity differences on categorical and visual scales (baseline (4%) in the propacetamol group, and 2 (3.8%) in the pain minus pain intensity at each time point), summary placebo group. Four patients were withdrawn because measures of efficacy (weighted total pain relief, sum of of AEs: 3 (5.9%) in the propacetamol group (local pain at pain intensity difference and pain relief as measured on infusion site) and 1 (1.9%) in the placebo group (fever a categorical scale, weighted summed pain intensity dif- necessitating treatment). Two patients were withdrawn ferences from baseline), peak effects, time to remedica- because of lack of compliance: 1 in the intravenous tion (defined as time to request for rescue medication), acetaminophen group and 1 in the propacetamol group. and PCA morphine use. For the entire 24-h study inter- Two patients in the placebo group did not meet eligibil- val: pain intensity, PCA morphine use, and patients’ ity criteria but were included in the intent-to-treat global evaluation. population. The pain relief and pain intensity scores, global mea- The treatment groups were comparable with respect sures of efficacy, and quantity of rescue medication ad- to demographics, anesthetic and surgical procedure, and

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Table 1. Baseline Patient Demographics (ITT Population)

Treatment Groups

1 g Intravenous Acetaminophen 2 g Propacetamol Placebo Overall P Value n 49 50 52 151 Age, yr Mean 61.7 59.5 59.2 60.1 0.656 SD 16.9 14.2 13.4 14.8 Sex Male, n (%) 28 (57.1) 27 (54) 22 (42.3) 77 (51) 0.288 Female, n (%) 21 (42.9) 23 (46) 30 (57.7) 74 (49)

Weight, kg Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 Mean 85.7 85.7 81 84.1 0.246 SD 13.0 18.8 17.3 16.6 Height, cm Mean 171.8 171.6 168.7 170.7 0.317 SD 10.7 12.8 10.6 11.4 ASA physical status classification I, n (%) 3 (6.1) 3 (6.0) 3 (5.8) 9 (6.0) II, n (%) 34 (69.4) 32 (64.0) 37 (71.2) 103 (68.2) 0.792 III, n (%) 12 (24.5) 15 (30.0) 12 (23.1) 39 (25.8) PAI (VAS), mm Mean 62.0 55.7 56.4 58.0 0.156 SD 19.1 17.6 16.9 18.0

ASA ϭ American Society of Anesthesiologists; ITT ϭ intent-to-treat; PAI ϭ pain intensity measure on visual analog scale; VAS ϭ visual analog scale. baseline pain intensity. The overwhelming majority of ment interval from 15 min (intravenous acetaminophen) patients had symptoms of severe debilitating or painful and 30 min (propacetamol) up to 6 h (P Ͻ 0.05; fig. 2). osteoarthritis. Patients were aged 22–87 yr, had Ameri- Summary measures of efficacy over 6 h were equiva- can Society of Anesthesiologists physical status of pre- lent in the intravenous acetaminophen and propaceta- dominantly II (68.2%) or III (25.8%), and were experi- mol groups and superior to that reported in the placebo encing moderate to severe pain (99%) after total hip group (P Ͻ 0.05; table 2). (57%) or knee replacement (43%) (standard cemented In general, the response was lower for all treatment arthroplasties) performed during general (64.2%), re- groups for the knee than for the hip surgery subjects. gional (21.8%), or combined general and regional anes- However, the magnitude of the active treatments effect thesia (13.9%). Before study drug administration, the (active vs. placebo) was statistically significant and sim- mean baseline pain intensity on the 100-mm VAS was ilar for the hip and knee patients. 58 Ϯ 18 mm (table 1). Median Time to First Rescue Medication. Time to first rescue medication was significantly (P Ͻ 0.001) Efficacy Measures longer for both active groups than for placebo but was Pain Intensity and Pain Relief Scores and Global not significantly different between the two active Measures of Efficacy. groups. The median (95% confidence interval) times to Six-hour Evaluation Period (Single Dose). The first rescue medication were 3 (1.4–4.0) h for intrave- primary efficacy criterion was pain relief. For both active nous acetaminophen, 2.6 (1.6–4.0) h for propacetamol, groups, intravenous acetaminophen and propacetamol, and 0.8 (0.6–1.1) h for placebo (fig. 3). The analyses of pain relief scores were significantly higher than those of median time to rescue medication performed among the placebo group from 15 min to6h(P Ͻ 0.05), with responders (defined as subjects who had a reduction in no significant difference between the two active groups pain intensity of at least one unit) showed that the median (fig. 1). times for first rescue medication were 4.0 (3.3–4.3) h for Maximal pain relief scores were similar in the two intravenous acetaminophen, 3.8 (2.5–5.2) h for propac- active groups (2.0 Ϯ 1.4) and significantly higher than etamol, and 1.6 (1.0–2.6) h for placebo (table 3). that observed in the placebo group (0.9 Ϯ 1.1). The Pain Intensity over 24-h Evaluation Period (Re- median time to peak effect for pain relief was 30 min in peated Dose). Throughout the 24-h evaluation period, both active groups. the mean VAS pain intensity scores were significantly Pain intensity differences (verbal scores and VAS) from reduced in both active groups as compared with the baseline were significantly higher for both active groups placebo group (Ϫ8 and Ϫ10 mm for intravenous acet- in comparison with the placebo group at each assess- aminophen and propacetamol, respectively; P Ͻ 0.01).

Anesthesiology, V 102, No 4, Apr 2005 826 SINATRA ET AL. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021

Fig. 1. Mean pain relief scores, single dose (intent-to-treat population). Comparisons versus placebo: * P < 0.05; ** P < 0.001. .intravenous ؍ Comparisons between active groups: not significant at each evaluation time. IV

Morphine Consumption. Morphine consumption morphine in the propacetamol group was 9 mg (Ϫ48%) over the 6 h after the first dose was significantly (P Ͻ after the first dose and 17 mg (Ϫ29%) over 24 h (re- 0.01) lower for both active groups (9.7 Ϯ 10 and 9.3 Ϯ peated doses). 8.9 mg for intravenous acetaminophen and propaceta- Patient Global Evaluation. The patients’ global eval- mol, respectively) than for the placebo group (17.8 Ϯ uations of satisfaction with study treatment after the 16.7 mg). This reduction was maintained over 24 h initial dose and at 24 h (repeated doses) were signifi- (repeated doses), with total doses of 38.3 Ϯ 35.1, 40.8 Ϯ cantly (P Ͻ 0.01) higher for both active treatment 30.2, and 57.4 Ϯ 52.3 mg for intravenous acetamino- groups than for the placebo group. The proportions of phen, propacetamol, and placebo, respectively. Reduc- subjects with fair to excellent satisfaction with the study tion of PCA morphine in the intravenous acetaminophen treatment at 24 h were 79.6, 83.7, and 65.4% for intra- group was 8 mg (Ϫ46%) after the first dose and 19 mg venous acetaminophen, propacetamol, and placebo, (Ϫ33%) over 24 h (repeated doses). Reduction of PCA respectively.

Fig. 2. Mean pain intensity differences categorical scale, single dose (intent-to-treat population). Comparisons versus placebo: * P < .intravenous ؍ P < 0.001. Comparisons between active groups: not significant at each evaluation time. IV ** ;0.05

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Table 2. Summary of Analgesic Efficacy Scores over 6 h (ITT intravenous acetaminophen (1 of 49 [2%]) than for Population) propacetamol (21 of 50 [38%]) and not different from 1 g Intravenous that of placebo (1 of 52 [2%]) (table 5). There was no Mean score Acetaminophen 2 g Propacetamol Placebo significant difference between the intravenous acetamin- Ϯ ϭ ϭ ϭ SD (n 49) (n 49) (n 52) ophen and placebo groups (table 5). In the propaceta- TOTPAR 6.6 Ϯ 5.9* 7.5 Ϯ 6.8* 2.2 Ϯ 3.8† mol group, all of the local AEs were considered related SPID 2.3 Ϯ 3.6* 2.5 Ϯ 4.3* Ϫ0.6 Ϯ 3.5† to the study drug. Nearly half of them led to reductions Ϯ Ϯ Ϯ SPRID 9.0 8.7* 10.0 10.7* 1.6 6.2† in infusion dose rate, interruption of the infusion, or *† When global test between all treatment groups was significant, individual even discontinuation of therapy. treatment group comparisons were examined. Means and medians associ- Eight patients (5.3%) experienced 11 treatment-emer- ated with different symbols are significantly different. gent serious AEs that were not considered related to the ITT ϭ intent-to-treat; SPID ϭ weighted sum of pain intensity differences, with Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 pain intensity measured on verbal scale; SPRID ϭ weighted sum of pain study drug. relief—intensity differences; TOTPAR ϭ weighted sums of pain relief. Intravenous acetaminophen and propacetamol infu- sions were not associated with clinically significant al- Adverse Events terations in vital signs. Regarding blood chemistry test There was no significant difference between treatment results, hemoglobin, hematocrit, and leukocyte and groups regarding the number of patients experiencing platelets counts, the incidence of treatment-emergent AEs. Ninety-seven patients (64.2%) experienced at least clinically significant values was low. There were no one AE after the first administration of the study medi- serious hepatic events related to treatment with intrave- cation: 32 (65.3%) in the intravenous acetaminophen nous acetaminophen. group, 33 (66%) in the propacetamol group, and 32 (61.5%) in the placebo group (table 4). Constipation, nausea, injection site pain, anemia, pruritus, and vomit- Discussion ing were the most frequently reported AEs (table 4). Adverse events were considered related to the trial This study demonstrates that 1 g intravenous acetamin- medication in 38 patients (25.2%), with the highest num- ophen is a safe and effective intravenous, nonopioid ber observed in the propacetamol group (25 patients analgesic for the treatment of postoperative pain in pa- [50%]) and significantly less in the intravenous acetamin- tients recovering from lower extremity joint replace- ophen (4 [8.2%]) and placebo groups (9 [17.3%]) (P Ͻ ment surgery. Intravenous acetaminophen was similar to 0.05). The proportion of subjects reporting local admin- propacetamol and consistently superior to placebo for istration site AEs was significantly (P Ͻ 0.001) lower for the main efficacy criterion of pain relief, as well as for

.intravenous ؍ Fig. 3. Time to first rescue medication (intent-to-treat population). IV

Anesthesiology, V 102, No 4, Apr 2005 828 SINATRA ET AL.

Table 3. Median Time to Rescue Medication

Pairwise Comparisons

Intravenous Intravenous 1 g Intravenous Overall Acetaminophen Propacetamol Acetaminophen vs. Acetaminophen 2 g Propacetamol Placebo P Value vs. Placebo vs. Placebo Propacetamol

ITT population n494852 Median time, h 3.0 2.6 0.8 0.0001 0.0001 0.0001 0.437 95% CI 1.4–4.0 1.6–4.0 0.6–1.1 Responder population* n353521 Median time, h 4.0 3.8 1.6 0.001 0.008 0.537 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 95% CI 3.3–4.3 2.5–5.2 1.0–2.6

* Per US Food and Drug Administration communication, time to rescue should be relevant to subset of subjects who responded to treatment. Subjects whose pain intensity reduction was at least 1 unit (on a four-point verbal score) were included in the analysis. CI ϭ confidence interval; ITT ϭ intent-to-treat. pain intensity changes from 15 min to 6 h after the first performed. Therefore, in the current investigation, acet- dose and throughout the 24-h evaluation period after re- aminophen infusions were started the day after surgery peated dose administration. In addition, intravenous acet- to allow patients to stabilize in the acute postoperative aminophen had significantly improved local tolerability. setting and to reduce confounding factors for drug as- Acetaminophen (paracetamol) is a widely prescribed sessment, e.g., the possible synergistic analgesic effect of analgesic devoid of clinically significant antiinflamma- the anesthetic on the study drug in the postoperative tory effects. Intravenous administration of acetamino- period. This also allowed the evaluation of the mono- phen either as intravenous acetaminophen or propaceta- therapeutic efficacy of intravenous acetaminophen in mol avoids variabilities associated with gastric reducing pain intensity. Onset and duration of analgesic absorption and first-pass hepatic metabolism, resulting in effect for intravenous acetaminophen and propacetamol higher plasma concentrations and greater analgesic effi- seemed comparable to data previously reported for cacy than orally administered drug.28 propacetamol.16 Although double-stopwatch assess- Major orthopedic surgery is extremely painful, and ments of perceptible and meaningful effect were not monotherapy with acetaminophen would not be ex- performed, the assessment used (a minimum of 10 mm pected to provide complete relief on the day surgery was decrease in VAS pain intensity) provided a reasonable

Table 4. Adverse Events Greater Than 5% in Any Treatment Group (Safety Population)

Treatment Groups

1 g Intravenous Acetaminophen 2 g Propacetamol Placebo n (%) (n ϭ 49) (n ϭ 50) (n ϭ 52)

No. of patients with Ն1 AE 32 (65.3) 33 (66.0) 32 (61.5) No. of patients with Ն1 AE 4 (8.2) 25 (50.0) 9 (17.3) Gastrointestinal system disorders* 21 (42.9) 16 (32.0) 16 (30.8) Constipation 10 (20.4) 8 (16.0) 12 (23.1) Nausea 13 (26.5) 9 (18.0) 7 (13.5) Vomiting 6 (12.2) 3 (6.0) 3 (5.8) Abdomen enlarged 3 (6.1) 0 0 Other gastrointestinal disorder 3 (6.1) 0 1 (1.9) Application site disorders 2 (4.1)† 21 (42) 1 (1.9) Injection site pain 2 (4.1)† 19 (38.0) 1 (1.9) Injection site reaction 0 3 (6.0) 0 Body-as-a-whole general disorders 4 (8.2) 3 (6.0) 10 (19.2) Fever 1 (2.0) 1 (2.0) 6 (11.5) Erythrocyte disorders 4 (8.2) 5 (10.0) 7 (13.5) Anemia 4 (8.2) 5 (10.0) 7 (13.5) Skin and appendage disorders 5 (10.2) 4 (8.0) 5 (9.6) Pruritus 5 (10.2) 4 (8.0) 5 (9.6) Respiratory system disorders 4 (8.2) 0 3 (5.8) Coughing 3 (6.1) 0 1 (1.9)

* Number of patients with at least one adverse event (AE) by body system or preferred term, percentages refer to total number of patients. † For one patient (number 144), two local AEs (injection site pain and extravasation occurred at the opposite intravenous site relative to the study drug infusion site (opposite arm). AE ϭ adverse event.

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Table 5. Summary of Local Treatment-Emergent Adverse Events

Treatment Groups

1 g Intravenous Acetaminophen 2 g Propacetamol Placebo P Value

Total No. of patients 49 50 52 Total No. of patients with Ն1 local AE, n (%) 1 (2.0) 21 (42.0) 1 (1.9) 0.001* Injection site pain 1 (2.0) 19 (38.0) 1 (1.9) Injection site reaction 0 3 (6.0) 0 Extravasation 0 0 0 No. of patients with serious local AEs, n (%) 0 0 0 No. of patients who discontinued because of local AEs, n (%) 0 3 (6.0) 0 Ն No. of patients with 1 related local AE, n (%) 1 (2.0) 21 (42.0) 1 (1.9) Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021

* Pairwise comparisons: intravenous acetaminophen vs. placebo: P ϭ 0.610; propacetamol vs. placebo: P ϭ 0.001; intravenous acetaminophen vs. propaceta- mol: P ϭ 0.001. AE ϭ adverse event. criterion as to time of analgesic onset. Using this calcu- sions required approximately one third less PCA mor- lated change in pain intensity, time to onset of analgesia phine than those treated with placebo. This percentage can be estimated as less than 15 min with either intra- reduction in 24-h morphine dose compares favorably venous acetaminophen or propacetamol. The median with morphine-sparing effects previously reported for time to peak analgesic effect was 30 min in both active propacetamol infusion17–19 and for injectable NSAIDs groups for pain relief, with no difference between active and selective COX-2 inhibitors.7,29,30 groups. Opioid sparing would be expected to provide clinical Analgesic duration was defined as the time to request advantages in patients who are sensitive to opioid-in- for restarting PCA morphine after intravenous infusion duced sedation, confusion, respiratory depression, and of study drug. This is an underestimate of the true anal- gastrointestinal complications. Despite significant reduc- gesic duration because subjects who do not experience tions in opioid exposure, no differences were observed analgesia do not contribute to the measurement of du- in nausea, vomiting, or constipation (their incidence was ration of analgesia. In the routine clinical setting, mono- low in all of the treatment groups). Evaluation of seda- therapy with nonopioid analgesics would not be ex- tion, confusion, and respiratory depression were not pected to eliminate opioid dosing in patients recovering endpoints of this study; a much larger number of sub- from major orthopedic surgery. Significant pain intensity jects would likely be required to determine any signifi- reductions and morphine sparing were noted beyond cant differences between study drugs. However, only the restart PCA time and continued through out the approximately 20% of the studies have demonstrated an entire 6-h interval for patients receiving active drugs, improvement in opioid-related symptoms,31 probably giving further evidence of analgesic duration. Further- because many of the opioid-related side effects may also more, the protocol allowed patients to adjust their opti- be reinforced by neural reflexes as components of sur- mal level of analgesia with self-administration of PCA gical stress.32 morphine before study drug infusion. Intravenous acet- It is possible that earlier administration of intravenous aminophen allowed responders to recapture a level of acetaminophen, starting the morning of surgery and con- analgesia equivalent to that provided by PCA morphine tinuing for up to 48 h, could have further reduced opioid and to maintain it for 4 h, while plasma concentrations consumption to the point that significant reductions in of morphine continued to decrease. Therefore, when nausea and constipation could have been detected. opioid rescue is finally required, only a small amount of Morphine has been considered the accepted standard PCA morphine is necessary to reach the level of analge- of analgesia. In the immediate postoperative setting, sia noted before randomization. optimal analgesia cannot always be achieved with intra- Advocates of multimodal analgesia suggest that coad- venous opiates used as monotherapy. As noted previ- ministration of nonopioid analgesics reduces opioid con- ously, the global measures of efficacy over 6 h were sumption and pain intensity and may reduce opioid- equivalent in the intravenous acetaminophen and related AEs.5,6 propacetamol groups and superior to those reported in In the current investigation, both active drugs reduced the placebo group (P Ͻ 0.05). A balanced, multimodal the need for rescue doses of PCA morphine administered approach may therefore provide better efficacy results. during the initial 6-h efficacy evaluation (46% for the This study and numerous other studies report that pain intravenous acetaminophen group) and over the entire intensity scores are significantly reduced in patients 24-h study interval (33% for the intravenous acetamino- treated with intravenous acetaminophen, propaceta- phen group). Patients treated with acetaminophen infu- mol,16 COX-2 inhibitors,29,30 or NSAIDs7 as adjuncts to

Anesthesiology, V 102, No 4, Apr 2005 830 SINATRA ET AL.

PCA morphine compared with PCA morphine alone. after major orthopedic joint replacement surgery is ef- Zhou et al.16 reported lower pain intensity scores in fective, safe, and well tolerated. Intravenous acetamino- patients treated with either ketorolac or propacetamol phen, 1 g, was similar to 2 g propacetamol with regard compared with placebo, despite the fact that all patients to efficacy and was superior to propacetamol with re- treated could self-administer additional PCA morphine gard to local AEs (pain at infusion site), a significant and theoretically achieve equivalent levels of analgesia. advantage for the patients in terms of tolerance and The risks and benefits of any treatment must be con- compliance. These data suggest that intravenous acet- sidered before implementation. Although NSAIDs and aminophen is a useful component of the multimodal COX-2 inhibitors offer effective augmentation of opioid- analgesia model, especially after major orthopedic based analgesia, concerns have been raised regarding surgery. their use perioperatively. NSAIDs inhibit platelet func- tion, increase perioperative bleeding, and have been The authors thank Jonathan S. Deutsch, M.D. (Bristol-Myers Squibb Company, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 Hillside, New Jersey), and Laurence Saya, M.D. (Altius Pharma CS, Paris, France), shown to have nephrotoxic effects in patients with and for reviewing the manuscript and Nathalie Schmidely (Statistician, Bristol-Myers without preexisting renal insufficiency.20,33–35 Selective Squibb Company, Rueil-Malmaison, France) and Selim Rachidi (Clinical Research Associate, Bristol-Myers Squibb Company, Hillside, New Jersey) for their contri- COX-2 inhibitors have been associated with salt and bution to the study. water retention and hypertension36 and inhibit bone remodeling in animal models. This latter observation has raised concerns of impaired healing and nonunion after various forms of orthopedic surgery.37–39 Recently, a References greater incidence in sternal wound infection and propor- 1. 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