Download Sinatra Anesthesiology

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.,储 Catherine Payen-Champenois, M.D.#
Background: Intravenous acetaminophen injection (paracetamol) is marketed in Europe for the management of acute
pain. A repeated-dose, randomized, double-blind, placebo-controlled, three–parallel group study was performed to evaluate
the analgesic efficacy and safety of intravenous acetaminophen
as compared with its prodrug (propacetamol) and placebo.
Propacetamol has been available in many European countries
for more than 20 yr.
Methods: After orthopedic surgery, patients reporting moderate to severe pain received either 1 g intravenous acetaminophen, 2 g propacetamol, or placebo at 6-h intervals over 24 h.
Patients were allowed “rescue” intravenous patient-controlled
analgesia morphine. Pain intensity, pain relief, and morphine
use were measured at selected intervals. Safety was monitored
through adverse event reporting, clinical examination, and laboratory testing.
Results: One hundred fifty-one patients (intravenous acetaminophen: 49; propacetamol: 50; placebo: 52) received at least
one dose of study medication. The intravenous acetaminophen
and propacetamol groups differed significantly from the placebo group regarding pain relief from 15 min to 6 h (P < 0.05)
and median time to morphine rescue (intravenous acetaminophen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous
acetaminophen and propacetamol significantly reduced morphine consumption over the 24-h period: The total morphine
doses received over 24 h were 38.3 ⴞ 35.1 mg for intravenous
acetaminophen, 40.8 ⴞ 30.2 mg for propacetamol, and 57. 4 ⴞ
52.3 mg for placebo, corresponding to decreases of ⴚ33%
(19 mg) and ⴚ29% (17 mg) for intravenous acetaminophen and
propacetamol, respectively. Drug-related adverse events were
reported in 8.2%, 50% (most of them local), and 17.3% of
䉫
patients treated with intravenous acetaminophen, propacetamol, and placebo, respectively.
Conclusion: Intravenous acetaminophen, 1 g, administered
over a 24-h period in patients with moderate to severe pain after
orthopedic surgery provided rapid and effective analgesia and
was well tolerated.
EFFECTIVE pain management is an important component of postsurgical care. Many patients, however, continue to experience inadequate pain relief.1 Despite improvements in analgesic delivery, including patientcontrolled analgesia (PCA) and sustained-release opioids,
several recent surveys have found that up to 80% of
patients report moderate to severe pain after surgery.2– 4
The ideal postoperative analgesic treatment should provide rapid and effective pain relief, have a low incidence
of adverse effects, and have minimal impact on major
organ systems or no significant interaction with other
pharmacologic agents.
Opioids remain the agents of choice for severe pain;
however, this class of analgesics is associated with dosedependent adverse effects and negative postoperative
outcomes.5,6 Nonopioid analgesics are commonly used
alone or as adjuncts to opioid-based analgesia to treat
moderate to severe pain. Perioperative administration of
acetaminophen and nonsteroidal antiinflammatory drugs
(NSAIDs) has been advocated to provide “multimodal”
or “balanced” analgesia that decreases opioid dose requirements and may reduce associated adverse events
while reducing postsurgical pain intensity.5–9
Acetaminophen has a well-established safety and analgesic profile. It has few contraindications and lacks significant drug interactions. Hepatic toxicity is relatively
rare but can occur with acetaminophen overdose. Its
possible potentialization by chronic alcoholism remains
controversial.10 –12
Until recently, there has not been an intravenous acetaminophen solution available because it is poorly soluble
in water and not stable in solution. As a result, propacetamol, an intravenous, water-soluble prodrug of acetaminophen with a well-established analgesic efficacy and
safety profile, has been widely prescribed in Europe for
the management of acute pain for the past 20 yr. It is not
available in the United States.
Propacetamol is rapidly hydrolyzed to acetaminophen
in the blood by the enzymatic action of esterases. Hydrolysis of 2 g propacetamol yields 1 g intravenous
This article is featured in “This Month in Anesthesiology.”
Please see this issue of ANESTHESIOLOGY, page 5A.
* Professor of Anesthesiology, Department of Anesthesiology, Yale University
School of Medicine. † Professor of Anesthesiology, David Geffen School of
Medicine, UCLA. Charles R. Drew University of Medicine and Science. ‡ Associate Professor of Anesthesiology, Loma Linda University School of Medicine.
§ Associate Professor of Anesthesiology, Jefferson Medical College of Thomas
Jefferson University. 储 Associate Professor of Anesthesiology, Albany Medical
College. # Project Leader, Medical Department, Bristol-Myers Squibb Company.
Received from the Department of Anesthesiology, Yale University School of
Medicine, New Haven, Connecticut; Departments of Anesthesiology and Pain
Medicine, University of California-Davis, Sacramento, California; Loma Linda
University School of Medicine, Loma Linda, California; Jefferson Medical College
of Thomas Jefferson University, Philadelphia, Pennsylvania; Albany Medical College, Albany, New York; and the Medical Department, Bristol-Myers Squibb
Company, Rueil-Malmaison, France. Submitted for publication May 26, 2004.
Accepted for publication October 22, 2004. Supported by Bristol-Myers Squibb
Company, Rueil-Malmaison, France.
Address correspondence to Dr. Sinatra: Department of Anesthesiology, Yale
University School of Medicine, 333 Cedar Street, TMP-3 New Haven, Connecticut
06520-8051. Address electronic mail to: [email protected]. Individual
article reprints may be purchased through the Journal Web site,
www.anesthesiology.org.
Anesthesiology, V 102, No 4, Apr 2005
822
IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN
acetaminophen.13 In clinical trials conducted in patients
with moderate to severe pain after orthopedic and gynecologic surgery, the analgesic efficacy of propacetamol was similar to that of NSAID comparators.14 –16
While providing fast and significant pain relief as well as
a significant morphine-sparing effect,17–19 it is not associated with the increased incidence of nausea, vomiting,
and respiratory depression observed with opioids or the
deleterious gastrointestinal, hematologic, and renal effects associated with NSAIDs and cyclooxygenase
(COX)-2 inhibitors.20 Lack of inhibition of COX-1 peripherally by paracetamol may explain its favorable safety
effect.21 However, propacetamol has some drawbacks: It
must be reconstituted into a solution, and rare cases of
contact dermatitis have been reported in healthcare professionals handling the drug.22 In addition, propacetamol can be associated with pain at the intravenous injection site or along the vein being infused.
A ready-to-use formulation of intravenous acetaminophen has recently been developed that does not require
reconstitution and is not associated with contact dermatitis or pain at the injection site. In the clinical development program, 1 g intravenous acetaminophen has been
found to be bioequivalent to 2 g propacetamol.23 Moreover, clinical studies have shown that intravenous acetaminophen offers improved local safety at infusion sites,
compared with propacetamol.23
The aim of this study was to evaluate the analgesic
efficacy and safety of a single dose and repeated doses of
1 g intravenous acetaminophen in comparison with 2 g
propacetamol and placebo in patients experiencing
moderate to severe pain after total hip or knee replacement. These procedures were chosen because patients
recovering from them consistently experience moderate
to severe postoperative pain and require high doses of
opioid analgesics.24 –26
Materials and Methods
Patients
Patients aged at least 18 yr who were recovering from
total hip or knee replacement performed during general
or regional anesthesia and had an American Society of
Anesthesiologists physical status of I–III were eligible for
the study. Other entry criteria included body weight
between 50 and 120 kg, ability to use the pain scales and
to operate an intravenous PCA device, and reporting
baseline pain of moderate to severe intensity on a categorical rating scale.
Exclusion criteria included known allergy or hypersensitivity or contraindication to opioids or acetaminophen,
impaired liver function (transaminases ⬎ twice upper
limit), renal dysfunction (creatinine ⬎ 2.0 mg/dl), uncontrolled chronic diseases, known or suspected history
of alcohol or drug abuse. Patients who were pregnant or
breast-feeding were excluded. Patients were also exAnesthesiology, V 102, No 4, Apr 2005
823
cluded if they had received NSAIDs within 8 h, any
analgesic drug within 12 h, or corticosteroids within 7
days before administration of study medication.
The study was conducted in accordance with Good
Clinical Practice and the Declaration of Helsinki and was
approved by an institutional review board for each clinical center. All participating patients provided written
informed consent.
Study Design
This was a repeated-dose, randomized, double-blind,
placebo-controlled, three–parallel group study comparing intravenous acetaminophen and propacetamol to
placebo and was conducted in seven centers in the
United States (see appendix). Patients were enrolled
from September 1999 to June 2000.
Propacetamol was chosen as a comparator because it
is the only injectable, prodrug form of acetaminophen
commercially available and because, having been widely
prescribed for many years in Europe, its analgesic efficacy and safety profile have been well characterized.
The dose of 2 g propacetamol was chosen because it
releases 1 g intravenous acetaminophen.
During the screening visit scheduled within 21 days
before the administration of study drug, informed consent and medical history were obtained, physical examination and laboratory testing were performed, and training on the use of the intravenous PCA device and pain
scales was provided.
Patients received either general, spinal, or epidural
anesthesia as judged appropriate by the attending anesthesiologist on the day of surgery. They did not receive
epidural or intrathecal opioids or local anesthetics for
postoperative pain control. Most patients received general anesthesia, which included premedication with midazolam, isoflurane– desflurane, fentanyl, and morphine
for maintenance. In the postanesthesia care unit, when
patients first requested analgesics, a PCA pump containing morphine (1 mg/ml) was connected to the intravenous infusion. The PCA device was programmed to deliver 1-ml boluses of morphine on demand, with a
lockout time interval of 6 min. If adequate pain relief was
not achieved with the intravenous PCA device alone,
supplemental “rescue” boluses of 2 mg intravenous morphine were administered as needed.
On the morning of the first postoperative day, after
completion of routine nursing activities, the PCA device
was temporarily discontinued, and the total amount of
morphine administered to the patient was recorded.
A study observer closely monitored and recorded the
patients’ pain intensity. Patients reporting moderate to
severe intensity on a four-point verbal pain intensity
categorical scale (0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate,
and 3 ⫽ severe) were randomly assigned to one of the
three treatment groups: 1 g intravenous acetaminophen,
2 g propacetamol, or placebo. The study medications
SINATRA ET AL.
824
were prepared by an unblinded hospital pharmacist who
was not involved in the data collection. All of the study
medications were administered as a 100-ml solution infused over 15 min at 6-h intervals for the next 24 h. To
properly evaluate the local tolerance of the study medication at the infusion site, no other drug was administered through the cannula dedicated to infusion of the
study solution.
Efficacy Measurements
Pain intensity was measured immediately before the
start of infusion of study medication. The start of the
study drug infusion was defined as time 0. Pain intensity
at rest was measured at selected intervals (15, 30, and 45
min and 1, 2, 3, 4, 5, 6, 18, 20, and 24 h after the first
dose) with a 100-mm visual analog scale (VAS; 0 ⫽ no
pain to 100 ⫽ worst possible pain) and on a four-point
verbal scale (0 ⫽ none to 3 ⫽ severe). Pain relief (primary endpoint) was measured on a five-point verbal
scale (0 ⫽ none to 4 ⫽ complete) at the same selected
intervals up to 6 h. Time to rescue medication, quantity
of morphine used, and patients’ global evaluations over
the 24-h study interval were recorded.
Safety Assessments
Adverse events (AEs) and serious AEs were monitored
throughout the study period. Safety was also assessed by
infusion site examination, vital signs measurements (systolic and diastolic blood pressure, heart rate, and respiratory rate on the first postoperative day just before the
first infusion, 2 h after infusion, and on the morning of
day 2), and routine laboratory testing (hematology and
biochemistry before and 48 h after the surgery).
Statistical Analysis
Sample Size. A sample size of 50 patients per group
was required to detect a difference of at least one point
of pain relief (on the five-point categorical scale) for
active treatments versus placebo, with a 90% power and
a type I error at 0.0167 (two-sided test adjusted for three
comparisons).
All of the analyses were performed in the intent-totreat population.27
Efficacy analyses included 6-h single-dose pain intensity differences on categorical and visual scales (baseline
pain minus pain intensity at each time point), summary
measures of efficacy (weighted total pain relief, sum of
pain intensity difference and pain relief as measured on
a categorical scale, weighted summed pain intensity differences from baseline), peak effects, time to remedication (defined as time to request for rescue medication),
and PCA morphine use. For the entire 24-h study interval: pain intensity, PCA morphine use, and patients’
global evaluation.
The pain relief and pain intensity scores, global measures of efficacy, and quantity of rescue medication adAnesthesiology, V 102, No 4, Apr 2005
ministered were analyzed with an analysis of covariance
for overall difference among treatments and the Fisher
protected least significant difference for multiple comparison procedure. Time to peak effect and time to first
rescue remedication were analyzed using the stratified
Gehan-Wilcoxon test with center as the stratum variable
applied as the Fisher protected least significant difference procedure and survival distribution using the
Kaplan-Meier estimator. The Cochran-Mantel Haenszel
test stratified by center and applied as the Fisher protected least significant difference procedure was used
for analysis of patients requiring rescue medication and
patient global evaluation. Responders were defined as
subjects who had a reduction in pain intensity of at least
one unit. All efficacy analyses were performed on the
intent-to-treat population.
Safety Analyses
Adverse events were analyzed using the chi-square or
Fisher exact test, and descriptive statistics were used for
vital signs and laboratory evaluations. These analyses
were performed on the safety population (defined as the
set of all enrolled study subjects who received at least
one dose of study treatment).
Results
Patients
A total of 156 patients were randomized (intravenous
acetaminophen: n ⫽ 51; propacetamol: n ⫽ 52; placebo:
n ⫽ 53), and 151 patients (intravenous acetaminophen:
n ⫽ 49; propacetamol: n ⫽ 50; placebo: n ⫽ 52) received at least one dose of study medication. All of these
151 patients were included in the intent-to-treat population and analyzed for demographics, efficacy, and safety.
Most of the patients (137 of 151 [90.7%]) received four
administrations of the study drug over 24 h. Fourteen
patients (9.3%) withdrew from the study after the first
study drug administration: 3 (6.1%) from the intravenous
acetaminophen group, 6 (12.0%) from the propacetamol
group, and 5 (9.6%) from the placebo group. Six of these
patients were withdrawn because of consent withdrawal: 2 (4%) in the intravenous acetaminophen group, 2
(4%) in the propacetamol group, and 2 (3.8%) in the
placebo group. Four patients were withdrawn because
of AEs: 3 (5.9%) in the propacetamol group (local pain at
infusion site) and 1 (1.9%) in the placebo group (fever
necessitating treatment). Two patients were withdrawn
because of lack of compliance: 1 in the intravenous
acetaminophen group and 1 in the propacetamol group.
Two patients in the placebo group did not meet eligibility criteria but were included in the intent-to-treat
population.
The treatment groups were comparable with respect
to demographics, anesthetic and surgical procedure, and
IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN
825
Table 1. Baseline Patient Demographics (ITT Population)
Treatment Groups
1 g Intravenous
Acetaminophen
n
Age, yr
Mean
SD
Sex
Male, n (%)
Female, n (%)
Weight, kg
Mean
SD
Height, cm
Mean
SD
ASA physical status classification
I, n (%)
II, n (%)
III, n (%)
PAI (VAS), mm
Mean
SD
2 g Propacetamol
Placebo
Overall
P Value
49
50
52
61.7
16.9
59.5
14.2
59.2
13.4
60.1
14.8
0.656
28 (57.1)
21 (42.9)
27 (54)
23 (46)
22 (42.3)
30 (57.7)
77 (51)
74 (49)
0.288
85.7
13.0
85.7
18.8
81
17.3
84.1
16.6
0.246
171.8
10.7
171.6
12.8
168.7
10.6
170.7
11.4
0.317
3 (6.1)
34 (69.4)
12 (24.5)
3 (6.0)
32 (64.0)
15 (30.0)
3 (5.8)
37 (71.2)
12 (23.1)
62.0
19.1
55.7
17.6
56.4
16.9
151
9 (6.0)
103 (68.2)
39 (25.8)
58.0
18.0
0.792
0.156
ASA ⫽ American Society of Anesthesiologists; ITT ⫽ intent-to-treat; PAI ⫽ pain intensity measure on visual analog scale; VAS ⫽ visual analog scale.
baseline pain intensity. The overwhelming majority of
patients had symptoms of severe debilitating or painful
osteoarthritis. Patients were aged 22– 87 yr, had American Society of Anesthesiologists physical status of predominantly II (68.2%) or III (25.8%), and were experiencing moderate to severe pain (99%) after total hip
(57%) or knee replacement (43%) (standard cemented
arthroplasties) performed during general (64.2%), regional (21.8%), or combined general and regional anesthesia (13.9%). Before study drug administration, the
mean baseline pain intensity on the 100-mm VAS was
58 ⫾ 18 mm (table 1).
Efficacy Measures
Pain Intensity and Pain Relief Scores and Global
Measures of Efficacy.
Six-hour Evaluation Period (Single Dose). The
primary efficacy criterion was pain relief. For both active
groups, intravenous acetaminophen and propacetamol,
pain relief scores were significantly higher than those of
the placebo group from 15 min to 6 h (P ⬍ 0.05), with
no significant difference between the two active groups
(fig. 1).
Maximal pain relief scores were similar in the two
active groups (2.0 ⫾ 1.4) and significantly higher than
that observed in the placebo group (0.9 ⫾ 1.1). The
median time to peak effect for pain relief was 30 min in
both active groups.
Pain intensity differences (verbal scores and VAS) from
baseline were significantly higher for both active groups
in comparison with the placebo group at each assessAnesthesiology, V 102, No 4, Apr 2005
ment interval from 15 min (intravenous acetaminophen)
and 30 min (propacetamol) up to 6 h (P ⬍ 0.05; fig. 2).
Summary measures of efficacy over 6 h were equivalent in the intravenous acetaminophen and propacetamol groups and superior to that reported in the placebo
group (P ⬍ 0.05; table 2).
In general, the response was lower for all treatment
groups for the knee than for the hip surgery subjects.
However, the magnitude of the active treatments effect
(active vs. placebo) was statistically significant and similar for the hip and knee patients.
Median Time to First Rescue Medication. Time to
first rescue medication was significantly (P ⬍ 0.001)
longer for both active groups than for placebo but was
not significantly different between the two active
groups. The median (95% confidence interval) times to
first rescue medication were 3 (1.4 – 4.0) h for intravenous acetaminophen, 2.6 (1.6 – 4.0) h for propacetamol,
and 0.8 (0.6 –1.1) h for placebo (fig. 3). The analyses of
median time to rescue medication performed among
responders (defined as subjects who had a reduction in
pain intensity of at least one unit) showed that the median
times for first rescue medication were 4.0 (3.3– 4.3) h for
intravenous acetaminophen, 3.8 (2.5–5.2) h for propacetamol, and 1.6 (1.0 –2.6) h for placebo (table 3).
Pain Intensity over 24-h Evaluation Period (Repeated Dose). Throughout the 24-h evaluation period,
the mean VAS pain intensity scores were significantly
reduced in both active groups as compared with the
placebo group (⫺8 and ⫺10 mm for intravenous acetaminophen and propacetamol, respectively; P ⬍ 0.01).
826
SINATRA ET AL.
Fig. 1. Mean pain relief scores, single dose (intent-to-treat population). Comparisons versus placebo: * P < 0.05; ** P < 0.001.
Comparisons between active groups: not significant at each evaluation time. IV ⴝ intravenous.
Morphine Consumption. Morphine consumption
over the 6 h after the first dose was significantly (P ⬍
0.01) lower for both active groups (9.7 ⫾ 10 and 9.3 ⫾
8.9 mg for intravenous acetaminophen and propacetamol, respectively) than for the placebo group (17.8 ⫾
16.7 mg). This reduction was maintained over 24 h
(repeated doses), with total doses of 38.3 ⫾ 35.1, 40.8 ⫾
30.2, and 57.4 ⫾ 52.3 mg for intravenous acetaminophen, propacetamol, and placebo, respectively. Reduction of PCA morphine in the intravenous acetaminophen
group was 8 mg (⫺46%) after the first dose and 19 mg
(⫺33%) over 24 h (repeated doses). Reduction of PCA
morphine in the propacetamol group was 9 mg (⫺48%)
after the first dose and 17 mg (⫺29%) over 24 h (repeated doses).
Patient Global Evaluation. The patients’ global evaluations of satisfaction with study treatment after the
initial dose and at 24 h (repeated doses) were significantly (P ⬍ 0.01) higher for both active treatment
groups than for the placebo group. The proportions of
subjects with fair to excellent satisfaction with the study
treatment at 24 h were 79.6, 83.7, and 65.4% for intravenous acetaminophen, propacetamol, and placebo,
respectively.
Fig. 2. Mean pain intensity differences categorical scale, single dose (intent-to-treat population). Comparisons versus placebo: * P <
0.05; ** P < 0.001. Comparisons between active groups: not significant at each evaluation time. IV ⴝ intravenous.
Anesthesiology, V 102, No 4, Apr 2005
IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN
Table 2. Summary of Analgesic Efficacy Scores over 6 h (ITT
Population)
Mean score
⫾ SD
TOTPAR
SPID
SPRID
1 g Intravenous
Acetaminophen
(n ⫽ 49)
2 g Propacetamol
(n ⫽ 49)
Placebo
(n ⫽ 52)
6.6 ⫾ 5.9*
2.3 ⫾ 3.6*
9.0 ⫾ 8.7*
7.5 ⫾ 6.8*
2.5 ⫾ 4.3*
10.0 ⫾ 10.7*
2.2 ⫾ 3.8†
⫺0.6 ⫾ 3.5†
1.6 ⫾ 6.2†
*† When global test between all treatment groups was significant, individual
treatment group comparisons were examined. Means and medians associated with different symbols are significantly different.
ITT ⫽ intent-to-treat; SPID ⫽ weighted sum of pain intensity differences, with
pain intensity measured on verbal scale; SPRID ⫽ weighted sum of pain
relief—intensity differences; TOTPAR ⫽ weighted sums of pain relief.
Adverse Events
There was no significant difference between treatment
groups regarding the number of patients experiencing
AEs. Ninety-seven patients (64.2%) experienced at least
one AE after the first administration of the study medication: 32 (65.3%) in the intravenous 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 vomiting were the most frequently reported AEs (table 4).
Adverse events were considered related to the trial
medication in 38 patients (25.2%), with the highest number observed in the propacetamol group (25 patients
[50%]) and significantly less in the intravenous acetaminophen (4 [8.2%]) and placebo groups (9 [17.3%]) (P ⬍
0.05). The proportion of subjects reporting local administration site AEs was significantly (P ⬍ 0.001) lower for
intravenous acetaminophen (1 of 49 [2%]) than for
propacetamol (21 of 50 [38%]) and not different from
that of placebo (1 of 52 [2%]) (table 5). There was no
significant difference between the intravenous acetaminophen and placebo groups (table 5). In the propacetamol group, all of the local AEs were considered related
to the study drug. Nearly half of them led to reductions
in infusion dose rate, interruption of the infusion, or
even discontinuation of therapy.
Eight patients (5.3%) experienced 11 treatment-emergent serious AEs that were not considered related to the
study drug.
Intravenous acetaminophen and propacetamol infusions were not associated with clinically significant alterations in vital signs. Regarding blood chemistry test
results, hemoglobin, hematocrit, and leukocyte and
platelets counts, the incidence of treatment-emergent
clinically significant values was low. There were no
serious hepatic events related to treatment with intravenous acetaminophen.
Discussion
This study demonstrates that 1 g intravenous acetaminophen is a safe and effective intravenous, nonopioid
analgesic for the treatment of postoperative pain in patients recovering from lower extremity joint replacement surgery. Intravenous acetaminophen was similar to
propacetamol and consistently superior to placebo for
the main efficacy criterion of pain relief, as well as for
Fig. 3. Time to first rescue medication (intent-to-treat population). IV ⴝ intravenous.
Anesthesiology, V 102, No 4, Apr 2005
827
SINATRA ET AL.
828
Table 3. Median Time to Rescue Medication
Pairwise Comparisons
ITT population
n
Median time, h
95% CI
Responder population*
n
Median time, h
95% CI
1 g Intravenous
Acetaminophen
2 g Propacetamol
Placebo
49
3.0
1.4–4.0
48
2.6
1.6–4.0
52
0.8
0.6–1.1
35
4.0
3.3–4.3
35
3.8
2.5–5.2
21
1.6
1.0–2.6
Overall
P Value
Intravenous
Acetaminophen
vs. Placebo
Propacetamol
vs. Placebo
Intravenous
Acetaminophen vs.
Propacetamol
0.0001
0.0001
0.0001
0.437
0.001
0.008
0.537
* 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 ⫽ confidence interval; ITT ⫽ intent-to-treat.
pain intensity changes from 15 min to 6 h after the first
dose and throughout the 24-h evaluation period after repeated dose administration. In addition, intravenous acetaminophen had significantly improved local tolerability.
Acetaminophen (paracetamol) is a widely prescribed
analgesic devoid of clinically significant antiinflammatory effects. Intravenous administration of acetaminophen either as intravenous acetaminophen or propacetamol avoids variabilities associated with gastric
absorption and first-pass hepatic metabolism, resulting in
higher plasma concentrations and greater analgesic efficacy than orally administered drug.28
Major orthopedic surgery is extremely painful, and
monotherapy with acetaminophen would not be expected to provide complete relief on the day surgery was
performed. Therefore, in the current investigation, acetaminophen infusions were started the day after surgery
to allow patients to stabilize in the acute postoperative
setting and to reduce confounding factors for drug assessment, e.g., the possible synergistic analgesic effect of
the anesthetic on the study drug in the postoperative
period. This also allowed the evaluation of the monotherapeutic efficacy of intravenous acetaminophen in
reducing pain intensity. Onset and duration of analgesic
effect for intravenous acetaminophen and propacetamol
seemed comparable to data previously reported for
propacetamol.16 Although double-stopwatch assessments of perceptible and meaningful effect were not
performed, the assessment used (a minimum of 10 mm
decrease in VAS pain intensity) provided a reasonable
Table 4. Adverse Events Greater Than 5% in Any Treatment Group (Safety Population)
Treatment Groups
n (%)
No. of patients with ⱖ1 AE
No. of patients with ⱖ1 AE
Gastrointestinal system disorders*
Constipation
Nausea
Vomiting
Abdomen enlarged
Other gastrointestinal disorder
Application site disorders
Injection site pain
Injection site reaction
Body-as-a-whole general disorders
Fever
Erythrocyte disorders
Anemia
Skin and appendage disorders
Pruritus
Respiratory system disorders
Coughing
1 g Intravenous
Acetaminophen
(n ⫽ 49)
32 (65.3)
4 (8.2)
21 (42.9)
10 (20.4)
13 (26.5)
6 (12.2)
3 (6.1)
3 (6.1)
2 (4.1)†
2 (4.1)†
0
4 (8.2)
1 (2.0)
4 (8.2)
4 (8.2)
5 (10.2)
5 (10.2)
4 (8.2)
3 (6.1)
2 g Propacetamol
(n ⫽ 50)
Placebo
(n ⫽ 52)
33 (66.0)
25 (50.0)
16 (32.0)
8 (16.0)
9 (18.0)
3 (6.0)
0
0
21 (42)
19 (38.0)
3 (6.0)
3 (6.0)
1 (2.0)
5 (10.0)
5 (10.0)
4 (8.0)
4 (8.0)
0
0
32 (61.5)
9 (17.3)
16 (30.8)
12 (23.1)
7 (13.5)
3 (5.8)
0
1 (1.9)
1 (1.9)
1 (1.9)
0
10 (19.2)
6 (11.5)
7 (13.5)
7 (13.5)
5 (9.6)
5 (9.6)
3 (5.8)
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 ⫽ adverse event.
Anesthesiology, V 102, No 4, Apr 2005
IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN
829
Table 5. Summary of Local Treatment-Emergent Adverse Events
Treatment Groups
Total No. of patients
Total No. of patients with ⱖ1 local AE, n (%)
Injection site pain
Injection site reaction
Extravasation
No. of patients with serious local AEs, n (%)
No. of patients who discontinued because of local AEs, n (%)
No. of patients with ⱖ1 related local AE, n (%)
1 g Intravenous
Acetaminophen
2 g Propacetamol
Placebo
49
1 (2.0)
1 (2.0)
0
0
0
0
1 (2.0)
50
21 (42.0)
19 (38.0)
3 (6.0)
0
0
3 (6.0)
21 (42.0)
52
1 (1.9)
1 (1.9)
0
0
0
0
1 (1.9)
P Value
0.001*
* Pairwise comparisons: intravenous acetaminophen vs. placebo: P ⫽ 0.610; propacetamol vs. placebo: P ⫽ 0.001; intravenous acetaminophen vs. propacetamol: P ⫽ 0.001.
AE ⫽ adverse event.
criterion as to time of analgesic onset. Using this calculated change in pain intensity, time to onset of analgesia
can be estimated as less than 15 min with either intravenous acetaminophen or propacetamol. The median
time to peak analgesic effect was 30 min in both active
groups for pain relief, with no difference between active
groups.
Analgesic duration was defined as the time to request
for restarting PCA morphine after intravenous infusion
of study drug. This is an underestimate of the true analgesic duration because subjects who do not experience
analgesia do not contribute to the measurement of duration of analgesia. In the routine clinical setting, monotherapy with nonopioid analgesics would not be expected to eliminate opioid dosing in patients recovering
from major orthopedic surgery. Significant pain intensity
reductions and morphine sparing were noted beyond
the restart PCA time and continued through out the
entire 6-h interval for patients receiving active drugs,
giving further evidence of analgesic duration. Furthermore, the protocol allowed patients to adjust their optimal level of analgesia with self-administration of PCA
morphine before study drug infusion. Intravenous acetaminophen allowed responders to recapture a level of
analgesia equivalent to that provided by PCA morphine
and to maintain it for 4 h, while plasma concentrations
of morphine continued to decrease. Therefore, when
opioid rescue is finally required, only a small amount of
PCA morphine is necessary to reach the level of analgesia noted before randomization.
Advocates of multimodal analgesia suggest that coadministration of nonopioid analgesics reduces opioid consumption and pain intensity and may reduce opioidrelated AEs.5,6
In the current investigation, both active drugs reduced
the need for rescue doses of PCA morphine administered
during the initial 6-h efficacy evaluation (46% for the
intravenous acetaminophen group) and over the entire
24-h study interval (33% for the intravenous acetaminophen group). Patients treated with acetaminophen infuAnesthesiology, V 102, No 4, Apr 2005
sions required approximately one third less PCA morphine than those treated with placebo. This percentage
reduction in 24-h morphine dose compares favorably
with morphine-sparing effects previously reported for
propacetamol infusion17–19 and for injectable NSAIDs
and selective COX-2 inhibitors.7,29,30
Opioid sparing would be expected to provide clinical
advantages in patients who are sensitive to opioid-induced sedation, confusion, respiratory depression, and
gastrointestinal complications. Despite significant reductions in opioid exposure, no differences were observed
in nausea, vomiting, or constipation (their incidence was
low in all of the treatment groups). Evaluation of sedation, confusion, and respiratory depression were not
endpoints of this study; a much larger number of subjects would likely be required to determine any significant differences between study drugs. However, only
approximately 20% of the studies have demonstrated an
improvement in opioid-related symptoms,31 probably
because many of the opioid-related side effects may also
be reinforced by neural reflexes as components of surgical stress.32
It is possible that earlier administration of intravenous
acetaminophen, starting the morning of surgery and continuing for up to 48 h, could have further reduced opioid
consumption to the point that significant reductions in
nausea and constipation could have been detected.
Morphine has been considered the accepted standard
of analgesia. In the immediate postoperative setting,
optimal analgesia cannot always be achieved with intravenous opiates used as monotherapy. As noted previously, the global measures of efficacy over 6 h were
equivalent in the intravenous acetaminophen and
propacetamol groups and superior to those reported in
the placebo group (P ⬍ 0.05). A balanced, multimodal
approach may therefore provide better efficacy results.
This study and numerous other studies report that pain
intensity scores are significantly reduced in patients
treated with intravenous acetaminophen, propacetamol,16 COX-2 inhibitors,29,30 or NSAIDs7 as adjuncts to
SINATRA ET AL.
830
PCA morphine compared with PCA morphine alone.
Zhou et al.16 reported lower pain intensity scores in
patients treated with either ketorolac or propacetamol
compared with placebo, despite the fact that all patients
treated could self-administer additional PCA morphine
and theoretically achieve equivalent levels of analgesia.
The risks and benefits of any treatment must be considered before implementation. Although NSAIDs and
COX-2 inhibitors offer effective augmentation of opioidbased analgesia, concerns have been raised regarding
their use perioperatively. NSAIDs inhibit platelet function, increase perioperative bleeding, and have been
shown to have nephrotoxic effects in patients with and
without preexisting renal insufficiency.20,33–35 Selective
COX-2 inhibitors have been associated with salt and
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
greater incidence in sternal wound infection and proportionally greater incidences of other serious AEs, including cerebrovascular complications, myocardial infarction, and renal dysfunction, have been reported with
COX-2 inhibitors in patients undergoing coronary artery
bypass surgery.40 Acetaminophen offers a historically
low incidence of adverse effects and untoward drug
interactions. However, higher-than-recommended doses
have been associated with hepatotoxicity and hepatic
failure.41 When used according to the labeling, propacetamol has been associated with liver dysfunction in less
than 1 case per 500,000 treated patients (postmarketing
surveillance). A similar safety record has been observed
with intravenous acetaminophen during the 2 yr after its
availability in the European Union. Consistent with this
historic safety profile, there was no difference in this
study between groups regarding clinically significant increases in liver function test results in patients receiving
up to four doses of active study medication or placebo
over the 24-h evaluation interval.
Intravenous acetaminophen was well tolerated in the
elderly and high-risk (American Society of Anesthesiologists physical status II and III) population included in the
current study. As reported previously, AEs with propacetamol and the need to discontinue therapy were primarily related to pain at the infusion site.16,28 In contrast,
and in accord with a previous clinical trial,23 the incidence of local AEs with intravenous acetaminophen was
similar to that observed with placebo and significantly
lower than that noted in the propacetamol group.
In addition to providing comparable analgesic efficacy
and an improved local safety profile, advantages of intravenous acetaminophen over propacetamol include ease
of use and cost effectiveness.16,22
In conclusion, 1 g intravenous acetaminophen administered as a single infusion and repeated infusions in
patients with moderate to severe postoperative pain
Anesthesiology, V 102, No 4, Apr 2005
after major orthopedic joint replacement surgery is effective, safe, and well tolerated. Intravenous acetaminophen, 1 g, was similar to 2 g propacetamol with regard
to efficacy and was superior to propacetamol with regard to local AEs (pain at infusion site), a significant
advantage for the patients in terms of tolerance and
compliance. These data suggest that intravenous acetaminophen is a useful component of the multimodal
analgesia model, especially after major orthopedic
surgery.
The authors thank Jonathan S. Deutsch, M.D. (Bristol-Myers Squibb Company,
Hillside, New Jersey), and Laurence Saya, M.D. (Altius Pharma CS, Paris, France),
for reviewing the manuscript and Nathalie Schmidely (Statistician, Bristol-Myers
Squibb Company, Rueil-Malmaison, France) and Selim Rachidi (Clinical Research
Associate, Bristol-Myers Squibb Company, Hillside, New Jersey) for their contribution to the study.
References
1. Dahl JL, Gordon D, Ward S, Skemp M, Wochos S, Schurr M: Institutionalizing pain management: The Post-Operative Pain Management Quality Improvement Project. J Pain 2003; 4:361–71
2. Warfield CA, Kahn CH: Acute pain management: programs in U.S. hospitals
and experiences and attitudes among U.S. adults. ANESTHESIOLOGY 1995;
83:1090 –94
3. Apfelbaum JL, Chen C, Mehta SS, Gan TJ: Postoperative pain experience:
Results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003; 97:534 – 40.
4. Huang N, Cunningham F, Laurito CE, Chen C: Can we do better with
postoperative pain management. Am J Surg 2001; 182:440 – 8
5. Kehlet H, Dahl JB: The value of “multimodal” or “balanced analgesia” in
postoperative pain treatment. Anesth Analg 1993; 77:1048 –56
6. Dahl JB, Rosenberg J, Dirkes WE, Mogensen T, Kehlet H: Prevention of
postoperative pain by balanced analgesia. Br J Anaesth 1990; 64:518 –20
7. Etches R, Warriner CB, Badner N, Buckley DN, Beotrie WS, Chan VW,
Parsons D, Girard M: Continuous intravenous administration of ketorolac reduces
pain and morphine consumption after total knee and hip arthroplasty. Anesth
Analg 1995; 81:1175– 80
8. Rueben S, Conely N: Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg 2000; 91:1221–5
9. Buvanendran A, Kroin J, Truman K, Lubenow T, Elmofty D, Moric M,
Rosenberg A: Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement. JAMA 2003; 290:2411– 8
10. Schiodt FV, Rochling FA, Casey DL, Lee WM: Acetaminophen toxicity in an
urban county hospital. N Engl J Med 1997; 337:1112–7
11. Bannwarth B, Péhourcq F: Pharmacological rationale for the clinical use of
paracetamol: pharmacokinetic and pharmacodynamic issues. Drugs 2003; 63:2–5
12. Day RO, Graham GG, Whelton A: The position of paracetamol in the
World of Analgesics. Am J Ther 2000; 7:51–54
13. Bannwarth B, Netter P, Lapicque F, Gillet P, Pere P, Boccard E, Royer RJ,
Gaucher A: Plasma and cerebrospinal fluid concentrations of paracetamol after
single intravenous dose of propacetamol. Br J Clin Pharmacol 1992; 34:79 – 81
14. Hynes D, Mc Carrol M, Gerin M, Van Holder K: Propacetamol versus
diclofenac and placebo for postoperative pain control after total hip arthroplasty.
Seattle: International Association for the Study of Pain Press. 8th World Congress
on Pain, August 17–22, 1996, pp 266 –7
15. Varrassi G, Marinangeli F, Agro F, Aloe L, De Cillis P, De Nicola A, Giunta
F, Ischia S, Ballabio M, Stefanini S: A double-blinded evaluation of propacetamol
versus ketorolac in combination with patient-controlled analgesia morphine:
Analgesic efficacy and tolerability after gynecologic surgery. Anesth Analg 1999;
88:611– 6
16. Zhou TJ, Tang J, White PF: Propacetamol versus ketorolac for treatment of
acute postoperative pain after total hip or knee replacement. Anesth Analg 2001;
92:1569 –75
17. Peduto VA, Ballabio M, Stefanini S: Efficacy of propacetamol in the treatment of postoperative pain: Morphine-sparing effect in orthopedic surgery.
Italian Collaborative Group on Propacetamol. Acta Anaesthesiol Scand 1998;
42:293– 8
18. Delbos A, Boccard E: The morphine-sparing effect of propacetamol in
orthopedic postoperative pain. J Pain Symptom Manage 1995; 10:279 – 86
19. Hernández-Palazón J, Tortosa JA, Martínez-Lage JF, Pérez-Flores D: Intravenous administration of propacetamol reduces morphine consumption after
spinal fusion surgery. Anesth Analg 2001; 92:1473– 6
IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN
20. Haas DA: An update on analgesics for the management of acute postoperative dental pain. J Can Dent Assoc 2002; 68:476 – 82
21. Bonnefont J, Courade JP, Allaoui A, Eschalier A: Mechanism of the antinociceptive effect of paracetamol. Drugs 2003; 63(suppl 2):1– 4
22. Schmitt E, Vainchtock A, Nicoloyannis N, Locher F, Mesrobian X: Ready to
use injectable paracetamol: Easier, safer, lowering workload and costs. Journal of
the European Association of Hospital Pharmacists 2003; 9:96 –102
23. Flouvat B, Leneveu A, Fitoussi S, Delhotal-Landes B, Gendron A: Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects. Int J Clin Pharmacol
Ther 2004; 42:50 –57
24. De Andrade JR, Maslanka M, Reines HD, Howe D, Rasmussen GL, Cardea
J, Brown J, Bynum L, Shefrin A, Chang YL, Maneatis T: Ketorolac versus meperidine for pain relief after orthopaedic surgery. Clin Orthop 1996; 325:301–12
25. Grace D, Fee JP: A comparison of intrathecal morphine-6-glucoronide and
intrathecal morphine sulfate as analgesics for total hip replacement. Anesth Analg
1996; 83:1055–9
26. Kinsella J, Moffat AC, Patrick JA, Prentice JW, Mc Ardle CS, Kenny GN:
Ketorolac trometamol for postoperative analgesia after orthopaedic surgery. Br J
Anaesth 1992; 69:19 –22
27. Gillings D, Koch G: The application of the principle of intention-to-treat to
the analysis of clinical trials. Drug Information J 1991; 25:411–24
28. Jarde O, Boccard E: Parenteral versus oral route increases paracetamol
efficacy. Clin Drug Invest 1997; 14:474 – 81
29. Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC: Intravenous
parecoxib sodium for acute pain after orthopedic surgery. Am J Orthop Surg
2002; 31:336 – 43
30. Malan TP, Marsh G, Hakki SI, Grossman E: Parecoxib sodium, a parenteral
cyclooxygenase-2 selective inhibitor improves morphine analgesia and is opioid
sparing following total hip arthroplasty. ANESTHESIOLOGY 2003; 98:950 – 6
31. Kehlet H, Rung GW, Callesen T: Postoperative opioid analgesia: Time for
a reconsideration? J Clin Anesth 1996; 8:441–5
32. Kehlet H, Werner MU: Role of paracetamol in acute pain management.
Drugs 2003; 63(suppl 2):15–21
33. Patel NY, Landercasper J: Ketorolac-induced postoperative acute renal
failure: A case report. Wis Med J 1995; 94:445–7
34. Strom BL, Berlin JA, Kinman JL, Spitz PW, Hennessy S, Feldman H, Kimmel
S, Carson JL: Parenteral ketorolac and risk of gastrointestinal and operative site
bleeding: A postmarketing surveillance study. JAMA 1996; 275:376 – 82
35. RuDusky BM: Severe postoperative hemorrhage attributed to single-dose
parenteral ketorolac-induced coagulopathy. Angiology 2000; 51:999 –1002
Anesthesiology, V 102, No 4, Apr 2005
831
36. Wright J: The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002;
167:1131–7
37. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B,
Cullinane D, Einhorn T: Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 2003; 21:670 –5
38. Simon AM, Manigrasso MB, O’Connor JP: Cyclo-oxygenase 2 function is
essential for bone fracture healing. J Bone Miner Res 2002; 17:963–76
39. Endo K, Sairyo K, Komatsubara S, Sasa T, Egawa H, Yonekura D, Adachi K,
Ogawa T, Murakami R, Yasui N: Cyclooxygenase-2 inhibitor inhibits the fracture
healing. J Physiol Anthropol Appl Human Sci 2002; 21:235– 8
40. Ott E, Nussmeier N, Duke P, Feneck R, Alston R, Snabes M, Hubbard R,
Hsu P, Saidman L, Mangano D: Efficacy and safety of the cyclooxygenase 2
inhibitors parecoxib and valdecoxib in patients undergoing coronary artery
bypass surgery. J Thorac Cardiovasc Surg 2003; 125:1481–92
41. Sheen CL, Dillon JF, Bateman DN, Simpson KJ, MacDonald TM: Paracetamol toxicity: Epidemiology, prevention and costs to the health-care system. Q
J Med 2002; 95:609 –19
Appendix: Participating Centers
Raymond S. Sinatra, M.D., Ph.D., Professor, Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut
(10 patients); Jonathan S. Jahr, M.D., Professor, University of California,
Sacramento, California (65 patients); Lowell W. Reynolds, M.D., Associate Professor, Center for Pain Management, Loma Linda, California
(49 patients); Robert Mandel, M.D., Attending Anesthesiologist, Department of Anesthesia, Cooper Hospital, Camden, New Jersey (1
patient); Brian Ginsberg, M.D., Professor of Anesthesiology, Duke University School of Medicine, Durham, North Carolina (3 patients); Eugene R. Viscusi, M.D., Associate Professor, Department of Anesthesiology, Jefferson Medical College, Philadelphia, Pennsylvania (16
patients); Scott B. Groudine, M.D., Associate Professor, Department of
Anesthesiology, Albany Medical College, Albany, New York (12
patients).