papr_426 290..

296
REVI EW ARTI CLE
A Literature Review of
Randomized Clinical Trials of
Intravenous Acetaminophen
(Paracetamol) for Acute
Postoperative Pain
Alex Macario, MD, MBA*; Mike A. Royal, MD, JD, MBA

*Departments of Anesthesia and Health Research and Policy, Stanford University School of
Medicine, Stanford;

Clinical DevelopmentAnalgesics, Cadence Pharmaceuticals, Inc., San
Diego, California, U.S.A.
Abstract
Introduction: This studys objective was to systematically
review the literature to assess analgesic outcomes of intra-
venous (IV) acetaminophen for acute postoperative pain in
adults.
Methods: We searched Medline and the Cochrane library
(January 1, 2000 to January 17, 2010, date of last search) for
prospective, randomized, controlled trials (RCTs) of IV
acetaminophen vs. either an active comparator or placebo.
Results: Sixteen articles from 9 countries published
between 2005 and 2010 met inclusion criteria and had a total
of 1,464 patients. Median sample size = 54 patients (range 25
to 165) and median follow-up = 1 day (range 1 hour to 7
days). Four of the 16 articles had 3 arms in the study. One
article had 4 arms. As a result, 22 study comparisons were
analyzed: IV acetaminophen to an active comparator (n = 8
studies) and IV acetaminophen to placebo (n = 14 studies).
The RCTs were of high methodological quality with Jadad
median score = 5. In 7 of 8 active comparator studies (IV
parecoxib [n = 3 studies], IV metamizol [n = 4], oral ibuprofen
[n = 1]), IV acetaminophen had similar analgesic outcomes as
the active comparator. Twelve of the 14 placebo studies
found that IV acetaminophen patients had improved anal-
gesia. Ten of those 14 studies reported less opioid consump-
tion, a lower percentage of patients rescuing, or a longer
time to rst rescue with IV acetaminophen. Formal meta-
analysis pooling was not performed because the studies had
different primary end points, and the IV acetaminophen
dosing regimens varied in dose, and duration and timing.
Conclusion: In aggregate, these data indicate that IV
acetaminophen is an effective analgesic across a variety of
surgical procedures.
Key Words: intravenous acetaminophen, analgesics,
non-narcotic, postoperative pain, systematic review
INTRODUCTION
Further efforts to reduce postoperative pain require
introduction of new analgesics into clinical practice.
Oral acetaminophen, or paracetamol that is the
Address correspondence and reprint requests to: Alex Macario, MD,
MBA, Department of Anesthesia H3580, Stanford University School of
Medicine, Stanford, CA 94305-5640, U.S.A. E-mail: amaca@stanford.edu.
Disclosures: This study was funded in part by Cadence Pharmaceuticals,
Inc. Dr. Macarios contribution to this publication was as a paid consultant
to Cadence Pharmaceuticals, Inc. Dr. Royal is VP, Clinical Development
Analgesics, Cadence Pharmaceuticals, Inc.
Submitted: July 1, 2010; Accepted: September 8, 2010
DOI. 10.1111/j.1533-2500.2010.00426.x
2010 The Authors
Pain Practice 2010 World Institute of Pain, 1530-7085/11/$15.00
Pain Practice, Volume 11, Issue 3, 2011 290296
international nonproprietary name for acetaminophen,
has been well known as a safe and effective analgesic,
and antipyretic for more than a century. In some con-
texts, it is abbreviated as APAP, for N-acetyl-para-
aminophenol. However, although intravenous (IV)
acetaminophen has been approved in approximately 80
countries, it is not currently available in the U.S.A.
IV acetaminophen (OFIRMEV, Cadence Pharma-
ceuticals, Inc., San Diego, CA, U.S.A.) is currently under
development for the treatment of acute pain and fever in
pediatric and adult populations. The objective of this
study was to systematically review the literature to
assess analgesic outcomes of IV acetaminophen for
acute postoperative pain in adults. Studies of IV propac-
etamol, the pro-drug to acetaminophen, were not
included in this study as it is being phased out of clinical
practice in Europe and is not approved for use in the
U.S.A.
METHODS
Systematic reviews apply strategies that limit bias to the
assembly, appraisal, and synthesis of relevant studies on
a specic topic.
1,2
We followed published guidelines
3,4
to
search the National Library of Medicines Medline and
the Cochrane library databases (January 1, 2000 to
January 17, 2010, date of last search) for prospective,
randomized, controlled trials (RCTs) of IV acetami-
nophen vs. either an active comparator (except for pro-
pacetamol) or placebo on adult patients undergoing
surgery and receiving general anesthesia, regional anes-
thesia, sedation, or local anesthesia. We limited our
review to English language articles. Data from posters/
abstracts, letters, retrospective trials, case reports, and
unpublished data were not considered. No minimum
sample sizes were required for inclusion of studies.
The following text word search terms were used:
Randomized AND prospective AND postopera-
tive analgesia AND clinical AND trial AND
pain AND patient AND surgery AND
acetaminophen OR paracetamol NOT spec-
trometry NOT cytokine NOT receptor NOT
children NOT damage NOT overdose NOT
temperature NOT suicide NOT hepatocyte
NOT bioavailability NOT oral paracetamol
NOT neonatal NOT osteoarthritis NOT oral
propacetamol NOT propacetamol.
After reviewing the titles and abstracts of these 1,562
unique citations, a full-text article was obtained for 74
potentially appropriate studies for further screening, of
which 58 were disqualied. The most common reasons
for disqualication were: suppository or oral tablets not
IV acetaminophen administered (n = 10), foreign lan-
guage (eg, Russian, Turkish) articles (n = 8), end point
(eg, renal colic, fever, cancer pain) not postoperative
pain (n = 7), pediatric studies (n = 6), study not on sur-
gical patients (n = 6), reviews (n = 5), IV acetaminophen
given in both study groups so comparison not possible
(n = 4), propacetamol studied instead of IV acetami-
nophen (n = 4), study confounded by another analgesic
in protocol (n = 2), letter to editor (n = 1), no anesthesia
required for surgery (n = 1), acetaminophen given for IV
regional technique (n = 1), no active comparator for IV
acetaminophen (n = 1), comparator is propacetamol
(n = 1), and no inferential statistics on end point (n = 1).
The reference lists of the articles were hand searched for
any additional articles (none were found).
The two authors independently abstracted data from
the studies on to a standardized data extraction form,
which included surgical procedure, sample sizes, IV
acetaminophen dose and schedule of administration,
active comparator drug if not placebo, primary end
point, other end points, rescue analgesic used, whether a
power analysis was done, length of follow-up, and
funding. Differences between the two reviewers were
resolved by reexamination of the original article until
consensus was obtained. The Jadad Scale was used to
assess the quality of the RCTs.
5
It includes ve criteria:
Is the study randomized? Is the study double blinded? Is
there a description of withdrawals (patients that
dropped out of study)? Is the randomization adequately
described? Is the method for blindness adequately
described?
These items elicit yes or no answers, such that
each study was scored from 0 to 5.
RESULTS
Sixteen full-length articles from 9 countries published
between 2005 and 2010 met our inclusion criteria and
were fully analyzed (Table 1).
Overall, there were 1,464 patients included in the 16
RCTs including a total of 780 patients who received IV
acetaminophen. The median sample size including
control groups equaled 54 patients (average 68, range
25 to 165), with median follow-up of 1 day (average
1.54 days, range 1 hour to 7 days).
Four of the 16 articles had 3 arms in the study: a
placebo group, an IV acetaminophen group, and an
active comparator or a second IV acetaminophen group
with different timing of dosing. One article had 4 arms,
Intravenous Acetaminophen Studies 291
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Intravenous Acetaminophen Studies 293
including an active comparator. Therefore, a study is a
single comparison and one article may contain more
than one study. A total of 22 study comparisons were
analyzed: IV acetaminophen to an active comparator
(n = 8 studies) and IV acetaminophen to placebo (n = 14
studies). Rescue analgesic was morphine (n = 9 studies),
meperidine (n = 5), oxycodone (n = 3), ibuprofen
(n = 3), and tilidine (n = 2), which is an opioid only
available in Europe.
STUDY QUALITY
The RCTs were of generally high methodological
quality as measured by the Jadad Scale, with median
score = 5 (range 2 to 5). Fifteen of the 22 studies had the
highest quality score of 5. All studies except one
reported an a priori power analysis.
RCTs WITH AN ACTIVE COMPARATOR
Overall, in 7 of the 8 studies with an active comparator
arm (IV parecoxib [n = 3 studies], IV metamizol [n = 4],
oral ibuprofen [n = 1]), IV acetaminophen was found to
have similar analgesic outcomes as the active compara-
tor. Three of these 8 studies also reported that IV
acetaminophen patients had a signicant reduction in
mean opioid consumption, a lower percentage of
patients rescuing (dened as the fraction needing any
rescue), or a longer time to rst rescue with IV acetami-
nophen compared with the active comparator patients.
RCTs WITH A PLACEBO CONTROL
Twelve of the 14 placebo-controlled studies found that
IV acetaminophen patients had improved analgesia. Ten
of the 14 placebo-controlled studies found either a sig-
nicant reduction in mean opioid consumption or a
lower percentage of patients rescuing with IV acetami-
nophen. One study that had no observed pain difference
found that IV acetaminophen patients did need less
rescue compared with placebo patients.
STATISTICS
Formal meta-analysis pooling of the efcacy results was
not performed because:
1. the IV acetaminophen dosing regimen varied
among studies (eg, a single 1-g dose given either
before surgery or during surgery, 1 g adminis-
tered every 6 hours for 24 hours, or 1 g given
once a day every day for 7 days).
2. the studies had different primary end points: pain
score at rest or with movement (11 studies),
opioid reduction (5 studies), need for rescue anal-
gesic (3 studies), pain relief on a 5-point categori-
cal scale (2 studies), or difference between mean
pain scores (1 study). Also, duration of follow-up
ranged from less than 1 hour to 3 days, with
median of 1 day.
Not enough articles were available to separate
surgery types into those associated with mild, moderate,
and severe pain. Also, it was not possible to assess
statistically whether IV acetaminophen affected the inci-
dence of opioid side effects, because the end point was
either not reported (eg, postoperative nausea and vom-
iting [PONV] not reported in n = 5 studies and pruritis
not reported in n = 13 studies), denitions differed (eg,
PONV on visual analog scale, nausea only, vomiting
only, or nausea and vomiting combined), or end points
occurred infrequently when measured such that the
trials were not appropriately powered to assess side
effect differences.
DISCUSSION
Overall, 12 of 14 placebo-controlled studies found that
patients receiving IVacetaminophen had improved anal-
gesia. When compared with IVparecoxib, IVmetamizol,
or oral ibuprofen, IV acetaminophen was found to have
similar analgesic outcomes as the active comparator in 7
of the 8 studies. Parecoxib is a cyclo-oxygenase (COX)-
2-specic anti-inammatory agent not approved in the
U.S.A. Metamizol is a nonsteroidal anti-inammatory
drug removed fromthe U.S. market in the 1970s because
of its side effect prole, particularly agranulocytosis.
In aggregate, the data from 1,464 patients (780
received IV acetaminophen) included in the 16 RCTs
indicate that IV acetaminophen is an effective analgesic
in a variety of inpatient and ambulatory surgical proce-
dures. The RCTs were of generally high methodological
quality, consistent with a recent analysis showing that
acute pain studies are not published unless they contain
specic statements describing the primary end points,
power analysis, and statistical treatment of data from
withdrawals, dropouts, and protocol violations.
6
However, the heterogeneity in methods and, in particu-
lar, the denitions of the primary end points, as well as
the variability in IV acetaminophen dosing regimens did
not permit a formal meta-analysis with pooling of
results. IV acetaminophen use was not associated with
increased adverse events compared with placebo within
the limited median follow-up duration for the placebo
studies analyzed being no longer than 3 days and usually
294 macario and royal
just 1 day. When prescribing IV acetaminophen for
surgical pain, attention must be paid to patients at risk
for hepatotoxicity.
7
The extent to which pain reduction is observed with
an analgesic in a RCT may depend on the surgical
procedure studied because if the procedure intrinsically
is not very painful, then it will be more difcult to
demonstrate a pain relief benet. In the available pub-
lished RCTS, IV acetaminophen was studied in surgeries
associated with varying levels of pain, including Cesar-
eans, total abdominal hysterectomy, tonsillectomy,
coronary artery bypass grafting, thyroidectomy, hip or
knee replacement, and laparoscopic cholecystectomy
procedures. The average postoperative rest pain scores
in the placebo arms of these studies ranged from 2.0 to
3.7 out of 10, and for dynamic pain, it ranged from 3 to
5 out of 10.
Two of the 14 placebo-controlled studies found no
pain improvement or less opioid use with IV acetami-
nophen. One study involved patients undergoing
lumbar discectomy who were administered a single 1-g
dose 45 minutes before the end of surgery and with pain
followed for 2 hours in the post-anesthesia care unit
(PACU) (reference 6 in Table 1). This study also found
no difference between IV acetaminophen and an active
comparator IV parecoxib, whereas IV metamizol
patients had lower pain scores on arrival to PACU with
fewer patients requiring rescue.
The second study involved patients undergoing
breast resection, or mastectomy with or without axillary
resection, with a 1-g dose 20 minutes before the end of
surgery and pain followed for 24 hours (reference 13 in
Table 1). Although no difference in total morphine use
was detected, 42% of IV acetaminophen patients did
not receive any morphine, compared with 4% in
placebo group. The authors also found that 2 of the 13
patients with more extensive surgical procedures (eg,
axillary dissection) that received IV acetaminophen did
not request morphine in the rst 24 hours postopera-
tively, whereas all placebo patients did. IV acetami-
nophen patients did have signicantly less pain only at
the 1-hour measurement when compared with placebo,
but from 2 to 24 hours postoperatively, average pain
ratings were below 2.5 in both groups and did not differ.
Five of the studies analyzed had opioid reduction as
the primary end point. However, this end point has
several limitations including inter-individual variability
in sensitivity to opioids and variability in the level of
tolerable pain.
8
For opioid delivered by patient-
controlled analgesia, other confounders include an
initial learning curve for proper pump use, and patients
may worry that they are pushing the button too often,
creating a self-imposed maximum. In addition, when
morphine consumption is used as an end point, the
sample sizes required for 80% power are approximately
twice that predicted unless one adjusts for age.
9
Although the exact site and mechanism of action of
acetaminophen is not clearly dened, the central nervous
system is the active compartment, and it likely involves
central COX inhibition and cannabinoidergic effects,
along with indirect analgesic serotoninergic effects.
10
Pain research efforts over the past 5 decades have not yet
yielded many other new analgesics for use in the periop-
erative setting. Explanations for this include: a lack of a
mechanism-based classication of pain syndromes that
makes it difcult to generate testable hypotheses, an
inadequate predictive validity of animal models that
translate into pain outcomes in humans, and the Food
and Drug Administrations (FDA) requirement of safety
and efcacy against placebo, rather than superiority to an
active comparator, which contributes to development of
me-too drugs.
11
Preemptive dosing to time the peak pharmacodynamic
effect of IV acetaminophen to optimize analgesic effec-
tiveness has been studied clinically. For example, in a
study of patients undergoing total abdominal hysterec-
tomy, IV acetaminophen 1 g administered 30 minutes
prior to surgical incision (prior to induction) resulted in a
greater reduction in total morphine consumption com-
pared with administering the same dose at the end of
surgery just prior to skin closure (reference 2 in Table 1).
Limitations
Our systematic review had several limitations, including
those that relate to the general use of a systematic review
and others that pertain specically to surgical analgesia
studies. In only 5 of 16 studies did the acetaminophen
group size exceed 40 patients. Small sample sizes studies
are unlikely to identify rare but clinically relevant
adverse effects. Because the best analgesic approach
needs to be individualized to the specic surgical proce-
dure, results from a specic study may not be applicable
to other surgery types or when other analgesic interven-
tions such as nerve blocks are added to a multimodal
approach.
12
In addition, the studies used different
systems for reporting the severity and duration of pru-
ritus, nausea, and vomiting. Publication bias also cannot
be excluded. Also, none of the active comparator studies
included often used nonsteroidal anti-inammatory
drugs such as ketorolac, ketoprofen, or diclofenac.
Intravenous Acetaminophen Studies 295
An FDA advisory committee recommended in 2009
to reduce the maximum daily dose of oral acetami-
nophen to less than 4 g because of concerns primarily
related to hepatotoxicity from acetaminophen over-
dose.
13
The FDA expressed concern that the relatively
free over-the-counter access to acetaminophen-
containing products and the lack of healthcare provider
control in the outpatient setting were part of the
problem. These access and control issues should not
apply to IV acetaminophen in the inpatient hospital
setting in which it will be administered.
The faster onset of IV acetaminophen compared with
oral or rectal administration should be helpful when
treating acute surgical pain particularly when oral
intake is not possible. In aggregate, the 16 RCTs selected
for analysis indicate that IV acetaminophen is an effec-
tive analgesic in a variety of surgical procedures.
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