Download The role of COX-2 inhibitors in the perioperative setting

The role of COX-2 inhibitors in the
perioperative setting: Efficacy and safety—
A systematic review
Melissa Holmes Zemmel, CRNA, MSNA
Miami, Florida
2004 Student Writing Contest Honorable Mention
A new class of nonsteroidal anti-inflammatory drugs
(NSAIDs) selective for cyclooxygenase-2 (COX-2) offers new
options for managing perioperative pain. However, new
and conflicting data have emerged regarding all nonsteroidal anti-inflammatory drugs, including those selective
for COX-2. The data highlight the potential for increased
risks of adverse cardiovascular events associated with all
NSAIDs and of potential serious skin reactions and gastrointestinal bleeding with specific agents. As of June 2005,
the National Institutes of Health and Food and Drug Administration suspended all clinical trials involving NSAIDs.
This article reviews 30 prospective studies on the role
of COX-2 selective inhibitors in the perioperative setting.
The studies examined a variety of variables, including
T
he management of acute perioperative pain
remains a controversial issue, in part due to
traditional pain management strategies that
have relied heavily on the use of opioids. Recent study of the development of pain has
prompted investigation into different treatment options focusing on nonopioid drugs.
Nonsteroidal anti-inflammatory agents (NSAIDs)
(Table 1) have long been the mainstay of nonopioid
pain relief. Their inhibition of the enzyme cyclooxygenase (COX) and the resulting attenuation of inflammation make them effective analgesics. However, the
use of NSAIDs in the perioperative setting is limited
due to concerns regarding their effects on platelet aggregation and renal function.
At least 2 isoforms of COX have been identified.
The specificity of COX is an essential factor in determining the pharmacologic action of the NSAIDs. The
recent development of COX-2 selective agents (Table
2) has provided additional options for the management of acute pain. Their unique pharmacologic profile makes them a promising alternative to nonselective COX-inhibitors.
The COX-2 selective agents were first approved
for the treatment of chronic pain, and indications exist for the treatment of osteoarthritis, rheumatoid ar-
www.aana.com/members/journal/
efficacy, perioperative opioid reduction, and effects on
platelet aggregation and renal function. The data reveal an
overall reduction in postoperative opioid use and significant patient satisfaction with perioperative COX-2 use, no
effect on platelet aggregation, and a minor negative effect
on renal function.
The literature suggests that perioperative use of selective COX-2 inhibitors can be well tolerated and efficacious
in carefully selected patient groups. Further data are needed to fully examine the role of these drugs in the perioperative setting. Intensive research into cardiovascular issues
surrounding all NSAIDs is warranted.
Key words: COX-2, cyclooxygenase-2, perioperative pain,
platelet aggregation, renal function.
Table 1. Commonly used nonselective NSAIDs*
Generic name
Trade name(s)
Ibuprofen
Motrin, Advil, Nuprin, Medipren
Indomethacin
Indocin
Sulindac
Clinoril
Diclofenac
Voltaren
Naproxen
Naprosyn, Anaprox, Aleve
Piroxicam
Feldene
Oxaprozin
Daypro
Ketorolac
Toradol
* NSAID indicates nonsteroidal anti-inflammatory drug.
thritis, dysmenorrhea, and a variety of musculoskeletal disorders. In October 2001, celecoxib became the
first COX-2 inhibitor approved for the management of
acute pain in adults.
In recent months, however, new and sometimes
conflicting data have emerged regarding all NSAIDs,
including those selective for COX-2. The data highlight
the potential for increased risk of adverse cardiovascular events (including myocardial infarction, stroke, and
death) associated with all NSAIDs and as increased risk
AANA Journal/February 2006/Vol. 74, No. 1
49
of potential serious skin reactions and gastrointestinal
bleeding associated with specific agents.
As of June 2005, the National Institutes of Health
and the US Food and Drug Administration (FDA)
suspended all clinical trials involving NSAIDs, and focus of pharmaceutical company and FDA researchers
is directed toward specific cardiovascular issues. In a
series of events that began in September 2004 (Table
3),1,2 the prescription COX-2 specific agents valdecoxib (Bextra) and rofecoxib (Vioxx) were removed
from the market. The prescription COX-2 specific
agent celecoxib (Celebrex) and all nonprescription
NSAIDs remain on the market at this time with FDAsanctioned revised labeling. In June 2005, the FDA
asked all manufacturers of NSAIDs to make labeling
changes to include a boxed warning highlighting the
potential for increased risk of potentially life-threatening cardiovascular events and gastrointestinal bleeding associated with their use.
The physiologic basis of surgical pain
Surgical pain can be defined as pain that is caused by
noxious stimulation due to injury. Postoperative pain
is most often mediated by inflammatory mechanisms
and is usually self-limiting. Inflammatory pain assoTable 2. Cyclooxygenase-2 selective inhibitors
Generic name
Trade name
Celecoxib
Celebrex
Rofecoxib
Vioxx
Valdecoxib
Bextra
Parecoxib
Dynastat (parenteral pro-drug of
valdecoxib)
ciated with surgery is characterized by a decrease in
the threshold of pain sensitivity followed by central
nervous system sensitization. This is accompanied by
an exaggerated response to painful stimuli (primary
hyperalgesia) and a spread of the hyperalgesic area to
nearby uninjured tissues (secondary hyperalgesia).
Primary hyperalgesia occurs mainly as a consequence
of excess inflammatory and excitatory pain mediators.3
Pain is mediated peripherally at nociceptors, at the
level of the spinal cord, and at the level of the brain.
There are 4 physiologic processes involved in the experience of pain: transduction, transmission, modulation, and perception (Figure 1). Transduction takes
place in the periphery by nociceptors. Transmission
then takes place along pain pathways. These pathways
conduct pain signals from the site of injury to the spinal cord and brain. Modulation is the chemical process
that involves many neurotransmitters, amino acids,
and inflammatory mediators to suppress or excite pain
transmission. Perception is the emotional, psychological, and physiologic response to pain and is largely a
subjective experience.
The most important of the excitatory neurotransmitters involved in pain modulation are substance P
and glutamate, which facilitate the transmission of pain
signals through the central nervous system. Substance
P is released peripherally at the site of tissue injury.
It sensitizes nociceptors, releases histamine from mast
cells, and is a potent vasodilator. Glutamate is a central mediator of pain transmission. It causes changes in
membrane excitability and facilitates the activation of
pain receptor systems in the central nervous system. It
also has an important role in the concept of “wind-up,”
which occurs when nociceptors increase the frequency
Table 3. Timeline of recent events surrounding the cardiovascular issues associated with NSAIDs*1,2
September 2004
• Merck and Company, Inc, announced voluntary withdrawal of Vioxx (rofecoxib) from US and
worldwide markets due to increased risk of cardiovascular events.
December 2004
• NIH halts research involving naproxen and Celebrex (celecoxib) and Alzheimer disease
prevention.
• NIH halts research involving Celebrex and colorectal cancer prevention.
• FDA issues public health advisory for all NSAIDs citing results of a long-term clinical trial that
suggested increased cardiovascular risk with long-term use of NSAIDs compared with placebo.
March 2005
• FDA alert is issued regarding increased risk of cardiovascular events (myocardial infarction,
stroke, death) in patients receiving Celebrex based on preliminary reports from an NIH study.
April 2005
• FDA asks Pfizer to voluntarily remove Bextra (valdecoxib) from the market.
June 2005
• FDA asks all manufacturers of NSAIDs to make labeling changes including “a boxed warning
highlighting the potential for increased risk of cardiovascular events and the well described,
serious, potential life threatening gastrointestinal bleeding associated with their use.”
* NSAID indicates nonsteroidal anti-inflammatory drug; NIH, National Institutes of Health; and FDA, Food and Drug Administration.
50
AANA Journal/February 2006/Vol. 74, No. 1
www.aana.com/members/journal/
Figure 1. The path of pain from surgical injury to the brain
www.aana.com/members/journal/
AANA Journal/February 2006/Vol. 74, No. 1
51
and intensity of their signals as a result of repeated
stimulation. The repeated stimulation of these neurons
also causes them to widen their sensory range, causing
previously unaffected adjacent neurons to begin firing.
Wind-up occurs after prolonged exposure to painful
stimuli and in the face of undertreated pain.3
Modulation of pain also includes the actions of inhibitory neurotransmitters. These include substances
such as β-endorphins, serotonin, γ-aminobutyric acid,
and enkephalins. These modulators function to reduce
the activity of mechanisms involved in pain transmission.4
Opioid pain control takes advantage of the inhibitory neurotransmitters and receptors to produce analgesia. The binding of the opioids to various inhibitory
receptors in the brain and spinal cord activates them
and interrupts the transmission of pain. This takes
place through the inhibition of presynaptic release or
postsynaptic response to excitatory substances.
Prostaglandins are the main inflammatory modulators released by injured tissues. They are formed as
a result of arachidonic acid metabolism. They produce inflammation and discomfort by vasodilation,
increased vascular permeability (edema), and sensitization of the tissues to pain. As inflammation progresses, more nociceptors (even those in surrounding
uninjured tissues) are recruited and sensitized to pain
mediators. In this way, inflammation also contributes
to wind-up.
When tissue is injured, phospholipases release free
arachidonic acid that then is metabolized into prostaglandins by the COX. There are 2 isoforms of COX:
COX-1 and COX-2. COX-1 is a constitutive enzyme
and has a homeostatic role in gastrointestinal mucosa
protection, platelet aggregation, and maintenance of
renal function. COX-2 is expressed at sites of tissue
injury to mediate pain and inflammation. COX-2 also
is expressed in the brain and kidney and contributes
to homeostatic mechanisms there (Figure 2).
The pharmacology of NSAIDs
The first recorded uses of the salicylic acid derivatives
that have become modern NSAIDs date back many
centuries. They were used as analgesics and antipyretics. Salicylic acid was synthesized in 1860 in Germany
and was indicated for use as an analgesic, anti-inflammatory, and antipyretic. In the years that followed,
other compounds were synthesized that mimicked the
action of salicylic acid. These drugs were collectively
referred to as NSAIDs.5
Until 1971, there was little understanding of the
mechanism of action of NSAIDs. It was the work of
British pharmacologist Harry Collier in the 1960s that
52
AANA Journal/February 2006/Vol. 74, No. 1
prompted modern inquiry into the biochemical basis
of NSAID action. Collier hypothesized that the drugs
acted by “inhibiting some underlying cellular mechanism that takes part, to different extents in different
responses, and mediated by different endogenous substances.”6 The work of prostaglandin researchers Vane7
showed that the NSAIDs were capable of blocking
prostaglandin synthesis in animal studies performed
on dogs and rabbits.
Cyclooxygenase was isolated in 1976. In the early
1990s, the existence of a second form of COX, one
that was inducible in the presence of inflammatory
stimuli, was suspected.8,9 The inducible form of cyclooxygenase, COX-2, was isolated in 1991.10,11
Nonselective NSAIDs are inhibitors of COX-1 and
COX-2. The side-effect profile of nonselective NSAIDs
is well known and is related to the inhibition of prostaglandins. These side effects include gastrointestinal
irritation and bleeding, platelet inhibition, and renal
dysfunction.12
Current research supports the fact that much of the
unfavorable side-effect profile of nonselective NSAIDs
is attributable to the inhibition of COX-1, while the
analgesic and anti-inflammatory profiles are the result
of the inhibition of COX-2. The recent identification
of COX-2 selective agents provides a novel strategy for
the relief of surgical pain. It is now possible to specifically target the prostaglandins that mediate inflammatory pain without inhibiting the gastric cytoprotective
and platelet aggregating properties.
Study of the perioperative use of COX-2 selective agents
It is well known that NSAIDs are very effective agents
for treating the pain associated with inflammation. It
is also well known that much of the pain that results
from surgery is caused by inflammation resulting from
direct tissue injury. Nonselective NSAIDs have been
used for the treatment of surgical pain for decades.
However, clinical use has not gained popularity for
surgical patients because of unattractive side effects,
specifically inhibition of platelet aggregation.
The unpleasant and sometimes dangerous side effects of opioids—nausea, vomiting, constipation, respiratory depression, and sedation—leave great room
for improvement in acute pain management. This fact,
coupled with the benefits of reduced inflammation
achieved by NSAIDs, has prompted in-depth study of
novel, nonopioid treatment options.
The World Health Organization developed a 3-step
strategy for the treatment of cancer pain (Figure 3).
All 3 steps include the use of nonopioid drugs for the
relief of pain. The first step consists of nonopioid an-
www.aana.com/members/journal/
Figure 2. Cascade of inflammation through the arachidonic acid pathway in response to surgical injury
Surgical tissue injury
Phospholipases cleave free arachidonic
acid in response to tissue injury
Arachidonic acid
Cyclooxygenase 1 (COX-1)
Cyclooxygenase 2 (COX-2)
Prostaglandins involved in:
Prostaglandins involved in:
Gastrointestinal mucosa protection
Platelet aggregation/hemostasis
Renal function homeostasis
Vasodilation
↑Sensitivity to pain (hyperalgesia)
↑Capillary permeability (edema)
Renal function homeostasis
algesia with or without the use of an adjuvant such as
an antidepressant or anxiolytic. The second step adds
a mild opioid to the first. Finally, the third step adds a
potent opioid. This regimen has provided satisfactory
pain relief in 80% to 90% of patients studied.13
Concern regarding nephrotoxic effects surrounds
the use of NSAIDs. Both isoforms of COX are known
to have an important role in renal blood flow homeostasis. Preservation of renal function is a concern in
surgical patients. The renal effects of perioperative selective COX-2 inhibitors, particularly in populations
at high risk for NSAID-induced nephropathy, merit
exploration.
The discovery of COX-2 selective agents stimulated
extensive and ongoing study into their efficacy and
safety in a variety of settings, the first of which was the
www.aana.com/members/journal/
management of chronic pain. Inquiry into the use and
benefits of the COX-2 selective inhibitors in the surgical arena also has become a promising focus. Recently, a tremendous increase in the body of knowledge
regarding COX-2 selective inhibitors has occurred.
A systematic review of the literature was initiated to
scrutinize the current data on perioperative use of selective COX-2 inhibitors.
The purposes of this review were as follows:
1. Examine the current data available on the efficacy
of COX-2 inhibitors in the management of acute postoperative pain across multiple surgical pain models.
2. Examine the current data available on the effects
of COX-2 inhibition on platelet function.
3. Examine the current data available on the effects
of COX-2 inhibition on renal function.
AANA Journal/February 2006/Vol. 74, No. 1
53
Figure 3. World Health Organization analgesic
ladder13
Freedom from cancer
Opioid for mild to moderate
Pain
± Nonopioid
± Adjuvant
3
Pain persisting or increasing
Opioid for mild to moderate pain
± Nonopioid
± Adjuvant
2
Pain persisting or increasing
1
± Nonopioid
± Adjuvant
Review of the literature
• Literature search. Three separate PUBMED searches were conducted for prospective, randomized, controlled studies dealing with COX-2 inhibitors in the
surgical setting. The first search addressed efficacy for
pain relief and was conducted for studies that included
the terms COX-2, cyclooxygenase-2, acute pain, surgical pain, perioperative pain, or postoperative pain. A
second search was conducted for studies dealing with
platelet aggregation and bleeding time as they relate
to COX-2 specific inhibitors. A third search was done
for studies that addressed the effects of COX-2 specific
inhibitors on renal function.
• Inclusion criteria. It was determined a priori that
only randomized, controlled studies that specifically
addressed the topic of COX-2 selective agents and
their relevance in the perioperative setting would be
reviewed. Criteria for relevance in the perioperative
setting included effects on platelet aggregation and
bleeding time, effects on renal function, use for preemptive analgesia, and use for postoperative analgesia.
Studies were assessed for sensitivity of pain scoring
tools and statistical analysis. Bibliographies of articles
on these subjects also were searched by hand for additional articles meeting the inclusion criteria.
Discussion
The 22 studies of the efficacy of pain relief were divided into groups according to established pain models.
54
AANA Journal/February 2006/Vol. 74, No. 1
The specific groups included oral surgery, abdominal
surgery, orthopedic surgery, and otolaryngologic surgery. Three randomized, controlled studies that addressed the effects of COX-2 inhibitors on platelet
function were identified. One study was identified
that specifically examined the effects of COX-2 inhibition on surgical blood loss. Four studies were identified that examined the effects of COX-2 inhibition on
renal function.
Efficacy in management of postoperative pain
• Orthopedic pain model (Table 4). Nine trials studying the efficacy of selective COX-2 inhibitors in the
orthopedic pain model were identified.14-22 Various
procedures were studied and included total knee arthroplasty, total hip arthroplasty, bunionectomy, and
spinal surgery. All studies examined a selective COX-2
inhibitor and compared efficacy with another selective
COX-2 agent, opioids, or placebo. Of the 9 studies,
6 examined the opioid-sparing effects of concurrent
perioperative treatment with selective COX-2 inhibitors.14,16,18-20,22 All 6 studies found a significant reduction in postoperative opioid requirements (P < .05). In
addition to the opioid-sparing effects, 5 of the 6 trials
also found improved patient satisfaction among patients who received COX-2 inhibitors as part of their
pain management regimen (P < .05).16,18-20,22 Buvanendran and Kroin22 found that in patients undergoing
total knee replacement, perioperative use of oral rofecoxib reduced opioid consumption, pain, vomiting,
and sleep disturbances. Improved knee range of motion and reduction in physical therapy time also was
noted. Compared with placebo alone, COX-2 inhibitors were associated with less consumption of rescue
medication, lower pain scores, and greater patient satisfaction.15,17,18,20
• Abdominal surgery pain model (Table 5). Four
trials examining the efficacy of COX-2 inhibitors on
postoperative pain after abdominal surgery were identified.23-26 Of the 4 studies, 3 reported significantly
lower postoperative pain scores in the patient groups
that received COX-2 inhibitors as part of the pain
management regimen (P < .05).24-26 Of the 4 studies, 3
also found significant reduction in total postoperative
opioid doses in groups receiving concurrent COX-2
inhibitors.22,24,25
Sinatra et al25 examined rofecoxib oral suspension
as an analgesic adjunct after lower abdominal surgery.
The effects of a single preoperative dose of rofecoxib
(25 or 50 mg) oral suspension on postoperative morphine requirements, effort-dependent pain, and pulmonary function were measured. Postoperative morphine requirements were reduced by 44% in the 25-mg
www.aana.com/members/journal/
www.aana.com/members/journal/
AANA Journal/February 2006/Vol. 74, No. 1
55
Valdecoxib, 20 or 40
1 preoperative
mg PO + MSO4 by PCA;
placebo + MSO4 by
PCA
Hip arthroplasty
Hip arthroplasty
Camu et al18
(n = 203)
Malan et al19
(n = 181)
Parecoxib, 20 or 40
mg IV; MSO4, 4 mg IV;
placebo
Rofecoxib, 50 mg
Preoperative and
PO 24 and 2 h
postoperative
preoperatively + 50 mg
daily for 5 d + 25 mg
daily for 8 d compared
with matching placebo
at same times
Rasmussen et Orthopedic knee
al21 (n = 208) surgery
Buvanendran Total knee
and Kroin22
replacement
(n = 70)
Median time
to first rescue
Total epidural analgesic
consumption and in-hospital
opioid consumption significantly
less in rofecoxib group
NA
NA
NA
NA
NA
NS
Significant
Significant all
groups
Significant for
both agents
Ouset similar with all 3 agents; levels and duration of analgesia
were significantly superior with
parecoxib than with MSO4
Patients receiving either
dose of parecoxib consumed
significantly less morphine
postoperatively, and duration
of analgesia was significantly
superior with parecoxib than
with MSO4
Parecoxib, 20 and 40 mg,
reduced total MSO4 in 36 h by
22.1% and 40.5%, respectively
Patients receiving either
valdecoxib dose required 40%
less morphine than placebo
Visual analog scale score
significantly greater in placebo
group at PACU admission
MSO4 consumption in 48 h
by both valdecoxib groups
significantly reduced
20 mg, significant to 18 h;
40-80 mg, significant to 24 h
Celecoxib, significant to 8 h;
rofecoxib, significant to 16 h
Quality of
pain relief Other
NA
NS
NA
Significant
Significant
Significant
Significant
Significant
NA
NA
In rofecoxib group, median
pain scores lower, knee flexion
greater, patient satisfaction
higher, sleep disturbances
significantly reduced
Greater patient satisfaction
noted in parecoxib groups
Patient satisfaction
significantly higher in
parecoxib groups; MSO4 PCA
discontinued earlier in both
parecoxib groups
Pain intensity levels
and patient satisfaction
significantly improved in both
valdecoxib groups
Patient satisfaction on global
evaluation significantly greater
in valdecoxib 80-mg group
All groups reported significant
improvement in patient
satisfaction in a dosedependent manner
Significant for Rofecoxib demonstrated
both agents
greater duration than
celecoxib
Opioid total
dose reduction
* PO indicates by mouth; PCA, patient-controlled analgesia; MSO4, morphine sulfate; bid, twice a day; IV, intravenous; PACU, postanesthesia care unit; NA, not applicable; and NS, not significant. Significant values were P ≤ .05 in favor of
the cyclooxygenase-2 inhibitor.
1 after
discontinuation
of IV PCA on
postoperative
day 1
Parecoxib, 20 or 40 mg Postoperative
bid IV; placebo
Postoperative on
request followed
by doses at 12 and
24 h
Hubbard et
Total knee
al20 (n = 195) replacement
Parecoxib, 20 or 40
mg + MSO4 by PCA;
placebo + MSO4 by
PCA
Rofecoxib, 50 mg PO;
placebo
Bekker et al17 Lumbar
(n = 61)
diskectomy
1 preoperative
Valdecoxib, 40 or 80
Postoperative
mg PO daily + MSO4 by
PCA; placebo + MSO4
by PCA
Reynolds and Total knee
Hoo16
arthroplasty
(n = 104)
1 preoperative
Celecoxib, 200 mg PO; 1 preoperative
rofecoxib, 50 mg PO;
MSO4 by PCA
Valdecoxib, 20, 40, or
80 mg PO; placebo
Spinal fusion
Analgesic agents
and doses
Dose timing
Desjardins et Bunionectomy
al15 (n = 223)
Reuben and
Connelly 14
(n = 60)
Reference
Type of surgery
Table 4. Orthopedic pain model*
AANA Journal/February 2006/Vol. 74, No. 1
* MSO4 indicates morphine sulfate; PCA, patient-controlled analgesia; PO, by mouth; IV, intravenous; NA, not applicable; FEV1, forced expiratory volume in 1 second; and FVC, forced vital capacity. Significant values were P ≤ .05 in
favor of the cyclooxygenase-2 inhibitor.
Parecoxib-valdecoxib
group reported
improved patient
global evaluation
Significant
NA
Parecoxib, 40 mg
IV preoperatively +
valdecoxib, 40 mg
postoperatively and daily
for 4 d
Joshi et al26 Laparoscopic
(n = 263)
cholecystectomy
Preoperative and Patients receiving parecoxib used
postoperative
21% less fentanyl immediately
postoperatively; pain intensity scores
significantly less in parecoxib group;
fewer patients receiving valdecoxib
required supplemental analgesics
after discharge
Pulmonary function
tests (FEV1 and FVC)
improved in both
rofecoxib groups
Significant
NA
Pain scores at 12 h significantly
lower in both rofecoxib groups at rest
and after vigorous cough
Preoperative
Rofecoxib, 25 or 50 mg;
placebo MSO4 by PCA
Sinatra et
Open abdominal
al25 (n = 48) surgery
Parecoxib and
ketorolac groups
had greater global
evaluation scores than
MSO4 group
NA
Significant
Pain intensity significantly less with
parecoxib (either dose) and ketorolac
than with MSO4
Gynecologic
laparotomy
Parecoxib, 20 or 40 mg IV; 1 postoperative
ketorolac, 30 mg IV; MSO4,
4 mg IV; placebo
Barton et
al24
(n = 200)
Median time to Opioid total
first rescue dose reduction
Other
NA
Significant No significant
difference noted
in patient global
evaluation
Quality of
pain relief
Postoperative pain scales similar in
all 3 groups
Type of
Analgesic agents
Reference
surgery and doses
Dose timing
Tang et al23 Major gynecologic MSO4 by PCA + parecoxib Postoperative
(n = 60)
surgery
20, or 40 mg PO on request
and 12 and 24 h after
initial dose
Table 5. Abdominal surgery pain model*
56
group and 59% in the 50-mg group (P <
.05). At 12 hours after drug administration, resting pain scores and pain scores
after spirometry were lower in both rofecoxib groups compared with placebo (P
< .05). Pulmonary function, measured by
forced vital capacity, was best preserved
in the rofecoxib 50-mg group.
• Oral surgery pain model (Table 6).
Six studies were identified for the oral
surgery pain model.15,27-31 All studies
compared a COX-2 specific inhibitor to
placebo, an oral codeine derivative, or
another NSAID.
Of the 6 studies, 3 compared a selective COX-2 inhibitor with a nonselective
NSAID.29-31 All 3 studies found analgesic
efficacy of the selective COX-2 inhibitor
comparable to that of the nonselective
NSAID. All 3 studies also found duration of the selective COX-2 inhibitor to
be longer. There were no adverse effects
of selective COX-2 inhibitors noted in
any of the studies.
Daniels et al31 found that valdecoxib,
20 and 40 mg, demonstrated longer duration than a combination of oxycodone,
10 mg, and acetaminophen, 1,000 mg,
after third molar extraction (P < .05). In
a study by Chang and Frick,28 rofecoxib, 50 mg orally, was compared with a
combination of codeine, 60 mg, and acetaminophen, 600 mg, after third molar
extraction. Peak pain scores were lower
in the rofecoxib group, and significantly
more patients in the codeine-acetaminophen group experienced nausea and
vomiting (P < .05).28
• Otolaryngologic surgery model (Table 7). Three studies were identified for
the otolaryngologic surgery model.32-34
All compared a selective COX-2 inhibitor with acetaminophen or placebo. All
3 studies found that the selective COX-2
inhibitor or the combination of a COX-2
with acetaminophen demonstrated significantly lower pain scores compared
with acetaminophen or placebo (P <
.05). Joshi et al,33 in a study of pediatric patients undergoing tonsillectomy,
found that postoperative pain scores
were significantly lower in the rofecoxib
www.aana.com/members/journal/
group at 2 and 24 hours. Nausea and vomiting also
were decreased in the rofecoxib group compared with
the placebo group.33
Effects on platelet function
Three studies were identified that specifically addressed the effects of selective COX-2 inhibitors on
platelet function.35-37 All studies compared the effects
of a supratherapeutic dose of a selective COX-2 agent
with standard doses of nonselective NSAIDs and placebo in adult volunteers. All 3 studies examined platelet aggregation responses, bleeding time, and serum
thromboxane B2 concentrations. All studies found that
the specific COX-2 inhibitors had no effects on platelet
function, whereas the nonselective NSAIDs significantly increased bleeding time and reduced platelet function and thromboxane B2 levels. It was determined that
the selective COX-2 inhibitors spared COX-1 function
and, therefore, did not interfere with normal mechanisms of platelet aggregation and hemostasis.
Hegi et al38 specifically compared rofecoxib and diclofenac and their effects on platelet aggregation and
surgical blood loss in patients undergoing vaginal hysterectomy or breast surgery. Rofecoxib showed less
platelet disturbance, intraoperative blood loss, and
hemoglobin decrease than did diclofenac. The study
did not determine the effects of rofecoxib compared
with placebo.
Five studies identified for the efficacy portion of
this review mentioned surgical blood loss as a secondary outcome measured.14,16,19,22,25 All 5 studies found
no difference in surgical blood loss when a COX-2 inhibitor was compared with opioid or placebo.
Effects on renal function
Four studies were identified that examined the effects
of selective COX-2 inhibition on renal function.39-42
Rossat et al39 examined the renal effects of celecoxib
and naproxen in salt-depleted normotensive subjects.
The results indicated that although celecoxib had no
effects on systemic blood pressure, transient decreases in renal blood flow and glomerular filtration rate
(GFR) were noted. Decreased urine output and sodium and potassium retention also were noted with
repeated administration.39
Swan et al40 examined the effects of rofecoxib on renal function in elderly patients on a low sodium diet.
The renal perfusion effects of rofecoxib and indomethacin were compared with placebo. The GFR was similarly decreased by rofecoxib and indomethacin after a
single dose and after multiple doses. It was determined
that the effects of COX-2 inhibition on renal function
are similar to the effects of nonselective NSAIDs and
www.aana.com/members/journal/
that COX-2 might have an important homeostatic role
in the maintenance of renal perfusion.40
Schwartz and Vandormael41 studied renal effects of
rofecoxib, celecoxib, and naproxen in elderly patients
on a normal-salt diet. Renal function was measured by
urinary sodium excretion, systolic and diastolic blood
pressure, creatinine clearance, and body weight. It was
found that influence on renal function did not differ
between selective COX-2 inhibitors and nonselective
NSAIDs.41
Whelton et al42 examined the renal effects of celecoxib and naproxen in elderly subjects. After an initial
dose, naproxen produced a greater reduction in GFR.
On day 6 of the 10-day study, the treatment difference
became statistically significant. It was noted on day 6
that the reduction in GFR was –7.53 mL/min/1.73m2
for naproxen and –1.11 mL/min/1.73m2 for celecoxib.
Although both agents reduced GFR, the reduction was
significantly greater for naproxen.42
Summary
New insight into the physiology and management of
acute postoperative pain calls for the incorporation
of multimodal analgesia. It has been demonstrated in
the literature across multiple pain models that COX2 inhibitors are safe and effective agents in the treatment of postsurgical pain in a carefully selected patient
population.
Current literature suggests that selective COX-2 inhibitors reduce postoperative opioid use, reduce the
complications associated with opioids, and increase
patient satisfaction.
Furthermore, selective COX-2 inhibition seems to
have no effect on platelet function in healthy subjects.
Although not all of the efficacy studies examined perioperative blood loss, several examined bleeding as an
outcome. None of those studies demonstrated any
increase in surgical bleeding with the use of selective
COX-2 inhibitors. Further investigation into the perioperative platelet effects of COX-2 inhibition and the
specific effects on surgical bleeding is warranted.
Cyclooxygenase-2 has an important homeostatic
role in renal function. Renal function seems to be decreased to some degree, most notably GFR, by selective COX-2 inhibitors; the effect on renal function is
similar to that caused by nonselective NSAIDs. The
data indicate that COX-2 inhibitors should be used
cautiously in patients with preexisting renal and cardiac disease. More studies are needed examining the
renal effects of selective COX-2 agents in the perioperative setting to further investigate their effect on surgical patients.
In light of recent controversy surrounding the use of
AANA Journal/February 2006/Vol. 74, No. 1
57
58
AANA Journal/February 2006/Vol. 74, No. 1
www.aana.com/members/journal/
Parcoxib, 20 or 40 mg 1 preoperative
IV or IM; ketorolac,
60 mg IM; placebo
Parecoxib comparable to
ketorolac in onset but had
longer duration
Analgesic efficacy of
parecoxib, 20 mg to 100
mg similar to ketorolac, 30
mg; parecoxib, 50 and 100
mg had significantly longer
duration than ketorolac
Effects, onset, and peak
analgesic effect not
significantly different from
ibuprofen
Peak pain score significantly
lower in rofecoxib group
NA
All groups significant to 24 h
Quality of
pain control
NS
Significant
NA
NA
NA
Significant, all
groups
NA
NA
NA
NA
Significant
NA
Other
Parecoxib had longer
duration than ketorolac
Parexocib doses <20 mg
had suboptimal analgesic
activity compared with
placebo and ketorolac
Rofecoxib demonstrated
longer duration than
ibuprofen
Significantly more patients
in codeine-acetaminophen
group reported nausea/
vomiting
Valdecoxib, 40 mg showed
greater analgesic duration
than 20 mg; both doses
of valdecoxib showed
significantly longer
duration than oxycodoneacetaminophen
All groups receiving
valdecoxib reported
significant increase in
patient satisfaction in a
dose-dependent manner
Median time Rescue medication:
to first rescue Total dose reduction * PO indicates by mouth; IV, intravenous; NA, not applicable; and NS, not significant. Significant values were P ≤ .05 in favor of the cyclooxygenase-2 inhibitor.
Extraction,
third molar
Daniels et al31
(n = 304)
1 postoperative
dose
Parecoxib, 1, 2, 5, 10, 1 postoperative
20, 50, or 100 mg IV;
ketorolac 30 mg IV;
placebo
Rofecoxib, 50 mg
PO; codeine, 60 mg
– acetaminophen,
600 mg PO
Mehlisch et al30 Extraction,
(n = 453)
third molar
Extraction,
third molar
Chang and
Frick28
(n = 393)
Valdecoxib, 20
1 postoperative
or 40 mg PO;
oxycodone, 10 mg
– acetaminophen,
1,000 mg PO;
acetaminophen,
1,000 mg PO; placebo
1 preoperative
Rofecoxib, 50 mg PO; 1 postoperative
ibuprofen, 400 mg
PO; placebo
Extraction,
third molar
Daniels et al27
(n = 406)
Valdecoxib, 10, 20,
40, or 80 mg PO;
placebo
Analgesic agents
and doses
Dose timing Morrison et al29 Dental
(n = 151)
surgery
Extraction,
impacted
third molar
Type of
surgery
Desjardins et
al15 (n = 284)
Reference
Table 6. Oral surgery pain model*
NA
Significant
REFERENCES
* PO indicates by mouth; NA, not applicable; and NS, not significant. Significant values were P ≤ .05 in favor of the cyclooxygenase-2 inhibitor.
Significant
Visual analog scale scores
and intraoperative and
postoperative opioid
requirements significantly
smaller in rofecoxib group
Rofecoxib, 50 mg
PO; placebo
Otolaryngologic
surgery
Turan et
al34 (n =
60)
1 preoperative
Decreased nausea/
vomiting with
rofecoxib
NA
Rofecoxib, 1 mg/kg
PO; placebo
Joshi et al33 Pediatric
(n = 66)
tonsillectomy
1 preoperative
Significant difference in
pain scale ratings at 2 and
24 h postoperatively
NA
Patient satisfaction
greater in celecoxib +
acetaminophen group
vs placebo
NS
NS
Maximum pain scores
lower in celecoxib +
acetaminophen group
Celecoxib, 200 mg
1 preoperative
PO; acetaminophen,
2,000 mg PO;
celecoxib, 200 mg
+ acetaminophen,
2,000 mg PO;
placebo
Outpatient
Issioui et
al32 (n =
112)
Other
Rescue medication:
Total dose reduction Median time
to first rescue
Quality of
pain relief
Analgesic agents
and doses
Dose timing
Type of
surgery
Reference Table 7. Otolaryngologic surgery model*
www.aana.com/members/journal/
all NSAIDs, intensive research into the use of NSAIDs
in specific patient populations is warranted. The cardiovascular issues surrounding the NSAIDs as a class
warrant specific randomized, controlled, prospective
studies in healthy patients to determine in which patient populations NSAIDs can be used safely.
This review suggests that selective COX-2 inhibitors can be used successfully as part of a multimodal
treatment strategy for perioperative pain in carefully
selected patients.
1. Food and Drug Administration Website. COX-2 selective and nonselective non-steroidal anti-inflammatory drugs (NSAIDS). Available at: www.fda.gov/cder/drug/infopage/COX2/default.htm. Accessed June 9, 2005.
2. NIH News. National Institutes of Health Website. Available at:
www.nih.gov/news/pr/dec2004/od-17Q&A.htm. Accessed June 9,
2005.
3. Sinatra R. Role of COX-2 inhibitors in the evolution of acute pain
management. J Pain Symptom Manage. 2002;24(suppl):S18-S27.
4. Morgan GE, Mikhail MS, Murray MJ, eds. Clinical Anesthesiology.
New York, NY: Lange Medical Books/McGraw-Hill; 2002:309-358.
5. Flower RJ. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev. 1974;26:33-67.
6. Vane JR, Botting RM. Mechanism of action of nonsteroidal antiinflammatory drugs. Am J Med. 1998;104:2S-8S.
7. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of
action for aspirin-like drugs. Nature. 1971;231:232-235.
8. Fu J-Y, Masferrer JL, Seibert K, Raz A, Needleman P. The induction
and suppression of prostaglandin H2 synthase (cyclooxygenase) in
human monocytes. J Biol Chem. 1990;265:16737-16740.
9. Masferrer JL, Zweifel BS, Seibert K, Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin
in mice. J Clin Invest. 1990;86:1375-1379.
10. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL.
Expression of a mitogen-responsive gene encoding prostaglandin
synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A.
1991;88:2692-2696.
11. O’Banion MK, Sadowski HB, Winn V, Young DA. A serum- and
glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem. 1991;266:23261-23267.
12. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-442.
13. World Health Organization. WHO Guidelines: Cancer Pain Relief.
2nd ed. Geneva, Switzerland: World Health Organization; 1996.
14. Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg.
2000;91:1221-1225.
15. Desjardins PJ, Shu VS, Recker DP, Verburg KM, Woolf CJ. A single
preoperative oral dose of valdecoxib, a new cyclooxygenase-2 specific inhibitor, relieves post-oral surgery or bunionectomy pain.
Anesthesiology. 2002;97:565-573.
16. Reynolds LW, Hoo RK. The COX-2 specific inhibitor, valdecoxib, is
an effective, opioid-sparing analgesic in patients undergoing total
knee arthroplasty. J Pain Symptom Manage. 2003;25:133-141.
17. Bekker A, Cooper PR, Frempong-Boadu A, Babu R, Errico T, Lebovits A. Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative
pain after lumbar disc surgery. Neurosurgery. 2002;50:1053-1057.
18. Camu F, Beecher T, Recker DP, Verburg KM. Valdecoxib, a COX2-specific inhibitor, is an efficacious opioid-sparing analgesic in
patients undergoing hip arthroplasty. Am J Ther. 2002;9:43-51.
AANA Journal/February 2006/Vol. 74, No. 1
59
19. Malan TP Jr, Marsh G, Hakki SI, Grossman E, Traylor L, Hubbard
RC. Parecoxib sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine analgesia and is opioid-sparing following total hip arthroplasty. Anesthesiology. 2003;98:950-956.
20. Hubbard RC, Naumann RM, Traylor L, Dhadda S. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anesthesia. Br J Anaesth. 2003;90:166-172.
21. Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC. Intravenous parecoxib sodium for acute pain after orthopedic knee
surgery. Am J Orthop. 2002;31:336-343.
22. Buvanendran A, Kroin JS. Effects of perioperative administration
of a selective cyclooxygenase 2 inhibitor on pain management and
recovery of function after knee replacement: a randomized controlled trial. JAMA. 2003;290:2411-2418.
23. Tang J, Li S, White PF, et al. Effect of parecoxib, a novel intravenous cyclooxygenase type-2 inhibitor, on the postoperative
opioid requirement and quality of pain control. Anesthesiology.
2002;96:1305-1309.
24. Barton SF, Langeland FF, Snabes MC, et al. Efficacy and safety of
intravenous parecoxib sodium in relieving acute postoperative
pain following gynecologic laparotomy surgery. Anesthesiology.
2002;97:306-314.
25. Sinatra RS, Shen QJ, Halaszynski T, Luther MA, Shaheen Y. Preoperative rofecoxib oral suspension as an analgesic adjunct after
lower abdominal surgery: the effects on effort-dependent pain and
pulmonary function. Anesth Analg. 2004;98:135-140.
31. Daniels SE, Grossman EH, Kuss ME, Talwalker S, Hubbard RC. A
double-blind, randomized comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and
placebo in a post–oral surgery model. Clin Ther. 2001;23:10181031.
32. Issioui T, Klein KW, White PF, et al. The efficacy of premedication
with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery. Anesth Analg. 2002;94:1188-1193.
33. Joshi W, Connelly NR, Reuben SS, Wolckenhaar M, Thakkar N. An
evaluation of the efficacy and safety of administering rofecoxib for
postoperative pain management. Anesth Analg. 2003;97:35-38.
34. Turan A, Emet S, Karamanlioglu B, Memis D, Turan N, Pamucku
Z. Analgesic effects of rofecoxib in ear-nose-throat surgery. Anesth
Analg. 2002;95:1308-1311.
35. Leese PT, Talwalker S, Kent JD, Recker DP. Valdecoxib does not
impair platelet function. Am J Emerg Med. 2002;20:275-281.
36. Leese PT, Recker DP, Kent JD. The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: results of a
randomized controlled trial. J Clin Pharmacol. 2003;43:504-513.
37. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet
function in healthy adults: a randomized, controlled trial. J Clin
Pharmacol. 2000;40:124-132.
38. Hegi TR, Bombeli T, Seifert B, et al. Effect of rofecoxib on platelet
aggregation and blood loss in gynaecological and breast surgery
compared with diclofenac. Br J Anaesth. 2004;92:523-531.
26. Joshi GP, Viscusi ER, Gan TJ, et al. Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral
COX-2 specific inhibitor. Anesth Analg. 2004;98:336-342.
39. Rossat J, Maillard M, Nussberger J, Brunner HR, Burnier M. Renal
effects of selective cyclooxygenase-2 inhibition in normotensive
salt-depleted subjects. Clin Pharmacol Ther. 1999;66:76-84.
27. Daniels SE, Desjardins PJ, Talwalker S, Recker DP, Verburg KM.
The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen
after oral surgery. J Am Dent Assoc. 2002;133:611-621.
40. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2
inhibition on renal function in elderly persons receiving a low-salt
diet. Ann Intern Med. 2000;133:1-9.
28. Chang DJ, Frick GR. Rofecoxib versus codeine/acetaminophen
in postoperative dental pain: a double-blind, randomized, placebo- and active comparator–controlled clinical trial. Clin Ther.
2001;23:1446-1455.
41. Schwartz JI, Vandormael K. Comparison of rofecoxib, celecoxib,
and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther. 2002;72:50-61.
29. Morrisson BW, Christensen S, Yuan W, Brown J, Amlani S, Seidenberg B. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled
trial. Clin Ther. 1999;21:943-953.
30. Mehlisch DR, Desjardins PJ, Daniels S, Hubbard RC. Single doses of parecoxib sodium intravenously are as effective as ketorolac in reducing pain after oral surgery. J Oral Maxillofac Surgery.
2003;61:1030-1037.
60
AANA Journal/February 2006/Vol. 74, No. 1
42. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib
and naproxen on renal function in the elderly. Arch Intern Med.
2000;160:1465-1470.
AUTHOR
Melissa Holmes Zemmel, CRNA, MSNA, is a nurse anesthetist at Baptist Hospital of Miami, Miami, Fla. She was a student at Virginia Commonwealth University, Richmond, Va, at the time this article was written. Email: [email protected]
www.aana.com/members/journal/