III
ACUTE PAIN
Chapter 9
PERIOPERATIVE USE
OF COX-2 AGENTS
Scott S. Reuben
INTRODUCTION
The primary goal of postoperative pain relief is to provide
subjective comfort, inhibit trauma-induced afferent pain trans-
mission, and blunt the autonomic and somatic reflex responses
to pain. By accomplishing this, we should enhance restoration of
function by allowing the patient to breath, cough, and ambulate
more easily. Subsequently, these effects should improve overall
postoperative outcome. Despite our increased knowledge of
the pathophysiology and pharmacology of nociception since the
late 1990s, acute postoperative pain still remains a major prob-
lem.1 Patients continue to report that their primary concern
before surgery is the severity of postoperative pain.1,2 This is
justified, because one survey revealed that 31% of patients
suffered from severe or extreme pain and another 47% from
moderate pain.1
Unrelieved postoperative pain may not only result in suffering
and discomfort but also lead to multiple physiologic and psycho-
logical consequences, which can contribute to adverse periop-
erative outcomes.3 This can potentially contribute to a higher
incidence of myocardial ischemia, impaired wound healing,4,5
and delayed gastrointestinal motility, resulting in prolonged
postoperative ileus.6 Further, unrelieved acute pain leads to
poor respiratory effort and splinting that can result in atelectasis,
hypercarbia, and hypoxemia, contributing to a higher incidence
of postoperative pneumonia.3 In addition, acute pain causes
psychological distress and anxiety, leading to sleeplessness and
helplessness, impairing postoperative rehabilitation, and poten-
tially causing long-term psychological consequences.7 Finally, it
has been recognized that unrelieved acute pain may contribute
to a higher incidence of chronic postsurgical pain.8 Therefore,
strategies aimed at reducing acute pain may not only provide
subjective comfort for our patients but also result in im-
proved postoperative outcomes and a reduction in health care
expenditures.
PATHOPHYSIOLOGYOF ACUTE PAIN
Peripheral sensitization, a reduction in the threshold of nociceptor
afferent peripheral terminals, is a result of inflammation
at the site of surgical trauma.9 Central sensitization, an
activity-dependent increase in the excitability of spinal neurons,
is a result of persistent exposure to nociceptive afferent input
from the peripheral neurons.10 Taken together, these two pro-
cesses contribute to the postoperative hypersensitivity state
(‘‘spinal windup’’) that is responsible for a decrease in the pain
threshold, both at the site of injury (primary hyperalgesia) and
in the surrounding uninjured tissue (secondary hyperalgesia)11
(Fig. 9–1).
As a result of this peripheral sensitization, low-intensity stimuli
that would normally not cause a painful response prior to sensiti-
zation now become perceived as pain, an effect termed allodynia
(Fig. 9–2).
The proinflammatory cytokine interleukin-1b (IL-1b) is up-
regulated at the site of inflammation and plays a major role in
inducing cyclooxygenase-2 (COX-2) in local inflammatory
cells by activating the transcription factor nuclear factor kB
(NF-kB).12 IL-1b is also responsible for the induction of COX-
2 in the central nervous system (CNS) in response to peripheral
inflammation. Interestingly, it is not the consequence either of
neural activity arising from the sensory fibers innervating
the inflamed tissue or of systemic IL-lb in the plasma. Instead,
peripheral inflammation produces some other signal molecule
that enters the circulation, crosses the blood-brain barrier, and
acts to elevate IL-lb, leading to COX-2 expression in neuronal
and nonneuronal cells throughout the CNS.13–15 Thus, there
appear to be two forms of input from peripheral inflamed
tissue to the CNS. The first is mediated by electrical activity in
sensitized nerve fibers innervating the inflamed area, which sig-
nals the location of the inflamed tissue as well as the onset,
duration, and nature of any stimuli applied to this tissue.16
This input is sensitive to peripherally acting COX-2 inhibitors
and to neural blockade with local anesthetics, as with epidural
or spinal anesthesia.17 The second is a humoral signal originating
from the inflamed tissue, which acts to produce a widespread
induction of COX-2 in the CNS. This input is not affected by
regional anesthesia13,14 and will be blocked only by centrally
acting COX-2 inhibitors.14,17,18 One implication of this is that
patients who receive neuraxial anesthesia for surgery might also
need a centrally acting COX-2 inhibitor to optimally reduce post-
operative pain and the postoperative stress response.14,17,18
Therefore, the permeability of the blood-brain barrier to cur-
rently used nonsteroidal anti-inflammatory drugs (NSAIDs) and
COX-2 inhibitors becomes important.19
59
60 Chapter 9  PERIOPER ATIVE USE OF COX-2 AGENTS

Central
sensitization

CNS
Spinal
wind-up

Inflammatory
mediators

Spinal cord Hydrogen ions, histamines, purines,

leukotrienes, norepinephrine,
potassium ions, cytokines,
Primary nerve growth factor, BK, PGs, 5-HT,
hyperalgesia neuropeptides

Surgical
trauma
Secondary
hyperalgesia

Peripheral
sensitization
Figure 9^1. Surgical trauma leads to the release of inflammatory mediators at the site of injury, resulting in a reduction in the pain threshold
at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia). Peripheral sensitization results from
a reduction in the threshold of nociceptor afferent terminals secondary to surgical trauma.Central sensitization is an activity-dependent increase
in the excitability of spinal neurons (spinal wind-up) as a result of persistent exposure to afferent input from peripheral neurons. BK, bradykinin;
CNS, central nervous system; 5-HT, serotonin; PGs, prostaglandins.

MULTIMODAL ANALGESIA
In July 2000, the Joint Commission for Accreditation of Health
Care Organizations (JCAHO) introduced a new standard for pain
Sensitized management, declaring pain level to be the ‘‘fifth vital sign.’’20
pain response
The Commission concluded that acute and chronic pain were
10 major causes of patient dissatisfaction in our health care
system, leading to slower recovery times, creating a burden for
8 patients and their families, and increasing the costs to the health
Pain intensity

Normal care system.20 However, the increased efforts aimed at reducing

pain patients’ postoperative pain scores may have further increased the
6 Injury response risk of adverse effects when health care providers attempted to
achieve sufficient analgesia by opioids alone.21–23
4 The concept of multimodal analgesia was introduced in the
late 1990s as a technique to improve analgesia and reduce the
incidence of opioid-related adverse events.24 The rationale for
2 this strategy is the achievement of sufficient analgesia through
the additive or synergistic effects between different analgesics.
0 This allows for a reduction in the doses of these drugs and,
Stimulus intensity
thus, a lower incidence of adverse effects. Currently, the
ALLODYNIA American Society of Anesthesiologists Task Force on Acute
Figure 9^2. Nociceptive afferent input from trauma can sensitize Pain Management25 and the Agency for Health Care Policy and
the nervous system to subsequent stimuli.The normal pain Research26 advocate the use of NSAIDs in a multimodal analge-
response as a function of stimulus intensity is depicted by the curve sic approach for the management of acute pain. The practice
on the right. After trauma, the pain response curve is shifted to guidelines for acute pain management in the perioperative
the left. As a result, noxious stimuli become more painful setting specifically state ‘‘unless contraindicated, all patients
(hyperalgesia), and nonpainful stimuli (shaded region) now become should receive around-the-clock regimen of NSAIDs, coxibs, or
painful (allodynia). acetaminophen.’’25
 III ACUTE PAIN 61

COX INHIBITION AND POSTOPERATIVE postoperative pain after dental, orthopedic, thoracic, abdominal,
PAIN MANAGEMENT and gynecologic surgeries.31,35 Although all NSAIDs inhibit the
COX enzyme, differences in their pharmacodynamic and pharma-
Currently, the administration of NSAIDs is one of the most com- cokinetic properties may make some NSAIDs more suitable as post-
mon nonopioid analgesic techniques utilized for the management of operative analgesics. Unfortunately, with the exception of dental
postoperative pain.27 NSAIDs are useful as the sole analgesic after surgery, there are very few studies comparing the analgesic efficacies
minor surgical procedures.28 Because of their ceiling effect for of NSAIDs for postoperative pain. The Oxford League Table of
analgesia,29 NSAIDs alone provide insufficient analgesia after analgesics36 may be used to indirectly compare the efficacy of
major surgery, but they demonstrate a significant opioid-sparing these NSAIDs against each other. This Table is based on using
effect.30 The use of NSAIDs has become increasingly popular because comparisons of different analgesics with placebo in similar clinical
of the concern over opioid-related side effects, such as nausea, vomit- circumstances, with similar patients included, similar pain measure-
ing, sedation, pruritus, ileus, and urinary retention. Advantages of ment, and similar outcome measures, and deriving the number-
utilizing NSAIDs as part of the perioperative ‘‘analgesic cocktail’’ needed-to-treat (NNT) (Table 9–2). The efficacy of analgesics is
include lack of sedation and respiratory depression, a low abuse commonly expressed as NNT, which represents the number of
potential, and no interference with bowel or bladder function.31
In addition, unlike opioids (which are effective for reducing sponta-
neous pain at rest), NSAIDs demonstrate comparable efficacy for
Table 9^2. Oxford LeagueTable of Analgesics
pain both at rest and with movement,32 the latter of which may be in Acute Pain
more important for causing postoperative physiologic impairment.33
For these reasons, it is recommended that unless contraindicated, Patients in At Least
nonselective NSAIDs should be considered the drugs of choice Comparison 50% Pain
for the management of mild to moderate postoperative pain.26 Analgesic (N) Relief (%) NNT CI
Nonselective NSAIDs encompass a chemically diverse group of Valdecoxib 40 mg 473 73 1.6 1.4–1.8
compounds including salicylates, proprionic acids, pyrazoles, acetic Ibuprofen 800 mg 76 100 1.6 1.3–2.2
acids, oxicams, fenamates, and naphthyl-alkanones34 (Table 9–1).
These NSAIDs have been reported efficacious in the management of Ketorolac 20 mg 69 57 1.8 1.4–2.5
Ketorolac 60 mg 116 56 1.8 1.5–2.3
(IM)
Table 9^1. Nonsteroidal Anti-inflammatory Drugs Rofecoxib 50 mg 1900 63 1.9 1.8–2.1
Diclofenac 100 mg 411 67 1.9 1.6–2.2
Generic Drug Name Trade Name Piroxicam 40 mg 30 80 1.9 1.2–4.3
p-Aminophenol Derivatives Lumiracoxib 400 252 56 2.1 1.7–2.5
Acetaminophen Tylenol mg
Salicylates Parecoxib 40 mg 349 63 2.2 1.8–2.6
(IV)
Aspirin
Diflunisal Dolobid Diclofenac 50 mg 738 63 2.3 2.0–2.7
Choline magnesium trisalicylate Trisalicylate, Trilisate Naproxen 440 mg 257 50 2.3 2.0–2.9
Salsalate Mono-Gesic Aspirin 1200 mg 279 61 2.4 1.9–3.2
Proprionic Acids Ketorolac 10 mg 790 50 2.6 2.3–3.1
Ibuprofen Motrin, Advil, Nuprin Piroxicam 20 mg 280 63 2.7 2.1–3.8
Fenoprofen Nalfon Diclofenac 25 mg 204 54 2.8 2.1–4.3
Naproxen Naprosyn, Anaprox, Meperidine 100 mg 364 54 2.9 2.3–3.9
Alleve (IM)
Ketoprofen Orudis Morphine 10 mg 946 50 2.9 2.6–3.6
Flurbiprofen Ansaid (IM)
Pyrazoles Parecoxib 20 mg 346 50 3.0 2.8–3.7
Phenylbutazone Butazolidin (IV)
Acetic Acids Naproxen 220/250 183 58 3.1 2.2–5.2
Indomethacin Indocin mg
Tolmetin Tolectin Ketorolac 30 mg 359 53 3.4 2.5–4.9
Sulindac Clinoril (IM)
Diclofenac Voltaren, Cataflam Acetaminophen 2759 46 3.8 3.4–4.4
Etodolac Lodine 1000 mg
Ketorolac Toradol Aspirin 1000 mg 716 46 4.0 3.2–5.4
Oxicams Aspirin 600/650 mg 5061 38 4.4 4.0–4.9
Piroxicam Feldene Celecoxib 200 mg 418 34 4.5 3.3–7.2
Meloxicam Mobic Codeine 60 mg 1305 15 16.7 11.0–48.0
Fenamates Placebo >10,000 18 N/A N/A
Meclofenamic acid Meclomen
Mefenamic Ponstel CI, confidence interval; IM, intramuscular; IV, intravenous; N/A, not
Naphthyl-alkanone applicable; NNT, number needed to treat.
*The medical coverage of mass-participation events presents a unique,
Nabumetone Relafen
exciting, and challenging opportunity to literally bring medical.
62 Chapter 9  PERIOPER ATIVE USE OF COX-2 AGENTS
patients who need to receive the active drug for one patient to
achieve at least 50% relief of pain compared with placebo over
a 4- to 6-hour treatment period.37 For example, an NNT of
2 means that for every two patients who receive the drug, one
patient will get at least 50% relief because of the treatment
(the other patient may or may not obtain relief, but it does not
reach the 50% level). The NNT is useful for comparison of relative
efficacy of analgesics because these NNT comparisons are treat-
ment-specific and are compared with placebo. NSAIDs do extre-
mely well in the single-dose postoperative comparison, with NNT
values ranging between 1.6 and 3.4.36 For example, the NNT is 1.6
for ibuprofen 800 mg, 1.9 for diclofenac 100 mg, 2.3 for naproxen
440 mg, 2.6 for ketorolac 10 mg, 2.7 for piroxicam 20 mg, and 3.4
for intramuscular ketorolac 30 mg.36 At these doses, the majority of
NSAIDs are more effective than single doses of either intramuscular
morphine 10 mg or meperidine 100 mg, which have an NNT of 2.9.
However, these opioids are more effective than both acetaminophen
1000 mg and aspirin 1000 mg, which have an NNT of 3.8 and 4.0,
respectively.36,38
Acetaminophen
Acetaminophen has demonstrated analgesic efficacy for acute post-
operative pain in a variety of analgesic models.39 A meta-analysis of
47 randomized, double-blind, placebo-controlled clinical trials
enrolling 4186 patients concluded that acetaminophen is an effec-
tive analgesic for acute postoperative pain and gives rise to few
adverse effects.39 Another meta-analysis of randomized, controlled
trials of acetaminophen for postoperative pain revealed that it in-
duced a morphine-sparing effect of 20% (9 mg) over the first
24 hours postoperatively (95% confidence interval [CI] –15 to –3
mg).40 A recent qualitative review of acetaminophen, NSAIDs, and
their combination concluded that acetaminophen may provide
analgesic efficacy similar to that of other NSAIDs after major ortho-
pedic surgery.40 It was concluded that acetaminophen may be
a viable alternative to NSAIDs in high-risk patients because of the
lower incidence of adverse effects.41 Further, it may be appropriate
to administer acetaminophen with an NSAID because these two
analgesics may confer an additive or synergistic effect.42
Acetaminophen may be administered via either oral, rectal, or intra-
venous routes for the management of postoperative pain. Oral
doses of 650 mg have been shown to be more effective than doses
of 300 mg; but little additional benefit is seen at doses above 1000
mg, indicating a possible ceiling effect.43 The bioavailability of rectal
acetaminophen is more variable, approximately 80% of that of
tablets and, the rate of absorption is slower, with maximum
plasma concentration achieved about 2 to 3 hours after adminis-
tration.44 Doses of 40 to 60 mg/kg of rectal acetaminophen have
been shown to have opioid-sparing effect in various postoperative
pain models.45 Propacetamol is a prodrug of acetaminophen that
can be administered parenterally. The drug is completely hydro-
lyzed within 6 minutes of administration, and 1 g of propacetamol
yields 0.5 g of acetaminophen.46 Under these conditions, the phar-
macokinetic profile is analogous to that observed after the oral
administration of acetaminophen 0.5 g, except for a significantly
higher maximal plasma concentration as a result of the complete
bioavailability of the injectable formulation.46 Similar to oral acet-
aminophen, intravenous propacetamol demonstrates a ceiling effect
for postoperative pain.47 The maximum effective intravenous dose
of paracetamol is 5 mg/kg, resulting in a serum concentration of
14 mg/ml, which is a lower dose than previously suggested.47 After
the intravenous injection of propacetamol, acetaminophen easily
crosses the blood-brain barrier, ensuring a central analgesic
effect.46 Injectable propacetamol has been shown to reduce opioid
consumption by about 35% to 45% in postoperative orthopedic
pain studies48–51 and has demonstrated analgesic efficacy similar
to that of ketorolac after gynecologic surgery.52 Although widely
utilized as an analgesic for decades in Europe, propacetamol
has not yet received approval by the U.S. Food and Drug
Administration (FDA).
Aspirin
Aspirin has been known to be an effective analgesic for many years
and is commonly used in the treatment of both acute and chronic
pain conditions. Aspirin has an elimination half-life that increases
from 2.5 hours at low doses to 19 hours at high doses.53 It is well
absorbed in the stomach and small intestine, with peak blood level
achieved 1 hour after an oral dose. There is then rapid conversion of
aspirin to salicylates from a high first-pass effect, which occurs in
the wall of the small intestine and the liver. The metabolic pathways
follow first-order and zero-order kinetics.53 A quantitative system-
atic review of 72 randomized single-dose trials with 3253 patients
given aspirin revealed a significant analgesic effect versus that of
placebo.38 Aspirin demonstrated a clear dose-response for pain
relief, even though these were single-dose studies. Significant benefit
of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg,
and 1200 mg, with NNT for at least 50% pain relief of 4.4, 4.0, and
2.4, respectively.38 No apparent ceiling effect for analgesia was
observed in this dose range. A comparison of the analgesic efficacy
of aspirin with acetaminophen has revealed that these two drugs
result in similar postoperative pain relief.38 These results are similar
to those of a previous study demonstrating that aspirin and aceta-
minophen are equianalgesic and, milligram per milligram, equipo-
tent in a variety of pain models.54 Although it possesses similar
analgesic efficacy to that of acetaminophen, the use of aspirin as a
postoperative analgesic has been limited by its greater side effect
profile. Unlike acetaminophen, the administration of aspirin causes
a significant inhibitory effect on platelet function,55 resulting in
greater perioperative blood loss.56 Aspirin, which irreversibly acet-
ylates the COX enzyme, causes inhibition of platelet aggregation for
the lifespan of the platelet, which is 10 to 14 days.55 In contrast,
nonselective NSAIDs reversibly inhibit the COX enzyme, causing a
transient reduction in the formation of thromboxane A2 (TXA2)
and inhibition of platelet activation, which resolves after most of the
drug is eliminated.55 In addition, even single doses of aspirin were
associated with significantly more drowsiness and gastric irritation
than placebo, with numbers-needed-to-harm of 28 and 38, respec-
tively.38 For these reasons, the widespread use of aspirin as a post-
operative analgesic has been curtailed.
Ketorolac
Ketorolac is currently the only parenteral NSAID for clinical anal-
gesic use in the United States. Ketorolac is almost entirely bound
to plasma proteins (>99%), which results in a small apparent
volume of distribution with extensive metabolism by conjugation
and excreted via the kidney.57 The analgesic effect occurs within
30 minutes, with maximum effect between 1 and 2 hours and dura-
tion of 4 to 6 hours.57 Ketorolac demonstrates analgesia well beyond
its anti-inflammatory properties, which are between those of indo-
methacin and naproxen; but ketorolac can provide analgesia
50 times that of naproxen.57 Ketorolac has antipyretic effects
20 times that of aspirin and, thus, can mask a febrile response
when administered during the postoperative period. Premarketing
clinical studies have demonstrated efficacy of ketorolac 30 to 90 mg
comparable with those of morphine 6 to 12 mg, meperidine 50 to
100 mg, and propacetamol 2 g for the treatment of moderate post-
operative pain.58 However, some studies have revealed that ketor-
olac is ineffective as the sole postoperative analgesic in the
management of moderate to severe postoperative pain.59,60
Similar to other NSAIDs, ketorolac demonstrates an analgesic
ceiling effect.29 Therefore, its efficacy as an analgesic monotherapy

is usually insufficient for moderately severe to severe pain after
major surgery. However, ketorolac can be utilized as an opioid-
sparing technique in the multimodal management of postoperative
pain. Depending upon the type of surgery, ketorolac demonstrated
an opioid-sparing effect of a mean of 36%.58 Despite this reduction
in opioid use, the administration of ketorolac was not associated
with a concomitant reduction in opioid side effects (e.g., nausea,
vomiting, pruritus, urinary retention).58
Oral ketorolac was approved for use in the United States
approximately 3 years after the parenteral form and has an
efficacy similar to that of naproxen and ibuprofen.61 The recom-
mended maximum total daily dose of oral ketorolac is 40 mg,
and it is indicated only as a continuation of the parenteral ther-
apy.62 The combined duration of use is not to exceed 5 days
because of the increased risk of serious adverse events.62
The appropriate analgesic dose of parenteral ketorolac is contro-
versial. Since ketorolac has been marketed, there have been
reports of death owing to gastrointestinal and operative site
bleeding.63 In the first 3 years after ketorolac was approved in
the United States (in 1990), 97 fatalities were reported.64 As
a consequence, the drug’s license was suspended in Germany
and France.65 In a response to these adverse events, the drug’s
manufacturer recommended reducing the dose of ketorolac from
150 to 120 mg per day.62 The European Committee for
Proprietary Medicinal Products recommended a further maximal
daily dose reduction to 60 mg for the elderly and 90 mg for the
nonelderly.66 Currently, there is consensus that the maximum
daily dose should be as low as 30 to 40 mg.29,67 Further, ketor-
olac is contraindicated as a preemptive analgesic before any
major surgery and is contraindicated intraoperatively when he-
mostasis is critical because of the increased risk of bleeding.62
COX-2^Specific Inhibitors (Coxibs)
Celecoxib was the first COX-2–specific inhibitor (coxib) approved
by the FDA in December 1998, followed by rofecoxib in May 1999,
and then valdecoxib in November 2001.68 Parecoxib (an injectable
prodrug of valdecoxib), etoricoxib, and lumiracoxib have not
received FDA approval but are available in several countries outside
the United States. Numerous review articles have documented the
efficacy of coxibs for the management of postoperative pain after
dental, orthopedic, thoracic, gynecologic, and otolaryngologic sur-
geries.69–75 A systematic review of COX-2 inhibitors compared with
traditional NSAIDs concluded that these two classes of NSAIDs
provided similar efficacy for the management of postoperative
pain.74
Although nonspecific NSAIDs are considered to play an
integral role in the management of postoperative pain,25,26 their
routine use has been limited in the perioperative setting because
of concerns of platelet dysfunction, renal toxicity, and gastroin-
testinal toxicity.28 Although short-term use of NSAIDs for the
management of acute pain does not seem to impair renal func-
tion,76 there are numerous reports of NSAID-induced renal fail-
ure when these drugs are utilized for the perioperative
management of pain.77–82 Similarly, there have been numerous
reports of gastrointestinal ulceration or bleeding associated with
brief exposure to NSAIDs for the perioperative management
of pain.83–87 Finally, the use of traditional NSAIDs may result
in an increased incidence of perioperative blood loss and blood
transfusion requirements, resulting in increased morbidity and
mortality after a variety of surgical procedures.99–101 Because
these major side effects are related to the inhibition of the
COX-1 enzyme, the perioperative use of coxibs appears to be
a safer alternative to traditional NSAIDs for the perioperative
management of pain.74,102 The specificity of COX-2–selective
inhibitors accounts for their safer gastrointestinal profile103 and
lack of antiplatelet activity55,68 relative to nonspecific NSAIDs.
III ACUTE PAIN 63
The coxibs pose a real and attractive alternative to traditional
NSAIDs in cases in which bleeding is a concern, including total
joint arthroplasty and tonsillectomy. Prior to the introduction of
coxibs, many patients undergoing elective total joint arthroplasty
were instructed to discontinue their use of NSAIDs 7 to 10 days
prior to surgery.104 Continuing conventional NSAIDs before total
joint arthroplasty has been associated with a twofold increase in the
incidence of perioperative bleeding, resulting in higher transfusion
requirements.90 The use of NSAIDs has been associated with other
postoperative complications, including wound hematoma, upper
gastrointestinal tract bleeding, and hypotension.89 The likelihood
of developing these complications was found to be 5.8 times greater
for patients using NSAIDs 24 hours before surgery than for those
without such usage.89 We have observed that discontinuing NSAIDs
before total joint arthroplasty results in an arthritic flare, not only in
the operative joint but also in other arthritic joints, leading to
increased preoperative pain.104 Increased pain before total joint ar-
throplasty is the leading cause for increased postoperative pain,
prolonged hospital admission, and impaired rehabilitation.105 The
administration of perioperative coxibs for total joint arthroplasty
has demonstrated a reduction in perioperative pain and improve-
ment in outcomes without an added risk of increased perioperative
bleeding.104,106
The use of traditional NSAIDs for tonsillectomy is also associ-
ated with an increased risk for perioperative bleeding and reopera-
tion for bleeding.101 A meta-analysis of randomized, controlled
trials involving the effects of NSAIDs on bleeding after tonsillec-
tomy concluded that ‘‘the use of NSAID therapy after tonsillectomy
should be abandoned both at the hospital and at home.’’101
However, these authors did not account for the use of coxibs in
their meta-analysis. A subsequent study evaluated the safety and
efficacy of administering rofecoxib 1 mg/kg prior to pediatric ton-
sillectomy.107 This study revealed a significant reduction in postop-
erative pain, opioid use, and the incidence of postoperative nausea
and vomiting without an increase in intraoperative surgical bleed-
ing or in the likelihood of reoperation for bleeding. These data
support previous findings that coxibs do not increase perioperative
blood loss68–75 and that these NSAIDs may prove useful for the
management of post-tonsillectomy pain.
In an attempt to determine whether an individual COX-2–selec-
tive inhibitor possesses greater analgesic efficacy for acute postop-
erative pain, several meta-analyses have been performed108–111 in
which the NNT for one patient to achieve 50% pain relief was
calculated. In these studies, the NNTs for the COX-2 inhibitors
valdecoxib 40 mg, rofecoxib 50 mg, and parecoxib 40 mg were
1.6, 1.9, and 2.2, respectively. These values are similar to those
reported for the traditional NSAIDs.36 The only COX-2 inhibitor
to perform less well than the other coxibs or most traditional
NSAIDs was celecoxib 200 mg with an NNT of 4.5.110 However,
subsequent to this meta-analysis, celecoxib received approval by the
FDA for the management of acute pain. The celecoxib dose for
acute pain is 400 mg followed by a 200-mg dose within the first
24 hours then 200 mg twice daily on subsequent days.112 Because
celecoxib is currently the only selective COX-2 inhibitor available in
the United States, future randomized, controlled clinical trials uti-
lizing these recommended doses are necessary to determine the
analgesic efficacy of this NSAID for acute pain postoperative
management.
Celecoxib
Celecoxib has approval for the relief of pain from osteoarthritis,
rheumatoid arthritis, acute pain, and dysmenorrhea and to reduce
the number of adenomatous colorectal polyps in familial adenom-
atous polyposis.112 The concomitant administration of celecoxib
with aluminum- or magnesium-containing antacids results in a
reduction of plasma levels of this NSAID. Peak plasma levels
occur 3 hours after oral administration, and the drug crosses into
64 Chapter 9  PERIOPER ATIVE USE OF COX-2 AGENTS
the central spinal fluid.19 Celecoxib is 97% protein bound, with an
apparent volume of distribution of 400 L, suggesting extensive dis-
tribution into tissues.112 It is metabolized via cytochrome P-450
2C9 and eliminated predominantly by the liver. It is not indicated
for pediatric use and is a category C drug for pregnancy. Celecoxib
can increase plasma lithium levels, and the concomitant adminis-
tration of diflucan can increase plasma levels of celecoxib.
The drug has a half-life of about 11 hours.112 Adverse events
noted in the various clinical trials include headache, edema, dys-
pepsia, diarrhea, nausea, and sinusitis. It is contraindicated in
patients who have a sulfonamide allergy or a known hypersensitivity
to aspirin or other NSAIDs. Celecoxib has been shown to have
no effect on platelet function measured by serum thromboxane
production and ex vivo platelet aggregation.113 In fact, celecoxib
in doses of 1200 mg/day administered for 10 consecutive days
in healthy adults demonstrated no effect on platelet aggregation
or bleeding time.113
Previous studies have shown analgesic efficacy with the periop-
erative administration of celecoxib 200 mg for dental, orthopedic,
and otolaryngologic surgeries.110,114–117 However, these clinical
investigations may have underestimated the analgesic efficacy of
celecoxib because they did not utilize the appropriate dose for post-
surgical pain. The need for an initial loading dose of celecoxib is
related to its large volume of distribution (400 L). In a dose-ranging
study after otolaryngologic surgery,118 celecoxib 400 mg was more
effective than 200 mg in reducing severe postoperative pain and the
need for rescue analgesic medication in the postoperative period.
However, even this study was flawed because these investigators
failed to administer a subsequent dose of celecoxib 200 mg within
the first 24 hours postoperatively. The first clinical investigation to
document the analgesic efficacy of celecoxib administered for post-
operative pain management according to the current acute pain
guidelines demonstrated a 31% reduction in 24-hour morphine
use and a significant decrease in pain scores.119 This represents
a significant improvement in analgesic efficacy compared with a pre-
vious study in which only a 9% reduction in morphine use was
reported with the administration of a single 200-mg dose of cele-
coxib prior to the same surgical model.114 In addition to lower
morphine use, celecoxib administration resulted in significantly
lower pain scores at all postoperative time intervals except at
12 and 24 hours postsurgery, which coincides with the time
at which this drug needs to be redosed.
ROUTE OF ADMINISTRATIONOF
NSAIDS
It is common belief that parenteral NSAIDs are more efficacious in
the management of acute pain than orally administered NSAIDs.
Many physicians continue to administer NSAIDs via the parenteral
route even though patients are tolerating oral intake after surgery.
Reasons for choosing the parenteral route are pharmacokinetic
based, that is, the rate of drug absorption may affect the efficacy
and onset of analgesia. However, one meta-analysis comparing
NSAIDs administered by different routes for the management of
acute and chronic pain failed to detect any difference in analgesic
efficacy.120 The intramuscular and rectal routes were associated with
more local adverse effects, and the intravenous route resulted in
a greater risk of postoperative bleeding.120 The risk of gastrointes-
tinal toxicity was similar with the administration of NSAIDs by
either the parenteral or the oral route. The authors concluded
that there is a strong argument to administer NSAIDs via the oral
rather than the parenteral route for the management of postoper-
ative pain as soon as patients are tolerating oral intake.120
In an attempt to provide a peripheral analgesic effect, some
investigators have utilized NSAIDs administered via either topical
application or local wound infiltration for the management of acute
pain. These routes provide for high concentrations of these agents at
the site of the inflammatory process, with the potential for a more
effective reduction of inflammation. Further, there is a potential for
fewer side effects because lower doses of the drug may be used,
resulting in lower plasma concentrations of the NSAID.121 It has
been demonstrated that even without a reduction in dose, the top-
ical administration of NSAIDs results in much lower plasma con-
centrations of the drug compared with the same dose of NSAID
administered orally.122,123 For these reasons, the topical administra-
tion of NSAIDs demonstrates a lower incidence of adverse events,
including gastrointestinal toxicity, compared with the oral route.124
A quantitative systematic review of topical NSAIDs for acute pain
confirmed the benefit of this route of administration.125 After a
review of the literature, it was concluded that both the topical
and the oral routes provided comparable analgesic efficacy for
acute pain. Further, the topical route was associated with a low
incidence of systemic adverse events that were no different from
those of placebo.125 Similarly, the local infiltration of NSAIDs into
the surgical site should provide for effective analgesia with minimal
side effects. NSAIDs have been administered intra-articularly for
knee surgery, as components of intravenous regional anesthesia
(IVRA) for hand surgery, and by wound infiltration for inguinal
herniorrhaphy, mastectomy, tonsillectomy, and hand surgery.126
A meta-analysis of local infiltration of NSAIDs revealed that there
was good evidence for a clinically relevant peripheral analgesic
action of intra-articular NSAIDs whereas the results of IVRA and
wound infiltration with NSAIDs in postoperative pain were incon-
clusive.126 Unfortunately, the incidence of systemic side effects was
not evaluated in any of these clinical studies.
In addition to targeting peripheral prostaglandin synthesis with
the use of local NSAID administration, alternative formulations
of ketorolac have been developed as a means of blocking the up-
regulation of COX-2 in the CNS after surgical trauma. Because
ketorolac is unable to cross the blood-brain barrier effectively,127
studies are under way to determine the efficacy of this drug when
administered via the intranasal route.128 Intranasal drug delivery is
one of the focused delivery options for brain targeting because the
brain and nose compartments are connected to each other via the
olfactory route and via the peripheral circulation.129 The adminis-
tration of an intranasal formulation of ketorolac provides for rapid
uptake, with significant levels of the drug measured in the cerebro-
spinal fluid.128 Further, minimal gastrointestinal side effects have
been reported with this route of administration.128 Another method
of targeting central prostaglandin synthesis is to administer NSAIDs
via the intrathecal route. Unfortunately, the current formulation of
ketorolac contains alcohol (10% wt/vol),62 which is neurotoxic,
thus precluding its use as an intrathecal analgesic. However, inves-
tigators have developed a preservative-free formulation of ketorolac,
which has been safely administered to humans via the intrathecal
route.130 These data support further investigation of this NSAID
when administered neuraxially for the management of acute
postoperative pain.
TIMING OF ADMINISTRATIONOF
NSAIDS (PREEMPTIVE ANALGESIA)
Preemptive analgesia as a concept began over 90 years ago, when
Crile131 proposed that blocking noxious signals prior to a surgical
incision may lead to some degree of CNS protection against postop-
erative pain, though at that time, the mechanism remained unclear. It
is now recognized that nociceptor function is dynamic and may be
altered after tissue injury, leading to the amplification and prolon-
gation of postoperative pain.132 As evidence continues to accumulate
concerning the role of neuroplasticity after surgery, many researchers
have focused on methods by which to not simply treat the symptoms
as they occur but also to prevent central sensitization from occurring
through the utilization of preemptive analgesic techniques.11
Currently, preemptive analgesia is taken to mean that a preoperative

dose of analgesic is more effective than the same dose of the same
drug given postoperatively.133 The evidence in support of preemptive
analgesia has been equivocal, with one systematic review of the lit-
erature demonstrating no beneficial effect134 whereas a more recent
review135 demonstrated an overall benefit of this concept.
The preemptive analgesic effect of NSAIDs has been previously
studied after a wide variety of surgical procedures demonstrating
equivocal results.11,134–136 Unfortunately, many methodological
problems have been encountered in these studies.137 Reuben and
coworkers138 were the first investigators to examine the analgesic
effects of administering the same dose of NSAID either before or
after arthroscopic knee surgery. The results of this study demon-
strated that preoperative NSAID administration produced a signif-
icantly longer duration of postoperative analgesia, less 24-hour
opioid use, and lower incidental pain scores compared with admin-
istering the same drug in the postoperative period. A review of 18
randomized, single- or double-blinded studies that used an NSAID
as the target intervention revealed that only 6 studies (33%) demon-
strated a preemptive analgesic effect.136 Furthermore, the beneficial
effects of preemptive NSAIDs observed in most studies were min-
imal. The review by Moniche and associates134 included 20 clinical
trials comparing preincisional with postincisional NSAIDs using a
parallel or crossover design. The authors concluded that some
aspects of postoperative pain were improved by preemptive treat-
ment in 4 of the 20 trials. Overall, the data demonstrated preemp-
tive NSAIDs to be of no analgesic benefit when compared with
postincisional administration of these drugs. In contrast, Ong and
colleagues135 reviewed data from 16 randomized, controlled trials
with preemptive NSAIDs, concluding that these drugs improved
analgesic consumption and time to first analgesic request but not
postoperative pain scores.
The administration of coxibs seems to possess a more favorable
pharmacokinetic profile than other NSAIDs when administered
orally during the preoperative period. Unlike conventional
NSAIDs, coxibs may be administered without food to the fasting
preoperative patient138 and do not inhibit platelet aggregation
resulting in increased perioperative blood loss.75 Further, all
coxibs have demonstrated the ability to block both peripheral and
central prostaglandin synthesis.19 A recent systematic review of pre-
operative COX-2–selective NSAIDs demonstrated the safety and
efficacy of this class of NSAIDs for the management of postopera-
tive pain.75 Only three studies139–141 compared the preoperative
administration of coxibs with traditional NSAIDs. Heigi and cow-
orkers139 compared rofecoxib 50 mg with diclofenac 50 mg just
before induction of anesthesia in vaginal hysterectomy or breast
surgery. Rofecoxib resulted in less intraoperative blood loss, less
postoperative nausea and vomiting, less antiemetic use, and greater
patient satisfaction. Celik and associates140 compared rofecoxib 50
mg with naproxen 550 mg before abdominal hysterectomy and
reported no difference with regard to postoperative pain, analgesic
use, or nausea and vomiting. Gopikrishna and Parmeswaran141
compared rofecoxib 50 mg and ibuprofen 600 mg before root
canal surgery and reported lower pain scores with rofecoxib at
12 and 24 hours postsurgery.
Although the concept of preemptive analgesia is controver-
sial,134,135 we need to move beyond the importance of reducing
only the nociceptive afferent input brought about by the surgical
incision. The term preventive analgesia142 was introduced to empha-
size the fact that central neuroplasticity is induced by pre-, intra-,
and postoperative nociceptive inputs. Thus, the goal of preventive
analgesia is to reduce central sensitization that arises from noxious
inputs occurring throughout the entire perioperative period and
not just from those occurring during the surgical incision. Thus,
NSAIDs should be utilized throughout the entire perioperative
period until the surgical wound has healed. Effective preventive
analgesic techniques utilizing NSAIDs may be useful in reducing
not only acute pain but also chronic postsurgical pain and
disability.143,144
III ACUTE PAIN 65
EFFECTOF PERIOPERATIVE NSAID
ADMINISTRATIONON POSTOPERATIVE
OUTCOMES
Although NSAIDs have been shown to reduce postoperative anal-
gesic requirements by 30% to 50% in most of the clinical trials,
concern still exists regarding the real clinical benefit of NSAIDs to
reduce opioid-related adverse effects, thereby hastening recovery
and reducing morbidity.3,21 Recently, several meta-analyses40,145,146
and systematic reviews75,147,148 have assessed the effects of NSAIDs
on opioid-related side effects. The first meta-analysis, which
included seven randomized, controlled trials (491 subjects), exam-
ined the effect of acetaminophen on morphine-related adverse
events.40 The studies compared the addition of acetaminophen
versus placebo to standard patient-controlled analgesia (PCA) mor-
phine for pain control after major surgery. Although the use of
acetaminophen decreased morphine use by 20% over the first
24 hours, there was no reduction in the risk of any opioid-related
side effects. Although the effect of acetaminophen on postoperative
pain was not quantitatively analyzed as a single-pooled estimate, the
authors noted that only two of the six studies found that the use of
acetaminophen improved pain scores compared with those of
placebo.
The second meta-analysis, which included 22 randomized,
controlled trials (2307 subjects), examined the effect of NSAIDs
on morphine-related adverse events.145 Clinical studies included
the addition of an NSAID versus placebo to standard PCA mor-
phine for postoperative pain management after a variety of surgical
procedures. This study demonstrated that NSAIDs decreased the
relative risk (RR) versus placebo of postoperative nausea and vom-
iting by 30% (RR = 0.70; 95% CI = 0.59–0.84) and of sedation by
29% (RR = 0.71; 95% CI = 0.54–0.95). However, NSAIDs did not
reduce the risk of developing pruritus, urinary retention, or respi-
ratory depression. The effects on pain were not assessed.
Another meta-analysis examined whether multimodal analgesia
with acetaminophen, NSAIDs, or selective COX-2 inhibitors pro-
vided benefit when added to PCA morphine.146 Included in this
meta-analysis were 10 randomized, controlled trials that examined
the addition of acetaminophen, 14 that examined the addition of
COX-2 inhibitors, and 33 that assessed the addition of an NSAID to
standard PCA morphine for pain control after surgery. The results
suggested all of the analgesics provided an opioid-sparing effect
(15%–55%); however, this decrease in opioid use did not consis-
tently result in a decrease in side effects. The use of NSAIDs was
associated with a significant decrease in the relative risks of post-
operative nausea, vomiting, and sedation, similar to those observed
in another meta-analysis.145 However, the use of acetaminophen or
COX-2 inhibitors did not significantly decrease the risk of opioid-
related adverse events compared with placebo. NSAIDs (multiple
dose and infusion only), but not acetaminophen or single-dose
NSAIDs, were associated with a statistically significant decrease in
pain scores. The analgesic efficacy of COX-2 inhibitors was not
assessed in this meta-analysis.
Finally, three systematic reviews were conducted of the analgesic
efficacy of a COX-2 inhibitor compared with placebo in addition to
a standard opioid analgesic regimen for postoperative pain manage-
ment.75,147,148 One systematic review examined the effect of pre-
operative COX-2 inhibitors on postoperative outcomes in
22 randomized trials with 2246 subjects.75 Compared with placebo,
preoperative administration of a COX-2 inhibitor reduced postop-
erative pain and opioid use in 15 of the 20 trials; however, no signif-
icant differences were observed between placebo and COX-2
inhibitors in the overall RR or incidence of postoperative nausea
and vomiting in 13 of 17 trials. A second systematic review examined
the effect of coxibs versus placebo in 19 randomized, controlled trials
including 26 comparisons of four COX-2 inhibitors (rofecoxib, cel-
ecoxib, parecoxib, and valdecoxib).147 Despite a significant opioid-
sparing effect averaging about 35% with coxibs, opioid-related
66 Chapter 9  PERIOPER ATIVE USE OF COX-2 AGENTS
adverse events were significantly reduced in only 4 of the 26 compar-
isons. Quantitative analysis of combined data revealed a reduced risk
for only dizziness. A third systematic review was a meta-analysis of
9 trials (1738 subjects) that examined patients’ global evaluation of
analgesia after intravenous parecoxib for postoperative pain.148
Compared with placebo, subjects that received parecoxib, especially
the 40-mg dose, had a significantly superior analgesic outcome (e.g.,
they more frequently rated their pain control as ‘‘good’’ or
‘‘excellent’’). However, parecoxib did not decrease the risk of
opioid-related adverse events compared with those of placebo.
On the basis of this available evidence,40,75,145–148 it appears that
the use of NSAIDs, acetaminophen, and COX-2 inhibitors results
in an opioid-sparing effect after surgery. However, this decrease in
opioid use does not consistently translate into a decrease in opioid-
related adverse events. One criticism of these findings is that many
of the studies relied exclusively on spontaneous reports of patients’
adverse events, which may be less than rates obtained through direct
assessment.149 The use of an opioid-related symptom distress scale
is valuable for the evaluation of symptom frequency, severity, and
distress after surgery.150 Utilizing this scale for patients receiving
COX-2 inhibitors after laparoscopic cholecystectomy,151 it became
evident that a linear relationship exists between opioid doses and
clinically meaningful opioid-related adverse events.150 Analysis of
available data suggests that once a threshold morphine dose in
24 hours is reached, every 3- to 4-mg increase of morphine require-
ments will be associated with one more clinically meaningful
opioid-related symptom. This linear correlation identifies for the
first time a connection between opioid-sparing effects and reduc-
tion of adverse effects. Further, many of the studies assessing
opioid-related adverse effects40,75,145–148 used methodology that
does not accurately reflect conditions in actual clinical practice.
NSAIDs are more likely to be used in multiple doses (which dem-
onstrate superior analgesia vs. placebo)146 rather than single doses
for the management of postoperative pain. In addition, a more
comprehensive multimodal approach (e.g., combinations of regio-
nal analgesic techniques, other adjuvant analgesics, and opioids) is
probably needed to demonstrate a reduction in opioid-related
adverse events and improvement in functional outcomes.
The beneficial effects of utilizing a multimodal analgesic
approach, including regional analgesia and sustained COX-2
inhibition, were demonstrated in a clinical investigation for patients
undergoing major knee surgery.106 This randomized, placebo-
controlled, double-blind trial evaluated the effect of combined pre-
operative and 13-day course of postoperative administration of
a COX-2 inhibitor on opioid consumption and outcomes after
total knee arthroplasty. This study documented a reduction in epi-
dural analgesic use, in-hospital opioid consumption, pain scores,
postoperative vomiting, sleep disturbance, and increased patient
satisfaction in patients administered COX-2 inhibitors compared
with the results with placebo. Finally, improved knee range of
motion was observed both at discharge and 1 month after surgery
in the group receiving perioperative COX-2 inhibition.
The benefits of utilizing NSAIDs as a component of a preventive
multimodal analgesic technique have also been demonstrated for
patients undergoing anterior cruciate ligament (ACL) surgery.143,150
A retrospective study of 1200 patients undergoing ACL surgery
examined the efficacy of administering a preventive multimodal
analgesic technique (n=500) versus a standard postoperative pain
protocol (n=700).143,152 Patients in the preemptive multimodal
group received acetaminophen 1000 mg every 6 hours and rofecoxib
50 mg daily starting 48 hours prior to surgery. In addition, 30 min-
utes prior to surgery, a femoral nerve block and an intra-articular
injection of bupivacaine/clonidine/morphine were performed.
Postoperative analgesia included acetaminophen, rofecoxib, con-
trolled-release oxycodone, and a cryotherapy cuff. In contrast,
patients in the standard postoperative analgesic group received
no preemptive analgesics prior to surgery and were administered
ibuprofen and acetaminophen with oxycodone on an as-needed
basis postoperatively. All patients were subsequently enrolled in a
6-month accelerated rehabilitation protocol. This study demon-
strated that patients who received preemptive multimodal analgesic
techniques had a reduction in the incidence of pain, opioid use,
postoperative nausea and vomiting, recovery room length of stay,
and unplanned admission to the hospital. In addition to an improve-
ment in short-term outcomes, patients receiving a preventive mul-
timodal analgesic technique had a reduction in long-term
complications at 1 year after surgery.143 Long-term complications
included a lower incidence of anterior knee pain (4% vs. 14%),
lower number of patients requiring repeat arthroscopy for lysis of
scar tissue (2% vs. 8%), and a lower incidence of complex regional
pain syndrome (1% vs. 4%) in the preventive multimodal analgesic
group compared with the standard analgesic group, respectively.
NSAIDs may play a pivotal role in the prevention of chronic
postsurgical pain syndromes. It has been hypothesized that because
COX-2 plays an integral role in the processes of peripheral and
central sensitization,13 it is possible that early and sustained treat-
ment with COX-2 inhibitors may thwart the progression of acute to
chronic pain.153 One study revealed that the administration of cel-
ecoxib both prior to surgical incision and continually for the first 5
postoperative days resulted in a significant reduction in both acute
postoperative pain and the incidence of chronic donor site pain
after spinal fusion surgery. Patients receiving celecoxib had a 74%
lower risk for developing this chronic neuropathic pain syndrome.
There are several potential explanations for the observed lower inci-
dence of chronic donor site pain in patients receiving perioperative
celecoxib. It has been suggested that effective treatment of acute
pain, particularly when accompanied by a neuropathic element,
prevents the development of chronic postsurgical pain syn-
dromes.154 This reduction in chronic pain may be attributed to a
preemptive or preventive analgesic effect in which a reduction in
spinal cord neuroplasticity derives from prompt reduction in the
perioperative noxious afferent input associated with surgery.155 It is
also possible that a reduction in COX-2 expression in the CNS after
surgical trauma may have contributed to a later reduction in
chronic pain. It has been demonstrated that allodynia and spinal
prostaglandins appear to be functionally linked in the early period
after nerve injury.156–158 However, several weeks after injury, this
prostaglandin-dependent allodynia recedes and leaves long-term,
prostaglandin-independent allodynia.159 Thus, spinal prostaglandin
synthesis may be important for the induction and initial expression
but not for the maintenance of spinal cord hyperexcitability.156,158
Thus, although NSAIDs are ineffective in the treatment of neuro-
pathic pain, they may be effective as a treatment strategy for pre-
venting the pathogenesis of this chronic pain syndrome.
ADVERSE EFFECTS OF COX INHIBITION
Allergy and Hypersensitivity
All NSAIDs, including acetylsalicylic acid, may induce two types of
hypersensitivity reactions, both of which are related to the inhibi-
tion of prostaglandin synthesis. These include (1) Samter’s triad
(asthma triad), in which some patients suffer from the triad of
intolerance to aspirin and aspirin-like chemicals, nasal polyposis,
and bronchial asthma, and (2) the syndrome of urticaria and an-
gioedema. Approximately 10% of patients with Samter’s triad will
develop angioedema and uticaria when exposed to NSAIDs.
The exact mechanism responsible for Samter’s triad is unknown,
but it is widely believed the disorder is caused by an anomaly in the
arachidonic cascade, which causes undue production of leukotrienes.160
When prostaglandin production is blocked by NSAIDs like aspirin, the
cascade shunts entirely to leukotrienes, producing the allergy-like
effects. Leukotriene antagonists and inhibitors such as montelukast
sodium (Singulair, Merck & Co., Inc., West Point, PA) show great

promise in treating patients with Samter’s triad.160 Because the intol-
erance reactions to aspirin and NSAIDs are caused by inhibition of the
COX-1 enzyme, COX-2–selective inhibitors should be a safer alterna-
tive in the management of pain for these patients. Several studies have
confirmed these findings, demonstrating that celecoxib may be admi-
nistered safely to patients with a history of uticaria/angioedema,
naso-ocular symptoms, bronchospasm, and/or anaphalactoid reaction
induced by aspirin and/or NSAIDs.161–163
In addition to these hypersensitivity reactions, patients must be
asked about possible allergic reactions to sulfonamides before
prescribing certain NSAIDs. The overall incidence of sulfonamide
hypersensitivity in the general population is low, at approximately
3%.164 All sulfonamides can be regarded as belonging to one of two
main biochemical categories: arylamines and nonarylamines.165 The
key to a sulfonamide allergy is believed to be related to the forma-
tion of a hydroxylamine metabolite unique to the arylamine
structure. Celecoxib, parecoxib, and valdecoxib belong to the non-
arylamine group of medications and are contraindicated in patients
allergic to sulfonamides.
Gastrointestinal
The first evidence that aspirin could damage the stomach was
reported in 1938 based on gastroscopic observations.166
Subsequently, endoscopic studies have consistently demonstrated
that gastric or duodenal ulcers develop in 15% to 30% of patients
who regularly take nonselective NSAIDs.167 Some of the risk factors
identified for the development of NSAID-induced ulcers include
advanced age, history of ulcer, concomitant use of corticosteroids,
higher doses of NSAIDs (including the use of more than one
NSAID), concomitant administration of anticoagulation, serious
systemic disorder, cigarette smoking, consumption of alcohol, and
concomitant infection with Helicobacter pylori.168 The mechanisms
by which NSAIDs cause ulceration in the stomach are by their
topical irritant effect on the epithelium and their ability to suppress
prostaglandin synthesis.169 The ability of NSAIDs to cause gastric
damage correlates with the duration of use, dose, and the ability to
inhibit COX-1 in the gastric mucosa.168,170 Three studies demon-
strated that some NSAIDs are associated with higher gastrointesti-
nal risks than others.171–173 In general, ibuprofen and etodolac have
the lowest risk among nonselective NSAIDs; diclofenac and naprox-
en have intermediate risks; and piroxicam, idomethacin, and ketor-
olac have the greatest risk for gastrointestinal complications.
In contrast, the selective COX-2 inhibitors were found to have a
significantly lower risk of gastrointestinal toxicity when compared
with traditional NSAIDs, with incidences similar to those of placebo.174
Evidence from four large-scale randomized, controlled trials showed
that COX-2–selective inhibitors have reduced gastrointestinal toxicity
compared with nonselective NSAIDs.175–178 The Vioxx Gastrointestinal
Outcomes Research (VIGOR) trial,175 Celecoxib Long-term Arthritis
Study (CLASS),176 Therapeutic Arthritis Research and Gastrointestinal
Event Trial (TARGET),177 and Successive Celecoxib Efficacy and
Safety Studies (SUCCESS)178 provided evidence that COX-2 inhibitors
minimize the risk of gastrointestinal complications compared with
those of traditional NSAIDs.
These findings174–178 combined with the possibility that even the
short-term perioperative use of NSAIDs has been associated with
gastrointestinal toxicity,83–87 suggest that coxibs may be safer alter-
natives in the management of acute pain for those patients with a
past history of peptic ulcer disease or at greater risk for perforation.
Hematologic
Platelet activity and hemostasis depend upon a constant balance
between the effects of prostaglandin I2 (PGI2) in the endothelium
and those of TXA2 in the platelets.55 TXA2 is converted from
III ACUTE PAIN 67
prostaglandin H2 (PGH2) in the platelets by the action of TXA2
synthase, whereas PGI2 is converted from PGH2 in the vascular
endothelium by the action of PGI2 synthase (Fig. 9–3).
Furthermore, activated platelets divert some of their endoperoxides
to vascular cells ("endoperoxide steal") to further provide substrate
for PGI2 formation. TXA2 functions as a platelet activator and
vasoconstrictor, whereas PGI2 is a platelet inhibitor and vasodilator.
Because platelets do not contain COX-2, all synthesis of TXA2 in
the platelet is mediated by COX-1. Therefore, therapeutic doses of
highly selective COX-2 inhibitors may be advantageous in the
perioperative period because there is no increased bleeding from
platelet effects.
Renal
Both COX-1 and COX-2 are constitutively expressed in the human
kidney. The predominant effect of COX-2 (constitutively expressed
in both the cortical thick limb of the loop of Henle and the med-
ullary interstitial cells) is in water and electrolyte homeostasis.179
COX-1 appears to influence renal hemodynamic regulation such
that inhibition of COX-1 has been shown to reduce glomerular
filtration rate.179 All NSAIDs including COX-2 inhibitors are asso-
ciated with transient sodium and water retention, hypertension, and
edema, all possible within the first few days of therapy. Most of
these events are of minor clinical significance and resolve within
1 to 8 weeks after discontinuation of NSAID therapy.180 Risk factors
for NSAID-induced renal toxicity include chronic NSAID use, mul-
tiple NSAID use, dehydration, volume depletion, congestive heart
failure, vascular disease, hyperreninemia, shock, sepsis, systemic
lupus erythematosus, hepatic disease, sodium depletion, nephrotic
syndrome, concomitant drug therapy (diuretics, angiotensin-
converting enzyme [ACE] inhibitors, b-blockers, potassium
supplements), and age 60 years or older.180 Although short-term
use of NSAIDs for the management of acute pain does not
seem to impair renal function,76 it would be sensible to delay
NSAID or coxib administration in the presence of compromised
renal function or perioperative dehydration, hypovolemia, and
hypotension.
Bone Healing
Another concern regarding the perioperative use of NSAIDs is
the possible deleterious effect on osteogenesis and spinal
fusion.181–184 Prostaglandins have been known for many years
to have potent effects on bone metabolism, including both
osteoblastic and osteoclastic activity, as well as being essential
in bone repair.185 The exact mechanism by which NSAIDs
impair spinal fusion has not yet been elucidated. It has been
hypothesized that the effect may be mediated by an inhibition
of the inflammatory process with concomitant reduction in blood
flow in the early period of osteogenesis, decreased mesenchymal
cell proliferation, or inhibition of calcification of the bone
matrix.181–183 Many investigators recommend that NSAIDs
should not be utilized in the multimodal management of acute
pain for patients undergoing spinal fusion surgery.181–183
Although the data are conflicting, a large body of literature
derived from laboratory animal studies suggests that COX-2
inhibitors either delay or inhibit bone healing.181–183 However,
in these studies, NSAIDs were administered over several weeks
to months at doses greater than that approved for acute pain. It
has been suggested that the deleterious effects of COX-2 inhibi-
tors on fracture healing may be reversible with short-term treat-
ment.186 Gerstenfeld and Einhorn187 concluded that
‘‘management of fracture-associated pain with inhibitors of
COX-2 should neither impair nor delay healing as long as the
duration of treatment is consistent with current standards of
68 Chapter 9  PERIOPER ATIVE USE OF COX-2 AGENTS

Membrane phospholipids

Phospholipase A2

Arachidonic acid

Cyclooxygenase
(constitutive COX-1)
_ (inducible COX-2)
NSAIDs
PGG2
Cyclooxygenase
(COX-1) or (COX-2)

PGI synthase TXA synthase

PGI2 PGH2 TXA2

(gastric mucosa, (platelets)

PGF synthase
platelets, PGD synthase
endothelium)
PGE isomerase

PGD2 PGF2-alpha
PGE2
(gastric mucosa,
kidney, peripheral nociceptor
spinal cord neurons)

Figure 9^3. The role of cyclooxygenase (COX) in prostaglandin (PG) synthesis. Prostaglandins (PGD2, PGE2, PGF2-a, and PGI2) and
thromboxanes (TXA2), which are mediators of inflammation and homeostasis, are products of a biochemical cascade by which membrane
phospholipids are converted to arachidonic acid, then to intermediate prostaglandins (PGG2 and PGH2) by COX, and to their final products by
a series of synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce postoperative pain by suppressing COX-mediated production of
PGE2. (Adapted from Gilron I, Milne B, Hong M.Cyclooxygenase-2 inhibitors in postoperative pain management. Anesthesiology 2003;99:1198^1208; used
with permission from the American Society of Anesthesiologists, copyright 2003 by Lippincott Williams & Wilkins.)

care.’’ In addition, limiting the use of NSAIDs for short-term
use, physicians should prescribe the lowest effective dose for
bone surgeries. In a retrospective study of 434 consecutive
patients undergoing elective decompressive posterior lumbar
laminectomy with instrumented spinal fusion by a single surgeon
within an 8-year period, we revealed that the short-term periop-
erative administration of celecoxib, rofecoxib, or low-dose ketor-
olac (110 mg/day) had no significant deleterious effect on
nonunion.188 In contrast, higher doses of ketorolac (120–240
mg/day), even when administered for less than 1 week, resulted
in a significant increase in the incidence of nonunion after spinal
fusion surgery. Further evidence for the safety of coxibs after
spinal fusion surgery was demonstrated in a recent prospective,
double-blind, randomized study in humans.119 This was the first
prospective study in humans that demonstrated that the periop-
erative administration of celecoxib for 5 consecutive days after
spinal fusion surgery resulted in no increased incidence of non-
union at 1 year follow-up compared with placebo.
Because the short-term administration of NSAIDs appears to
have no deleterious effects on spinal fusion, it is possible that
denying patients these medications may pose a greater risk than
nonunion. We must be cognizant of the fact that unrelieved acute
pain may be associated with significant morbidity, including
chronic postsurgical pain,8 that may be reduced with perioperative
coxib administration.144
Cardiovascular
With a large surge in the clinical use of COX-2–selective inhibitors
came a growing body of evidence that implicated their role (espe-
cially that of rofecoxib—currently unavailable) in contributing to
an increased risk of serious cardiovascular thrombotic events, myo-
cardial infarction, and stroke (first receiving a great deal of atten-
tion with the VIGOR study).175 Although mechanisms of this risk
remain uncertain, one theory holds that it relates to alteration of the
PGI2 balance favoring TXA2 with subsequent promotion of platelet-
dependent thrombosis.
In the normal state, COX-1 is the major source of PGI2 in
endothelial cells; however, COX-2 plays a significantly greater role
in generating PGI2. Therefore, COX-2 inhibition in atherosclerosis,
and thus PGI2 generation, may have important effects on the
‘‘antithrombotic balance.’’ Gislason and colleagues189 estimated
that in patients with a previous myocardial infarction, the excess
risk of mortality is roughly 6 deaths per 100 person-years of treat-
ment with a COX-2 inhibitor compared with no NSAID treatment.

The Multinational Etoricoxib and Diclofenac Arthritis Long-
term (MEDAL) Study Program (consisting of the Etoricoxib
Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness
[EDGE], EDGE II, and MEDAL trials) evaluated the highly
COX-2–selective inhibitor etoricoxib (not currently marketed in
the United States) versus diclofenac (a traditional NSAID that has
a bit more COX-2–inhibitory activity than COX-1–inhibitory activ-
ity) and found that both agents similarly increased the risks of
thrombotic events.190–193
The American Heart Association (AHA) published a scientific
statement essentially stating the need to be somewhat cautious of
the use of all nontraditional NSAIDs (excluding aspirin, acetami-
nophen, and nonacetylated salicyclates) in patients with cardiovas-
cular disease because it is conceivable that all of these agents may be
associated with some degree of increased risks of thrombotic
events.194 Furthermore, although uncertain, the AHA statement194
hypothesized that NSAID agents with the least COX-2 inhibition
and a relative preference of COX-1 inhibition (e.g., naproxen) may
be associated with the ‘‘best cardiovascular risk profile,’’ albeit
perhaps with an increase in gastrointestinal risk).
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