enhanced by COX-2mediated

prostaglandins from already inflamed

or damaged tissue.5,6 Coxibs may reduce
this type of pain.

Mechanisms of Pain Enhancement

Traditional nonsteroidal anti-inflammatory drugs are contraindicated for sur-
gical or short-term posttraumatic analgesia. Selective cyclooxygenase inhibitors
(coxibs) do not inhibit platelets and can be used in these settings. Coxibs
reduce sensitization of the nervous system. The use of coxibs as part of a mul-
timodal analgesia results in a reduction in the amount of opioids needed to con-
trol pain. Reduced opioid toxicity may hasten recovery.
S elective cyclooxygenase-2 (COX-2)
inhibitors (coxibs; Table) differ from
traditional nonsteroidal anti-inflamma-
tory drugs (NSAIDs) in two major ways.
Coxibs are less likely to result in NSAID-
induced gastropathy, and they do not
inhibit platelet function.1 As a result, the
major benefits of coxibs are the reduction
in gastric ulcer formation and bleeding
from those ulcers.2 Another benefit of
the platelet-sparing coxibs is their use
as analgesics and anti-inflammatory
Correspondence to Raymond M. Pertusi, DO, Asso-
ciate Professor of Medicine, Division of Rheuma-
tology, Department of Internal Medicine, Univer-
sity of North Texas Health Science Center at Fort
WorthTexas College of Osteopathic Medicine,
855 Montgomery St, Fort Worth, TX 76107-2553.
Dr Pertusi is on the speakers bureau and is a
consultant for Merck & Co and Pfizer Inc. He has
conducted research and has received grant support
from both of these companies.
E-mail: rpertusi@hsc.unt.edu
This continuing medical education
publication supported by an unrestricted
educational grant from Merck & Co
Selective Cyclooxygenase
Inhibition in Pain Management
Raymond M. Pertusi, DO
agents in situations in which bleeding
may limit the use of traditional NSAIDs,
such as trauma and surgical procedures.
Classification of Pain
Pain is typically classified as acute or
chronic. Cancer and many chronic
inflammatory disorders can result in
acute pain superimposed on chronic
pain. Typically, acute pain is a response
to injury. It is primarily nociceptive, and
designed to stimulate a withdrawal from
the noxious source. Chronic pain per-
sists long after any appreciable tissue
damage has resolved, and it may be due
to a windup or sensitization of the cen-
tral nervous system (CNS) resulting in
hyperalgesia or allodynia, whereby
minor stimulation is perceived as
painful.3 Differentiating acute pain from
chronic pain can be difficult because eval-
uation tools are largely subjective.
Coxibs have little effect on primary
nociceptive pain, the pain associated with
reflexive withdrawal from noxious
stimuli.4 Sensitivity to nociceptive stimuli
(pressure, impact, burn, etc) can be
by Prostaglandins
The mechanism by which inflammatory
prostaglandins enhance pain perception
is incompletely understood. The
enhancement of pain perception occurs
(in part) as the result of prostaglandin-
mediated sensitization of the peripheral
and central nervous systems.7-10
Inhibition of COX-2 prevents the
conversion of arachidonic acid into
inflammatory prostaglandins. Arachi-
donic acid is derived from normally
sequestered membrane phospholipids.
Trauma or inflammation exposes mem-
brane-bound phospholipids to phos-
pholipase A2, which converts them into
arachidonic acid. COX-2 converts arachi-
donic acid into inflammatory
prostaglandins (Figure 1).
Inflammatory prostaglandins have
numerous effects on local tissue. They
cause vasodilation and the resultant clin-
ical features of erythema and warmth.
Local edema occurs in response to
prostaglandin-related fluid shifts. Pain
perception is enhanced through
prostaglandin-mediated reduction in the
threshold for postsynaptic stimulation
and enhanced excitability in conduction
of pain impulses (action potentials) along
the peripheral neuron.10 This process is
known as peripheral sensitization (Figure 2).
Inflammatory prostaglandin levels
increase along the entire CNS in response
to local injury or inflammation, such as
trauma to a single limb or inflammation
in one or more joints .3,6 This increase in
inflammatory prostaglandins along the
CNS may be due to a systemic increase
in cytokines originating from the local
site of inflammation or injury, or per-
haps a neural intermediary. The cytokine,
interleukin 1 (IL-1), induces transcrip-
tion of COX-2, thereby increasing pro-
duction of prostaglandins that sensitize
the entire CNS within 6 to 12 hours of
the onset of local injury or inflamma-
tion.11 In the dorsal horn, presynaptically,
these prostaglandins increase transmitter
release. Postsynaptically, they reduce the
threshold for stimulation (similar to

Pertusi Selective Cyclooxygenase Inhibition in Pain Management JAOA Supplement 8 Vol 104 No 11 November 2004 S19
 Cell membrane
(protein-lipid bilayer)
{ Phospholipase

Arachidonic acid

CO
-1
COX Traditional

X-
2
NSAIDs
Housekeeping
prostaglandins Coxibs
Inflammatory
Preserve Preserve prostaglandins
GI mucosa platelet function

Figure 1. Prostaglandin formation and inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs.
(GI indicates gastrointestinal.)

Table
Currently Available and Future Coxibs

Coxib Administration Half-life, h Pain Indications*

Currently Available
 Celecoxib Oral 811 Osteoarthritis,
rheumatoid arthritis,
acute pain,
dysmenorrhea

 Valdecoxib Oral 8 Osteoarthritis,

rheumatoid arthritis,
dysmenorrhea

Future
 Etoricoxib Oral 24 Osteoarthritis,
rheumatoid arthritis,
back pain, pain,
dysmennorrhea,
gout, acute pain,
spondyloarthropathy

 Lumiracoxib Oral 36 Osteoarthritis,

rheumatoid arthritis,
acute pain,
dysmenorrhea

 Parecoxib Intravenous or 8 Acute pain, surgical pain

intramuscular

* Potential pain indications are listed for the coxibs likely to be available in the future.
Available until just before this issue went to press, rofecoxib (Vioxx) was withdrawn from the market by the manufacturer (Merck & Co) because of the risk
of cardiovascular events associated with long-term use. It had been indicated for the pain of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis,
acute pain, dysmenorrhea, and migraine.

S20 JAOA Supplement 8 Vol 104 No 11 November 2004 Pertusi Selective Cyclooxygenase Inhibition in Pain Management
 2mediated prostaglandin
production may explain
some of the features of the
sickness syndrome seen
in patients with chronic
diffuse inflammatory con-
ditions. This syndrome
CNS comprises fatigue, fever,
loss of appetite, weight
loss, and other constitu-
tional symptoms.13
Clinical Application
of Coxibs
Traditional NSAIDs have
been used in the manage-
ment of various types of
acute and chronic pain.
PNS Most coxibs have similar
+ B + indications to those of the
traditional NSAIDs (Table).
A Traditional NSAIDs are
generally contraindicated
+ in acute traumatic and sur-
gical pain owing to inhibi-
tion of platelets and
bleeding potential. Because
of the platelet-sparing
properties of coxibs, their
COX-2 Mediated PGs role in the management of
surgical and traumatic
pain is currently under
intense investigation.14-16
Tissue inflammation
Multimodal analgesia
often combines opioids,
Figure 2. Peripheral nervous system (PNS) sensitiztion sec- anesthetic blocks, coxibs,
ondary to tissue inflammation. COX-2mediated and other agents. Opioids
prostaglandins (PGs) reduce threshold for postsynaptic stim- are preferred over tradi-
ulation (A) and enhance excitability in conduction of impulses tional NSAIDs for anal-
along peripheral nerve (B). (CNS indicates central nervous
gesia when the potential
system; COX-2, cyclooxygenase-2.)
for bleeding exists. Opioids
peripheral sensitization). Additionally, bind multiple receptors, most notably
glycine receptormediated inhibition the
receptor. However, their analgesic
pathways are themselves inhibited by effect in acute pain management may in
these prostaglandins.12 These mecha- part be related to their sedative effects
nisms contribute to delayed sensitization mediated by other receptors. During
of the CNS (Figure 3). acute pain (surgical or traumatic), opi-
Peripheral and central sensitization oids do not appear to affect peripheral
of the nervous system may result in and central sensitization mechanisms.
intensification of response to painful or Patients may be unaware of the acute
ordinarily nonpainful stimuli. Significant pain as the result of
-agonist activity
windup of the nervous system may and sedation, but their nervous system
result in intense pain from minor stimu- may be reacting vigorously to the insult
lation of the injured tissue as well as of via peripheral and central sensitization.
noninjured tissue. Therefore, postoperative or posttraumatic
Significant elevations of systemic pain may be enhanced for considerable
cytokines and upregulation of COX- periods following the initial pain-pro-
Pertusi Selective Cyclooxygenase Inhibition in Pain Management JAOA Supplement 8 Vol 104 No 11 November 2004 S21
voking surgical or traumatic episode.
Local anesthetic blocks and coxibs may
prevent continued bombardment of the
nervous system with pain impulses and
therefore prevent sensitization from
occurring.17-19 Coxibs are an option in
these settings where traditional NSAIDs
are contraindicated because of platelet
inhibition.
The timing of the use of coxibs has
received considerable attention based on
research models that have investigated
the time line for upregulation of COX-2
in the peripheral and central nervous
systems. The impact of constitutively
produced CNS COX-1 and COX-2 on
pain perception is also being considered
when developing approaches toward
pain management.20-23 Animal models
suggest that central sensitization is a late
phenomenon, occurring hours after the
initial injury or inflammation.24 The most
critical time to prevent this windup of
the CNS may be before these COX-
2mediated prostaglandins are produced
in the CNS.
The role of long-acting COX-2
inhibitors in preoperative and preemptive
pain management has been studied in
several models. Most models demon-
strate a reduction in the need for opioids
when coxibs are used. The most signifi-
cant advantage may be the reduction of
opioid toxicity which often acts as a major
obstacle to recovery.
Celecoxib, rofecoxib, and valdecoxib
have been administered preoperatively
and perioperatively in several surgical
settings. Reuben et al25 showed that rofe-
coxib provided effective postoperative
analgesia for arthroscopic meniscectomy
when administered at a 50-mg preoper-
ative dose. Less opioid was used and
lower pain scores resulted with preoper-
ative dosing in comparison to postoper-
ative dosing. In another study involving
anterior cruciate ligament repair, Reuben
et al26 showed that preemptive use of
rofecoxib as part of multimodal analgesia
resulted in reduced pain and greater like-
lihood for patients to complete an accel-
erated rehabilitation program than a post-
operative pain protocol.
For thyroid surgery, Karamanholu
et al27 showed that preoperative admin-
istration of rofecoxib, 50 mg, or celecoxib,
200 mg, resulted in significantly less post-
 COX-2
Tissue Cytokines
(Bloodstream) mediated
inflammation (IL - 1) B
PGs
C
A

Figure 3. Central nervous system sensitization secondary to tissue inflammation. Systemic cytokines increase prostaglandins (PGs) throughout
central nervous system, enhancing presynaptic transmitter release (A), reducing the threshold for postsynaptic excitability (B), and dampening
postsynaptic inhibition (C). (IL indicates interleukin; COX-2, cyclooxygenase-2.)

operative pain and a decrease in addi-
tional opioid requirement than placebo in
the first 4 postoperative hours. Rofecoxib
resulted in significantly less pain than
celecoxib or placebo from the 6th through
the 24th hour of the study.
Recart et al28 studied celecoxib pre-
operative management of postoperative
pain from ambulatory ear-nose-throat
(ENT) surgery. The authors concluded
that celecoxib at a dose of 400 mg was
superior to celecoxib at a dose of 200 mg
and placebo in reducing postoperative
pain scores. Both doses of celecoxib were
better than placebo in reducing postop-
erative opioid consumption.
For elective single-level microdis-
cectomy or laminectomy (or both),
Bekker et al29 showed that 50 mg of rofe-
coxib given preoperatively reduced post-
operative narcotic consumption. Similar
results were reported for rofecoxib by
Shen et al30 for lower abdominal surgery;
however, analgesic benefits of rofecoxib
were not maintained beyond 12 hours.30
For abdominal hysterectomy, pre-
emptive celecoxib at a dose of 100 mg or
200 mg resulted in use of less opioid than
placebo. Significantly higher pain scores
were noted in the group receiving
placebo over the group receiving cele-
coxib.31
Daniels et al32 evaluated valdecoxib
for preoperative management of post-
operative pain after the extraction of two
impacted third molars. In their study,
the median time to rescue medication
was significantly longer for valdecoxib
(10 mg, 20 mg, 40 mg, and 80 mg) than
for placebo, and less overall rescue med-
ication was required with valdecoxib.32
Pain scores were significantly lower for
all valdecoxib doses than for placebo.
The effect of the 40 mg and 80 mg doses
were similar but generally superior to
the lower doses of valdecoxib. Similar
findings were reported in a bunionec-
tomy study by Desjardins et al33; how-
ever, the 10 mg dose of valdecoxib was
not evaluated.
Whether perioperative or immediate
posttraumatic use of coxibs reduces
chronic pain (phantom limb, neuropathic,
allodynia, hyperalgesia) has yet to be fully
determined. Animal models of neuro-
pathic pain (nerve injury models) clearly
suggest a central and peripheral increase
in COX-2mediated prostaglandins. The
potential for long-term pain relief by lim-
ited use of coxibs in the initial phases of
injury or inflammation exists.34-36
Future Coxibs
Newer coxibs may soon become avail-
able (Table). These include etoricoxib,
parecoxib, and lumiracoxib. Etoricoxibs
new drug application to the US Food
and Drug Administration includes mul-
tiple acute and chronic pain models.37-42
Lumiracoxib also has been studied in
several acute and chronic pain models.43-46
Parecoxib, a parenteral formulation of
valdecoxib for intravenous or intramus-
cular administration, will likely be posi-
tioned for use in acute pain because of its
rapidity of onset, or when patients are
not allowed oral intake.47,48 Patients may
be switched to valdecoxib when appro-
priate. Preoperative or perioperative use
of parecoxib may be considered, though
oral coxibs with long half-lives may also
be used in this setting when given before
all oral intake is suspended.
Cyclooxygenase-3 (COX-3) has been
discovered, but it may be an isoform of
COX-1 rather than a unique enzyme.49
COX-3 has an affinity for acetaminophen.
The inhibition of COX-3 may result in
centrally mediated analgesia and
antipyretic effects. Preliminary evidence
suggests that COX-1 is increased in the
CNS during early sensitization.50,51 Parac-
etamol (acetaminophen) has been shown
to inhibit this enzyme.52 Issioui et al52
reported that preoperatively adminis-
tered celecoxib at a dose of 200 mg in
combination with acetaminophen
(2000 mg) was significantly more effec-
tive than placebo in reducing postoper-
ative ENT surgical pain. However, nei-
ther treatment alone was significantly
more effective than placebo. Adding
acetaminophen to the multimodel
approach may synergistically enhance
the dampening of central sensitization.

S22 JAOA Supplement 8 Vol 104 No 11 November 2004 Pertusi Selective Cyclooxygenase Inhibition in Pain Management
Comment
The platelet-sparing effects of coxibs has
opened the door for potential applica-
tions in settings where traditional
NSAIDs are contraindicated. Applica-
tions for surgical pain and acute trau-
matic pain are being explored. The patho-
physiologic rationale for coxibs in these
settings is rapidly evolving. Future coxibs
may be specifically designed to manage
traumatic and surgical pain as the result
of a better understanding of the under-
lying pathophysiologic mechanisms of
pain and the actions of coxibs.
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CME APPLICATION FORM
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S24 JAOA Supplement 8 Vol 104 No 11 November 2004
45. Tannenbaum H, Berenbaum F, Reginster JY,
Zacher J, Robinson J, Poo G, et al. Lumiracoxib is
effective in the treatment of osteoarthritis of the
knee: a 13-week, randomized, double-blind study
versus placebo and celecoxib. Ann Rheum Dis.
2004; Feb 27 (Epub ahead of print).
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Dawson J, Urban L, et al. Anti-hyperalgesic activity
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1. a b c d e f
2. a b c d
3. a b
4. a b
5. a b
6. a b
7. a b
Answer sheet to Supplement 8 JAOA November 2004 CME quiz
Pertusi Selective Cyclooxygenase Inhibition in Pain Management
51. Zhu X, Conklin D, Eisenach JC. Cyclooxygenase-
1 in the spinal cord plays an important role in post-
operative pain. Pain. 2003;104(1-2):15-23.
52. Issioui T, Klein KW, White PF. The efficacy of
premedication with celecoxib and acetaminophen
in preventing pain after otolaryrgologic surgery.
Anesth Analg. 2002;94:1188-1193.
Editors Note
Merck voluntarily withdrew rofe-
coxib from the market after identi-
fying an increased rate of cardio-
vascular events in comparison to
placebo while conducting a study of
the effect of rofecoxib on colon
polyps (www.vioxx.com). It has yet
to be determined whether cardio-
vascular events are a class-effect.
The medical community awaits
direction from the US Food and
Drug Administration.
8. a b
9. a b c d
10. a b c d
11. a b c d e
12. a b c d e
13. a b c d e