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Articles  |   November 2004
Selective Cyclooxygenase Inhibition in Pain Management
Author Notes
  • 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. 
  • Correspondence to Raymond M. Pertusi, DO, Associate Professor of Medicine, Division of Rheumatology, Department of Internal Medicine, University of North Texas Health Science Center at Fort Worth—Texas College of Osteopathic Medicine, 855 Montgomery St, Fort Worth, TX 76107-2553. E-mail: rpertusi@hsc.unt.edu 
Article Information
Pain Management/Palliative Care
Articles   |   November 2004
Selective Cyclooxygenase Inhibition in Pain Management
The Journal of the American Osteopathic Association, November 2004, Vol. 104, 19S-24S. doi:
The Journal of the American Osteopathic Association, November 2004, Vol. 104, 19S-24S. doi:
Abstract

Traditional nonsteroidal anti-inflammatory drugs are contraindicated for surgical 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 multimodal analgesia results in a reduction in the amount of opioids needed to control pain. Reduced opioid toxicity may hasten recovery.

Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs; Table) differ from traditional nonsteroidal anti-inflammatory 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 agents in situations in which bleeding may limit the use of traditional NSAIDs, such as trauma and surgical procedures. 
Table
Currently Available and Future Coxibs

Coxib

Administration

Half-life, h

Pain Indications*
Currently Available
□ CelecoxibOral8-11Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ ValdecoxibOral8Osteoarthritis, rheumatoid arthritis, dysmenorrhea
Future
□ EtoricoxibOral24Osteoarthritis, rheumatoid arthritis, back pain, pain, dysmennorrhea, gout, acute pain, spondyloarthropathy
□ LumiracoxibOral3-6Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ Parecoxib
Intravenous or intramuscular
8
Acute pain, surgical pain
 *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.
Table
Currently Available and Future Coxibs

Coxib

Administration

Half-life, h

Pain Indications*
Currently Available
□ CelecoxibOral8-11Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ ValdecoxibOral8Osteoarthritis, rheumatoid arthritis, dysmenorrhea
Future
□ EtoricoxibOral24Osteoarthritis, rheumatoid arthritis, back pain, pain, dysmennorrhea, gout, acute pain, spondyloarthropathy
□ LumiracoxibOral3-6Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ Parecoxib
Intravenous or intramuscular
8
Acute pain, surgical pain
 *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.
×
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 persists long after any appreciable tissue damage has resolved, and it may be due to a “windup” or sensitization of the central 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 evaluation 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 enhanced by COX-2–mediated prostaglandins from already inflamed or damaged tissue.5,6 Coxibs may reduce this type of pain. 
Mechanisms of Pain Enhancement 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. Arachidonic acid is derived from normally sequestered membrane phospholipids. Trauma or inflammation exposes membrane-bound phospholipids to phospholipase A2, which converts them into arachidonic acid. COX-2 converts arachidonic acid into inflammatory prostaglandins (Figure 1). 
Figure 1.
Prostaglandin formation and inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs. (GI indicates gastrointestinal.)
Figure 1.
Prostaglandin formation and inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs. (GI indicates gastrointestinal.)
Inflammatory prostaglandins have numerous effects on local tissue. They cause vasodilation and the resultant clinical 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). 
Figure 2.
Peripheral nervous system (PNS) sensitiztion secondary to tissue inflammation. COX-2–mediated prostaglandins (PGs) reduce threshold for postsynaptic stimulation (A) and enhance excitability in conduction of impulses along peripheral nerve (B). (CNS indicates central nervous system; COX-2, cyclooxygenase-2.)
Figure 2.
Peripheral nervous system (PNS) sensitiztion secondary to tissue inflammation. COX-2–mediated prostaglandins (PGs) reduce threshold for postsynaptic stimulation (A) and enhance excitability in conduction of impulses along peripheral nerve (B). (CNS indicates central nervous system; COX-2, cyclooxygenase-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 perhaps a neural intermediary. The cytokine, interleukin 1 (IL-1), induces transcription of COX-2, thereby increasing production of prostaglandins that sensitize the entire CNS within 6 to 12 hours of the onset of local injury or inflammation.11 In the dorsal horn, presynaptically, these prostaglandins increase transmitter release. Postsynaptically, they reduce the threshold for stimulation (similar to peripheral sensitization). Additionally, glycine receptor–mediated inhibition pathways are themselves inhibited by these prostaglandins.12 These mechanisms contribute to delayed sensitization of the CNS (Figure 3). 
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.)
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.)
Peripheral and central sensitization of the nervous system may result in intensification of response to painful or ordinarily nonpainful stimuli. Significant windup of the nervous system may result in intense pain from minor stimulation of the injured tissue as well as of noninjured tissue. 
Significant elevations of systemic cytokines and upregulation of COX-2–mediated prostaglandin production may explain some of the features of the “sickness syndrome” seen in patients with chronic diffuse inflammatory conditions. This syndrome comprises fatigue, fever, loss of appetite, weight loss, and other constitutional symptoms.13 
Clinical Application of Coxibs
Traditional NSAIDs have been used in the management of various types of acute and chronic pain. Most coxibs have similar indications to those of the traditional NSAIDs (Table). Traditional NSAIDs are generally contraindicated in acute traumatic and surgical pain owing to inhibition of platelets and bleeding potential. Because of the platelet-sparing properties of coxibs, their role in the management of surgical and traumatic pain is currently under intense investigation.14-16 
Multimodal analgesia often combines opioids, anesthetic blocks, coxibs, and other agents. Opioids are preferred over traditional NSAIDs for analgesia when the potential for bleeding exists. Opioids bind multiple receptors, most notably the μ receptor. However, their analgesic effect in acute pain management may in part be related to their sedative effects mediated by other receptors. During acute pain (surgical or traumatic), opioids do not appear to affect peripheral and central sensitization mechanisms. Patients may be unaware of the acute pain as the result of μ-agonist activity and sedation, but their nervous system may be reacting vigorously to the insult via peripheral and central sensitization. Therefore, postoperative or posttraumatic pain may be enhanced for considerable periods following the initial pain-provoking 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-2–mediated 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 demonstrate a reduction in the need for opioids when coxibs are used. The most significant 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 rofecoxib provided effective postoperative analgesia for arthroscopic meniscectomy when administered at a 50-mg preoperative dose. Less opioid was used and lower pain scores resulted with preoperative dosing in comparison to postoperative 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 likelihood for patients to complete an accelerated rehabilitation program than a postoperative pain protocol. 
For thyroid surgery, Karamanholu et al27 showed that preoperative administration of rofecoxib, 50 mg, or celecoxib, 200 mg, resulted in significantly less postoperative pain and a decrease in additional 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 preoperative 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 postoperative opioid consumption. 
For elective single-level microdiscectomy or laminectomy (or both), Bekker et al29 showed that 50 mg of rofecoxib given preoperatively reduced postoperative 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, preemptive 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 celecoxib.31 
Daniels et al32 evaluated valdecoxib for preoperative management of postoperative 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 medication 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 bunionectomy study by Desjardins et al33; however, 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 neuropathic pain (nerve injury models) clearly suggest a central and peripheral increase in COX-2–mediated prostaglandins. The potential for long-term pain relief by limited use of coxibs in the initial phases of injury or inflammation exists.34-36 
Future Coxibs
Newer coxibs may soon become available (Table). These include etoricoxib, parecoxib, and lumiracoxib. Etoricoxib's new drug application to the US Food and Drug Administration includes multiple 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 intramuscular administration, will likely be positioned 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 appropriate. 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 Paracetamol (acetaminophen) has been shown to inhibit this enzyme.52 Issioui et al52 reported that preoperatively administered celecoxib at a dose of 200 mg in combination with acetaminophen (2000 mg) was significantly more effective than placebo in reducing postoperative ENT surgical pain. However, neither treatment alone was significantly more effective than placebo. Adding acetaminophen to the multimodel approach may synergistically enhance the dampening of central sensitization. 
Comment
The platelet-sparing effects of coxibs has opened the door for potential applications in settings where traditional NSAIDs are contraindicated. Applications for surgical pain and acute traumatic pain are being explored. The pathophysiologic 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 underlying pathophysiologic mechanisms of pain and the actions of coxibs. 
 This continuing medical education publication supported by an unrestricted educational grant from Merck & Co
 
 Editor's Note
 
 Merck voluntarily withdrew rofecoxib from the market after identifying an increased rate of cardiovascular 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 cardiovascular events are a class-effect. The medical community awaits direction from the US Food and Drug Administration.
 
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Figure 1.
Prostaglandin formation and inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs. (GI indicates gastrointestinal.)
Figure 1.
Prostaglandin formation and inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs. (GI indicates gastrointestinal.)
Figure 2.
Peripheral nervous system (PNS) sensitiztion secondary to tissue inflammation. COX-2–mediated prostaglandins (PGs) reduce threshold for postsynaptic stimulation (A) and enhance excitability in conduction of impulses along peripheral nerve (B). (CNS indicates central nervous system; COX-2, cyclooxygenase-2.)
Figure 2.
Peripheral nervous system (PNS) sensitiztion secondary to tissue inflammation. COX-2–mediated prostaglandins (PGs) reduce threshold for postsynaptic stimulation (A) and enhance excitability in conduction of impulses along peripheral nerve (B). (CNS indicates central nervous system; COX-2, cyclooxygenase-2.)
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.)
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.)
Table
Currently Available and Future Coxibs

Coxib

Administration

Half-life, h

Pain Indications*
Currently Available
□ CelecoxibOral8-11Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ ValdecoxibOral8Osteoarthritis, rheumatoid arthritis, dysmenorrhea
Future
□ EtoricoxibOral24Osteoarthritis, rheumatoid arthritis, back pain, pain, dysmennorrhea, gout, acute pain, spondyloarthropathy
□ LumiracoxibOral3-6Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ Parecoxib
Intravenous or intramuscular
8
Acute pain, surgical pain
 *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.
Table
Currently Available and Future Coxibs

Coxib

Administration

Half-life, h

Pain Indications*
Currently Available
□ CelecoxibOral8-11Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ ValdecoxibOral8Osteoarthritis, rheumatoid arthritis, dysmenorrhea
Future
□ EtoricoxibOral24Osteoarthritis, rheumatoid arthritis, back pain, pain, dysmennorrhea, gout, acute pain, spondyloarthropathy
□ LumiracoxibOral3-6Osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea
□ Parecoxib
Intravenous or intramuscular
8
Acute pain, surgical pain
 *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.
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