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 66 Chapter 9 PERIOPER ATIVE USE OF COX-2 AGENTS
promise in treating patients with Samter’s triad.160Because 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%.164All sulfonamides can be regarded as belonging to one of two main biochemical categories: arylamines and nonarylamines.165The 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.167Some 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.168The 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.168,170Three studies demon- strated that some NSAIDs are associated with higher gastrointesti- nal risks than others.171–173In 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.175–178The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial,175Celecoxib Long-term Arthritis Study (CLASS),176Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET),177 and Successive Celecoxib Efficacy and Safety Studies (SUCCESS)178provided evidence that COX-2 inhibitors minimize the risk of gastrointestinal complications compared with those of traditional NSAIDs.
These findings174–178combined with the possibility that even the short-term perioperative use of NSAIDs has been associated with gastrointestinal toxicity,83–87suggest 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
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 PGI2is a platelet inhibitor and vasodilator.
Because platelets do not contain COX-2, all synthesis of TXA2in
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.179All 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.180Risk 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 67 III ACUTE PAIN
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,8that 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).175Although mechanisms of this risk remain uncertain, one theory holds that it relates to alteration of the PGI2balance favoring TXA2with 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. Membrane phospholipids Arachidonic acid (gastric mucosa, platelets, endothelium) (gastric mucosa, kidney, peripheral nociceptor
spinal cord neurons)
PGE isomerase PGF synthase TXA synthase PGI synthase PGD synthase (constitutive COX-1) (inducible COX-2) Phospholipase A2 Cyclooxygenase Cyclooxygenase (COX-1) or (COX-2) PGI2 NSAIDs PGE2 PGD2 TXA2 (platelets) PGF2-alpha PGG2 _ PGH2
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 (PGG2and 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.) 68 Chapter 9 PERIOPER ATIVE USE OF COX-2 AGENTS
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.194Furthermore, 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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