NSAIDs and COX-2 Inhibitors

Matthew R. Eng

Kapil Anand

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase 2 (COX-2) inhibitors have become valuable anti-inflammatory and analgesic medications in the perioperative environment for their effectiveness and low side effect profile. With increasing economic pressures, patient satisfaction demands, and unfavorable adverse effects of opioids, multimodal techniques in pain management has become increasingly important. Commonly utilized NSAID medications for acute pain management include paracetamol, ibuprofen, ketorolac, diclofenac, and naproxen (Table 34.1). Commonly utilized COX-2 inhibitor drugs include rofecoxib, valdecoxib, and celecoxib (see Table 34.1).

Mechanism of Action

NSAIDs inhibit an enzyme in the prostaglandin synthesis pathway called cyclooxygenase. Prostaglandins are released during local tissue injury and decrease the pain threshold at the site of injury as well as local surrounding tissue. The inflammation and hyperalgesic state of the tissue notifies the nociceptors of increased pain and inflammation. NSAIDs prevent the production of prostaglandins at the periphery and spinal cord by inhibition of the cyclooxygenase enzyme.

NSAIDs are nonspecific in their inhibition of the cyclooxygenase enzyme. Consequently, the blockade of the cyclooxygenase 1 isoenzyme results in gastrointestinal adverse events and platelet inhibition. COX-1 isoenzymes and COX-2 isoenzymes in a reduced effect are associated with gastrointestinal bleeding, ulceration, and perforation. The production of arachidonic acid metabolites including the gastric protective prostacyclin PGI2 is likely responsible. COX-2 isoenzyme inhibiting medications present the ability to block prostaglandin synthesis conferring analgesic and anti-inflammatory benefits with reduced gastrointestinal side effects. The reversible inhibition of thromboxane A2 production causes inhibition of platelet aggregation. Compared with placebo, in patients undergoing tonsillectomy, a higher risk of rebleeding was present when administering conventional NSAIDs. Platelet inhibition has not been demonstrated in COX-2 inhibitor medications.

Analgesic and Anti-inflammatory Properties

As acute pain management has become increasingly more important, the benefits of NSAIDs and COX-2 inhibitors should be well understood. A multimodal approach to acute pain management utilizing opioid sparing analgesics has been associated with faster resumption of daily activities, faster discharge times, improved patient satisfaction, and a reduction in complications. Further, the reduction of postoperative acute pain has been associated with a reduction in the development of chronic pain.

TABLE 34.1 COMMON PERIOPERATIVE NSAIDs

NSAID	Mechanism of Action	Half Life (h)
Paracetamol	Nonselective COX inhibition	1.5-2.5
Ketorolac	Nonselective COX inhibition	5.2-5.6
Ibuprofen	Nonselective COX inhibition	2
Diclofenac	Nonselective COX inhibition	1-2
Naproxen	Nonselective COX inhibition	12-17
Celecoxib	COX-2 selective inhibition	11
Rofecoxib	COX-2 selective inhibition	17
Valdecoxib	COX-2 selective inhibition	8-11

COX-2 inhibitors and NSAIDs have been demonstrated to be effective in a wide variety of surgical procedures for acute pain management.

Ketorolac

One of the older NSAID medications, ketorolac, has been used in practice since 1976. Ketorolac may be used for moderate to severe pain and may be used in a wide variety of surgical operations for acute pain management. Ketorolac has been demonstrated to be effective in patients undergoing ambulatory outpatient procedures, orthopedic procedures, and major abdominal operations.¹,²,³ Either 30 mg or 60 mg has been demonstrated to be effective in patients undergoing outpatient or abdominal surgery in reducing acute pain.³ The potency of ketorolac is impressively equivalent to morphine 4 mg as demonstrated when administered 10 mg or 30 mg for postsurgical pain.¹ In a review of patients receiving ketorolac between 1986 and 2001, the authors found that the potent analgesic ketorolac reduced opioid consumption by 36%.⁴ Over 90% of the medication is metabolized in the kidney, and it has been associated in kidney failure in patients with a predisposition to kidney failure. Further, theoretical risks remain regarding the NSAID platelet inhibition properties and gastrointestinal side effects.

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