Same-Day Surgery Reports: Role of COX-2 Specific Inhibitors for Pain Management after Ambulatory Surgery
Role of COX-2 Specific Inhibitors for Pain Management after Ambulatory Surgery
Author: Girish P. Joshi, MB, BS, MD, FFARCSI, Professor of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas.
Peer Reviewer: J. Lance Lichtor, MD, Professor, Department of Anesthesia, University of Iowa, Iowa City.
The practice of ambulatory surgery is rapidly expanding with more extensive and potentially more painful surgical procedures being performed on an outpatient basis. One factor affecting the outcome of outpatient surgery is the adequacy of postoperative pain management. Uncontrolled pain increases the duration of stay in the post-anesthesia care unit (PACU), delays discharge home, and increases the incidence of unanticipated hospital admission. Furthermore, inadequate pain relief delays return to daily living functions and decreases patient satisfaction. These factors have increased the need for providing adequate pain relief after ambulatory surgery.1,2
Many receptors are involved in the processing and alteration of the pain signal. For this reason, a combination of analgesic medications including nonsteroidal anti-inflammatory drugs (NSAIDs), local anesthetics, and opioids can be used to treat postoperative pain. Combining different analgesic modalities can provide more effective pain relief with fewer side effects.3 Furthermore, multimodal interventions may lead to a reduction in undesirable sequelae of surgical injury and improved functional recovery and reduction in postoperative morbidity.
NSAIDs Grow in Popularity
When NSAIDs are used in combination with opioids (usually for moderate-to-severe pain), they enhance the quality of opioid-analgesia and reduce opioid requirements.1 Furthermore, the opioid-sparing effects of NSAIDs lower the incidence of opioid-related side effects and facilitate postoperative recovery. In addition, NSAIDs have a more prolonged analgesic effect, which may reduce the risk of breakthrough pain. Therefore, NSAIDs are valuable in postoperative pain management. Use of nonopioids (e.g., NSAIDs) prior to surgery decreases intraoperative opioid requirements, which may reduce the incidence of postoperative nausea, vomiting, dizziness, and drowsiness, and facilitate recovery and discharge from the hospital.4
In addition, several studies have reported that premedication with NSAIDs given 60-90 minutes prior to surgery can reduce the degree of postoperative pain, analgesic requirements, and discharge times.3,5 However, Moniche, et al6 in their review of preemptive analgesia, concluded that NSAIDs should not routinely be given preoperatively because of the lack of enhanced analgesic effects and the potential for increased intraoperative bleeding. (See adverse effects below.) The other concern with preoperative oral administration of NSAIDs is the increased risk of gastric side effects when these drugs are administered on an empty stomach.
Adverse Effects of NSAIDS
The major concern regarding the use of NSAIDs in the perioperative period is that their antiplatelet effect may increase the risk of perioperative bleeding.7,8 Current practice guidelines recommend that the administration of NSAIDs be delayed until surgical bleeding is no longer a risk. Furthermore, it is recommended that NSAIDs should not be used in patients with preexisting coagulation defect, in those undergoing procedures with an extensive tissue dissection (e.g., surgery involving skin flaps), or in surgical procedures with high possibility of bleeding (e.g., tonsillectomy). Some authors recommend that if a patient is chronically receiving NSAIDs before elective surgery, they should be discontinued.9 The limitations of NSAIDs prevent their use even when they would otherwise be desirable. The development of cyclooxygenase (COX)-2 specific inhibitors, a new group of anti-inflammatory drugs, may avoid some of the side effects associated with traditional NSAIDs.10
Cyclooxygenase Enzyme Physiology
COX exists as two distinct isoforms: COX-1 and COX-2.10 Although these isoforms share size and substrate specificity, they differ in their expression and distribution. The COX-1 enzyme is expressed constitutively by most tissues including gastrointestinal tract, kidneys, platelets, and brain. COX-1 is responsible for the physiological production of prostaglandins and confers protective effects on the gastric mucosa, platelet function, and renal function.
In contrast, the COX-2 enzyme is induced in response to tissue injury, inflammation, and pain. Although COX-2 is expressed constitutively in the kidneys and brain, its significance in these areas is still unknown. Unlike traditional NSAIDs, which block COX-1 and COX-2, the COX-2 specific inhibitors avoid the side effects associated with COX-1 inhibition while providing anti-inflammatory and analgesic efficacy.
Exploration of COX-2 Specific Inhibitors
Celecoxib, rofecoxib, and valdecoxib are the COX-2 specific inhibitors that are currently used clinically. Parecoxib is a parenteral COX-2 inhibitor undergoing phase III clinical trials for the management of acute and severe postoperative pain. It is a prodrug of valdecoxib. Clinical studies have shown that these drugs provide pain relief and spare NSAID-induced side effects.
• Celecoxib. Celecoxib is an oral COX-2 specific inhibitor, which has a 375-fold greater selectivity for COX-2 than COX-1 inhibition. It has a 22-40% bioavailability, with analgesic onset of 30-60 minutes and time to peak concentration of two hours after oral administration. It is eliminated predominantly by hepatic metabolism and has no active metabolites. The elimination half-life of celecoxib is approximately 11 hours. The analgesic efficacy of celecoxib has been evaluated in patients undergoing dental, orthopedic, and gynecologic procedures. The analgesic dose for postoperative pain relief is 200 mg twice a day.11
After orthopedic surgery, celecoxib 200 mg TID provided superior analgesia than hydrocodone 10 mg and acetaminophen 1,000 mg combination TID hydrocodone and acetaminophen combination. Furthermore, the patients in the celecoxib group had significantly fewer side effects (e.g., nausea, somnolence, dizziness, and constipation). 11
• Rofecoxib. Rofecoxib has an 800-fold greater selectivity for COX-2 than COX-1. It has a 92-93% bioavailability after oral administration. The elimination half-life of rofecoxib is 17 hours (approximately 50% greater than celecoxib). The effective dose for postoperative pain relief is 50 mg once a day.12,13 However, it is recommended that the 50 mg dose should not be used for more than five days due to concerns about potential renal side effects.
Reuben et al12 evaluated the benefits of preoperative analgesia in patients undergoing arthroscopic knee surgery. Compared with postoperative administration, rofecoxib 50 mg given one hour prior to surgery significantly increased the time to first analgesic. In addition, patients in the preoperative group had less pain and required significantly less rescue analgesics (i.e., oxycodone and acetaminophen). Another placebo-controlled study compared the analgesic efficacy of a single dose of rofecoxib 50 mg and celecoxib 200 mg given orally before spinal fusion surgery.13 Postoperative patient-controlled analgesia (PCA) was provided with intravenous (IV) morphine. The results showed that compared with placebo, both analgesics had a significant postoperative opioid-sparing effect.13 However, rofecoxib provided a longer duration of analgesia as compared with celecoxib (24 hours vs. eight hours).
• Valdecoxib. Valdecoxib is a new COX-2 specific inhibitor that is approximately 28,000-fold more selective for COX-2 than COX-1. It has an active metabolite SC-66905, which is a highly selective and potent inhibitor of COX-2, with a selectivity 6,800-fold greater for COX-2 than COX-1. The elimination half-life of valdecoxib is approximately 11-13 hours. Effective postoperative analgesic dose of valdecoxib is 40 mg once a day or 20 mg twice a day.14, 15
Camu, et al15 evaluated the analgesic efficacy of valdecoxib 20 mg and 40 mg administered preoperatively and then twice daily postoperatively after total hip arthroplasty. The patients receiving valdecoxib required 40% less morphine over the 48-hour study period as compared with those receiving the placebo. In addition, the pain intensity levels and patient satisfaction were significantly superior in the valdecoxib groups. However, the morphine requirements and pain scores between the two doses of valdecoxib were similar suggesting that valdecoxib 20 mg BID may be the "ceiling" dose.
• Parecoxib. Parecoxib is a second-generation parenteral COX-2 inhibitor, which is an inactive prodrug that is enzymatically hydrolyzed in the liver into valdecoxib. Pharmacokinetic studies have shown that after intravenous administration, peak concentrations of parecoxib are achieved within two to three minutes with an elimination half-life of five minutes. The plasma concentrations of valdecoxib peak within 45 minutes with an elimination half-life 11-13 hours. Because an intravenous formulation of COX-2 inhibitors would be ideal for moderate-to-severe perioperative pain, it is possible that parecoxib will fulfill some of the desirable characteristics of ketorolac, which lacks the specificity of COX-2 inhibitors.
Clinical trials in various surgical models reported that parecoxib compared favorably with ketorolac.16-18 A placebo-controlled study evaluated the analgesic efficacy and safety of a single intravenous doses of parecoxib 20, 40, and 80 mg administered prior to oral surgery.17 The results showed that all doses of parecoxib provided significantly superior analgesia compared to placebo. Parecoxib 40 mg and 80 mg were superior to parecoxib 20 mg. However, there were no differences between the parecoxib 40 mg and 80 mg groups suggesting that a plateau is reached at the dose of 40 mg.
Safety of COX-2 Inhibitors
The safety profile of the COX-2 inhibitors has been extensively investigated. These group of drugs are associated a lower incidence of symptomatic ulcers and ulcer complications, as compared with standard doses of NSAIDs.19,20 Unlike traditional NSAIDs, platelet function is not affected by the coxibs and is similar to that of a placebo. A double-blind, placebo-controlled randomized study compared the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg BID) with a standard dose of naproxen (500 mg BID).21 The results showed that unlike celecoxib and placebo, naproxen produced statistically significant reduction in platelet aggregation and serum thromboxane B2 levels and increased the bleeding time. Similar results have been observed with rofecoxib and valdecoxib.22, 23 However, the effects of these drugs on renal function are not understood completely. Recent studies suggest that COX-2 inhibitors produce effects on renal function similar to traditional NSAIDs.19, 20 Compared with rofecoxib 50 mg, celecoxib 200 mg has been reported to be associated with less cardiorenal effects (i.e., peripheral edema and hypertension).24, 25
Summary
Adequate pain control facilitates early ambulation and improves patients’ perception of the quality of their surgical experience. However, the management of pain after ambulatory surgery poses some unique challenges for the practitioner. Outpatients undergoing day-case procedures require an analgesic technique that is effective, is devoid of side effects, is intrinsically safe for the patient, and can be managed easily away from the hospital or surgery center. The goal of pain management should be to minimize pain not only at rest, but also during mobilization and exercise. This has increased the emphasis on multimodal techniques of providing pain relief. It is well recognized that opioid-related side effects including nausea, vomiting, drowsiness, dizziness, and constipation contribute to delayed recovery. Therefore, it is recommended that nonopioid analgesics (e.g., NSAIDs/COX-2 inhibitors and local anesthetics) should be used as the first line of treatment, or combine the use of NSAIDS/COX-2 inhibitors and narcotics instead of using narcotics alone.
COX-2 specific inhibitors avoid some of the side effects associated with the use of traditional NSAIDs. In order to provide optimal analgesia, it is imperative that these analgesics are administered on a regular "round-the-clock" basis to minimize the occurrence of breakthrough pain with, opioids used as "rescue" analgesics to provide for superior analgesia.
References
1. Joshi GP. Pain management after ambulatory surgery. Amb Surg 1999; 7:3-12.
2. Joshi GP. Fast tracking in outpatient surgery. Curr Opin Anaesthesiol 2001; 14:635-639.
3. Kehlet H. Multimodal approach to control postoperative pathology and rehabilitation. Br J Anaesth 1997; 78:606-617.
4. Kehlet H, Rung GW, Callesen T. Postoperative opioid analgesia: Time for reconsideration? J Clin Anesth 1996; 8:441-445.
5. Norman PH, Daley MD, Lindsey RW. Preemptive analgesic effects of ketorolac in ankle fractures surgery. Anesthesiology 2001; 94:599-603.
6. Moniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief. Anesthesiology 2002; 96:725-741.
7. Schafer AI. Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995; 35:209-219.
8. Fragan RJ, Stulberg SD, Wixson R, et al. Effect of ketorolac tromethamine on bleeding and on requirements for analgesia after total knee arthroplasty. J Bone Joint Surg Am 1995; 77:998-1,002.
9. Connelly CS, Panush RS. Should nonsteroidal anti-inflammatory drugs be stopped before elective surgery? Arch Intern Med 1991; 151:1,963-1,966.
10. Kam PC, See AU. Cyclooxygenase isoenzymes: Physiological and pharmacological role. Anaesthesia 2000; 55:442-449.
11. Gimbel JS, Brugger A, Zhao W, et al. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults. Clin Ther 2001; 23:228-241.
12. Reuben SS, Bhopatkar, Sklar J, et al. Preemptive analgesic effect of rofecoxib after ambulatory arthroscopic knee surgery. Anesth Analg 2002; 94:55-59.
13. Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg 2000; 91:1,221-1,225.
14. Fricke J, Varkalis J, Zwillich S, et al. Valdecoxib is more efficacious than rofecoxib in relieving pain associated with oral surgery. Am J Ther 2002; 9:89-97.
15. Camu F, Beecher DP, Verburg KM. Valdexocib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty. Am J Ther 2002; 9:43-51.
16. Cheer SM, Goa KL. Parecoxib (Parecoxib Sodium). Drugs 2001; 61:1,133-1,141.
17. Daniels S, Grossman E, Kuss M, et al. A double-blind, randomized, comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in post-oral surgery pain model. Clin Ther 2001; 23:1,018-1,1031.
18. Desjardins PJ, Grossman EH, Kuss ME, et al. The injectable cyclooxygenase-2-specific inhibitor parecoxib sodium has analgesic efficacy when administered preoperatively. Anesth Analg 2001; 93:721-727.
19. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-Term Arthritis Safety Study. JAMA 2000; 284:1,247-1,255.
20. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1,520-1,528.
21. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: A randomized, controlled trial. J Clin Pharmacol 2000; 40:124-132.
22. Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: Efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatic arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum 1998; 41:1,591-1,602.
23. Noveck RJ, Laurent A, Kuss M, et al. Parecoxib sodium does not impair platelet function in healthy elderly and non-elderly individuals: Two randomized controlled trials. Clin Drug Invest 2001; 21:465-476.
24. Whelton A, Fort JG, Puma JA, et al: Cyclooxygenase-2-specific inhibitors and cardiorenal function: A randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001; 8:85-95.
25. Whelton A, Maurath CJ, Verburg KM. Geis GA: Renal safety and tolerability of celecoxib: A novel cyclooxygenase-2-inhibitor. Am J Ther 2000; 7:159-175.
CE/CME Objectives
After participating in the CE/CME activity, the participant will be able to:
- identify the reason for increased popularity of nonsteroidal anti-inflammatory drugs (NSAIDs);
- list the result of multimodal analgesia techniques for postoperative pain management;
- identify the difference between traditional NSAIDS and COX-2 specific inhibitors;
- list the result of administration of COX-2 specific inhibitor prior to surgery;
- describe parecoxib.
CE/CME Questions
1. Multimodal analgesia techniques for postoperative pain management:
A. Increases the incidence of side effects.
B. Increases postoperative morbidity.
C. Improves postoperative analgesia.
D. Consists of combining different groups of nonsteroidal anti-inflammatory drugs (NSAIDs).
2. Increased popularity of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of postoperative pain is because:
A. NSAIDs are available over the counter.
B. NSAIDs are cheaper than other analgesics.
C. NSAIDs have shorter duration of action.
D. NSAIDs enhance the quality of analgesia and reduce opioid requirements.
3. Compared to traditional NSAIDs, COX-2 specific inhibitors:
A. Provide superior postoperative analgesia.
B. Do not affect the platelet function.
C. Are associated with increased incidence of gastrointestinal side effects.
D. Are less expensive.
4. Administration of COX-2 specific inhibitor prior to surgery:
A. Improves postoperative analgesia.
B. Increases perioperative complications.
C. Increases perioperative opioid requirements.
D. Does not improve postoperative analgesia.
5. Parecoxib:
A. Is a new oral COX-2 specific inhibitor.
B. Is a prodrug that is converted to rofecoxib by the liver.
C. Is an injectable COX-2 specific inhibitor.
D. Increases the incidence of perioperative bleeding.
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