Written by Steven M. Cho, DDS, and Seth M. Black, DDS Sunday, 31 March 2002 19:00
|Figure 1. Rofecoxib: Specific inhibition of COX-2.|
The dental practitioner has many ways of controlling pain during surgery. Examples include the administration of local anesthesia, nitrous oxide, intravenous sedation, and general anesthesia, all of which keep the patient safe and comfortable. However, pain control does not end once the surgery is completed. The patient must also be made to feel comfortable and pain free during the recovery period. The availability of a variety of pain medications has significantly improved the ability to manage postoperative pain in dentistry. This article reviews an alternative to opioids in the management of dental and surgical pain.
Dental clinicians frequently prescribe narcotic analgesics for moderate to severe postoperative surgical pain. Narcotic analgesics act on the central nervous system to relieve the pain. Furthermore, the combination of acetaminophen and both narcotic and non-narcotic medication can be used together, (ie, hydrocodone/acetaminophen, codeine/acetaminophen, propoxyphene/acetaminophen, ibuprofen/codeine, and aspirin/codeine). These combinations can provide safer pain relief than either medication used alone.
It has been shown that narcotics use for a prolonged period of time results in a tolerance to the medicine, which creates the need for larger and larger doses. The narcotic eventually becomes habit-forming, leading to complete mental or physical dependence. Physical dependence, of course, can lead to potentially disturbing withdrawal symptoms when the medication is discontinued. Adding acetaminophen allows the dose of narcotic to be reduced. Acetaminophen has not been proven to be habit-forming when taken for a long time or in large doses; however, caution must always be used because large doses of acetaminophen may cause other unwanted effects, including liver damage.
Pain often occurs in conjunction with inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen and diflunisal, have been very effective in the management of postoperative inflammation and pain, in both dentistry and medicine.1,2 The indications for NSAIDs are numerous. They have been used to relieve some of the symptoms caused by arthritis, particularly inflammation, swelling, stiffness, and joint pain.3,4 They have also been used successfully to relieve the pain associated with gout attacks, bursitis, tendonitis, menstrual cramps, chronic myofacial pain, and temporomandibular joint disorders. They have even been indicated for their antithrombotic effects in the prevention of heart attack and stroke, as well as for the antipyretic properties.5 These drugs are often more effective than codeine or synthetic narcotics and have fewer side effects. Side effects include nausea, vomiting, constipation, sedation, and respiratory depression.6-8
NSAIDs have the anti-inflammatory properties that are desired and beneficial, while opioids do not. NSAIDs are valuable to the dental practitioner and have been proven safe and effective in relieving moderate to severe postoperative pain in the outpatient setting. In fact, dental practitioners now rely more on NSAID analgesics alone, versus narcotic analgesic combinations.
NSAIDs have been the mainstay of non-opioid therapy for pain related to a variety of conditions. Arthritis, joint and musculoskeletal injuries, inflammation, and postoperative pain can all be treated with NSAIDs. They are frequently prescribed, and can be purchased as nonprescription products. It is estimated that there are over 30 million prescriptions filled annually, with 13 million Americans regularly using NSAIDs for various types of arthritis. When NSAIDs are prescribed for long-term use, or in large doses, it should be noted that there are side effects and risks. All of the available NSAIDs have been associated with toxicities involving the GI tract, liver, kidneys, central nervous system, and skin, and they modify platelet function.9 NSAIDs should be avoided, although they are not absolute contraindications, if a patient is hypersensitive to aspirin or has a history of asthma, kidney failure, liver disease, or bleeding dyscrasias.10 It has been reported that there are 103,000 NSAID-related hospitalizations per year and 16,500 NSAID-related deaths annually.11
NEW ANTI-INFLAMMATORY ANALGESIC AGENTS
The undesirable risks associated with NSAIDs have created an impetus in research to develop a medication without side effects. Two new anti-inflammatory analgesic agents have been introduced, colecoxib and rofecoxib. They are currently being used primarily for the management of osteoarthritis, rheumatoid arthritis, and acute dental and surgical pain.12,13
Both colecoxib and rofecoxib are COX-2 inhibitors.12,13 These cyclo-oxygenase-2 or COX-2 inhibitors have been developed to limit the adverse effects observed with chronic use of traditional NSAIDs, which inhibit both COX-1 and COX-2 enzymes.3,13-15
|Figure 2. Comparison of analgesic drugs.|
The primary function of the COX-1 enzyme is to stimulate stomach and duodenal blood flow, as well as mucus and bicarbonate secretion. This “constitutive function” is critically important in normal gastric and duodenal functioning.16 The cyclo-oxygenase-1 or COX-1 enzyme is continuously secreted in the GI tract, kidneys, and elsewhere.17 The majority of NSAIDs available today are selective for COX-1. The COX-1 enzyme found in the endoplasmic reticulum of all cells is responsible for synthesizing prostanoids that have cytoprotective functions.18 The inhibition of COX-1 enzymes cause many of the adverse effects associated with the traditional NSAIDs (Figure 1).10,17
COX-2 enzymes, on the other hand, are stimulated when there is tissue injury and inflammation. This promotes the vasodilatation, pain, and fever characteristic of an inflammatory response.19 The drugs that selectively inhibit COX-2 enzymes and leave the cytoprotective COX-1 enzymes intact provide analgesia, anti-inflammatory effects, and antipyresis, while eliminating the adverse side effects on platelet activity and GI toxicity of COX-1 enzyme inhibition.20
The new COX-2 inhibitor rofecoxib (Vioxx) is available in 12.5-, 25-, or 50-mg tablets and in 12.5 mg/5 ml and 25 mg/5 ml oral suspensions. Rofecoxib is well absorbed after oral dosing and can be taken with or without food. Therapy with rofecoxib should be initiated at the lowest recommended dose. Rofecoxib has been shown to provide analgesia comparable with that of other NSAIDs, but it has longer duration of action (> 24 hours) and is not associated with GI side effects.21,22 For analgesia, 50 mg rofecoxib should be used once daily as needed.23
Two recent studies have compared rofecoxib with acetaminophen 600 mg/codeine 60 mg and rofecoxib with acetaminophen 325 mg/oxycodone 5 mg, in single-dose postsurgical models. Management of acute pain beyond 5 days has not been studied; acute pain studies were designed to last only up to 5 days.24 It should be noted that the usual adult dosage for codeine is 15 to 60 mg, with acetaminophen 300 to 1,000 mg. These doses may be repeated up to every 4 hours, with a maximum 24-hour dosage of 360 mg codeine and 4,000 mg acetaminophen (Figure 2).
Celecoxib, the other new COX-2 inhibitor, is available in 100- and 200-mg doses. It has not been shown to be consistently effective in management of acute pain, such as after a third-molar extraction.
Of the two COX-2 inhibitors, only rofecoxib is indicated for management of acute pain. COX-2 inhibitors may be contraindicated in patients who are hypersensitive to aspirin or NSAIDs or who have a history of asthma or urticaria. Additionally, unlike all other NSAIDs, rofecoxib does not have a silfonamide group and therefore, patients who are allergic to sulfur can use it.
The advantages of COX–2 inhibitors are infrequent dosing, limited GI toxicity, and patient acceptability. The COX-2 inhibitors may in some cases be given to patients who have a history of NSAID intolerance, GI sensitivity, GI ulceration, or renal and liver disease.21,25-27
No single drug is the answer to every pain problem. The use of opioids, however, continues to be one of the principal modalities for management of postoperative pain and other symptoms. The opioids are extremely useful in management of pain, but one must also deal with the side effects such as drowsiness, nausea, constipation, dizziness, vomiting, itching, and mood swings. The practitioner currently has many choices of pain medication, for example, the opioids, NSAIDs, acetaminophen, and COX-2 inhibitors to maintain good effect on postoperative pain control. Our patients deserve and are entitled to the best modes of pain control; thus all options must be considered.
One approach to pain management prior to oral surgery involves the use of 50 mg rofecoxib (Vioxx) the night before surgery. This will prevent the production of peripheral prostaglandins from forming arachidonic acid along the COX-2 pathway. After this, intraoperatively, the patients receive at least one IV dose of Toradol, as well as standard general anesthetic agents. The postoperative analgesia is managed with 50 mg Vioxx qd for 5 to 10 days. This protocol is used for all dento-alveolar procedures, such as removal of impacted third molars, apicoectomies, implant surgery, and sinus grafts. This drug has also been used following major surgery, including an iliac crest bone graft, genioplasty, maxillary and mandibular osteotomies, and TMJ surgery. In addition, a single dose of extra-strength Tylenol 4 to 6 hours postoperatively can be used to counteract the central stimulation that occurs as the local anesthetics wear off.
In addition to the chemotherapeutic methods, good surgical pain control is achieved through profound local anesthesia and sharp clean incisions, along with gentle wound and tissue handling to avoid tissue injury. Adequate and precise tissue coaptation is important, and the use of cold packs as much as possible for the first 24 hours is necessary to minimize postoperative pain. One should also consider use of capsacian topical qid for chronic pain in closed/intact sites, and platelet rich plasma in grafts and under flaps.
There are satisfactory alternatives to opioids in the management of surgical pain. While no method of pain management is without its complications, the variety of options and new medications gives clinicians more variety in terms of treatment, often with less severe side effects than opioids. It must always be remembered that pain control does not end once the surgery is completed. The patient must also be made to feel comfortable and pain free during the recovery period as well. With this responsibility comes the need to find effective medications with the least amount of side effects.
1. Lichtenstein DR, Syngal S, Wolfe MM. Review: nonsteroidal antiinflammatory drugs and the gastrointestinal tract: the double-edged sword. Arthritis Rheum. 1995;38:5-18.
2. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium. Artritis Rheum. 2000;43:978-987.
3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;33:1520-1528.
4. Siegel I, Klein T, Backman JT, et al. Expression of cyclooxygenase 1 and 2 in human synovial tissue. Arthritis Rheum. 1998;41:122-129.
5. Karim A, Tolbert D, Piergies A, et al. Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects. J Clin Pharmacol. 2000;40:655-663.
6. Rodriguez LAG, Jick H. Risk of upper gastrointestinal bleeding and perforation associate with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343:769-772.
7. Schnitzer TJ, Truitt K, Fleishmann R, et al. The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Therapeutics. 1999;21:1688-1702.
8. Laine l, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2- specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology. 1999;117:776-783.
9. Mandell BF. General tolerability and use of nonsteroidal anti-inflammatory drugs. Am J Med. 1999;107:72S-77S.
10. Langman MJ, Jensen DM, Wason DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDS. J Am Med Assoc. 1999;282:1929-1933.
11. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. NEJM. 1999;340:1888-1899.
12. Celebrex Prescribing Information 2000. Searle.
13. Vioxx Prescribing Information 2000. Merck and Co.
14. Wallace JL. Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiologic roles, and the categorization of nonsteroidal anti-inflammatory drugs (NSAIDS). Am J Med. 1999;107:11S-17S.
15. Furst DE. Pharmacology and efficacy of cyclooxygenase (COX) inhibitors. Am J Med. 1999;107:18S-26S.
16. Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. Clin Pharmacol. 2000;40:1109-1120.
17. Crofford, LJ, Lipsky PE, Brooks P, et al. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000;43:4-13.
18. Cada DJ, Baker DE, Levien T. Meloxicam. Hospital Pharmacy. 2000;35:852-865.
19. Depre M, Ehrlich E, Van Hecken A, et al. Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans. Eur J Clin Pharmacol. 2000;56:167-174.
20. 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.
21. Freston JW. Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events. Am J Med. 1999;107:78S-89S.
22. Day R, Morrison B, Luza A, et al. A randomized trial of the efficacy and tolerability of the cox-2 inhibitor rofecoxib vs. ibuprofen in patients with osteoarthritis. Arch Intern Med. 2000;160:1781-1787.
23. Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg. 2000;91:1221-1225.
24. Morrison BW, Christensen S, Yuan W, et al. Analgesic efficacy of the cyclooxygenase-2 specific inhibitor rofecoxib inpost dental surgery pain: a randomized cpmtrolled trial. Clin Therapeutics. 1999;21:943-953.
25. Davies NM, McLachlan AJ, Day RO, et al. Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet. 2000;38:225-242.
26. Emery P, Ziedler H, Kvien TK, et al. Celecoxib versus diclofenac in long term management of rheumatoid arthritis: randomized double blind comparison. Lancet. 1999;354:2106-2111.
27. Hawkey C, Laine L, Simon T, et al. Comparison of the effect of rofecoxib, ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis. Arthritis Rheum. 2000;43:370-377.
Dr. Cho has a private practice in Manhattan limited to oral and maxillofacial surgery. He is an assistant attending at St. Vincent’s Hospital and Metropolitan Hospital and a clinical instructor at the New York Medical College.
Dr. Black has a private practice in Manhattan limited to oral and maxillofacial surgery. He is an assistant attending at St. Vincent’s Hospital, Metropolitan Hospital and St. Clare’s Hospital. He is also a clinical associate professor at the New York Medical College.
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