Excellent pain control in dentistry is essential for the delivery of optimal dental care and for the well-being of patients. Although our current armamentarium of local anesthetics and analgesic drugs generally is adequate for most clinical requirements, occasional failures to control pain are frustrating. These failures result in dentists’ being inclined to try new local anesthetics and analgesics as soon as they are marketed to the profession. Unfortunately, therapeutic decisions involving new drugs often are made on the basis of unscientific anecdotal reports, marketing hype and unscientific field testing, in which a group of dentists compares a new product with whatever they use routinely.
Patients deserve—and evidence-based dentistry mandates—therapies that are based on sound scientific evidence whenever possible. Nearly all drugs are developed for use in medicine; after dental indications and dental efficacy are established, they are marketed to the dental profession. The findings of numerous, scientifically sound, double-blind, controlled clinical trials have been reported in peer-reviewed journals on which to base the use of a new drug in dentistry. For various reasons, some aspects of these clinical studies, with serious implications for dentistry, have gone unreported or underemphasized in the flurry of marketing that follows introduction of a new agent. The purpose of this article is to briefly review the attributes of valid scientific studies of drugs and to use the example of a recently introduced drug to illustrate the need for thorough consideration before adopting a new analgesic drug into dental practice.
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EVIDENCE-BASED SELECTION OF DRUGS
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Controlled clinical trials must incorporate many strict scientific criteria if they are to be considered valid1:
- – Subjects should be representative of the patients who will actually receive the drug in clinical practice.
- – The size of the study population should be large enough to satisfy the criteria for adequate statistical analysis.
- – The experimental outcome measures should be appropriate and valid for the drug being studied.
- – Experimental treatments should be randomly and equally allocated among the subjects.
- – The conditions of the study should be double-blinded (that is, the health care provider does not know which medication is being administered, and the subject does not know which medication he or she is receiving).
- – The study should incorporate a placebo (inactive drug) and a positive control (a drug known to be effective for the pain condition being studied).
There are, of course, numerous other considerations in determining the validity of a clinical trial of an analgesic (for example, dose schedule vs. pharmacokinetics). It is neither possible nor appropriate for an individual dentist to attempt to conduct his or her own controlled clinical trials simply to decide whether to use a new drug or dental product. However, in spite of the availability of published reports of well-designed clinical trials, anecdotal reports and marketing hype frequently result in dentists making therapeutic decisions without considering all of the scientifically studied characteristics of the new product.
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‘CLINICAL TRIALS OF ONE’
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Regardless of the type of new product introduced into the dental marketplace, there is a tendency to try the new product, especially if it promises better pain control. In what can be termed "clinical trials of one," these one, two or even three experiences with a new drug often form the basis for continued use of a new analgesic or local anesthetic. Such evaluations cannot be compared with valid clinical trials for several reasons, including the following:
Lack of controls.
For example, if a new analgesic is prescribed, did a second group of patients receive another drug or placebo after having undergone the same pain-provoking procedure?
Lack of blinding.
In-office evaluations generally preclude a double-blind study, because both the patient and the dentist must know about the drug being used. An exception would be if a dentist does not disclose the fact that a new local anesthetic is being administered, in which case the study is still single-blinded.
Psychological bias.
Patients frequently are informed that they are being given a new and better drug, especially if the dentist believes that such suggestions will improve the patient’s response. In addition, dentists may contact patients at home to inquire about the efficacy of the new analgesic, introducing more psychological support and, therefore, more bias into the interpretation of the outcome. In a controlled clinical trial, this sort of psychological bias can dramatically alter the placebo component of the response, in a process termed "deceptive administration."2
In two randomized, controlled clinical trials of rofecoxib in the dental pain model, rofecoxib produced post–oral-surgical analgesia greater than that produced by placebo but equal to that produced by ibuprofen.
Lack of standard measurement criteria.
Most dentists do not request that their patients use visual analog scales or other metric instruments for assessing pain before and after a new analgesic is used. Instead, patients usually are questioned about their impressions of the medication, and the dentist bases his or her judgment about the analgesic on this subjective measure.
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SCIENTIFIC PERSPECTIVES ON A RECENTLY INTRODUCED DRUG
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The introduction of nonsteroidal anti-inflammatory drugs, or NSAIDs, that are selective for the cyclo-oxygenase-2, or COX-2, enzyme has resulted in a significant improvement in the long-term treatment of patients with osteoarthritis and other chronic, inflammatory pain disorders. This is because gastrointestinal, or GI, irritation, which is characteristic of drugs that nonselectively inhibit both COX-1 (the constitutive enzyme that synthesizes physiologically protective prostaglandins) and COX-2, occurs less frequently with selective COX-2 inhibitors when used long-term.3 However, package inserts for both rofecoxib4(pp2049–53) and celecoxib4(pp2482–5) carry warnings and contraindications similar to those of conventional, nonselective NSAIDs (for example, ibuprofen and naproxen). Although they are relatively selective for the COX-2 enzyme, they are not completely specific for it and some inhibition of COX-1 can occur, especially at higher doses (the selectivity is dose-dependent).5
Although it appears that rofecoxib would be preferable to conventional NSAIDs for dental pain control because it is expected to produce less GI irritation, dentists must compare the length of time patients are treated with analgesic drugs with the extended treatment periods for patients who receive these types of medications for chronic pain conditions. In most cases, dental analgesics are prescribed for two to three days after surgery or other procedures, after which patients generally are out of pain or can switch to over-the-counter doses of similar analgesics.
For this short period, the risk of developing serious upper-GI toxicity with conventional, nonselective NSAIDs is very low (about 0.25 percent after one month, or approximately the same as that for rofecoxib).3 Moore and Hersh6 suggested that currently available selective COX-2 inhibitors are appropriate for prolonged treatment of chronic pain associated with temporomandibular disorders and facial pain; however, their high price and other factors limit the routine use of these agents.
Analgesic efficacy.
In 1993, well before the actual introduction of selective COX-2 inhibitors, Wallace and Cirino7 correctly postulated (at least for those agents marketed to date) that if the COX-2 isoenzyme mediates pain and inflammation, "it is unlikely that highly selective inhibitors of COX-2 will be more therapeutically effective than existing NSAIDs, since many of the existing NSAIDs are very effective inhibitors of COX-2" and "it is possible that prostanoids produced via COX-1 contribute to pain, inflammation and fever." This prediction has been valid for rofecoxib when used to treat dental pain. In two randomized, controlled clinical trials of rofecoxib in the dental pain model,8 rofecoxib produced post–oral-surgical analgesia greater than that produced by placebo but equal to that produced by ibuprofen (400 milligrams).9,10
In another trial that compared rofecoxib with naproxen, researchers reached a similar conclusion—that is, while rofecoxib was superior to placebo, the analgesic efficacy of rofecoxib (50 mg) was generally similar to that of naproxen (550 mg).11 In most studies, the duration of analgesic effect of rofecoxib has been significantly longer than that of ibuprofen or naproxen.9–11 (Celecoxib and valdecoxib, the other selective COX-2 inhibitors, do not carry label indications for short-term management of postoperative pain.)
For purposes of this article, however, the question we must ask is this: What is the scientific basis for prescribing rofecoxib instead of conventional NSAIDs for moderate pain in dentistry? Some clinicians would still reply that it seems to work better, but only on the basis of their private, unscientific clinical trials (the weaknesses of which are discussed above), and superior efficacy has not been observed when the drug is tested under controlled scientific conditions. One might postulate that because rofecoxib is effective for treating moderate dental pain with a once-a-day dosage regimen (using the 50-mg dose), patient compliance will be improved, which compensates for the increased per-tablet cost.
Short-term use of robecoxib in dentistry is unlikely to produce significantly better patient tolerance than that seen with other nonsteroidal anti-inflammatory drugs.
Need for rescue medication.
The longer duration of action of the 50-mg dose (the maximum daily dose) seems to be the basis for the commercial recommendation of rofecoxib for dental pain, but a significant downside exists that is rarely discussed. This is the underemphasized observation in clinical trials9–12 that approximately half of the patients receiving rofecoxib treatment for dental pain require rescue medication within the first 24 hours.
In a clinical trial conducted by Malmstrom and colleagues,12 49 percent of patients treated with rofecoxib after oral surgery required rescue medication within the first 24 hours. In the same study, the median time to rescue medication for patients treated with 400 mg of ibuprofen was 8.9 hours, which means that an additional 2,800 mg of ibuprofen could be administered to a healthy adult within the first 24-hour period (maximum daily dose, 3,200 mg).
These findings have been confirmed by other studies. Chang and colleagues13 reported a median time to rescue medication of 9.6 hours for patients treated with rofecoxib, and Ehrich and colleagues10 reported that approximately 25 percent of patients in both the 50-mg rofecoxib and 400-mg ibuprofen groups required rescue analgesia after six hours.
The clinical implication of these findings is that a dentist can expect up to half of his or her patients to need additional medication before the next scheduled dose of rofecoxib (every 24 hours). However, since the 50-mg dose is the maximal recommended daily dose,4(pp2049–53) the dentist cannot simply advise the patient to take another 50-mg dose or even another NSAID. Instead, the dentist would need to direct the patient to take acetaminophen or prescribe an opioid-acetaminophen combination product. This situation probably would arise at an inconvenient time for both the dentist and patient, and definitely would represent additional cost to the patient.
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CONCLUSION
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Therapeutic decisions involving analgesic drugs should be based on sound scientific evidence and consideration of all pharmacological properties of a drug, especially when one is considering changing from well-established, efficacious agents to new ones. In this article, I compared a new COX-2 inhibitor with conventional NSAIDs for its potential usefulness based on the results of controlled, double-blind clinical trials. Although the incidence of adverse effects with long-term administration of rofecoxib is significantly lower than that with other NSAIDs, its once-daily, short-term use in dentistry is unlikely to produce significantly better patient tolerance than that seen with other NSAIDs.
At the same time, the relatively high probability of needing to administer additional analgesic appears to outweigh the advantages of rofe-coxib, especially since it is no more efficacious in relieving dental pain than are its traditional counterparts. When confronted with new analgesic agents, dentists should remember that "a drug [analgesic] is considered to have a true pharmacologic advantage if it results in greater analgesic activity without a proportionate increase in side effects."14
It appears that, for those clinicians who quickly switched to the COX-2–selective analgesics for the management of acute, postoperative pain, COX-2 selectivity was mistaken for increased efficacy. I hope that the newer COX-2–selective analgesics currently in development will prove to have greater analgesic efficacy than that of the nonselective NSAIDs. If that happens, they will be truly useful in both the short-term management of postoperative pain as well as in the management of chronic inflammatory pain states.
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EVIDENCE-BASED SELECTION OF...
