Acute Pain

Current Concepts in Acute Pain Management

Mai-Phuong Huynh, DDS, and John A. Yagiela, DDS, PhD

Copyright 2003 Journal of the California Dental Association.

Authors

Mai-Phuong Huynh, DDS, is a dental anesthesiology resident in the Division of Diagnostic and Surgical Sciences at the University of California at Los Angeles School of Dentistry.

John A. Yagiela, DDS, PhD, is professor and chair of the Division of Diagnostic and Surgical Sciences at UCLA School of Dentistry.

Analgesics most commonly prescribed in dentistry for acute pain relief include the nonsteroidal anti-inflammatory drugs, acetaminophen, and various opioid-containing analgesic combinations. The NSAIDs and presumably acetaminophen act by inhibiting cyclooxygenase enzymes responsible for the formation of prostaglandins that promote pain and inflammation. Opioids such as codeine, hydrocodone, and oxycodone stimulate endogenous opioid receptors to bring about analgesic and other effects. Numerous clinical studies have confirmed that moderate to severe pain of dental origin is best managed through the use of ibuprofen or another NSAID whose maximum analgesic effect is at least equal to that of standard doses of acetaminophen-opioid combinations. If an NSAID cannot be prescribed because of patient intolerance, analgesic preparations that combine effective doses of an orally active opioid with 600 to 1,000 mg of acetaminophen are preferred in the healthy adult. On occasion, prescribing both an NSAID and an acetaminophen-opioid combination may be helpful in patients not responding to a single product. In all cases, however, the primary analgesic should be taken on a fixed schedule, not on a “prn” (or as needed) basis, which only guarantees the patient will experience pain.

The prescription illustrated in Figure 1 has most likely been written more frequently in dentistry for the management of moderate to severe pain (as may accompany the surgical extraction of third molars) than any other during the past three decades and remains highly popular today. Nevertheless, modern guidelines for acute pain management identify three significant problems involving this prescription with respect to the typical dental patient. In addressing these problems, this paper reviews the currently available oral analgesics used in dentistry and summarizes how these drugs may be prescribed to best advantage for acute pain relief.

History

The first “prescription” for pain management can be traced back 2,400 years, when Hippocrates suggested using juices of the poplar and willow bark to alleviate the pain of childbirth. Millennia later, it was found that these juices contained the compound salicin. In 1853, Charles Frederich Gerhardt synthesized aspirin by treating sodium salicylate (a simple derivative of salicin) with acetyl chloride. Aspirin was introduced clinically in 1899 by Heinrich Dresser of the Bayer Company in Germany and remains one of the most common remedies for acute pain.

Opioid use dates back even further, to the early civilizations of Persia, Egypt, and Mesopotamia. A Sumerian text from 4,000 B.C. was the first to refer to opium derived from the poppy plant. In 1805, Wilhelm Sertürner isolated morphine from opium, giving clinicians for the first time a chemically pure, highly effective analgesic.

Continued advances in the development of aspirin-like and morphine-like drugs have made available a broad spectrum of agents to manage acute pain. In addition, there has been a new understanding of how these analgesics should be used for optimal pain relief in the outpatient setting.

Pain and Analgesia

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage.”1 Pain can be separated into two broad categories: acute and chronic. Acute pain lasts from seconds to days. It generally has a known cause and subsides with removal of the stimulus and healing. Acute pain may be associated with heightened arousal, leading to tachycardia, tachypnea, and anxiety. In contrast, chronic pain typically lasts from months to years. The body has become adapted to this level of pain, and often there is no increased sympathetic response. Chronic pain is associated with depression and decreased function.

Role of Cyclooxygenase and Prostaglandins

Tissue damage stimulates at the site of injury the release of inflammatory mediators such as prostaglandins, kinins, leukotrienes, substance P, and histamine. These mediators help initiate and subsequently magnify nociceptive impulses that are transmitted to the central nervous system for the perception of pain. Of these mediators, prostaglandins are especially important in sensitizing peripheral neurons to the local stimulus. Prostaglandins are also synthesized in the spinal cord and possibly higher brain centers in response to nociceptive impulses and enhance pain sensitivity by recruiting additional secondary neurons that respond to the primary stimulus.

Aspirin and related nonsteroidal anti-inflammatory drugs work at the site of tissue damage, the spinal cord, and/or higher brain centers to prevent prostaglandin formation by inhibiting cyclooxygenase, or COX, activity. With the partial exception of acetaminophen, which has minimal anti-inflammatory effects in most settings, these drugs exert a combination of analgesic, antipyretic, and anti-inflammatory effects.

Tissue COX exists in two well-known subtypes: COX-1 and COX-2. COX-1 is a constitutive form that supports hemostasis (where synthesis of the prostaglandin analogue thromboxane A2 increases platelet degranulation and adhesion), stomach mucosal integrity (where synthesis of prostaglandins protects against acid damage), and kidney function (where prostaglandins help regulate normal renal blood flow). COX-2 is a largely inducible form whose synthesis is activated in damaged or stimulated tissues and leads to the formation of pro-inflammatory prostaglandins. COX-2 plays a major role in inflammation, pain, and fever. It is also constitutively active in regulating renal blood flow.2

There is increasing evidence that one or more additional subtypes of COX may exist. A new COX-3 has been described that is produced by the same gene that encodes COX-1. This COX-3 is found in the brain and is inhibited by clinically achievable concentrations of acetaminophen.3 An additional form of COX that is induced with high concentrations of NSAIDs and is selectively inhibited by acetaminophen may be derived from the COX-2 gene.4

Role of Endogenous Opioids

Nociceptive pathways in the central nervous system are subject to modulation by neurons that release inhibitory transmitters at synaptic sites important for the perception of pain. Brain sites involved in affective responses to pain are also inhibited. Endogenous opioid peptides that stimulate specific opioid receptors play a pivotal role in blunting pain. Evidence has accumulated in recent years that peripheral nerves in inflamed tissues also contain opioid receptors whose activation can produce analgesia.5

Morpine and related opioid analgesics exert most of their pharmacologic effects by stimulating the µ opioid receptor. In addition to relieving pain, µ-receptor stimulation can cause a tranquil euphoria, nausea and vomiting, and constipation. In overdose, respiratory depression is the primary concern; chronic use can lead to physical and psychological dependence.

Pentazocine, nalbuphine, and related opioid agonist-antagonists promote analgesia by stimulating the ? opioid receptor. Analgesic and respiratory depressant effects are similar to those elicited by morphine in normal clinical doses; however, a ceiling effect limits these responses in overdose. Sedation is a common side effect of the agonist-antagonists, but stimulation of ? receptors is more likely to produce dysphoria than euphoria, and psychotomimetic reactions are common with large doses. Physical dependence is possible but less problematic with ? agonists. Precipitation of an acute opioid withdrawal reaction may occur when pentazocine or nalbuphine is administered to an opioid-dependent individual.

Nonsteroidal Anti-Inflammatory Drugs (Including Acetaminophen)

As the prototypical NSAID, aspirin remains a standard against which other orally active analgesics are compared. It is relatively selective for COX-1 and is therefore prone to causing gastric bleeding and ulceration, especially with high doses and chronic use. Aspirin is unique in that it acetylates the COX enzyme. This property, plus the drug’s relative COX-1 selectivity and the inability of platelets to synthesize new COX, provides the basis for the use of low-dose aspirin to prevent thromboembolic heart attack and stroke in susceptible patients. Typical doses of 325 to 650 mg encompass most of aspirin’s analgesic dose-response curve in the average adult.

Acetaminophen’s analgesic and antipyretic properties are comparable to those of aspirin. However, it does not elicit gastrointestinal irritation or prolong bleeding, which are hallmarks of aspirin use. Acute toxicity is minimal unless an overdose occurs, which may lead to hepatotoxicity. Analgesia by acetaminophen in the average adult becomes readily measurable at a dose of 300 mg and plateaus at 1,000 mg.6

Ibuprofen was the first NSAID to demonstrate analgesic superiority to aspirin. A 400 mg dose of ibuprofen has been shown to have a greater peak analgesic effect and a longer duration than 600 to 1,000 mg of aspirin or acetaminophen, or 60 mg of codeine, and at least comparable efficacy to traditional opioid analgesic combinations (Figures 2a and b).7,8 One meta-analysis has suggested there is a dose-dependent increase in analgesia with ibuprofen up to 800 mg.9 However, the published source from which the statistically analyzed data were obtained for this assertion actually revealed little analgesic improvement with doses beyond 400 mg.10 It is likely that the principal effect of prescribing doses of ibuprofen larger than 400 mg for pain relief is that the duration of maximum analgesia is prolonged.

Naproxen, an NSAID structurally related to ibuprofen, has a half-life of about 13 hours, which allows for less frequent dosing compared to ibuprofen (half-life of two hours).6 A 220 mg dose of naproxen sodium is equivalent to 200 mg of ibuprofen in analgesic onset and peak effect but has a longer duration of action.11 A similar comparison holds for 440 mg of naproxen sodium compared with 400 mg of ibuprofen.12 Diclofenac, ketoprofen, flurbiprofen, meclofenamate, and diflunisal are additional NSAIDs with analgesic activity in the dental setting similar to that of ibuprofen or naproxen. Fenoprofen is also approved for the management of acute pain, but its slow absorption retards the onset of analgesia. Ketorolac, an NSAID commonly used for parenteral administration, is restricted in its oral dosage form to patients who have already received the drug by injection. Lastly, etodolac is a well-tolerated NSAID; however, it has not been proved superior to aspirin for relieving pain of dental origin.

The introduction of selective COX-2 inhibitors has allowed specific targeting of inflammatory prostaglandin production while minimizing adverse side effects such as gastrointestinal ulceration and bleeding problems.13 Clinically available COX-2 inhibitors include rofecoxib, celecoxib, and valdecoxib. As yet, valdecoxib has not been approved for the treatment of acute pain (although recent studies indicate it has strong potential for such use).14 Rofecoxib enjoys two advantages over celecoxib and valdecoxib in that its duration of action is sufficiently long to permit single daily dosing, and it is not contraindicated in patients with a history of sulfonamide allergy. In a dose of 50 mg, rofecoxib is comparable to 400 mg of ibuprofen in onset and peak pain relief.15,16

Opioids and Related Agents

In contrast to NSAIDs, opioids do not have an obvious ceiling effect for analgesia. Thus, increasing the dose increases the pain relief. Unfortunately, opioids cause undesirable side effects that limit their dosing, especially in the outpatient setting. These adverse effects include nausea and vomiting, constipation, sedation, and, in large doses, respiratory depression. Some opioids (e.g., morphine and codeine) also cause anti-inflammatory effects and even immunosuppression; the clinical significance of these findings for dental surgery remains unknown.17,18

Morphine, the prototypical opioid analgesic, is rarely prescribed orally for the management of acute pain because most of the drug is metabolized in the liver before it can reach the systemic circulation. Meperidine and many other opioids have similar problems with the oral route. The three most commonly used opioids for oral administration are codeine, hydrocodone, and oxycodone. These agents have a high oral:parenteral efficacy ratio, in part because a fraction of each drug is converted by the hepatic enzyme cytochrome P450 2D6 (CYP2D6) to a much more active metabolite (codeine?morphine, hydrocodone?hydromorphone, oxycodone?oxymorphone) and released into the bloodstream.19 About 5 percent to 10 percent of Caucasians and 1 percent to 3 percent of African-Americans and Asians have a polymorphic gene for CYP2D6 that cannot support these conversion reactions. In the case of codeine, no analgesia is obtained, nor are such dose-dependent side effects as constipation or respiratory depression. On rare occasions, oral methadone may be prescribed for analgesia. It is chemically unrelated to the aforementioned opioids and requires no metabolic conversion for its opioid action. Propoxyphene is structurally related to methadone but is a much weaker analgesic. At best, 100 mg of propxyphene napsylate is equivalent to 60 mg of codeine.

Tramadol is an analgesic with two complementary mechanisms of action. It is a weak µ-receptor agonist, imbuing the drug with opioid-like activity. In addition, tramadol inhibits the reuptake of norepinephrine and 5-hydroxytryptamine, an antidepressant-like action. Because of its weak opioid activity, tramadol exhibits less respiratory depression, drug dependence, and other side effects commonly associated with opioid use. However, studies have shown that relief of acute oral surgery pain with 50 mg of tramadol is similar to that of 60 mg of codeine but less than that of a full therapeutic dose of codeine in combination with aspirin or acetaminophen. Tramadol with acetaminophen may be a suitable choice for patients who do not tolerate NSAIDs or opioid analgesics well.20

The agonist-antagonist pentazocine is another alternative to the codeine-like opioids. A dose of 50 mg pentazocine is approximately equianalgesic as 60 mg of codeine. Other agonist-antagonists are not available in oral dosage forms.

Combination Analgesics

No analgesic agent for oral administration is currently available that can relieve all intensities of acute pain. The NSAIDs, acetaminophen, and the opioid agonist-antagonists exhibit a ceiling effect for analgesia in that no greater pain relief can be obtained by increasing the dose beyond a certain limit. In the case of the morphine-like opioids, dose-dependent toxicity restricts the analgesic effect that can usually be obtained. In fact, standard doses of opioids (e.g., codeine 30 to 60 mg, hydrocodone 5 to 10 mg, oxycodone 5 to 10 mg) produce pain relief for dentistry that only approaches the analgesia of two aspirin tablets (650 mg, see Figure 2).

A strategy commonly used to enhance the analgesic benefit of oral medication is to combine two (or more) drugs with different mechanisms of action. The combination of acetaminophen or an NSAID with an opioid allows for increased analgesia because the drugs act through dissimilar mechanisms.21 Because they also have dissimilar side effects, summation of the intensity of these effects does not occur.

Combining an NSAID with another NSAID, or an opioid with another opioid, provides no such benefit. In the case of NSAIDs, the maximum pain relief is already achieved by using a fully effective dose of a single agent. The combination can only produce increased adverse effects. With opioids, the increased analgesia, which could also have been obtained by using a larger dose of a single drug, is accompanied by heightened adverse effects that make such combinations intolerable.

Some practitioners prescribe acetaminophen with an NSAID for postoperative pain control. Clearly, if acetaminophen is insufficient by itself, then an NSAID with a stronger analgesic effect may produce more pain relief than can acetaminophen alone. It is unclear, however, if adding acetaminophen to any NSAID already being taken at a ceiling analgesic dose provides any benefit.22-24 Resolution of this question may ultimately depend on whether acetaminophen and the NSAIDs act on the same or different prostaglandin pathways involved in nociception.

Caffeine is an analgesic adjuvant that exerts no analgesic action by itself in humans but can enhance the potency of such drugs as acetaminophen, aspirin, and ibuprofen. In the case of ibuprofen given after third-molar surgery, the analgesic potency of 100 to 200 mg doses is increased more than twofold by 100 mg of caffeine.25 There are few data, however, to suggest that caffeine can improve the analgesic effect of “ceiling” doses of NSAIDs or acetaminophen.26

Adverse effects of combination analgesics include those for each drug in the combination. In addition, the chronic use of aspirin, phenacetin (an acetaminophen analogue), and caffeine, as once commonly formulated in the “APC” tablet, has long been associated with end-stage kidney disease. The simultaneous use for several days of an acetaminophen-opioid preparation and an NSAID has not been linked to increased renal toxicity.

Precautions and Drug Interactions

Adverse responses to analgesics are more likely to occur in patients who have certain medical conditions or are taking specific drugs. In the case of NSAIDs, all such drugs (including the COX-2-specific agents) should be avoided in any patient who has exhibited an allergic-like (anaphylactoid) reaction, such as urticaria, angioneurotic edema, bronchial asthma, and acute hypotension, to any NSAID.6 It is believed that inhibition of COX in these patients may result in overproduction of leukotriene mediators of anaphylaxis. NSAID intolerance is also particularly common in patients with rhinitis, nasal polyps, and asthma for which systemic corticosteroids must be used to control bronchospasm. Patients with bleeding disorders or platelet deficiency, or with a history of gastrointestinal inflammatory or ulcerative disease, should not receive NSAIDs with COX-1 activity. Although it is probably safe to prescribe a short course of a COX-2-selective inhibitor in a patient with an ulcer history, such drugs are best avoided in individuals with an existing or recent ulcer because COX-2 is expressed locally during the healing phase. Other conditions in which NSAIDs are not recommended include pregnancy in the second and third trimester (possible premature closure of the ductus arteriosus, excessive bleeding, or depressed uterine contractions during labor and delivery) and congestive heart failure or significant renal impairment (possible fluid retention). The use of aspirin in children may trigger Reye’s syndrome in the presence of a viral infection and is best avoided in pediatric and adolescent patients.27

Opioid analgesics are problematic in patients with impaired respiration, as may accompany advanced emphysema or poorly controlled myasthenia gravis. Severe inflammatory bowel disease is also a contraindication to opioid use. Patients with a history of opioid drug abuse present a special set of issues. These patients tend to have a relatively low pain threshold, which may be coupled with a relatively high tolerance to opioids. Consultation with the patient’s physician is advised to help balance the need for effective analgesic medication against the concern that such medication may trigger addiction relapse. (It should be noted that there is an extremely low incidence of drug addiction when short courses of opioids are given for analgesia to patients without a history of drug abuse.28)

Geriatric patients often exhibit diminished clearance of analgesic medications, increased plasma concentrations of free drug, and increased pharmacologic effects. There is also a heightened risk for drug interactions since many elderly patients are already taking multiple medications, including analgesic/anti-inflammatory drugs.

Drug interactions of concern in dentistry are listed for the NSAIDs and acetaminophen and for the opioid-like drugs in Tables 1 and 2, respectively.

Analgesic Selection

The selection of an analgesic for the management of acute dental pain is ideally based on the pain’s actual or expected intensity, the patient’s medical history, the drug’s pharmacologic profile, and the ease and cost of obtaining the medication. Table 3 lists the authors’ recommendations for the typical healthy adult.

Pain of mild to moderate intensity, as may follow extensive restorative dentistry or simple periodontal surgery, is best managed with analgesics listed in Table 3 that are usually found in the home. These drugs, including acetaminophen and ibuprofen, are effective for this level of discomfort; they are also inexpensive and sold over the counter. Patients who have purchased specific analgesics are generally experienced in their use and regard them as effective and well-tolerated.

The NSAIDs listed in Table 3 are the drugs of first choice for controlling moderate to severe pain in dentistry. This degree of pain is characteristically caused by acute pulpitis or the surgical removal of impacted third molars. In doses that produce ceiling analgesia, these NSAIDs are better-tolerated and at least as effective as the more traditional acetaminophen-opioid combinations. Ibuprofen is unusual in that the over-the-counter unit dose of 200 mg can easily be used to duplicate prescription doses (400, 600, 800 mg) of ibuprofen that produce ceiling analgesic effects. While the COX-2 inhibitor rofecoxib exhibits an extended duration of action compared to other NSAIDs, the authors found the cost of a prescription for 50 mg of rofecoxib, every day for three days, to be approximately 15 times that of 800 mg ibuprofen (four 200 mg tablets), three times a day for three days ($14.69 versus $1.09).

Acetaminophen-opioid combinations are the drugs of choice for moderate to severe pain when NSAIDs are contraindicated. The formulations listed in Table 3 ensure that the acetaminophen, which provides most of the pain relief, is taken in a dose of at least 600 mg and that the opioid is used in a dose (codeine 60 mg, hydrocodone 7.5 to 10 mg, oxycodone 7.5 to 10 mg) that significantly and consistently increases pain relief in the oral surgery pain model without usually producing intolerable side effects. Hydrocodone as formulated in Lortab 5/500 or Vicodin (two tablets each, Table 3) is arguably the preferred opioid, since codeine may be less effective in certain patients and oxycodone combined with acetaminophen is a Schedule II drug requiring a triplicate prescription form.

Opioids -- generally combined with acetaminophen for prescribing convenience -- may also be used as a supplement to an NSAID for additional pain relief if needed (for example, if the analgesic effectiveness of the NSAID is shorter in duration than the dosing interval). Here, a formulation such as Lortab 10/650 or Vicodin HP reduces the acetaminophen dose somewhat. Ibuprofen-hydrocodone, the only NSAID-opioid combination currently available, is not recommended for routine use because the standard dosing schedule of one tablet, containing 200 mg of ibuprofen and 7.5 mg of hydrocodone, does not provide a ceiling analgesic effect for the ibuprofen.

Several combinations (acetaminophen with either pentazocine, propoxyphene, or tramadol) are listed in Table 3 for patients who are truly allergic to morphine-like opioids. Acetaminophen-tramadol may be the preferred choice based on recent efficacy studies in the oral surgery model.29

On rare occasion, severe dental pain is not satisfactorily relieved with standard analgesic doses. Table 3 lists two regimens in which maximum tolerated doses of an NSAID and an opioid are combined that may provide some additional analgesia beyond the drugs already mentioned. The first example combines 800 mg of ibuprofen with 15 mg of hydrocodone, a dose greater than generally recommended but nevertheless tolerable in the majority of nonambulatory patients. The second example involves diflunisal and methadone. This approach requires a triplicate prescription for the methadone but may be superior in patients with inherited or acquired CYP2D6 deficiency. Either of these combinations should be prescribed only for a healthy adult patient whose refractory pain is sufficient to require home rest.

Analgesic Use

When prescribing an analgesic for dentistry, the dentist should direct the patient to take the initial dose as soon as feasible and then follow a fixed dosing schedule for at least the expected duration of the most intense pain (i.e., for two days after surgical tooth extractions). This practice ensures the maintenance of effective drug concentrations at the sites of action. Prescribing drugs on a “prn” (pro re nata, Latin for “as needed”) basis only helps ensure that pain will be felt. Particularly with NSAIDs, analgesics should be ingested before the pain becomes significant. It takes about two hours after tissue injury for the induction of COX-2 and formation of pro-inflammatory prostaglandins.30,31 Therefore, administration of an NSAID within two hours of tissue injury will be effective in preventing postoperative discomfort.

Because most NSAIDs inhibit both COX-1 and COX-2 nonselectively, their administration before hemostasis is achieved may promote postoperative bleeding. A significant advantage of rofecoxib and other selective COX-2 inhibitors is that they may be given preoperatively for “pre-emptive analgesia” without the worry of decreased platelet function. For surgical cases of extended duration, a single dose of rofecoxib may be beneficial in tiding the patient over until the prescribed analgesics can be taken postoperatively.

Age and body size can significantly influence the use of analgesics in dentistry. Pediatric patients rarely require analgesics beyond those obtainable without a prescription. Ibuprofen oral suspension (100 mg/5 mL) at a dose of 10 mg/kg every four hours (to a maximum of 40 mg/kg/day) probably is the most effective oral analgesic for children; if acetaminophen with codeine oral suspension or solution (125 mg acetaminophen and 12 mg codeine/5 mL) is prescribed, the dose for children 3 to 7 years old is 5 mL (1 teaspoon) every six hours and twice that for children 7 to 12. For elderly patients, regular doses of analgesics listed in Table 3 should be reduced by 50 percent. Dosage reduction is especially important for opioid-containing products because of the marked increase in opioid sensitivity that accompanies advanced age.

Conclusion

Returning to the prescription at the beginning of this paper, three errors that compromise effective pain relief are readily identifiable:

* Tylenol with codeine #3 contains 300 mg acetaminophen and 30 mg of codeine. It is not a preferred drug for a patient who can receive NSAIDs.

* Giving the patient the option of taking one tablet may well result in analgesia inferior to that produced by a standard dose of acetaminophen alone. The clinician should determine the amount of analgesic to be used, not the patient.

* The use of “prn” dosing helps ensure the patient will experience postoperative pain before attempting to treat it. Patient comfort is improved if analgesics are taken on a fixed schedule for the first few days. Thereafter, the patient may reduce intake in response to the waning noxious stimulus. Thus, a prescription for moderate to severe pain in dentistry that meets current knowledge might read as shown in Figure 3.

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For a printed copy of this article, please contact/John A. Yagiela, DDS, PhD, UCLA School of Dentistry, 10833 Le Conte Ave., Los Angeles, CA 90095-1668 or johny@dent.ucla.edu.

Legends

Figure 1. A highly popular prescription for management of moderate to severe dental pain. It has three significant problems.

Figure 2a. Pain relief after removal of impacted third molars. Data from Cooper SA, Engel J, et al, Analgesic efficacy of an ibuprofen-codeine combination. Pharmacotherapy 2:162-7, 1982.

Figure 2b. Pain relief after removal of impacted third molars. Data from Forbes JA, Kehm CJ, et al, Evaluation of ketorolac, ibuprofen, acetaminophen, and an acetaminophen-codeine combination in postoperative oral surgery pain. Pharmacotherapy 10(suppl 6, part2):94S-105S, 1990. (Slightly negative pain intensity difference scores for placebo after two hours are not shown in the graph.)