Selection of analgesics for the management of acute and postoperative dental pain: a mini-review

Acetaminophen and tNSAIDs

The tNSAIDs currently available on the market include aspirin, diflunisal, ibuprofen, naproxen, ketoprofen, flurbiprofen, indomethacin, sulindac, etodolac, diclofenac, ketorolac, piroxicam, mefenamic acid, and nabumetone. To choose the most appropriate analgesics for pain relief, dentists should consider both the potential benefits and the risks. From the perspective of benefit-risk analysis, the primary drugs of choice for the relief of dental pain are acetaminophen and ibuprofen [5].

Acetaminophen (also known as paracetamol) is one of the most widely used analgesic antipyretic drugs and has minimal anti-inflammatory activity. Despite its long history as a painkiller, the mechanism of action of acetaminophen is still not completely understood. The current understanding is that while tNSAIDs inhibit the COX activity of the COX enzyme, acetaminophen inhibits the peroxidase activity of COX at low peroxide levels; this peroxide-dependent inhibition of COX allows acetaminophen to act preferentially within the central nervous system without peripheral anti-inflammatory activity, as the peroxide level is much higher at peripheral inflammatory sites than in the brain [4]. Due to its lack of inhibitory effect on the peripheral COX activity, acetaminophen is less likely than tNSAIDs to induce gastrointestinal and cardiovascular adverse effects and does not prolong bleeding time. Unlike aspirin, acetaminophen does not increase the risk of Reye syndrome, which causes brain and liver damage in children recovering from viral infection. Acetaminophen has no noteworthy limitations for use in pregnant women. Acetaminophen is therefore especially suitable for patients who do not tolerate tNSAIDs due to their adverse effects, such as the increased risk of gastrointestinal ulcer disease. However, acetaminophen may cause serious liver damage if excessive quantities of its toxic metabolite are generated through the phase I biotransformation induced by the hepatic cytochrome P450 system. Therefore, this drug should not be taken in excess of 4 g per day (the United States Food and Drug Administration recently suggested a maximum daily dose of 3 g), and those with serious liver disease or who regularly and continuously consume large volumes of alcohol should exercise extra caution. Since patients may unknowingly take acetaminophen combination products, dentists should ensure that the patient will not consume too much acetaminophen when prescribing the drug. Acetaminophen is used for mild pain and can be combined with tNSAIDs and/or opioid analgesics to increase effectiveness.

Ibuprofen is very effective for relieving mild or moderate pain and is one of the most frequently prescribed analgesics by dentists. Generally, the analgesic effect of 200 mg of ibuprofen is similar to or stronger than that of 500–1,000 mg of acetaminophen. For mild dental pain, 200 mg to 400 mg of ibuprofen every 4 to 6 hours is recommended [3, 5]. Within this dose range, the potential of ibuprofen to cause adverse gastrointestinal, liver, or cardiovascular effects is relatively low compared with other tNSAIDs [6]. However, if this regimen does not provide sufficient analgesia, the dose may be increased to 400 mg to 600 mg to provide greater pain relief, and such a dosage increase is accompanied by increased gastrointestinal and cardiovascular risks.

Naproxen has a longer duration and a stronger anti-inflammatory effect than ibuprofen. However, despite its advantages over ibuprofen, naproxen has a higher risk of adverse effects such as gastrointestinal toxicity [7]. Thus, naproxen should be reserved for pain that is not relieved by ibuprofen. The gastrointestinal and cardiovascular risks associated with acetaminophen, ibuprofen, and naproxen are compared in Table 2.

Table 2
Gastrointestinal and cardiovascular risks of acetaminophen, ibuprofen, naproxen, and COX-2 inhibitors

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Other tNSAIDs, such as diclofenac, ketoprofen, and etodolac, may have analgesic effects similar to or stronger than those of ibuprofen or naproxen, but dentists should bear in mind that these drugs may also have more adverse gastrointestinal or cardiovascular effects, especially when used at high dosages.

Although tNSAIDs are safe if used for a short period of time, they may cause heartburn, nausea, vomiting, diarrhea, and in some cases potentially serious adverse effects such as gastric ulcer and gastric perforation. This is primarily due to their inhibition of prostaglandin production in the gastric mucosa, leading to decreased mucus and bicarbonate generation and increased gastric acid secretion. In patients at high risk of gastrointestinal disease, therefore, tNSAIDs may be prescribed in combination with mucosal protective agents or gastric acid secretion inhibitors, such as proton pump inhibitors. Alternatively, acetaminophen or COX-2 inhibitors can be prescribed.

Aspirin irreversibly inhibits COX and thus is distinguished from non-aspirin tNSAIDs, which are competitive reversible inhibitors. The irreversible mode of action of aspirin prevents thromboxane A2 synthesis by platelets for their circulating lifetime; thus, the antithrombotic effect of aspirin may last for 5 to 7 days [8]. Other tNSAIDs reversibly inhibit COX, such that the antiplatelet effect of these drugs declines as their plasma concentrations decrease via metabolism and excretion. Apart from their antithrombotic effect, tNSAIDs may cause renal toxicity because prostaglandins also play a role in the maintenance of renal function; thus, dentists should take care when prescribing tNSAIDs to patients with compromised renal function [9].

NSAIDs are associated with various drug interactions. For example, tNSAIDs such as ibuprofen and naproxen have been reported to interact with aspirin [10]. Many patients with cardiovascular diseases take low dose of aspirin regularly (often 81 mg daily) to decrease the risk of ischemic heart disease and stroke. If ibuprofen or naproxen is prescribed to patients taking aspirin, it will interfere with the antiplatelet effect of aspirin by antagonizing the acetylation of COX-1 and will thus reduce aspirin's cardioprotective effects [11, 12]. If these tNSAIDs are deemed necessary, patients should be informed about this drug interaction and should be advised to take aspirin at least 30 minutes prior to taking such tNSAIDs. Drug interactions associated with NSAIDs are summarized in Table 3.

Table 3
Drug interactions associated with NSAIDs

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Selective COX-2 inhibitors

Inhibition of COX-1 by tNSAIDs is responsible for NSAID-induced gastropathy, nephropathy, and prolonged bleeding time. Selective COX-2 inhibitors were developed to avoid the adverse gastrointestinal and bleeding-associated effects caused by COX-1 inhibition [13]. However, these drugs increase the risk of thrombosis and have been reported to have serious cardiovascular adverse effects, such as ischemic heart disease, heart failure, hypertension, and stroke. Therefore, COX-2 inhibitors should be used carefully, and dentists are advised to avoid these drugs in patients at high risk of cardiovascular disease [9]. Various COX-2 inhibitors (known as coxibs) have been developed; however, due to such cardiovascular side effects, some drugs, such as rofecoxib, have been withdrawn from the market. In Korea, celecoxib, etoricoxib, and polmacoxib are currently available. The anti-inflammatory, analgesic, and antipyretic effects of COX-2 inhibitors are reported to be similar to those of tNSAIDs.