Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain

Abstract

Postsurgical dental pain is mainly driven by inflammation, particularly through the generation of prostaglandins via the cyclooxygenase system. Thus, it is no surprise that numerous randomized placebo-controlled trials studying acute pain following the surgical extraction of impacted third molars have demonstrated the remarkable efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen sodium, etodolac, diclofenac, and ketorolac in this prototypic condition of acute inflammatory pain. Combining an optimal dose of an NSAID with an appropriate dose of acetaminophen appears to further enhance analgesic efficacy and potentially reduce the need for opioids. In addition to being on average inferior to NSAIDs as analgesics in postsurgical dental pain, opioids produce a higher incidence of side effects in dental outpatients, including dizziness, drowsiness, psychomotor impairment, nausea/vomiting, and constipation. Unused opioids are also subject to misuse and diversion, and they may cause addiction. Despite these risks, some dental surgical outpatients may benefit from a 1- or 2-d course of opioids added to their NSAID regimen. NSAID use may carry significant risks in certain patient populations, in which a short course of an acetaminophen/opioid combination may provide a more favorable benefit versus risk ratio than an NSAID regimen.

Keywords: acute pain; analgesics; inflammation; opioid abuse; prostaglandins; randomized controlled clinical trials.

Figure 1.

Peripheral and central pain and pain control neuronal pathways. Pain-sensitizing (prostaglandins) and pain-provoking (histamine, bradykinin, and adenosine triphosphate [ATP]) molecules generated or released from damaged tissue from the impacted third molar surgical site induce depolarization and action potentials of A delta and C fiber free nerve endings (damaged tissue panel). These action potentials travel through these nerve fibers (shown in orange) toward the central nervous system (CNS) through the trigeminal ganglion (TG) entering the CNS at the level of the pons. The fibers then descend on the ipsilateral side to the medulla where they make their first synapse with the second-order neuron (shown in blue). The influx of calcium at the central terminal of the first-order neuron causes the release of peptides, including substance P, calcitonin gene-related peptide (CGRP), and the amino acid glutamate (caudal medulla panel), which depolarizes the second-order neuron, which crosses to the contralateral side of the medulla. These nerve fibers ascend to higher levels of the CNS, including the thalamus, where they synapse with third-order neurons. These third-order neurons then send projections to the cerebral cortex, where the pain suffering is perceived, and to other regions of the CNS such as the hippocampus (not shown in diagram). Pain-reducing neuronal pathways (shown in purple) originate in midbrain and descend and synapse, releasing norepinephrine (NE) or serotonin (5-HT) with enkephalinergic interneurons. The enkephalinergic interneurons subsequently synapse on the central terminal of the primary afferent neuron and the dendrites of the second-order neuron with the neuropeptides met and leu enkephalin being released. It is thought that enkephalins induce a reduction of calcium influx in the first-order neuron and an enhancement of potassium efflux at the second-order site, resulting in a reduction of substance P, CGRP, and glutamate release in the former and hyperpolarization of the latter. Illustration by Brittany C. Bennett, MA.

Figure 2.

Some physiologic roles of cyclooxygenase (COX) isoforms and their products. Note the opposing cardiovascular effects of COX-1 and COX-2 products. Ketorolac, being 300-fold more selective for blocking COX-1, has a higher potential than other nonsteroidal anti-inflammatory drugs (NSAIDs) of inducing gastrointestinal (GI) bleeding and ulceration. Celecoxib, by being 8-fold selective for blocking COX-2, produces less GI toxicity but greater cardiovascular risk than other NSAIDs. With permission from Hersh et al. (2005).

Figure 3.

Time-action curves of mean pain intensity difference scores following dental impaction surgery. Pain intensity was scored as 0 = none, 1 = slight, 2 = moderate, and 3 = severe. Pain intensity difference scores are calculated as baseline pain intensity minus the pain intensity at that time point following study drug administration. Research patients were not allowed to ingest study medication until their pain had reached a moderate (2) or severe intensity (3). Adapted with permission from Cooper et al. (1980).

Figure 4.

Time-action curves of mean pain relief scores of various treatments following dental impaction surgery. Research patients were not allowed to ingest study medication until their pain had reached a moderate or severe intensity. Pain relief after study drug intake was scored as 0 = none, 1 = a little, 2 = some, 3 = a lot, and 4 = complete. Adapted with permission from Cooper et al. (1982).

Figure 5.

Numbers needed to treat (NNT) to obtain benefit and harm of selected analgesics. Benefit is defined as a patient reaching at least 50% of the maximum theoretic total pain relief (TOTPAR) score, which is 16 (50% max = 8) or 24 (50% max = 12) in a 4- or 6-h study, respectively. Harm is defined as a reported or observed side effect. Adapted from data presented by Barden et al. (2004), Derry et al. (2011), and Moore et al. (2015a, 2015b).