Pharmacotherapy forms an integral part of acute dental pain management. In a majority of cases, safe and effective management of acute dental pain can be accomplished with a non-opioid medication regimen. Nonetheless, in certain circumstances use of opioid medications may be needed. Furthermore, there are various pain management regimens, such as pre-emptive analgesia, post-procedural cold compression, use of long acting anesthetic, and compound drug therapy that can improve the efficacy of analgesics to achieve a desired therapeutic response without compromising patient safety.
Key points
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Pharmacotherapy forms an integral part of acute dental pain management.
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For an appropriate pain management regimen, it is essential to consider the underlying cause of pain, and the medical and medication history of the patient.
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Mostly safe and effective management of acute dental pain can be accomplished with a non-opioid medication regimen. However, in certain circumstances opioid-medication regimen is needed.
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Opioids result in strong analgesia. However, they have a significant adverse effect profile, and can interact and potentiate the depressant effects of other centrally-acting medications.
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Pain management regimens, such as pre-emptive analgesia, post-procedural cold-compression, long-acting anesthetic and compound drug therapy can improve the efficacy of analgesics without compromising patient safety.
Introduction
Acute pain is inherent in dentistry. Definitive treatment consists primarily of surgical dental procedures. Analgesic medications, however, often form an intricate part of the treatment strategy. Safe and effective management of acute pain can be accomplished using non–opioid-based and opioid-based analgesics. To formulate a pharmacologic plan, a thorough history and physical examination, in addition to appropriate investigations, are essential. This article reviews the pharmacology of non–opioid-based and opioid-based analgesics and the use of additional strategies to enhance therapeutic response required for optimal pain relief. These guidelines are in concordance with those published by American Dental Association.
Evaluation of acute dental pain
There is a broad differential diagnosis for dental, oral, and facial pain. Many of these conditions have unique and distinctive characteristics that typically distinguish them. , In order to diagnose the cause of dental pain accurately, careful and thorough history and examination are required. These should be supplemented with appropriate and valid clinical and radiological investigations.
Management of acute dental conditions
Once diagnosis and cause of acute dental pain have been established, appropriate dental treatment should be undertaken. This usually results in rapid de-escalation of symptoms and resolution of the disease process. In addition, there may be need for pain control, prior to, during, or after definitive treatments. , The use of analgesic drugs to manage pain should be restricted to appropriate medications, dosage, and number of pills and used, whenever possible, as an adjunct to the definitive dental treatment. Most of the acute painful dental conditions that require analgesics are secondary to inflammation in the pulp, periodontal ligament space, or associated tissues. The inflammation can be a consequence of infection, trauma, or operative procedure. Contingent on the etiology of the underlying cause, pain medications may need to be used in conjunction with other medications, for example, the presence of infection may necessitate the use of antibiotics.
The medications used most frequently for management of acute dental pain consist of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and combination therapy ( Table 1 ).
| Medication | Number Needed to Treat (95% CI) |
|---|---|
| Acetaminophen, 1000 mg, with ibuprofen, 400 mg | 1.5 (1.4–1.7) |
| Acetaminophen, 1000 mg, with oxycodone, 10 mg | 1.8 (1.6–2.2) |
| Ibuprofen, 200 mg, with caffeine, 100 mg | 2.1 (1.8–2.5) |
| Ibuprofen, 400 mg, with oxycodone, 5 mg | 2.2 (1.8–2.9) |
| Acetaminophen, 1000 mg, with codeine, 60 mg | 2.2 (1.8–2.9) |
| Diclofenac, 50 mg | 2.3 (2.0–2.7) |
| Oxycodone, 15 mg | 2.4 (1.4–4.4) |
| Ibuprofen, 400 mg | 2.4 (2.3–2.6) |
| Naproxen, 550 mg | 2.6 (2.2–3.2) |
| Acetaminophen, 650–975 mg, with tramadol, 75 mg | 2.6 (2.3–3.0) |
| Acetaminophen, 500 mg | 3.5 (2.7–4.8) |
| Acetaminophen, 1000 mg | 3.6 (3.2–4.1) |
| Celecoxib, 200 mg | 4.2 (3.4–5.6) |
| Tramadol, 75 mg | 9.9 (6.9–17.0) |
| Codeine, 60 mg | 12.0 |
| Codeine, 30 mg | 16.7 |
Acetaminophen
Acetaminophen is a centrally acting analgesic. There is limited understanding, however, regarding the exact site and mechanism of its action. It has been postulated that it depresses nociceptive activity evoked in thalamic neurons by electrical stimulation of nociceptive afferents and also may result in central analgesia (independent of endogenous opioids). Likewise, it has been suggested that it inhibits the function of cyclooxygenase-3 enzymes. However, genomic and kinetic analyses indicate this inhibitory effect to be clinically irrelevant. , ,
Single doses of acetaminophen are effective analgesics for acute postoperative pain. The number needed to treat (NNT) after a single dose of acetaminophen, 500 mg, was 3.5 (2.7–4.8). For acute dental pain, acetaminophen, 975 mg to 1000 mg, the NNT was 3.6 (3.2–4.1). Multiple studies have suggested acetaminophen, 975 mg to 1000 mg, has a similar analgesic effect to aspirin, 650 mg. Conversely, other studies have found ibuprofen, 400 mg, and diclofenac, 50 mg, superior to acetaminophen in reducing pain and swelling in patients undergoing third molar extraction. , ,
Acetaminophen is a relatively safe medication, with a large therapeutic window and fewer long-term gastrointestinal side effects. Common adverse effects include rash and hypothermia. Long-term use of acetaminophen has been associated with renal and hepatic issues. Caution is advised in alcohol abusers (>3 alcoholic drinks per day) and in patients with liver disease. Acetaminophen is the analgesic of choice during pregnancy or lactation (pregnancy category B). Recent studies suggest, however, that high-dose usage in the third trimester may result in premature ductus arteriosus closure. , ,
Acetaminophen is available in various combinations. Acetaminophen plus caffeine (20 mg–65 mg) has shown superior to acetaminophen alone in management of acute dental pain, but it was found similar to ibuprofen. Similarly, acetaminophen plus codeine (30 mg) has been shown superior to NSAIDs, acetaminophen alone, and acetaminophen with caffeine. The NNT of acetaminophen, 800 mg to 1000 mg, plus codeine, 60 mg, was 2.2 (1.8–2.9). The analgesic effectiveness of acetaminophen also has been studied in combination with NSAIDs, such as ibuprofen. Acetaminophen and ibuprofen combinations have been shown to have more analgesic efficacy than acetaminophen-codeine and ibuprofen-codeine combinations and than oxycodone alone. The NNT of acetaminophen, 1000 mg, and ibuprofen, 400 mg, was 1.5 (1.4–1.7).
To summarize, acetaminophen alone, at 500-mg to 1000-mg oral dosage (every 4–6 hours, as needed to a maximum of 4000 mg/d), is appropriate for management of mild to moderate acute dental pain. Furthermore, in combination with other agents, such as caffeine, or analgesics, such as NSAIDs and opioids, it can be used for management of severe acute dental pain.
Nonsteroidal anti-inflammatory drugs
NSAIDs are a group of analgesics that function by inhibiting enzymatic activity of cyclooxygenase (COX)-1 and COX-2 enzymes. COX enzymes are responsible for production of prostaglandins, which are associated with pain and inflammation. NSAIDs either can specifically block a particular type of enzyme (COX-2 selective NSAIDs) or have a generalized inhibitory effect on both COX-1 and COX-2 enzymes (nonselective NSAIDs). ,
Commonly used NSAIDs include ibuprofen, naproxen, diclofenac, and celecoxib. Ibuprofen, naproxen, and diclofenac are nonselective COX inhibitors. Ibuprofen is an effective analgesic and available in various strengths. The NNT for ibuprofen, 400 mg, in managing acute dental pain has been established to be 2.4 (2.3–2.6). This has shown superior to acetaminophen, 1000 mg, and aspirin, 600 mg to 650 mg. Naproxen has analgesic efficacy and onset similar to ibuprofen. The NNT of naproxen, 550 mg, for management of acute pain was found to be 2.6 (2.2–3.2). Diclofenac, as discussed previously, is a nonselective NSAID; however, it has a preferential inhibitory nature toward COX-2 enzymes. Nonetheless, the efficacy of diclofenac is similar to that of ibuprofen and naproxen. The NNT of diclofenac, 50 mg, was calculated to be 2.3 (2.0–2.7) for managing acute dental pain. Currently, the only COX-2 selective NSAID available is celecoxib. It has been shown effective in controlling postprocedure pain and inflammation. The effectiveness of celecoxib, however, in comparison to conventional nonselective NSAIDs has been inferior. The NNT for celecoxib, 200 mg, has been reported to be 4.2 (3.4–5.6).
NSAIDs can be associated with multiple adverse effects. This is due to the interference of NSAIDs with the production of prostaglandins and thromboxanes. Furthermore, they result in upregulation of leukotrienes, which are responsible for inducing hyperalgesia and sensitivity reactions. Recent studies have suggested, however, that the occurrence of such adverse effects is low. There were no statistically significant differences observed in occurrence of adverse effects between ibuprofen, 400 mg; naproxen, 500 mg to 550 mg; diclofenac, 25 mg to 75 mg; and placebo. Common side effects associated with nonselective NSAIDs are due to inhibition of prostaglandins including gastrointestinal toxicity (diarrhea, constipation, abdominal pain, ulceration, heartburn, nausea, and vomiting) and renal failure. Inhibition of thromboxanes may result in prolonged bleeding and increase in leukotriene levels can result in hypersensitivity reactions, such as asthma and utricaria. Other common side effects associated with use of NSAIDs include, rash, tinnitus, somnolence, and dizziness. COX-2 selective NSAIDs have relatively less acute gastrointestinal side effects. They are associated, however, with increase in cardiovascular events, such as myocardial infarction and ischemic stroke. Relative contraindications for use of NSAIDs include a history of asthma, renal disease, gastrointestinal bleeding, ulceration or perforation, and cardiovascular disease. Use of NSAIDs should be avoided during pregnancy. They have been reported to increase risk for perinatal mortality, neonatal hemorrhage, decreased birth weight, prolonged gestation and labor, and possible teratogenicity.
NSAIDs have been studied as combination analgesics. Studies have suggested that analgesic effectiveness of ibuprofen is enhanced with the addition of acetaminophen, caffeine, and opioid-based analgesics. The NNTs for these combinations were calculated to be 1.5 (1.4–1.7), 2.1 (1.8–2.5), and 2.2 (1.8–2.9), respectively. , ,
To summarize, commonly used NSAIDs are appropriate for management of moderate-severe intensity, acute dental pain. They are associated with various adverse effects; however, the prevalence of such events has been reported to be low. For patients with severe acute pain, NSAIDs can be used in combination with other agents, such as caffeine, acetaminophen, and opioids.
Opioid analgesics
Opioids are a group of medications that produce analgesia by acting on the opioid receptors. There are 3 major classes of opioid receptors: mu, kappa, and delta. These are distributed across several levels of the nervous system and in many peripheral tissues. Opioids inhibit release of neurotransmitters from the primary afferent nerve terminals and activate the descending inhibitory controls in the midbrain. A majority of opioid medications exert their analgesic response by binding preferentially to the mu receptors. Morphine has the highest relative preference for the mu receptors. Codeine has a poor binding capability to mu receptors, however, and for this reason it is considered a prodrug, which eventually metabolizes into morphine to exert its pharmacologic action. Likewise, oxycodone metabolizes into oxymorphone and exerts its antinociceptive response via kappa receptors. Tramadol, unlike the rest of the opioids, is a synthetic centrally acting opioid analgesic. It binds poorly to mu receptors and has low affinity for delta and kappa receptors. It induces its analgesic response by additionally inhibiting norepinephrine and serotonin pathways in the central nervous system.
Several investigations have been conducted on the effectiveness of opioids on the management of acute dental pain. Examples of commonly used opioids include codeine, oxycodone, hydrocodone, and tramadol. Codeine has been studied alone and in combinations with acetaminophen and NSAIDs. Recommended dose for codeine is 30 mg to 60 mg, every 4 hours to 8 hours. It has poor analgesic effectiveness, however, when used alone for management of acute dental pain. The NNTs for codeine, 30 mg and 60 mg, alone to relieve acute dental pain have been established to be 16.7 and 12, respectively. As a combination analgesic with acetaminophen, 1000 mg, plus codeine, 60 mg, however, it was found significantly better, with an NNT of 2.2 (1.8–2.9). Likewise, tramadol, 75 mg to 112.5 mg, has shown to have a poor antinociceptive effect on the management of moderate to severe acute dental postoperative pain. The NNT for tramadol, 75 mg, to relieve acute dental pain by 50% was calculated to be 9.9 (6.9–17). This improved significantly with combination with acetaminophen, 650 mg to 975 mg. The NNT for this combination was 2.6 (2.3–3). It was statistically similar, however, in efficacy to the analgesic effect of ibuprofen, 400 mg. , ,
Oxycodone is considered a relatively strong opioid. The recommended dose is 5 mg to 15 mg every 4 hours to 8 hours. Oxycodone, 5 mg, however, has been shown to not have any beneficial effect in management of acute postoperative pain. On the other hand, a single dose of oxycodone, 15 mg, may provide significant relief in symptoms. The NNT for oxycodone, 15 mg, to result in at least 50% relief in symptoms in patients with moderate to severe postoperative pain was reported to be 2.4 (1.4–4.4). This was similar to the NNT for oxycodone, 10 mg, with acetaminophen, 650 mg, combination therapy. Hydrocodone is another strong opioid that commonly is used in combination in the management of acute dental pain. The recommended dose for hydrocodone is 7.5 mg to 15 mg every 4 hours to 8 hours. Hydrocodone, 7.5 mg, with acetaminophen, 500 mg, has been shown superior to placebo in managing moderate to severe postoperative pain. It was found inferior, however, to the efficacy of oxycodone, 5 mg, plus ibuprofen, 400 mg, and ketorolac, 10 mg. , , ,
The use of the opioids is associated with several adverse effects. These are dose-dependent effects, so the incidence varies. The severity and inconvenience of these effects often are high. Studies on opioids have reported up to 22% patients withdrawing due to intolerance to opioids induced adverse effects. Furthermore, studies comparing acetaminophen, NSAIDs, and opioids reported that most adverse effects took place in patients using opioids. Short-term opioid use commonly is associated with gastrointestinal issues (nausea, vomiting, constipation, and dry mouth), respiratory depression, somnolence, headache, itching, and mood changes (dysphoria and euphoria). Long-term opioid use has been associated with physical dependence and tolerance, hormonal imbalance, and potential drug abuse. The relative contraindications for using the opioids are severe chronic respiratory disease, severe inflammatory bowel disease, and concurrent use of alcohol and cannabis.
Opioid analgesics may interact with other medications through multiple mechanisms. These can take place from induction or inhibition of the hepatic cytochrome P450 monooxygenase system. Opioids undergo hepatic metabolism, and drug interactions affecting this mechanism can have a clinically significant effect. For example, antibiotics, such as erythromycin, can increase the effect of opioids, and rifampicin, carbamazepine, and barbiturates can decrease the effect of opioids. Likewise, concurrent use of centrally acting medications, such as benzodiazepine, tricyclic antidepressants, serotonin and norepinephrine uptake inhibitors, hypnotics, muscle relaxants, and monoamine oxidase inhibitors, increases the risk of profound central nervous system and respiratory depression, psychomotor impairment, and severe constipation and alters seizure control.
Irrespective of the duration of use, opioid use is associated with potential for accidental overdose and death. Given the relative ratio of therapeutic benefits versus risks, the opioids are not considered the analgesic of choice in management of acute dental pain. They should be used as an adjunct to nonopioid medications, such as acetaminophen and NSAIDs, and their use should be limited to second line or third line of therapy in management of severe acute dental pain. Several opioid-based combinations have been studied for management of acute dental pain. Most effective combinations are acetaminophen, 1000 mg, plus oxycodone, 10 mg (NNT of 1.8 [1.6–2.2]); acetaminophen, 1000 mg, plus codeine, 60 mg (NNT of 2.2 [1.8–2.9]); ibuprofen, 400 mg, plus codeine, 60 mg (NNT of 2.2 [1.8–2.6]); and ibuprofen, 400 mg, plus oxycodone, 10 mg (NNT of 2.3 [2–2.8]). Caution is advised, however, when using opioid-based combinations, because they have been associated with significantly more adverse effects than placebo controls. This is contrary to non–opioid-based combinations that have shown to have significantly fewer such effects than placebo.
Combination drug therapy
As discussed previously, several combinations of analgesics (opioid-based and non–opioid-based) have been investigated in the management of acute dental pain. Studies have suggested that combination drug therapy improves analgesic efficacy, facilitates better absorption of medications, decreases likelihood of adverse effects, reduces cost of care, allows concurrent management of multiple symptoms, and improves patient adherence to the recommended pharmacologic plan. ,
There are multiple mechanisms that allow combination drug therapy to be superior to single-agent analgesic therapy. There is additive effect when 2 pharmacologically different analgesic agents are used in combination. The pain pathway is complex, with multiple pathways that are activated or inhibited from the point nociceptive signals are generated to the point where pain is processed and interpreted in the prefrontal cortex. Specific analgesics act on particular set of receptors that are spread across these pathways. By using 2 different pharmacologic analgesics, more than 1 type of pathway is targeted. This clinically translates as improved and more extensive analgesia than either agent used alone. Similarly, it has been postulated that when analgesics are used in combination, 1 drug alters the nociceptive sensitivity of the other medication. For example, NSAIDs alter the form of COX enzymes. This alteration provides greater sensitivity to acetaminophen, resulting in a synergistic analgesic response.
Lastly, pharmacogenetics plays a role in success of combination drug therapy. Genetic variations in sensitivity or metabolism of medications play a vital role in a patient experiencing better response to 1 medication or another. Genetic polymorphisms may result in a patient not having the specific enzymes required for metabolic activation of a prodrug. For example, approximately 8% to 10% of the population does not have enzymes required for metabolism of codeine to morphine. In combination analgesic therapy, however, there is a likelihood that at least 1 of the agents will result in pain relief.
One of the most effective and safest combinations in terms of incidence of adverse effects is the combination of acetaminophen plus ibuprofen. Acetaminophen, 1000 mg, with ibuprofen, 400 mg, has shown superior to ibuprofen, 400 mg, plus codeine, 25.6 mg; acetaminophen, 1000 mg, plus codeine, 30 mg; and acetaminophen or ibuprofen alone in providing relief in acute dental pain. In addition, a recent systematic review has suggested that acetaminophen plus ibuprofen, in both 1000 mg and 400 mg, respectively, and 500 mg and 200 mg, respectively, strengths, have the least NNTs, 1.5 (1.4–1.7) and 1.6 (1.5–1.8), respectively. , This review reported that both these combinations had statistically less incidence of adverse effects than placebo controls. Due to this, it is recommended as first-line pharmacotherapy for management of moderate or severe acute dental pain.
Role of preemptive analgesia
Preemptive analgesia is defined as a treatment modality that is initiated before a traumatic event, such as surgical incision or extraction, is introduced. The intention is to preempt the establishment of peripheral and central sensitization while leaving physiologic nociceptive mechanisms intact so that they can continue to function as an early warning system. Studies on preemptive analgesia suggest that it results in more extensive analgesia during the procedure, delays the time to first analgesic after intervention, reduces postprocedural consumption of analgesics, improves postsurgical swelling, and lessens medication-associated adverse effects. Multiple medications have been investigated as preemptive analgesics. Current literature suggests that acetaminophen, NSAIDs, gabapentinoids, opioids, and corticosteroids can be used as preemptive analgesics. ,
Preemptive analgesics are administered 1 hour to 3 hours before the time of procedure. The recommended dosages for preemptive analgesics are provided in Table 2 .
