Acetaminophen was first used in medicine in 1893; however, it has gained popularity only since 1949, after it was discovered to be the active metabolite of the pain reliever phenacetin. Indications for use, as stated on the package, are temporary relief of pain from headache, colds, flu, muscle aches, backache, toothache, menstrual cramps, minor arthritic pain, and reduction of fever. The adult dosage is 325–1,000 mg three to four times daily, not to exceed 4 grams over a 24-hour period [2]. Acetaminophen is considered free of any side effects at these doses [3]. There are several warnings of use of acetaminophen imprinted on the package, including not to take the medication for more than 10 days, or for fever no more than 3 days, unless directed by a physician. Patients who are pregnant or nursing should seek the advice of a health professional before using the product, and if individuals consume three or more alcoholic drinks every day, a physician should be consulted before acetaminophen or other pain relievers/fever reducers are taken [4].

The rationale for combining acetaminophen with an NSAID has been described in the literature. Theoretically, this approach can lead to greater efficacy and fewer adverse events [21]. A review of randomized controlled trials that compared combinations of acetaminophen with various NSAIDs (i.e., ibuprofen, diclofenac, ketoprofen, ketorolac, aspirin, tenoxicam, rofecoxib) found that the combination of acetaminophen and an NSAID was more effective than either acetaminophen or NSAID alone in 85% and 64% of relevant studies, respectively [22]. Using this idea of an NSAID/acetaminophen combination, it has been suggested that the combination of acetaminophen and ibuprofen should be a useful analgesic regimen against dental pain [23].

Self-medication with acetaminophen carries the risk of taking large quantities over a long period of time. The population and the dental profession should be aware that doses of greater than 4 grams daily for several weeks may produce severe, often fatal liver damage [2]. Additionally, toxicity has been associated with a single acute ingestion of 7–10 grams in adults [30]. Acetaminophen hepatotoxicity is potentiated by chronic alcohol consumption [2,31]. One report described 67 patients (all regular users of alcohol) who developed hepatic injury after ingestion of acetaminophen at therapeutic doses [32]. In 1998, the FDA began requiring warning labels on acetaminophen products based on evidence that thousands of Americans may mistakenly take toxic doses that could harm their livers [31,33]. An FDA review found more than 56,000 emergency room visits a year due to acetaminophen overdoses, with about one-fourth of them unintentional. Chronic and unintentional overdoses account for more than 50% of cases of acetaminophen-related acute liver failure. Labeling of over-the-counter acetaminophen products warns not to use the medication if more than three alcoholic drinks have been or will be consumed because the combination may harm the liver [4,31,34].

Ibuprofen was originally approved for prescription status in 1974 as the brand name Motrin. In 1984, the FDA approved it for sale without a prescription with a lower daily recommended dosage compared to the prescription product [50]. The dosing instructions imprinted on the package are for adults to take one tablet (200 mg) every four to six hours while symptoms persist. Also imprinted on the package is the statement that if pain or fever does not respond to one tablet, two tablets may be used, but that use should not exceed six tablets in 24 hours unless directed by a physician [4]. It is interesting to note that the recommended dose of prescription ibuprofen to treat mild-to-moderate dental pain is 200–400 mg every four to six hours [26].

In a statement released in 2006, the FDA notified consumers and healthcare professionals that the administration of ibuprofen for pain relief to patients taking aspirin for cardioprotection may interfere with aspirin's cardiovascular benefits. The FDA stated that ibuprofen could interfere with the antiplatelet effect of low-dose aspirin (i.e., 81 mg daily). This could result in diminished effectiveness of aspirin as used for cardioprotection and stroke prevention [78]. Although ibuprofen and aspirin may be taken together, the FDA has recommended that consumers talk with their healthcare providers for additional information [2]. In situations in which these drugs could be used concomitantly, the FDA has provided the following recommendations [26,78,79,80,81]:

A second product combines ibuprofen and the narcotic oxycodone under the brand name Combunox. This product contains 400 mg ibuprofen and 5 mg oxycodone. Like Vicoprofen, Combunox is approved by the FDA for the short-term (i.e., less than seven days) treatment of moderate-to-severe acute dental pain. One tablet should be taken every six hours as needed; the maximum dose is four tablets in 24 hours. Combunox should not be taken for longer than seven days [26].

Studies involving the COX-2 inhibitors, such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have indicated an increased risk of heart attack and stroke associated with long-term use of some of the drugs in this group. Specifically, Vioxx was voluntarily withdrawn from the market by the manufacturer in late 2004.

Bextra was taken off the market in April 2005, at the recommendation of the FDA. The FDA cited a risk of serious skin reactions as a major cause for concern in addition to an increased risk of heart attack and stroke.

Celecoxib, a COX-2 inhibitor, was approved by the FDA for two new indications: management of arthritis and acute pain in adults and treatment of primary dysmenorrhea [2]. The FDA approval was based on acute analgesic models of post-oral surgery pain, post-orthopedic surgery pain, and primary dysmenorrhea. The recommended dose for both indications is 400 mg initially, followed by an additional 200 mg dose on the first day if needed. Thereafter, 200 mg twice daily is recommended as needed [4,26]. These newer indications are in addition to the previous indications for the relief of the symptoms of osteoarthritis and rheumatoid arthritis in adults. Celecoxib is supplied as the brand name, Celebrex, in 50 mg capsules (opaque white encircled by two red bands), 100 mg capsules (opaque white encircled by two blue bands), 200 mg capsules (opaque white encircled by two gold bands), and 400 mg capsules (opaque white encircled by two green bands) [2,4]. The package label states that the adverse events caused by celecoxib when used to manage acute pain were similar to those in arthritis studies [4].

Celecoxib is contraindicated in patients with a history of allergy to sulfa drugs. Celecoxib is a sulfonamide derivative [4].

The nonselective NSAIDs, such as ibuprofen, are known to reversibly decrease platelet aggregation through mechanisms that differ from those of aspirin. According to the manufacturer, celecoxib at a single dose up to 800 mg and multiple doses of 600 mg twice daily had no effect on platelet aggregation or bleeding time [4,26]. Comparative NSAIDs (i.e., naproxen 500 mg twice daily, ibuprofen 800 mg three times daily, or diclofenac 75 mg twice daily) significantly reduced platelet aggregation and prolonged bleeding times. Thus, celecoxib does not appear to inhibit platelet aggregation at recommended doses [4].

Hydrocodone and oxycodone are semisynthetic opioids with multiple actions qualitatively similar to those of morphine. Codeine is an opioid that occurs naturally as a component of the poppy plant, along with morphine, and may be recovered as such from the opium extract of the plant. Codeine has actions similar to morphine and may also be synthesized in the laboratory. All three opiates are chemically very similar to morphine. Meperidine is chemically dissimilar to morphine and is a synthetic compound having similarities of opiate receptor binding and analgesic effect. Hydrocodone, oxycodone, codeine, and meperidine may all produce drug dependence of the morphine type and have the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration, and all of these agents are subject to the Federal Controlled Substances Act [2,4]. As stated, these agents are the subject of the FDA safety warning and label change requirement [109]. Codeine combination products are controlled substances within the Drug Enforcement Administration (DEA) schedule III (C-III), and hydrocodone combination products, oxycodone, and meperidine are controlled substances within DEA schedule II (C-II) [26,110,111].

The most frequently observed adverse reactions with these drugs include lightheadedness, dizziness, sedation, nausea, and vomiting. These effects are more prominent in ambulatory than in nonambulatory patients. Some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include euphoria, dysphoria, constipation, skin rash, and pruritus. At higher doses, any of these agents can depress medullary respiratory centers resulting in decreased rate and depth of respirations [4].

Hydrocodone, oxycodone, and codeine are available in combinations with acetaminophen. There is a variety of strengths of each combination product available to the prescriber, providing numerous pharmacologic options for pain reduction. Some preparations also contain aspirin and other ingredients. Oxycodone and codeine are also available alone. Hydrocodone is only available as a combination product. Hydrocodone and oxycodone are available in combination with ibuprofen [26].

The following are the usual adult doses of the hydrocodone oral products [4]:

Tramadol represents a unique class of analgesics. To reduce pain, it acts on opiate-mediated systems and monoaminergic pain-inhibitory pathways. This latter effect predominates over its opiate actions. Monoaminergic neural pathways originate in the medullary regions of the brain and descend the spinal cord to modulate and attenuate ascending pain tracts from the periphery and the dorsal horn of the spinal cord. These pathways use monoaminergic transmitters (serotonin and norepinephrine), which reduce or inhibit propagated pain impulses within ascending tracts. Tramadol blocks neuronal re-uptake of serotonin and norepinephrine to permit excesses of these transmitters. Pain reduction by tramadol through enhancement of serotonin and norepinephrine is consistent with the activity of tricyclic antidepressants in reducing chronic pain [2,4,124].

The most common side effects of tramadol (1% to 10% incidence) are dizziness, constipation, and sleep disorder [4,26]. The manufacturer emphasizes that these effects may include symptoms of underlying disease or side effects of other medications used concomitantly. These incidence rates of adverse reactions to tramadol were the same for the two active control-group medications: acetaminophen/codeine (300/30 mg) and aspirin/codeine (325/30 mg) [50]. There also were no significant differences in side effects between the two submucosal groups [130].

Neurontin, which is the brand name for gabapentin, is a unique antiepileptic agent approved for use as an add-on treatment for partial epileptic seizures. This GABA-mimetic compound also has been shown to have effect in the treatment of chronic pain syndromes, particularly neuropathic pain [134]. In 2002, the FDA issued approval to Pfizer to allow marketing of Neurontin for the management of postherpetic neuralgia, or pain in the area affected by herpes zoster after the disease has been treated [135]. The suggested dose from the manufacturer for adults older than 18 years of age is to be titrated to a maximum dose of 1,800 mg per day according to the following schedule: 300 mg once a day on day 1; 300 mg twice a day on day 2; and 300 mg three times a day on day 3. Thereafter, the dose may be increased using increments of 300 mg per day given in three divided doses. Neurontin is supplied in capsules containing 100 mg, 300 mg, or 400 mg, or in tablets containing 600 mg or 800 mg. It is also available as an oral solution containing 250 mg/5 mL of gabapentin [4,26].

Pregabalin (Lyrica) is a newer drug within the same family as gabapentin. It gained FDA approval for the management of pain associated with diabetic peripheral neuropathy, management of postherpetic neuralgia, and adjunctive therapy for partial-onset seizure disorder in adults. Pregabalin's mechanism of action is an ability to bind to the alpha2-delta subunit of voltage-gated calcium channels within the CNS, inhibiting excitatory neurotransmitter release. Although structurally related to GABA, it does not bind to GABA or benzodiazepine receptors. It exerts antinociceptive and anticonvulsant activity. It decreases the symptoms of painful peripheral neuropathies and, as adjunctive therapy in partial seizures, decreases the frequency of seizures [26].