#55044: Analgesics in Dentistry

Studies cited on the evaluation of analgesic efficacy, for the most part, use the third-molar extraction model of acute dental pain developed by Cooper and Beaver [5]. This model provides a snapshot of the levels of pain intensity over time with various available analgesics based on patients who have undergone third-molar extraction. Extraction of an impacted third molar is a model that has been recognized by the FDA as an accepted paradigm for evaluation of analgesic and anti-inflammatory therapies [6,7]. The extraction of third molars generally produces pain that is reproducible and consistent in severity. The model tests moderate-to-severe postoperative pain that usually occurs within the first three hours postoperatively and that may last for three to five days.

Initial studies of the analgesic efficacy of acetaminophen evaluated acetaminophen alone (1,000 mg) and an acetaminophen-caffeine combination (1,000 mg/100 mg) compared to placebo. The relative potency of the combination was significantly greater than either acetaminophen alone or placebo [8]. A systematic review of acetaminophen-caffeine (1,000 mg/130 mg) found the combination to be more effective than either acetaminophen alone (1,000 mg) or placebo after third-molar extraction [9]. The intent of adding caffeine to acetaminophen products is to improve analgesic effectiveness while reducing the total amount of analgesic present. One study has shown that the addition of caffeine 65 mg to acetaminophen 500 mg appeared to enhance the analgesic effectiveness of acetaminophen in treating post-extraction pain [10]. It is important to note that the analgesic adjuvant effects of caffeine have not been seriously investigated since this study was published. Clinical trials have suggested that caffeine in doses of more than 65 mg may be useful for enhancement of analgesia; however, doses that are either too low or too high may lead to no analgesic enhancement [11]. When evaluated alone in a post-third-molar extraction pain model, it was reported that caffeine 65 mg was no more effective than placebo [12]. A 2012 systematic review of 19 studies of common pain conditions in adults, including postoperative dental pain, found a small but statistically significant benefit with doses of 100 mg or greater of caffeine as an analgesic adjuvant [13]. A 2014 update to this review reported similar findings [14].

When used as a single agent for pain relief, acetaminophen is effective in relieving mild dental pain but appears to have limitations in reducing moderate-to-severe postoperative dental pain. For example, acetaminophen 1,000 mg has been shown to be more effective than placebo in reducing pain after extraction of third molars [15,16]. However, it is suggested that because of its ceiling-dose effect, acetaminophen is a limited analgesic against postoperative dental pain [17,18]. Limited analgesic effect has also been shown against postoperative pain resulting from other oral surgeries, including difficult extractions, alveolectomy, multiple extractions, apicoectomy, biopsy, and deep gingival curettage [17]. There is no question that acetaminophen provides better pain relief than placebo. A large meta-analysis examining the efficacy of acetaminophen 500 mg, 600–650 mg, and 975–1,000 mg as monotherapy showed it to be superior to placebo as a postoperative analgesic [18].

In terms of duration of pain relief after acetaminophen administration, peak effect appears to occur within one hour. In one study, acetaminophen 500 mg was superior to placebo for treatment of dental pain associated with third-molar extraction, although pain relief was brief and peaked at one hour [19]. In another study, acetaminophen 1,000 mg provided significant pain relief compared to placebo as determined by pain intensity and pain relief scores for up to four hours after oral surgery, and pain relief was maximal at one to two hours after administration [20].

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].

The demonstration that additive analgesia results from the combination of an over-the-counter NSAID and acetaminophen without an increase in side effects may provide an alternate strategy for increasing pain relief when an NSAID alone is inadequate. Novel analgesics containing both paracetamol (acetaminophen) and ibuprofen are available in the United Kingdom, but no over-the-counter marketed drug combination in the United States contains an NSAID and acetaminophen [24,25]. The proposed usual analgesic dose of ibuprofen is 200–400 mg (one to two 200 mg tablets) administered every four to six hours, not to exceed 2,400 mg over a 24-hour period [2,26]. Acetaminophen is administered in a range of 650–1,000 mg (two to three 325 mg tablets) every four to six hours, not to exceed 4,000 mg (4 grams) in 24 hours [26]. Thus, a combination of ibuprofen 400 mg with acetaminophen 650 mg may be administered every four to six hours without exceeding the maximum recommended doses for either drug. For more intense pain, ibuprofen 600 mg (three 200 mg tablets) plus acetaminophen 1,000 mg (three 325 mg tablets) may be administered every six hours without exceeding the maximum 24-hour dose of either drug [26].

Several studies have evaluated the analgesic effectiveness of ibuprofen plus acetaminophen following oral surgery. In one systematic review, the authors identified three studies that examined several dose combinations [27]. The three studies provided data from 508 participants for the comparison of ibuprofen/paracetamol combination (200 mg/500 mg) with placebo; 543 participants for the comparison of ibuprofen/paracetamol combination (400 mg/1,000 mg) with placebo; and 359 participants for the comparison of ibuprofen/paracetamol combination (400 mg/1,000 mg) with ibuprofen 400 mg alone. The proportion of participants achieving at least 50% maximum pain relief over six hours was 69% with ibuprofen 200 mg/paracetamol 500 mg combination; 73% with ibuprofen 400 mg/paracetamol 1,000 mg combination, and 7% with placebo. For the ibuprofen 400 mg alone group, the proportion was 52%.

In another systematic review, the authors found high-quality evidence that ibuprofen alone is superior to paracetamol for pain relief following third molar removal. Most of the evidence reviewed compared ibuprofen 400 mg with paracetamol 1,000 mg, but the authors found ibuprofen to be superior to paracetamol at doses of 200–512 mg and 600–1,000 mg respectively, based on pain relief measures and use of rescue medication data collected six hours postoperatively [28].

The aim of a third study was to define the analgesic dose-response relationship of different fixed dose combinations of paracetamol/ibuprofen following third molar extraction [29]. Patients 16 to 60 years of age with moderate-to-severe pain were randomized to receive one of the following: a two-tablet combination full dose (paracetamol 100 mg/ibuprofen 300 mg); one tablet combination half dose (paracetamol 500 mg/ibuprofen 150 mg); half a tablet combination quarter dose (paracetamol 250 mg/ibuprofen 75 mg); or placebo. The medications were administered every six hours for 24 hours and the primary outcome measure was the pain intensity over 24 hours. The authors found that all combination dose groups were superior to placebo [29].

On the assumption that a combination of acetaminophen and aspirin provides more effective pain relief than either agent alone, some over-the-counter products offer both analgesics in the same preparation, usually along with caffeine. Goody's Headache Powders, Excedrin Extra-Strength Tablets, Excedrin Migraine Tablets, and Vanquish Tablets are examples of some of these combination products. These products, in general, usually contain 250 mg of each agent along with 65 mg of caffeine [4]. Clinical studies are lacking in the evaluation of the pain relief properties of a combination of acetaminophen with aspirin compared to each individual agent against postoperative dental pain.

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].

One prospective study followed a case series of consecutive patients 12 years of age or older with acetaminophen dosage greater than 4 grams per 24 hours who were referred to a poison center [35]. Of 249 individuals, serum aspartate aminotransferase levels less than 50 IU/L were found in 126 patients, aspartate aminotransferase levels of 50–1,000 IU/L were present in 47 patients, and levels were greater than 1,000 IU/L in 47 patients. No one with aspartate aminotransferase levels less than 50 IU/L developed hepatotoxicity. This study concluded that injury caused by supratherapeutic ingestion of acetaminophen is apparent at presentation and related to the dose and duration. All the individuals who developed hepatotoxicity had aspartate aminotransferase levels greater than 50 IU/L [35].

A 2007 review of the literature found that drug-induced liver injury remains an important concern for many existing drugs, including acetaminophen [36]. When given in therapeutic doses over 14 days, acetaminophen produced significant asymptomatic elevations in alanine transferase among healthy volunteers, suggesting that subclinical injury may be more common than previously thought [36]. In the United States, acetaminophen is the most common cause of acute hepatic failure [30,34,37,38].

Two cyclooxygenase enzymes, COX-1 and COX-2, are known to produce prostaglandins responsible for pain and inflammation. Both of these enzymes are blocked by aspirin. They are also inhibited by the standard group of NSAIDs. The mechanism of how acetaminophen reduces pain and fever has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes [39,40]. A third distinct COX enzyme, identified as COX-3, has been isolated from the cerebral cortex and, in lesser amounts, other tissues [39,41]. This COX-3 enzyme is selectively inhibited by acetaminophen. It has been proposed that the COX-3 enzyme plays a role in central prostaglandin production, which in turn produces pain and fever. Its inhibition by acetaminophen would represent a primary central mechanism by which acetaminophen and possibly other types of analgesics can decrease pain and fever.

It has been suggested that although the COX-3 enzyme might have cyclooxygenase activity in dogs, and this activity might be inhibited by acetaminophen, its low expression levels in humans indicate unlikely clinical relevance [39,42]. In humans, COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity. Thus, it is improbable that COX-3 in humans plays any role in prostaglandin-mediated fever and pain. The actions of acetaminophen at the molecular level are still unclear [39,42,43].

A case-control study suggested that the combination of acetaminophen with warfarin (Coumadin) may cause enhanced anticoagulation [44]. For patients who reported taking the equivalent of at least four regular-strength (325 mg) tablets for longer than one week in combination with average therapeutic doses of warfarin, the odds of having an International Normalized Ratio (INR) greater than 6.0 were increased tenfold compared to those not taking acetaminophen. The risk decreased with lower intakes of acetaminophen, reaching a background level of risk at a dose of six or fewer tablets per week. The mechanism for this interaction is unknown [45,46,47]. In patients taking acetaminophen along with warfarin, the dose and duration of acetaminophen should be as low as possible, individualized, and monitored.

A study evaluated this acetaminophen-warfarin interaction [48]. It was shown that individuals receiving acetaminophen 2 grams daily had a significantly higher mean INR versus a matched placebo group at week 2 after taking the drugs. At weeks 1, 2, and 3, the acetaminophen 4 grams per day group had significantly higher mean INRs compared with those in the placebo group. These findings supported the existence of a clinically significant interaction between warfarin and daily use of acetaminophen 2–4 grams daily [45,47,49]. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 grams daily [2,45,47].

A review of 72 studies that compared ibuprofen and placebo found that ibuprofen at 200 mg and 400 mg produced a high level of pain relief in approximately 50% of participants who reported moderate-to-severe acute postoperative pain. Within six hours postoperatively, 48% of participants required remedication with 200 mg ibuprofen and 42% required remedication with 400 mg. Adverse events were uncommon and not reportedly different from placebo [51].

The analgesic effects of a new immediate-release/extended-release (IR/ER) (formulation A or B) 600-mg tablet preparation of ibuprofen were evaluated in two randomized, double-blind, placebo-controlled dental pain studies [52]. The participants were 16 to 40 years of age with moderate-to-severe pain following third molar extraction. The primary outcome measure was a 12-hour summed pain intensity difference. The first study included 196 participants who received either a single dose of ibuprofen 600 mg IR/ER (A or B), naproxen sodium 200 mg, or placebo. Pain scores at 12 hours were most improved with ibuprofen IR/ER A (16.87) and ibuprofen IR/ER B (17.34). The second study included 106 participants who received four doses of ibuprofen 600 mg IR/ER or placebo. Pain scores at 12 hours were significantly better with ibuprofen IR/ER compared with placebo [52]. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses.

The efficacy of ibuprofen compared to aspirin in dental pain has been well studied. Ibuprofen 400 mg (two nonprescription tablets) has been shown to be as effective as aspirin 600 mg or 900 mg daily in models of moderate pain, but superior to aspirin or acetaminophen in models of dental pain [53]. Anecdotal reports, however, have indicated that many patients seem to have better pain relief and inflammatory reduction with ibuprofen compared to aspirin [12].

Finally, it has been reported that monotherapy with ibuprofen is as or more efficacious than acetaminophen for the management of dental pain [54].

Ibuprofen is commercially available in a liquid form encapsulated within gelatin capsules under the brand name Advil Liqui-Gels. Each capsule contains 200 mg of liquid ibuprofen [4,50]. Absorption from the gastrointestinal tract into the bloodstream is faster with this preparation compared to ibuprofen tablets. The gelatin capsule breaks down immediately within the gastrointestinal tract with the quick release and absorption of the liquid ibuprofen contents. The tablet formulation takes longer to breakdown and dissolve prior to release of the ibuprofen for gastrointestinal tract uptake into the bloodstream.

A published study has compared the maximum approved over-the-counter dosing regimen (i.e., three 400 mg capsules every four to six hours) of Advil Liqui-Gels compared to a single dose (200 mg) of celecoxib or placebo in 174 patients with moderate or severe pain following surgical extraction of impacted third molars. Ibuprofen 400 mg every 6 hours provided superior efficacy to celecoxib 200 mg over a 12-hour time period following surgery. Onset of pain relief was 88 minutes faster for ibuprofen compared to celecoxib (median time: 46 minutes for ibuprofen and 135 minutes for celecoxib). In addition, more than 50% of the patients in the Advil Liqui-Gels group achieved meaningful relief by one hour compared with only 18% in the celecoxib group [55].

The pain-relieving efficacy of naproxen is similar to ibuprofen. An initial dose of naproxen 500 mg followed by 250 mg every six to eight hours is equivalent to ibuprofen 400 mg every four to six hours for mild-to-moderate dental pain. For the over-the-counter product, 200 mg naproxen (equivalent to 220 mg naproxen sodium) every 8 to 12 hours is equivalent to 200 mg of ibuprofen every six hours for minor pain [2].

As previous studies have established the rationale of achieving enhanced analgesia using a combination of an NSAID with acetaminophen, the combination of over-the-counter naproxen sodium and acetaminophen appears to have the potential for effective pain relief. Although there are no published studies evaluating the effectiveness of this combination, there is no reason why both of these agents could not be used to treat dental pain as long as the maximum daily doses of naproxen sodium and acetaminophen, as printed on the packaging, are not exceeded.

A published review has evaluated the cardioprotective actions of naproxen [56]. Naproxen inhibits thromboxane production by 95% and inhibits platelet aggregation by 88%. This suggests that naproxen may have a cardioprotective effect similar to aspirin. Three studies have presented convincing evidence that naproxen decreases the incidence of myocardial infarction compared to other NSAIDs and control subjects [57,58,59]. The average dose to achieve this effect was 275 mg every 8 to 12 hours.

Acetaminophen has been marketed by McNeil-PPC, Inc. as an eight-hour extended-release formulation containing 650 mg of acetaminophen in each gelatin-coated tablet. The product brand name is Tylenol 8 Hour. The gelatin-coated tablets are called gelcaps. The uses listed on the package label include the treatment of pain resulting from toothache and headache. The adult dose is two gelcaps every eight hours with water, with no more than six gelcaps to be taken within 24 hours [4,50].

This medication is supplied as an 8-ounce bottle containing a flavored liquid consisting of 500 mg acetaminophen in each 15 mL (tablespoon) [4].

NSAIDs have been shown over the years to be very effective in relieving pain and inflammation resulting from dental surgery, and a large body of literature and clinical reports have confirmed their pain-relieving effectiveness. They are considered the first-line standard treatment for pain relief in dentistry. Ibuprofen at 200 mg and 400 mg has been shown to be superior to placebo at providing pain relief over four to six hours postoperatively. Remedication within six hours was less frequent at doses of 400 mg [51]. Also, monotherapy with ibuprofen has been reported to be as or more efficacious than acetaminophen for the management of dental pain [54,62]. Ketoprofen 100 mg has been reported to have analgesic efficacy similar to that of acetaminophen 1,000 mg for pain after third-molar extraction [62,63]. The combination of ketoprofen 100 mg plus acetaminophen 1,000 mg has been shown to provide a more rapid onset of analgesia than either drug given alone in the management of dental pain [64]. Several studies have demonstrated the greater efficacy of diflunisal, flurbiprofen, ibuprofen, and ketorolac in reducing pain after dental surgery compared to acetaminophen 600 mg with codeine 60 mg and acetaminophen 650 mg with codeine 60 mg [65,66]. A listing of the NSAIDs useful for reducing dental pain and the usual suggested doses are summarized in Table 1.

All the brand name NSAIDs used in dentistry have a generic equivalent. Unless the prescriber indicates on the prescription to the pharmacist to dispense the brand name product, by law the pharmacy will dispense the generic equivalent. The FDA evaluates the efficacy and other standards of generic brands in comparison to the respective brand name product prior to approval to assure similar efficacy and similar incidence of side effects. The prescriber should feel confident that the generic product is equivalent in actions to the brand name product. In general, generic brands are priced at a lower cost to the consumer because the developmental costs were much lower than the costs of developing the initial brand name product.

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].

In addition, reports have shown that celecoxib does not generally affect platelet counts, prothrombin times (PTs), or partial thromboplastin time (PTT). Studies of the effect of celecoxib on the anticoagulant effect of warfarin found no alteration of anticoagulant effect, as determined by PT, in patients taking warfarin 2 mg and 5 mg daily. However, the manufacturer has issued a caution when using celecoxib with warfarin because those patients are at increased risk of bleeding complications [4,26].

Celecoxib has not been shown to alter the anticoagulant effects of warfarin. The manufacturer states, however, that bleeding complications may be increased with concomitant administration of these drugs [4]. The effects of celecoxib on the steady-state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers were investigated. Twenty-four adults taking 2–5 mg daily maintenance doses of racemic warfarin and stabilized to PTs of 1.2 to 1.7 times pretreatment PT values for three days were given celecoxib 200 mg twice daily or placebo twice daily for seven days. PT values were not significantly different in subjects receiving warfarin-celecoxib compared to warfarin-placebo. In addition, steady-state exposure of S-warfarin and R-warfarin (area under the curve [AUC] and maximum plasma concentrations [Cmax]) in subjects receiving celecoxib was within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo. This study concluded that concomitant administration of celecoxib had no significant effect on PT or steady-state pharmacokinetics of S-warfarin or R-warfarin in healthy volunteers [96].

A subsequent study investigated whether celecoxib potentiates the anticoagulant effect of warfarin, as measured by the INR. Fifteen patients who were receiving warfarin therapy and required analgesic treatment were evaluated to assess the effect on INR of celecoxib versus codeine (control treatment). During the first phase of the study, patients were randomly allocated to receive celecoxib 200 mg daily or codeine phosphate 7–15 mg three to four times daily for five weeks. During the second phase, patients stopped the first study medication and started the other study medication, with no drug-free interval between phases. Weekly INR testing was performed during the 10-week study period. Investigators found no significant difference in the mean INR values during each five-week treatment period when patients received either celecoxib or codeine. They concluded that treatment with celecoxib does not potentiate the INR when taken with warfarin and recommended that larger randomized trials be conducted to address the effects of co-administration of warfarin and celecoxib [97].

The COX-2 inhibitors have been reported to offer improved gastric tolerance as compared to the conventional, nonselective NSAIDs [74,98,99,100,101]. While patients, particularly young patients, may benefit from NSAIDs without the risk of serious adverse gastrointestinal events, patients with a previous history of serious gastrointestinal complications as well as the elderly (who could be at risk) require alternatives [102,103]. It is important to note, however, that there is an ongoing discussion about whether the slightly better gastrointestinal tolerability (which is lost if acetylsalicylic acid is co-administered) of the COX-2 inhibitors is offset by their elevated risks for cardiovascular events [2,104]. In addition, the higher costs for COX-2 inhibitors, when compared to NSAIDs, should be considered if a COX-2 inhibitor will be selected for certain patients with a high risk for gastrointestinal complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure also is advisable. Further controlled studies are needed to better define the therapeutic place of the COX-2 inhibitors [105].

The following interactions with celecoxib and other drugs are ranked according to significance. Of the interactions of greater significance, the lithium interaction with celecoxib is similar to the lithium interaction with the nonselective NSAIDs. All the interactions of less significance are similar to the nonselective NSAIDs.

In summary, the COX-2 inhibitor presently approved for use in treating pain of dental origin is celecoxib. Table 2 presents the significant information on celecoxib as reference for the dental health professional.

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].

Narcotic analgesics block pain perception in the cerebral cortex by binding to specific receptor molecules (opiate receptors) within neuronal membranes of synapses. This binding results in a decreased synaptic chemical transmission throughout the CNS, thus inhibiting the flow of pain sensations into the higher centers. Mu and kappa receptors are the two subtypes of the opiate receptor that narcotics bind to in order to cause analgesia. The narcotics are not anti-inflammatory in nature and do not inhibit cyclooxygenase or block the production of inflammatory factors, such as the prostaglandins [26].

These four narcotic analgesics are recommended only for limited acute dosing (i.e., three days or less). These agents should be given with caution to certain patients, such as the elderly or debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison disease, or prostatic hypertrophy or urethral stricture. Any of these agents may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient taking these drugs should be cautioned accordingly. Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, or other CNS depressants (including alcohol) concomitantly with these narcotic preparations may exhibit an additive CNS depression [4,26].

The use of monoamine oxidase (MAO) inhibitors or tricyclic antidepressants with narcotic preparations may increase the effect of either the antidepressant or the narcotic. The concurrent use of anticholinergics with opioids may produce paralytic ileus [4,26].

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 available hydrocodone oral products useful in dentistry are listed in Table 3. All the products are scheduled as C-II controlled substances, indicating that prescriptions may not be oral, telephone, email, or fax-transmission (except in specifically outlined emergency situations), and no refills may be authorized [111,112,113]. As of 2019, a new California law, AB149, requires prescribers of any schedule C-II controlled substance to obtain and use new tamper-resistant prescription forms ordered only from state-approved security printers [115,116]. An additional California law, AB2789, requires all prescribing healthcare practitioners to submit prescriptions electronically as of January 2022; however, paper prescription forms that conform with AB149 should be available in the case of technology or electrical failure [114]. All the formulations are combined with acetaminophen except for one containing ibuprofen. All products are available under the various listed brand names and are also available generically, except for Vicoprofen and Xodol. The pharmacist will dispense the generic equivalent, if available, to any brand name that is prescribed, unless the prescriber indicates not to substitute for the brand name.

The strength of hydrocodone in these products ranges from 5–10 mg. Acetaminophen strength ranges from 325–750 mg. Ibuprofen is available in a single-strength combination of 200 mg each. The varied strengths of hydrocodone and acetaminophen allow for prescribing options on the part of the clinician. Thus, the lower dose of hydrocodone, 5 mg, in combination with 500 mg acetaminophen can be prescribed to the patient who may be sensitive to the adverse effects of the narcotic. On the other end of the spectrum, a maximum strength of hydrocodone, 10 mg, is available in combination with 750 mg of acetaminophen. The combination of 5 mg hydrocodone and 500 mg acetaminophen is available in either tablet or capsule dose forms. A liquid dose form (elixir) is available for those adults who have difficulty swallowing tablets or capsules. Neither hydrocodone nor acetaminophen elicits anti-inflammatory responses. Anti-inflammatory effects may be achieved by prescribing the ibuprofen combination product, assuming, of course, that the patient is not taking warfarin-type oral anticoagulants. Ibuprofen may enhance the anticoagulant effects of warfarin-type drugs. Because of addiction liability of opiate analgesics, the use of hydrocodone should be limited to two to three days postoperatively for the treatment of dental pain. Nausea is the most common adverse effect seen after use in dental patients; sedation, dizziness, and constipation are collectively the second most common effects. Nausea caused by narcotic analgesics is centrally mediated, and the presence or absence of food will not affect the degree or incidence of nausea [26].

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

For the elixir dose form, the recommended dose is 1 tablespoon every four to six hours when necessary for pain. For the ibuprofen products, the recommended dose is one tablet every four to six hours as needed. The maximum dose of the ibuprofen products should not exceed five tablets in 24 hours [2,4].

The usual adult prescribing limits for the combination hydrocodone-acetaminophen products is up to 40 mg of hydrocodone and up to 4,000 mg of acetaminophen in a 24-hour period. The maximum dose of hydrocodone may be limited by the acetaminophen content of the specific product [26].

The available oxycodone analgesic combination oral products are listed in Table 4. All the products are scheduled as C-II controlled substance, indicating that oxycodone has a high potential for abuse and that all prescriptions must be written in ink or typewritten on approved forms and signed by the practitioner. Verbal prescriptions are not allowed under normal circumstances and may be given only in a genuine emergency. The oxycodone combination formulations all contain acetaminophen except for two products, one containing aspirin and one containing ibuprofen. Similar to hydrocodone, all products are available under the various listed brand names and available generically. The pharmacist will dispense the generic equivalent, if available, to any brand name that is prescribed, unless the prescriber indicates not to substitute for the brand name.

The strength of oxycodone in the combination products ranges from 2.5–10 mg. Acetaminophen strength ranges from 325–650 mg. Aspirin and ibuprofen are available in a single-strength combination. The varied strengths of oxycodone and acetaminophen allow for prescribing options on the part of the clinician. Thus, a low dose of oxycodone, 2.5 mg, in combination with 325 mg acetaminophen can be prescribed to the patient who may be sensitive to the adverse effects of the narcotic. On the other end of the spectrum, a high dose of oxycodone, 10 mg, may be given in combination with 650 mg of acetaminophen. The combination of 5 mg oxycodone and 500 mg acetaminophen is available in either tablet or capsule dose forms [4]. A liquid dose form (solution) is also available for those adults who have difficulty swallowing tablets or capsules. Oxycodone has a recognized addictive liability. It is recommended only for limited acute dosing (i.e., four days or less) [4,26]. Nausea is the most common adverse effect seen after use of oxycodone in dental patients, and virtually every patient will experience some degree of stomach upset after taking any dose of oxycodone. Sedation, dizziness, and constipation are also frequent complaints of patients taking oxycodone products. If the adverse effects outweigh the beneficial effects of pain reduction, then oxycodone products should be discontinued in favor of a non-narcotic agent. The nausea caused by oxycodone is centrally mediated, and the presence or absence of food will not affect the degree or incidence of nausea [4,26].

Oxycodone products are usually reserved for patients experiencing severe intensities of pain because of the high degree to which the adverse effects of nausea, sedation, and dizziness are experienced. Oxycodone is not ordinarily recommended for the management of moderate to moderately severe pain.

According to the manufacturer, the dosage of oxycodone combination products should be adjusted according to the severity of the pain and the response of the patient [2,4]. It may occasionally be necessary to exceed the usual dosage recommended in cases of more severe pain or in those patients who have become tolerant to the analgesic effects of opioids.

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

For the liquid dose form (5 mg oxycodone/325 mg acetaminophen/5 mL), the recommended dose is one teaspoonful every four to six hours when necessary for pain [2,4].

For the aspirin product, the recommended dose is one tablet every six hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams [2,4]. The total daily dose of acetaminophen from any product should not exceed 4 grams [2,4].

The first pain reliever containing oxycodone and ibuprofen within the same tablet, Combunox (manufactured by Forest Pharmaceuticals, Inc.), was approved by the FDA to treat acute pain. The brand-name product, Combunox, has been discontinued, but generic versions are available [117]. Combunox is formulated as oxycodone 5 mg with ibuprofen 400 mg in a film-coated tablet. It is indicated to treat acute, moderate-to-severe pain. The dosage to treat pain in adults is one tablet every 6 hours as needed with a maximum of four tablets over a 24-hour period. Combunox is indicated for short-term (i.e., no more than seven days) treatment for acute pain. It is scheduled as C-II under the DEA classification of controlled substances [4,50].

This combination provides additional options in pain relief and pain control after dental surgery [117]. The two components within this formulation, oxycodone and ibuprofen, both have proven track records and strong evidence as an effective narcotic analgesic (oxycodone) and an effective non-narcotic/anti-inflammatory agent (ibuprofen) in treating postoperative dental pain. Similar type products include Vicoprofen (containing hydrocodone bitartrate 7.5 mg and ibuprofen 200 mg), Reprexain (containing hydrocodone bitartrate 10 mg and 200 mg ibuprofen), and Ibudone (containing hydrocodone bitartrate 10 mg and 200 mg ibuprofen) [4].

There are two studies that have been published comparing Combunox to oxycodone alone, ibuprofen alone, oxycodone with acetaminophen, hydrocodone with acetaminophen, and placebo in dental pain models. The first study compared Combunox to oxycodone 5 mg alone, ibuprofen 400 mg alone, and placebo [118]. Subjects underwent third-molar extraction (two or more ipsilateral partially or completely bony impacted third molars completely removed). To qualify for one of the drugs after surgery, subjects had to have a pain intensity score of over 50 mm on a 100 mm visual analog scale (VAS) and a moderate or severe pain-intensity rating within five hours after surgery using a scale following the statement: "My pain at this time is: 0 = none, 1 = slight, 2 = moderate, 3 = severe."

A single dose of each was evaluated in terms of analgesic efficacy, time to onset of pain relief, and a global score of treatment effectiveness. Analgesic efficacy was measured as both total pain relief through six hours derived from the pain relief scores (defined as the area under the observed pain relief-time curve from zero to six hours, with pain relief = 0 at time zero; range: 0 to 24), and the sum of pain intensity difference over six hours derived from the pain intensity difference from baseline pain intensity and defined as the area under the observed pain intensity difference-time curve from zero to six hours. The incidences of nausea, vomiting, and dizziness were also observed for each group. The authors of this study concluded that a single dose of Combunox was fast-acting, effective, and well-tolerated in subjects with moderate-to-severe pain after dental surgery (Table 5).

The second study compared Combunox to oxycodone 5 mg/acetaminophen 325 mg (Percocet), hydrocodone 7.5 mg/acetaminophen 500 mg (Lortab), and placebo [119]. Subjects underwent third-molar extraction. Qualifying conditions were similar as the first study. The drugs were evaluated in terms of analgesic efficacy, time to onset of pain relief, and a global score of treatment effectiveness, as described. Each treatment was given as a single dose. The authors of the second study concluded that Combunox provided significantly better analgesia in patients with moderate-to-severe pain after third-molar extraction compared with the other opioid/nonopioid combination drugs tested and was associated with fewer adverse events.

Given that narcotics have a history of causing nausea, vomiting, and dizziness, it was of interest to compare the differences of these effects observed in the various treatments. In the first study, the protocol did not allow for statistical comparisons. In the second study, the incidences of nausea and vomiting observed after Combunox were significantly lower than the two other active treatments.

A more recent systematic review assessed the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus oxycodone for moderate-to-severe postoperative pain [120]. Studies that the authors included provided data comparing the combination: ibuprofen 400 mg/oxycodone 5 mg with placebo (603 participants); ibuprofen 400 mg/oxycodone 5 mg with ibuprofen 400 mg alone (717 participants); and ibuprofen 400 mg/oxycodone 5 mg with oxycodone 5 mg alone (471 participants). Researchers found that 60% of participants given combination ibuprofen 400 mg/oxycodone 5 mg achieved at least 50% pain relief compared with 50% with ibuprofen 400 mg alone, 23% with oxycodone 5 mg alone, 17% with placebo [120]. The prevalence of adverse events was the same for combination ibuprofen 400mg/oxycodone 5 mg, placebo, and ibuprofen 400 mg alone (25%) but slightly higher (35%) with oxycodone 5 mg alone [120].

OxyContin is a long-acting formulation of oxycodone used for moderate-to-severe operative pain. It is most useful when extended use is required [4,50].

Codeine is available alone and in combination with acetaminophen. A codeine/aspirin combination was previously available but has been discontinued [26]. Codeine alone is scheduled as a C-II controlled substance, and a combination of codeine with acetaminophen is scheduled as a C-III controlled substance [26]. Codeine alone is supplied generically as tablets (as the sulfate salt) in 15 mg, 30 mg, and 60 mg strengths; as tablets (as the phosphate salt) in 15 mg, 30 mg, and 60 mg strengths; and as an oral solution at 30 mg/5 mL concentration. In dental practice, codeine alone is not recommended as an analgesic agent because of moderate efficacy along with a relatively high incidence and severity of nausea, sedation, dizziness, and constipation. In addition, codeine alone has some worrisome narcotic addiction liability. If codeine is desired as a dental analgesic, it should be used in combination with acetaminophen [4,26].

The available codeine combination oral products are listed in Table 6. Codeine, when combined with acetaminophen, may be given at a lower dose than that of codeine alone to achieve similar efficacy with less side effects. In theory, the lower codeine dose should result in less severe nausea and sedation compared to the degree of nausea and sedation seen with codeine alone. The optimal dose of codeine in combination with acetaminophen in most patients seems to be 30 mg every four to six hours as needed. Some patients may require up to 60 mg codeine every four to six hours. In any case, no more than 360 mg of codeine should ever be given within a 24-hour period [26].

Meperidine (Demerol) is not indicated as a first-choice narcotic analgesic for dental pain due to its abuse and addictive liabilities. All meperidine preparations fall under DEA schedule C-II, requiring a written prescription in ink and the signature of the prescriber. Meperidine is recommended to be used in codeine-allergic patients when a narcotic analgesic is indicated [26]. In this regard, meperidine has developed a niche in pain management and should be kept under consideration as an optional narcotic analgesic. It should not be used as the narcotic drug of first choice. Additionally, it is important to note that the American Pain Society and the Institute for Safe Medication Practices do not recommend the use of meperidine as an analgesic [26].

Other narcotic agents, such as hydrocodone and oxycodone, have a similar chemical makeup to codeine, and cross allergy between narcotics may exist. Meperidine is chemically dissimilar to codeine. Meperidine is not an anti-inflammatory agent. Also, it is not available in combination with acetaminophen, aspirin, or other NSAIDs. Meperidine preparations are listed in Table 7. It is supplied as meperidine only in tablet and oral liquid form. Meperidine has a proven and well-recognized efficacy against moderate-to-severe pain. However, the unwanted effects of dizziness, nausea, sedation, hypotension, weakness, nervousness, and confusion, which often occur, may outweigh any gain in pain management.

Meperidine is recognized as an alternate oral narcotic in patients allergic to codeine in treatment of moderate or moderate-severe pain. Dose for adults is 50–150 mg every two to four hours as needed for pain. Dose for children is 1–1.5 mg/kg/dose every three to four hours as needed for pain [26].

Meperidine is unique from the other narcotics in that it forms a compound via hepatic metabolism known as normeperidine, an active metabolite and CNS stimulant. In patients with seizure disorders, normeperidine may precipitate twitches, tremors, or seizures. Therefore, caution is warranted in the use of meperidine in patients with a history of seizure disorders [26].

The number of drugs that have the potential to interact with narcotic analgesics is much fewer than the number with the potential to interact with the NSAIDs. In general, because all narcotics can produce sedation, other sedative drugs and alcohol would have the potential to enhance narcotic-induced sedation.

Tramadol (Ultram) was approved by the FDA in 1995. It has been used in more than 39 million patients in 39 countries since 1977 [123]. As stated, tramadol is included in the 2016 FDA safety warning and label change requirement [109]. It is scheduled IV, meaning it has a slight abuse potential.

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].

Chemically, tramadol is related vaguely to codeine and has a weak action at opiate receptors. Thus, tramadol is not a controlled substance and does not seem to be addictive [26]. In the clinical literature, tramadol is referred to as an atypical opioid analgesic. It is converted to the M1 active metabolite in the liver. This metabolite has a better affinity for the opiate receptor and contributes to the analgesic actions of the parent tramadol. The narcotic antagonist naloxone partially blocks the analgesic effects of tramadol, which is blocked almost totally by a monoaminergic antagonist yohimbine, thus confirming the dual mechanism of analgesic action [4,125].

In 2001, the FDA approved a tablet formulation of the combination tramadol and acetaminophen under the brand name Ultracet [4]. Each tablet contains tramadol hydrochloride 37.5 mg and acetaminophen 325 mg and is indicated for the short-term (i.e., five days or less) management of acute pain [4]. Because it contains tramadol, Ultracet is considered a controlled substance (C-IV). Its mechanism of analgesic action is based on the tramadol component, inhibition of the re-uptake of norepinephrine and serotonin, which modifies the ascending pain pathways. It also binds to mu opiate receptors within the CNS to cause inhibition of ascending pain pathways, thus altering the perception and response to pain. Based on the acetaminophen component, it inhibits the synthesis of prostaglandins in the CNS and peripherally blocks pain impulse generation; it produces antipyresis from inhibition of the hypothalamic heat-regulating center [4,26]. The usual dose to treat acute pain, including dental pain, is two tablets every four to six hours as needed for pain relief, with a maximum of eight tablets daily. Treatment with Ultracet should not exceed five days [26].

The efficacy of Ultracet against dental pain has been reported in the literature [129]. Three centers conducted a randomized, double-blind, parallel group, active controlled, single-dose trial with a placebo control. Twelve hundred patients were enrolled, and 400 were randomized equally at each of three sites with five treatment groups per site. Active drugs were Ultracet (tramadol 37.5 mg; acetaminophen 325 mg), tramadol alone (37.5 mg), acetaminophen alone (325 mg), and ibuprofen (200 mg). The pain model was evaluation of pain relief and pain intensity following extraction of third molars. The results showed that all treatments were superior to placebo. Ultracet was superior to tramadol alone and acetaminophen alone with respect to pain relief after eight hours and superior in overall changes in pain intensity. Onset of pain relief was 17 minutes for Ultracet compared to 51 minutes for tramadol alone, 18 minutes for acetaminophen alone, and 34 minutes for ibuprofen. Median time for supplemental analgesia in the Ultracet group was longer than with the individual tramadol and acetaminophen and comparable with that of ibuprofen. Adverse effects were transient, mild-to-moderate in severity, and comparable in incidence between Ultracet and tramadol alone. The adverse effects included nausea, vomiting, and dizziness. The study concluded that Ultracet was a rapidly acting, long-duration analgesic that was effective and well-tolerated for the treatment of acute pain [129].

A randomized, triple-blind clinical trial was conducted to evaluate the analgesic efficacy of ketorolac alone versus its combination with tramadol/acetaminophen (Ultracet) for pain control after mandibular third molar surgery [132]. A total of 52 patients were divided into two groups: the first group received ketorolac 10 mg plus tramadol 37.5 mg/acetaminophen 325 mg; the second group received ketorolac 10 mg plus placebo. Treatment was administered one hour prior to surgery and repeated four times per day for 48 hours. Comparisons of pain intensity between the two groups showed significant differences at nine hours, with a lower level of pain intensity in group one. Adverse effects were also higher in group one [132]. Both ketorolac alone and the combination of ketorolac plus tramadol/acetaminophen showed relatively similar pain control [132].

The packet label states that seizures may occur when Ultracet is taken at recommended doses. Also, risk of seizures is increased in patients receiving carbamazepine, tricyclic antidepressants, SSRIs, MAO inhibitors, and amphetamines [4]. Carbamazepine decreases the half-life of tramadol by 33% to 50%. Carbamazepine and hydantoin anticonvulsants may increase the hepatotoxic potential of acetaminophen [26].

Ultracet is contraindicated in opioid-dependent patients. It is also contraindicated in patients with hepatic dysfunction. The drug should not be given in combination with any of the traditional narcotics [26].

Although a niche has yet to be achieved for Ultracet in dental practice, it would seem to be useful in those situations where NSAIDs are not indicated. The patient with a history of gastric ulcers may benefit from Ultracet rather than risking gastric effects with an NSAID. Also, there are indications that NSAIDs should not be given to patients taking certain platelet aggregation inhibitors, such as clopidogrel (Plavix) [4,133]. Ultracet may be a good alternative in these situations.

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].

A multicenter, eight-week trial of 229 subjects from sixteen outpatient clinical centers was conducted to evaluate gabapentin for the treatment of postherpetic neuralgia [136]. The objective of this early study was to determine the efficacy and safety of gabapentin in reducing postherpetic neuralgia pain. The 229 subjects were randomized with approximately half receiving gabapentin and the other half receiving a placebo. The primary measure of efficacy was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. The dosing consisted of following an initial dose of 300 mg daily, increased over the next four weeks in a step-up manner to 900 mg, 1,800 mg, 2,400 mg, and 3,600 mg/day divided in three doses. Treatment was then maintained for another four weeks at the maximum tolerated dose. If any dose was intolerable, the dose was decreased by one level. Of 113 subjects, 83.3% received at least 2,400 mg/day and 65.0% received 3,600 mg/day.

One hundred thirteen subjects received gabapentin, and 89 completed the study; 116 received placebo, and 95 completed the study. Subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects who received placebo. Also, changes in sleep interference showed improvement with gabapentin. Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the two groups. The gabapentin group had 15 withdrawals, and the placebo group had 11 withdrawals. The investigators concluded that gabapentin was effective in the treatment of pain and sleep interference associated with postherpetic neuralgia [136].

A study published in 2022 involving 3,357 patients with dental extraction indicates that a combination of non-opioid pain medication and gabapentin is as effective in controlling dental pain as opioid combinations. Prescription data found that nearly 35% of patients in the study received an opioid combination for dental pain in 2012; in 2022, no patients received opioids, 49.4% received acetaminophen/ibuprofen, and 13.1% received gabapentin multimodal analgesia. Researchers concluded that gabapentin is a safe and effective alternative to reduce opioid use in dental extractions [131].

There have been other reports on the effectiveness of gabapentin in treating neuropathic pain [137,138,139,140]. In addition, gabapentin seems to have a favorable safety profile and a lack of drug interactions compared to other pharmacologic agents used for the treatment of neuropathic pain [139,140]. Gralise, a once-daily extended-release formulation of gabapentin, has been shown to provide comparable drug exposure with an identical daily dose of the immediate-release formulation when administered three dimes daily. Patients given Gralise 1,800 mg daily showed a significant reduction in average daily pain intensity scores, reduced interference in sleep caused by pain, and a greater reported improvement in patient-reported impression of change [141]. Results of one systematic review and meta-analysis indicate that increasing the dose of gabapentin to twice daily results in no significant differences in efficacy or safety but an increased risk of adverse events [142]. Gralise should be titrated to an 1,800-mg dose taken orally once daily with the evening meal. It is not interchangeable with other gabapentin products due to differing pharmacokinetic profiles that affect the frequency of administration [4].

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].

The dosing in adults for diabetes-associated neuropathic pain is initially 150 mg/day in divided doses (50 mg three times/day); this may be increased within one week based on tolerability and effect. The maximum dose is 300 mg/day. Dosages of up to 600 mg/day were evaluated with no significant additional benefit and an increase in adverse effects. For postherpetic neuralgia, the initial dose is 150 mg/day in divided doses (75 mg two times/day or 50 mg three times/day), which may be increased to 300 mg/day within one week based on tolerability and effect. Further titration (to 600 mg/day) after two to four weeks may be considered in patients who do not experience sufficient relief of pain, provided they are able to tolerate pregabalin. The maximum dose for postherpetic neuralgia is 600 mg/day [26].

Adverse effects reported in more than 10% of users are [26]: