55045 • Analgesics in Dentistry

Table of Contents

55045 • Analgesics in Dentistry

How to Receive Credit

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. ACETAMINOPHEN

EFFICACY STUDIES IN DENTAL PAIN

ACETAMINOPHEN AS MONOTHERAPY

ADDITIVE ANALGESIA: ACETAMINOPHEN/NSAID COMBINATIONS

ADDITIVE ANALGESIA: ACETAMINOPHEN/ASPIRIN COMBINATION

ACETAMINOPHEN HEPATOTOXICITY

IS COX-3 ENZYME INHIBITION THE MECHANISM OF ACETAMINOPHEN?

REPORTS ON THE ACETAMINOPHEN/WARFARIN INTERACTION

3. NONPRESCRIPTION IBUPROFEN PRODUCTS

EFFICACY STUDIES IN DENTAL PAIN

ADVIL LIQUI-GELS COMPARED TO CELECOXIB IN DENTAL PAIN

4. NONPRESCRIPTION NAPROXEN SODIUM

EFFICACY IN DENTAL PAIN

COMBINATION WITH ACETAMINOPHEN

NAPROXEN IS CARDIOPROTECTIVE AND SIMILAR TO ASPIRIN

5. OTHER NONPRESCRIPTION PRODUCTS FOR DENTAL PAIN

ACETAMINOPHEN EXTENDED-RELEASE CAPSULES

EXTRA-STRENGTH ACETAMINOPHEN ADULT RAPID BURST CHERRY

6. NSAIDs: NONSELECTIVE COX-1 AND COX-2 INHIBITORS

EFFICACY STUDIES OF NSAIDs IN RELIEVING DENTAL PAIN

CARDIOVASCULAR EFFECTS OF NONSELECTIVE NSAIDs

7. IBUPROFEN/OPIOID COMBINATIONS

8. DRUG INTERACTIONS WITH NSAIDs

INTERACTIONS OF GREATER SIGNIFICANCE

INTERACTIONS OF LESSER SIGNIFICANCE

9. COX-2 INHIBITORS

CELECOXIB (CELEBREX): EFFICACY IN DENTAL PAIN

CARDIOVASCULAR EFFECTS OF CELECOXIB

EFFECTS ON THE GASTROINTESTINAL TRACT

DRUG INTERACTIONS WITH CELECOXIB

SUMMARY OF CELECOXIB

10. OPIOID ANALGESICS FOR DENTAL PAIN

GENERAL INFORMATION

HYDROCODONE PRODUCTS

OXYCODONE PRODUCTS

CODEINE PRODUCTS

MEPERIDINE PRODUCTS

DRUG INTERACTIONS

11. NONTRADITIONAL ANALGESICS

TRAMADOL (ULTRAM)

TRAMADOL AND ACETAMINOPHEN (ULTRACET)

GABAPENTIN (NEURONTIN)

PREGABALIN (LYRICA)

12. CONCLUSION

Works Cited

55045 • Analgesics in Dentistry

Richard L. Wynn, BSPharm, PhD

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

There are a myriad of analgesic products sold over-the-counter in drug stores and supermarkets as nonprescription pain relievers. People experiencing dental pain are likely to self-medicate with these nonprescription pain relievers before seeing the dentist. In order for a drug product to achieve nonprescription status, the U.S. Food and Drug Administration (FDA) requires it to be safe and effective. The nonsteroidal anti-inflammatory drugs (NSAIDs) that were originally approved only as prescription drugs and are now also sold over-the-counter include ibuprofen and naproxen sodium. These two have joined aspirin, which has always had a status of over-the-counter availability. Acetaminophen, ibuprofen and naproxen sodium have established a niche over the years as over-the-counter products for the relief of dental pain. The latest information on their use and effectiveness is included in this course.

55045 • Analgesics in Dentistry

Education Category. Pharmacology

Release Date. 10/01/2025

Expiration Date. 09/30/2028

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/3201 in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

Course Overview

There are a myriad of analgesic products sold over-the-counter in drug stores and supermarkets as nonprescription pain relievers. People experiencing dental pain are likely to self-medicate with these nonprescription pain relievers before seeing the dentist. In order for a drug product to achieve nonprescription status, the U.S. Food and Drug Administration (FDA) requires it to be safe and effective. The nonsteroidal anti-inflammatory drugs (NSAIDs) that were originally approved only as prescription drugs and are now also sold over-the-counter include ibuprofen and naproxen sodium. These two have joined aspirin, which has always had a status of over-the-counter availability. Acetaminophen, ibuprofen and naproxen sodium have established a niche over the years as over-the-counter products for the relief of dental pain. The latest information on their use and effectiveness is included in this course.

Audience

This course is designed for all dental professionals.

Accreditations & Approvals

NetCE Nationally Approved PACE Program Provider for FAGD/MAGD credit. Approval does not imply acceptance by any regulatory authority or AGD endorsement. 10/1/2021 to 9/30/2027 Provider ID #217994. NetCE is an ADA CERP Recognized Provider. ADA CERP is a service of the American Dental Association to assist dental professionals in identifying quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses or instructors, nor does it imply acceptance of credit hours by boards of dentistry. Concerns or complaints about a CE provider may be directed to the provider or to ADA CERP at www.ada.org/cerp. NetCE is approved as a provider of continuing education by the Florida Board of Dentistry, Provider #50-2405. NetCE is a Registered Provider with the Dental Board of California. Provider Number RP3841. Completion of this course does not constitute authorization for the attendee to perform any services that he or she is not legally authorized to perform based on his or her license or permit type. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this activity for 5 continuing education credits. AGD Subject Code 200. This course meets the Dental Board of California's requirements for 5 unit(s) of continuing education. Dental Board of California course #05-3841-25481. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program.

Course Objective

The purpose of this course is to describe new reports and new information on analgesics for the dental professional to use in determining the best pharmacotherapeutic approach in those situations requiring oral analgesics.

Learning Objectives

Upon completion of this course, you should be able to:

1. Compare and contrast the analgesic effectiveness of the nonprescription pain relievers in treating dental pain.

2. Compare and contrast the analgesic effectiveness of the nonselective NSAIDs in dental pain.

3. Describe the cardiovascular effects of ibuprofen.

4. Discuss the role of ibuprofen/opioid combinations in the treatment of dental pain.

5. Describe the dosage and efficacy of COX-2 inhibitors.

6. List the hydrocodone and oxycodone products for dental pain.

7. Describe the unique mechanisms of action and uses of nontraditional analgesics.

Faculty

Richard L. Wynn, BSPharm, PhD, is the lead author of Lexi-Comp's Drug Information Handbook for Dentistry, now in its 25th edition, a recognized reference source in dentistry in North America. He is the recognized authority in the use of drugs in dental practice, and his credibility as an information resource to the dental health professional has been well established. Dr. Wynn has been teaching pharmacology to dental students and has been doing research in analgesia and pain control over the last 25 years.

Faculty Disclosure

Contributing faculty, Richard L. Wynn, BSPharm, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Mark J. Szarejko, DDS, FAGD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

In order for a drug product to achieve nonprescription status, the U.S. Food and Drug Administration (FDA) requires it to be safe and effective. Safe is defined as (1) a low incidence of adverse reactions or low incidence of significant side effects under adequate directions for use, and (2) low potential for harm, which may result from abuse under conditions of widespread availability. The requirement for effectiveness means that there is a reasonable expectation that, in a significant proportion of the target population, the drug will provide clinically significant relief of the type of pain claimed when used appropriately [1].

The nonsteroidal anti-inflammatory drugs (NSAIDs) that were originally approved only as prescription drugs and are now also sold over the counter include ibuprofen and naproxen sodium. These two have joined aspirin, which has always had a status of over-the-counter availability. Thus, almost all nonprescription pain-relieving products contain either aspirin, acetaminophen, ibuprofen, or naproxen sodium. Also common is a combination of aspirin and acetaminophen or aspirin and acetaminophen in combination with other ingredients, such as caffeine [2].

Acetaminophen, ibuprofen, and naproxen sodium have established a niche over the years as over-the-counter products for the relief of dental pain, while prescription opioids are used for more severe dental pain. Information on their use and effectiveness follows.

2. ACETAMINOPHEN

Acetaminophen is known chemically as N-acetyl-p-aminophenol. The acronym for the chemical name is APAP, and many products use this acronym to identify the acetaminophen component. The common U.S. brand name is Tylenol. Acetaminophen is known as paracetamol in the United Kingdom [2].

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 of acetaminophen 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].

EFFICACY STUDIES IN DENTAL PAIN

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]. The intent of adding caffeine to acetaminophen products is to improve analgesic effectiveness while reducing the total amount of analgesic present. An early study from 1983 found that the addition of caffeine 65 mg to acetaminophen 500 mg appeared to enhance the analgesic effectiveness of acetaminophen in treating post-extraction pain [9]. A 2014 systematic review of 20 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 [10]. In 2019, another 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 [11].

ACETAMINOPHEN AS MONOTHERAPY

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 [12,13]. However, it is suggested that because of its ceiling-dose effect, acetaminophen is a limited analgesic against postoperative dental pain [14,15]. 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 [14]. 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 [15].

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 [16]. 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 [17].

ADDITIVE ANALGESIA: ACETAMINOPHEN/NSAID COMBINATIONS

The rationale for combining acetaminophen with an NSAID is that the combination produces greater efficacy and fewer adverse events when compared with acetaminophen-only and NSAID-only drug regimens [17]. 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 [18]. Using this idea of an NSAID/acetaminophen combination, it has been suggested that the combination of acetaminophen and ibuprofen is a useful analgesic regimen against dental pain.

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 several countries but only gained FDA approval in the United States in 2020 [2]. The dose for over-the-counter ibuprofen/acetaminophen combination drugs is ibuprofen 250 mg with acetaminophen 500 mg (two tablets of ibuprofen 125 mg/acetaminophen 250 mg) administered every eight hours, with a maximum dose of 750 mg ibuprofen/1,500 mg of acetaminophen per 24 hours. For more intense pain, a prescription ibuprofen/acetaminophen drug was approved in 2023. Prescription dosing is ibuprofen 2,925 mg with acetaminophen 975 mg (three tablets of ibuprofen 97.5 mg/acetaminophen 325 mg) administered every six hours with a maximum dose of 1,170 mg ibuprofen/3,900 mg of acetaminophen per 24 hours [2,17].

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 [19]. 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% [19].

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 [20].

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 [21]. 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 [21].

ADDITIVE ANALGESIA: ACETAMINOPHEN/ASPIRIN COMBINATION

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.

ACETAMINOPHEN HEPATOTOXICITY

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 [22]. Acetaminophen hepatotoxicity is potentiated by chronic alcohol consumption [2,23]. One report described 67 patients (all regular users of alcohol) who developed hepatic injury after ingestion of acetaminophen at therapeutic doses [24]. 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 [3,23]. 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 [4,23,25].

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 [26]. 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 [26].

The literature indicates that drug-induced liver injury remains an important concern for many existing drugs, including acetaminophen. When given in therapeutic doses over 14 days, acetaminophen produced significant asymptomatic elevations in alanine transferase among healthy volunteers, suggesting that subclinical injury is more common than previously thought. In the United States, acetaminophen is the most common cause of acute hepatic failure [4,22,25].

IS COX-3 ENZYME INHIBITION THE MECHANISM OF ACETAMINOPHEN?

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 [27,28]. A third distinct COX enzyme, identified as COX-3, has been isolated from the cerebral cortex and, in lesser amounts, other tissues [27,29]. 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 [27,30]. 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 [27,30].

REPORTS ON THE ACETAMINOPHEN/WARFARIN INTERACTION

A case-control study suggested that the combination of acetaminophen with warfarin (Coumadin) may cause enhanced anticoagulation [31]. 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 [32,33,34]. 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 [35]. 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 [32,34,36]. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 grams daily [2,32,34].

3. NONPRESCRIPTION IBUPROFEN PRODUCTS

Nonprescription ibuprofen is available in a single strength of 200 mg tablets. It is sold under the generic name and a variety of brand names, such as Advil and Motrin IB [37].

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 [2,38]. 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. 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 [2,37].

The FDA-approved indications for nonprescription ibuprofen include temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, arthritis, menstrual cramps, and the reduction of fever [2,4,37].

FDA-required boxed (label) warnings for the use of nonprescription ibuprofen include that it [2,4,39]:

- Not be taken longer than 10 days unless directed by a physician.

- May cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: hives, wheezing, skin reddening, facial swelling, shock, rash, or blisters.

- Contains an NSAID, which may cause stomach bleeding. The risk of stomach bleeding is higher if the individual is 60 years of age or older, has had stomach ulcers or bleeding problems, takes other drugs containing an NSAID (e.g., aspirin, ibuprofen, naproxen, or others), takes blood thinning (i.e., anticoagulant) or steroid drugs, has three or more alcoholic drinks every day while taking this product, or takes more than directed or for a longer period of time than directed.

- Not be used right before or after heart surgery.

- May increase the risk of heart attack or stroke as early as the first few weeks of use; the risk may increase if used on a long-term continuous basis. Risk of heart attack or stroke appears to increase with higher doses.

- Requires a healthcare professional should be consulted if the individual is pregnant or breastfeeding. It is especially important not to use ibuprofen during the last three months of pregnancy unless definitely directed to do so by a physician because it may cause problems in the unborn child or complications during delivery.

EFFICACY STUDIES IN DENTAL PAIN

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 [40].

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 [41]. 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 [41]. 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 [42]. 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 [43].

ADVIL LIQUI-GELS COMPARED TO CELECOXIB IN DENTAL PAIN

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 [4,38]. 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 break down 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 [44].

4. NONPRESCRIPTION NAPROXEN SODIUM

In January 1994, the FDA approved the status change for naproxen sodium from prescription only to an over-the-counter product [38]. This product joined ibuprofen, aspirin, and acetaminophen as an over-the-counter analgesic and was the first over-the-counter analgesic to receive approval since ibuprofen. Naproxen sodium is an NSAID available under the product name Aleve. Indications are for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, arthritis, menstrual cramps, and the reduction of fever. Aleve is supplied as 220-mg tablets, although other brands offer varying doses. The over-the-counter labeling indicates that the adult dose is one tablet every 8 to 12 hours while symptoms persist, not to exceed three tablets in 24 hours unless directed by a physician. FDA-required boxed (label) warnings are similar to those for ibuprofen [2,37].

EFFICACY IN DENTAL PAIN

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].

COMBINATION WITH ACETAMINOPHEN

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 also appears to have the potential for effective pain relief. Researchers are beginning to evaluate the effectiveness of this combination as a fixed dose. However, there is no reason why both of these agents could not be considered for dental pain as long as the maximum daily doses of naproxen sodium and acetaminophen, as printed on the packaging, are not exceeded and all label warnings are taken into account [2,45].

NAPROXEN IS CARDIOPROTECTIVE AND SIMILAR TO ASPIRIN

Several studies have evaluated the cardioprotective actions of naproxen, finding that naproxen is the only NSAID that can, at high doses, inhibit thromboxane production by 95% and inhibit platelet aggregation by 88%. This suggests that naproxen may have a cardioprotective effect similar to aspirin. In contrast to the irreversible modification of COX-1 in aspirin, naproxen is a reversible inhibitor of COX-1 [2,46].

5. OTHER NONPRESCRIPTION PRODUCTS FOR DENTAL PAIN

Acetaminophen, ibuprofen, and naproxen sodium are commercially available in drugstores and supermarkets as both generic and brand name products. Usually, the generic products are priced at a lower retail cost than the brand name products. Evidence supports the fact that there are no differences in efficacy between the generic and brand name products in terms of pain relief. Two commercial dose forms for pain relief, including acute dental pain, are described below.

ACETAMINOPHEN EXTENDED-RELEASE CAPSULES

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 [4,38].

EXTRA-STRENGTH ACETAMINOPHEN ADULT RAPID BURST CHERRY

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

6. NSAIDs: NONSELECTIVE COX-1 AND COX-2 INHIBITORS

The ibuprofen family of NSAIDs inhibits both COX-1 and COX-2 enzymes. These drugs are traditionally referred to as the nonselective NSAIDs as they inhibit both COX enzymes. This group of NSAIDs, useful as dental pain relievers, includes ibuprofen, etodolac, flurbiprofen, ketoprofen, diclofenac, diflunisal, ketorolac, and naproxen sodium. The COX-1 enzyme is distributed throughout the body and produces prostaglandins that have a protective role in preventing gastrointestinal ulcers, regulating platelet action, and are necessary for kidney function. The COX-2 enzyme produces prostaglandins, but only as a result of inflammation, pain, or other noxious-type stimuli. Inhibition of both COX-1 and COX-2 enzymes not only reduces inflammation and pain but also has the potential to inhibit the protective actions of COX-1 resulting in gastrointestinal toxicity. Long-term use of NSAIDs also has been associated with renal toxicity [2,47].

EFFICACY STUDIES OF NSAIDs IN RELIEVING DENTAL PAIN

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 [40]. Also, monotherapy with ibuprofen has been reported to be as or more efficacious than acetaminophen for the management of dental pain [43]. Ketoprofen 100 mg has been reported to have analgesic efficacy similar to that of acetaminophen 1,000 mg for pain after third-molar extraction [48]. 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 [49]. 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 [50,51]. A listing of the NSAIDs useful for reducing dental pain and the usual suggested doses are summarized in Table 1 [2,52].

Table 1: NONSELECTIVE NSAIDs APPROVED FOR USE TO RELIEVE ACUTE PAIN IN DENTISTRY

Drug (Brand Name)

Usual Adult Dose

Diclofenac (Voltaren)

50 mg tab three times daily; max 150 mg/day

Diflunisal (Dolobid )

Initial: 500–1,000 mg tabs, followed by 250–500 mg every 8 to 12 hours; max 1.5 g/day

Etodolac (Lodine)

200–400 mg tab every six to eight hours; max 1,000 mg/day

Flurbiprofen (Lurbiro)

Off-label use: 100 mg tab every 12 hours

Ibuprofen (Motrin)

200–400 mg every four to six hours; max 1.2 g/day (3.2 g/day under physician supervision)

Ketoprofen (Orudis)

25–50 mg tab every six to eight hours; max 300 mg/day

Ketorolac (Toradol)

IM: 60 mg as single dose or 30 mg every six hours; max 120 mg/day

IV: 30 mg as a single dose or 30 mg over 6 hours; max 120 mg/day

Oral (as a continuation of IM or IV therapy only): 20 mg, followed by 10 mg tab every four to six hours; max 40 mg/day

The maximum combined duration of treatment (for parenteral and oral) is five days.

Naproxen sodium (Aleve)

Initial: 500 mg, followed by 250 mg every six to eight hours; max 1,250 mg/day

Source: [26]

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.

CARDIOVASCULAR EFFECTS OF NONSELECTIVE NSAIDs

NSAIDs and Congestive Heart Failure

The prevalence of NSAID use in patients 65 years of age and older is as high as 96% in the general practice setting [53]. The use of NSAIDs in the previous week by individuals 65 years of age and older has been associated with a doubling of the odds of a hospital admission with congestive heart failure (CHF). Also, the use of NSAIDs by patients in the same age group with a history of heart disease had an odds ratio of 10.5 for first admission with heart failure compared to an odds ratio of 1.6 for first admission in those without such a history [54]. This study was conceived from previous reports that showed that NSAIDs were able to raise systemic vascular resistance and reduce renal perfusion in susceptible individuals. In addition, in some individuals, it was thought that these mechanisms could exacerbate the tendency to develop CHF [55,56].

Subsequent studies have confirmed that NSAID use is associated with a significantly elevated risk of developing CHF. In addition, results of a case-control study published in 2016 found that the risk varied between individual NSAIDs and was dose dependent [57,58,59].

Use of NSAIDs has also been associated with a small increase in risk of a first hospitalization for heart failure (HF). In patients with prior clinical diagnosis of HF, the use of NSAIDs may lead to a worsening of pre-existing HF that triggers their hospital admission [60,61]. This increased risk, although small, may result in considerable public health impact, particularly among the elderly [61]. Additionally, because the magnitude of risk may vary with individual agents, physicians should consider patterns of risk and benefit, as well as individual cardiovascular risk profile, when selecting the most appropriate agent [62].

NSAIDs and Heart Attack/Stroke

In 2015, the FDA strengthened an existing label warning that NSAIDs increase the chance of a heart attack or stroke. A review of clinical trials, observational studies, and other scientific publications found additional risks of NSAID use not previously noted in the labeling. Updated NSAID labels and patient education should include the following information [63]:

- The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID and the risk may increase with longer use.

- The risk appears greater at higher doses.

- It is unknown if any particular NSAID has a higher or lower risk than that of another.

- NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease.

- In general, patients with current heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.

- Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.

Ibuprofen and Reversal/Block of Aspirin Cardioprotection

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. Although ibuprofen and aspirin may be taken together, the FDA has recommended that consumers talk with their healthcare providers for additional information. In situations in which these drugs could be used concomitantly, the FDA has provided the following recommendations [2,64,65]:

- Patients who use immediate-release aspirin (not enteric-coated aspirin) and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion or more than eight hours before aspirin ingestion to avoid attenuation of aspirin's effect.

- Recommendations about the timing of ibuprofen 400 mg in patients taking enteric-coated, low-dose aspirin cannot be made based upon available data. However, one study has shown that the antiplatelet effect of enteric-coated, low-dose aspirin was attenuated when ibuprofen 400 mg was dosed 2, 7, and 12 hours after aspirin.

- With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low-dose aspirin because of a long-lasting effect of aspirin on platelets.

- There is no clear data regarding the potential effect of chronic ibuprofen dosing greater than 400 mg on the antiplatelet effect of aspirin.

- Other over-the-counter NSAIDs (e.g., naproxen sodium, ketoprofen) should be viewed as having the potential to interfere with the antiplatelet effect of low-dose aspirin until proven otherwise. However, the FDA is unaware of any studies that have looked at the same type of interference by ketoprofen with low-dose aspirin. One study of naproxen and low-dose aspirin has suggested that naproxen may interfere with aspirin's antiplatelet activity when they are co-administered. However, naproxen 500 mg administered two hours before or after aspirin 100 mg did not interfere with aspirin's antiplatelet effect. The FDA has stated that there are no data looking at doses of naproxen less than 500 mg. Naproxen sodium over-the-counter strength is 220 mg tablets.

- Acetaminophen 1,000 mg appears to not interfere with the antiplatelet effect of low-dose aspirin (i.e., 81 mg daily) when taken concomitantly.

- Existing data using platelet function tests have suggested there is a pharmacodynamic interaction between 400 mg ibuprofen and low-dose aspirin when dosed concomitantly. The FDA is unaware of data addressing whether taking less than 400 mg of ibuprofen interferes with the antiplatelet effect of low-dose aspirin.

- It is emphasized that the clinical implication of 400 mg ibuprofen interfering with the effect of aspirin may be important because the cardioprotective effect of aspirin, when used for secondary prevention of myocardial infarction, could be attenuated.

The mechanism of ibuprofen's interference with the antiplatelet effect of low-dose aspirin is probably through competitive inhibition of the acetylation site of cyclooxygenase in the platelet. Ibuprofen is a reversible inhibitor of cyclooxygenase, and aspirin is an irreversible inhibitor of cyclooxygenase. Both occupy nearby sites on cyclooxygenase such that the presence of ibuprofen interferes with aspirin binding. Once the ibuprofen leaves the site, the cyclooxygenase will not be inhibited by aspirin because the aspirin will have been excreted due to its short half-life. Thus, the ibuprofen interference diminishes or attenuates the inhibition in platelet aggregation by aspirin [65].

Ibuprofen as a Dental Pain Reliever in Patients Taking Cardioprotective Aspirin

The use of ibuprofen in dentistry is usually on a very short-term basis, and some evidence indicates that this presents little reason to be concerned. The FDA has stated that with occasional use of ibuprofen, a clinically significant interaction with aspirin is unlikely [64]. If ibuprofen is the preferred pain reliever, patients may require counseling about the appropriate timing of ibuprofen dosing in relationship to aspirin therapy. Patients who use immediate-release aspirin (not enteric-coated) and take a single dose of ibuprofen 400 mg should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion or more than eight hours before aspirin ingestion to avoid attenuation of aspirin's effect. To avoid interference during chronic ibuprofen dosing, a single dose of ibuprofen should be taken at least 30 minutes or longer after aspirin or at least eight hours should elapse after ibuprofen dosing before taking aspirin [64].

Based on available information, acetaminophen or an acetaminophen-opioid combination analgesic would be suitable for patients taking cardioprotective aspirin who require analgesics for postoperative pain relief. The FDA has recommended that other nonselective NSAIDs should be viewed as having the potential to interfere with the antiplatelet effect of low-dose aspirin until proven otherwise [64].

7. IBUPROFEN/OPIOID COMBINATIONS

When ibuprofen is combined with an opioid for pain relief, two different mechanisms of analgesic action are being utilized, which should result in a more effective action than either agent alone. In addition, ibuprofen allows for a significant dose reduction of the opioid to minimize opioid side effects. Studies have been published on the evaluation of ibuprofen combined with codeine, hydrocodone, or oxycodone to manage acute dental pain. Although historically the potency and efficacy of non-opioid analgesics have been thought to be lower than those of opioids, clinical studies have repeatedly shown that non-opioid analgesics, such as ibuprofen, are more effective than opioids in suppressing postoperative dental pain. Among opioids discussed in this course (hydrocodone, oxycodone, codeine, and meperidine), only hydrocodone has an ibuprofen combination formulation [2,52].

8. DRUG INTERACTIONS WITH NSAIDs

The following drugs or drug groups have been documented to interact with the nonselective NSAIDs. Below are brief descriptions of these interactions. Some of the interactions are more significant than others and are categorized accordingly [2,4,37].

INTERACTIONS OF GREATER SIGNIFICANCE

Anticoagulants

Nonselective NSAIDs may enhance the anticoagulant effect of warfarin derivatives, such as Coumadin. It is suggested that NSAIDs not be used concomitantly with anticoagulants. Acetaminophen is an acceptable analgesic choice in patients taking oral anticoagulants.

Antiplatelet Agents

Nonselective NSAIDs may enhance the effects of antiplatelet agents (e.g., clopidogrel [Plavix]). An increased risk of bleeding may occur. It is suggested that NSAIDs not be used concomitantly with antiplatelet agents. Acetaminophen is an acceptable analgesic choice in patients taking antiplatelet agents. If you must use NSAIDs in patients on antiplatelet therapy, use the lowest dose possible for the briefest duration.

Bisphosphonate Derivatives

NSAIDs may enhance the adverse effects of bisphosphonate derivatives. There may be an increased risk of developing symptoms of gastrointestinal ulceration. Alternative therapy for the NSAID should be considered.

Methotrexate

NSAIDs may decrease the renal excretion of methotrexate. This could result in methotrexate toxicity, including hematologic effects and renal toxicity. If a patient is receiving antineoplastic doses of methotrexate, an alternative agent other than an NSAID should be considered. There is a lesser risk associated with lower doses of methotrexate, such as when it is used to treat rheumatoid arthritis.

Lithium

NSAIDs may increase the serum concentration of lithium. This could result in signs of acute lithium toxicity, including dizziness, restlessness, and confusion. It is suggested that a non-NSAID analgesic be used in patients taking lithium.

INTERACTIONS OF LESSER SIGNIFICANCE

ACE Inhibitors

The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors may be decreased with concurrent therapy with NSAIDs. Blood pressure increases have been noted with both chronic NSAID therapy and following a single NSAID dose. In patients with a history of CHF, consider alternative therapy to avoid the potential negative consequences of concomitant NSAID therapy (e.g., fluid retention, fluid accumulation, edema).

Aspirin (Salicylates)

Aspirin and other salicylate drugs may decrease the serum concentration of NSAIDs. NSAIDs may not achieve full therapeutic effectiveness in the presence of aspirin.

Antacids

Antacids containing aluminum or magnesium may decrease the absorption of NSAIDs from the gastrointestinal tract into the bloodstream. NSAIDs may not achieve full therapeutic effectiveness when taken with these types of antacids.

Loop Diuretics

NSAIDs may diminish the diuretic effect of loop diuretics. This could result in a decreased effect of the medication.

Beta-Blockers

NSAIDs may diminish the antihypertensive effect of beta-blockers. This interaction could be important if NSAIDs are used long-term.

Calcium Channel Blockers

NSAIDs may diminish the antihypertensive effect of calcium channel blockers.

9. COX-2 INHIBITORS

Currently, the only COX-2 inhibitor approved by the FDA is celecoxib (Celebrex). Two other COX-2 inhibitors, rofecoxib (Vioxx) and valdecoxib (Bextra), were withdrawn from the market in 2004 and 2005 due to an increased risk of heart attack and stroke associated with long-term use. In addition, the FDA cited a risk of serious skin reactions as a major cause for concern in patients prescribed Bextra. Celecoxib, however, has a demonstrated safety profile [2,37]

As discussed, NSAIDs exert their effects through the inhibition of the enzyme cyclooxygenase. In the mid-1990s, literature reports described the discovery of at least two cyclooxygenase isoenzymes, COX-1 and COX-2. The COX-1 enzyme is expressed in most tissues and is responsible for the physiologic production of prostaglandins. The COX-2 enzyme is induced by various endogenous compounds such as cytokines, mitogens, and endotoxins in inflammatory cells and is responsible for the elevated production of prostaglandins during inflammatory processes. Although both COX isoforms contribute to the inflammatory process, only COX-2 is induced to enhance the formation of more prostaglandins during acute, as well as chronic, inflammation [28,29,30].

The discovery of the COX-1 and COX-2 isoenzymes has led to the development of a selected class of drugs that show preference to elicit inhibitory effects on the COX-2 enzyme. Conventional NSAIDs, such as ibuprofen and naproxen, are nonselective COX inhibitors and inhibit both isoenzymes. These new drugs, with a high selectivity for COX-2, are generally better tolerated in the gastrointestinal tract and lower the incidence of gastrointestinal bleeding when compared with nonselective NSAIDs. Celecoxib and rofecoxib are about 100 to 1,000 times more selective on the COX-2 than on the COX-1 [28,29,30].

CELECOXIB (CELEBREX): EFFICACY IN DENTAL PAIN

Celecoxib, a COX-2 inhibitor, is approved by the FDA for acute pain, including pain from dental procedures. The recommended dose 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. Celecoxib is available in 50-, 100-, 200-, and 400-mg capsules. The package label states that celecoxib is contraindicated in patients with a hypersensitivity to sulfonamide-containing drugs, although the scientific basis of this cross-sensitivity has been challenged due to unique differences in the chemical structure of the sulfonamide found in celecoxib [38,52,67].

CARDIOVASCULAR EFFECTS OF CELECOXIB

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. 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 [38,67].

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 [38,67].

Celecoxib and Risk of Cardiovascular Events

The FDA requires a label warning of an increased risk of cardiovascular thrombotic events when using a COX-2 inhibitor. Providers should be aware and patients advised that use of NSAIDs increases the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [38,67].

EFFECTS ON THE GASTROINTESTINAL TRACT

The COX-2 inhibitors have been reported to offer improved gastric tolerance as compared to the conventional, nonselective NSAIDs. 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) may require alternatives. Although less likely to cause GI events than nonselective NSAIDs, celecoxib still carries an increased risk of bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms [2,67].

When compared with nonselective NSAIDS, drawbacks include higher costs for COX-2 inhibitors and availability only as a prescription. Therefore, COX-2 inhibitors should only 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 [38,67].

DRUG INTERACTIONS WITH CELECOXIB

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 [2,38,67].

Interactions of Greater Significance Involving Celecoxib

Aspirin

Concurrent use with celecoxib could result in higher likelihood of gastrointestinal ulceration. Celecoxib may be used with low-dose aspirin; however, rates of gastrointestinal bleeding may be increased with co-administration.

Fluconazole (Diflucan)

Fluconazole will inhibit the metabolism of celecoxib through the inhibition of the hepatic P450 2C9 isoform. Concomitant administration of fluconazole at 200 mg once daily has resulted in a twofold increase in the blood levels of celecoxib after a therapeutic dose. If celecoxib is co-administered with fluconazole, the lowest recommended dose of celecoxib should be used.

Lithium

Celecoxib at a dose of 200 mg has been shown to significantly increase lithium blood levels (approximately 17%) in patients receiving therapeutic doses of lithium. It is essential that the blood levels of lithium be monitored when the two drugs are administered concomitantly.

Interactions of Lesser Significance Involving Celecoxib

ACE Inhibitors

Concurrent use with celecoxib may decrease the antihypertensive effects of ACE inhibitors.

Antacids Containing Aluminum or Magnesium

Concurrent administration with certain antacids has resulted in a 37% decrease in peak blood levels of celecoxib, presumably by interference in gastrointestinal tract absorption of celecoxib. Celecoxib, at doses up to 200 mg twice daily, may be administered without regard to timing of meals. Higher doses (i.e., 400 mg twice daily) should be administered with food to improve absorption.

Diuretics

Celecoxib, and the NSAIDs in general, may decrease the natriuretic effects of diuretics, presumably through the inhibition of renal prostaglandin synthesis.

Digoxin

Concomitant use of digoxin with celecoxib may increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin.

Diuretics

Celecoxib, and the NSAIDs in general, may decrease the natriuretic effects of diuretics, presumably through the inhibition of renal prostaglandin synthesis.

SUMMARY OF CELECOXIB

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 [2,38,67].

Table 2: CELECOXIB SUMMARY

Brand Name

Celebrex, also available as a generic medication

Manufacturer

Searle (a division of Pfizer)

Use

Osteoarthritis

Rheumatoid arthritis, juvenile idiopathic rheumatoid arthritis

Ankylosing spondylitis

Acute pain

Primary dysmennorheadysmenorrhea

Mechanism

More selective on COX-2 than COX-1

Usual Dose

Osteoarthritis = 200 mg/day

Rheumatoid arthritis = 100–200 mg twice a day

Pain = 400 mg initially, followed by 200 mg dose, if needed on first day; 200 mg twice a day as needed on subsequent days

Documented Drug Interactions

Aspirin, fluconazole, lithium

Probable Interaction with Warfarin

None apparent, but may have increased risk of bleeding complications

Gastrointestinal Effects

Less than NSAIDs

Effects on Platelets

None at normal doses

Contraindications

Allergy to aspirin, NSAIDs, sulfonamides

How Supplied

Capsules, 50 mg, 100 mg, 200 mg, 400 mg

Source: [2,38,67]

10. OPIOID ANALGESICS FOR DENTAL PAIN

While opioid analgesics are extremely effective in reducing acute dental and postoperative pain, the ADA recommends NSAIDs as the first-line treatment for the management of mild-to-moderate dental and postoperative pain, and recommends that opioid analgesics may be considered if pain intensifies or remains untreated. Hydrocodone, oxycodone, codeine, and occasionally meperidine are the opioids used to treat dental pain [2,68].

In 2016, the FDA issued a warning about safety issues (e.g., serotonin syndrome, adrenal insufficiency, androgen deficiency) with the entire class of opioid analgesics [71]. In 2018, the agency issued another safety warning that required significant labeling changes for drug companies with approved opioid analgesic products intended for use in an outpatient setting. The letters require the companies to include new safety information regarding the Opioid Analgesic Risk Evaluation and Mitigation Strategy (OA REMS) in the boxed warning and warnings and precautions sections of prescribing information to mitigate the general lack of awareness of the REMS among all opioid analgesic prescribers. The OA REMS program requires training for all healthcare providers involved in the management of patients with pain [70]. The FDA also maintains the Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain, last updated in 2023. The Blueprint contains a high-level outline of the core educational messages included in the OA REMS [69]. Specific opioids mentioned in this course and included in the FDA safety communication include codeine, hydrocodone, meperidine, oxycodone, and tramadol [69,70,71].

GENERAL INFORMATION

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.

Opioid 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 opioids bind to in order to cause analgesia. The opioids are not anti-inflammatory in nature and do not inhibit cyclooxygenase or block the production of inflammatory factors, such as the prostaglandins [37].

Opioid analgesics are recommended only for limited acute dosing (i.e., three days or less) and 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 opioid preparations may exhibit an additive CNS depression [4,37].

The use of monoamine oxidase (MAO) inhibitors or tricyclic antidepressants with opioid preparations may increase the effect of either the antidepressant or the opioid. The concurrent use of anticholinergics with opioids may produce paralytic ileus [4,37].

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, codeine, and meperidine may all produce drug dependence and have the potential for misuse. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration. In addition, all of these agents are subject to the Federal Controlled Substances Act [2,4]. As stated, these agents were the subject of the FDA safety warning and label change requirement [69,70]. Codeine combination products are controlled substances within the Drug Enforcement Administration (DEA) Controlled Substance Schedule III (C-III), while hydrocodone, oxycodone, meperidine, and codeine alone are controlled substances within DEA Schedule II (C-II). The DEA defines Schedule II Controlled Substances as drugs, substances, or chemicals "with a high potential for abuse, with use potentially leading to severe psychological or physical dependence. These drugs are also considered dangerous. Some examples of Schedule II drugs are combination products with less than 15 mg of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin" [37,72].

As C-II controlled substances, it is required that all prescriptions for these medications must be in the form of a valid written or electronic prescription on approved forms and signed by the practitioner. Verbal and/or facsimile (fax) prescriptions are not allowed under normal circumstances and may be given only in a genuine emergency. In addition, no refills may be authorized. Federal and state laws may vary, and it is important to be aware of local prescribing and documentation requirements. For example, in 2019 California began requiring prescribers of any Schedule C-II controlled substance to obtain and use new tamper-resistant prescription forms ordered only from state-approved security printers [73]. Additionally, California law began requiring all prescribing healthcare practitioners to submit prescriptions electronically as of January 2022; however, paper prescription forms that conform with existing tamper-resistant requirements should be available in the case of technology or electrical failure [74].

Hydrocodone is available alone or in combination with either acetaminophen or ibuprofen. Both oxycodone and codeine are available alone and in combination with acetaminophen. Meperidine is only available as a single drug product. 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 [2,37]. Some products are available under the various listed brand names, and all are 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 [75,76].

In 2024, the ADA released clinical practice guidelines for the pharmacologic management of acute postoperative dental pain. In regard to postoperative acute pain after simple and surgical tooth extraction(s), the ADA recommends first-line treatment of pain using an NSAID alone (e.g., 400 mg of ibuprofen or 440 mg of naproxen sodium) or NSAID in combination with acetaminophen (e.g., 500 mg). If pain control using one of these two options is inadequate, the ADA recommends using the previous first-line therapy (NSAID plus 325 mg acetaminophen) plus an opioid (e.g., 5–7.5 mg of hydrocodone or 5 mg of oxycodone)/325 mg acetaminophen combination (for a total of 650 mg acetaminophen) at the lowest effective dose, fewest tablets, and shortest duration, which rarely exceeds three days [66].

HYDROCODONE PRODUCTS

Hydrocodone is available alone or in combination with acetaminophen or ibuprofen as a generic formulation. Previous well-known brand names, including Vicodin, Norco, and Vicoprofen, have been discontinued in favor of generic combinations available.

Hydrocodone/Acetaminophen

Hydrocodone/acetaminophen is available in tablet form in the following combinations [2,4]:

- 2.5 mg hydrocodone bitartrate/325 mg acetaminophen

- 5 mg hydrocodone bitartrate/300 or 325 mg acetaminophen

- 7.5 mg hydrocodone bitartrate/300 or 325 mg acetaminophen

- 10 mg hydrocodone bitartrate/300 or 325 mg acetaminophen

Additionally, varying dosages of generic hydrocodone alone may be used in combination with acetaminophen alone, allowing for many prescribing options on the part of the clinician. Thus, a lower dose of hydrocodone (e.g., 5 mg) in combination with 500 mg acetaminophen can be prescribed to the patient who may be sensitive to the adverse effects of the opioid. On the other end of the spectrum, a maximum strength of hydrocodone (10 mg) may be taken with greater amounts of acetaminophen. Neither hydrocodone nor acetaminophen elicits anti-inflammatory responses [2,4].

Hydrocodone/acetaminophen is also available as Lortab (brand name), an elixir that consists of 10 mg hydrocodone bitartrate and 300 mg acetaminophen per 15 mL. A generic oral solution is also available as hydrocodone bitartrate 7.5 mg OR 10 mg/acetaminophen 325 mg per 15 mL. The recommended dose is 1 tablespoon every four to six hours when necessary for pain [2,4].

The adult dose of the hydrocodone/acetaminophen oral products for postoperative dental pain is hydrocodone 5–10 mg every four to six hour (not to exceed 60 mg/day) and limiting acetaminophen to <4,000 mg per day (less in patients with hepatic impairment or alcohol use). Use of both single and combination drugs may be useful to obtain pain management and maintain a lower dose of opioid medication [37].

Hydrocodone/Ibuprofen

Hydrocodone/ibuprofen combinations are available in the following combinations [2,4]:

- 5 mg hydrocodone bitartrate/200 mg ibuprofen

- 7.5 mg hydrocodone bitartrate/200 mg ibuprofen

- 10 mg hydrocodone bitartrate/200 mg ibuprofen

Anti-inflammatory effects may be achieved by prescribing an ibuprofen combination product, assuming, of course, that the patient is not taking warfarin-type oral anticoagulants, as ibuprofen may enhance the anticoagulant effects of warfarin-type drugs. Because of addiction liability of opioid 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 opioid analgesics is centrally mediated, and the presence or absence of food will not affect the degree or incidence of nausea [2,37]. 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].

OXYCODONE PRODUCTS

Oxycodone is available alone or in combination with acetaminophen as brand name and generic formulations. Oxycodone/acetaminophen is available in tablet form in the following combinations [2,4]:

- Tablet: 2.5, 5, 7.5, 10 mg oxycodone hydrochloride/300 or 325 mg acetaminophen: available as a generic formulation or brand name (e.g., Prolate, Endocet, Percocet)

- Solution: Oral dosage 10 mg oxycodone hydrochloride/300 mg acetaminophen per 5 mL

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 opioid. 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., three days or less) [2,4,37].

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-opioid 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. 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 [2,4,37].

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 for dental pain [2,4]:

- Mild-to-moderate pain: initial dose, based on oxycodone content is 2.5– 5 mg every four to six hours

- Severe pain: initial dose, based on oxycodone content is 10–30 mg every four to six hours

- Liquid dose form: 5 mg oxycodone/325 mg acetaminophen/5 mL, one teaspoonful every four to six hours

It is important to note that the initial dose is based on the oxycodone content; however, the maximum daily dose is based on acetaminophen content, not to exceed 4 g per day.

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 [77]. 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 [4,38].

This combination provides additional options in pain relief and pain control after dental surgery [77]. The two components within this formulation, oxycodone and ibuprofen, both have proven track records and strong evidence as an effective opioid analgesic (oxycodone) and an effective non-opioid/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 [78]. 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 3).

Table 3: RESULTS OF STUDY COMPARING IBUPROFEN, OXYCODONE, AND COMBUNOX IN DENTAL PAIN MODELS

Factors

Ibuprofen 400 mg

Oxycodone 5 mg

Combunox

Study group

186 subjects (101 female, 85 male)

63 subjects (33 female, 30 male)

187 subjects (118 female, 69 male)

Median time to onset of pain relief

29.7 minutes

Not available

21.4 minutes

Global evaluation score (Range: 0–4)

2.26

0.66

2.63

Total pain relief through six hours

Mean score: 12.2

Mean score: 4.3

Mean score: 13.3

Sum of pain intensity difference through six hours

Mean score: 6.54

Mean score: 0.14

Mean score: 6.54

Incidence of nausea

3.8%

9.5%

10.2%

Incidence of vomiting

2.7%

7.9%

7.5%

Incidence of dizziness

1.1%

4.8%

2.7%

Source: [78]

The second study compared Combunox to oxycodone 5 mg/acetaminophen 325 mg (Percocet), hydrocodone 7.5 mg/acetaminophen 500 mg (Lortab), and placebo [79]. 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 opioids 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 [80]. 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 [80]. 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 [80].

OxyContin is a long-acting formulation of oxycodone used for moderate-to-severe operative pain. It is most useful when extended use is required [4,38].

CODEINE PRODUCTS

Codeine is available alone and in combination with acetaminophen. A codeine/aspirin combination was previously available but has been discontinued. 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. 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; as an oral syrup at 5 mg/mL concentration; and as an oral liquid at 0.2%. 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 opioid addiction liability. If codeine is desired as a dental analgesic, it should be used in combination with acetaminophen to achieve similar efficacy, at lower doses, and with less side effects than codeine alone. 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 [2,37].

MEPERIDINE PRODUCTS

Meperidine (Demerol) is not indicated as a first-choice opioid analgesic for dental pain due to its potential for misuse and addictive liabilities. As noted, 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 an opioid analgesic is indicated [37]. In this regard, meperidine has developed a niche in pain management and should be kept under consideration as an optional opioid analgesic. It should not be used as the opioid drug of first choice, as several other non-opioid and opioid options with a better proven safety profile are available. 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 [37].

Other opioid agents, such as hydrocodone and oxycodone, have a similar chemical makeup to codeine, and cross allergy between opioids 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 4. 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 neurotoxicity, serious drug interactions, dizziness, nausea, sedation, hypotension, weakness, nervousness, and confusion, which may occur, often outweigh any gain in pain management [2,37].

Table 4: MEPERIDINE ANALGESIC ORAL PRODUCTS

Meperidine Hydrochloride

Brand Name

Generic Available

Form

50 mg

Demerol HCl

Yes

Tablet

100 mg

Demerol HCl

Yes

Tablet

50 mg/5 mL

Demerol HCl

Yes

Syrup

Source: [2,37]

Meperidine is recognized as an alternate oral opioid 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 [2,37].

Meperidine is unique from the other opioids 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 [37].

DRUG INTERACTIONS

The number of drugs that have the potential to interact with opioid analgesics is much fewer than the number with the potential to interact with the NSAIDs. In general, because all opioids can produce sedation, other sedative drugs and alcohol would have the potential to enhance opioid-induced sedation [2,4,37].

Interactions with Opioid Analgesics: Hydrocodone, Oxycodone, Codeine

Antipsychotics (Phenothiazines)

These drugs may enhance the hypotensive effect of opioid analgesics.

CYP2D6 Inhibitors

This class of drugs may diminish the therapeutic effect of the opioid analgesics. CYP2D6 is a specific enzyme system within the P-450 (CYP) drug metabolizing enzyme complex in hepatic cells. Opioids are CYP2D6 substrates. Part of the therapeutic effects of CYP2D6 substrates is due to active metabolites of the substrates. The active metabolites are produced by CYP2D6 actions. Inhibiting this enzyme will reduce metabolism of the opioids and thereby diminish their therapeutic effectiveness. Some important CYP2D6 inhibitors include cimetidine, chlorpheniramine, fluoxetine, and quinidine.

Selective Serotonin Re-uptake Inhibitors (SSRIs)

The opioids may enhance the serotonergic effect of SSRIs. This may result in serotonin syndrome, a complex of neurologic symptoms including confusion, agitation, myoclonus, and hyperreflexia. SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. As stated, the FDA has issued a safety warning regarding a potential association between opioids and serotonin syndrome. The syndrome can occur during concomitant use of opioids with SSRIs, even within the recommended dosage range. Careful patient monitoring during treatment initiation and dose increases is recommended.

Interactions with Opioid Analgesics: Meperidine

Barbiturates

These sedatives may increase the CNS depressant effect of meperidine. Prolonged CNS depression (including sedation) may occur in patients receiving phenobarbital and meperidine concurrently.

MAO Inhibitors

MAO inhibitors may enhance the serotonergic effect of meperidine, which may cause serious serotonergic syndrome. This combination should be avoided.

Phenytoin

This anticonvulsant may increase the metabolism of meperidine. This may reduce its analgesic action and may also increase the rate at which normeperidine, a neuroexcitatory metabolite, is formed.

11. NONTRADITIONAL ANALGESICS

There are several analgesics that are available to treat dental pain that are referred to as nontraditional analgesics. These drugs include tramadol (Ultram), tramadol with acetaminophen (Ultracet), and gabapentin (Neurontin), and pregabalin (Lyrica). These drugs are not NSAIDs nor are they opioids, and their mechanisms of actions all differ from the traditional analgesics.

TRAMADOL (ULTRAM)

Tramadol (Ultram) was approved by the FDA in 1995 and is a DEA Controlled Substance Schedule IV (C-IV), meaning that 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 [2,4,37].

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. 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 opioid 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 [2,4,37].

Efficacy Studies in Dental Pain

An early study of the effectiveness of tramadol in relieving dental pain showed that up to 2.5 mg/kg of tramadol taken orally after dental procedures provided good to satisfactory pain relief in cases of chronic periodontitis, pulpitis, and alveolitis [81]. Tramadol inadequately relieved pain from deep caries and acute purulent pulpitis. Ibuprofen enhanced the efficacy of tramadol.

A study of 128 healthy subjects who had undergone surgical extraction of the third molar was conducted to compare the analgesic efficacy of tramadol 75 mg/acetaminophen 650 mg to codeine 20 mg/acetaminophen 500 mg/ibuprofen 400 mg in the management of acute pain after oral surgery. When patients reported at least moderate pain after dental surgery (i.e., score greater than 5 on a 10-point scale), they were randomized to one of two treatment groups, which were similar in terms of baseline pain severity and demographic characteristics. The median times to onset of perceptible pain relief were 21.0 and 24.4 minutes, respectively, and the median times to the onset of meaningful pain relief were 56.4 and 57.3 minutes, respectively. Both the safety profile and the efficacy of the tramadol/acetaminophen combination were comparable to the codeine/acetaminophen/ibuprofen combination. Tramadol/acetaminophen provided rapid and effective analgesia for acute postoperative dental pain in this study group [82].

A controlled study of 200 patients compared the efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg, hydrocodone bitartrate 10 mg/acetaminophen 650 mg, and placebo in the treatment of postoperative dental pain. Patients were randomized to receive one or two tramadol/acetaminophen tablets, one hydrocodone bitartrate/acetaminophen tablet, or placebo. Scores for hourly pain relief, pain intensity difference, and combined pain relief/pain intensity difference were based on reported pain at 30 minutes and each successive hour for eight hours. Primary efficacy measures were summary pain intensity and pain relief scores, sum of pain intensity differences, and sum of pain relief/pain intensity differences for zero to four hours, four to eight hours, and zero to eight hours. Tramadol/acetaminophen tablets provided effective, rapid (i.e., less than 34 minutes), and dose-dependent analgesia for the treatment of postoperative dental pain. Two tramadol/acetaminophen tablets provided analgesia comparable to that provided by hydrocodone bitartrate/acetaminophen, but with better tolerability [83].

A meta-analysis of more than 1,000 patients compared the efficacy and time to analgesia of tramadol/acetaminophen combination tablet to tramadol or acetaminophen alone. Patients in each of three studies were evenly randomized to a single dose of tramadol 75 mg/acetaminophen 650 mg, tramadol 75 mg, acetaminophen 650 mg, or placebo. The results demonstrated that the combination tramadol/acetaminophen was superior to either tramadol or acetaminophen alone with respect to pain relief and duration of action [84]. A randomized, placebo-controlled study was conducted to evaluate the efficacy of a submucosal application of tramadol for acute postoperative pain following third molar extraction [85]. Sixty patients were randomly divided to receive either tramadol 1 mg or saline 2 mL, applied submucosally following surgery. There were no significant differences in the difficulty of the procedure or the duration of extraction between the two groups. Pain was evaluated using a visual analog scale postoperatively. The authors found no significant group differences in the visual analog scores both 24 and 48 hours postoperatively. The first analgesic was taken significantly later in the tramadol group compared to the saline group, and total analgesic intake in the saline group was significantly higher. Although further studies are needed to validate the efficacy of submucosal tramadol, it appears to be an effective, safe, and reliable method of reducing facial pain following third molar extraction [85].

Dosage and Side Effects

When taken orally, 75% of tramadol is absorbed into the bloodstream, and the onset of analgesia occurs within one hour. Food does not affect the rate or extent of absorption from the stomach. The time to peak serum concentration is two to three hours, and the serum half-life elimination is six hours [2,37].

The most common side effects of tramadol (1% to 10% incidence) are dizziness, constipation, and sleep disorder [4,37]. 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) [38].

Concomitant administration of tramadol and carbamazepine (Tegretol) increases tramadol metabolism significantly and is not recommended [38]. Quinidine inhibits liver metabolism of tramadol, thus increasing tramadol blood levels. The results of this interaction are presently unknown [38]. Concomitant administration of tramadol and MAO inhibitors increases the risk of seizures [38]. Tramadol has weak binding affinity to plasma proteins and, therefore, may be administered with protein-bound drugs, such as oral hypoglycemics and warfarin, with no fear of protein displacement of these agents causing toxic levels in the bloodstream [4].

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Seizure risk is increased with doses of tramadol above the recommended range [4]. Administration of tramadol may increase seizure risk in patients with epilepsy, and tramadol should be prescribed with caution to patients who use alcohol, opiates, phenothiazines, tranquilizers, or sedative hypnotics [4].

Suggested doses are 50–100 mg every four to six hours (up to 400 mg daily) as needed for pain. For moderate pain, 50 mg may be an adequate initial dose; for severe pain, 100 mg usually is more effective as an initial dose. Tramadol is supplied in tablets of 50 mg [2].

When to Use Tramadol

Tramadol is an interesting compound and is the first agent in a new class of analgesics that differs from the NSAIDs and traditional opioids. Although its efficacy in relieving dental pain resembles that of other analgesics, tramadol may be useful in cases in which NSAIDs are contraindicated (e.g., in patients who use anticoagulants, oral hypoglycemics, or lithium). Unlike NSAIDs, however, tramadol is not an anti-inflammatory agent. Tramadol causes nausea, constipation, and dizziness, and it may offer no advantage over opioid analgesics in terms of side effects. On the other hand, tramadol is neither a controlled substance nor addictive. Development of new analgesics like tramadol, which are more effective and cause fewer side effects than current dental analgesics, should be of therapeutic benefit.

TRAMADOL AND ACETAMINOPHEN (ULTRACET)

In 2001, the FDA approved a tablet formulation of the combination tramadol and acetaminophen under the brand name Ultracet. 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 [4,37]. 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 [37].

The efficacy of Ultracet against dental pain has been reported in the literature. 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 [84].

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 [86]. 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 [86]. Both ketorolac alone and the combination of ketorolac plus tramadol/acetaminophen showed relatively similar pain control [86].

The product 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 [37].

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 opioids [37].

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) [4,87]. Ultracet may be a good alternative in these situations.

GABAPENTIN (NEURONTIN)

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. The suggested dose 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, up to a maximum of 3,600 mg/day; however, daily doses >1,800 mg do not generally show greater benefit. Gabapentin is supplied in capsules containing 100, 300, or 400 mg; in tablets containing 100, 400, 600, or 800 mg; and in extended-release tablets containing 300, 450, 600, 750, or 900 mg. It is also available as an oral solution containing 250 mg/5 mL [2,4,37].

A multicenter, eight-week trial of 229 subjects from sixteen outpatient clinical centers was conducted to evaluate gabapentin for the treatment of postherpetic neuralgia. 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 [88].

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 [88].

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 [89].

There have been other reports on the effectiveness of gabapentin in treating neuropathic pain. 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 [2,90,91]. 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 [92]. 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 [93]. 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)

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 [2,37].

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 [2,37].

Adverse effects reported in more than 10% of users are [2,37]:

- Peripheral edema (up to 16%)

- Dizziness (8% to 45%)

- Somnolence (4% to 36%)

- Ataxia (1% to 20%)

- Weight gain (up to 16%)

- Xerostomia (1% to 15%)

- Tremor (up to 11%)

- Blurred vision (1% to 12%)

- Diplopia (up to 12%)

12. CONCLUSION

There is a myriad of analgesic products sold over the counter in drug stores and supermarkets as nonprescription pain relievers. People experiencing dental pain are likely to self-medicate with these nonprescription pain relievers before seeing the dentist. Therefore, it is important for dental professionals to have a clear understanding of the available agents for the control of dental pain.

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