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Following dental surgery, the oral administration of prescription analgesics is a common practice in dentistry.1 A recent survey of 384 oral and maxillofacial surgeons found only two respondents who do not prescribe an immediate-release opioid pain reliever following third molar extractions.2 Yet, the remarkable efficacy of many nonopioid analgesics has been repeatedly reported following this common dental surgery. Adjunctive strategies to manage acute postoperative pain in oral surgery, such as the use of long-acting local anesthetics and preoperative analgesics, have relied on findings that have used the third molar extraction model. Because pain following third molar extraction is a clinical research model used for the development of almost all analgesics currently marketed, our knowledge of safety and efficacy of analgesic drugs, particularly nonopioid analgesics, is immense.
The Cochrane Collaborative has used clinical publications of individual drug trials to complete meta-analyses that establish the relative efficacy of available analgesics when studied following third molar surgery. These quantitative systematic reviews are possible by creating a common analgesic statistic that can be then used to compare results of one study to another. The calculated statistic used in the Cochrane Reviews is the “number needed to treat” (NNT) and is defined as “the number of patients needed to be treated to obtain one additional patient achieving at least 50% maximum pain relief over 4 to 6 hours compared to placebo.”3,4 When comparing different medications, one can see that the lower the NNT, the more effective the analgesic drug therapy (Table 1). One should note that the nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, are at least as effective in managing postoperative dental pain as the opioid pain relievers (OPRs).
Strategy 1:NSAIDs and Steroids
Postoperative pain is an expected consequence of dental surgery, and its severity can often be predicted. Postoperative pain is associated with inflammation and may be accompanied by significant swelling. Inflammation and edema may be particularly significant when the surgery is prolonged and when large areas of gingiva, oral mucous, and bone are manipulated. Although inflammation normally occurs postoperatively and is a functional part of the healing process, when severe, healing may be compromised. Pain and trismus associated with swelling may inhibit adequate oral hygiene and may limit food intake. Careful surgical technique that avoids prolonged tissue retraction is effective in limiting tissue damage and inflammation. Ice packs immediately following surgery may have additional benefit.
Because postoperative pain can be expected, an effective strategy to decrease its severity and onset is to administer a peripherally acting analgesic preoperatively.5-7 In recent years, the use of NSAIDs administered prior to surgery to prevent expected postoperative pain in dentistry has been advocated.5 Administering NSAIDs prior to surgery (eg, ibuprofen 400 to 600 mg) has been shown to delay the onset of pain and decrease the overall severity of discomfort.6-8
NSAIDs such as ibuprofen may limit the pain associated with boney impaction removal.9 However, the anti-inflammatory properties of preoperative NSAIDs are modest at best. When the surgery is expected to produce significant edema, a short-term therapeutic regimen using an anti-inflammatory steroid is recommended.
Glucocorticoids appear to inhibit all phases of inflammation, blocking the increased capillary permeability, migration of leukocytes, and the synthesis of a protein inhibitor of phospholipase A2, as well as blocking inflammatory metabolites of arachidonic acid such as prostaglandins, thromboxanes, and prostacyclins.10
Several authors have demonstrated the efficacy of glucocorticoids for oral surgical procedures. Hooley and Frances11 performed a double-blind, randomized, controlled study and observed six times less edema within patients receiving steroid treatment. In addition, patients treated with glucocorticoids had one half the pain and one half the trismus as patients receiving placebo. Similarly, Skjelbred and Lokken12 report that even when the corticosteroid was injected 3 hours after oral surgery, swelling was reduced 47% compared to placebo. In addition, an average of 11 codeine tablets were taken for pain in the steroid group compared to 26 tablets when a placebo was injected. Mouth opening was reduced 18% on the third postoperative day versus 46% decreased opening with placebo. There is some indication that the combination of a NSAID and a steroid may provide additional pain relief after surgery.13
The authors suggest several principles for short-term steroid therapy. The chosen steroid should have minimal mineralocorticoid effects. The drug should be administered before or during surgery, allowing an optimal effectiveness at the time of initial tissue trauma. It is preferably given in the morning, when the body naturally releases cortisol. This schedule interferes least with the normal adrenal system. The steroid regimen should not exceed 3 days. The dose should not exceed 300 mg of cortisol equivalence, administered the morning of surgery, which corresponds to the maximum reported amount of natural glucocorticoid released during trauma, surgery, or infection.
Steroid dosing varies a great deal among clinicians. Doses that have been recommended include dexamethasone 8 to 10 mg10,13,14, or methylprednisolone 16 to 32 mg.15-17 Utilizing this approach to short-term steroid therapy, the practitioner is optimizing the benefits while minimizing the risks. A steroid regimen is not indicated if the patient has a history of tuberculosis, ocular herpetic simplex, or acute glaucoma or if active infection exists because of their immunosuppressant effects.
Strategy 2:Cautious Use of Acetaminophen
Acetaminophen or APAP (the acronym for its chemical name, acetyl-p-aminophenol) is a recognized safe and effective analgesic and antipyretic medication. Known as paracetamol outside of the United States, it is available as an over-the-counter (OTC) agent throughout the world, and is commonly marketed under the brand name of Tylenol® (McNeil-PPC, www.mcneil-consumer.com). The popularity of acetaminophen has been attributed to its relative safety, efficacy, and affordability.
The Food and Drug Administration (FDA) has alerted practitioners of potential liver toxicity associated with excessive dosing with APAP.18 Acute liver failure caused by intentional and unintentional consumption of excessive APAP has been reported.19 Toxicity induced by APAP has been reported when a daily dose of 4,000 mg is exceeded.20 To prevent excessive consumption, the FDA has requested that the dose of APAP contained in prescription opioid/APAP analgesics be limited to a maximum of 325 mg.21 Consequently, formulations such as Vicodin HP® (AbbVie Inc., www.abbvie.com), which previously contained APAP 750 mg/hydrocodone 7.5 mg have recently been reformulated to contain a maximum of APAP 300 to 325 mg.22
When prescribing APAP for the management of acute postoperative pain, one must be careful to limit the dosing regimen to avoid potential overdose. Although the FDA has not mandated a reduction of APAP’s total daily dose, continuing concerns of potential hepatic toxicity have resulted in Tylenol’s manufacturer voluntarily reducing its APAP daily dose recommendation from 4,000 mg to 3,000 mg. The FDA has additionally strengthened warnings on acetaminophen labeling and packaging with regard to the risks of possible liver damage from an overdose, concurrent use of multiple acetaminophen-containing products, and concomitant use of alcohol.
While a single dose of APAP 1000 mg may be tolerated, multiple daily doses of APAP should not exceed 500 mg every 4 hours or 650 mg every 6 hours. Patients should be cautioned to follow dosing instructions and avoid consuming any of the many other OTC products that contain APAP. If a rescue medication containing an opioid is believed to be necessary, an equally or more effective hydrocodone or oxycodone formulation containing ibuprofen instead of APAP (ie, Vicoprofen®, AbbVie Inc.; Combunox®, Forest Laboratories, Inc., www.frx.com) are alternatives.
Strategy 3:Long-Acting Local Anesthesia
The primary local anesthetics used in dentistry today are classified as amide agents. Lidocaine and mepivacaine, two of the most commonly used agents, have proven to effectively and safely provide local anesthesia for dental therapies. The amide local anesthetics are preferred because they more rapidly, reliably, and safely produce profound anesthesia.23 One of these amide local anesthetics, bupivacaine, has found a place in dentists’ pain management armamentarium; with its long duration, bupivacaine plays a valuable role in the overall management of surgical and postoperative pain associated with dental care.24,25
Bupivacaine is structurally similar to mepivacaine except for a butyl (four carbon) substitution of the methyl (one carbon) group in the molecule. This addition to the chemical structure of mepivacaine alters the clinical characteristics of bupivacaine by enhancing the lipid solubility, increasing its pKa, and strengthening its protein binding properties as compared to its shorter-acting analogues. Bupivacaine’s long duration is due, in part, to its distinctly different protein binding characteristics. The difference in its ionized properties may contribute to bupivacaine’s longer duration and somewhat slower onsets times for anesthesia.26
Following mandibular blocks, Chapnick found onset times until maximum surgical anesthesia of 8.5 minutes for bupivacaine compared to 4.5 minutes for lidocaine.27 Nespaca also reported a slight delay of initial onset for bupivacaine compared to lidocaine.28 Similarly, Trieger and Gillen29 reported a slightly slower onset (<2 minutes difference) when bupivacaine and mepivacaine were compared.
The use of long-acting local anesthetics to alleviate pain following third molar extractions has consistently and repeatedly been demonstrated. Trieger and Gillen’s evaluation in 1979 provides a good example of bupivacaine’s clinical efficacy.29 Patients undergoing third molar extractions involving bone removal were administered 0.5 % bupivacaine without epinephrine, 0.5% bupivacaine 1/200,000 epinephrine, or 3% mepivacaine. The patients receiving bupivacaine with epinephrine had a mean duration of anesthesia of 7.0 hours (versus 2.9 hours for mepivacaine) and required the fewest doses of postoperative narcotic analgesics. A recent evaluation of bupivacaine used in combination with the steroid prednisolone determined that the combination provide excellent reduction of pain and swelling following third molar extractions.17 Pain management using bupivacaine has also been demonstrated following endodontic and periodontic procedures.30,31
Formulations of 0.5% bupivacaine 1/200,000 epinephrine are marketed as Marcaine® (Carestream Health Inc, www.carestreamdental.com) and Vivacaine® (Septodont, www.septodontusa.com) and are available in 1.8-cc dental cartridges. When moderate to severe pain is expected, a long-acting local anesthetic can delay the onset of pain, reduce the severity of pain, and decrease the need for strong oral analgesics. A combination strategy using a prophylactic NSAID, a long-acting anesthetic, and then dosing around the clock with the NSAID rather than as needed for the first 48 hours may provide maximal comfort.32 Overall patient satisfaction for this pain management strategy requires some explanation of expectations. Because of possible lip and tongue self-mutilation, bupivacaine is not recommended for children younger than 12 years of age.
Strategy 4:Combinations of APAP and NSAIDs
Several recent publications have stirred interest in providing postoperative pain relief by combining two nonopioid analgesics: ibuprofen and APAP.33,34 The rationale for this combination is that one should see additive effects if the two analgesic drugs work at different pathways in the body. In 2013, Moore and Hersh35 assessed the clinical evidence supporting an ibuprofen-APAP analgesic drug combination by reviewing quantitative reports published by the Cochrane Collaborative that assessed the efficacy and safety of NSAIDs, APAP, and analgesic combinations when administered for postoperative dental pain management.
The Cochrane Database of Systematic Reviews Library contains 59 reviews categorized as pharmacologic treatments for anesthesia and pain control.3,4 The NNTs for common oral analgesics used for treatment of postoperative pain (Table 1) indicate the relative effectiveness of single-entity drugs and drug combinations. The combination of APAP and ibuprofen has the lowest NNT (1.6), demonstrating its possible superiority to ibuprofen alone (NNT = 2.7) and APAP alone (NNT = 3.2). Care must be taken when interpreting this calculation because of the relatively small number of studies compared to the other analgesic drugs analyzed.
The most recent evaluation of an ibuprofen-APAP combination was completed by Daniels and colleagues.36 This comprehensive clinical trial enrolled 678 subjects to compare placebo and four combination therapies. Subjects who received the higher dose combination of ibuprofen 400 mg/APAP 1000 mg had significantly less pain than subjects receiving the ibuprofen/codeine combination, the APAP/codeine combination, the lower dose combination of ibuprofen 200 mg/APAP 500 mg, or placebo.
In establishing a drug strategy of this combination, one must be alert to exceeding APAP maximum daily dose recommendations (Strategy #2 above). A dosing recommendation of APAP 500 mg combined with ibuprofen 400 mg taken every 6 hours maximizes benefits and safety for this nonopioid combination analgesic therapy. As indicated in Table 2, the combination of APAP and ibuprofen has been included in published guidelines for management of postoperative pain and provides an alternative to prescribing opioids for moderate to severe pain.35
Strategy 5:Responsible Prescribing of Opioid Analgesics
Prescription opioid analgesics are widely accepted as essential medications for treating severe postoperative pain. However, opioid analgesics have both unpleasant side effects (ie, nausea, vomiting, constipation) and pleasant side effects (ie, feelings of well being, euphoria). The euphoria associated with opioid pain relievers may attract patients to misuse or abuse opioid prescriptions. It is important for dentists to be informed of the potential for drug abuse and misuse associated with prescribing opioid analgesics, particularly to adolescents.37
Opioid analgesics, such as Vicodin® (AbbVie Inc.), Percocet® (Endo Pharmaceuticals, www.endo.com), and Oxycontin® (Purdue Pharma L.P., www.purduepharma.com) are the most frequently abused of the prescription drugs.38 For the management of severe pain, OPRs are formulated with the hydrocodone, oxycodone, and codeine. These three opioids, usually formulated in combination with acetaminophen, were ranked 1st, 19th, and 67th, respectively, among the 200 most frequently prescribed drugs in the United States.39
A survey of the analgesics prescribed by practicing oral and maxillofacial surgeons found similar ranking when selecting opioids for postoperative pain management.25 Among those who responded to this national survey, the most common analgesic prescriptions written to manage postoperative pain following the extraction of third molars were the combination of hydrocodone with acetaminophen (eg, Vicodin; Lorcet®, Forest Laboratories, Inc., www.frx.com; etc) and the combination of oxycodone with acetaminophen (eg, Percocet; Roxicet®, Roxane Laboratories, Inc, www.roxane.com). Instruction for use almost always directed the patient to take these analgesics “as needed” for pain. The average number of tablets dispensed following the removal of third molars was 20 tablets.1,2
The quantities of opioid analgesics prescribed for the management of postoperative pain are often greater than required for pain relief. Although oral surgeons were found to write a prescription for an average of 20 tablets of Vicodin or Percocet, significantly fewer (ie, 8-12 tablets) are likely required or used by most surgical dental patients. Welland and colleagues reported results of telephone interviews with patients who had been prescribed on average 20 tablets of hydrocodone/APAP following third molar surgery. They found that only 10 tablets were taken on average during the week following surgery.40
Unused drugs left in a medicine cabinet certainly have the potential for misuse. The American Dental Association (ADA) has posted written guidelines for opioid use and a research agenda to assist other agencies.41 As described in Table 3, it is the dentist’s responsibility to limit the number of tablets that are being prescribed. One should consider alternatives for pain control, inform patients not to share their medications with anyone, and alert patients (and parents) to maintain secure storage of OPRs as well as dispose of excess drugs properly.
Conclusion
Prescribing oral postoperative analgesics should not be the sole strategy for postoperative pain control. Adjunctive pain control therapies can limit postoperative discomfort to an extent that severe pain is less likely (Table 4). NSAID analgesics administered prior to surgery have been found to limit and delay postoperative pain. The use of the glucocorticoid dexamethasone has been reported to be effective in limiting trismus, swelling, and pain following third molar surgery. The use of the long-acting local anesthetic bupivacaine to provide extended soft tissue and periosteal anesthesia/analgesia has been demonstrated to be an effective strategy to limit the need for oral analgesics. Additionally, the use of a combination of peripherally acting analgesics such as ibuprofen with APAP has been demonstrated to enhance pain relief. All of these strategies should be included in a dentist’s armamentarium to provide safe and effective methods to limit the need for prescription opioids following dental surgery.
Disclosures
Within the past 10 years, Dr. Paul A. Moore has served as medical director and/or research consultant to several pharmaceutical companies regarding development of new local anesthetics for dentistry. These companies include DENTSPLY Pharmaceutical Division, Kodak Dental Systems, Septodont USA, St. Renatus, and Novocol of Canada Inc. He has also served as an investigator for FDA-required Phase II and Phase III clinical research contracts awarded to the University of Pittsburgh by Wyeth Consumer Healthcare, Novocol of Canada Inc., and Novalar Pharmaceutical Inc.
Within the past 10 years, Dr. Elliot V. Hersh has served as a consultant for McNeil Pharmaceutical, the maker of Tylenol products. In addition, he has served as a principal investigator for FDA-required Phase II and Phase III clinical research grants awarded to the University of Pennsylvania by Pfizer Consumer Healthcare, Charleston Laboratories, Novocol of Canada Inc., and Novalar Pharmaceutical Inc.
About the authors
Paul A. Moore, DMD, PhD, MPH
Professor of Pharmacology and Dental Public Health
Department of Dental Public Health
University of Pittsburgh School of Dental Medicine
Pittsburgh, Pennsylvania
Elliot V. Hersh, DMD, MS, PhD
Professor of Pharmacology
Department of Oral Surgery and Pharmacology
University of Pennsylvania School of Dental Medicine
Philadelphia, Pennsylvania
Dr. Paul A. Moore received his DMD and a PhD in pharmacology from the University of Pittsburgh School of Dental Medicine. His professional career has included private practice in Oakmont, Pennsylvania, a hospital residency in dental anesthesiology at the Presbyterian Hospital Medical Center in Pittsburgh, a postdoctoral fellowship in chronic pain management at the University of North Carolina, and faculty appointments at Harvard School of Dental Medicine, University of Massachusetts Medical Center, and Forsyth Dental Center. Dr. Moore has served as Director of the Oral Health Science Institute, Director of Research, Director of Graduate Education, and Chair of the Department of Dental Anesthesiology for the University of Pittsburgh School of Dental Medicine. He is a member of the editorial boards of several journals including the Journal of American Dental Association. He has recently been asked to serve on the U.S. Surgeon General’s Expert Panel of Prescription Drug Abuse.
Dr. Moore is active in clinical dental research, having served as the principal investigator of over 40 clinical research projects sponsored by the NIH as well as the pharmaceutical industry. Additionally, he has authored over 250 scientific articles on clinical pharmacology/dental therapeutics in peer reviewed journals and has presented over 150 invited lectures throughout the world on the topics of local anesthetics, antibiotics, analgesics, sedation, drug interactions, and oral complications of diabetes.
Queries to the authors regarding thisCE may be submitted toauthorqueries@aegiscomm.com.
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