Editor’s note: This is part two of a two-part series. Read part one here.
Pain, or the fear of pain, may be a powerful demotivator for patients to seek treatment from their dental hygienist, leading to poor outcomes for those patients in maintaining good oral health. Proper management of dental pain is essential to ensure our patients’ therapeutic success. However, dental pain is complex and multifactorial, and, thus, quite challenging to manage effectively and efficiently.
In the first installment of this two-part column, we discussed the concept and physiology of pain and the pharmacology of nonsteroidal anti-inflammatory drugs (NSAIDs) used in its management. In this second installment, we will explore the pharmacology of other agents used in the management of dental pain, specifically acetaminophen and opioid analgesics.
Acetaminophen is one of the most widely used over-the-counter (OTC) drugs in the United States today.1 Millions of consumers worldwide use an acetaminophen-containing product to manage fever and mild to moderate acute or chronic pain.1 For the treatment of more severe pain, acetaminophen is often formulated with nonopioid agents, such as ibuprofen, as well as opioids, such as codeine, hydrocodone, and oxycodone.
- Pharmacology in pediatric dentistry: Local anesthetics, analgesics, and antibacterial agents
- Local anesthetics, analgesics, and antibacterial agents in pediatric dentistry
Given the widespread use and accessibility of acetaminophen, it is interesting to note that there is still much we don’t know about the medication. For example, acetaminophen’s exact mechanism of action is still unknown. Acetaminophen is thought to act within the central nervous system to increase the pain threshold by inhibiting an enzyme called cyclooxygenase (COX), which is involved in prostaglandin synthesis. Prostaglandins are responsible for facilitating inflammation, pain, and fever. Acetaminophen inhibits both forms of the COX enzyme (COX-1 and COX-2) in the brain, but it does not inhibit prostaglandin synthesis in peripheral tissues. This explains why acetaminophen has very little peripheral anti-inflammatory effect.2 However, other research indicates that acetaminophen’s mechanism of action may involve inhibition of nitric oxide synthesis, downregulation of serotonergic pathways, interaction with endocannabinoid receptors, or perhaps a combination of all of these.2
To this day, confusion remains as to the maximum daily dose of acetaminophen that may be taken safely. Numerous sources available in a basic online search indicate that the maximum daily dose of acetaminophen for a healthy adult is 4,000 mg. However, to help encourage the safe use of acetaminophen, in 2011, the manufacturer of Tylenol (acetaminophen) lowered the labeled maximum daily dose for single-ingredient Tylenol Extra Strength (acetaminophen) 500 mg products sold in the United States from eight doses per day (4,000 mg) to six doses per day (3,000 mg). The recommended dosage interval also changed from two doses every four to six hours to two doses every six hours.3 However, the manufacturer of Tylenol also states that if pain or fever persists at this total labeled daily dose, health-care professionals may exercise their discretion and recommend up to 4,000 mg per day, adding that the efficacy and safety of Tylenol at 4,000 mg per day are well established.3
The relative “safety” of acetaminophen as an analgesic has also come under intense scrutiny. The number of cases of acetaminophen-induced liver toxicity has steadily increased, due to overdoses as a result of either acute ingestion of supratherapeutic doses or chronic ingestion of high therapeutic doses.4 Acetaminophen is metabolized in the liver via three separate pathways: glucuronidation, sulfation, and cytochrome P450 (CYP450) oxidation. While glucuronidation and sulfation are the primary routes of metabolism, a small amount of acetaminophen undergoes oxidative metabolism to create a liver-toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Normally, NAPQI is rapidly conjugated and inactivated with glutathione in the liver.3,5 However, acute ingestion of supratherapeutic doses or chronic ingestion of high therapeutic doses can deplete glutathione stores in the liver, resulting in liver toxicity.3,5
In addition, recent research has suggested that prenatal exposure to acetaminophen may alter fetal development, increasing the risks of some behavioral problems and hyperkinetic disorders.6 However, in its 2015 Safety Announcement, the US Food and Drug Administration (FDA) stated that the weight of evidence presented in the research is inconclusive regarding a possible connection between acetaminophen use in pregnancy and attention deficit hyperactivity disorder (ADHD) in children.7
The strategy of combining two analgesic agents having distinct mechanisms or sites of action has been advocated for many years. The combination of ibuprofen and acetaminophen has been promoted as an alternative therapy for opioids in the management of postoperative pain. In its Statement on the Use of Opioids in the Treatment of Dental Pain, the American Dental Association (ADA) indicated that “dentists should consider nonsteroidal anti-inflammatory analgesics as the first-line therapy for acute pain management and should recognize multimodal pain strategies for management for acute postoperative pain as a means of sparing the need for opioid analgesics.”8
The results of the many systematic reviews indicated that the combination of ibuprofen with acetaminophen may be a more effective analgesic, with fewer adverse effects, than many opioid-containing formulations. Several randomized controlled trials indicated that this combination provided greater analgesia without significantly increasing the adverse effects that often are associated with either drug as monotherapy or with opioid-containing analgesic combinations.9
Opioid analgesics produce their therapeutic effects by acting as agonists at the same receptors in the central nervous system that are normally activated by endogenous opioids called endorphins.10 The two opioid receptors responsible for opioid analgesic activity are the mu and kappa receptors. When stimulated, both mu and kappa receptors produce effects of analgesia, sedation, and, unfortunately, respiratory depression. In addition, stimulation of mu receptors in the peripheral gastrointestinal tissues may result in constipation.
Analgesia produced by mu receptor stimulation is seemingly unlimited with increasing doses. However, doses necessary to produce complete analgesia may also produce such significant adverse effects that their use is unwarranted.11 It is well known that stimulation of mu receptors may also cause dependence.11 After repeated administration, patients develop tolerance to the effects of opioids. Although tolerance to analgesia, sedation, and respiratory depression occurs simultaneously, no tolerance occurs to the constipating effects. Opioids may produce dependence in as little as five to seven days of therapy, and thus must be prescribed cautiously for patients who may become addicted to other substances.12
Opioid analgesics used in dentistry include codeine, hydrocodone, and oxycodone. Codeine only weakly binds to the mu receptor. It is considered a prodrug because 10% of each dose is converted to morphine by the cytochrome P450 enzyme CYP2D6. Therefore, drugs that inhibit the activity of CYP2D6, such as the selective serotonin reuptake inhibitor (SSRI) antidepressants fluoxetine (Prozac) and paroxetine (Paxil), may make codeine less effective. Hydrocodone is also acted upon by CYP2D6 whereas oxycodone is not.13 This makes oxycodone a better choice for patients taking medications known to inhibit CYP2D6.
Hydrocodone and oxycodone are more effective analgesics than codeine due to their greater affinity for the mu receptor. Their potency allows for lower doses of these agents and reduces the incidence of nausea compared to codeine. While it is not uncommon for patients to report episodes of nausea as an “allergy,” almost all opioids are capable of triggering degranulation of mast cells, leading to the direct release of histamine.14
Tramadol is an analgesic that inhibits the reuptake of norepinephrine and serotonin, thereby altering descending neural pathways that transmit incoming pain impulses. While this action may be effective in managing chronic pain, it may not be as beneficial in managing acute odontogenic pain.15 In addition, a metabolite of tramadol, O-desmethyltramadol, does have agonist activity at mu receptors.15 Once again, formation of this metabolite is accomplished by the CYP2D6 enzyme, so tramadol is also subject to the same risk for drug interactions as codeine and hydrocodone.
Summing it up
While dental pain is very subjective and often difficult to measure, it is very real to our patients and may keep them from seeking dental hygiene treatment. Dental hygienists can help improve patient outcomes by understanding the complexity of pain, the factors that determine its expression, and the agents employed in its management.
Editor's note: This article appeared in the September 2022 print edition of RDH magazine. Dental hygienists in North America are eligible for a complimentary print subscription. Sign up here.
- Acetaminophen. Consumer Healthcare Products Association. Accessed July 1, 2022. https://www.chpa.org/our-issues/otc-medicines/acetaminophen
- Hersh EV, Dionne RA. Nonopioid analgesics. In: Dowd FJ, Johnson BS, Mariotti AJ, eds. Pharmacology and Therapeutics for Dentistry. 7th ed. Mosby Elsevier; 2011:257-276.
- Tylenol professional product information. Johnson & Johnson Consumer Inc. McNeil Consumer Healthcare Division. Accessed July 1, 2022. https://www.tylenolprofessional.com/adult-dosage
- Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure [published erratum appears in Am J Gastroenterol. 2008;103(1):255]. Am J Gastroenterol. 2007;102(11):2459-2463. doi:10.1111/j.1572-0241.2007.01388.x
- McGill MR, Hinson JA. The development and hepatotoxicity of acetaminophen: reviewing over a century of progress. Drug Metab Rev. 2020;52(4):472-500. doi:10.1080/03602532.2020.1832112
- Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320. doi:10.1001/jamapediatrics.2013.4914
- FDA has reviewed possible risks of pain medicine use during pregnancy. US Food and Drug Administration. Drug Safety Communications. January 9, 2015. Accessed July 1, 2022. https://www.fda.gov/media/90209/download
- Oral analgesics for acute dental pain. American Dental Association. Updated September 15, 2020. Accessed July 1, 2022. https://www.ada.org/en/member-center/oral-health-topics/oral-analgesics-for-acute-dental-pain
- Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice. J Am Dent Assoc. 2013;144(8):898-908. doi:10.14219/jada.archive.2013.0207
- Stein CS. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995;332(25):1685-1690. doi:10.1056/NEJM199506223322506
- Piletta P, Porchet HC, Dayer P. Central analgesic effect of acetaminophen but not aspirin. Clin Pharmacol Ther. 1991;49(4):350-354. doi:10.1038/clpt.1991.40
- Gutstein HB, Akil H. Opioid analgesics. In: Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. McGraw-Hill; 2006.
- Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613-624. doi:10.1016/S0025-6196(11)60750-7
- Weiss ME, Adkinson Jr NF, Hirshman CA. Evaluation of allergic drug reactions in the perioperative period. Anesthesiology. 1989;71(4):483-486.
- Moore PA, Crout RJ, Jackson DL, Schneider LG, Graves RW, Bakos L. Tramadol hydrochloride: analgesic efficacy compared with codeine, aspirin with codeine, and placebo after dental extraction. J Clin Pharmacol. 1998;38(6):554-560.