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Topical anesthetics are used for a variety of purposes in dentistry, including pre-injection pain management, minimization of gag reflexes, localized soft-tissue procedures, and, in some instances, profound anesthesia of tissues in treatment areas. Available in a variety of forms, topicals are dispensed as liquids, gels, creams, ointments, metered and unmetered sprays, subgingival gels, compounded formulations (that sometimes include vasoconstrictors), and eutectic mixtures. For examples of topical anesthetic categories, see Table 1.
Compounded topical anesthetics are prescription alternatives, formulated by compounding pharmacists, to standard commercially prepared agents. These preparations have similar effects to commercial products. Many include long-acting topical anesthetics and/or vasoconstrictors that provide greater depths and durations of anesthesia.
When considering compounded products, it is important to be familiar with the pharmacy compounding law, which is part of the Food and Drug Administration (FDA) Modernization Act of 19971 as well as the Drug Quality and Security Act that was subsequently enacted in 2013.2 Among other provisions, the 2013 revision makes a clear distinction between traditional pharmacy compounding (exempted from the act) and pharmacies making large volumes of compounded drugs without a prescription in hand.3 FDA-registered 503B outsourcing facilities are "not required to be a licensed pharmacy, and … may or may not obtain prescriptions for identified individual patients."4 Before purchasing, clinicians should familiarize themselves with these guidelines as well as those in the jurisdictions in which they practice. Copies of the acts, including further information, are available at www.fda.gov.
Eutectic topical local anesthetic mixtures provide for faster onsets and greater depths of penetration on both skin and mucosa. Enhanced properties of eutectic mixtures result in part from higher concentrations of base molecules when compared with any of their individual ingredients.5
Extensively used in medicine, refrigerants provide a non-pharmaceutical means of topical anesthesia by inhibiting neural function via rapid evaporation.6,7 Refrigerant topical agents offer a more rapid pre-injection anesthesia onset than topicals commonly used in dentistry, without adding to the maximum recommended dosage of drugs administered.
Overuse and Toxicity
The FDA has issued public health advisories reminding health care professionals that benzocaine anesthetic sprays can cause methemoglobinemia. Methemoglobinemia, a serious life-threatening condition characterized by higher-than-normal levels of methemoglobin in the blood, is a known side effect of benzocaine sprays. The risk is increased when practitioners use multiple sprays and/or sprays of longer duration than recommended; however, the FDA has noted that instances of a single spray have also resulted in methemoglobinemia. This is likely because of the varying applications of the term, single spray, and differences in the remaining volumes in cans. Variations exist among manufacturers regarding the volume of benzocaine each spray delivers, the concentration of benzocaine in each solution, differences in instructions for actuator use, and overall spray technique.8 The FDA provides the following information regarding potential benzocaine spray toxicity:
A review of the cases indicates that the development of methemoglobinemia after treatment with benzocaine sprays may not be related to the amount applied. In many cases, methemoglobinemia was reported following the administration of a single benzocaine spray. In other cases, methemoglobinemia resulted after excessive amounts were used. The amount of benzocaine contained in a single spray varies across the different products. It depends on the concentration of the solution, the amount of time the actuator is depressed, the residual volume in the can, and the spatial orientation of the can during spraying. Symptoms may appear within minutes to one or two hours after using benzocaine.8
Benzocaine sprays are used to anesthetize mouth and throat mucous membranes when preparing patients for minor surgery, endoscopic procedures, and endotracheal intubation. These practices are not unlike benzocaine sprays to manage gagging during radiographic procedures and prior to taking impressions in dentistry.
Warnings regarding non-spray benzocaine applications primarily focus on OTC oral drug products, including infant teething remedies. When discussing the safety of benzocaine-containing oral products, the FDA makes the following statement:
Benzocaine can cause a serious condition in which the amount of oxygen carried through the blood is significantly reduced. This condition, called methemoglobinemia, is life-threatening and can result in death. Therefore, the FDA is warning that OTC oral drug products containing benzocaine should not be used to treat infants and children younger than two years. We also warn that benzocaine oral drug products should only be used in adults and children two years and older if they contain specific warnings on the drug facts label. These products carry serious risks and provide little to no benefit for treating oral pain, including teething.9
In the absence of spray benzocaine, excessive application, and benzocaine use in children two years and younger or other susceptible populations, typical pre-injection pain management is widespread and does not appear in warnings. The FDA is constantly reviewing safety data for these products to determine if and when additional action is warranted.
Topical preparations of prilocaine are unlikely to result in serious adverse reactions; however, prilocaine's metabolite, ortho-toluidine, can induce the formation of methemoglobinemia, particularly in doses that exceed prilocaine's maximum recommended dosage. This is usually not an issue when the maximum recommended doses are observed and are applied topically; however, methemoglobinemia has occurred in at least one case when less than the maximum dose of prilocaine was administered by oral injection, and specific dose recommendations for young people are not yet definitive .10
Package inserts for Oraqix® (Dentsply Sirona), a subgingival 2.5% lidocaine, 2.5% prilocaine topical preparation, include the following language:
Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.
Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ORAQIX and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.11
While primarily referring to injectable dosing, a 2009 summary of 242 episodes of methemoglobinemia recommended that prilocaine doses be limited.12
Although more typically acquired, methemoglobinemia may be either acquired or congenital. Prilocaine consistently reduces the oxygen-carrying capacity of blood and has been described as having a stronger methemoglobinemia-inducing potential than benzocaine.13
Clinicians should be aware of a 2006 FDA advisory, which was updated and re-issued in 2011, that states, "Patients who have breathing problems such as asthma, bronchitis, or emphysema, patients with heart disease, and patients who smoke are at greater risk for complications related to methemoglobinemia…"8 Fortunately, while the potential for adverse reaction exists, most incidents that led to FDA advisories regarding benzocaine and prilocaine did not occur due to their use in dentistry. However, dental professionals must evaluate the products they use to avoid adverse reactions.
Many available topicals are formulated in higher concentrations compared to their injectable counterparts.5 It is also important to note that maximum dose recommendations do not always exist for many topical products, and the FDA has noted that product instructions can be confusing and may lead to product misuse even when manufacturers have provided maximum recommended doses.5 For example, one manufacturer's package insert included more than one set of instructions. Another did not refer to dose, while another indicated that the recommended dose was a half-second spray from an unmetered delivery device. To reduce the risk of adverse reactions and avoid confusion, clinicians are advised to read the manufacturer's instructions, watch for updates, and ask for clarification whenever instructions are unclear.
Some product literature recommends reducing doses in debilitated, medically compromised patients, and young children. Questions sometimes arise when following these recommendations; for example, how are appropriate doses determined? Are dose recommendations realistic to apply? If maximum safe limits are not provided, and actual uptake percentages are unknown because of dilution and loss of topical agents through saliva, how are clinicians expected to add these amounts to the overall amount of drug delivered? These questions pose specific risk-benefit concerns, especially when using topicals without established maximum safe limits. They also pose questions when maximum safe limits are provided, but reliable dose metering methods are lacking. It is always advisable to deliver the least amount of topical anesthetic needed for the desired pain management.
Despite these precautions, topical anesthetic is delivered safely to a significant global patient population daily, and for many, if not most, has an important role when providing comfortable therapeutic and diagnostic procedures.
Commonly Used Topical Agents
Benzocaine, one of the most common topical anesthetics, is an ester that is nearly 100% in the nonionic (neutral base) form, with only limited absorption occurring into the systemic circulation.14,15 Benzocaine, therefore, has a very low potential for CNS and CVS toxicity in healthy individuals.14,15 It is available in liquid, gel, and spray forms in concentrations ranging from 6% to 20%. The most commonly used concentration in dentistry is 20%, which provides an adequate topical effect in 30 seconds and an optimal effect in 2 minutes to 3 minutes. Duration is 5 minutes to 15 minutes.
Lidocaine, an amide, is an excellent alternative to esters and is especially useful whenever esters are contraindicated, such as sensitivity, medication conflict, or when patients cannot safely metabolize esters.5 Lidocaine is available in 2% to 5% concentrations in ointment, liquid, and gel forms. Onset is 2 minutes to 10 minutes, and duration is approximately 15 minutes.
Prilocaine, an amide, is used in combination with other topicals in dentistry. It has a favorable metabolic pathway that detoxifies the drug in the lungs and kidneys, in addition to the liver.5 The alternate metabolic pathways largely provide prilocaine with the highest maximum recommended dosage of all amide anesthetics. The contribution of prilocaine to the overall maximum recommended doses of combinations is variable, depending on dose and the specific product in which it is contained. When reported, the maximum recommended dose of each product can be found in its package inserts. Typical percentages of prilocaine in topical combinations range from 2.5% for subgingival application to 10% in compounded formulations.
Dyclonine hydrochloride is available in 0.5% and 1% solutions. It is a non-ester, non-amide, ketone topical anesthetic. Dyclonine provides a relatively safe and durable alternative to other topical agents.5 With a slow onset of between 2 minutes to 10 minutes and a duration of about 30 minutes, it is particularly useful for patients who have experienced hypersensitivity to esters or amides and in all patients when longer topical durations are desired. In addition to its use as a topical anesthetic in dentistry, dyclonine hydrochloride is an active ingredient in several over-the-counter products.5 Similar to benzocaine, dyclonine lacks an injectable formulation.
Tetracaine is a potent ester local anesthetic currently only used in topical combinations in dentistry. As a non-addictive cocaine substitute, it is many times more potent than cocaine with a significant potential for toxicity compared to other commonly used topicals.5 Excessive doses and too frequent administrations should be avoided.5 Providing deep and durable topical anesthesia, it is found in many compounded products and at least one non-compounded 2% mixture with 14% benzocaine, a fast-onset, short-acting topical, and 2% butamben (n-butyl p-aminobenzoate), an intermediate-onset, intermediate-acting topical. Along with benzocaine and butamben, tetracaine's slow-onset, long-acting topical effect adds significantly to the product's rapid onset and profound, highly durable effect.16
Eutectic mixtures of local anesthetics (EMLAs) provide enhanced topical benefit due to their more efficient diffusion through the skin when compared with individual ingredients acting alone.5 While non-eutectic topicals in dentistry frequently provide equally effective diffusion through more easily penetrated mucosal barriers; eutectics provide greater depth and duration of anesthesia. One eutectic mixture designed explicitly for subgingival use in dentistry is supplied as a combination of 2.5% lidocaine and 2.5% prilocaine.11 After a relatively rapid onset of 30 seconds, this subgingival formulation provides up to 20 minutes of soft tissue anesthesia. Its unique formulation transitions from a low-viscosity liquid (oil) at room temperature to an elastic gel once placed subgingivally (referred to as a microemulsion in a thermosetting mixture with reversible temperature-dependent gelation).17 Another unique feature of this topical is its neutral pH, which may protect tooth structures in subgingival environments.
Precautions and Contraindications
As previously stated, many topical anesthetics are formulated in higher concentrations than injectable anesthetics to be effective when applied directly onto skin or mucosa. Although toxic reactions are rare, adverse reactions may be due to excessive application and/or rapid absorption, idiosyncrasy, hypersensitivity, or decreased patient tolerance.5 These risks should be considered when applying topicals. All providers are obligated to read package inserts, track time intervals between successive applications, and monitor administered doses when maximum recommended doses are provided.
Common, non-life-threatening, local reactions include tissue sloughing, delayed hypersensitivity, redness, pain, and/or burning at application sites. Because many topical anesthetics, such as benzocaine (pH 2.0), are acidic, observing manufacturer maximum limits on application times decreases the potential for tissue injury. Pre-existing tissue trauma at application sites, prolonged mucosal contact, and hypersensitivity increases the likelihood of a local reaction. Discontinuation of the specific agent or agents and palliative treatment are usually sufficient to resolve any issues.
Considerations may be given to selecting topicals when they are placed subgingivally for multiple teeth, for example, during periodontal therapy. Many topicals have low pH levels that may contribute to demineralization of tooth structures and/or post-operative sensitivity, below a pH of 5.5.
Of the most frequently used topicals, benzocaine and tetracaine are more likely to cause contact sensitivity.15 Allergic reactions to ester topical agents occur with greater frequency than with amides, where allergy reports are rare.5,13 Despite the very low allergenic potential of topical amide anesthetics, some multidose preparations of amides may contain methylparaben. This ester preservative was banned in cartridges in 1984 due to an increased risk of hypersensitivity.5 Its use is infrequent today, but some multidose topical preparations may contain methylparaben.
Systemic reactions are possible with both injectable and topical drugs. Excessive volumes increase risk significantly. As with injectable counterparts, systemic reactions to topical agents range from subclinical to life-threatening. They may manifest as mild symptoms of CNS depression, such as restlessness, agitation, and increased heart rate, to more severe signs and symptoms, such as convulsions and respiratory depression. They may also manifest as mild to severe complications of methemoglobinemia, including lethargy, cyanosis, and respiratory difficulty.17-19 While the potential for adverse reactions exists, most incidents that have led to FDA advisories did not occur due to the use of topical anesthetics in dentistry; however, dental professionals must evaluate the products they use to avoid the overuse of all anesthetics. Evaluating compounded topical anesthetic agents, particularly, to ensure they are properly dispensed is also key to patient safety.
Summary
Topical anesthetics have a long, well-deserved record of safety in dentistry and will continue to provide comfort into the foreseeable future. As questions arise regarding the safest use of topical products, dental clinicians should consider the risks and benefits for each patient while keeping in mind that more is not better and that topicals should be applied judiciously. Consulting product and safety information, communicating with product representatives and local anesthesia experts when questions arise, and seeking out published product data from research are recommended best practices.
About the Authors
Arthur C. DiMarco, DMD
RIDE Director and Affiliate
Assistant Professor
University of Washington
School of Dentistry
Spokane, Washington
Kathy B. Bassett, BSDH, RDH, MEd, QOM
Professor of Dental Hygiene
Pierce College
Lakewood, Washington
Affiliate Professor, Department of Oral Health Sciences
School of Dentistry, University of Washington
Seattle, Washington
Mustafa Radif, BDS, RDHAP, MA
Assistant Professor of Periodontics/Dental Hygiene
Arthur A. Dugoni School of Dentistry
University of the Pacific
San Francisco, California
References
1. Food and Drug Administration Modernization Act of 1997, S 830, 105th Cong, Public Law 115 (1997). Congress.gov website. https://www.congress.gov/105/plaws/publ115/PLAW-105publ115.pdf. Published November 21, 1997. Accessed June 7, 2022.
2. Drug Quality and Security Act, HR 3204, 113th Cong, Public Law 113-54 (2013-2014). Congress.gov website. https://www.congress.gov/bill/113th-congress/house-bill/3204/text. Published November 27, 2013. Accessed June 8, 2022.
3. Vivian JC. New rules for compounding drug products. US Pharm. 2014;39(2):40-42.
4. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act Guidance for Industry. FDA website. https://www.fda.gov/media/97359/download. Published May 2018. Accessed June 8, 2022.
5. Bassett KB, DiMarco AC, Naughton DK. Chapter 5: Dental local anesthetic drugs. In: Bassett KB, DiMarco AC, Naughton DK. Local Anesthesia for Dental Professionals. 2nd ed. Pearson; 2015:55-58.
6. DiMarco AC, Wetmore AO. Clinical comparison: fast-acting and traditional topical dental anesthetic. Anesth Prog. 2016;63(2):55-61.
7. Kosaraju A, Vandewalle KS. A comparison of a refrigerant and a topical anesthetic gel as preinjection anesthetics: a clinical evaluation. J Am Dent Assoc. 2009;140(1):68-113.
8. FDA drug safety communication: FDA continues to receive reports of a rare, but serious and potentially fatal adverse effect with the use of benzocaine sprays for medical procedures. FDA website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-continues-receive-reports-rare-serious-and-potentially-fatal. Updated May 22, 2018. Accessed June 8, 2022.
9. Safety information on benzocaine-containing products. FDA website. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/safety-information-benzocaine-containing-products. Updated June 25, 2018. Accessed June 8, 2022.
10. Shibuya M, Hojo T, Hase Y, et al. Methemoglobinemia caused by a low dose of prilocaine during general anesthesia. J Dent Anesth Pain Med. 2021;21(4):357-361.
11. Oraqix Prescribing Information. Dentsply Sirona website. https://www.dentsplysirona.com/content/dam/master/product-procedure-brand-categories/preventive/product-categories/anesthetics/non-injectable-anesthesia/oraqix/documents/PRE-IFU-Oraqix-EN-2019-06.pdf. Updated June 2019. Accessed June 8, 2022.
12. Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg. 2009;108(3):837-845.
13. Malamed SF. Handbook of Local Anesthesia. 5th ed. Elsevier Mosby; 2004.
14. Yagiela JA. Safely easing the pain for your patients. Dimensions of Dental Hygiene. 2005;3(5):20,22.
15. Tetzlaff JE. Clinical Pharmacology of Local Anesthetics. 1st ed. Butterworth Heinemann; 2000:105.
16. Cetacaine prescribing information. Cetylite website. https://www.cetylite.com/sites/default/files/resources/Cetacaine%20Prescribing%20Information.pdf. Reviewed October 2018. Accessed June 8, 2022.
17. Oraqix. RxList website. https://www.rxlist.com/oraqix-drug.htm. Updated March 14, 2022. Accessed June 8, 2022.
18. Jastak JT, Yagiela JA, Donaldson D. Local Anesthesia of the Oral Cavity. 2nd ed. WB Saunders; 1995:110-116.
19. Abu-Laban RB, Zed PJ, Purssell RA, Evans KG. Severe methemoglobinemia from topical anesthetic spray: case report, discussion and qualitative systematic review. CJEM. 2001;3(1):51-56.
