Topical Anesthetics

Topical anesthetics are substances that can cause surface anesthesia of skin or mucosa. In dentistry these agents are used to temporarily anesthetize the tiny nerve endings located on the surfaces of the oral mucosa, with the aim of reducing the discomfort of dental injections and other minimally invasive procedures. The agents are supplied in various forms—gels, ointments, sprays, and solutions—and can be obtained in flavors such as strawberry, mint, cherry, banana, and bubble gum. The concentrations of topical anesthetic solutions are higher than those of injectable anesthetics but take longer for the full effect in comparison with the injectable anesthetics. In general, 1 to 5 minutes of contact time is required for topical anesthetics to reach their full effectiveness (up to 2–3 mm from the surface) so patience is required on the part of the dentist. For maximum effectiveness, the area of the mucosa where the topical anesthetic is to be placed should be dry.

Most of the widely used topical anesthetics use 20% benzocaine in either a gel or liquid form. The 20% benzocaine has virtually no systemic absorption. Compound topical anesthetics are used to relieve pain and discomfort in minimally invasive or noninvasive procedures (orthodontic bands application, root planing, and scaling). These combination agents are neither regulated nor unregulated by the US Food and Drug Administration (FDA). Studies have shown that combination topical anesthetic products are considerably more efficacious than topical benzocaine when used as the sole anesthetic. One widely used combination topical anesthetic is One Touch (Hager Worldwide, Inc, Odessa, FL, USA), which is composed of 18% benzocaine and 15% tetracaine.

Benzocaine

Benzocaine is one of the ester local anesthetics (the ethyl ester of p -aminobenzoic acid [PABA]) and is poorly soluble in water. It is poorly absorbed into the cardiovascular system, and will remain at the site of application, giving it a long duration of action. In comparison with amide anesthetics, ester anesthetics are more allergenic because of the PABA structure. Benzocaine is available in 5 different forms: aerosol, gel, gel patch, ointment, and solution. These different forms can be used for different cases. For instance, aerosol can be used to administer palatine anesthesia to decrease gag reflex in patients during impressions; gel forms can be used before application of local anesthetic injection to minimize the discomfort of injection; and ointment and solutions usually are used to provide comfort in cases that a patient has oral aphthous ulcer.

Benzocaine is a well-known cause of methemoglobinemia, and should never be used on patients who have had methemoglobinemia in the past or on children 2 years or younger. Because most dental preparations are used in a concentration of 20%, it will not be difficult to administer a dose sufficient to cause this problem. Methemoglobinemia may occur after only one application or even after the patient has had several uneventful applications. The signs and symptoms may occur within minutes or up to 2 hours after the use of benzocaine topical in the mouth or if it is sprayed into the throat to prevent gagging. The FDA still maintain notification to health care professionals and patients that methemoglobinemia associated with benzocaine products is still being reported, and that it may be a serious and potentially fatal adverse effect.

Combination topical anesthetics

Compounding is the process by which drugs are combined or the ingredients altered to create a custom-made medication. In the case of topical anesthetics the aim is to produce a strong topical anesthetic that can be used for minimal to moderately painful procedures. These preparations contain higher concentrations of topical anesthetics, making them stronger and capable of maintaining their efficacy for longer durations after application. Compound topical anesthetics are used on children by pediatric dentists for restorative procedures, by periodontists and hygienists for scaling and root-planing procedures, and by orthodontists for the placement of orthodontic temporary anchorage devices.

These combination preparations of local anesthetics are commonly referred to as eutectic mixtures of local anesthesia (EMLA). When mixed together in certain ratios they form a “eutectic mixture” in which the melting point of the mixture is lower than the melting point of the individual components. This blending allows the mixture to be more in a liquid state that will allow the agents to be better absorbed through the oral mucosa. In 2004, the FDA approved an EMLA product called Oraqix for use in dentistry. Oraqix (Dentsply Pharmaceutical, Philadelphia, PA, USA) is a gel that can be inserted into the gingival sulcus to produce sufficient anesthesia to permit deep-cleaning procedures such as scaling and root planing. Two compound topical anesthetics used during placement of orthodontic appliances are TAC 20% Alternate Anesthetic Gel (tetracaine 4%, phenylephrine 2% and lidocaine 20%; Professional Arts Pharmacy, Lafayette, LA, USA) and Profound (lidocaine 10%, prilocaine 10% and tetracaine 40%; Stevens Pharmacy + Compounding, Costa Mesa, CA, USA). Table 1 gives a more complete list of topical anesthetic agents.

To date, there have not been many problems reported with these agents and they appear to be relatively safe. The most common adverse reactions seem to be tissue irritation (usually after prolonged application) and transitory taste alterations. The maximum recommended dosage of these topical anesthetics is unknown, but they are thought to have a low therapeutic index. Because some may contain several active anesthetics, often resulting in a mixture of esters and amides, they may pose the risk of allergic reactions. Ester-type anesthetics (benzocaine, tetracaine) are contraindicated in patients with PABA allergy or atypical pseudocholinesterase activity. Tetracaine is associated with a higher incidence of allergic reactions than are other local anesthetics.

Injectable Anesthetics

Lidocaine

Lidocaine hydrochloride (HCl) is the first amino amide type of local anesthetic, and has been in use for more than 60 years. It is considered as the prototype for amide local anesthetics, and is very familiar to dentists ( Table 2 ). As a local anesthetic, lidocaine is characterized by a rapid onset of action and intermediate duration of efficacy, making it suitable for infiltration and nerve block anesthesia, and the “perfect” local anesthetic for dentistry. The maximum recommended dose of lidocaine with epinephrine is 3.2 mg/lb or 7 mg/kg of body weight for adult patients, and should not exceed 500 mg in total. The dose of lidocaine without epinephrine is 2 mg/lb or 4.4 mg/kg, not to exceed 300 mg in total. It must be noted, however, that as with all local anesthetics, the dose will depend on the area to be anesthetized, the vascularity of the tissues, and individual tolerance.

Lidocaine is metabolized by the liver via microsomal fixed-function oxidases and is converted to monoethylglycerine and xylidine. It is excreted through the kidneys with 10% unchanged and 80% as their metabolites. It has pregnancy classification of B. Allergic reaction to lidocaine is virtually nonexistent and has not been documented. Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most of the ADRs have been related to administration techniques—mainly intravascular injections resulting in systemic exposure.

Some contraindications for the use of lidocaine include :

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  Heart block, second or third degree (without pacemaker)

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  Serious adverse drug reaction to lidocaine or amide local anesthetics

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  Concurrent treatment with Class I antiarrhythmic agent

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  Severe hepatic disease.

Mepivicaine

Mepivicaine is another of the amide class of local anesthetics, and has been available in the United States since 1960. It has a reasonably rapid onset (2–3 minutes after infiltration in the maxilla and about 5 to 8 minutes for inferior alveolar nerve block for full effect) and medium duration of action. The duration of action of mepivacaine without vasoconstrictor when infiltrated is about 20 to 40 minutes and about 2 hours for regional anesthesia. Its half life is 1.9 hours. Mepivicaine 3% causes slight vasoconstriction, and this effect will give it a longer duration of action, as the anesthetic will remain at the site of injection. Mepivacaine 2% with levonordefrin or epinephrine provides anesthesia of longer durations. Levonordefrin is a sympathomimetic amine used as a vasoconstrictor in local anesthetics. It has pharmacologic activity similar to that of epinephrine, but is more stable. In equal concentrations, levonordefrin is less potent than epinephrine in raising blood pressure and as a vasoconstrictor.

The maximum recommended dose of mepivacaine is 3.0 mg/lb or 6.6 mg/kg of body weight, and should not exceed 400 mg in an adult patient. In children the recommended dose is 3.0 mg/lb up to a maximum of 5 cartridges of form 2% to 3%. The maximum recommended dose of mepivacaine without a vasoconstrictor is 2 mg/lb or 4.4 mg/kg, not to exceed a total dose of 300 mg.

Like lidocaine, the clearance of mepivacaine is almost entirely due to liver metabolism, and depends on the liver blood flow and the activity of the metabolizing enzymes. It is metabolized by hepatic microsomal fixed-function oxidases, hydroxylation, and N -demethylation reactions. Mepivicaine is pregnancy category C and therefore should not be used for pregnant patients.

Local anesthetics exist in both an ionized (cation) and un-ionized (base) form. The un-ionized form of local anesthetic can pass through the nerve membrane and take effect. During infection, local tissue becomes acidic and therefore anesthetic remains mainly in cation (ionized) form. Mepivacaine has a higher pH than lidocaine; therefore when it is used in an acidic environment it has more base form and thus will pass through nerve membrane, and is more effective. This characteristic makes mepivacaine a good choice of local anesthetic when there is infection.

Prilocaine

Prilocaine is another amide local anesthetic that is currently most often used for infiltration anesthesia in dentistry. It differs from lidocaine and mepivacaine because it is a secondary amide. Prilocaine is available in two formulations, prilocaine 4% plain and prilocaine 4% with 1:200,000 epinephrine. The recommended dose of prilocaine both with and without epinephrine is 2.7 mg/lb or 6.0 mg/kg of body weight for adult patients. The maximum total dose for adult patients should not exceed 400 mg. Prilocaine is pregnancy category B and therefore it is safe for use in pregnant women.

When used for infiltration anesthesia in dental patients, the time of onset of prilocaine 4% with epinephrine 1/200,000 (Citanest Forte; Dentsply Pharmaceutical, York, PA, USA) averages 2 minutes with a duration of soft-tissue anesthesia of approximately 2 hours. Operative anesthesia lasts up to 45 minutes. When used for infiltration anesthesia, prilocaine 4% (Citanest 4% Plain) has a rapid onset time of approximately 2 to 3 minutes, and a duration of approximately 1 to 1.5 hours for soft-tissue anesthesia. Prilocaine 4% plain has a short duration for operative anesthesia of approximately 15 minutes. When used for inferior alveolar nerve block, the time of onset of the Forte solution averages approximately 2 to 4 minutes with an average duration of soft-tissue anesthesia of approximately 3 hours, providing 1.5 hours of operative anesthesia. Prilocaine 4% plain requires 5 minutes or more to take full effect. The duration of soft-tissue anesthesia is approximately 2.5 hours while the operative anesthesia has a duration of 1 to 1.5 hours.

Prilocaine is metabolized in both the liver and the kidney and is excreted via the kidney, thus hepatic and renal dysfunction may alter prilocaine kinetics. Most of it is metabolized and only a small fraction of intact prilocaine is secreted in urine. Hydrolysis of prilocaine by amidases yields orthotoluidine and N -propylalanine. Both of these compounds may undergo ring hydroxylation.

In some patients, the metabolite orthotoluidine may cause the unusual side effect of methemoglobinemia when large doses of prilocaine are used. The formation of methemoglobin will reduce the blood’s oxygen-carrying capacity, and this can lead to cyanosis. The total dose of prilocaine should be limited to 600 mg to eliminate symptomatic cyanosis. Because prilocaine can decrease the oxygen-carrying capacity of blood, it should be avoided in patients with idiopathic or congenital methemoglobinemia, sickle cell anemia, chronic anemia, and cardiac or respiratory failure with hypoxia. Its use should also be avoided in patients who take acetaminophen or phenacetin, as these both elevate levels of methemoglobin.

Articaine

Articaine is the most recently introduced local anesthetic, approved by the FDA in 2000. It is a member of the amino amide class of local anesthetics, but its structure is unique among this group in that it does not contain a benzene ring like the others but instead contains a thiophene ring. This thiophene ring increases its liposolubility, making it more effective in crossing lipid barriers. It also contains an additional ester group, which enables articaine to undergo biotransformation in the plasma (hydrolysis by plasma esterase) as well as in the liver (by hepatic microsomal enzymes). Articaine HCl is available in 4% strength with 1:100,000 or 1:200,000 epinephrine.

Articaine has very low systemic toxicity, and with its wide therapeutic range it may be used in higher concentrations than other amide-type local anesthetics. Also, because it is hydrolyzed very quickly in the blood, the risk of systemic intoxication seems to be lower than with other anesthetics, especially if repeated injection is performed. The maximum recommended dose of 4% articaine HCl should not exceed 7 mg/kg or 3.2 mg/lb of body weight. It is pregnancy category C and should not be used in pregnant patients.

The main quality of articaine that makes it an attractive local anesthetic is the fact that it diffuses through bone and soft tissue better than other local anesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. This higher ability to diffuse through bone and soft tissue has made articaine useful in giving profound anesthesia via infiltration without the need for mandibular block.

Persistent paresthesia of the lips, tongue, and oral tissues have been reported with the use of articaine HCl, with slow, incomplete, or no recovery. These adverse events have been reported chiefly following inferior alveolar nerve blocks, and seem to involve the lingual nerve most often. Such reports have caused some early and persistent controversy concerning articaine. However, this is no longer considered as a complication of articaine 4%. In a detailed review of paresthesia cases due to nerve blocks evaluated by the Oral and Maxillofacial Surgery Department of the University of California at San Francisco, Pogrel and colleagues reported that 35% of the cases involved the use of lidocaine and 30% involved the use of articaine. The investigators concluded that nerve blocks can cause permanent damage to the nerves, independent of the local anesthetic used, and that they did not find any disproportionate nerve involvement from articaine but that articaine is associated with this phenomenon in proportion to its usage.

Bupivacaine

Bupivacaine is another amino amide type of local anesthetics that is 4 times as potent as lidocaine, mepivacaine, and prilocaine. It has a longer duration of action than lidocaine—approximately 6 to 8 hours as opposed to 1 to 2 hours for lidocaine. Bupivacaine is often administered after the extraction of impacted third molars to reduce pain for up to 12 to 20 hours after the surgery. It is also commonly injected into surgical wound sites to achieve long-term postoperative pain control.

Bupivacaine is available in concentrations of 0.25%, 0.5%, and 0.75%, either plain or combined with epinephrine (1:200,000) The 0.25% form is the concentration most widely used in dentistry. The maximum recommended dose is 0.6 mg/lb or 1.3 mg/kg for adult patients, and the total maximum dose should not exceed 90 mg. Bupivacaine is pregnancy category C and should not be used in pregnant patients. Compared with other local anesthetics, bupivacaine is markedly cardiotoxic and should be used with caution in patients taking β-blockers (eg, atenolol) or digoxin because the risk of side effects such as abnormal heartbeat may be increased. Bupivacaine is metabolized in liver by amidases and is excreted via kidneys.

Epinephrine

Epinephrine or adrenaline is a sympathomimetic amine that is added to local anesthetic to cause vasoconstriction. Some of the adverse effects of local anesthetic use such as tachycardia and tremor are caused by epinephrine. It is added to local anesthetics to oppose the vasodilating effects of local anesthetics and therefore increase their duration of action. Furthermore, the vasoconstriction effect decreases systemic absorption of local anesthetics and therefore lowers systemic toxicity. Another purpose of adding epinephrine to local anesthetics is to achieve hemostasis at the surgical site, as it causes vasoconstriction by stimulating α and β2 receptors in vessels supplying skeletal muscles.

The action of epinephrine on β1 receptors in the myocardium is to increase the heart rate and the contractility. It can trigger ventricular tachycardia and premature ventricular contractions, due to stimulation of cardiac pacemaker cells. The overall effect of epinephrine on the cardiovascular system is to increase cardiac efficiency. Epinephrine has a bronchodilatory effect on the respiratory system, due to its action on β2 receptors.

Epinephrine action is terminated mainly by reuptake in the adrenergic nerve terminals. The remainder of epinephrine will be inactivated by catechol- O -methyltransferase and monoamine oxidase, and only 1% of epinephrine is excreted unchanged in urine.

Adverse reactions to epinephrine include palpitations, tachycardia, arrhythmia, anxiety, headache, tremor, and hypertension. Patients with coronary artery disease are usually more sensitive to epinephrine and can have episodes of angina due to the increase in heart rate. The administration of epinephrine will not cause heart failure by constricting coronary arteries, because coronary arteries only have β2 receptors, which cause vasodilation in the presence of epinephrine. As a general rule, use of epinephrine in patients with cardiovascular disease should be limited to 2 carpules of local anesthetic with epinephrine. All patients with cardiovascular disease and elderly patients at risk for cardiovascular disease need to have their blood pressure taken before administration of local anesthetics with epinephrine.

Patients with a heart transplant have a heart that has been surgically denervated. Loss of adrenergic nerve terminals that control both release and reuptake of epinephrine will make a transplanted heart more sensitive to epinephrine. Therefore, in this special class of patients epinephrine use should be minimized and heart function should be continuously monitored for any changes in rhythm.

Caine Allergy

When a patient gives a history of being “allergic” to local anesthetics it will be very difficult for the clinician to dismiss the claim, even in the absence of proper documentation. It must be noted, however, that true allergic reactions to the commonly used local anesthetics are rare, and adverse reactions are more common. Differentiating between allergic and adverse reactions is often difficult because of the similarity of the symptoms, and physicians may label patients as “allergic” to “-caine” drugs even when the signs and symptoms are consistent with an adverse reaction.

Local anesthetics are grouped, depending on their chemical structure, into two categories: esters and amides. The esters are derivatives of para -aminobenzoic acid, which is known to be allergenic, hence a certain percentage of the population will demonstrate allergic reactions to this group of drugs. True allergic reactions to amides are extremely rare. In a study conducted to determine the incidence of true local anesthetic allergy in patients with an alleged history of local anesthetic allergy, the researchers concluded that “a history of allergy to local anesthesia is unlikely to be genuine and local anesthetic allergy is rare.” Other investigators have also concluded that a true immunologic reaction to a local anesthetic is rare, and that patients who are allergic to ester local anesthetics can be treated with a preservative-free amide local anesthetic.

When a patient presents with a history of allergy to a local anesthetic, the first step should be to ascertain the signs and symptoms of the reaction and to try to determine, by history, whether it could have been an allergic reaction. The quantity of anesthetic that was used should also be questioned, as the reaction may have been toxic arising from either large amounts of local anesthetic (as used in liposuction or extensive facelift procedures) or an intravascular injection. Question also if the individual underwent any dental procedures since being told of the allergy. If doubt persists, the patient may be sent to an allergist to do a progressive challenge with dilute solutions and then undiluted intradermal injection of local anesthetics, to diagnose allergy to the agent.