Articaine hydrochloride is an amide local anesthetic, 4-methyl-3[2-(propyl-amino) propionamido]-2-thiophenecarboxylic acid, methyl ester hydrochloride. It was synthesized in 1969 in Germany, where it entered clinical use in 1976; in April 2000, the U.S. Food and Drug Administration granted approval for the sale of 4 percent articaine with 1:100,000 epinephrine in the United States under the name of Septocaine (Septodont).

Articaine is unique among amide local anesthetics in that it contains a thiophene group, which increases its liposolubility, and is the only widely used amide local anesthetic that also contains an ester group. The ester group enables articaine to undergo biotransformation in the plasma (hydrolysis by plasma esterase) as well as in the liver (by hepatic microsomal enzymes). The primary metabolite, articainic acid, is inactive.¹ Articaine and its metabolites are eliminated via the kidneys. Approximately 5 percent to 10 percent of articaine is excreted unchanged.²

Articaine reversibly blocks nerve conduction through a mechanism of action similar to that of other amide local anesthetics. Epinephrine is included in the clinical formulation both to retard absorption of articaine, thereby prolonging the duration of clinically adequate anesthesia, and to minimize systemic absorption of the active drug.

Articaine is used clinically as a 4 percent solution with epinephrine 1:100,000 or 1:200,000. The onset of anesthesia with articaine 4 percent with epinephrine 1:200,000 is 1.5 to 1.8 minutes for maxillary infiltration and 1.4 to 3.6 minutes for inferior alveolar nerve block.^3,4 The duration of soft-tissue anesthesia is 2.25 hours for maxillary infiltration and approximately four hours for nerve block.⁴ The anesthetic activity of articaine/epinephrine combinations has been demonstrated to be comparable to that of other anesthetic combinations, including lidocaine/epinephrine, mepivacaine/levonordefrin and prilocaine/epinephrine.⁵

The anesthetic activity of articaine/epinephrine combinations has been demonstrated to be comparable to that of other anesthetic combinations.

This article reports the results of a three-study clinical program designed to compare the safety and efficacy of articaine 4 percent with epinephrine 1:100,000 with that of lidocaine 2 percent with epinephrine 1:100,000. An earlier article in JADA reported the study’s results regarding the efficacy of articaine.⁶

	METHODS

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Three identical single-dose, randomized, double-blind, parallel-group, active-controlled multi-center studies were conducted to compare the safety and efficacy of articaine (4 percent with epinephrine 1:100,000) with that of lidocaine (2 percent with epinephrine 1:100,000). The studies were conducted at a total of 27 sites (eight in Great Britain, 19 in the United States).

At each site, subjects 4 to 80 years of age undergoing general dental procedures were stratified according to the complexity of the procedure being performed:

– simple—single extractions with no complications, routine operative procedures, single apical resections and single-crown procedures;

– complex—multiple extractions, multiple-crown and/or bridge procedures, multiple apical resections, alveolectomies, mucogingival operations and other osseous surgical procedures.

Exclusion criteria included the following: pregnancy; bony, fully impacted teeth or maxillofacial surgery; known or suspected allergies or sensitivities to sulfites or amide-type local anesthetics or any ingredients in the anesthetic solutions; concomitant cardiac or neurologic disease; a history of paroxysmal tachycardia, frequent dysrhythmia, severe untreated hypertension or bronchial asthma; evidence of soft-tissue infection near the proposed injection site (localized periapical or periodontal infections were permitted); an expectation of requiring nitrous oxide or any topical or general anesthetic (topical anesthetic was allowed in the British study); or subjects who had taken aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs or other analgesic agents within 24 hours before administration of the study medication.

Within each stratum, subjects were randomized in a 2:1 ratio to receive articaine or lidocaine (so as to gather more data on the test drug, articaine). Both formulations contained epinephrine 1:100,000. Patients received the lowest effective dose of anesthesia, to be administered as sub-mucosal infiltration and/or nerve block. Total dose was not to exceed 7.0 milligrams per kilogram of body weight.

Safety evaluations included vital signs obtained before and after administration of the anesthetic and assessment of adverse events during the treatment visit. Additionally, reports of adverse events were elicited during telephone follow-up at 24 hours and seven days after the procedure. Subjects were questioned specifically regarding the presence of persistent numbness and/or tingling of the mouth or face (a condition called paresthesia).

The numbers of subjects enrolled and treated in the three trials are summarized in Table 1. All studies were conducted in compliance with good clinical practice guidelines and received approval from, as appropriate, ethics review committees (in Great Britain) or institutional review boards (in the United States).

	RESULTS

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Drug volumes. Patients were administered as much of the study drug as was necessary to achieve adequate anesthesia. The average volume of anesthetic administered was comparable for the articaine and lidocaine groups. Table 2 summarizes drug administration for simple and complex procedures in both treatment groups.

Adverse events. Adverse events were determined in telephone interviews conducted by the primary investigators with the patient at 24 hours and seven days after treatment. Therefore, the vast majority of these events are related by patients and are alleged as opposed to confirmed. In the articaine group, 191 of 882 patients (22 percent) reported at least one adverse event. In the lidocaine group, 89 of 443 patients (20 percent) reported at least one adverse event. One patient in the articaine group had an adverse event reported as serious but unrelated to the study medication (squamous cell carcinoma). One patient in the lidocaine group discontinued participation in the study owing to chest pain and dizziness, considered to be possibly related to the study medication. No deaths were associated with these studies.

In the articaine group (n = 882), the most common adverse event was postprocedural pain (13 percent), followed by headache (4 percent). Facial edema, infection, gingivitis and paresthesia each was reported by 1 percent of patients. All other adverse events each were reported by less than 1 percent of patients.

The incidence of adverse events in the lidocaine group (n = 443) was similar, with postprocedural pain reported most frequently (12 percent), followed by headache (3 percent). Facial edema, gingivitis and hypesthesia each was reported by 1 percent of patients in the lidocaine group; all other adverse events each were reported by less than 1 percent of patients.

The total number of adverse events reported by 1 percent or more of patients in either study group are summarized in Table 3. The incidence of adverse events was not greatly affected by race, sex or age, although patients aged 4 to 12 years tended to report fewer adverse events.

Drug-related adverse events. Of the 882 patients in the articaine group, 37 (4 percent) had adverse events considered by the investigator to be related to the study medication, compared with 16 of the 443 patients (4 percent) in the lidocaine group (Table 4). For both treatment groups, each adverse event considered to be related to the study medication was reported by less than 1 percent of patients. In the articaine group, the most commonly reported drug-related adverse events were paresthesia (0.9 percent), hypesthesia (0.7 percent), headache (0.55 percent), infection (0.45 percent), rash (0.3 percent) and pain (0.3 percent). In the lidocaine group, the most common drug-related adverse events were headache (0.7 percent), rash (0.7 percent), paresthesia (0.45 percent) and dizziness (0.45 percent).

All study drug–related adverse events were mild to moderate in intensity, except for one case of infection and one case of mouth ulceration, each of which was rated as severe in intensity.

All study drug–related adverse events were mild to moderate in intensity, except for one case of infection and one case of mouth ulceration, each of which was rated as severe in intensity. Both events occurred in the articaine group in white males between 13 and 64 years of age.

Vital signs. Supine systolic and diastolic blood pressures were measured before the study drug was administered and at one and five minutes postadministration and postprocedure. Mean supine blood pressure values changed very little, decreasing slightly from baseline at all time points after administration of the study drug. These changes were not clinically significant, and there were no statistically significant differences in mean supine blood pressure between treatment groups.

Mean standing systolic and diastolic blood pressures, obtained before and after the procedure, also changed very little from baseline values, with mean standing systolic blood pressure very slightly increased and mean standing diastolic blood pressure very slightly decreased from baseline values after the procedure. These changes were not clinically significant, and there were no statistically significant differences in mean standing blood pressure between treatment groups.

Heart rate and respiratory rates were measured before the study drug was administered, at one and five minutes postadministration, and after the procedure. For both heart rate and respiratory rate, mean values increased slightly at one and five minutes, but by the postprocedure measurement point, mean values had decreased slightly below baseline values. The changes from baseline were not statistically or clinically significant, and there were no statistically significant differences between treatment groups.

	DISCUSSION

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The overall incidence of adverse events in the combined studies was 22 percent in the articaine group and 20 percent in the lidocaine group. The most frequently reported adverse events in the articaine group, excluding postprocedural dental pain, were headache (4 percent), facial edema, gingivitis, paresthesia/hypesthesia and infection (1 percent each). The incidence of these events was similar in the lidocaine group. Adverse events most frequently reported as drug-related in the articaine group were paresthesia (0.9 percent), hypesthesia (0.7 percent), headache (0.55 percent), infection (0.45 percent), rash (0.3 percent) and pain (0.3 percent). Among the 50 children (aged 4 to 12 years) who received articaine in these studies, one adverse event (lip injury) was considered related to treatment.

The most frequently reported adverse events in the articaine group, excluding post-procedural dental pain, were headache (4 percent), facial edema, gingivitis, paresthesia/hypesthesia and infection (1 percent each).

Haas and Lennon⁷ published a retrospective analysis of paresthesia after local anesthetic administration for nonsurgical dental procedures over a 21-year period. Paresthesia was defined as numbness or tingling of the mouth or face. The analysis revealed a higher-than-expected frequency of paresthesia with articaine, based on the number of cartridges used (2.27 per 1 million injections vs. an expected frequency of 1.20 per 1 million injections).

Because of the Haas and Lennon⁷ report, an attempt was made in these studies to obtain data regarding paresthesia after injection. During telephone follow-up 24 hours and seven days after the procedure, and using the Haas and Lennon definition of paresthesia, researchers specifically asked subjects if they had any ongoing numbness or tingling of the mouth or face. The total number of subjects who reported these symptoms four to eight days after the procedure was eight (1 percent) for the articaine group and five (1 percent) for the lidocaine group. Although more articaine patients than lidocaine patients were believed by investigators to have drug-related symptoms, in five cases (four with articaine, one with lidocaine), the symptoms did not begin on the day of study drug administration, suggesting that they were caused by the procedure rather than the anesthetic. In cases for which resolution dates were available, we determined that the duration of these events was less than one day to 18 days after the procedure. In all cases, the paresthesia ultimately resolved.

Minor fluctuations in vital signs are common during administration of local anesthetic. There were no consistent changes in vital signs observed at one and five minutes after injection or at the end of the dental procedure. Transient increases and decreases in blood pressure, heart rate and respiratory rate were observed, but they were not clinically significant, and neither were the changes statistically significant between treatment groups. Analysis of combined data for these studies did not indicate any trends in vital signs related to age or sex among subjects receiving articaine. Tachycardia was reported as an adverse event in one subject who received articaine. Anxiety regarding the injection itself or the impending dental procedure may contribute to transient alterations in vital signs.

In a study by Hidding and Khoury,⁸ which evaluated the safety of four commonly used dental anesthetics administered via nerve block techniques in 1,518 adults, 2.6 percent of all subjects had an increase in blood pressure equal to or greater than 20 millimeters of mercury, or mm Hg, and 7.4 percent had a drop in blood pressure equal to or greater than 20 mm Hg at two minutes after injection. Increases in heart rate of more than 20 beats per minute were observed in 4.2 percent of subjects. Vital sign changes in our studies, thus, were well within those expected with the use of dental anesthetics.

The immunogenic potential of articaine is very low. Historical experiences indicate that allergic reactions resulting from sensitivity to articaine are rare. However, articaine solutions with epinephrine contain an antioxidant, sodium bisulfite, which can cause allergic-type reactions. In addition, some commercially available forms of articaine with epinephrine (although not the study drug) also contain the antibacterial preservative methylparaben, which may have contributed to allergic reactions reported with articaine.⁹ Allergic-type reactions that have been reported with articaine include edema, urticaria, erythema and anaphylactic shock. In the three studies discussed here, reports of rash or pruritis were no more frequent with articaine (n = 2) than with lidocaine (n = 4), and no serious allergic reactions were seen in either treatment group. Patients allergic to articaine likely would be allergic to lidocaine and the other amide local anesthetics.

Published data support the overall safety and tolerance of articaine with epinephrine. In a prospective, randomized, double-blind comparison of articaine 4 percent with epinephrine 1:200,000 (n = 383), articaine 4 percent with epinephrine 1:100,000 (n = 408), prilocaine 3 percent with felypressin 1:1,185,000 (n = 364), and lidocaine 2 percent with epinephrine 1:100,000 (n = 363) administered via nerve block technique, there was no difference among the four groups with respect to effects on blood pressure and heart rate.^8,10 The most frequent postoperative complaint, headache, was observed with similar frequency (15 percent to 22 percent) in all treatment groups. One subject who received articaine 4 percent with epinephrine 1:100,000 experienced diplopia after injection; it resolved after 15 minutes. Reviews of clinical experience with articaine 4 percent with epinephrine 1:200,000 reported no local reactions or secondary effects in 500 injections¹¹ (1.8 milliliters) and 7,500 injections¹² (1.0 to 3.6 mL). Evaluation of 84 subjects who received articaine 4 percent with epinephrine 1:100,000 (0.3 to 4.5 mL) revealed postsurgical complications of mucosal ulcerations, localized osteitis and sharp pain.¹³

Dentistry’s clinical experience with articaine/epinephrine formulations through the years supports the assertion that the risk of systemic toxicity with articaine is low.

Methemoglobinemia has been shown to develop with some types of local anesthetics. Clinical tests of articaine, bupivacaine and etidocaine administered as central nerve block anesthetic for urological procedures (n = 103) indicated no elevation of methemoglobin with articaine.¹⁴

	CONCLUSIONS

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Articaine 4 percent with epinephrine 1:100,000 is a safe local anesthetic for use in clinical dentistry. Articaine can be used effectively in both adults and children. Articaine was well-tolerated in 882 subjects who received the drug in these clinical trials and had a toxicity profile comparable to that of lidocaine. Dentistry’s clinical experience with articaine/epinephrine formulations through the years supports the assertion that the risk of systemic toxicity with articaine is low. Articaine with epinephrine is contraindicated in patients with known sensitivity to amide-type local anesthetics and in patients with sulfite sensitivity (such as some people with allergic-type asthma). Articaine should be used with caution in patients with hepatic disease and significant impairments in cardiovascular function—both of which conditions place patients in the American Society of Anesthesiologists classification of ASA IV (having severe systemic disease that is a constant threat to life)—since amide-type local anesthetics undergo biotransformation in the liver and possess myocardial depressant properties. Safe use in pregnancy and lactation has not been established. Use in children younger than 4 years of age is not recommended, since no data exist to support such usage.

The use of articaine with epinephrine for local anesthesia is well-established in clinical dental practice in continental Europe and Canada, with more than 100 million cartridges having been sold. Articaine 4 percent with epinephrine 1:100,000 provides effective anesthesia with a low risk of toxicity that appears comparable to that of other local anesthetics.