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J Am Dent Assoc, Vol 137, No 11, 1572-1581.
© 2006 American Dental Association |  |
RESEARCH |
Two controlled clinical trials
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. During separate testing sessions, members of the authors’ research team used three articaine study formulations to induce either inferior alveolar nerve block anesthesia (Trial 1) or maxillary infiltration anesthesia (Trial 2). In each trial, subjects received, in a randomized sequence, each of the three formulations to determine efficacy (success rate) and anesthetic characteristics (onset time and duration). The authors evaluated pulpal anesthesia via subjects’ response to electric pulp testing (EPT).
Results. A total of 126 subjects were enrolled in the two studies (63 subjects in each trial). In both mandibular and maxillary trials, the success rates for inducing profound anesthesia (EPT score > 80), the mean onset times and the mean durations of anesthesia were similar for both epinephrine-containing formulations (A200 and A100). In subjects who received the formulation containing no epinephrine (Aw/o), the success rate for profound anesthesia was significantly less.
Conclusion. These studies demonstrated that the inclusion of epinephrine in 4 percent articaine anesthetic formulations is essential for achieving profound anesthesia. The authors found that the A200 formulation provided a level of pulpal anesthesia comparable with that of the A100 formulation.
Key Words: Articaine; epinephrine; dentistry; local anesthesia; clinical trial
The local anesthetic articaine hydrochloride (HCl) has been widely used for dental anesthesia in Europe and Canada for more than three decades. However, articaine, formulated as a 4 percent solution with 1:100,000 epinephrine, only recently has been made available to the dental profession in the United States. Similarly to other amide local anesthetics, it inhibits nerve conduction by diminishing the sodium ion influx that initiates a peripheral nerve’s action potential. It is unique among amide anesthetics because it contains a thiophene ring containing a methyl ester side linkage that contributes to articaine’s rapid conversion to articainic acid, its primary metabolite.
Epinephrine, an adrenergic vasoconstrictor, is added to articaine formulations in concentrations of either 1:100,000 or 1:200,000 to slow systemic absorption of articaine from the site of injection, thus prolonging the tissue concentration of the anesthetic. The risks of adverse reactions or toxicity resulting from single injections of anesthetic formulations containing epinephrine are minimal. However, when multiple injections are administered, particularly injections of the 1:100,000 epinephrine formulation, the potential for adverse drug reactions increases. This increased risk may be most significant among patients with severe cardiovascular disease or patients taking medications that interact with epinephrine and potentiate adverse drug reactions.1–3
Epinephrine normally is released from the adrenal medulla at a basal rate of 2.5 to 7.5 nanograms per kilogram per minute, and that rate of release may increase 20- to 40-fold during severe stress.4 Investigators have reported that plasma epinephrine concentrations associated with exogenous administration of 20 micrograms of epinephrine (2 milliliters of 4 percent articaine, 1:100,000 epinephrine) elevated above baseline levels as much as threefold within seven minutes of administration.5 The exogenous epinephrine in approximately one or two dental cartridges of a 1:100,000 epinephrine–containing dental anesthetic (18–36 µg) has been shown to increase plasma epinephrine levels to an equivalent of the physiological activities of public speaking and moderate exercise. With the administration of the maximum dose of local anesthetic (approximately 18 mL of 1:100,000 epinephrine), researchers found that plasma epinephrine levels can reach levels equivalent to those found after strenuous exercise, a level not appropriate for subjects who are medically compromised.6 Inadvertent intravascular injection may result in even higher plasma epinephrine concentrations.5
Adverse reactions to articaine are characteristic of the amide-type local anesthetic.7–10 They generally are dose-related and are the result of inadvertent intravascular administration, relative overdosage or reduced tolerance.11,12 Idiosyncratic and hypersensitivity reactions also have been reported.12 High plasma concentrations of anesthetic are associated with central nervous system stimulatory reactions, followed by depression. Additionally, investigators have reported prolonged and permanent paresthesias associated with the intraoral administration of articaine.13
When 4 percent articaine formulations containing epinephrine were introduced, investigators reported high success rates and clinically useful anesthetic characteristics.14 Wide variations in times of onset and duration have been reported as a result of different experimental testing procedures, conflicting definitions of soft-tissue and pulpal anesthesia, dissimilarities in injected volumes and concentrations of the drug formulations. In one investigation involving the administration of a 1.0-mL maxillary infiltration of 4 percent articaine 1:200,000 epinephrine, investigators reported a 100 percent success rate, pulpal anesthesia duration of 55 (± 29 standard deviation [SD]) minutes and soft-tissue durations of 199 (± 57 SD) minutes.9 Cowan7 observed that a 1.0-mL maxillary infiltration of 4 percent articaine and 1:200,000 epinephrine provided onset times of one to three minutes and soft-tissue durations of one to three hours, while 1.8-mL inferior alveolar blocks provided onsets of one to five minutes and soft-tissue durations of three to five hours. In a clinical setting permitting a wide range of injection volumes of either 4 percent articaine 1:00,000 epinephrine or 1:200,000 epinephrine, Lemay and colleagues10 reported soft-tissue durations of 156 to 270 minutes for maxillary infiltrations and 258 to 318 minutes for inferior alveolar block anesthesia. They noted that the 1:100,000 epinephrine formulation had a somewhat shorter onset time after the inferior alveolar blocks.10 However, in a study comparing the anesthetic efficacy of the 4 percent articaine 1:100,000 epinephrine with that of 4 percent articaine 1:200,000 epinephrine for inferior alveolar nerve blocks, investigators found no differences in the onset times (seven-eight minutes) and durations (61–66 minutes).15
This article describes two clinical trials we conducted to assess the efficacy and anesthetic characteristics of 4 percent articaine HCl with 1:200,000 (A200) when used for inferior alveolar nerve block and maxillary infiltration anesthesia. We compared the currently available articaine formulation, 4 percent articaine HCl with 1:100,000 epinephrine (A100), with the A200 formulation. The 4 percent articaine HCl without epinephrine served as the control for assessing the enhanced efficacy of the epinephrine-containing formulations.
Eligibility criteria for participation in the studies required subjects to be 18 to 65 years of age. In addition, we required female subjects of childbearing potential to engage in an acceptable method of birth control (such as abstinence, use of oral contraceptive steroids or use of an intrauterine device) for at least one month before and throughout the study. We required a negative urine pregnancy test at screening and at all subsequent treatment visits. Likewise, lactating women were not eligible. Specific study exclusion criteria included known or suspected allergies or sensitivities to sulfites or amide-type local anesthetics; significant history of cardiac or neurological diseases; severe or frequent cardiac arrhythmias; treated or untreated hypertension equal to or greater than 140 millimeters of mercury (Hg) systolic or 90 mm Hg diastolic pressure; severe or currently symptomatic bronchial asthma; severe psychiatric condition; or evidence of soft-tissue infection near the proposed injection site. Exclusion criteria also included current use of specific medications (nonselective beta-blockers, monoamine oxidase inhibitors, tricyclic antide-pressants, phenothiazines, butyrophenones, vaso-pressor drugs or ergot-type oxytocic drug, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, opioids or other analgesic agents within 24 hours of administration of study medication) and/or having taken an investigational drug or participated in another study within the four weeks preceding initiation of treatment. We also excluded subjects who required sedation therapy (oral, inhalational or intravenous) to tolerate the injection procedure. Subjects signed an IRB-approved informed consent form before beginning any study procedures.
The two trials consisted of a single one-hour screening visit and three treatment visits of three to four hours, each requiring a follow-up telephone call 24 hours later. At the screening visit, subjects who met all eligibility criteria provided a medical history and underwent a brief physical examination conducted by the study’s principal investigators that included recording of vital signs (blood pressure, pulse rate, respiratory rate, body weight) and, for female subjects, urine pregnancy testing. Subjects who met all entry criteria had the first treatment visit scheduled within eight days. We scheduled subsequent treatment sessions at no less than one week (to eliminate possible carry-over effects) and no greater than three-week intervals. At the first treatment visit, we enrolled subjects and assigned them to a randomized sequence for drug allocation. The study sponsor (Novocol Pharmaceutical, Cambridge, Ontario, Canada) prepared identical-appearing dental cartridges of the three study formulations and coded them properly to ensure blinded administration.
Practicing dentists (an oral surgeon, a dental anesthesiologist and a periodontist) administered three articaine study formulations to induce either inferior alveolar nerve block anesthesia (Trial 1) or maxillary infiltration anesthesia (Trial 2). In Trial 1, they administered an inferior alveolar nerve block injection of one cartridge (1.7 mL) using an aspirating dental syringe and a 27-gauge long disposable needle (Septodont, New Castle, Del.). In Trial 2, they administered a maxillary infiltration injection of 1.0 mL using an aspirating dental syringe and a 27-gauge short disposable needle (Septodont). The local anesthesia techniques used were standard intraoral injections for inferior alveolar block or maxillary infiltration anesthesia.16,17 In both trials, the clinicians injected the anesthetic solutions slowly with frequent aspirations over a one-minute span. They applied no topical anesthetics before injection. They administered all injections on the same side of the mouth.
At each treatment session, a research assistant recorded supine blood pressure and heart rate at three times: five minutes before injection, immediately after injection of the study formulation (five minutes in Trial 1 and 10 minutes in Trial 2) and on completion of the treatment session. All subjects remained at the testing site for 180 minutes or until the clinicians determined anesthetic duration time by means of electric pulp testing (EPT). The anesthetic efficacy (success rate), onset and duration were assessed via measurement of maximal changes in sensory threshold of the dental pulp after electric tooth stimulation using a commercially available electrical pulp tester (Kerr Vitality Scanner Model 2006, Sybron Dental Specialties, Orange, Calif.). We calibrated the EPT instruments at each investigational site before and at completion of the study. In Trial 1, we assessed the mandibular canine on the anesthetized side, while in Trial 2, we monitored the maxillary first premolar. (If the maxillary first premolar was missing, we tested the maxillary second premolar.) For inclusion in the study, we required these teeth (mandibular canine or maxillary premolar) to have no dental restorations, no gross caries and a normal EPT sensitivity value (10–50 units). The site of tooth contact was the midpoint of the occlusal one-third of the buccal surface. We isolated the tooth being tested with cotton rolls and air dried it before testing it. We ensured contact with the electrode by applying a fluoride gel toothpaste to the probe tip.
We defined onset time for anesthesia as the time, in minutes, from completion of the injection (T = 0 minutes) to the time when profound anesthesia (EPT
At the conclusion of the testing session, a member of the research team recorded any adverse reactions that occurred. Team members telephoned subjects approximately 24 hours after each treatment session to determine if any adverse reactions had occurred after discharge and elicited information on any adverse events by asking the subject, "Have you noticed any changes in your health since yesterday’s testing session?" If the subject responded in the affirmative, the team member asked a series of specific questions regarding location and description. The representative also elicited information on specific oral symptoms or complaints previously reported as being related to local anesthetic injections (swelling, headache, infection, pain, gingivitis, numbness or tingling).8 We included in the safety evaluations all subjects who received study medication.
For each trial, we calculated an estimated sample size of 54 subjects to be large enough to detect a 15 percent difference in the success rate between the two epinephrine-containing formulations (A100 versus A200) at a .05 significance level and a power of 0.90. To allow for a possible 15 percent rate for dropout or loss to follow-up, we targeted an enrollment of 63 subjects (21 per site). For each trial, the initial statistical plan involved summarizing subject demographic characteristics (including age, sex, weight and screening EPT values). We applied contingency tables and appropriate pairwise analyses (
MATERIALS AND METHODS
TOP
ABSTRACT
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONCLUSIONS
REFERENCES
To characterize articaine’s anesthetic properties, we performed two similarly designed human experimental studies: one assessing inferior alveolar block nerve anesthesia (Trial 1) and one assessing maxillary infiltration anesthesia (Trial 2). Both of these randomized, double-blind, controlled clinical trials compared 4 percent articaine HCl with 1:200,000 epinephrine (A200), 4 percent articaine HCl with 1:100,000 epinephrine (A100) and 4 percent articaine HCl without epinephrine (Aw/o). Three investigational sites (University of Pittsburgh; University of Pennsylvania, Philadelphia; and The Forsyth Institute, Boston) obtained approval from their institutional review boards (IRBs). Each site enrolled 21 subjects to provide an expected total enrollment of 63 subjects in each of the two trials. 
80) was established. We required three consecutive tests (at 30-second intervals) above the maximum threshold (EPT 80) to ensure that profound anesthesia had occurred. If we found that profound anesthesia was not achieved in 10 minutes as evidenced by three consecutive EPT rates of 80 or greater, we considered the injection an anesthetic failure. We assessed duration of anesthesia at five-minute intervals and calculated it as the time from establishment of profound anesthesia (onset) to the initial loss of profound anesthesia. We required three consecutive tests (at five-minute intervals) below the maximum threshold (EPT 80) to ensure that the loss of profound anesthesia had occurred. We simultaneously elicited a descriptive self-report of anesthesia characteristics. At baseline and immediately after each EPT testing, we asked subjects to select one of the following categories of sensory function: no change or alteration in sensation, slight feeling of numbness, moderate but not complete feeling of numbness and complete numbness on one side of the mouth. 
2 test, McNemar test) to determine differences in success rates associated with subject age, sex, weight and investigational site. We used the McNemar test to compare the anesthetic success rate of formulations (A200 versus A100, A200 versus Aw/o or A100 versus Aw/o). We used an unconditional exact test to determine the noninferiority of differences in success rate on the basis of a margin of 15 percent. We summarized clinical characteristics (onset and duration) using means and SDs for each of the treatments. After adjustments for normality, we used multiple comparison analysis of varience and t tests to determine significant differences between A200 and A100, A200 and Aw/o, and A100 and Aw/o. We also prepared a summary of vital signs using descriptive statistics, including mean and SD. We evaluated vital signs for changes from preinjection to immediate postinjection and at completion of the testing procedure using pairwise t tests or the Wilcoxon rank sum test.
RESULTS
TOP
ABSTRACT
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONCLUSIONS
REFERENCES
Trial 1.
We enrolled 63 subjects in Trial 1 and randomized them to treatment. One subject withdrew consent after the first drug treatment session. Sixty-two subjects completed all sessions of the study protocol: 63 received A100, 62 received A200 group and 62 received Aw/o. As shown in Table 1
, 27 (42.9 percent) subjects were female and 36 (57.1 percent) were male. The mean age of the subjects was 30.4 (± 10.0 SD) years (range: 19–60). Mean values for vital signs were similar for all treatment groups and were within normal range at screening.
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, the overall success rate for the three drug formulations for inferior alveolar block anesthesia was 42.8 percent. We found the Aw/o group to have the lowest success rate (25.8 percent). We did not detect a difference in the success rate between A200 (34/62, 54.8 percent) and A100 (30/63, 47.6 percent). However, there were statistically significant differences in the success rate between A200 and Aw/o (P < .001) and between A100 and Aw/o (P = .019). The unconditional exact test provided a confidence interval for the difference in mandibular anesthesia success rates between A200 and A100 (–5.6 percent to 22.3 percent) that did not cover the prespecified inferiority margin of –15 percent, indicating A200’s noninferiority (P = .001). The success rates, based on a descriptive self-report rating of "3" or "4" within 10 minutes of injection, were 85.5 percent for A200, 87.3 percent for A100 and 77.4 percent for Aw/o (P = not significant). Neither sex, weight nor the sequence for receiving the three different drug formulations affected the success rate. Overall success rates with respect to sex (male, 42.6 percent; female, 43.0 percent) and weight (below 150 pounds, 39.7 percent; 150–199 lbs, 47.4 percent; 200 lbs and above, 36 percent) were similar (P = not significant). The anesthetic success rate was significantly higher for subjects younger than 30 years compared with subjects 30 years and older (51.2 percent versus 24.1 percent, P = .0006). We also should note that one investigational site had overall success rates significantly higher (68.3 percent) than those of the other sites (P < .0186).
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As Table 3 (page 1578) shows, we compared baseline vital signs for blood pressure and pulse rate to the vital signs taken five minutes postinjection and at the completion of the testing procedure. Statistically significant differences from baseline for the vital signs included the following:
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All changes we saw in cardiovascular function after drug administration were small, and we considered them to be of minimal clinical significance.
Twenty-five subjects reported 44 adverse events immediately after treatment or during the 24-hour follow-up call (Table 4, page 1579). Adverse events were reported by 12 (19.4 percent) A200 subjects, 12 (19.0 percent) A100 subjects and 11 (17.7 percent) Aw/o subjects. By total number of exposures, we rated five events with A200, eight events with A100 and five events with Aw/o as being possibly or probably related to the study drug. No serious adverse events occurred during the study. We saw no statistically significant differences between treatment groups in the frequency of adverse events overall. The most common adverse events by total number of exposures were soreness at injection site, positive aspiration and headache. One A100 subject reported symptoms of numbness and tingling associated with the injection site that resolved within 24 hours.
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, 35 (55.6 percent) subjects were female and 28 (44.4 percent) were male. The mean age of the subjects was 30.4 ± 8.4 years (range: 20–55 years). All mean vital signs were similar for all treatment groups and within normal range at screening.
Table 2 summarizes the EPT results for efficacy, onset and duration after maxillary infiltration injections of each formulation. The overall success rate for the three drug formulations was 88.2 percent. Aw/o had the lowest success rate (75.8 percent). There was no significant difference in the success rate between the two epinephrine-containing formulations (A200 = 93.5 percent and A100 = 95.2 percent). There were statistically significant differences in success rates between A200 and Aw/o (P = .0076) and between A100 and Aw/o (P = .0013). The unconditional exact test provided a confidence interval (–10.9 to 7.1 percent) indicating noninferiority for efficacy of the A200 formulation (P = .0048). The success rates based on the self-report ratings of "3" or "4" at 10 minutes postinjection were 100 percent for A200, 98.4 percent for A100 and 93.5 percent for Aw/o (P = not significant). All investigational study sites achieved similar success rates. The sequence in which the subjects received the three study formulations and the investigational site had no apparent effect on the success rate for maxillary infiltration anesthesia. The overall success rates with respect to sex (male, 86.6 percent; female, 89.5 percent), weight (below 150 lbs, 93.3 percent; 150–199 lbs, 82.1 percent; 200 lbs and above, 91.2 percent), or age (< 30 years, 91.0 percent; 30 years, 85.3 percent) were similar (P = not significant).
Only data for subjects who achieved profound anesthesia (A200 = 58 subjects, A100 = 60 subjects and Aw/o = 47 subjects) were available for the evaluation of anesthesia onset and duration. The overall mean (± SD) onset time for all three drug formulations was 3.0 ± 2.1 minutes (range: 0.5–9.5 minutes). There was no difference in the onset time between A200 (3.1 ± 2.3 minutes), A100 (3.0 ± 2.1 minutes) and Aw/o (3.0 ± 2.0 minutes). The overall duration for the three drug formulations was 34.8 ± 23.5 minutes (range: 2.0–103.0 minutes). A significant difference was not apparent in anesthesia duration between A200 (41.6 ± 21.1 minutes) and A100 (45.0 ± 23.6 minutes). However, the duration of anesthesia after Aw/o (13.3 ± 6.8 minutes) was significantly shorter than that after both A100 (P < .001) and A200 (P < .01).
We compared baseline vital signs for blood pressure and pulse rate with the vital signs taken 10 minutes postinjection and at the completion of the testing procedure. Statistically significant differences from baseline for the vital signs included the following:
Table 3 summarizes the heart rate and blood pressure results. All changes we saw in cardiovascular functions after drug administration were small, and we considered them to be of minimal clinical significance.
Fifteen subjects—six A200 subjects, six A100 subjects and three Aw/o subjects—reported 18 adverse events immediately after treatment or during the follow-up call at 24 hours postinjection (Table 4). By total number of exposures, we rated two events with A200, two events with Aw/o and one event with A100 as being possibly or probably related to the study drug. There were no serious adverse events during the study. We did not see statistically significant differences between treatment groups in the frequency of adverse events overall. The most common adverse events by total number of exposures were headache and soreness at injection site. One A200 subject reported numbness or tingling of the mouth or face immediately after the first treatment visit, which resolved within six hours.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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It is important to recognize that onset and duration times can be calculated only for the subjects who successfully achieved anesthesia. Therefore, the onset and duration values calculated for the formulation without epinephrine (Aw/o) overestimate clinical reality; owing to the low success rate of Aw/o, we operationally defined onsets delayed beyond 10 minutes as failures and did not include them in the calculation. To include failures in the onset and duration calculations, a predetermined input rule based on the specific methodology of this study (that is, failed onset times assigned a value of 11 minutes) would have been arbitrary and would have altered the values of A100 and A200. The mean values for onset and duration shown in Table 2 exclude data for unsuccessful anesthesia, and they represent a more clinically meaningful estimate of the effective formulations containing epinephrine. Because the Aw/o formulation had an unsatisfactory success rate, the onset and duration values shown do not represent clinical reality.
The overall success rate assessed using EPT was lower than expected after inferior alveolar block, while the subjective ratings were much higher. McLean and colleagues19 similarly found a higher incidence of soft-tissue anesthesia than of pulpal anesthesia, as tested with EPT, after inferior alveolar injections. After injection of either 4 percent prilocaine, 3 percent mepivacaine or 2 percent lidocaine 1:100,000 epinephrine, McLean and colleagues found that effective soft-tissue anesthesia was achieved between 73 and 100 percent of the time, while mandibular pulpal anesthesia was achieved 30 to 67 percent of the time. While EPT provides a precise assessment of complete and profound anesthesia, clinically adequate anesthesia for many restorative procedures may not require complete pulpal anesthesia. In addition, our definition for anesthetic success may have been overly robust, necessitating three successive EPT scores of 80 or greater within 10 minutes. Thus, anesthesia in patients with only one such EPT score or even two successive such scores within this period still was considered to have failed. Our lower overall success rates also were due in part to administration technique, as shown by the differences in success rates between investigational sites after inferior alveolar nerve block (Trial 1). With maxillary infiltration (Trial 2), in which injection technique is not as critical, success rates for the epinephrine formulations were consistently high (93.5 percent and 95.2 percent).
Overall, the changes in vital signs after drug administration were minor and most likely were caused by the low doses used (1.0 mL and 1.7 mL). Interpreting cardiovascular changes after dental anesthetic injections is difficult because cardiovascular functions before injection often are elevated due to anxiety, and the initial postinjection changes may be due, in part, to responses to injection pain. Differences in heart rate and blood pressure seen after a local anesthetic injection likely represent multiple factors influencing the subjects’ cardiovascular systems, including homeostatic cardiovascular reflex responses, more prominent vasodilatation responses (ß-2) seen at relatively low plasma concentrations of epinephrine and, possibly, reduction of anxiety. The maximum mean increase in heart rate compared with the preinjection rate occurred 10 minutes after inferior alveolar injection (+ 3.5 beats/minute). It is interesting to note that heart rate actually decreased after Aw/o (–1.9 beats/minute). These minor differences in heart rate likely are due to the presence and absence of epinephrine contained in the study formulations.
We calculated the study sample size for an anesthetic efficacy outcome; it is not adequate for an assessment of relative safety. Additionally, the design assessed only articaine formulations and did not include an alternative anesthetic (such as lidocaine) for comparison. More adverse events were reported in Trial 1, in which a larger dose of anesthetic (1.7 mL versus 1.0 mL) was administered. Additionally, the inferior alveolar nerve block involves a more complex anatomical site that can result in needle trauma and related adverse events. Although our results did not find statistically significant differences in the frequency or severity of adverse events between formulations, a large clinical assessment of local anesthesia complications among 2,731 patients reported that articaine formulations containing 1:100,000 epinephrine were associated with more sympathomimetic side effects (such as tachycardia) than were formulations containing 1:200,000 epinephrine.15
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CONCLUSIONS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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FOOTNOTES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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