Local anesthesia is essential for pain management in dentistry. Dexmedetomidine (DEX), a selective α-2 adrenoceptor agonist, is intravenously administered to patients as a sedative. DEX, when combined with a local anesthetic agent, has been found to extend the duration of peripheral nerve blocks.1–3 This action is suggested to be due to local vasoconstriction in peripheral nerves.3–5 In a previous study, on administration of 2.5 to 7.5 ppm of DEX, it was found that it dose dependently enhances the local anesthetic action of lidocaine in inferior alveolar nerve block (IANB).6 Furthermore, a previous study reported that the duration of anesthetic action of addition of 5.0 and 7.5 ppm of DEX was significantly longer than the addition of adrenaline (AD), and the mean duration of anesthetic action of the addition of 2.5 ppm DEX was also longer than the addition of AD.6 We hypothesized that it is possible to safely achieve equal local anesthesia effect as with 1:80,000 AD, without using AD or felypressin, by the addition of <2.5 ppm DEX to the local anesthetic solution.
The aim of this study was to determine the appropriate concentration of DEX that should be added to local anesthetics to enhance their potency and duration of action in humans. We examined the local anesthetic and cardiovascular effects of lidocaine with various low-level concentrations of DEX and lidocaine with AD, administered as IANB.
MATERIALS AND METHODS
This prospective, cross-over design clinical trial was conducted with the approval of the institutional review board of Kyushu University Medical Dental Hospital in August 2017 (29), in accordance with the Consolidated Standards of Reporting Trials recommendations on randomized trials and the principles of the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labor and Welfare in Japan. It was registered with the University Hospital Medical Information Network Clinical Trials Registry (number: UMIN000025928), which was established for national medical schools in Japan. The study included American Society of Anesthesiologists physical status I patients who were in good health and were not taking any medications.
The necessary number of participants required for the study was determined on the basis of a past study on vasopressor addition to local anesthetics using the same method, in which the estimated duration (±SD) of local anesthetic action with AD addition to local anesthetics was 218.7±33.5,6 according to which at least 18 patients in each group were considered necessary to achieve an ∼20% increase in the duration of local anesthetic action by the addition of DEX at an α risk of 0.05 and (1−β) of 0.95. Although the DEX concentrations used in this study (1.0 to 2.0 ppm) have not been previously evaluated, addition of DEX at 2.5, 5.0, or 7.5 ppm concentrations to local anesthetics resulted in as follows. The duration of local anesthetic action was increased by 20% at 5.0 ppm and 32% at 7.5 ppm compared to AD. The sample size for each group of 2 groups comparison above was applied to the sample size for 3 groups comparison. Thus, 19 healthy volunteers were enrolled in the present study, and written consent was obtained. It was confirmed that no volunteer fulfilled the exclusion criteria, defined as having or possibly having an allergy or hypersensitivity to local anesthetics or DEX, hypertension, diabetes mellitus, hyperthyroidism, renal or hepatic disease, cardiovascular disease or serious dysrhythmia, using antipsychotic drugs or α-blockers, catecholamines or adrenergic drugs, having a psychoneurosis or using cocaine, having a dental phobia, or pregnant or lactating. This study not only evaluated 2 different DEX concentrations but also compared the effects of the addition of AD and different DEX concentrations to lidocaine.
The order in which the 3 drug combinations were administered and the side of administration (right or left) were randomly determined by a computer, resulting in participants being assigned, in turn, to each of 3 groups: AD, 1.0 ppm DEX, or 2.0 ppm DEX. Three appointments at least 2 days apart were scheduled for each of the participants. Through use of a repeated-measures design, each participant received an IANB at each of 3 successive appointments, randomly receiving a different drug combination at each appointment.
Lidocaine (lidocaine hydrochloride) was purchased from Astra Zeneca (Osaka, Japan). Dexmedetomidine (Precedex), a specific α-2 adrenoceptor agonist, was purchased from Maruishi Pharmaceutical (Osaka, Japan). The drugs were dissolved and diluted with saline to create the following solutions (1.8 mL of each): 1:80,000 AD (22.5 μg) in 1.8% lidocaine, 1.0 ppm (1.8 μg) DEX in 1.8% lidocaine, and 2.0 ppm (3.6 μg) DEX in 1.8% lidocaine.
Studies were carried out in a quiet room maintained at a comfortable ambient temperature (∼25°C). Neither the author conducting the study nor the volunteers knew which solution was injected. Equal numbers of right and left sides of the mandible were tested, with premolars as the test teeth. Clinical examinations indicated that all teeth were free of caries, large restorations, and periodontal disease; none of the teeth had histories of trauma or sensitivity. At the beginning of each appointment and before any injections were administered, the experimental teeth were tested 3 times with the pulp tester (Vitality Scanner Model 2006; Sybron Endo, Orange, CA) to record baseline vitality. After the tooth to be tested was isolated with cotton rolls and dried with gauze, an electric conductive paste was applied to the probe tip, which was then placed midway between the gingival margin and the occlusal/incisal edge of the tooth. The current rate was set to increase from no output (0) to the maximum output (80) (cutoff latency) in 15 seconds. The number associated with the initial sensation was recorded.
The sedation level of participants was evaluated using the Mackenzie and Grant Sedation Score (score 1, fully awake; score 2, drowsy with eyes open and/or brisk response to command; score 3, drowsy with eyes closed and/or slow response to command; score 4, eyes closed, but rousable with mild physical stimulus; score 5, eyes closed and unrousable with mild physical stimulus). Furthermore, all participants continuously underwent noninvasive blood pressure (BP) and electrocardiography monitoring using a standard automated monitoring device (MU613R; Nihon Kohden, Tokyo, Japan) throughout the experiment, and systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded.
Before the IANB, the premolar was pulp tested, and SBP, DBP, and HR were recorded. Next, using pick-up tweezers, each participant was asked if his or her lip/tongue was numb. The IANB was performed with a 27 G 19 mm needle (NN-2719S; Terumo, Tokyo, Japan) using the randomly preselected anesthetic solution. After the target area was reached and aspiration was performed, the anesthetic solution was injected over 10 seconds and the participant was asked to rate the discomfort associated with deposition of the solution. The discomfort rating scale ranged from 0 to 3, with 0 indicating no pain, 1 indicating mild pain that was recognizable, but did not cause discomfort, 2 indicating moderate pain that was uncomfortable but bearable, and 3 indicating severe pain that caused considerable discomfort and was difficult to bear.
After the IANB, the premolar was pulp tested, lower lip and tongue numbness were tested, and sedation level, BP, and HR were recorded. This cycle of testing was repeated every 2 minutes for 10 minutes, every 5 minutes from 10 to 20 minutes, and every 10 minutes from 20 to 60 minutes. The time when the numbness appeared on both the lips and tongue was defined as the time of anesthesia effect onset. If profound lip numbness was not recorded within 20 minutes, the block was considered unsuccessful; the participant was then reappointed. All testing was stopped at 60 minutes after injection. To determine anesthesia recovery time, lower lip numbness was tested by the participants touching both sides of their lower lips every 15 minutes from 60 minutes after injection until recovery of lip sensation.
The pulp test latency value was used to calculate the maximum possible effect (MPE) of the local anesthetic according to the following formula:
The pulp test latency value was then evaluated as %MPE.
Pulp test latency, BP, and HR changes over time were compared using repeated-measures analysis of variance, whereas comparisons to baseline were performed using a post hoc Dunnett multiple comparison test and intergroup comparisons were analyzed using Tukey multiple comparison test, as indicated. Anesthesia onset time and recovery time were compared using repeated-measures analysis of variance, whereas a post hoc Tukey multiple comparison test compared values between the 3 groups. In multiple comparison tests, the P-values are presented after adjustment for multiple comparisons. The discomfort value was analyzed using the χ2 test. JMP software (version 10; SAS Institute Inc., Japan) was used for statistical analysis, and P-value <0.05 was considered to be statistically significant. Prism software (version 6; GraphPad Software Inc., San Diego, CA) was used for analysis of the graph. The results of %MPE are presented as mean±SE, whereas the other values are presented as mean±SD.
All 19 volunteers (7 men and 12 women; 21 to 31 y old) were thoroughly investigated in the present study. Their age, height, and weight were 25.4±3.7 years, 161.7±7.4 cm, and 56.1±9.5 kg, respectively.
The discomfort ratings associated with solution deposition for the IANB are presented in Table 1. There were no significant differences between the AD, DEX 1.0, and DEX 2.0 groups (P=0.6402). Anesthesia onset time is presented in Table 2. There were no significant differences between the 3 groups in the onset of lip (P=0.9240) and tongue anesthesia (P=0.2772). Anesthesia duration time is presented in Table 3. There were no significant differences between the 3 groups in the anesthesia duration time (P=0.3196). The mean value of DEX 2.0 ppm produced similar duration as AD than DEX 1.0 ppm.
Baseline pulp test latency in each tooth was not significantly different between the 3 groups. In premolar pulp test latency, %MPE increased significantly from 4 minutes until 60 minutes in all groups, compared with baseline values (P<0.05) (Fig. 1). At each timepoint, there were no significant differences between the 3 groups in the pulp test latency (P>0.05).
In terms of the level of sedation, there were no significant intergroup differences between baseline, immediate, 2, 8, 10, 15, 20, 30, 40, 50, and 60 minutes after IANB values (baseline to 8 min score in all participants was 1; 10 to 60 min, P>0.05) (Table 4).
Comparison of SBP with baseline values indicated no significant differences in any of the groups (P>0.05). Comparison of DBP with baseline values indicated no significant differences in any of the groups (P>0.05) (Fig. 2). HR comparisons showed no significant difference compared with baseline values in any of the groups, and no intergroup differences at any timepoint (P>0.05) (Fig. 3).
The study flow diagram is presented in Figure 4. There were no important adverse events in any of the groups.
Local anesthesia is essential for pain management in dentistry. Local anesthetics reversibly block nerve conduction, enabling dental procedures to be performed.7 In the past study, we examined the local anesthetic effect of DEX at a concentration of 2.5 to 7.5 ppm. This previous study reported that DEX dose dependently enhances the local anesthetic action of lidocaine in IANB.6 Furthermore, the duration of anesthetic action of the addition of 5.0 and 7.5 ppm of DEX was significantly longer and the mean duration of anesthetic action of the addition of 2.5 ppm DEX was longer than the addition of AD.6 We hypothesized that it is possible to safely achieve equal local anesthesia effect as with 1:80,000 AD by the addition of <2.5 ppm DEX to the local anesthetic solution. Therefore, in the present study, the local anesthetic action of the addition of 1.0 or 2.0 ppm DEX was examined. Furthermore, DEX is added to 2% lidocaine products; thus, the concentration of lidocaine in the adjusted drug decreased <2%. In our previous study, lidocaine concentration was 1%. In the dental procedure, lidocaine at a concentration of 2% has been used.8 In the present study, the concentration of lidocaine was set at 1.8%, which is close to the concentration of local anesthetic used for dental procedures.
New drugs that can replace AD and felypressin for the safe enhancement of local anesthesia effect in patients with cardiovascular diseases are much required. α-2 adrenoceptor agonists, such as DEX, which produce sympatholytic, sedative, analgesic, antihypertensive, and bradycardiac effects when combined with a local anesthetic agent, have been found to extend the duration of local anesthesia effect by causing local vasoconstriction. DEX produces clinically useful sedation through α-2 adrenoceptors.2,9 On the basis of the mechanism that the local anesthesia reinforcement action of DEX depends on local vasoconstriction, we previously reported that prolongation of the local anesthetic effect by DEX in IANB was concentration dependent.6 In the present study, we compared the effect of the addition of AD 1:80,000, which is the standard vasopressor added to the local anesthetic during dental procedures, and low concentrations of DEX. Our results demonstrated that the mean value of DEX 2.0 ppm produced a similar duration as AD in IANB. To the best of our knowledge, the present study is the first to show the enhancing effect of DEX equivalent to AD as an adjuvant to a local anesthetic administered for IANB, being applicable to local anesthesia for dental procedures or oral surgery. The present results indicated that the addition of 2.0 ppm DEX to local anesthetics prolongs the duration of action of lidocaine equivalent to AD. Two possible mechanisms, main possible and minor possible mechanisms, have been proposed for this action. The main mechanism is vasoconstriction around the site of injection, resulting in a delay in the absorption of the local anesthetic and prolongation of the local anesthesia effect.2,5,10 DEX is a selective α-2 adrenoceptor agonist. The α-2 adrenoceptors are subdivided into 4 subtypes: α-2A, α-2B, α-2C, and α-2D. The α-2A, α-2B, and α-2C adrenoceptors have been well identified pharmacologically and have been shown to cause vasoconstriction.11–14 The minor possible mechanism for the enhancement and prolongation of local anesthetic action by DEX is its direct effect on peripheral nerve activity.15,16 However, it is reported that DEX administered alone, at the concentration of 5.0 ppm, which was higher than the concentration of this study, which was shown to enhance the local anesthetic effect, produced no local anesthesia effects.2 In contrast, it has been reported that the mechanism of action of DEX is not related to vasoconstriction, but involves the hyperpolarization-activated cation current.16–18
In our previous study, lip anesthesia onset time indicated a trend in favor of DEX, especially with higher concentrations.6 This indicates that DEX might have direct effects on peripheral nerve activity. However, this previous study was not powered to detect a difference in lip anesthesia onset because the measurement interval for lip anesthesia onset was every 5 minutes. Hence, the present study narrowed the measurement interval; the measurement interval was set every 2 minutes. In the present study result, lip anesthesia onset time showed no differences between 1.0 and 2.0 ppm DEX and AD. Therefore, it was indicated that DEX has no direct effects on peripheral nerve activity.
Dental local anesthetics contain vasoconstrictors, such as AD and felypressin, to enhance the anesthetic effects and reduce bleeding in the surgical field.19 Several reports have warned against the use of dental local anesthetics containing AD in patients with cardiovascular diseases.19–21 Therefore, felypressin, a noncatecholamine vasopressor that is chemically related to vasopressin, has been used as a safe vasoconstrictor in patients with compromised cardiovascular status in Japan and nations in the European Union.22 However, there have been reports that, in a rabbit study, clinical doses of felypressin are capable of inducing myocardial ischemia during surgery,22 and, in a dog study, clinical doses of felypressin caused decreases in coronary blood flow.23 Hence, the use of a new drug, such as DEX, which can replace AD and felypressin for the safe enhancement of local anesthesia effect in patients with cardiovascular diseases, is recommended. It would be interesting to determine the concentration of DEX that has equal action as AD because AD is usually used as an additive for local anesthetics. In the present study, the anesthesia duration was not significantly different between groups: AD (245.5 min), DEX 1.0 ppm (217.7 min), and DEX 2.0 ppm (238.1 min). Although the difference was not significant, the mean duration of local anesthetic action with the solution containing DEX 2.0 ppm (238.1 min) produces an equivalent effect as AD (245.5 min).
In this study, DEX did not change BP and HR. Our previous study reported that 5.0 and 7.5 ppm DEX decreased BP.6 Intravenously administered DEX is known to induce adverse clinical reactions, such as bradycardia and hypotension, in some sedated patients, depending on the administered dose.24 However, it is reported that the administration of a dose of 1 μg/kg does not considerably influence the cardiovascular system.25 In this study, DEX was administered at a volume of 1.8 mL and a concentration of 1.0 to 2.0 ppm. This means that the administered dose was 1.8 to 3.6 μg, a dose ∼15- to 31-fold lower than the dose of 1 μg/kg reported in the above-mentioned study. Moreover, this concentration means that ∼2 to 8 fold lower than the concentration of 5.0 to 7.5 ppm reported in our past study. In this study, the sedation effect compared with AD was not observed with any of the concentrations of DEX used. These findings suggest that DEX can be safely administered as an additive to local anesthetics for IANB without the risk of excessive sedation.
Application of DEX to nerves, as was used in this study, is considered off-label usage. In Japan, off-label usage for clinical trials is acceptable when the clinical trial is conducted with the approval of the concerned institutional review board. Off-label usage in this study was approved by the institutional review board of our institute because the amount and concentration of DEX used were within the safe range. Our previous study on the addition of DEX to local anesthetics evaluated a much larger dose 3.75- to 7.5-fold the dose required to achieve the concentration of 1.0 to 2.0 ppm used in this study.6 In terms of the DEX concentration, according to internal data of the manufacturer (Maruishi Pharmaceutical, Osaka, Japan), application of an undiluted DEX solution and twice the concentration of the undiluted DEX solution to local tissue does not lead to a tissue reaction, whereas application of 10 times the concentration of the undiluted DEX solution causes slight irritation of the tissue. The amount of DEX in the 1.0 ppm DEX solution used in this study was equivalent to 0.01-fold the undiluted solution, and that in the 2.0 ppm solution was 0.02-fold the amount in the undiluted solution. Thus, in this study, off-label usage of DEX was performed within the bounds of acceptance of the rules of Japan.
This study has a limitation. It has a small sample size. The sample size for the present study was determined as described in the methods section. However, a larger study might be necessary to pass Food and Drug Administration requirements. Perhaps, future study should include studies that are targeted to medically compromised patients (eg, cardiac disease). The present study can also be regarded as a preliminary study that awaits confirmation in a larger and more robust trial.
In conclusion, our results demonstrate that the addition of DEX at a concentration of 1.0 to 2.0 ppm enhances the local anesthetic action of lidocaine. Also, the addition of DEX at a concentration of 2.0 ppm produces similar enhancement of the local anesthesia effect as the addition of 1:80,000 AD in IANB. This finding suggests that it is possible to safely achieve equal local anesthesia effect as with 1:80,000 adrenaline without using adrenaline or felypressin, by the addition of 2.0 ppm DEX to the local anesthetic solution.
The authors is very grateful to Dr Shigeki Joseph Luke Fujiwara, DDS, PhD (an old colleague of our department) for his help with the pulp test, to Vice Director Junji Kishimoto, PhD from Center for Clinical and Translational Research, Kyushu University, Japan for his help with data analysis, to Dr Takeshi Yokoyama, DDS, PhD (professor and chair of our department) for approving this study, to Dr Ryozo Sendo, DDS (a colleague of author’s previous affiliation) for his help with obtaining a reference article, and to Dr Kazuna Sugiyama, DDS, PhD (the author’s previous chair and professor) for his help with the referenced study.
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