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Articaine is More Effective than Lidocaine or Mepivacaine in Rat Sensory Nerve Conduction Block in vitro

I. Potonik^1,*, M. Tomi², J. Sketelj³ and F.F. Bajrovi³

¹ Department of Restorative Dentistry & Endodontics, University of Ljubljana, Dental School, Hrvatski trg 6,1000 Ljubljana, Slovenia;
² Institut Jozef Stefan, Ljubljana; and
³ Institute of Pathophysiology, Medical Faculty, University of Ljubljana

Correspondence: ^* corresponding author, igor.potocnik{at}mf.uni-lj.si

	ABSTRACT

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The reasons for the relatively high failure rate after inferior alveolar nerve block in dentistry are not fully understood. Therefore, the effectiveness of different anesthetic solutions (2% and 4% lidocaine, 3% mepivacine, 2% and 4% articaine) in depressing the compound action potential amplitude of the sensory fibers in the rat sural nerve was examined under strictly controlled conditions in vitro. After application of an anesthetic solution and stimulation of the nerve with a supramaximal electrical stimulus, a complete disappearance of the compound action potential of the C fibers, but not of the A fibers, was observed in all the experimental groups. Both 2% and 4% articaine more effectively depressed the compound action potential of the A fibers than did other anesthetic solutions. These results are discussed in the light of recent clinical reports finding no differences in the effectiveness between 4% articaine and 2% lidocaine regarding the inferior alveolar nerve block.

Key Words: compound action potential • local anesthetic • nerve block • sensory nerve • rat

	INTRODUCTION

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Inferior alveolar nerve block (IANB) is the standard method used to achieve analgesia for endodontic procedures on mandible molars. However, a fairly high failure rate of IANB, ranging between 38% and 77%, has been reported (Vreeland et al., 1989; Hinkley et al., 1991; Cohen et al., 1993; Childers et al., 1996; Claffey et al., 2004; Mikesell et al., 2005). Anatomical differences, choice of anesthetic solution, or inflammation in the target tissue has been implicated in this high failure rate (for review, see Potonik and Bajrovi, 1999).

Mepivacaine (3%) is as effective as 2% lidocaine in obtaining analgesia in healthy or inflamed lower molars after IANB (Hinkley et al., 1991; Cohen et al., 1993). An earlier report suggested the inferiority of 4% articaine in comparison with 2% lidocaine or 3% mepivacaine in this regard (Cowan, 1977). In contrast, in some clinical studies, 4% articaine was superior to 2% lidocaine as a general-purpose anesthetic for dentistry (Ferger and Marxkors, 1973; Ruprecht and Knoll-Kohler, 1991). However, in recent clinical studies, no differences were found between 2% lidocaine and 4% articaine in healthy or inflamed lower molars after IANB (Malamed et al., 2000; Claffey et al., 2004; Mikesell et al., 2005).

In animal studies, 3% mepivacaine depressed the compound action potential (CAP) of the rat sciatic nerve better than did 2% lidocaine (Pateromichelakis and Prokopiou, 1988). Articaine (4%) was more effective than 2% lidocaine in blocking conduction in the frog (Muschaweck and Rippel, 1974) or rat peripheral nerve (Stankoviova and tolc, 1993). The efficacy of both 2% lidocaine and 4% articaine was concentration-dependent (Muschaweck and Rippel, 1974; Fink et al., 1975).

The reported results are difficult to compare among themselves, because different concentrations of local anesthetics, as well as different experimental animals, protocols, and conditions, were used. Therefore, the effects of the standard anesthetic solutions used for IANB in humans (2% lidocaine, 3% mepivacine, 4% articaine) on the CAP amplitude of the sensory axons were studied in the rat sural nerve in vitro, at body temperature, and after application to a standardized length of the nerve segment. In addition, the effects of 4% lidocaine and 2% articaine were examined for comparison.

	MATERIALS & METHODS

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Surgical Procedures
The experiments, approved by the Veterinary Administration of the Ministry for Agriculture, Forestry and Food of Slovenia, Permit No. 323-02-74/00, were conducted on 44 male Wistar rats weighing from 300 to 350 g, anesthetized by an intraperitoneal injection of sodium pentobarbital (Nembutal, Abbott Labs, Chicago, IL, USA; 50 mg/kg).

Each animal’s sciatic nerve and its branches were exposed by a longitudinal skin incision in the hind legs. The sural nerve, which is a predominantly (95%) sensory nerve (Swett et al., 1991), was dissected free from the surrounding connective tissue, and a nerve segment approximately 30 mm long was excised with the epineurium intact.

Compound Action Potential (CAP) Recording
The excised sural nerve segment was placed on the electrodes and immersed in liquid paraffin in a thermostatically controlled recording chamber (37 ± 1°C). Small weights (0.9 g) were attached by microclips to the proximal and distal ends of the nerve segment, to ensure tight contact with the electrodes. Two bipolar silver (Ag/AgCl) hook electrodes were used to stimulate the distal end of the sural nerve segment. Three recording electrodes were placed 10 mm proximally from the stimulating electrodes. The square wave stimulus (12 V) lasted for 10 µsec or 1 ms for the stimulation of A and C groups of sensory fibers, respectively. Stimuli were delivered at a frequency of 1 Hz. We determined the supramaximal level of the nerve stimulation by increasing the duration of the stimulus until no further increase in CAP amplitude was observed. Biphasic CAPs were displayed on a digital storage oscilloscope (Hewlett-Packard, 54601A, Santa Clara, CA, USA), and were recorded differentially at the sampling frequency of 20 kHz by a data acquisition system (DaqBook 200, Iotech, Inc., Cleveland, OH, USA), connected to a computer in which the data were stored for later analysis.

The CAP amplitude was measured as the voltage difference from the baseline to the top of the initial positive peak. The response peak latency was measured from the beginning of the stimulus artefact to the top of the positive CAP peak. We calculated conduction velocity by dividing the conduction distance (10 mm) by the peak latency.

Anesthetic Solution Application
Five different anesthetic solutions were examined: 2% and 4% lidocaine, 2% and 4% articaine, and 3% mepivacaine. A 3-mm-long piece of silicon tube was cut longitudinally and placed around the nerve segment 2 mm proximally to the stimulating electrodes (Fig. 1). We induced nerve block by injecting 0.1 mL of an anesthetic solution into the silicon tube, using a 25-gauge needle. The blocking effect was considered maximal when the amplitude of the CAP after the application of an anesthetic did not change during a 10-minute period.

View larger version (12K): [in this window] [in a new window]   Figure 1. Registration of the Compound Action Potential (CAP) of the isolated sural nerve (SN) in a liquid paraffin bath. Local anesthetic solution (LA) was injected into the silicone tube (ST), which had been cut longitudinally and placed between the stimulating (S) and recording (R) electrodes.

	RESULTS

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CAPs recorded from the sural nerves before the nerve block induction showed two distinct components, corresponding to the A and C fibers (Fig. 2). Control values of the CAP amplitudes, conduction velocities, and the supramaximal values of stimulus intensity, obtained before the initiation of the conduction blockade, were not statistically significantly different (p > 0.05) among the experimental groups. These data were therefore pooled, and the means and SDs were calculated (Table).

View larger version (10K): [in this window] [in a new window]   Figure 2. The Compound Action Potential (CAP) of A-fibers (a) and C-fibers (b) of the rat sural nerve before nerve block induction. The voltage and duration (intensity) of the supramaximal electrical stimulus were about 10 V-10 µsec for the A-fiber signal and about 12 V-1 msec for the C- fiber signal.

The mean amplitudes of the CAP of the A fibers decreased with time after nerve block induction and stabilized at about 15% of the control values, after the application of either the 2% lidocaine, 4% lidocaine, or 3% mepivacaine solutions. The differences among these anesthetics were not statistically significant (p > 0.05) (Fig. 3a). However, both 2% and 4% articaine solutions reduced the mean amplitude of the CAP of the A fibers to only about 1 – 2% of the control value, respectively. The difference between the effects of both articaine solutions and those of the other 3 solutions was statistically highly significant (p < 0.001). There were no statistically significant differences between the articaine solutions (p > 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 3. The amplitude of the CAPs (a) and conduction velocities (b) of rat sural nerve (mean ± SD) A-fibers before (black bars) and after (white bars) nerve block induction with 2% (n = 8) and 4% (n = 9) lidocaine (L), 3% (n = 10) mepivacaine (M), and 2% (n = 9) and 4% (n = 8) articaine (A).

The nerve block induced by either of the anesthetic solutions examined had no statistically significant effect on the conduction velocity of the residual CAP in the A fibers (Fig. 3b).

Further experiments revealed that, by increasing the duration of the electrical stimulus, applied 20 min after the conduction block induction, we could completely restore the average amplitude of the CAP of the A fibers in the case of the 2% and 4% lidocaine solutions, as well as the 2% articaine and 3% mepivacaine solutions. The duration of the stimulus had to be increased, on average, 19-, 9-, 15-, and 11-fold, respectively, but the differences were not statistically significant (p > 0.05). In contrast, even maximal possible prolongation of the stimulus (150-fold) did not significantly restore the amplitude of the CAP of the A fibers after the application of 4% articaine (7.5 ± 6.2% of the normal CAP amplitude). Interestingly, the amplitude of the CAP of the C fibers could not be restored by the maximal available stimulus duration after application of any of the anesthetic solutions examined. At the end of the experiment, after the nerves had been washed with the physiological saline solution, the amplitudes of the CAP increased to more than 80% of their control values. There were no statistically significant differences among different anesthetics in this regard.

	DISCUSSION

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The attenuating effect of a local anesthetic on the CAP in isolated nerves has been accepted as an index of the comparative efficacy of a local anesthetic (Jefferson, 1963; Camougis and Takman, 1971). Our study examined the efficacy of different anesthetic solutions, clinically used in dentistry, under strictly controlled conditions in vitro. All of the anesthetic solutions examined produced complete disappearance of the CAP of the C fibers, but not of the A fibers. This is in accord with the view that the C fibers in a sensory nerve are more susceptible to local anesthetics than are the A fibers, probably because of their smaller diameter (size principle of a differential conduction block) (Nathan and Sears, 1961; Franz and Perry, 1974; Ford et al., 1984). However, the reduction of the CAP amplitude might also be due to the temporal dispersion of action potentials as a result of altered conduction velocities (Jaffe and Rowe, 1996). Nevertheless, the size principle is supported by our observation that no change in conduction velocity of the residual CAP in the A fibers took place after the application of local anesthetics.

In contrast, the mean amplitudes of the CAP of the A fibers stabilized at about 15% of the control values after application of either 2% lidocaine, 4% lidocaine, or 3% mepivacaine solutions. We found no differences among these anesthetic solutions in this regard. This is in agreement with the clinical studies in which no differences in the efficacy of 2% and 4% lidocaine after IANB were found (Vreeland et al., 1989). However, it was reported that the anesthetic effect of lidocaine in animals was concentration-dependent (Fink et al., 1975). It is possible that a lidocaine concentration higher than 4% might display a significantly stronger effect; however, clinically, the use of lidocaine concentrations higher than 4% might result in toxic side-effects (Lambert et al., 1994).

In contrast to these 3 anesthetic solutions, 2% and 4% articaine almost completely depressed the CAP of the A fibers. In this regard, both 2% and 4% articaine were superior to 2% lidocaine. However, with increased intensity of nerve stimulation, the CAP amplitudes recovered after both 2% lidocaine and 2% articaine. In contrast, in the case of 4% articaine, the CAP amplitude displayed virtually no recovery of the control value, even after the maximal possible intensity of the electrical stimulus. These results are in line with the observations of higher potency of 4% articaine, compared with a standard lidocaine solution, in the peripheral nerve of the frog and rat in vitro (Muschaweck and Rippel, 1974; Stankoviova and tolc, 1993), and of the concentration-dependent action of articaine (Muschaweck and Rippel, 1974). In addition, we demonstrated that 4% articaine is also more effective than 4% lidocaine as well as 3% mepivacaine.

Normally, pain impulses are conducted by A and C fibers (Närhi et al., 1982). In our study, the remaining CAP after local anesthetic application originated mainly in Aβ fibers. Thus, the additional suppression of Aβ fibers by 4% articaine may not necessarily predict better analgesia in the normal clinical setting. Inflammation of the target tissue induces several changes in the nociceptive pathway that may contribute to pain hypersensitivity (Djouhri and Lawson, 2001), including changes in the chemical phenotype in Aβ fibers (Woolf and Costigan, 1999). Alterations in phenotype include the acquisition by A fibers of neurochemical features typical of C fibers, enabling the A fibers to induce stimulus-evoked hypersensitivity, something that normally only the C fibers can do. Therefore, in the case of dental pulp inflammation, Aβ fibers may also contribute to pain sensation and should be blocked by a local anesthetic for analgesia to be achieved. Moreover, IANB is clinically used in such conditions in most of cases.

The mechanism of reversible nerve conduction block by articaine is similar to that of other amide local anesthetics (Oertel et al., 1997). However, articaine is unique among them, because it contains a thiophene group, which increases its liposolubility. Therefore, articaine diffuses better through soft tissues than do other anesthetics (Oertel et al., 1997), thereby achieving higher intraneural concentration, more extensive longitudinal spreading, and better conduction blockade (Raymond et al., 1989). In addition, the thiophene derivative (carticaine) blocks ionic channels at lower concentrations than the benzene derivative (lidocaine) (Borchard and Drouin, 1980).

Clinical studies comparing the success rate of 4% articaine with that of other anesthetic solutions in dentistry gave variable results. Inferiority of 4% articaine after infiltration or conduction block, when compared with 2% lidocaine or 3% mepivacaine, has been suggested (Cowan, 1977). In contrast, when combined with epinephrine, articaine was superior to the standard solution of lidocaine as a general-purpose anesthetic for dentistry (Ferger and Marxkors, 1973; Ruprecht and Knoll-Kohler, 1991). The earlier study reported lower efficacy for IANB, and the more recent one did not include any IANB. However, in more recent clinical studies, no differences were found between 4% articaine and 2% lidocaine for anesthesia for general dental procedures (Malamed et al., 2000). Similarly, no differences were found between 2% lidocaine and 4% articaine in healthy or pulpitic lower molars after IANB (Claffey et al., 2004; Mikesell et al., 2005).

To conclude, our results showed that even 2% articaine more effectively depressed the CAP of the A fibers in the isolated rat sural nerve than either 2% or 4% lidocaine, or 3% mepivacaine. Although 4% articaine was more effective in this regard, these observations suggest that it may be worth considering replacing the 4% articaine with the 2% articaine solution, because of the risk of an intravenous injection of the anesthetic solution during the induction of IANB, and the possibility that the 4% articaine solution may increase the incidence of non-surgical paresthesia (Ruprecht and Knoll-Kohler et al., 1991; Haas and Lennon, 1995). In contrast, superiority of the articaine over other anesthetic solutions in regard to CAP depression in vitro, and the absence of differences in success rates between 4% articaine and 2% lidocaine observed in clinical studies (Claffey et al., 2004; Mikesell et al., 2005) suggest that factors other than the type of anesthetic solution or its concentration are responsible for the IANB failure.

	ACKNOWLEDGMENTS

 
This study was supported by grants P0-0518-0381 and Z3-3348-0381-02 from the Ministry of Science and Technology of the Republic of Slovenia. No consultants were involved in this study, and none of the authors received any fee paid directly or from any other financial agreements.

Received for publication May 19, 2004. Revision received August 19, 2005. Accepted for publication September 11, 2005.

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Journal of Dental Research, Vol. 85, No. 2, 162-166 (2006)
DOI: 10.1177/154405910608500209


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