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From the *Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan; and Department of Anesthesiology, Kaohsiung Medical University Chun-Ho Memorial Hospital, Kaohsiung, Taiwan.
Address correspondence and reprint requests to Jhi-Joung Wang, MD, PhD, Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan. Address e-mail to 400002{at}mail.chimei.org.tw.
Abstract
BACKGROUND: Local anesthetics, when applied to nerves, produce reversible loss of sensation by blocking Na+ channels. Because all Class I antiarrhythmic drugs are Na+ channel blockers, theoretically, they may have local anesthetic effects. In this study, we sought to define the cutaneous local anesthetic actions of three Class I antiarrhythmic drugs.
METHODS: Using a subcutaneous infiltration model in rats, the potencies and durations of action of quinidine (Class IA), mexiletine (IB), and flecainide (IC) were determined and compared with the actions of lidocaine and bupivacaine. Saline injection was used as control.
RESULTS: Three Class I antiarrhythmic drugs produced a dose-related cutaneous analgesia with ranking of potencies of bupivacaine > flecainide > quinidine > mexiletine > lidocaine (P < 0.05 for the differences among drugs). On an equipotent basis, the ranking of durations of action was flecainide > quinidine and bupivacaine > mexiletine and lidocaine (P < 0.05 for the differences among drugs).
CONCLUSION: Three Class I antiarrhythmic drugs, quinidine (IA), mexiletine (IB), and flecainide (IC) have a local anesthetic effect on cutaneous analgesia.
Sodium channel blockade is a common feature of Class I antiarrhythmic drugs and local anesthetics. A variety of drugs, such as lidocaine and mexiletine, have both antiarrhythmic and local anesthetic properties (1–3). Currently, Class I antiarrhythmic drugs are used for treating various forms of cardiac rhythm disorders (3–5). They block rapid inward Na+ currents in cardiac tissues, thereby inhibiting automaticity and decreasing the conduction velocity of cardiac tissues (3–5). This action causes a widening of the QRS complex (3,5). Class I antiarrhythmic drugs are further subclassified into Class IA, IB, and IC, based on their electrophysiologic actions on the cardiac tissues. Among these drugs, Class IB drugs (e.g., lidocaine and mexiletine) unbind from the Na+ channels rapidly, whereas Class IC drugs (e.g., flecainide) unbind slowly from the Na+ channels. Class IA drugs (e.g., quinidine) have intermediate binding characteristics to the Na+ channels (3–5).
Local anesthetics, when applied to the nerves, produce reversible loss of sensation (1,6–8). They inhibit the initiation and propagation of action potentials by blocking voltage-gated Na+ channels (1,6–8). Because all Class I antiarrhythmic drugs block these channels in cardiac tissues (3,5), they may also block them in nerve tissues and have local anesthetic effects. The aim of this study was to define the cutaneous local anesthetic actions of three Class I antiarrhythmic drugs. Using a subcutaneous infiltration model in rats, the potencies and durations of action of quinidine (Class IA), mexilitine (IB) and flecainide (IC) were determined and compared with the actions of lidocaine and bupivacaine. Saline injection was used as control.
METHODS
Male Sprague Dawley rats, purchased from the National Laboratory Animal Center, Taipei, Taiwan, were used. They were housed in groups of three for at least 1 wk in a climate-controlled room maintained at 21°C with approximately 50% relative humidity. Lighting was set to a 12-h light–dark cycle (light on at 6:00 am), with food and water available ad libitum up to the time of testing. During testing, the rats’ weights were around 225–275 g. All tests were performed in accordance with the recommendations and policies of the International Association for the Study of Pain, and the protocol was approved by the animal investigation committee of Chi-Mei Medical Center.
Quinidine gluconate, mexiletine hydrochloride, flecainide acetate, lidocaine hydrochloride, and bupivacaine hydrochloride were purchased from Sigma Chemical CO (St Louis, MO). All medications were freshly prepared and dissolved in 5% dextrose.
Two studies were performed. In Study 1, the potencies of Class I antiarrhythmic drugs on cutaneous analgesia were evaluated. In Study 2, the durations of their effects on cutaneous analgesia were evaluated.
Before experiments, rats were handled daily up to 7 days to familiarize them with the behavioral investigator, the experimental environment and the specific experimental procedures. This familiarization minimized the contamination of rats from stress during experiments, and generally improved experimental performance (9,10). One day before the experiments, the hairs of the dorsal surface of the thoracolumbar region (10 x 10 cm2) of rats were mechanically removed. There were six rats in each group for different treatments.
Subcutaneous injections of drugs (on micromole basis) were performed according to the method reported previously (9,10). In brief, these procedures were performed in conscious and unanesthetized rats using a 30-gauge needle injected 0.6 mL subcutaneously into the dorsal surface of the thoracolumbar region. To reduce the number of experimental animals used, the rats’ backs were further divided into left and right parts, both of which, with a washout period of 1 wk, received one drug injection. For consistency, one experienced investigator (Dr. Tzeng), who was blinded to injected drugs, was responsible for evaluating cutaneous analgesia. The drugs were prepared and injected by another investigator (Mr. Huang).
Subcutaneous injection caused a circular elevation of the skin—a wheal, approximately 2 cm in diameter—which was marked with ink within 1 min after injection. The effect of cutaneous analgesia was evaluated using the cutaneous trunci muscle reflex (9,10). The reflex was characterized by reflex movement of the skin over the back produced by twitches of the lateral thoracispinal muscle in response to local dorsal cutaneous stimulation. A Von Frey filament (No. 15), to which the cut end of an 18-gauge needle was affixed, was used to produce the standardized nociceptive stimulus (19 g). Six pinpricks (at six different points within each wheal) with a frequency of 0.5–1 Hz were used at each testing. The complete absence of six responses was defined as complete nociceptive block (100% of possible effect; 100% PE). The test was applied every 5 min for the first 30 min and then every 10–15 min to 2–3 h until the cutaneous reflex completely recovered from the block. For each dose of each drug, the maximal effect was presented as percentage maximal possible effect (% MPE).
In Study 1, the potencies of drugs on cutaneous analgesia were evaluated. After subcutaneous injections (n = 6 rats for each dose of each drug), the % MPEs of doses of drugs were obtained. The dose– response curves of drugs were then constructed using the % MPEs and fitted with a computer-derived SAS NLIN analysis (version 9.1, SAS Institute, NC). The values of 50% effective doses (ED50s) of drugs, which were defined as the doses of drugs that caused a 50% block of the cutaneous trunci muscle reflex, were obtained (11).
In Study 2, the duration of drug effects on cutaneous analgesia were evaluated. As in the method for ED50s, the ED25s, and ED75s of the drugs were obtained from the computer-derived curve fitting (SAS NLIN). Rats were then treated with subcutaneous injections of drugs with doses of ED25, ED50, and ED75 (n = 6 rats for each dose of each drug). After treatments, drug duration, defined as the intervals from injection to complete recovery, was measured. In the study, two control groups were used. One group (n = 6 rats) received subcutaneous injection of saline to exclude the possibility of vehicle effect on cutaneous analgesia; another group (n = 6 rats for each drug) received subcutaneous injection of saline combined with intraperitoneal injection of testing drug (quinidine, mexiletine, flecainide, bupivacaine, or lidocaine) with a dose of two ED75 to exclude the possibility of systemic effects of drugs on local analgesia.
Values were presented as mean ± sem. The differences in ED50s among drugs were evaluated by a one-way analysis of variance (ANOVA), followed by the pairwise Tukey’s honest significance difference (HSD) test. The differences in durations among drugs were evaluated by a two-way ANOVA, followed by the pairwise Tukey’s HSD test. In the control groups, a one-way ANOVA followed by the Dunnett test was used to evaluate the effects of medications. A statistical software, SPSS for Windows (version 10.0.7), was used. A P value <0.05 was considered statistically significant.
RESULTS
Because of similarities in the figures, only those obtained from drugs at a dose of 3 µmol are shown (Fig. 1). At this dose, bupivacaine, flecainide, quinidine, mexiletine, and lidocaine showed 100%, 97%, 88%, 85%, and 46% of cutaneous analgesia (% MPE), with durations of action of about 116, 78, 68, 44, and 18 min, respectively (Fig. 1).
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After subcutaneous injections, the dose–response curves of the drugs were constructed (Fig. 2). As local anesthetics, the three Class I antiarrhythmic drugs also produced a dose-related cutaneous analgesia, with ranking of potencies of bupivacaine > flecainide > quinidine > mexiletine > lidocaine (P < 0.05 for the differences between drugs; Table 1). The ED25s, ED50s, and ED75s of drugs are shown in Table 1.
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Drug durations were evaluated and compared at the doses of ED25s, ED50s, and ED75s (Fig. 3). On this basis, the ranking of durations was flecainide, quinidine and bupivacaine > mexiletine and lidocaine (P < 0.05 for the differences among drugs; Fig. 3). Neither the subcutaneous injections of saline nor the intraperitoneal injections of testing drugs produced cutaneous analgesia.
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DISCUSSION
Local anesthetics exert their anesthetic/analgesic effects by blocking voltage-gated Na+ channels of neurons in a use-dependent manner (1,6,7). Morphologically, the Na+ channel is a multimolecular complex composed of one 
-subunit and two auxiliary ß-subunits (1,8,12,13). The -subunit, composed of approximately 2000 amino acids, forms the channel pore and gating mechanism, and contains the principal drug binding sites. The ß-subunits modulate the activation and inactivation states of -subunit. Morphologically, the -subunit is composed of four highly homologous domains (I–IV) and has its own six transmembrane -helical segments (S1–6). The S5–6 linking regions are believed to form the channel pore. The channel itself has a fairly large outer pore (extracellular) and a relatively small inner pore (intracellular). Local anesthetics bind to the inner pore of the channel in an open (inactivated) state (1,8,12,13). There are at least nine variants of -subunits (i.e., Nav 1.1 to Nav 1.9), which are present by different gene sequences and distribute in different tissues and organs (1,8,12,13). In general, Nav 1.1 to Nav 1.3 distribute in brain, Nav 1.4 distributes in muscle, Nav 1.5 distributes in heart, and Nav 1.6 to 1.9 distribute in peripheral nerve tissues (13).
Local anesthetics block all these Na+ channels (1,8,12,13). Because all Class I antiarrhythmic drugs effectively block Na+ channels (Nav 1.5) in heart, they would be expected to block the other Na+ channels and exert local anesthetic effects. In our study, the cutaneous analgesic effect of these drugs was tested. As expected, we found that the three Class I antiarrhythmic drugs (IA: quinidine; IB: mexiletine; IC: flecainide) produced a dose-related cutaneous analgesic effect. We also found that the Class IC drug (flecainide) had a strong effect with a long duration of action; the Class IB drug (mexiletine), a weak effect with a short duration of action; the Class IA drug (quinidine), an intermediate effect with a duration similar to that of Class IC drug (Fig. 2 and Table 1). The ranking of potencies and duration of drug effects on cutaneous analgesia was quite similar to that of those effects on cardiac dysrhythmia.
In general, Class IC drugs have a strong effect on cardiac dysrhythmia with a long duration of action; the Class IB drugs, a weak effect with a short duration of action; the Class IA drugs, an intermediate effect with an intermediate duration of action (3–5). The similarity in drug effects between cutaneous and cardiac tissues might be explained by the following. Although there are nine variants of -subunit in Na+ channels, the differences among these -subunits are minor (13). All the -subunits share very similar gene sequences and conformations, and are considered members of one family (13). Therefore, the characteristics of pharmacologic responses of drugs (i.e., potencies and durations of action) on Na+ channels among different tissues and organs might be similar.
To exclude the possibility of systemic effects of drugs on cutaneous analgesia, a relatively large dose of drugs (two ED75; traditional local anesthetics and Class I antiarrhythmic drugs) was injected intraperitoneally. We found that no cutaneous analgesia was detected. Also, no analgesic effect was found after local injection of saline. These two pieces of evidence supported the local effect of Class I antiarrhythmic drugs on cutaneous analgesia.
Infiltrative cutaneous analgesia by local anesthetics is an attractive option for surgical anesthesia and management of postoperative pain (6). Currently, bupivacaine and lidocaine are commonly used in this field (6). In our study, the three Class I antiarrhythmic drugs also produced cutaneous analgesic effects with potencies and durations of action ranging between that of bupivacaine and lidocaine. Class I antiarrhythmic drugs may be the alternatives to traditional local anesthetics for infiltrative cutaneous analgesia and, therefore, offer the anesthesiologists more drug selections.
Class I antiarrhythmic drugs also have other characteristics which make them suitable as local anesthetics. First, they may have acceptable cardiac-related side effects because they are antiarrhythmic drugs (3). Second, they may also have acceptable central nervous system-related side effects because some of these drugs have therapeutic effects on central nervous system-related disorders (14–17). For example, quinidine is an anticonvulsant (14); mexiletine can protect brain from ischemic insult (15); both mexiletine and flecainide are effective in treating neuropathic pain through central mechanisms (16,17). In our study, we did not evaluate whether Class I antiarrhythmic drugs have a toxic effect on subcutaneous nerve tissues. This should be evaluated before their clinical application.
In conclusion, all three Class I antiarrhythmic drugs produced a dose-related cutaneous analgesia. The Class IC drug (flecainide) had a strong effect with a long duration of action; the Class IB drug (mexiletine), a weak effect with a short duration of action; and the Class IA drug (quinidine), an intermediate effect with a duration similar to that of the Class IC drug. The suitability of Class I antiarrhythmic drugs as clinical local anesthetics for infiltrative cutaneous analgesia is worth further evaluation.
Footnotes
Accepted for publication December 14, 2006.
REFERENCES
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