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Anesthesia & Analgesia:
doi: 10.1213/01.ane.0000260330.18745.a8
Pain Mechanisms: Research Report

Dextromethorphan or Dextrorphan Have a Local Anesthetic Effect on Infiltrative Cutaneous Analgesia in Rats

Chen, Yu-Wen PhD*; Chu, Koung-Shing MD*; Lin, Ching-Nan MD*; Tzeng, Jann-Inn MD, MS*; Chu, Chin-Chen MD*; Lin, Mao-Tsun PhD*; Wang, Jhi-Joung MD, PhD*

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From the *Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; and †Department of Anesthesiology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.

Accepted for publication January 11, 2007.

Address correspondence and reprint requests to Dr. Jhi-Joung Wang, MD, PhD, Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan. Address e-mail to 400002@mail.chimei.org.tw.

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Abstract

BACKGROUND: Dextromethorphan blocks sodium channels, the site of action of local anesthetics. In this study we evaluated whether dextromethorphan has a local anesthetic effect.

METHODS: We administered dextromethorphan and its active metabolite— dextrorphan, and lidocaine subcutaneously to rats and tested them for cutaneous anesthesia. Drug–drug interactions and systemic safety indices (LD50s/ED50s) were also evaluated.

RESULTS: Dextromethorphan and dextrorphan had a local anesthetic effect after cutaneous infiltration. The ranking of potencies was dextromethorphan > dextrorphan > lidocaine (P < 0.01 for each comparison). A combination of dextromethorphan or dextrorphan with lidocaine produced an additive effect. Dextromethorphan and dextrorphan had 2.4- and 1.9-fold higher system safety indices than did lidocaine.

CONCLUSION: Dextromethorphan and dextrorphan were more potent local anesthetics than lidocaine, but with higher systemic safety indices. Coadministration of dextromethorphan or dextrorphan with lidocaine produced an additive effect.

Dextromethorphan is a dextrorotatory morphinan with a chemical structure closely related to the levorotatory morphinans of levorphanol, codeine, and morphine (1–3). From its early beginning more than 50 yr ago, dextromethorphan was synthesized as a pharmacological alternative to morphine (3). However, in contrast to the levorotatory morphinans, dextromethorphan has little or no opioid activity, despite a remarkably complex pharmacology (3). In receptor binding assays, dextromethorphan binds to the N- methyl-d-aspartate (NMDA) glutamate and nicotine/ neuronal nicotinic receptors as an inhibitor (3,4). Dextromethorphan also binds to the receptor-gated (NMDA receptor mediated) and voltage-gated calcium channels, and the voltage-gated sodium channels as a blocker (3,5). In animal studies, dextromethorphan enhances the antinociceptive effect of opioids, reduces tolerance and dependence to morphine, has an anticonvulsant property, and decreases the neuronal damage induced by ischemia or excitatory amino acids (6–8). Clinically, dextromethorphan has been used primarily as an antitussive for more than 50 yr. Recently, it has also been used as part of multimodal analgesic therapy, e.g., for acute pain and neuropathic pain (1–3). During these applications, dextromethorphan has been shown to have a wide safety margin with a low rate of untoward systemic side effects (9).

Although dextromethorphan has a long history of clinical usage, the therapeutic effects related to its channel bindings were not totally explored, e.g., the sodium channel blocking effect. Sodium channel blockade is the principal mechanism of action of local anesthetics (10,11). Because dextromethorphan blocks sodium channels, (5,8) it may have a local anesthetic effect. The aim of the study was to evaluate, using a rat model of cutaneous infiltration, whether dextromethorphan is a local anesthetic. The potency of dextromethorphan on infiltrative cutaneous analgesia in rats was evaluated. We also studied dextrorphan, the major and active metabolite of dextromethorphan, as well as lidocaine, an active control.

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METHODS

The experimental protocols were approved by the animal investigation committee of Chi-Mei Medical Center, Tainan, Taiwan and conformed to the recommendations and policies of the International Association for the Study of Pain. Experiments were performed on 200–250 g male Sprague–Dawley rats. They were purchased from the National Laboratory Animal Center, Taipei, Taiwan and then housed in a climate-controlled room maintained at 21°C with approximately 50% relative humidity. Lighting was on 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.

Dextromethorphan hydrobromide monohydrate, dextrorphan tartrate, and lidocaine HCl were purchased from Sigma (St. Louis, MO). All drugs were dissolved in 0.9% NaCl (saline).

The study consisted of three parts. In Part 1, we determined the potencies of dextromethorphan, dextrorphan, and lidocaine on cutaneous analgesia. In Part 2, we determined the interactions of dextromethorphan or dextrorphan with lidocaine on cutaneous analgesia. In Part 3 we determined the systemic safety indices of the three drugs.

Prior to experiment sessions the 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 rats' stress during experiments and generally improved their experimental performance (12,13). One day before the subcutaneous injections of drugs, the rats' hair on the dorsal surface of the thoracolumbar region (10 × 10 cm2) was mechanically removed.

Subcutaneous injections were performed according to the method reported previously (12,13). In brief, 0.6 mL of drug was injected subcutaneously using a 30-gauge needle into the dorsal surface of the thoracolumbar region of the unanesthetized rats. To reduce the number of experimental animals used, the rat's back was further divided into left and right parts, either of which received one drug injection with a washout period of 1 wk. The subcutaneous injection produced a circular skin wheal approximately 2 cm in diameter. The wheal was marked with ink within 1 min after injection. For consistency, one experienced investigator (Dr. Chen), who was blinded to the injected drugs, was responsible for evaluating cutaneous analgesia. The drugs were prepared and injected by another investigator (Dr. Tzeng).

Cutaneous analgesia was evaluated using the cutaneous trunci muscle reflex (CTMR), which was characterized by the reflex movement of the skin over the back produced by twitches of the lateral thoracispinal muscle in response to local dorsal cutaneous stimulation (12,13). A Von Frey filament (No.15; Somedic Sales AB, Sweden), 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 in each testing. The cutaneous analgesic effect of drugs was evaluated quantitatively as the number of times the pinprick failed to elicit a response; for example, the complete absence of six responses was defined as complete nociceptive block (100% of possible effect; 100% PE). The test of six pinpricks was applied 10 min before drug injection and then every 5 min after injection for the first 30 min and every 10–15 min thereafter until the CTMR fully recovered from the block (no more than 3 h). During the test, the maximum value of % PE of each dose of each drug was presented as % maximum possible effect (% MPE). The duration of the drug's action was defined as the time from drug injection (i.e., time = 0) to full recovery of CTMR (no analgesic effect was found).

In Part 1, after subcutaneous injections (n = 8 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 method of nonlinear regression by a computer-derived SAS NLIN program (version 9.1, SAS Institute, Cary, NC). After fitting, the values of 50% effective doses (ED50s) of drugs, which were defined as the doses of drugs that cause a 50% block of the CTMR at its maximum effect, were obtained (14). The values of ED50s and ED75s of drugs were also obtained after fitting (SAS NLIN). After the above testings, two control groups were further added into the study to exclude the possibility of vehicle or systemic effect of drugs on cutaneous analgesia. One group (n = 8 rats) received subcutaneous injection of saline; another group (n = 8 rats for each drug), subcutaneous injection of saline combined with intraperitoneal injection of testing drug (dextromethorphan, dextrorphan, or lidocaine) with a dose of 2ED75.

In Part 2, a method of isobolographic analysis (version 1.27, Pharm Tools Pro, McCary Group, Wynnewood, PA) was used (15,16). In this method, the dose–response curves of combined drugs under equipotent doses (e.g., dextromethorphan combined with lidocaine under a ratio of ED50 versus ED50) were constructed (n = 8 rats for each combination). After curve fitting with the SAS NLIN program, the ED50s of combined drugs were obtained. The isobologram was then constructed using a standard method (15). In brief, a theoretical additive line was constructed using the ED50s of dextromethorphan or dextrorphan, and lidocaine on the y and x axes, respectively. Then, the ED50s of combined drugs were plotted against the theoretical additive line. The differences between the theoretical ED50s values (obtained from the theoretical additive lines by computer simulation) and the experimental ED50s values (obtained from the dose–response curves of combined drugs) were calculated (15,16).

In Part 3, after intraperitoneal injections of drugs with different doses (n = 8 rats in each dose of each drug), the rats were observed for 24 h and the percent of mortality of each dose of each drug was counted. Each rat received only one injection. The dose–mortality curves were constructed and fitted with a computer-derived SAS probit analysis (version 9.1, SAS Institute). After fitting, the values of 50% lethal doses (LD50s), which were defined as the doses of drugs that caused 50% of rat deaths, were obtained. The safety indices (LD50s/ED50s) of drugs were then calculated.

Values are presented as mean ± sem, or ED50 (or LD50) values with 95% confidence interval (95% CI). 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 interactions of drugs were evaluated by an isobolographic analysis. The differences between the theoretical and experimental values were evaluated by Student's t-test. During testing, Bonferroni correction was used if appropriate. Statistical calculations were performed using SPSS for Windows (version 10.0.7). A P value <0.05 was considered statistically significant.

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RESULTS

Dextromethorphan, dextrorphan, and lidocaine produced significant infiltrative cutaneous analgesia (Fig. 1A). The dose–response curves and the ED50s of drugs are shown in Figure 1A and Table 1. The ranking of potencies of drugs was found to be dextromethorphan > dextrorphan > lidocaine on an ED50 basis (Fig. 1A and Table 1). Because of the similarities in the figures, the time course of drugs' effects at a dose of ED75 are shown as examples (Fig. 1B). At this dose, dextromethorphan, dextrorphan, and lidocaine produced 71 ± 8, 73 ± 7, and 72 ± 7% MPEs of cutaneous analgesia with durations of action of 50 ± 5, 48 ± 3, and 33 ± 4 min, respectively. All rats recovered completely after subcutaneous injections of drugs with different doses. In the control groups, no sedation or loss of motor activity occurred after intraperitoneal injections of a relatively large dose (2ED75) of drugs. Also, neither the subcutaneous injections of saline nor the intraperitoneal injections of testing drugs produced cutaneous analgesia.

Figure 1
Figure 1
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Table 1
Table 1
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The interactions of drugs were evaluated by an isobolographic analysis (Figs. 2A, B and Table 2). The dose–response curves of combined drugs were constructed (Figs. 2A and B). After testing, the differences between the experimental values of ED50s and the theoretical additive values of ED50s were not significant (Table 2). Coadministration of dextromethorphan or dextrorphan with lidocaine produced an additive effect on infiltrative cutaneous analgesia (15,16).

Figure 2
Figure 2
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Table 2
Table 2
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After intraperitoneal injections of drugs with different doses, the dose–mortality curves were constructed and the LD50s of drugs were obtained (Fig. 3; Table 1). The safety indices (LD50s/ED50s) for dextromethorphan and dextrorphan were 2.4 and 1.9 times higher than the safety index for lidocaine (Table 1).

Figure 3
Figure 3
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DISCUSSIONS

Dextromethorphan is an antitussive with a long history of clinical use and a wide safety margin (1–3,9). In this study, we tested its local anesthetic effect. Dextromethorphan has a more potent local anesthetic effect on infiltrative cutaneous analgesia than lidocaine (Fig. 1, Table 1). Coadministration of dextromethorphan with lidocaine produced an additive effect (Fig. 2A, Table 2).

We also tested the local anesthetic effect of dextrorphan, the active metabolite of dextromethorphan (17). Dextromethorphan is primarily metabolized either by O-demethylation to dextrorphan or, to a lesser extent, by N-demethylation to 3-methoxymorphinan in the liver (17). In in vitro binding assays, dextrorphan inhibits the NMDA and nicotine/neuronal nicotinic receptor channels, and the voltage-gated calcium and sodium channels similar to dextromethorphan (4,8). Unlike dextromethorphan, dextrorphan further binds to the phencyclidine receptors and exerts phencyclidine- like effects (18). In animal studies, dextrorphan was found to have anticonvulsant and neuroprotective properties and could decrease nicotine, methamphetamine, and morphine self-administration (18–20). Because dextrorphan also has sodium channel blocking activity (8), it may have a local anesthetic effect. In our study, dextrorphan had a local anesthetic effect after cutaneous infiltration. (Figs. 1A and B). Coadministration of dextrorphan with lidocaine also produced an additive effect (Fig. 2B and Table 2).

We did not evaluate whether dextromethorphan or dextrorphan had local anesthetic effects other than after cutaneous infiltration. However, a study related to the local anesthetic effect of dextromethorphan and dextrorphan on sciatic nerve blockade was recently performed in our laboratory (21). In that study, both dextromethorphan and dextrorphan produced a dose-related blockade of the sciatic nerve. In that study coadministration of dextromethorphan or dextrorphan with lidocaine also produced an additive effect (21).

Two control groups were added to the study to exclude the possibility of vehicle or systemic effects. Neither local injection of vehicle nor systemic administration of a large dose of the test drugs produced cutaneous analgesia. These results supported the local action of testing drugs on skin.

Differential permeability of drugs into the central nervous system (CNS) may explain the higher safety indices of dextromethorphan and dextrorphan, as dextromethorphan has a limited permeability to the CNS (22). Lidocaine has no limit in CNS permeability. We did not evaluate whether dextromethorphan and dextrorphan induce local toxicity in the injected tissues. This question should be investigated before their clinical application.

In conclusion, dextromethorphan and dextrorphan are potent local anesthetics with better systemic safety indices than lidocaine.

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