Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats

https://doi.org/10.1016/j.ejphar.2006.06.013Get rights and content

Abstract

Dextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of the study was to evaluate whether dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had local anaesthetic effects. Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of dextromethorphan and its metabolites on sciatic nerve blockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception. The ranks of potencies were lidocaine > dextromethorphan > 3-methoxymorphinan > dextrorphan (P < 0.01 for each comparison). Under an equi-potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P < 0.05 for each comparison). Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion, dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had a local anaesthetic effect on sciatic nerve blockades of motor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of dextromethorphan and its metabolites produced an additive effect on sciatic nerve blockades.

Introduction

Dextromethorphan, a dextrorotatory morphinan, has been used clinically as a cough suppressant for more than 40 years and is considered a drug with a good margin of safety (Bem and Peck, 1992, Carlsson et al., 2005, Duedahl et al., 2006, Weinbroum et al., 2000). Dextromethorphan was synthesized originally as a pharmacological alternative to morphine. However, in contrast to the levorotatory morphinans, dextromethorphan has little or no opioid activity (Weinbroum et al., 2000). Dextromethorphan has a complex pharmacology. In in vitro binding assays, dextromethorphan inhibits the N-methyl-d-aspartate (NMDA) glutamate and nicotine/neuronal nicotinic receptor channels, and the voltage-gated Ca2+ and Na+ channels (Carlsson et al., 2005, Damaj et al., 2005, Netzer et al., 1993, Trube and Netzer, 1994). Dextromethorphan has been used as an antitussive and proposed as a treatment for stroke, brain ischemia (Moses and Choi, 1991, Steinberg et al., 1993), seizure disorders (Fisher et al., 1990), morphine dependence (Glick et al., 2001, Mao et al., 1996), and acute or neuropathic pain (Carlsson et al., 2005; Duedahl et al., 2006, Joshi, 2005, Weinbroum et al., 2000). The NMDA receptor antagonist effects of dextromethorphan seem to be the primary rationale for these uses.

Although dextromethorphan has a long history of clinical uses with a good margin of safety, the pharmacologic effects with respect to its channel bindings were not well studied, e.g., the Na+ channel blockade. The Na+ channel blockade is an essential activity of the local anaesthetics (Fozzard et al., 2005, McLure and Rubin, 2005, Scholz, 2002). With this activity, local anaesthetics produce infiltrative cutaneous analgesia, peripheral nerve block, and spinal/epidural anaesthesia (McLure and Rubin, 2005). Because dextromethorphan has a Na+ channel blocking effect (Netzer et al., 1993), theoretically, it may have a local anaesthetic effect. However, this was never tested. The aim of the study was to evaluate whether dextromethorphan has a local anaesthetic effect. We focused on the sciatic nerve blockade. The potency and duration of action of dextromethorphan on sciatic nerve blockade in rats were evaluated. Two major metabolites of dextromethorphan — 3-methoxymorphinan and dextrorphan— (Mordecai et al., 1995) were also studied. Lidocaine, a commonly used local anaesthetic, was used as control. The effects of co-administration of dextromethorphan or its metabolites with lidocaine on sciatic nerve blockade were evaluated, too.

Section snippets

Animals

Experiments were performed on 200–250 g male Sprague–Dawley rats (the National Laboratory Animal Center, Taipei, Taiwan). Rats were 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 a.m.), with food and water available ad libitum up to the time of testing. The experiments protocols were approved by the animal investigation committee of Chi-Mei Medical Center, Tainan, Taiwan and conformed to

Time courses of sciatic nerve blockade

The time courses of sciatic nerve blockades in motor function, proprioception, and nociception by dextromethorphan, 3-methoxymorphinan, dextrorphan, and lidocaine were performed. Due to the similarities of the figures, only the figures obtained from dextromethorphan and lidocaine at a dose of 6.7 mg/kg are shown (Fig. 1). At the given dose, dextromethorphan produced 71 ± 16, 78 ± 17, and 83 ± 26% of blockades (% MPE) in motor function, proprioception, and nociception with durations of action of about

Discussion

In this study, the local anaesthetic effects of dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan — on sciatic nerve blockades of motor function, proprioception and nociception were studied. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception and nociception. Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on the

References (27)

  • T.H. Duedahl et al.

    A qualitative systematic review of peri-operative dextromethorphan in post-operative pain

    Acta Anaesthesiol. Scand.

    (2006)
  • R.S. Fisher et al.

    Dextromethorphan for treatment of complex partial seizures

    Neurology

    (1990)
  • H.A. Fozzard et al.

    Mechanism of local anesthetic drug action on voltage-gated sodium channels

    Curr. Pharm. Des.

    (2005)
  • Cited by (13)

    • The use of carbetapentane for spinal anesthesia and use-dependent block of sodium currents

      2013, European Journal of Pharmacology
      Citation Excerpt :

      Carbetapentane has been known as a non-opioid antitussive drug with anticonvulsant properties (Leander, 1989). Antitussive dextromethorphan has a local anesthetic effect (Chen et al., 2007, 2008; Hou et al., 2006). In the present study, we showed that intrathecal carbetapentane produced spinal/local anesthesia.

    • Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats

      2013, Pharmacological Reports
      Citation Excerpt :

      At each testing time, only one pinch was given to each of the four testing sites, and the time interval between stimulations at different sites was around 2 s. The nociceptive blockade was graded as 4 (normal or 0% MPE), 3 (25% MPE), 2 (50% MPE), 1 (75% MPE), and 0 (absent or 100% MPE) [1, 10]. After injecting the rats with four different doses of each drug (n = 8 for each dose of each drug) intrathecally, the dose-response curve was constructed.

    • Isobolographic Analysis of Epinephrine With Bupivacaine, Dextromethorphan, 3-Methoxymorphinan, or Dextrorphan on Infiltrative Anesthesia in Rats: Dose-Response Studies

      2008, Regional Anesthesia and Pain Medicine
      Citation Excerpt :

      Our study showed that 3MM produced a dose-dependent local anesthetic effect of cutaneous analgesia. The local anesthetic effect of 3MM in rat sciatic nerve block9 and spinal anesthesia11 has also been proven. In order to rule out the possibility of vehicle or systemic analgesic effect of the drugs, 2 control groups were used.

    View all citing articles on Scopus
    View full text