Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State

Abstract

Background: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. Methods: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. Results: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. Conclusions: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain. P AIN is essential for survival as it serves as an alert to engage protective behavior. Neuropathic pain, caused by a lesion or disease of the somatosensory nervous system, affects 7% of the population 1 and possesses no protective purpose. Sodium channels are major targets for the development of new drug to treat neuropathic pain.2 Nerve injury changes the expression of sodium channels 3 which affects peripheral nerve hyperexcitability and ectopic discharges along the nerve, in the dorsal root ganglion or at the injury site.4,5 They are composed of a α-pore forming subunit associated to one or two β-modulating subunits. Nine genes encode for the α-subunits, Nav1.1-1.9. Current therapy for neuropathic pain involves adjuvant medications-not primarily developed for this purposesuch as anticonvulsants, antidepressants, or local anesthetics. Address correspondence to Dr. Suter: Pain Center, Department of Anesthesiology, CHUV, Avenue du Bugnon 46, 1011 Lausanne, Switzerland. marc.suter@chuv.ch. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLOGY's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.

What are the treatment options for paroxysmal extreme pain disorder?

“…Sodium channel blocking anticonvulsants, such as lacosamide or rufinamide [17], showed preclinical efficacy and could warrant a clinical trial while waiting for specific Nav1.7 blockers to be available.…”

p.L1612P, a Novel Voltage-gated Sodium Channel Nav1.7 Mutation Inducing a Cold Sensitive Paroxysmal Extreme Pain Disorder

“…No power calculation was performed; our sample size was based on previous experiment. 13 Statistical analysis was performed on GraphPad Prism, version 5.03 (GraphPad Software, La Jolla, CA).…”

“…29 Overall, the effects of amitriptyline were similar in mutant L1612P, a New PEPD Cold Sensitive Nav1.7 Mutation and WT channels and consistent with previous findings. 13 Of note, the hyperpolarizing SSI shift induced by amitriptyline was far from being large enough to compensate for the depolarizing shift induced by the mutation, hallmark of electrophysiological change in PEPD inducing mutant, which might explain the lack of clinical benefit. Sodium channel blockers are used to treat chronic pain syndromes and there have been attempt to correlate in vitro effect of drugs to their clinical efficacy.…”

“…13 Other sodium channel blockers such as lidocaine have been used successfully in neuropathic pain of different etiologies [14][15][16][17] including Nav1.7 mutations. 18 However, administration of lidocaine requires an intravenous line and despite some patients reporting prolonged improvement after the infusion, 16 an orally available sodium channel blocker is preferable for long term therapy.…”

“…The t 1/2 value of recovery from inactivation was calculated by interpolation from a linear relation between the 2 points juxtaposing half recovery (y1 < 0.5 < y2), using the relation x = [0.5−(y1x2−y2x1)/ (x2−x1)]×(x2−x1)/(y2−y1). 13 For slow inactivation the curve was fitted with a Boltzmann y = Imin + (Imax−Imin)/1 + exp((V50-X)/slope). For Drug Testing.…”