Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy Bettina Beyreuther a, ⁎ , Noëlle Callizot b , Thomas Stöhr a a Schwarz BioSciences GmbH, Department Pharmacology/Toxicology, Alfred-Nobel-Str. 10, 40789 Monheim, Germany b Neurofit, Parc d'Innovation, Rue J Sapidus, 67400 Illkirch, France Received 27 October 2005; received in revised form 27 March 2006; accepted 3 April 2006 Available online 7 April 2006 Abstract Lacosamide was tested in the streptozotocin rat model of diabetic neuropathic pain in comparison to drugs which are commonly used in the treatment of diabetic neuropathic pain, i.e. antidepressants and anticonvulsants. In diabetic rats, lacosamide attenuated cold (10, 30 mg/kg, i.p.), warm (3, 10, 30 mg/kg, i.p.) and mechanical allodynia (30 mg/kg, i.p.). Streptozotocin-induced thermal and mechanical hyperalgesia were reduced by lacosamide at doses of 10 and 30 mg/kg, i.p. Morphine (3 mg/kg) showed similar efficacy on allodynia and hyperalgesia. Amitriptyline (10 mg/ kg), venlafaxine (15 mg/kg), levetiracetam (180 mg/kg) and pregabalin (100 mg/kg) exhibited significant effects on thermal allodynia and mechanical hyperalgesia. Only treatment with amitriptyline (30 mg/kg, i.p.) produced full reversal of thermal allodynia comparable to lacosamide. Lamotrigine (45 mg/kg, i.p.) had no effect on both behavioral readouts. Lacosamide's potency and efficacy in reversing pain behavior might be due to its new, yet unknown mechanism of action. © 2006 Elsevier B.V. All rights reserved. Keywords: Allodynia; Hyperalgesia; Anticonvulsant drug; Diabetic neuropathy; Neuropathic pain; Lacosamide 1. Introduction The most common precipitating cause of neuropathic pain is diabetes particularly where blood glucose control is poor (Morley et al., 1984). Approximately 20–24% of diabetes patients experience neuropathic pain (Schmader, 2002). Dia- betic neuropathic pain can occur either spontaneously, as a result of exposure to normally mildly painful stimuli (i.e. hyperalgesia), or to stimuli that are not normally perceived as being painful (i.e. allodynia) (Brown and Asbury, 1984). The cause of painful diabetic neuropathy, like other neuropathic pain states, is still unclear (Calcutt, 2002; Sommer, 2003). However, behavioral and physiological studies have revealed indices of sensory dysfunction in animal models of diabetes that include hyperalgesia to mechanical and noxious chemical stimuli and allodynia to light touch. Currently, the three major classes of drugs recognized as being effective in neuropathic pain treatment are antidepres- sants, anticonvulsants and opioids (Galer, 1995; McQuay et al., 1996; Sindrup and Jensen, 1999). There remains a clear unmet medical need for drugs that provide greater efficacy/responder rates, with reduced side effects commonly experienced with current therapies. A number of agents that are effective in the treatment of patients suffering from diabetic neuropathic pain have been shown to partially alleviate mechanical hyperalgesia in the streptozotocin-induced diabetes animal model of painful diabetic neuropathy (Courteix et al., 1994), the most commonly used model in the field of diabetic pain research (Fox et al., 1999). Lacosamide (R-2-acetamido-N-benzyl-3-methoxypropiona- mide, SPM 927, also formerly called harkoseride or ADD 234037) has been shown to be active in animal models for neuropathic and inflammatory pain at doses of 8 mg/kg to 40 mg/kg i.p. (Morrow et al., 2001; Stohr et al., 2006). In addition, oral lacosamide produced analgesia in an open label European Journal of Pharmacology 539 (2006) 64 – 70 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +49 2173 481128; fax: +49 2173 481574. E-mail address: bettina.beyreuther@schwarzpharma.com (B. Beyreuther). 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2006.04.009