Ambroxol, a Nav 1.8-preferring Na+ channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain

Neuropathic pain affects many patients, and treatment today is far from being perfect. Nav1.8 Na+ channels, which are expressed by small fibre sensory neurons, are promising targets for novel analgesics. Na+ channel blockers used today, however, show only limited selectivity for this channel subtype, and can cause dose-limiting side effects. Recently, the secretolytic ambroxol was found to preferentially inhibit Nav1.8 channels. We used this compound as a tool to investigate whether a Nav1.8-preferring blocker can suppress symptoms of chronic, neuropathic and inflammatory pain in animal models. The drug was tested in the formalin paw model, two models of mononeuropathy, and a model of monoarthritis in rats. Ambroxol's effects were compared with those of gabapentin. Ambroxol at a dose of 1 g/kg had to be administered to rats to achieve the plasma levels that are reached in clinical use (for the treatment of infant and acute respiratory distress syndrome). Ambroxol (1 g/kg) was only weakly effective in models for acute pain, but effectively reduced pain symptoms in all other models; in some cases it completely reversed pain behaviour. In most cases the effects were more pronounced than those of gabapentin (at 100 mg/kg). These data show that a Nav1.8-preferring Na+ channel blocker can effectively suppress pain symptoms in a variety of models for chronic, neuropathic and inflammatory pain at plasma levels, which can be achieved in the clinic. (c) 2005 Elsevier Ltd. All rights reserved.