|Novel translational approaches for the pharmacological treatment of chronic pain associated with central plasticity changes. |
According to a recent survey on the prevalence of chronic pain in Europe (Breivik et al., Eur J Pain 2006), almost 20% of the adult population suffer from chronic pain. In almost 60% of these patients pain persisted for more than 2 years and almost two third of the patients were unsatisfied with their pharmacological pain treatment either for insufficient pain relief or for side effects of their pain medications. Most currently available analgesic drugs fall into two groups. They either belong to the so called antipyretic analgesics including acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, metamizole and the cyclooxygenase-2 selective (coxibs) or to the opioids (morphine and pharmacologically related compounds). Chronic pain, which significantly persists after injury or inflammation beyond tissue healing, is to a large extent caused by plastic changes in the peripheral or central nervous system. Changes in the expression of Na+ channels are an important aspect of such peripheral nervous system plasticity. Accordingly, Na+ channel blockers are effective in several neuropathic pain conditions, but their wide-spread use is limited by their unfavourable pharmacokinetic properties and undesired side-effects.
In the central nervous system, diminished synaptic inhibition in the spinal dorsal horn, a key structure in nociceptive processing and pain related CNS plasticity, is a major factor contributing to the generation and maintenance of chronic pain. Subtype selective GABA-A receptor ligands have recently been shown to reverse pathological pain sensitization in animal models of inflammatory and neuropathic pain.
Both aspects of pain related neuroplasticity shall be addressed in the research proposal. A newly developed Na+ channel blocker at present approved for the treatment of epilepsy and GABA-A receptor ligands are investigated here in an integrative approach. Groups from Berne, Geneva, Lausanne and Zurich address these topics in a joint translational approach involving in vitro assays, animal models of chronic pain, human experimental models of hyperalgesia and a clinical study in patients with chronic pain.