What role does multiple sclerosis play in the development of untreatable painful conditions?

Clinical data outline the high incidence of pain syndromes in patients with multiple sclerosis, with a significant prevalence of craniofacial manifestations, including trigeminal neuralgia and migraine, which are very difficult to be managed pharmacologically. The common explanation of a localization of demyelinating plaques in areas devoted to pain modulation and integration as a trigger for pain development seems now partially unsatisfactory, since pain is often manifested well before the clinical signs of the pathology and its severity does not correlate with disease progression. This review focuses on additional mechanisms which could be at the basis of pain development in multiple sclerosis, whose identification will help identifying new targets to design more effective analgesic strategies.