Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial

The voltage-gated sodium channel Na(V)1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. Na(V)1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that Na(V)1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant Na(V)1.7 that causes pain.

Several issues regarding diagnosis, pharmacological treatment, and surgical treatment of trigeminal neuralgia (TN) are still unsettled. The American Academy of Neurology and the European Federation of Neurological Societies launched a joint Task Force to prepare general guidelines for the management of this condition. After systematic review of the literature the Task Force came to a series of evidence-based recommendations. In patients with TN MRI may be considered to identify patients with structural causes. The presence of trigeminal sensory deficits, bilateral involvement, and abnormal trigeminal reflexes should be considered useful to disclose symptomatic TN, whereas younger age of onset, involvement of the first division, unresponsiveness to treatment and abnormal trigeminal evoked potentials are not useful in distinguishing symptomatic from classic TN. Carbamazepine (stronger evidence) or oxcarbazepine (better tolerability) should be offered as first-line treatment for pain control. For patients with TN refractory to medical therapy early surgical therapy may be considered. Gasserian ganglion percutaneous techniques, gamma knife and microvascular decompression may be considered. Microvascular decompression may be considered over other surgical techniques to provide the longest duration of pain freedom. The role of surgery versus pharmacotherapy in the management of TN in patients with multiple sclerosis remains uncertain.

Background The guidelines on trigeminal neuralgia management that have been agreed and jointly published by the American Academy of Neurology and the European Federation of Neurological Societies recommend carbamazepine (CBZ) and oxcarbazepine (OXC) as the first-choice medical treatments in patients with trigeminal neuralgia (TN). The aim of this retrospective study was to analyze the natural history of classical trigeminal neuralgia in a large cohort of patients, focusing on drug responsiveness, side effects related to CBZ and OXC, and changes in pain characteristics during the course of disease. Findings We selected the last 100 consecutive patients with typical TN who began treatment with CBZ and the last 100 with OXC. All had MRI scans and a complete neurophysiological study of trigeminal reflexes. Among them, 22 were excluded on the basis of neuroradiological or neurophysiological investigations, to avoid the inclusion of patients with possible secondary TN. The initial number of responders was 98% with CBZ with a median dose of 600 mg (range 200–1200), and of 94% with OXC, with a median dose of 1200 mg (range 600–1800). In a mean period of 8.6 months, 27% of responders to CBZ incurred in undesired effects to a level that caused interruption of treatment or a dosage reduction to an unsatisfactory level. In a mean period of 13 months, the same occurred to 18% of responders to OXC. Among patients who had a good initial response, only 3 patients with CBZ and 2 with OXC developed late resistance. During the course of disease, paroxysms worsened in intensity in 3% of patients, and paroxysms duration increased in 2%. We did not observe the onset of a clinically manifest sensory deficit at any time in any patient. Conclusions Unlike common notion, in our large patient sample the worsening of pain with time and the development of late resistance only occurred in a very small minority of patients. CBZ and OXC were confirmed to be efficacious in a large majority of patients, but the side effects caused withdrawal from treatment in an important percentage of patients. These results suggest the opportunity to develop a better tolerated drug.