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The sodium channels SNS/PN3 and NaN/SNS2 are regulated by the neurotrophic factors-nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF), and may play an important role in the development of pain after nerve injury or inflammation. These key molecules have been studied in an amputated causalgic finger and control tissues by immunohistochemistry. There was a marked increase in the number and intensity of SNS/PN3-immunoreactive nerve terminals in the affected finger, while GDNF-immunoreactivity was not observed, in contrast to controls. No differences were observed for NGF, trk A, NT-3 or NaN/SNS2-immunoreactivity. While further studies are required, these findings suggest that accumulation of SNS/PN3 and/or loss of GDNF may contribute to pain in causalgia, and that selective blockers of SNS/PN3 and/or rhGDNF may provide effective novel treatments.

This study was performed to determine the efficacy and safety of oral cizolirtine citrate, a novel agent, in the treatment of chronic neuropathic pain. Cizolirtine was tested in a double-blind, placebo-controlled, two-way crossover study, having previously been shown to have significant analgesic and anti-hyperalgesic action in neuropathic pain models and preliminary human studies. Twenty-five patients with neuropathic pain, which was persistent for at least three months, and scored > 30 mm on a 100 mm visual analogue scale (VAS), were included. A subgroup of five patients had primary skin allodynia, i.e. pain evoked by non-noxious stimuli in the territory of the injured nerve. Cizolirtine 200 mg or placebo was administered twice daily for a treatment period of 21 days, each separated by a washout interval of 7 days. Assessments of skin allodynia were performed using the graded monofilaments (von Frey hairs) on days 1 (predose), 14 and 21 (90 min postdose). All patients were instructed to maintain a daily pain diary throughout the study. Results showed that the differences in VAS and allodynia scores between cizolirtine and placebo treatments were not significant in the overall analysis (p > or = 0.05); cizolirtine was well tolerated. In a subgroup of five patients with primary allodynia, a 53% reduction in VAS score from baseline at rest (p = 0.007) and 55% on movement (p = 0.0002) at day 21 was observed with cizolirtine, as compared to 8% at rest (p = 0.5215) and 13% on movement (p = 0.4187) with placebo. Similarly, allodynia improved with cizolirtine (p = 0.03) but not with placebo (p = 0.9) in this subgroup. Cizolirtine may be effective in primary allodynia after peripheral nerve injury, and a further trial in a larger number of such subjects is warranted.

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