We have used the rat formalin test to compare the anti-nociceptive properties of several voltage-activated Na(+) channel blockers. The antiarrhthymic mexiletine (37.5 and 50 mg/kg, i.p.) attenuated flinching behaviour in both first and second phases of the test compared with vehicle (P<0.05). The anti-convulsants lamotrigine (15 and 30 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) also inhibited second phase flinching behaviour compared with vehicle (P<0.05), although phenytoin (up to 40 mg/kg, i.p.) was without effect. Riluzole (5 mg/kg, i.p.), in contrast to lubeluzole (up to 10 mg/kg, i.p.) also inhibited second phase flinching behaviour compared with vehicle (P<0.05). When tested against an acute thermal nociceptive stimulus mexiletine, lubeluzole and riluzole exhibited anti-nociceptive effects. The anti-nociceptive doses used in the formalin test produced no motor impairment in the rotarod test. Thus, voltage-activated Na(+) channel blockers can attenuate nociceptive behaviour in the formalin test, and a specific mechanism of action on Na(+) channel function may be required for this to occur.