Background and Objectives Regional anesthesia includes application of local anesthetics (LAs) into the vicinity of peripheral nerves. Prolongation or improvement of nerve blocks with LAs can be accomplished by coapplication with adjuvants, including buprenorphine, ketamine, and clonidine. While the mechanisms mediating prolonged or improved LA-induced effects by adjuvants are poorly understood, we hypothesized that they are likely to increase LA-induced block of voltage-gated Na⁺ channels. In this study, we investigated the inhibitory effects of the LA bupivacaine alone and in combination with the adjuvants on neuronal Na⁺ channels.

Methods Effects of bupivacaine, buprenorphine, ketamine, and clonidine on endogenous Na⁺ channels in ND7/23 neuroblastoma cells were investigated with whole-cell patch clamp.

Results Bupivacaine, buprenorphine, ketamine, and clonidine are concentration- and state-dependent inhibitors of Na⁺ currents in ND7/23 cells. Tonic block of resting channels revealed an order of potency of bupivacaine (half-maximal inhibitory concentration [IC₅₀] 178 ± 8 μM) > buprenorphine (IC₅₀ 172 ± 25) > clonidine (IC₅₀ 824 ± 55 μM) > ketamine (IC₅₀ 1377 ± 92 μM). Bupivacaine and buprenorphine, but not clonidine and ketamine, induced a strong use-dependent block at 10 Hz. Except for clonidine, all substances enhanced fast and slow inactivation. The combination of bupivacaine with one of the adjuvants resulted in a concentration-dependent potentiation bupivacaine-induced block.

Conclusions We demonstrate that buprenorphine, ketamine, and clonidine directly inhibit Na⁺ channels and that they potentiate the blocking efficacy of bupivacaine on Na⁺ channels. These data indicate that block of Na⁺ channels may account for the additive effects of adjuvants used for regional anesthesia.