Prolonged sensory-selective nerve blockade

Abstract

Sensory-selective local anesthesia has long been a key goal in local anesthetic development. For example, it allows women to be pain-free during labor without compromising their ability to push. Here we show that prolonged sensory-selective nerve block can be produced by specific concentrations of surfactants-such as are used to enhance drug flux across skin-in combination with QX-314, a lidocaine derivative that has relative difficulty penetrating nerves. For example, injection of 25 mM QX-314 in 30 mM octyltrimethylammonium bromide (OTAB) lasted up to 7 h. Sensory selectivity was imparted to varying degrees by cationic, neutral, and anionic surfactants, and also was achieved with another lidocaine derivative, QX-222. Simultaneous injection of OTAB at a s.c. injection site remote from the sciatic nerve did not result in prolonged sensory-specific nerve blockade from QX-314, suggesting that the observed effect is due to a local interaction between the surfactant and the lidocaine derivative, not a systemic effect.

Fig. 1.

Duration of nerve blockade from QX-314. Sample size (n): 5 mM, 8; 15.4 mM, 4; 25 mM, 20; 45 mM, 8; 70 mM, 8; 100 mM, 8. Data are medians with 25th and 75th percentiles. ^† P < 0.05 in comparison of duration of sensory and motor block when zero-duration blocks are discarded.

Fig. 2.

Nerve blockade with 25 mM QX-314 and OTAB. (A) Duration of block from 25 mM QX-314 with increasing concentrations of OTAB. Sample size (n): 10 mM, 6; 20 mM, 20; 30 mM, 10; 40 mM, 4; 120 mM, 4. Asterisks refer to comparison of duration of sensory and motor block. (B) Percent suppression of thermal nociception and motor function over time from 25 mM QX-314 + 20 mM OTAB. n = 19. (C) Effect of increasing the QX-314 concentration beyond 25 mM with 30 mM OTAB. Sample size (n): 5 mM, 4; 25 mM, 10; 45 mM, 4; 70 mM, 4; 100 mM, 4. Data are medians with 25th and 75th percentiles. *P < 0.05; **P < 0.01; ***P < 0.001, comparison of sensory and motor block. ^†See Fig. 1.

Fig. 3.

Nerve blockade with 25 mM QX-314 and SOS. (A) Effect of increasing concentrations of SOS on the duration of nerve blockade. Sample size (n): 0 mM, 20; 5 mM, 4; 10 mM, 4; 20 mM, 4; 30 mM, 4. (B) Percent suppression of thermal nociception and motor function over time from 25 mM QX-314 + 5 mM SOS; n = 4. (C) Percent suppression of thermal nociception and motor function over time from 25 mM QX-314 + 20 mM SOS. Data are medians with 25th and 75th percentiles; n = 4. *P < 0.05, comparison of sensory and motor block. ^†See Fig. 1.

Fig. 4.

Nerve blockade with 25mM QX-314 and Tween 20. (A) Effect of increasing concentrations of Tween 20 on the duration of nerve blockade. n = 8 for all except for 0 mM (i.e., 25 mM QX-314 alone), where n = 20. (B) Percent suppression of thermal nociception and motor function over time from 25 mM QX-314 + 4 mM Tween 20; n = 4. Data are medians with 25th and 75th percentiles. *P < 0.05; **P < 0.01, comparison of sensory and motor blocks. ^†See Fig. 1.

Fig. 5.

Effect of OTAB on duration of nerve blockade from 100 mM QX-222; n = 4. Data are medians with 25th and 75th percentiles. ^†See Fig. 1. ^§ P < 0.05, comparison of sensory and motor blocks when the groups with 20 and 30 mM OTAB are pooled.

Fig. 6.

Effect of remote (s.c. [SC], thus presumably systemic) administration of QX-314 and OTAB on the duration of nerve blockade. Data are medians with 25th and 75th percentiles. Sample size (n): OTAB 30 mM, 4; QX-314 25 mM, 12; OTAB 30 mM + QX-314 25 mM SC, 4; QX-314 25 mM + OTAB 30 mM SC, 4; OTAB 30 mM+ QX-31425 mM, 10. *P < 0.05, comparison of duration of sensory block.

Fig. 7.

Comparison of median durations of thermal nociceptive nerve blockade and sensorimotor indices in animals injected with 25 mM QX-314 (dotted line) alone or with varying concentrations of surfactants. The numbers next to data points are the sensorimotor indices (see Methods); 1 implies only sensory block, 0 denotes equality of block duration for sensory and motor function. Values < 0.05 are not shown.