Site 1 sodium channel blockers prolong the duration of sciatic nerve blockade from tricyclic antidepressants

Abstract

Many recent reports in the literature address the local anesthetics efficacy of tricyclic antidepressants (TCAs). Here we investigated whether nerve block from TCAs is prolonged by site 1 sodium channel blockers such as tetrodotoxin and saxitoxin, which are known to prolong block from conventional local anesthetics. Tetrodotoxin and saxitoxin greatly prolonged block from TCAs. For example, the median duration of thermal nociceptive blocks for 10 mM amitriptyline, nortriptyline and doxepin were 0, 0, and 124 min; co-injection with 20 microM TTX (median block duration=0), yielded blocks lasting 404, 325, and 697 min, respectively. Co-injection of 12 microM saxitoxin (median block duration=0) with 10 mM amitriptyline resulted in a thermal nociceptive block duration of 373 min. Co-injection of 7.7 mM bupivacaine and 7.7 mM amiptriptyline did not result in block prolongation. Systemic (subcutaneous) delivery of tetrodotoxin or amitriptyline did not result in prolongation of block from the other class of drug injected at the sciatic nerve. In TCA-containing formulations, motor blockade was consistently longer than thermal nociceptive block; motor blockade was also prolonged by tetrodotoxin and saxitoxin. In summary site 1 sodium channel blockers prolong the duration of TCAs via a locally mediated mechanism.

Prolonged duration local anesthesia with minimal toxicity

“…The presence of particles themselves enhances local anesthetic myotoxicity in vivo (3), and can cause inflammatory responses at the nerve that may considerably outlast the duration of blockade (2,3,8). In contrast, site 1 sodium-channel blockers do not cause myo-or neurotoxicity (9,10), which would make them desirable for an extended release formulation. However, these extremely potent local anesthetics (11), being very hydrophilic, are difficult to encapsulate effectively in polymeric particles, and the systemic toxicity from their initial rapid release is dose-limiting (12,13).…”

Effects of Adding Dexmedetomidine to Amitriptyline on Sciatic Nerve Blockadge in Rats

“…Consistent with the literature, amitriptyline alone and amitriptyline in combination with dexmedetomidine was found to have longer duration of anesthetic effect compared to bupivacaine in the present study. On the other hand, some recent studies have suggested that amitriptyline, as a local anesthetic, does not have a higher potency compared to bupivacaine [12,13]. In the study by Barnet et al [12], in which bupivacaine and amitriptyline were compared with respect to neurotoxicity and tissue damage after sciatic nerve blockade, the amitriptyline and bupivacaine concentrations required to achieve block for 100 minutes were found to be 20 mmol/L and 3 mmol/L, respectively.…”

Pharmacological Management of Neuropathic Pain: Current Trends and Possible Approaches

“…This is mainly because of enhancement of descending monoaminergic inhibitory pathways via central blockade of serotonin and noradrenalin reuptake process. Apart from it, their effects on alpha-adrenergic, histaminergic (H1), muscarinic cholinergic receptor, N-methyl-D-aspartate (NMDA) antagonistic effects and blockage of sodium (17) and voltage gated calcium channel (18) are also reported (19). This category mainly consists of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRI) and serotoninnorepinephrine reuptake inhibitors (SNRIs).…”