Tissue Injury from Tricyclic Antidepressants Used as Local Anesthetics

Abstract

Neurotoxicity has been reported with tricyclic antidepressants (TCAs) used as local anesthetics. We examined the hypothesis that TCAs cause tissue injury, particularly myotoxicity, as occurs with many local anesthetics. Animals were given sciatic nerve injections with 0-80 mM doxepin, amitriptyline, or bupivacaine (1.5 mL for histological studies, 0.3 mL for neurobehavioral studies). Four days after injection, the TCAs caused ischemic tissue injury. Subcutaneous tissue showed expansion and hardening, with hemorrhage and adhesion to overlying skin. Muscle was diffusely pale. Histopathology showed coagulative necrosis of muscle and surrounding soft tissues, with thrombus formation in vasculature near affected areas. These findings were much reduced with bupivacaine. TCA-injected and bupivacaine-injected animals also developed characteristic local anesthetic myotoxicity. Amitriptyline proved less potent than bupivacaine as a local anesthetic: the concentrations required to provide 100 min of nerve block were 20 mM and 3 mM, respectively. Some animals receiving large concentrations of amitriptyline developed spontaneous recrudescence of nerve blockade or had irreversible nerve blockade, both of which may reflect nerve injury. Neither finding occurred in animals injected with bupivacaine. TCAs do not appear to offer any advantages over conventional local anesthetics and do appear to risk substantially increased toxicity.

Prolonged duration local anesthesia with minimal toxicity

“…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). These considerations make the development of particulate systems based entirely on such compounds (i.e., without inclusion of conventional local anesthetics) very difficult.…”

Prolonged sensory-selective nerve blockade

“…Very high concentrations of QX-314 caused irreversible nerve blockade, which may be a sign of neurotoxicity, as it is after injection of high-dose tricyclic antidepressants as local anesthetics (13,14). Neurotoxicity is not uncommon in compounds with local anesthetic activity: capsaicin, which also has been used for sensory-selective nerve blockade (1), can be neurotoxic when used as a local anesthetic (15), as can amino-amide and aminoester local anesthetics (16).…”

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…By way of comparison, 0.5% (w/v) bupivacaine reliably yields a nerve block lasting approximately 150 min, 19,47 with minimal tissue toxicity. 42,48 These observations are not consistent with the lack of difference in toxicity being simply due to excessive levels of local anesthetic.…”