Neosaxitoxin in Rat Sciatic Block: Improved Therapeutic Index Using Combinations with Bupivacaine, with and without Epinephrine

• Published in: Anesthesiology (Philadelphia) Vol. 123; no. 4; pp. 886 - 898
• Main Authors: Templin, Jay S, Wylie, Matthew C, Kim, Joseph D, Kurgansky, Katherine E, Gorski, Grzegorz, Kheir, John, Zurakowski, David, Corfas, Gabriel, Berde, Charles
• Format: Journal Article
• Language: English
• Published: United States Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc 01.10.2015
• Subjects: Anesthetics, Local - administration & dosage; Animals; Autonomic Nerve Block - methods; Bupivacaine - administration & dosage; Drug Therapy, Combination; Epinephrine - administration & dosage; Male; Pain Measurement - drug effects; Pain Measurement - methods; Rats; Rats, Sprague-Dawley; Saxitoxin - administration & dosage; Saxitoxin - analogs & derivatives; Sciatic Nerve - drug effects; Treatment Outcome
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000000832

BACKGROUND:Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker undergoing clinical trials as a prolonged-duration local anesthetic. Rat sciatic block and intravenous infusion models were used to assess efficacy and local and systemic toxicities for NeoSTX in saline (NeoSTX-Saline), bupivacaine (Bup), and their combination (NeoSTX-Bup). Exploratory studies evaluated the effects of addition of epinephrine to NeoSTX-Bup (NeoSTX-Bup-Epi). METHODS:Rats received percutaneous sciatic blocks with escalating doses of NeoSTX-Saline or NeoSTX-Bup. Sensory-nocifensive block was assessed using modified hotplate and Von Frey filaments. Motor-proprioceptive function was assessed by extensor postural thrust. Nerves were examined histologically after 7 days and scored on the Estebe–Myers scale. Median lethal dose was estimated for NeoSTX-Saline and in combinations. Accidental intravenous overdose was simulated in isoflurane-anesthetized, spontaneously breathing rats receiving NeoSTX-Saline (n = 6), Bup (n = 7), or NeoSTX-Bup (n = 13), with respiratory, hemodynamic, and electrocardiographic endpoints. Additional groups received blocks with NeoSTX-Bup-Epi (n = 80). Investigators were blinded for behavioral and histologic studies. RESULTS:NeoSTX-Bup produced more prolonged sensory and motor block compared with NeoSTX-Saline or Bup. NeoSTX-Bup-Epi further prolonged median time to near-complete recovery for 3 μg/kg NeoSTX-Bup (hotplate48 vs. 6 h, P < 0.001). With sciatic injections, addition of Bup did not worsen the systemic toxicity (median lethal dose) compared with NeoSTX-Saline. Intravenous NeoSTX-Saline infusion had significantly longer times to apnea, first arrhythmia, and asystole compared with Bup (P < 0.001 for each). Histologic injury scores overall were low for all groups, with median scores of 0 (interquartile range, 0 to 0) on a 5-point scale. CONCLUSION:NeoSTX-Bup and NeoSTX-Bup-Epi hold promise for prolonged-duration local anesthesia.