Neosaxitoxin Provides Long-Lasting Anesthesia with Minimal Adverse Events

A first-in-human Food and Drug Administration (FDA)—regulated phase 1 safety study of subcutaneous infiltration of sodium channel blocker Neosaxitoxin (NeoSTX) with bupivacaine produced long-lasting anesthesia but no serious adverse events, according to a study in Anesthesiology.

The finding is important because currently available amino ester and amino amide local anesthetics do not reliably provide analgesia beyond approximately eight to 12 hours after subcutaneous infiltration or single-shot peripheral nerve block. “While the duration of analgesia can be extended by catheter infusions, catheters introduce the potential for migration, infection, and the inconvenience of tethering the patient to a pump,” the study authors explained. “In addition, overdoses (or intravascular injection) of amino ester and amino amides can cause systemic and/or local toxicities.”

NeoSTX, which binds to the outer pore of the voltage-gated sodium channels, thereby blocking impulse generation and propagation, produced benign local effects on nerve and muscle in animal studies. The current study aimed to examine the relation between plasma NeoSTX concentration and adverse symptoms or physiologic changes. It also analyzed the addition of epinephrine to reduce peak plasma NeoSTX concentration and reduce systemic symptoms compared with groups receiving NeoSTX without epinephrine. Epinephrine is known to slow drug uptake from the injection site, presumably by decreasing local blood flow via vasoconstriction, thereby reducing the absorption rate of NeoSTX and the occurrence of side effects presented. A third goal was to evaluate the safety and efficacy of NeoSTX when used alone and in combination with bupivacaine (Bup) with and without epinephrine.

The study was a double-blind, randomized, controlled trial involving healthy male volunteers ages 18 to 35 receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 μg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 μg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 μg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX.

A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. The anesthetic, however, did cause perioral numbness and tingling with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose.

Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup. NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 μg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). The addition of epinephrine reduced circulating NeoSTX concentrations and perioral tingling and numbness and further prolonged sensory block.

“These results are consistent with previous animal studies that showed that neuromuscular, respiratory, and cardiovascular effects of NeoSTX were mild and dose dependent using the dose range anticipated for clinical use,” the authors noted. “In addition, in human studies where subjects received similar NeoSTX doses, no gross signs of weakness or cardiovascular toxicities were observed even with doses significantly higher than those used here.”

The researchers explained that future studies will better define whether further increases in NeoSTX dose in NeoSTX-Bup-Epi combinations can be tolerated with minimal symptoms, particularly in patients with a range of medical conditions.

One limitation of the study is that due to mandated truncation of the trial when symptoms became significantly bothersome, dose escalation was limited by the occurrence of bothersome numbness and tingling sensations in awake volunteers at a dose of 40 μg. “We were therefore unable to escalate NeoSTX dosing to a range that would define a human threshold for clinically important respiratory, neuromuscular, or cardiovascular impairments,” the authors concluded.