A Phase 1, Dose-escalation, Double-blind, Block-randomized, Controlled Trial of Safety and Efficacy of Neosaxitoxin Alone and in Combination with 0.2% Bupivacaine, with and without Epinephrine, for Cutaneous Anesthesia.
BACKGROUND
Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine.


METHODS
The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr 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. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia.


RESULTS
A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased 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 (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). 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).


CONCLUSIONS
NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.
From the Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts (K.L., C.D., L.C., J.K., R.O., D.Z., K.E.K., J.P., A.B., K.B., M.E.M., C.B.B., J.C.); Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts (R.W.A.P., M.K.); and Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts (M.E.A.).
Kimberly
K
Lobo
Carolina
C
Donado
Laura
L
Cornelissen
Joseph
J
Kim
Rebeca
R
Ortiz
Roy W A
RW
Peake
Mark
M
Kellogg
Mark E
ME
Alexander
David
D
Zurakowski
Katherine E
KE
Kurgansky
James
J
Peyton
Aykut
A
Bilge
Karen
K
Boretsky
Mary Ellen
ME
McCann
Charles B
CB
Berde
Joseph
J
Cravero
D000328:Adult; D000772:Anesthesia, Local / Q000009:adverse effects / Q000379:methods*; D000779:Anesthetics, Local; D002045:Bupivacaine / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004837:Epinephrine / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006987:Hypesthesia / Q000139:chemically induced; D008297:Male; D010147:Pain Measurement / Q000009:adverse effects / Q000379:methods; D012530:Saxitoxin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
D000779:Anesthetics, Local; D012530:Saxitoxin; C034902:neosaxitoxin; D002045:Bupivacaine; D004837:Epinephrine