A3052
October 13, 2014
3:00 PM - 4:30 PM
Room Room 231-232
Prolonged Local Anesthesia With Neosaxitoxin in Combination With 0.2% Bupivacaine Versus Bupivacaine Alone: A Randomized, Controlled, Double-Blind, Dose Escalation Trial
Laura Cornelissen, Ph.D., Carolina Donado, M.D., Joseph Kim, M.A., Kimberly Lobo, M.S., M.P.H., Mary Ellen McCann, M.D., M.P.H., Karen R. Boretsky, M.D., Joseph Cravero, M.D., Charles B. Berde, M.D., Ph.D.
Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States
Background and Aim: Neosaxitoxin (NeoSTX) is a site 1 sodium channel blocker that has produced prolonged local anesthesia and/or postoperative analgesia, either alone or in combinations with bupivacaine and/or epinephrine in animals1 and preliminary human studies 2. Under an FDA-approved investigator-initiated IND, we studied safety (reported in a separate abstract for ASA2014) and efficacy (current abstract) with NeoSTX (alone) and in combination with 0.2% bupivacaine (BUPI), compared to 0.2% bupivacaine (alone) and placebo. An add-on exploratory study (separate abstract ASA2014) evaluated additional effects of epinephrine (EPI) combined with NeoSTX-bupivacaine.
Methods: After IRB approval and registration at ClinicalTrials.gov (NCT01786655), we performed a double-blind, randomized controlled trial involving healthy male volunteers aged 18-35 years. Subjects were randomized to receive one of 3 injections in the calf (10ml SC): (1) NeoSTX + BUPI (2) NeoSTX alone, or (3) saline placebo. All subjects received 0.2% bupivacaine (BUPI control) in the contralateral calf. The dose range of NeoSTX was 5mcg - 40mcg escalated in a step-wise fashion. Allocation was randomized by a block design. For each dose, one subject received saline placebo, and the remaining subjects were equally divided between NeoSTX+BUPI or NeoSTX alone. Mechanical touch detection (MDT), pain threshold (MPT), and cool temperature detection threshold (CDT) were recorded at baseline, 5min, 30min, 1hr, 2hr, 4hr, 6hr, 12hr, 24hr and then daily for the first 7 days post-injection or until cutaneous sensitivity returned to baseline.
Outcome measures included (1) duration of block and (2) density of block at 12hr and 24hr for each parameter. Complete block was defined as the threshold greater than 4 standard deviations (SD) from the baseline mean. Partial block was defined as the threshold between 2-4 SD from the baseline mean. All bupivacaine data were pooled (n=66). Data reported as median (IQR), ANOVAS with Dunnett´s correction, and Fisher-exact test were used, significance was determined at p<0.05.
Results: 66 subjects completed the study. At all NeoSTX doses, NeoSTX+BUPI provided more prolonged block and more intense block at 12 and 24 hours compared to NeoSTX alone or BUPI alone. For MPT, the duration of complete block for BUPI was 5.0 hrs (IQR 9.7) as compared to NeoSTX+BUPI (18.0 hrs, IQR 23.9; p<0.05); NeoSTX alone (0.5 hrs, IQR 0.4; p<0.05). For MDT, the duration of complete block for BUPI was 7.5 hrs (IQR 12.2) as compared to NeoSTX+BUPI (30.9 hrs, IQR 21.3; p0.1). We were unable to find dose-dependent differences for complete block duration within NeoSTX+BUPI, or within NeoSTX dose cohorts (5-40mcg) in any parameter. Block density at 12 hrs post-injection showed a higher percentage of subjects treated with NeoSTX+BUPI remained completely blocked compared to BUPI (MPT, p<0.001; MDT, p<0.001; CDT, p=0.08; Fisher’s test); Fig 1A. This was also seen at 24hr post injection (MPT, p<0.001; MDT, p<0.001; CDT, p=0.05; Fisher’s test); Fig 1B.
Conclusion: Our data indicate that 5-40mcg NeoSTX given in combination with BUPI is more effective in producing blockade than BUPI alone as measured by mechanical pain detection and mechanical touch detection.
1. Kohane D. et al. RAPM (1):52-9,2000
2. Rodriguez-Navarro A. et al. RAPM. 36(2):103-9, 2011