Novel Compound from Algae Yields Long-Acting Anesthetic Effect

New Orleans—The duration of sensory blockade was significantly prolonged by a novel site 1 sodium channel blocker that belongs to the class of paralytic shellfish toxins.

This first-in-human trial was reported at the American Society of Anesthesiologists 2014 annual meeting and was named the “Best Clinical Abstract.”

“Neosaxitoxin has prolonged local anesthesia when given either alone or with bupivacaine or epinephrine, while reducing the risk of systemic toxicity,” said Carolina Donado, MD, of Boston Children’s Hospital and Harvard Medical School.

Neosaxitoxin belongs to a class of natural neurotoxic alkaloids known as the paralytic shellfish toxins, explained senior investigator Charles B. Berde, MD, PhD, professor of anesthesia (pediatrics) at Harvard Medical School. In nature, neosaxitoxin is produced by algae blooms, but the compound is now being manufactured from bioreactor-grown algae by the Chilean-based company Proteus SA. Dr. Berde acknowledged the involvement of Dan Kohane, MD, PhD, in the compound’s development and in facilitating Boston Children’s Hospital’s collaboration with Proteus SA.

In healthy volunteers, neosaxitoxin significantly prolonged the time to partial and complete recovery when administered with the other agents. Duration of effect exceeded 24 hours for some parameters.

This characteristic of prolonged blockade should give neosaxitoxin advantages over current anesthetics, especially in settings where high volumes of local anesthetic are required, according to Dr. Berde, who said this would help avoid the adjunctive use of systemic opioids, which can lead to longer hospitalizations, and the need for perineural catheter infusions to prolong the anesthetic effect.

“With combination formulations using site 1 sodium channel blockers, we can provide local anesthesia for periods of several days with a single injection before or during surgery,” he predicted.

Compound Was Evaluated In Healthy Volunteers

Dr. Donado presented the results of a randomized, controlled, double-blind Phase I trial of neosaxitoxin. The study examined the intensity and duration of cutaneous blockade with combinations of neosaxitoxin plus 0.2% bupivacaine (NB) and with epinephrine (5 mcg/mL) (NBE). Outcomes were compared with those seen with 0.2% bupivacaine alone.

In the dose-escalation study (part 1), 66 healthy adult men received two simultaneous 10-mL subcutaneous injections in a 3 x 3-cm square, one on each posterior calf. In the five NB dose cohorts evaluated for safety, no serious adverse events or need for medical intervention were observed.

Numbness and tingling, however, did occur in a dose-dependent fashion after injection. At the highest dose (40 mcg), all of the participants experienced notable numbness and tingling that lasted at least 30 minutes. In part 2 of the study, epinephrine was added to the regimen, which eliminated the numbness and tingling.

The second part of the study aimed at determining the duration and density of the block at 24 (partial recovery) and 48 hours (full recovery), evaluating several parameters. Eighteen individuals received one of three formulations: 10 mcg NBE; 30 mcg NBE; or saline placebo. The comparison of outcomes also included previous patients who received 0.2% bupivacaine alone, neosaxitoxin 10 mcg and 30 mcg alone, or NB.

Mechanical touch detection, pain threshold and cool temperature detection threshold were recorded at baseline, at eight time points during the first 24 hours, and then daily for seven days postinjection or until cutaneous sensitivity returned to baseline.

“The neosaxitoxin combinations had prolonged time to partial recovery versus bupivacaine or neosaxitoxin alone. The time to partial recovery was almost three times longer in the combinations compared with bupivacaine alone. All the differences were statistically significant,” Dr. Donado reported, noting that similar trends favoring neosaxitoxin were observed across all parameters.

NBE (both 10 and 30 mcg) resulted in significantly prolonged block compared with bupivacaine. For the mechanical pain threshold, the complete blockade lasted 5.3 hours with bupivacaine compared with 22 hours for 10 mcg NBE (P<0.01) and 22 hours for 30 mcg NBE (P<0.05). For mechanical touch detection, the complete block duration with bupivacaine was 7.03 hours compared with 33.9 hours for 10 mcg NBE (P<0.05) and 35.14 hours for 30 mcg NBE (P<0.05).

At 24 and 48 hours, differences in block density between bupivacaine and NBE (both doses) were seen in all block parameters for mechanical touch detection and pain threshold (P<0.05). At 24 hours, 100% of the NBE groups reported some degree of block compared with about 60% in the NB group and 25% in the bupivacaine-alone group, she said.

Time for a New Compound

Alan R. Bielsky, MD, assistant professor at the University of Colorado School of Medicine, and director of the Acute Pain Service at Children’s Hospital Colorado in Aurora, commented for Anesthesiology News.

“The [potential] appearance of neosaxitoxin as a local anesthetic adjuvant is an exciting addition to regional anesthesia and science as a whole. In historical terms, our most recent addition to classic local anesthetics was in 1996 with the introduction of ropivicaine, proving that new compounds are overdue,” he said.

“As a daily regional anesthesia practitioner, my ‘wish list’ includes medicines that are long-lasting, have limited toxicity and are motor-sparing,” he said. “Specific questions that will hopefully be addressed by future studies will include the performance of the drug in the perineural space, effect on motor function, ability to administer in the neuraxial space, and utility in targeting ectopic activity in neuropathic pain.”


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