Neosaxitoxin, a novel site 1 sodium channel blocker, significantly prolonged sensory blockade when combined with bupivacaine, with or without epinephrine, in the first-in-human trial of this compound.
The study, presented here at Anesthesiology 2014, was distinguished as the Best Clinical Abstract.
“Neosaxitoxin prolonged local anesthesia, when given either alone or with bupivacaine or epinephrine, while reducing the risk of systemic toxicity,” said Carolina Donado, MD, from Boston Children’s Hospital and Harvard Medical School. “Our data support further development.”
Neosaxitoxin belongs to a broad group of natural neurotoxic alkaloids commonly known as the paralytic shellfish toxins. In nature, neosaxitoxin is produced by algal blooms. Proteus SA, a Chilean company, is producing the compound from bioreactor-grown algae.
The involvement of a Chilean biotech company was a natural fit, given the work done in that country on shellfish toxins, explained senior investigator Charles Berde, MD, also from Boston Children’s Hospital and Harvard Medical School.
The prolonged duration of blockade with neosaxitoxin formulations — exceeding 24 hours for some parameters — points to advantages over current anesthetics, Dr Berde noted. It is likely to be especially useful in clinical settings where high volumes of local anesthetic are required, such as large-field infiltration anesthesia and analgesia and multiple large-volume peripheral blocks, he explained.
The randomized controlled double-blind phase 1 trial examined the intensity and duration of cutaneous blockade with neosaxitoxin in combination with neosaxitoxin plus 0.2% bupivacaine with or without epinephrine 5 mµ/mL.
The 18 healthy adult males enrolled in the study received one of three formulations: 10 µg neosaxitoxin plus bupivacaine and epinephrine; 30 µg neosaxitoxin plus bupivacaine and epinephrine, or saline placebo.
Investigators compared outcomes with those from previous subjects who received bupivacaine alone, neosaxitoxin alone (10 µg or 30 µg), or neosaxitoxin plus bupivacaine.
To determine duration and density of the block at 24 and 48 hours (partial and full recovery), the researchers examined several parameters. Mechanical touch detection, pain threshold, and cool temperature detection threshold were recorded at baseline, at 8 points during the first 24 hours, and then daily for 7 days after injection or until cutaneous sensitivity returned to baseline.
“The neosaxitoxin combinations prolonged time to partial recovery, compared with bupivacaine or neosaxitoxin alone,” Dr Donado reported. “The time to partial recovery was almost three times longer with the combinations than with bupivacaine alone. All the differences were statistically significant.” However, she noted, time to partial recovery was not prolonged with neosaxitoxin alone.
The block was significantly longer with the combination of neosaxitoxin plus bupivacaine and epinephrine than with bupivacaine alone.
Table. Complete Block Duration
Parameter Bupivacaine Alone Neosaxitoxin 10 µg Combination Neosaxitoxin 30 µg Combination PValue
Mechanical pain threshold 5.30 h 22.00 h 22.00 h <.05
Mechanical touch detection 7.03 h 33.90 h 35.14 h <.05
At 24 and 48 hours, block density for mechanical touch detection and pain threshold was significantly better with neosaxitoxin plus bupivacaine and epinephrine than with bupivacaine alone (P < .05).
At 24 hours, some degree of block was experienced by more patients treated with neosaxitoxin plus bupivacaine and epinephrine than with neosaxitoxin plus bupivacaine or with bupivacaine alone (100% vs 60% vs 25%).
“The results for the mechanical detection threshold and time to partial recovery exemplified all the results; we saw similar trends for the rest of the parameters,” Dr Donado reported.
The anesthetic was generally well tolerated, and all systemic numbness and tingling resolved without medical intervention, she added.
“Currently available local anesthetics generally wear off after about 8 hours after a single injection,” Dr Berde said. “We usually must resort to giving patients systemic opioid analgesics, which can cause a wide range of effects, from nausea to sedation to shallow breathing. These effects can prolong a patient’s time in the hospital,” he explained.
Local anesthesia can be prolonged using perineural catheter infusions, but these are cumbersome because they tether patients to tubing and an infusion pump, add to the cost, and have the potential for technical problems, he noted.
Neosaxitoxin acts on the site in a different manner than our current local anesthetics.
“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,” Dr Berde said. “If future clinical trials confirm what we have observed in this phase 1 volunteer study, we believe we will be able to diminish opioid side effects and provide prolonged pain control without the need for pumps and catheters.”
The findings on neosaxitoxin are “really interesting and exciting,” said session moderator Michael Avram, PhD, from the Northwestern University Feinberg School of Medicine in Chicago, who is executive editor ofAnesthesiology. “It appears to provide you with a longer duration of block without producing adverse effects.”
“Neosaxitoxin acts on the site in a different manner than our current local anesthetics,” he told Medscape Medical News. “While bupivacaine enters neurons and blocks sodium channels from the inside, this drug blocks them from the outside. The investigators added epinephrine so the drug stays where it is injected, and its absorption into the systemic circulation, which creates perioral effects, is stopped. I think this could be used as a regional anesthetic. If you wanted to do a block on an extremity, for example, it could provide you with a dependable long duration of effect.”
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