Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres

Abstract

There is interest in developing prolonged duration local anesthesics. Here we examine whether tetrodotoxin (TTX) can be used to prolong the block from bupivacaine microspheres with and without dexamethasone. Rats received sciatic nerve blocks with 75 mg of microspheres containing 0.05% (w/w) TTX, 50% (w/w) bupivacaine and/or 0.05% (w/w) dexamethasone. 0.1% (w/w) TTX microspheres were also tested. The carrier fluid contained 1:100,000 epinephrine. Nociceptive and motor blockade of the hindpaw were quantified. Nerves and adjacent muscles were harvested 2 weeks after injection for histological assessment by light microscopy. The median nociceptive block duration in hours from the microsphere groups were: bupivacaine=6.2, 0.05% TTX=0, bupivacaine+TTX=35.3, bupivacaine+dexamethasone=31.3, TTX+dexamethasone=8.1, TTX+bupivacaine+dexamethasone=221.7. Some animals receiving particles containing 0.05% TTX had deficits in the uninjected extremity; all animals receiving 0.1% (w/w) TTX particles died. Pockets of particles were associated with localized inflammation, and all samples showed some evidence of myotoxicity in the vicinity of the injection. The nerves themselves appeared intact. In summary, coencapsulation of TTX in controlled release devices containing bupivacaine and dexamethasone resulted in very prolonged nerve blocks. As formulated here, this preparation had a narrow margin of safety. While the myotoxicity appears consistent with the well-known reversible myotoxicity associated with local anesthetics, its long-term significance remains to be established.

Prolonged duration local anesthesia with minimal toxicity

“…They did not require synergistic compounds such as bupivacaine and dexamethasone, although block duration was greatly extended by their use. For example, incorporation of dexamethasone produced blocks lasting Ͼ7 days without any systemic toxicity detectable by our neurobehavioral testing methods and clinical examination (2). This prolonged blockade from STX-only liposomes was in contrast to our experience with polymeric microspheres containing TTX, where particles with the highest nontoxic dose of TTX alone produced a median duration of block of 0 min, and addition of dexamethasone prolonged their duration of block to only 8 h. Polymeric microspheres containing TTX also had to be injected with epinephrine to avoid systemic toxicity.…”

“…Polymeric microspheres with TTX alone had been ineffective (2). Nerve blockade from fluid liposomes containing STX alone lasted Ϸ13.5 h. Solid liposomes containing STX alone produced even longer blocks, lasting 48 h, with no signs of systemic toxicity.…”

“…Coencapsulation of site 1 sodiumchannel blockers [tetrodotoxin (TTX), saxitoxin (STX), etc., which block the sodium channel at site 1 on the outer surface] with conventional local anesthetics also greatly prolonged sciatic nerve blockade. Addition of dexamethasone prolonged the sciatic nerve blockade to Ͼ9 days in the rat when dexamethasone was added (2). However, tissue reaction to such formulations has been problematic.…”

“…Conventional local anesthetics are also neurotoxic (6,7). The presence of particles themselves enhances local anesthetic myotoxicity in vivo (3), and can cause inflammatory responses at the nerve that may considerably outlast the duration of blockade (2,3,8). In contrast, site 1 sodium-channel blockers do not cause myo-or neurotoxicity (9,10), which would make them desirable for an extended release formulation.…”

Microparticles and nanoparticles for drug delivery

“…doubling the number of hours by co-encapsulating dexamethasone (Colombo et al, 2005). In contrast, the addition of dexamethasone to 60 mm particles increases the duration of block from hours to days (Castillo et al, 1996;Kohane et al, 2003b), and the further addition of tetrodotoxin increases the duration to more than 9 days (Kohane et al, 2003b). Such durations of block could be difficult for smaller particles to achieve.…”