Prolonged duration local anesthesia with minimal toxicity

Abstract

Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague–Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…32,38,39,49 There are reports of bupivacaine-containing PDLA formulations where no neurotoxicity was documented. 1,32 However, as noted in the introduction, neurotoxicity was a major factor leading to withdrawal of the Investigational New Drug application (IND#53,441) 44 of a sustainedrelease bupivacaine-dexamethasone formulation. 3 The hematoxylin-eosin staining used here was not sufficiently sensitive to detect any but severe nerve injury.…”

“…Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe. That tissue injury can be a crucial issue with sustained release formulations is seen in the example of a sustained-release bupivacaine-dexamethasone formulation; 3 nerve and muscle injury in preclinical animal studies and clinical human trials led to withdrawal of its Investigational New Drug application (IND#53,441).…”

“…All three are wellrecognized sequelae of amino-amide and amino-ester local anesthetics. [27][28][29][30][31][32] The degree of toxicity is agent specific. 28,30 In a comparison of multiple drugs in rats, single injections of lidocaine produced milder muscle damage than bupivacaine.…”

“…6,21,37 Conventional local anesthetics are also neurotoxic, but generally at higher concentrations than those that cause myotoxicity and inflammation. 32,[38][39][40] Reporting of local tissue injury from local anesthetic controlled release formulations has been variable, in both animal and human studies. Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug.…”

Novelty without toxicity: a quest for a safer local anesthetic

“…This outcome quickly prompted further exploration of prolonging its duration with a sustained-release vehicle, such as liposomal formulations. 20 The efficacy of saxitoxin as a local anesthetic sounds too good to be true and one must not be overly enthusiastic. The preliminary results were based on a small group of healthy individuals, and there exists a relatively narrow therapeutic index.…”