Corneal Anesthesia With Site 1 Sodium Channel Blockers and Dexmedetomidine.

Conventional amino-ester and amino-amide local anesthetics are used to reduce ocular pain related to corneal injury and ophthalmic surgery.1,2 They act by binding to an intracellular domain of the sodium channel and blocking sodium influx.3 They produce corneal anesthesia for 15 to 20 minutes when applied topically, with return of normal sensation after 60 minutes4 and so require repeated administration. Brief ophthalmic procedures, such as cataract extraction, are routinely performed under local anesthesia with conventional local anesthetics, which are administered by a variety of techniques, including topical application onto the cornea, injection into or around the muscle cone, and injection under the Tenon's capsule.5 Given frequently, these agents may delay epithelial healing, cause anterior segment inflammation,6 corneal ulceration, and occasionally neurotrophic keratopathy.1 Their short durations of action and the potential for tissue toxicity exclude their use in lengthier ophthalmic procedures, and limit their use for other causes of corneal pain such as traumatic abrasions and recurrent erosions.1,6 An ocular anesthetic formulation with prolonged effect and minimal toxicity is needed. Such a formulation could be used to prevent pain more effectively during longer surgical procedures and for outpatient management of minor corneal injury during the period when ocular pain is most intense. Tetrodotoxin (TTX) and saxitoxin (STX) are potent local anesthetics that act by binding to site 1 on the extracellular part of the sodium channel and blocking sodium influx.7 Tissue toxicity from site 1 sodium channel blockers (S1SCBs) after injection at peripheral nerves is minimal,8 even when delivered for prolonged periods.9 Site 1 sodium channel blockers also produce corneal analgesia with minimal toxicity to the corneal epithelium,2,6,10 although systemic toxicity from ocular application has been reported.11 Coadministration of local anesthetics with adjuvant agents can enhance anesthetic effect and/or (in the case of S1SCBs) prevent potential systemic toxicity by reducing the dose required for a given effect. For example, we have shown that corneal analgesia can be prolonged by combining S1SCBs with conventional local anesthetics.12 Similarly, addition of the α2-adrenergic receptor (α2-AR) agonists clonidine or dexmedetomidine to conventional amino-amide or amino-ester local anesthetics extends the duration of peripheral nerve block13–17 and ocular anesthesia.18 However, in both of those cases, the conventional local anesthetic is believed to be toxic to the cornea, which could limit usefulness. Here, we hypothesize that coadministration of S1SCBs and α2-AR agonists for ocular anesthesia will prolong corneal block. This hypothesis is supported by the fact that clonidine can enhance the duration of sciatic nerve blockade from TTX.19 Moreover, α2-AR agonists are likely to have minimal toxicity to the cornea. In fact, dexmedetomidine has been shown to reduce local tissue inflammation from conventional local anesthetics.17,20 Here, we report prolonged corneal anesthesia from local anesthetic formulations comprised of dexmedetomidine and TTX or STX, and compare them with the widely used amino-ester ocular anesthetic, 0.5% (wt/vol) proparacaine. We also characterize in vitro cytotoxicity to corneal cells and in vivo corneal healing in the setting of repeated drug administration of those compounds.