High-frequency, low-intensity ultrasound and microbubbles enhance nerve blockade

Abstract

Site 1 sodium channel blockers (S1SCBs such as tetrodotoxin [TTX] and the saxitoxins) are ultrapotent local anesthetics that bind extracellular domains of voltage-dependent sodium channels [1]. S1SCBs do not cross the blood brain barrier and have low affinity for the cardiac sodium channel isoform [2,3], and so do not cause seizures [4] or arrhythmias, making TTX an attractive alternative to conventional local anesthetics [5,6]. Local anesthesia with S1SCBs has been described in numerous reports in animal models [7–11], and is now starting to be applied in humans [12] [13]. However, due to their very hydrophilic nature S1SCBs have limited penetration to peripheral nerves even with local injection, and require relatively high concentrations to achieve consistent nerve blockade [9]. Those high concentrations can be associated with systemic toxicity. One approach to enhancing the effect of S1SCBs has been to co-inject them with second or third drugs with adjuvantic effects [7,8,14,15]. However, such couplings can entail the side-effects of the second drugs, such as the local tissue toxicity of “conventional” amino-amide and amino-ester local anesthetics or the vasoconstriction and/or tachycardia seen with epinephrine. An alternative approach is to enhance the penetration of S1SCBs to the nerve. Previously we have shown that co-injection of TTX with chemical permeation enhancers could enhance the effect of S1SCBs, albeit with some adverse tissue reaction at high concentrations [16,17]. Ultrasound-mediated drug delivery has the potential to enhance nerve blockade without adverse tissue reaction. Acoustic waves can enhance drug delivery through the sclera [18], the stratum corneum [19,20], across barriers within the gastrointestinal tract [21,22], and the blood brain barrier [23,24]. The effect of high-frequency ultrasound on drug flux across skin (sonophoresis) can be enhanced by exogenous microbubbles [25,26]. In this study, we hypothesized that ultrasound treatment would increase the flux of hydrophilic molecules, such as S1SCBs, across biological barriers to the surface of the peripheral nerve. We used TTX as a model S1SCB. We studied high-frequency, low-intensity ultrasound (HFLIU), parameters similar to those used in clinical imaging. This frequency and intensity range is theoretically safe for a broad range of applications. We evaluated the effects of HFLIU with and without the addition of exogenous microbubbles on TTX-mediated nerve blockade. We also verified whether effects of ultrasound and microbubbles were applicable to local anesthetics in general by testing their effect on the amino-amide local anesthetic bupivacaine.