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Local anesthesia enhanced with increasing high-frequency ultrasound intensity

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Abstract

The effect of local anesthetics, particularly those which are hydrophilic, such as tetrodotoxin, is impeded by tissue barriers that restrict access to individual nerve cells. Methods of enhancing penetration of tetrodotoxin into nerve include co-administration with chemical permeation enhancers, nanoencapsulation, and insonation with very low acoustic intensity ultrasound and microbubbles. In this study, we examined the effect of acoustic intensity on nerve block by tetrodotoxin and compared it to the effect on nerve block by bupivacaine, a more hydrophobic local anesthetic. Anesthetics were applied in peripheral nerve blockade in adult Sprague-Dawley rats. Insonation with 1-MHz ultrasound at acoustic intensity greater than 0.5 W/cm2 improved nerve block effectiveness, increased nerve block reliability, and prolonged both sensory and motor nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. These effects were not enhanced by microbubbles. There was minimal or no tissue injury from ultrasound treatment. Insonation did not enhance nerve block from bupivacaine. Using an in vivo model system of local anesthetic delivery, we studied the effect of acoustic intensity on insonation-mediated drug delivery of local anesthetics to the peripheral nerve. We found that insonation alone (at intensities greater than 0.5 W/cm2) enhanced nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin.

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Abbreviations

TTX:

Tetrodotoxin

S1SCB:

Site-one sodium channel blocker

PBS:

Phosphate-buffered saline

CPE:

Chemical permeation enhancer

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Funding

This research was funded by the National Institutes of Health R35 GM131728 (to DSK).

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Authors and Affiliations

  1. Laboratory for Biomaterials and Drug Delivery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Kathleen Cullion, Laura C. Petishnok, Claudia M. Santamaria, Grant L. Pemberton & Daniel S. Kohane

  2. Department of Medical Critical Care, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Kathleen Cullion & Laura C. Petishnok

  3. Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Tao Sun & Nathan J. McDannold

  4. Department of Anesthesiology, Critical Care, and Pain Management, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Enders Building, Room 361, Boston, MA, 02115, USA

    Daniel S. Kohane

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  1. Kathleen Cullion
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  4. Claudia M. Santamaria
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  7. Daniel S. Kohane
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Contributions

K.C. and D.S.K. designed the research, analyzed the data, and wrote the manuscript. K.C., L.C.P., C.M.S., T.S. G.L.P, and N.M. performed the experimentation. All authors read the manuscript and contributed to its final presentation.

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Correspondence to Daniel S. Kohane.

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Cullion, K., Petishnok, L.C., Sun, T. et al. Local anesthesia enhanced with increasing high-frequency ultrasound intensity. Drug Deliv. and Transl. Res. 10, 1507–1516 (2020). https://doi.org/10.1007/s13346-020-00760-1

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