Focused ultrasound enhances the anesthetic effects of topical lidocaine in rats

Abstract

Background: High-intensity ultrasound has been used to induce acoustic cavitation in the skin and subsequently enhances skin permeability to deliver hydrophobic topical medications including lidocaine. In contrast, instead of changing skin permeability, pulsed application of low-intensity focused ultrasound (FUS) has shown to non-invasively and temporarily disrupt drug-plasma protein binding, thus has potential to enhance the anesthetic effects of hydrophilic lidocaine hydrochloride through unbinding it from serum/interstitial alpha 1-acid glycoprotein (AAG). Methods: FUS, operating at fundamental frequency of 500 kHz, was applied pulse-mode (55-ms pulse duration, 4-Hz pulse repetition frequency) at a spatial-peak pulse-average intensity of 5 W/cm(2). In vitro equilibrium dialysis was performed to measure the unbound concentration of lidocaine (lidocaine hydrochloride) from dialysis cassettes, one located at the sonication focus and the other outside the sonication path, all immersed in phosphate-buffered saline solution containing both lidocaine (10 mu g/mL) and human AAG (5 mg/mL). In subsequent animal experiments (Sprague-Dawley rats, n = 10), somatosensory evoked potential (SSEP), elicited by electrical stimulations to the unilateral hind leg, was measured under three experimental conditions-applications of FUS to the unilateral thigh area at the site of administered topical lidocaine, FUS only, and lidocaine only. Skin temperature was measured before and after sonication. Passive cavitation detection was also performed during sonication to evaluate the presence of FUS-induced cavitation. Results: Sonication increased the unbound lidocaine concentration (8.7 +/- 3.3 %) from the dialysis cassette, compared to that measured outside the sonication path (P < 0.001). Application of FUS alone did not alter the SSEP while administration of lidocaine reduced its P23 component (i.e., a positive peak at 23 ms latency). The FUS combined with lidocaine resulted in a further reduction of the P23 component (in a range of 21.8 - 23.4 ms after the electrical stimulations; F(2,27) = 3.2 - 4.0, P < 0.05), indicative of the enhanced anesthetic effect of the lidocaine. Administration of FUS neither induced cavitation nor altered skin conductance or temperature, suggesting that skin permeability was unaffected. Conclusions: Unbinding lidocaine from the plasma proteins by exposure to non-thermal low-intensity ultrasound is attributed as the main mechanism behind the observation.