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. 2019 Dec 16:rapm-2019-100714.
doi: 10.1136/rapm-2019-100714. Online ahead of print.

Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain

Thomas Ottoboni  1 , Barry Quart  2 , Jayne Pawasauskas  3 , Joseph F Dasta  4   5 , Richard A Pollak  6 , Eugene R Viscusi  7
Affiliations

Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain

Thomas Ottoboni et al. Reg Anesth Pain Med. .

Abstract

Background and objectives: Obtaining consistent efficacy beyond 12-24 hours with local anesthetics, including extended-release formulations, has been a challenging goal. Inflammation resulting from surgery lowers the pH of affected tissues, reducing neuronal penetration of local anesthetics. HTX-011, an investigational, nonopioid, extended-release dual-acting local anesthetic combining bupivacaine and low-dose meloxicam, was developed to reduce postsurgical pain through 72 hours using novel extended-release polymer technology. Preclinical studies and a phase II clinical trial were conducted to confirm the mechanism of action of HTX-011.

Methods: In a validated postoperative pain pig model and a phase II bunionectomy trial, the analgesic effects of HTX-011, oral meloxicam (preclinical only), liposomal bupivacaine (preclinical only) and saline placebo were evaluated. The optimal meloxicam:bupivacaine ratio for HTX-011 and the effect of HTX-011 on incisional tissue pH were also evaluated preclinically.

Results: Preclinical data demonstrate the ability of HTX-011 to address local tissue inflammation as demonstrated by a less acidic tissue pH, which was associated with potentiated and prolonged analgesic activity. In the phase II bunionectomy study, HTX-011 achieved superior and sustained pain relief through 72 hours after surgery compared with each component in the polymer.

Conclusions: Preclinical animal and clinical results confirm that the low-dose meloxicam in HTX-011 normalizes the local pH in the incision, resulting in superior and synergistic analgesic activity compared with extended-release bupivacaine. HTX-011 represents an extended-release local anesthetic with a dual-acting mechanism of action that may provide an important advancement in the treatment of postoperative pain.

Trial registration number: NCT02762929.

Keywords: animal studies; pain medicine; pharmacology: local anesthetics; postoperative pain.

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Conflict of interest statement

Competing interests: TO and BQ are employees of Heron Therapeutics and receive salary and stock options. JP received consulting fees from Heron Therapeutics, Acacia Pharma, and Mallinckrodt Pharmaceuticals and is on the speaker’s bureau for Mallinckrodt Pharmaceuticals. JFD receives consulting fees from Heron Therapeutics, AcelRx Pharmaceuticals, Neumentum Pharmaceuticals, Aries Pharmaceuticals, and Pacira Pharmaceuticals. EV receives consulting fees from AcelRx, Concentric, Heron Therapeutics, Innacoll, Merck, Neumentum, Pfizer, Recro, Salix, and Trevena.

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