Thomas Ottoboni 1 , Barry Quart 2 , Jayne Pawasauskas 3 , Joseph F Dasta 4,5 , Richard A Pollak 6 , Eugene R Viscusi 7 Show Affiliations »
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. © American Society of Regional Anesthesia & Pain Medicine 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.
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. © American Society of Regional Anesthesia & Pain Medicine 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.
Entities: Chemical
Disease
Species
Keywords:
animal studies; pain medicine; pharmacology: local anesthetics; postoperative pain
Year: 2019
PMID： 31843865 DOI： 10.1136/rapm-2019-100714
Source DB: PubMed Journal: Reg Anesth Pain Med ISSN： 1098-7339 Impact factor: 6.288