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Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain
  1. Jason Hafer and
  2. Ken B Johnson
  1. Department of Anesthesiology, University of Utah Health, Salt Lake City, UT 84132, USA
  1. Correspondence to Dr Jason Hafer, Department of Anesthesiology, University of Utah Health, Salt Lake City, UT 84132, USA; jason.hafer{at}

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To the Editor

We read with great interest the paper on the mechanism of action of HTX-011.1 The mechanism of reducing local tissue inflammation to maintain physiologic tissue pH and potentiate and prolong analgesic activity is intriguing. We applaud the authors for innovation in local anesthetic drug development though we identified several critiques and questions for them to consider.

The data show analgesic benefit during the first 24 hours following administration (including decreased pain intensity and opioid consumption). However, beyond that timeframe, it is not clear whether the data show analgesic benefit. Questions arise with careful analysis of figure 6 and table 2.1 Figure 6 shows cumulative decreased mean pain intensity scores using an area under the curve approach.1 Most, if not all, of the differences in the area under the curve is within the first 36 hours. From that time on, the HTX-011 curve tracks within the confidence intervals of the saline placebo curve and statistical difference is only present because all of the area under the curve back to time 0 is included. Perhaps it would be more accurate to present the area under the curve in separate 24 hour intervals.

The same analytic approach was used with the data in table 2.1 There, the difference in mean total opioid consumption is 8.20 mg morphine equivalents at 24 hours and remains 8.95 mg at 72 hours. Again, a significant statistical difference in the first 24 hours is carried on through 72 hours only because the data are not broken into separate 24 hour time intervals. Might this form of data presentation lead to misconceptions in actual pain relief each postoperative day?

Finally, the investigators propose HTX-011 functions by reducing local tissue inflammation to maintain physiologic tissue pH. Because figure 5 shows the difference in pH is not present until greater than 24 hours following administration, and the benefit after 24 hours is unclear, this calls the proposed mechanism into question.

We believe the data regarding novel drug HTX-011 demonstrate potential clinical benefits in the first 24 hours after administration, but beyond 24 hours the data are inconclusive. We suggest further investigation of HTX-011 is required to confirm a 72 hour duration of action.



  • Twitter @JaseHafer

  • Contributors JH and KBJ contributed to the conception and design of this work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests KBJ is the executive section editor for Anesthetic Clinical Pharmacology, Anesthesia and Analgesia and is an equity partner for Applied Medical Visualizations.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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