Extended-release local anesthetics (LAs) are used for the continuous administration of a low and safe dose of anesthesia over a prolonged period of time. [1] Conventional LAs are frequently used during surgery but, despite their safety and efficacy, have significant downsides, including limited duration and potential toxicity at high concentrations, the latter of which can lead to convulsions, arrythmias, and cardiovascular and metabolic complications. [2] Administration of anesthesia using catheters can prolong its duration, but the use of catheters has also been shown to increase the risk of infection and trauma during the procedure. [3] Extended-release LAs are not toxic and do not pose a significant risk of infection, and can induce prolonged analgesia.

To understand how extended-release LAs function, it is necessary first to establish the mechanism by which LAs operate. Pain transmission occurs along peripheral nerves and is caused by the influx of sodium ions into these cells through voltage-gated Na+ channels. LAs bind to the intracellular domain of these channels, blocking the import of Na+ and thus preventing the transmission of pain signals. [4] Extended-release LAs operate in the same manner, but the anesthetic is packaged or administered in such a way that allows for it to continually act against the voltage-gated channels. One such way of achieving this is to encapsulate the drug into a liposome, a lipid nanoparticle that can carry and transport small molecules. [5] After entering the bloodstream, liposomes can interact with cell membranes, and release their cargo through the gradual degradation of its lipid bilayer. For this reason, liposomes that contain multiple vesicles can prolong drug release. [6]

Extended-release anesthesia is most commonly used for postoperative pain management and are an attractive alternative to opioids. In May 2021, the FDA approved ZYNRELEFTM, an extended-release dual-acting local anesthetic that delivers the anesthetics bupivacaine and meloxicam in fixed, low doses. [7] The drug was shown to significantly reduce pain in patients for up to 72 hours after they had undergone operations such as inguinal herniorrhaphy and total knee arthroplasty. [7] Most patients in the Phase 3 studies did not require opioids.

The first liposomal extended-release LA to receive FDA approval was EXPARAL, which has been found to be safer and more effective than catheter insertion, nerve blocks, and epidural analgesia. [1] While EXPARAL does not induce more neurotoxicity than free bupivacaine, it does induce more regional inflammation around the site of injection compared to bupivacaine. Additionally, the cost of EXPARAL is significantly greater than that of traditional LAs. These factors are motivating the discovery and development of new extended-release LAs, which include ZYNRELEF.

A new type of extended-release anesthesia was described by Zhan et al. in 2016. [8] They attached gold nanorods that can convert near-infrared light into heat to liposomes containing the anesthetic. Irradiation with near infrared light produced heat, which in turn caused the liposome to release its cargo. This technology, once tested and developed further, could allow for the precise and controlled administration of anesthesia by adjusting the irradiance (the amount of light hitting the liposome) and duration of irradiation according to patient needs. We will likely see the introduction and development of other types of extended-release LAs in the very near future.

References 

1. He, Y., Qin, L., Huang, Y. & Ma, C. Advances of Nano-Structured Extended-Release Local Anesthetics. Nanoscale Research Letters 2020 15:1 15, 1–18 (2020). 
2. Zorzetto, L. et al.From micro- to nanostructured implantable device for local anesthetic delivery. International Journal of Nanomedicine 11, 2695 (2016). 
3. Balocco, A. L., van Zundert, P. G. E., Gan, S. S., Gan, T. J. & Hadzic, A. Extended release bupivacaine formulations for postoperative analgesia: an update. Current Opinion in Anaesthesiology 31, 636–642 (2018). 
4. Fenton, B. W., Shih, E. & Zolton, J. The neurobiology of pain perception in normal and persistent pain. Pain Management 5, 297–317 (2015). 
5. Moradkhani, M. R., Karimi, A. & Negahdari, B. Nanotechnology application to local anaesthesia (LA). Artificial Cells, Nanomedicine, and Biotechnology 46, 355–360 (2018). 
6. Mantripragada, S. A lipid based depot (DepoFoam technology) for sustained release drug delivery. Progress in Lipid Research 41, 392–406 (2002). 
7. Heron Therapeutics Announces U.S. FDA Approval of ZYNRELEFTM(HTX-011) for the Management of Postoperative Pain for up to 72 Hours – Heron Therapeutics. https://herontherapeutics.gcs-web.com/news-releases/news-release-details/heron-therapeutics-announces-us-fda-approval-zynreleftm-htx-011.
8. ​8. Zhan, C. et al. Phototriggered Local Anesthesia. Nano Letters 16, 177–181 (2016).