Pain is a very common clinical problem, causing suffering in millions. Treatment of pain that lasts longer than a brief procedure can be difficult and can entail the use of opioids, with their side effects and potential for addiction and diversion. In this research we seek to develop injectable drug delivery systems (DDS) using sustained release technology to provide continuous prolonged local anesthesia (PLA) lasting many hours to days for perioperative pain, or even weeks for chronic pain. In addition, will develop DDS where the patient could determine when they receive local anesthesia, how intense the anesthesia is, and how long it lasts. Those on-demand DDS (termed triggered local anesthetics, TLA) are controlled by external energy sources such as near-infrared light and ultrasound. Both the continuous and triggered DDS have the potential to revolutionize pain management and advance the science of drug delivery. These PLA and TLA systems could mitigate or obviate opioid use. All the DDS should ideally: be delivered by a single injection; be easy to administer; not require general anesthesia or surgery to initiate; last days to weeks; cause minimal local inflammation and no local neuro- or myotoxicity, or systemic toxicity; be fully biodegradable and reversible. Triggerable systems should be easy to use with a safe and convenient device. Our strategy has been to develop novel sustained release vehicles to extend the release of local anesthetics, thus prolonging duration of effect and reducing systemic toxicity. To minimize local (tissue) toxicity we have used site 1 sodium channel blockers (S1SCBs) such as saxitoxin and tetrodotoxin, and taken advantage of interactions with compounds that are known to enhance their duration of nerve blockade, such as conventional local anesthetics and steroids. In PLA, we have greatly extended the duration of effect of our previous designs and reduced their toxicity, such that 3-4 days of nerve block can be achieved without using drug synergy, and at least a week with. In TLA, we have used photo-labile linkages to produce formulations that only release drugs upon photo-triggering (i.e. do not cause nerve block unless the site of injection is irradiated), and where nerve block can be safely and repeatedly re-induced by irradiating the injection site with near-infrared light or ultrasound. This work has produced 17 papers in the past 4 years (actually 3 years if accounting for the lab shutdown due to COVID-19), many in prominent journals (5 in Nature communications, 1 in Nature Biomedical Engineering, 2 in Nano Letters). In PLA, we propose a spectrum of approaches to produce yet longer blocks while improving safety. In TLA, we propose means to extend the number of triggerable events, and extend the time frame over which they can be triggered – allowing use in prolonged perioperative and chronic pain. Addressing these challenges will entail overcoming challenges in biomaterials / drug delivery / nanoscience...