Fig. 1. Various analgesic agents can be added to an inserted polymeric matrix to alleviate pain following a surgery.

Selection of the API will depend on the targeted biological process that is intended to be aided or impeded. Pain is a neurological process and as such, analgesic APIs act on the central and peripheral nervous system (A). Each of three classes of analgesic drug acts upon a site or multiple sites of the pain pathway to block or mitigate the signal transduction necessary for pain (B). NSAIDs act on the cyclo-oxygenase (COX) enzyme to block the production of inflammatory mediators, such as prostaglandins (e.g., PGE₂), as well as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF), that are responsible for the initiation of nociception (C)¹⁴². Local anesthetics block ion channels in the periphery to create an inactive state, preventing the signal from continuing (D). Opioids work on the central and peripheral terminals and spinal cord and brain neurons to suppress pain signaling. Their mechanisms of action involve the G-protein-coupled receptors in nociceptive neurons in the PNS and CNS to inhibit the influx of calcium ions via calcium channels on primary sensory neurons, leading to an inhibition of neurotransmitter release and blockade of pain transmission¹⁴³. In postsynaptic neurons in the CNS (e.g., spinal cord dorsal horn), opioids also activate potassium channels and create an influx of potassium ions to hyperpolarize neurons, therefore, decreasing their activities (E). DRG (Dorsal Root Ganglion), B (unprotonated local anesthetic/base), and BH⁺ (protonated local anesthetic/base).