Degradable polymeric vehicles for postoperative pain management

Abstract

Effective control of pain management has the potential to significantly decrease the need for prescription opioids following a surgical procedure. While extended release products for pain management are available commercially, the implementation of a device that safely and reliably provides extended analgesia and is sufficiently flexible to facilitate a diverse array of release profiles would serve to advance patient comfort, quality of care and compliance following surgical procedures. Herein, we review current polymeric systems that could be utilized in new, controlled post-operative pain management devices and highlight where opportunities for improvement exist.

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). 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 transmission. 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).

Fig. 2. Schematic of the circulatory system to depict different drug distribution effects from various administration methods.

A Oral administration is the most common and simplest method for analgesic delivery to date, however, first pass metabolism limits bioavailability to the active site and exposes even healthy tissue to the drug, therefore making it inefficient and uneconomical. Both (B) injectable (mainly subcutaneous or intramuscular) and (C) implantable controlled delivery methods afford a more localized exposure of the drug when administered, especially when impregnated into a controlled release matrix. If implanted at the site of injury, therapeutic effects should stay localized to a radius relative to the site of insertion, which will depend on the system itself (i.e., drug solubility and absorption).

Fig. 3. Polymeric drug delivery systems afford many different size scales due to the flexibility in processing of synthetic polymers.

Each scale class offers it’s own benefits and application methods that prove useful for targeting specific types of pain.

Fig. 4. Degradable polymeric systems can erode by different mechanisms depending on their chemical structure and mechanial properties. This factor, along with how the drug is incorporated into the matrix will ultimately impact how drug elution from the system occurs.

Controlled delivery systems can incorporate drug in a matrix (A, B) or a reservoir (B, C) system. Depending on the application, this will alter the drug release from the system in a specific manner. Reservoir systems are characteristic of a delayed release as the polymer surrounding the drug core degrades whereas matrix systems will depend more highly on the polymer-drug interactions among other factors (B). If solely based on polymer degradation, however, the release will either be more exponential (bulk erosion) or continual (surface erosion). Bulk erosion usually provides the system a “burst” release at early time points, followed by a continuous decrease in rate.