Although chronic pain affects about 1% of the US population, it remains largely resistant to treatment. Despite great variability in pain outcomes, the application of autologous platelet-rich plasma (PRP) has become increasingly popular in attempts to reduce chronic pain. The variability in PRP efficacy raises the question of whether PRP actually has an analgesic capacity, and if so, can that capacity be made consistent and maximized. The best explanation for the variability in PRP analgesic efficacy is the failure during PRP preparation and application to take into account variables that can increase or eliminate its analgesic capabilities. This suggests that if the variables are reduced and controlled, a PRP preparation and application protocol can be developed leading to PRP inducing reliable, complete, and long-term pain relief. The goal of this study was to examine some of the variables that influence platelets and see how they might be controlled to increase the analgesic potential of PRP. Among the variables examined are the physiological status of the patient, methods used to prepare PRP, and methods of PRP application. The goal of modifying these variables is to minimize platelet serotonin content, maximize platelet content of factors that reduce inflammation and pain, while maintaining their bioactivity, maximize platelet capacity to aggregate at injury sites, induce rapid and simultaneous release of their contents, and optimize PRP application protocols. It is concluded that controlling some or many of these variables will lead to PRP that induces reliable, maximum, and long-term relief of chronic pain.