The currently available drugs to treat neuropathic pain do not provide adequate pain management. As such, other treatments including stem cells, platelet-rich plasma and plasma-derived molecules such as alpha-2 macroglobulin (A2M) are being explored because they show promising potential for neuropathic pain. The various mechanisms and immunomodulatory effects could be a desirable approach in targeting neuropathic pain. This review indicates that A2M can be highly efficacious due to its conformational change during activation and specificity of action on various cytokines. Its ability to reduce neuropathic pain can further the future of neuropathic intervention. However, there is a lack of robust clinical studies and thus further research is needed to verify and expand the understanding of its therapeutic effects.