A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Endocannabinoids, anandamide, and 2-arachidonoyl-sn-glycerol (2-AG) are produced in injured tissues through distinct biochemical pathways to suppress sensitization and inflammation by activation of cannabinoid (CB) receptors. Anandamide can act as an autocrine or paracrine messenger and follows one of two pathways. In a reaction catalyzed by fatty acid amide hydrolase, it can be broken down to arachidonic acid and ethanolamine or, alternatively, it can be directly transformed by COX-2 into proalgesic prostamides. Anandamide mobilizes in response to inflammation and nerve injury and modulates nociceptive signals by activating local CB1 receptors.