The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective phytocannabinoid Δ9-THC produces analgesia and potentiates opioid analgesia in animal models, CB2 ligands studies aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB2 receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This review is an update of our previously manuscript "A survey of recent patents on CB2 agonists in the management of pain" and provides an overview of patents and advances in CB2 agonist studies in the treatment of pain.