Researchers reviewed evidence linking GLP-1 and GLP-1 receptor agonists to chronic pain modulation through gut microbial, neuroimmune, vagal, and metabolic pathways, with the strongest clinical evidence currently involving knee osteoarthritis and idiopathic intracranial hypertension headache. Much of the proposed biology remains supported by preclinical research, and human studies have yet to establish that GLP-1RA-induced changes in the gut microbiome directly cause pain relief.