Leukotriene-receptor antagonists Leukotrienes are released from mast cells along with histamine. The medications, montelukast and zafirlukast block leukotriene receptors and can be used as add on treatment or in isolation for people with CU. It is important to note that these medications may be more beneficial for people with NSAID induced CU. Other Other options for refractory symptoms of chronic hives include anti-inflammatory medications, omalizumab, and immunosuppressants. Potential anti-inflammatory agents include dapsone, sulfasalazine, and hydroxychloroquine. Dapsone is a sulfone antimicrobial agent and is thought to suppress prostaglandin and leukotriene activity. It is helpful in therapy-refractory cases and is contraindicated in people with G6PD deficiency. Sulfasalazine, a 5-ASA derivative, is thought to alter adenosine release and inhibit IgE mediated mast cell degranulation, Sulfasalazine is a good option for people with anemia who cannot take dapsone. Hydroxychloroquine is an antimalarial agent that suppresses T lymphocytes. It has a low cost however it takes longer than dapsone or sulfasalazine to work. Omalizumab was approved by the FDA in 2014 for people with hives 12 years old and above with chronic hives. It is a monoclonal antibody directed against IgE. Significant improvement in pruritus and quality of life was observed in a phase III, multicenter, randomized control trial. Immunosuppressants used for CU include cyclosporine, tacrolimus, sirolimus, and mycophenolate. Calcineurin inhibitors, such as cyclosporine and tacrolimus, inhibit cell responsiveness to mast cell products and inhibit T cell activity. They are preferred by some experts to treat severe symptoms. Sirolimus and mycophenolate have less evidence for their use in the treatment of chronic hives but reports have shown them to be efficacious. Immunosuppressants are generally reserved as the last line of therapy for severe cases due to their potential for serious adverse effects. Research Afamelanotide is being studied as a hives treatment. Opioid antagonists such as naltrexone have tentative evidence to support their use. History The term urticaria was first used by the Scottish physician William Cullen in 1769. It originates from the Latin word urtica, meaning stinging hair or nettle, as the classical presentation follows the contact with a perennial flowering plant Urtica dioica. The history of urticaria dates back to 1000–2000 BC with its reference as a wind-type concealed rash in the book The Yellow Emperor's Inner Classic from Huangdi Neijing. Hippocrates in the 4th century first described urticaria as "knidosis" after the Greek word knido for nettle. The discovery of mast cells by