Mast cell stabilizer ketotifen fumarate reverses inflammatory but not neuropathic-induced mechanical pain in mice

Supplemental Digital Content is Available in the Text.Our preclinical findings indicate that ketotifen fumarate's analgesic effects are MC-dependent, and the case series report presented supports its use for the treatment of chronic pain. Introduction:Mast cell (MC) activation could establish a positive feedback loop that perpetuates inflammation and maintains pain. Stabilizing MCs with ketotifen fumarate (KF) may disrupt this loop and relieve pain.Objective:We aimed to test the effect of treatment with KF in pain assays in mice and in a case series of patients with chronic widespread pain.Methods:The analgesic effect of KF was tested in CD-1 mice injected with formalin, complete Freund's adjuvant, or subjected to spared nerve injury. In addition, wild-type (C57BL/6) and MC-deficient (C57BL/6-KitW-sh/W-sh) mice were injected with formalin or complete Freund's adjuvant and treated with KF. Patients with chronic widespread pain (n = 5; age: 13-16 years) who failed to respond to standard of care participated in a 16-week treatment trial with KF (6 mg/d). Ketotifen fumarate's therapeutic effect was evaluated using the patient global impression of change.Results:In the mouse experiments, KF produced dose- and MC-dependent analgesic effects against mechanical allodynia in the acute and chronic inflammatory pain but not neuropathic pain assays. In the patient case series, 4 patients reported that activity limitations, symptoms, emotions, and overall quality of life related to their pain condition were "better" or "a great deal better" since beginning treatment with KF. This was accompanied by improvements in pain comorbid symptoms.Conclusion:Treatment with KF is capable of reducing established inflammatory-induced mechanical nociception in an MC-dependent manner in mice, and it may be beneficial for the treatment of chronic pain conditions.