What Actually Causes Fibromyalgia? The Mitochondrial, Mast Cell, and Small Fiber Neuropathy Mechanisms Standard Treatment Misses — The clinical pattern that defines treatment-resistant fibromyalgia

A patient presents with widespread musculoskeletal pain that has progressed over years, fatigue that is profound and unrefreshing despite sleep, cognitive dysfunction that the patient calls "fibro fog," sleep that feels disrupted even when duration is adequate, sensitivities to light, sound, temperature, and chemical exposure, and a constellation of overlapping conditions that include irritable bowel syndrome, migraine, restless legs, anxiety, and depression. The diagnostic journey has typically taken 5 to 10 years and involved multiple specialists. Rheumatology workup has ruled out connective tissue disease. Neurological workup has ruled out demyelinating disease. The fibromyalgia diagnosis arrives by exclusion, often with the implicit message that the workup has not found anything organic and the symptoms are largely psychological. The treatment cascade follows the standard guidelines. Pregabalin (Lyrica). Duloxetine (Cymbalta) or milnacipran. Cyclobenzaprine for sleep. Tramadol for pain breakthroughs. Cognitive behavioral therapy. Graded exercise. Sleep hygiene education. Mindfulness-based stress reduction. Some patients respond meaningfully to this combination. Many do not. The clinical trials of pregabalin and duloxetine in fibromyalgia show modest effect sizes; approximately 30 to 40 percent of patients achieve a 30 percent reduction in pain in randomized trials. That mea