What Actually Causes Fibromyalgia? The Mitochondrial, Mast Cell, and Small Fiber Neuropathy Mechanisms Standard Treatment Misses — Why Lyrica and Cymbalta produce variable response

The pharmacological mechanism of pregabalin (Lyrica) is binding to the alpha-2-delta subunit of voltage-gated calcium channels in the CNS, reducing release of glutamate, norepinephrine, and substance P. This reduces the central pain amplification. It does not address the peripheral input. For patients whose central sensitization is being driven by ongoing peripheral input from any of the four drivers above, pregabalin reduces the amplification while the input continues. Response is partial. The pharmacological mechanism of duloxetine (Cymbalta) is serotonin and norepinephrine reuptake inhibition, increasing the activity of descending pain inhibition. This increases the brain's capacity to dampen incoming pain signals. It does not reduce the signal itself. Same outcome: partial response. Tramadol acts as both a weak opioid agonist and a serotonin/norepinephrine reuptake inhibitor. It addresses central processing without addressing peripheral input. Same outcome. Cyclobenzaprine, gabapentin, and other commonly prescribed medications operate similarly: downstream effects on pain processing without addressing the upstream lesions. Each is reasonable as containment. None addresses the lesion. This explains the partial response, the variable response, the response that decays over time, and the substantial side effect burden. The medications are doing what they are designed to do. Wh