• Sergio Rosini, Stefano Rosini, Gianantonio Saviola, and Luigi Molfetta.
• Biomaterial Research Center, Livorno, Italy.
• Minerva Med. 2024 Aug 5.

AbstractThe complex regional pain syndrome type 1 (CRPS-1) is one of the most discussed painful syndromes due to the variability and severity of its symptoms. CRPS-1 generally occurs after a trauma, a fracture or a sprain followed by an immobilization. Classical diagnostic criteria are not always clear; hence, the diagnosis is difficult. The definition of CRPS itself defines and considers the pain as key symptom neglecting the bone damage. Early CRPS involves the activation of the innate cutaneous immune system with altered sensory and sympathetic signaling, activation and proliferation of keratinocytes and mast cells in addition to the release of inflammatory mediators and pain. The role of the immune system and the response to the disease is becoming clearer as the microglia is activated as a result of injury and can induce a central sensitization while astrocytes can maintain the process. Adenosine triphosphate (ATP) exerts a fundamental role in the activation of innate cutaneous immune system, in the proliferation of keratinocytes and mast cells, in the release of several proinflammatory cytokines and in the microglia activation. It is essential to intervene on this pathology as soon as possible with drugs, as clodronate, able to reduce bone marrow edema and pain through the inhibition of the primary inflammatory process and the immune reaction, limiting the activation of macrophages and the release of cytokines activating nuclear growth factor (NGF). In this review the role of ATP, bisphosphonates and rehabilitation are discussed.

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