Treatment of complex regional pain syndrome type I with bisphosphonates

Complex regional pain syndrome type I (CRPS-I) is a common and disabling disorder affecting a peripheral limb, usually developing after a trauma to an extremity. CRPS-I is characterised by presence of spontaneous pain, allodynia and hyperalgesia, disproportionate to the inciting event and by a variety of autonomic disturbances and trophic abnormalities. The pathophysiology of CRPS-I has not been fully understood. Experimental models have suggested that an initial triggering event may produce the release of proinflammatory neuropeptides and cytokines, generating a sort of neurogenic inflammation. Thereafter, increased microvascular permeability and intramedullary pressure, reduced oxygen extraction and cellular hypoxia maintain and make the disease worse, producing metabolic tissue acidosis. In this context, it is probable that, far from being a key player, the sympathetic nervous system contributes interacting with these mechanisms and producing vasomotor disturbances. Bisphosphonates (BPs) are potent inhibitors of osteoclastic activity widely used for the management of osteoporosis and other metabolic bone diseases. Their primary pharmacological action is the reduction of bone turnover. An enhanced osteoclastic activity has never been clearly demonstrated in CRPS-I. Therefore, it is likely that the positive effects of BPs in this condition are not related to their antiresorptive properties, but to a more complex interaction between these pharmacological agents and the pathophysiological mechanisms underlying CRPS-I. Results of several clinical trials have suggested the potential beneficial effects of BPs in CRPS-I. In five randomised controlled trials, oral and intravenous alendronate and intravenous clodronate, pamidronate and neridronate demonstrated to be effective in reducing pain and improving physical function in patients presenting with CRPS-I, with a good profile of safety and tolerability. Although these trials have a number of limitations, including the small samples enrolled, there is sufficient evidence to support the use of BPs as agents of choice in the management of CRPS-I.