Restless legs syndrome, neuroleptic-induced akathisia, and opioid-withdrawal restlessness: Shared neuronal mechanisms?

Restlessness is a core symptom underlying restless legs syndrome (RLS), neuroleptic-induced akathisia and opioid withdrawal. These three conditions also share other clinical components suggesting some overlap in their pathophysiology. Recent prospective studies demonstrate the frequent incidence of RLS-like symptoms during opioid withdrawal and supervised prescription opioid tapering. Based also on the therapeutic role of µ-opioid receptor (MOR) agonists in the three clinical conditions and recent pre-clinical experimental data in rodents, we provide a coherent and unifying neuropathological basis for the restlessness observed in these three clinical syndromes and propose a heuristic hypothesis of a key role of the specific striatal neurons that express MORs in akathisia/restlessness.