The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study

Opioids have been shown to provide symptomatic relief from dysaesthesias and motor symptoms in restless legs syndrome (RLS). However, the mechanisms by which endogenous opioids contribute to the pathophysiology of RLS remain unknown. We have studied opioid receptor availability in 15 patients with primary RLS and 12 age-matched healthy volunteers using PET and [11C]diprenorphine, a non-selective opioid receptor radioligand. Ligand binding was quantified by generating parametric images of volume of distribution (V(d)) using a plasma-derived input function. Statistical parametric mapping (SPM) was used to localize mean group differences between patients and controls and to correlate ligand binding with clinical scores of disease severity. There were no mean group differences in opioid receptor binding between patients and controls. However, we found regional negative correlations between ligand binding and RLS severity (international restless legs scale, IRLS) in areas serving the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex and orbitofrontal cortex). Pain scores (affective component of the McGill Pain Questionnaire) correlated inversely with opioid receptor binding in orbitofrontal cortex and anterior cingulate gyrus. Our findings suggest that, the more severe the RLS, the greater the release of endogenous opioids within the medial pain system. We therefore discuss a possible role for opioids in the pathophysiology of RLS with respect to sensory and motor symptoms.