Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome.

Background And Purpose: Therapeutic studies of the opioids in restless legs syndrome (RLS) are reviewed.

Patients And Methods: Opioids appear to be a good short and long-term treatment for RLS as shown in open-label, double-blind and long-term follow-up studies. However, the number of studies is more limited than for other therapeutic modalities in RLS such as dopaminergic agents. Furthermore, the one long-term study on the therapeutic effect of opioids on RLS published in full paper form is retrospective; prospective long-term studies are needed.

Results: Little addiction and tolerance were noted in any of the studies. Sleep apnea was not induced or exacerbated in short-term studies, but this was not the case in the long-term study. We have recommended that RLS patients treated with chronic opioid therapy be monitored clinically for the development of sleep apnea. Studies consistently show that the opiate receptor blocker naloxone reverses the improvement in RLS induced by the opioids, implicating the endogenous opiate system with its endorphins and enkephalins in the pathogenesis of RLS. Studies are mostly consistent in showing that naloxone does not worsen RLS symptoms in patients not treated with opioids. This result may be related to the differential ability of naloxone to antagonize exogenous opioids as opposed to endogenous opioids at the site of the opiate receptor. Naloxone does not block the therapeutic effect of dopaminergic agents on RLS symptoms, but dopamine receptor blockers do block the therapeutic effects of opioids on RLS symptoms. This suggests that the endogenous opioids act upon dopamine systems to improve the symptoms of RLS. Some of these receptor blocking studies are blinded and, in some cases, the results are dramatic. However, with one exception, there were limited numbers of patients studied with receptor blocking agents.

Conclusion: The results of such studies therefore need further verification. In addition, future studies should focus on other methodologies, such as opiate receptor PET scanning, that might further implicate the endogenous opiate system in the pathogenesis of RLS.