Project Summary/Abstract Restless Legs Syndrome (RLS) is a movement disorder characterized by a powerful urge to move the legs, usually accompanied by unpleasant dysesthesias, precipitated by rest, relieved by movement, and most pronounced in the evening or at night. The primary morbidity of RLS is severe sleep disturbance, interfering with both falling and staying asleep as well as overall sleep quality due to the presence of periodic limb movements of sleep (PLMS). We have recently confirmed prior anecdotal reports that RLS symptoms are common among those experiencing both acute and protracted opioid withdrawal. “Restlessness” and “aching” dysesthesias are two of the core items in the subjective (SOWS) and clinician-administered (COWS) withdrawal scales - two primary tools used to assess the severity of opioid withdrawal. The mischaracterization of these restlessness symptoms narrowly as simply opioid withdrawal rather than RLS precludes treatment of these symptoms with established and efficacious approaches to RLS. It is not surprising that opioid withdrawal commonly produces RLS symptoms as opioids are an established effective treatment for refractory RLS. Opioid withdrawal symptoms are some of the most powerful factors driving the maintenance of opioid use disorder (OUD). Thus, appropriate RLS treatment may constitute a previously unrecognized modifiable risk factor for treatment of this devastating disorder. We hypothesize that effective treatment of RLS symptoms with the dopamine agonist pramipexole (an FDA approved medication for primary RLS) is an effective treatment for RLS symptoms in patients during protracted opioid withdrawal (e.g., stabilization after acute opioid detoxification). Further, we hypothesize that treatment of RLS in this context will improve overall symptoms of protracted opioid withdrawal, as assessed by the SOWS and COWS, and through this mechanism will improve patients' retention in sub-acute care, and successful referral to after-care. We propose a randomized double-blind placebo-controlled trial of pramipexole, an FDA-approved medication for RLS, in patients transferred to an inpatient opioid stabilization unit after acute post-opioid withdrawal. This will be the first controlled clinical trial of FDA-approved RLS treatment in protracted opioid withdrawal. If our hypotheses are correct, a potential new (and already FDA-approved) non-opioid treatment for a symptom known to affect relapse rate in OUD would be identified. Many OUD patients are aware that RLS symptoms are common during opioid withdrawal and may not begin detox to avoid these symptoms. Thus, effective treatment of these opioid withdrawal symptoms with pramipexole has the potential to reduce the overall burden of OUD by increasing initiation, engagement, and retention in treatment, and the probability of successful transition into longer-term treatment. Follow-up studies would include a multi-center trial of pramipexole treatment, assessing optimal treatment duration, and treatment effects on objective sleep metrics.

Narrative We have recently found that core opioid withdrawal symptoms in Opioid Use Disorder (OUD) include symptoms of Restless Legs Syndrome (RLS). This is not surprising since opioids are efficacious treatments for refractory RLS. We propose to test the use of pramipexole, a non-opioid dopaminergic agonist medication that is FDA approved for RLS, in patients being treated for OUD to test its ability to reduce symptoms of both RLS and protracted opioid withdrawal and thereby promote initiation, engagement, and retention in treatment.