# Treatment of Restless Legs Symptoms with Pramipexole to Improve the Outcomes of Protracted Opioid Withdrawal in OUD: A Pilot Double-blind, Randomized Clinical Trial

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $252,000

## Abstract

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 trea...

## Key facts

- **NIH application ID:** 10110984
- **Project number:** 1R21DA052861-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** John W Winkelman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $252,000
- **Award type:** 1
- **Project period:** 2021-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110984

## Citation

> US National Institutes of Health, RePORTER application 10110984, Treatment of Restless Legs Symptoms with Pramipexole to Improve the Outcomes of Protracted Opioid Withdrawal in OUD: A Pilot Double-blind, Randomized Clinical Trial (1R21DA052861-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10110984. Licensed CC0.

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