Restless Legs Syndrome Foundation Blog

The 2022 CDC Opioid Prescribing Guidelines released on November 3, 2022, replace earlier guidelines that had led to confusion, misinterpretation, and faulty application by medical providers. Like the 2016 guidelines, the new guidelines focus on acute, subacute, and chronic pain.

Unfortunately, the new Guidelines fail to recognize that restless legs syndrome (RLS), a serious disease affecting millions of Americans, can only be relieved by daily small doses of opioids in many cases. This omission is surprising in light of the fact that the guidelines call out three medical conditions (sickle cell disease, cancer, or end-of-life care) that may require sustained doses of opioids. RLS, like these three conditions, should have an exemption from this Guideline.

RLS Foundation Board Member and Chair-Elect, Dr. Shalini Paruthi says, “RLS symptoms can occur anywhere along the spectrum from an urge to move the limbs to a painful sensation. RLS can be a chronic disorder for many people. Furthermore, patients with RLS face significant impacts on physical health, mental health, access to care and barriers to treatment. These health disparities disproportionately affect individuals with refractory RLS who require daily medical treatment. The RLS ODYSSEY II study found a four-fold risk for depression and suicidal ideation in patients with RLS, signifying the heavy burden of disease in this population.”

We are disappointed to learn that RLS was not included in the exemption of medical conditions, given the scientific validation of population prevalenceⁱ, strong genetic basisⁱⁱ and impacts on health-related quality of lifeⁱⁱⁱ.

RLS Foundation Scientific and Medical Advisory Board Chair, Dr. Christopher J. Earley says, “These guidelines have the potential to affect the 1 in 33 Americans with severe RLS who require daily medical treatment. Patients with moderate to severe RLS live every day with awareness of the burden of this disease; forever conscious of the limitations and barriers to appropriate and effective treatment.” Many RLS patients have experienced the negative consequences of the prior CDC Opioid Prescribing Guidelines as they find physicians and pharmacists unwilling to prescribe or supply the only medications that bring them relief. Without explicit mention of RLS in the new guidelines, they fear that federal and state agencies will use the revised guidelines to continue to deny them treatment.

The new guidelines are an improvement from those they replace, recognizing that no “one-size fits all approach” is appropriate and that provider clinical judgment is fundamental to making decisions on the use of opioids to manage pain.

The RLS Foundation and its Science and Medical Advisory Board will sharpen and clarify the recommendations to minimize their impact on long-term prescriptions of opioids to treat refractory RLS. In the interim, we urge members to report any problems they face in maintaining a relationship with their healthcare provider and/or obtaining prescription access to opioid therapy to manage refractory RLS. We ask that you provide your contact information and permission to use your experience to explain to policymakers the barriers facing the RLS community.

The RLS Foundation thanks the nearly 500 individuals that responded to the call to action during the public comment period on the proposed draft of the 2022 CDC Opioid Prescribing Guidelines. We are disappointed by the CDC’s lack of an exemption for RLS and plan to accelerate our advocacy efforts on Capitol Hill to ensure patients with refractory RLS have appropriate treatment access to opioid therapy. The RLS Foundation will continue to provide updates on our outreach activities and opportunities for you to voice your concerns with public officials in Washington, DC and at the CDC.

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New Study Funded by RLS Foundation

By Kris Schanilec

The RLS Foundation has awarded a grant of $36,398 to Sergi Ferré, MD, PhD, of the National Institute on Drug Abuse, for a study to explore how opioid medications work in the brain to relieve RLS symptoms. This research builds on several Foundation-funded studies previously conducted by Dr. Ferré, who is a member of the RLS Foundation Scientific and Medical Advisory Board.

“Dopamine agonists, alpha-2 delta agents and opioids are highly effective in treating RLS,” says Christopher J. Earley, MB, ChB, PhD, FRCPI, chair of the Scientific and Medical Advisory Board. “Dr. Ferré’s grant is the first to try and understand the biologic elements that may be common to these three classes of drugs that makes them so effective in treating RLS, thus opening the door for future drug development.”

Opioid medications act on three types of opioid receptors in the brain. One of these – the mu opioid receptor – is the target of the opioid medications, such as methadone, that are a very effective treatment for severe RLS when used in low total daily doses. RLS is a neurological disease that has a distinctly different underlying neuropathology than that associated with typical pain syndromes. Clinical experience among experts who use opioids to treat severe RLS has not shown the degree of drug misuse, dependency or addiction that is commonly associated with opioid use to treat chronic pain.*

In the current study, “Elucidating the mechanisms of the therapeutic effects of opioids in RLS,” Dr. Ferré’s team aims to identify the locations of mu opioid receptors involved in improving RLS symptoms with opioids. With this information, they hope to determine if specific opioid medications could selectively act on these mu opioid receptors, reducing the risk of unwanted side effects.

In previous studies funded by the RLS Foundation, Dr. Ferré’s laboratory developed an animal model for RLS using a brain iron-deficient rodent that models the brain iron deficiency that is characteristic of RLS in humans. Their model combines two techniques, optogenetics and microdialysis, to trigger and measure the release of glutamate from brain cells in live animals. The researchers used this model to confirm that brain iron deficiency increases the release of glutamate in the brain area known as striatum; other studies have reported increased glutamate in the RLS brain.

Dr. Ferré’s team also validated that several RLS drugs – the dopaminergic drugs pramipexole and ropinirole, and the alpha- 2-delta ligand gabapentin – work by counteracting this high release of glutamate. In addition, the researchers pinpointed a subtype of receptor in the brain – the dopamine D4 receptor – as a main target for the effects of the dopaminergic drugs in the striatum, and therefore, as a new target for drug development.

In a more recent study, Dr. Ferré’s laboratory reported that low levels of receptors of the neurochemical adenosine are responsible for the high levels of glutamate released in the striatum. This finding has led to exploration of drugs that increase adenosine levels in the brain – for example, dipyridamole – as a new treatment approach for RLS. According to Dr. Ferré, the reduced levels of adenosine receptors (specifically, the adenosine A1 receptors) may be the underlying cause of not only restless legs, but also the state of enhanced wakefulness (hyperarousal) experienced by people who have RLS.

In the current study, the researchers will focus on a specific neuron in the striatum, the cholinergic interneuron, which releases the neurotransmitter acetylcholine and has a high number of both adenosine A1 receptors and mu opioid receptors. The researchers hypothesize that in RLS, there are fewer adenosine A1 receptors in these cholinergic interneurons, which therefore become overactive and release more acetylcholine. The researchers also hypothesize that opioids should be able to counteract this by activating mu opioid receptors in the cholinergic interneurons. Dr, Ferré’s team will use its animal model to explore these questions.

“If the results of the study confirm our hypotheses, we will have probably found the main mechanism of the therapeutic effect of opioids in RLS,” says Dr. Ferré. “Those results would then stimulate the search for opioids with a preferential efficacy for the mu opioid receptors localized in the striatum, in the cholinergic interneurons, which should be absent of unwanted side effects.”

The RLS Foundation is grateful for the generosity of individuals whose financial gifts make this work possible, says Executive Director Karla Dzienkowski. “The Foundation’s research grant program is dedicated to find better treatments and, ultimately, a cure for RLS. This study will help us to understand why opioid medications are effective at relieving severe, unrelenting symptoms of restless legs syndrome, which will lead to an improved quality of life for people with RLS,” Dzienkowski says.

*If opioid therapy is a treatment option to manage your RLS symptoms, your healthcare provider will work closely with you to find the dose that manages your symptoms while minimizing side effects of therapy.