April 24, 2023

Help! I Think I Have Augmentation and Don’t Know What to Do!

Each day at the RLS Foundation we receive calls from individuals seeking support, information and help with augmentation, a distressing challenge to their RLS treatment.

The good news is that, thanks to ongoing research, augmentation is manageable and treatment options are available. This article provides an overview of augmentation that will help you to understand this unfortunate side effect of treatment and the available strategies to manage it.

What is Augmentation?

Augmentation is a worsening of RLS symptoms that occurs after starting a medication that increases dopamine levels in the brain. These dopaminergic medications include levodopa/carbidopa, ropinirole, pramipexole and the rotigotine patch. At first, medications in this category are very effective, but over time, in a period from six months to several years, RLS symptoms worsen from what they were prior to initiating therapy. The rate of augmentation in people taking dopamine drugs for RLS is 5%- 10% per year; in eight years nearly half of individuals taking dopaminergic medication will experience augmentation.

If an individual with RLS notices symptoms progressively worsening after starting treatment with a dopaminergic drug, then augmentation may be occurring. Simply put, the treatment initially prescribed to alleviate symptoms is worsening the disease.

What are the Symptoms of Augmentation?

Augmentation is an insidious process, and symptoms often go unnoticed. The first indication of an underlying problem is when a patient feels the need to request an increase in medication dose.

All individuals with RLS should recognize the symptoms of augmentation, which include:

• Earlier onset of symptoms, beginning in the afternoon and evening, rather than at bedtime
• Increase in the intensity of symptoms compared to their level prior to starting treatment
• Spread of symptoms to other body parts (trunk, arms or face), rather than being limited solely to the legs
• Shorter period of rest or inactivity before symptoms begin, and treatment medication is not working as long as it did previously
• Loss of effectiveness of the medication at the dose that previously managed symptoms
• Paradoxical response to the medication; in other words, the prescribed medication triggers symptoms rather than alleviating them

Three factors predispose an individual with RLS to developing augmentation:

• Daily administration of carbidopa/levodopa to treat RLS
• Exceeding the maximum dosages approved by the Food and Drug Administration (FDA) for dopaminergic drugs used to treat RLS
• Low body iron stores as measured by a laboratory test of serum ferritin

When someone is experiencing augmentation, aggressive iron supplementation is extremely important. Intravenous formulations effective in raising blood iron storage levels in RLS patients include: Ferumoxytol (Feraheme); low molecular iron dextran (INFeD); ferric derisomaltose (Monoferric) and ferric carboxymaltose (Injectafer). Ferrous sulfate 365 mg pills taken once daily can be used for ferritin levels higher than 75–100 mcg/L or transferrin saturation less than 20%. However, RLS patients with deteriorating symptoms need rapid iron repletion, and oral iron takes months to improve iron status.

If you, as a patient, suspect augmentation, the first course of action is to make an appointment with your healthcare provider; do not stop taking the medications, as prescribed, to manage your RLS.

How is Augmentation Diagnosed?

Before a diagnosis of augmentation can be made, the first step is to schedule an appointment with your RLS healthcare provider for a thorough medical examination to rule out any underlying medical conditions that can exacerbate RLS symptoms. Two additional aspects of RLS that are often confused with augmentation are night-to-night variability of symptoms and exacerbation of symptoms for several days; neither is indicative of augmentation.

Factors that can worsen RLS include the use of sedating antihistamines; all antidepressants except for bupropion or trazadone; low body iron stores or unexpected blood loss due to surgery or undiagnosed gastrointestinal bleeding (ulcers, polyps); commonly reported triggers of symptoms such as caffeine, alcohol, sugar, salt or nicotine; a secondary undiagnosed sleep disorder such as sleep apnea; or rebound (the prescribed medication is not lasting as long as it did previously and disrupts sleep at the end of the sleep cycle in the early morning hours). Two additional factors that can cause an increase in RLS symptoms are stress and changes in activity level, such as immobility due to surgery or changes in exercise, activity or routines.

Augmentation Diagnosis: What’s Next?

RLS is a chronic progressive disease, and it is often difficult to distinguish between disease progression (natural worsening of the disease) and augmentation. Healthcare providers need to be aware of the key indicators of augmentation, which include:

• The patient requests a dose increase of a dopaminergic medication.
• The prescribed dose currently exceeds FDA maximums for the dopaminergic medication.
• The patient reports breakthrough RLS symptoms with an accompanying increase in symptom intensity.
• The RLS involves other body parts (trunk, arms, face).
• Symptoms occur 24/7.
• Symptoms previously appearing only in the evening or nighttime now present earlier in the day, and the patient requests additional medication doses earlier in the day.

There is no test for the diagnosis of RLS augmentation. A thorough medical examination by your healthcare provider who reviews current medications (over-the-counter medications, supplements, prescriptions) to look for drugs that can worsen RLS symptoms, along with a comprehensive history of symptom progression, will help to determine if augmentation is present.

How is Augmentation Managed?

There are four treatment strategies to manage RLS augmentation. Working with your doctor you can determine the approach that best works for you.

The first approach involves changing the dosing schedule to “split-dose” the dopaminergic medication. Half the dose of the medication is given earlier in the day, and the second half is given at the regularly scheduled time; the total dose is not to exceed FDA maximums. If this approach does not resolve symptoms, a second medication from another medication class is added to the treatment regimen. Alpha-2-delta ligand drugs such as gabapentin, gabapentin enacarbil, and pregabalin are added to the treatment plan while reducing the dose of the dopaminergic agent. This approach may be effective, but the alpha-2-delta ligands may not be sufficient to control RLS symptoms in the absence of the dopaminergic agents.

A second treatment option to manage augmentation is to switch from a short-acting dopamine agonist to a long-acting one, but this approach is not recommended by RLS experts. The FDA approved the Neupro (rotigotine) patch for the treatment of RLS, and the oral medications pramipexole ER and ropinirole XL are also available. There are no studies to determine if the change to a long-acting dopamine agonist will reduce or mask RLS symptoms. RLS experts have found that tapering off long- acting dopamine agonists with preexisting augmentation is considerably more difficult. Although symptoms improve in the short term, the underlying augmentation remains, and in time symptoms will return.

The third approach involves adding an opioid medication such as buprenorphine, suboxone, methadone or oxycodone to the dopamine agonist, then tapering down the dopamine agonist. Once the transition from dopamine agonist to opioids has occurred, the dose of the opioid is reduced. If symptoms persist, an alpha-2-delta ligand can be added to the treatment protocol, or it can be used to decrease the dose of opioid used.

The final approach to address augmentation is to slowly decrease the dose of the dopamine medication, without any other RLS treatment, followed by 12 drug-free nights before reassessing the need for further treatment. The RLS Foundation handout Drug Holidays and RLS provides a thorough outline of this approach to the treatment of augmentation.

For patients with severe augmentation who have taken high dopamine medication doses, it may be difficult to completely eliminate these drugs, due to the worsening of RLS upon withdrawal. A small dose of a dopamine drug in combination with an alpha-2-delta ligand and/or opioid may be necessary to manage symptoms. However, it is important to note that, once a dopamine drug is successfully discontinued, reintroducing any drug in the dopamine class will lead to a rapid reappearance of augmentation. In other words, all drugs in the dopamine class are no longer a treatment option.

How Do I Find a Provider to Manage RLS Augmentation?

A provider who is knowledgeable and experienced in treating RLS can be found at an RLS Foundation Quality Care Center. The doctors who practice at these centers are certified RLS providers who treat patients with augmentation and are familiar with the available treatment options. There are 10 RLS Foundation Quality Care Centers in the United States and two in Europe; travel to receive expert care is an option available to individuals with RLS, though not all patients can afford to do so. For a list of RLS Foundation Quality Care Centers, visit www.rls.org/QCC or contact the Foundation.

A second option is to work with the healthcare provider managing your RLS treatment. You will want to determine that they have experience in managing augmentation and are willing to work with you through the entire process. Finding a treatment plan to manage your RLS augmentation is not a one- size-fits-all approach, so finding a provider who is willing to work with you is essential.

The RLS Foundation maintains a list of providers who have expressed an interest in treating RLS, and this may be an option for you. To view this list, visit www.rls.org/Find-a-doc or contact the Foundation. However, these healthcare providers are not certified RLS experts like those practicing at an RLS Quality Care Center.

I Think I Have Augmentation. What Can I Do to Help Myself?

You can do several things before an appointment with your healthcare provider that will give them insight into the state of your RLS. Below is a helpful checklist of items to prepare you for your appointment:

1. Resist the urge to make any changes to your current treatment plan. Your healthcare provider needs to get a clear picture of your RLS symptoms under your current treatment plan; any changes could make this more difficult.
2. Schedule an appointment with your healthcare provider as soon as possible. Because scheduling delays are common, ask whether your name can be added to a cancellation list when you book your appointment. That way, if there is a cancellation, you may be called to fill the slot in the schedule.
3. Make a list of all medications that you currently take (prescriptions, over-the-counter medications, supplements).
4. Make a chronological list of all medications that you have taken in the past for RLS and note why you stopped taking them.
5. Gather copies of all laboratory test results for iron, and any other recent laboratory test results for your provider to review.
6. Complete an RLS Sleep Diary, included in this issue of NightWalkers. The Sleep Diary will provide your healthcare provider with an overview of your sleep patterns and RLS symptoms.
7. Make and bring copies of the following open-access articles from Mayo Clinic Proceedings: “The Management of Restless Legs Syndrome: An Updated Algorithm” (2021) and “The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome” (2018). For copies of these articles, visit www.mayoclinicproceedings.org or contact the Foundation.

For more information about augmentation and RLS, visit the RLS Foundation’s Member Portal on www.rls.org to find educational resource materials. We invite you to attend the Foundation’s monthly webinar series presented by RLS experts and to watch past webinars online to become more knowledgeable about RLS. The Foundation also sponsors four monthly online Virtual Support Group Meetings, so you can connect with others in the RLS community for support, tips and helpful information.

July 26, 2022

The drug ecopipam shows promise for bringing relief to RLS patients who develop augmentation, a common side effect of dopamine medications.

Stefan Clemens, PhD, HdR, a professor of physiology at East Carolina University, is a member of the RLS Foundation’s Scientific and Medical Advisory Board, and chair of the Foundation’s Research Grant Committee. Regarding the worsening of RLS symptoms known as augmentation, Clemens developed the hypothesis, “Augmentation may be a consequence of increased D1-receptor activation in the nervous system” and that “identifying a new pharmacological target that specifically tackles the long-term side effects of standard dopaminergic treatments in RLS may keep the treatments effective for a longer time or avoid augmentation altogether.”

In other words, a dopamine-1 (D1)-receptor antagonist medication might be a new way to treat RLS and the symptoms of augmentation.

This new concept was first presented by Clemens and his group at the 2015 meeting of the International Restless Legs Syndrome Study Group. In 2016, a small pilot study funded by the RLS Foundation and performed by William Ondo, MD, suggested a positive clinical outcome when patients with RLS augmentation took ecopipam, a D1- receptor antagonist drug.

Clemens obtained a US patent for ecopipam to treat RLS augmentation, and East Carolina University has entered into a licensing agreement with Emalex Biosciences to study this first-in-class medication.

Many regular readers of NightWalkers know the basic facts about RLS treatments and the risks of augmentation, but a bit of history is useful to understand the importance of the new approach. For the 7% to 8% of the adult US population affected by RLS, some 3% need regular daily medication to control their symptoms. The Food and Drug Administration (FDA) has approved three dopaminergic drugs (pramipexole, ropinirole and rotigotine patch) for the treatment of RLS, and for decades these medications were considered first-line therapies for RLS.

Unfortunately, recent research has shown that of the patients on dopaminergic drugs, 7-8% per year develop augmentation so that by 10 years, almost 80% will be augmented and will experience a worsening of their symptoms caused by the drugs themselves. Augmentation typically includes an earlier onset of symptoms, an increase in intensity, a shorter period of rest or inactivity before symptoms start, and the involvement of other body parts (arms, torso or face). There are no FDA-approved medications for the treatment of RLS augmentation.

New clinical guidelines published in 2021 in the Mayo Clinic Proceedings no longer recommend dopaminergic drugs, but rather name iron and alpha-2 delta-ligands, such as gabapentin, first–line treatments for RLS. When a patient’s RLS becomes unresponsive to first- or second–line therapies due to augmentation or other side effects, it is considered refractory (resistant to treatment), and a low-total-daily-dose opioid therapy is the only option currently available. That is why new approaches and new drug therapies are urgently needed.

According to Clemens, ecopipam works by selectively blocking the dopamine D1-receptor subtype, whereas other dopaminergic medications that are used to treat RLS activate other dopamine receptor classes, in particular D3 and D2 subtypes. D3 and D2 receptors mediate inhibitory actions in the nervous system, meaning that they reduce excitability and thus reduce RLS symptoms. Over time, however, those effects wane and the nervous system responds with an upregulation of the D1-receptor subtype, the target of this new drug. In contrast to D3 and D2 receptor-mediated actions, the D1- receptor subtype mediates excitatory action in the nervous system, thus increasing its excitability and increasing the severity of the symptoms. The new drug, ecopipam, is thought to reduce the activation of the D1 receptor and in turn decrease the severity of augmentation symptoms.

The RLS Foundation’s executive director, Karla Dzienkowski says, “RLS augmentation is an untoward side effect of dopaminergic therapy. The potential for a new treatment for this side effect gives hope for the future for those living with the daily impacts of RLS augmentation. It could be a game changer.”

Dopamine Agonists and the Worsening of RLS Symptoms

Augmentation, as many with restless legs syndrome know, is one of the most common and least understood problems with current RLS treatment. This phenomenon occurs after a patient starts a dopaminergic medication to treat their RLS - and over time it can make symptoms much worse.

Unfortunately, many who initially start on dopaminergic medications say that it is extremely effective in alleviating symptoms, at first. It may take years for augmentation to kick in, or just mere months. Warning signs of augmentation include an increase in symptom intensity, a shorter period of rest or inactivity before symptoms begin, an appearance of symptoms earlier in the day, or a return to what symptoms were like prior to starting treatment (worsening of symptoms). Many also report experiencing RLS symptoms that spread to their arms, trunk or even the face.

"Augmentation is a condition where RLS symptoms start to worsen after initially improving, while on dopamine agonist treatments such as pramipexole, ropinirole, rotigotine, and levodopa," said Dr. William Ondo, director of the Houston Methodist Neurological Institute RLS Quality Care Center. "Since most patients with an urge to move initially respond to properly dosed dopaminergic medicines, augmentation is arguably the biggest practical impediment to successful chronic management of RLS."

In 2015, to combat this gap in information and awareness, the RLS Foundation rolled out a far-reaching "Year of Augmentation" awareness and education program. This included distributing and promoting an augmentation consensus white paper, a collaboration between the International Restless Legs Study Group, the European Restless Legs Study Group and the RLS Foundation. The white paper was distributed by the RLS Foundation to nearly 50,000 US healthcare providers. Foundation volunteer support group leaders were provided with informational "augmentation toolkits" for their meetings. The RLS Foundation also released its first ever long-form video, RLS and Augmentation , which has been viewed by over 10,000 people.

If you think you may be experiencing augmentation, there is help. The Foundation's free What is Augmentation? handout discusses several approaches used to manage augmentation. Prior to making any changes in your treatment plan, it is important consult your healthcare provider to determine if you have augmentation and the treatment approach best suited for you. If you think that your doctor may lack an understanding of RLS, you can find an RLS Quality Care Center or RLS healthcare provider near you. You can also view and share the "Prevention and Treatment of Augmentation" webinar, presented by Dr. Mark Buchfuhrer of Stanford Sleep Medicine Center (an RLS Quality Care Center), from the Foundation's 2017 Webinar Series, available for free on our YouTube channel.

In the days since augmentation first surfaced, significant strides have been made. In 2016, Dr. William Ondo was awarded a $37,000 grant from the RLS Foundation's Research Grant Program to study a new treatment modality for RLS patients who are augmenting. His research team is currently recruiting subjects in Houston, Texas, to study the effectiveness of a new therapy specifically to RLS patients who are currently suffering from augmentation while still taking dopamine agonist medications. Learn more about how to participate here.

If you need additional information on augmentation, please call the RLS Foundation at 512-366-9109 or email info@rls.org and we will be happy to assist you. You are not alone!

New Approach to Treat Augmentation

The RLS Foundation's Scientific and Medical Advisory Board (SMAB) recently approved funding for a research proposal by Dr. William Ondo of Houston Methodist Neurological Institute, an RLS Quality Care Center.

After a rigorous selection process, the committee approved Dr. Ondo's grant for Foundation funding for a research study. Dr. Ondo explains:

"Augmentation is a condition where RLS symptoms start to worsen after initially improving, while on dopamine agonist treatments such as pramipexole, ropinirole, Neupro, and levodopa. Since most patients with an urge to move initially respond to properly dosed dopaminergic medicines, augmentation is arguably the biggest practical impediment to successful chronic management of RLS.

"The exact mechanism of augmentation is not known, however, based on animal studies we performed, we hypothesize that it is caused by increased activity of dopamine type I (D1) receptors. In animal models these receptors in the spinal cord increased when mice models of RLS were chronically treated with typical dopamine drugs, specifically pramipexole. Dopamine type I receptors have many features which are the exact opposite of dopamine type 2 (D2) and 3 (D3) receptors in the spinal cord. The dopamine medicines still stimulate these D1 and the D2/D3 receptors, which we feel results in the contradictory effect that they both improve and worsen RLS at the same time.

"We have identified an investigational drug which blocks D1 receptors without blocking D2 and D3 receptors, ecopipam. In this small trial, we will administer this drug in a blinded manner to patients already on dopamine medications who have augmentation, to see if it can reverse the augmentation and improve their symptoms."

Dr. Ondo serves as director of the Movement Disorder Clinic at the Houston Methodist Neurological Institute. Throughout his career, Dr. Ondo has written more than 250 articles and book chapters. A movement disorder specialist, he is board certified in adult neurology and sleep medicine. Dr. Ondo's research specializes in Parkinson's disease, essential tremors, the use of botulinum toxins in treating movement disorders, and restless legs syndrome. At the RLS Foundation, Dr. Ondo is an active member of the SMAB Opiates Committee.

“Dr. Ondo’s proposal presents an exciting opportunity to investigate a new approach to treat RLS augmentation," says RLS Foundation Executive Director Karla Dzienkowski. "As the only organization with a dedicated RLS Research Grant Program, it is our hope that research like Dr. Ondo’s will lead to new and better treatments and one day, a cure for patients living with RLS.”

Since its inception in 1997, The RLS Foundation's research grant program has funded nearly $1.6 million in competitive research grants for the study of restless legs syndrome. In 2016, the Foundation committed to develop this program even further by:

• Increasing research funding to $200,000 annually for up to eight pilot grants
• Accepting grant proposals on a continual basis, rather than just once per year, using a rigorous NIH review to evaluate grant proposals
• Providing counsel to RLS Foundation grant seekers to improve the strength and outcomes of their research studies
• Identifying potential sources (NIH) of later-stage funding for grantees
• Expanding the reach to biotech and medical technology companies as collaborators that can help achieve progress toward a cure

Interested in applying for a research grant on RLS? Read about the guidelines and application here.

Awareness and Education

The RLS Foundation Surpasses Goals for the Year

Nearly 25 years ago, the Foundation began as a tiny group of dedicated individuals meeting around a kitchen table in Raleigh, North Carolina. We grew to become a bustling organization located in Austin, Texas, with an expansive network of nearly 5,000 dedicated members.

Since its inception, the Foundation has provided over $1.6 million in support of RLS research, and we are still the leading organization for science-based education and patient services for those suffering from RLS.

Just consider what we have accomplished over the past 12 months alone:

1. Certified five additional RLS Quality Care Centers

2. Reinvigorated our research grant program by committing to award up to eight new pilot grants totaling $200,000

3. Developed a teen guide and children’s booklet to help our youth manage the challenges of RLS

4. Created a multidisciplinary Scientific and Medical Advisory Board

5. Launched research into the economic impact of RLS and its treatment

6. Rolled out a far-reaching Year of Augmentation awareness and education program – distributing and promoting an augmentation white paper research summary to nearly 50,000 healthcare providers

The Foundation also created a support group leader "RLS and Augmentation" tool kit, and released our RLS and Augmentation video, which has already been watched by thousands.



The Foundation has also been active in educating the medical community this year by attending SLEEP, a joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society, in Denver, Colorado. We were also present in November at the annual conference for the Society of Neuroscience in San Diego. Both events attract thousands of researchers and healthcare providers that are eager to learn more about RLS and other sleep disorders.


We are so proud of all we have accomplished this year on behalf of the RLS community, but we could not have done any of it without the generous donations given by both members and nonmembers alike. Together, we have hit incredible milestones - big achievements executed by a small staff and a network of dedicated volunteers.

To everyone who has helped us get to where we are, we thank you!

The RLS Foundation is proud to share this important project to educate others about RLS and augmentation.  Hear from RLS experts who practice at certified RLS Quality Care Centers across the US, as well as some of our foundation members and volunteers as they discuss the challenges they face every day in their journey with RLS.