Restless Legs Syndrome Foundation Blog

Progress Report #12: National RLS Opioid Registry

Relevance:

This project continues to be relevant to the Restless Leg Syndrome Foundation’s mission to improve the quality of life for those living with RLS. The National RLS Opioid Registry is collecting much-needed data on the efficacy and safety of long-term opioid treatment for RLS. Opioids have been shown to successfully treat the symptoms in patients with severe RLS, even when current approved treatments lost effectiveness; however, there is a lack of concrete data to support opioids as a treatment option. Given the current overdose crisis, data on the efficacy and safety of opioids for the treatment of RLS is needed so that providers and patients can make informed treatment decisions, especially in the face of increasingly strict opioid regulations.

Research Goals and Methodology:

By asking questions about specific opioid dosages over time (including the first stable dose) and validated questions about RLS severity (IRLS, RLS-QLI), we aimed to assess the efficacy of opioid medications in the treatment of RLS. By asking questions about specific side effects over time, we aimed to assess the tolerability and safety of opioid medications. By obtaining a medical and psychiatric history, a list of concomitant medications, and information on habits, behaviors, and mood, we aimed to further understand how these factors may influence the efficacy and safety of opioid medications in this population.

We originally set a goal to enroll 200 subjects within 2 years. We surpassed that goal, having enrolled 502 subjects. Enrollment was closed in September 2019. Upon enrollment, participants completed a phone interview lasting approximately 45 minutes. Information about RLS symptoms, past and current medications, specific dosages, and opioid side effects was collected during this interview, in addition to more sensitive information related to psychiatric conditions and opioid risk factors.

After the phone interview, participants were sent an online survey that took approximately 15 minutes to complete and was completed within 7 days of the phone interview (extensions were given under certain circumstances). This online survey collected information on medical history, sleep behavior, habits, recreational drug use, and mood. A total of 500 of 502 enrolled subjects completed the baseline survey. Every 6 months following the initial enrollment interview, participants are sent a follow-up survey that takes approximately 20 minutes to complete. The follow-up survey consists of a combination of questions from the baseline phone interview and baseline online survey, and it should be completed within 7 days. The links to access both the baseline and follow-up online surveys are sent to personal email addresses.

Recruitment

We recruited participants from established RLSF Quality Care Centers around the country, and via RLSF circulated media. Designated and interested clinicians were provided with study brochures to give to potentially eligible patients. The brochure contained the necessary contact information to enroll in the Registry, and this contact information was also provided on the RLSF website and newsletter.

Enrollment

Enrollment was limited to individuals with: a diagnosis of RLS, confirmed by the Hening-Hopkins Telephone Interview at the start of the baseline phone interview; an opioid prescription, which may be confirmed by state prescription drug monitoring programs; and a past medication history that includes a positive response to dopamine agonists for RLS treatment, as confirmed by a question about past RLS treatments.

Longitudinal follow-up

We continue to send 6-month follow-up surveys to all remaining participants (excluding those who have discontinued opioids and those who are deceased). A total of 467 participants completed the 1-year follow-up survey (97.7% retention), 458 completed the 2-year follow-up survey (95.2% retention of eligible participants), 441 completed the 3-year follow-up survey (94.1% retention), 425 completed the 4-year follow-up survey (93.6% retention), and 288 completed the 5-year follow-up survey.

At this time (December 2023), 23 subjects are considered lost to follow-up, 9 subjects withdrew, 18 subjects are deceased, and 38 subjects discontinued their opioid treatment (see Figure 1). Retention is high as a result of participant commitment and our continuing efforts to encourage participation through vigilant follow-up with participants (emails, phone calls) as well as emailing quarterly analyses data updates.

Data analyses

As of this date, we have assessed baseline, 1-year, 2-year, 3-year, and 4-year longitudinal data from the RLS Registry. These analyses revealed that in refractory RLS, prescribed opioids are generally used at low doses with good efficacy. Longitudinally over 4 years, roughly one-half of participants increased their prescribed opioid dose, though generally by small amounts, with larger dose increases accounted for by predictable features. Our 1-year data has been published in Sleep. We have also analyzed data relating to the effects of COVID on the severity of RLS symptoms just prior to, and following, the national lockdown in March 2020. Our 2-year data was presented at the annual APSS meeting (June 2021) and published in Neurology. A poster on suicidality in the Registry using the 2-year data was presented at APSS Sleep 2023 in Indianapolis, and we are in the process of publishing a manuscript on the same subject. Findings from the 3-year data were presented at World Sleep 2023 in Rio de Janeiro, and we intend to present our 4-year findings at APSS Sleep 2024 in Houston, Texas.

Ten data updates using Registry data have been sent to participants. These include data summaries such as RLS and mental health, RLS severity during the COVID-19 pandemic, the stigma of opioid treatment for RLS, suicidality in the RLS Registry, and much more. All of the quarterly updates can be accessed on the RLS Registry webpage. We plan to continue sending updates to participants on a quarterly basis.

The Registry remains open to collaborators who desire to examine specific questions relating to RLS which can be addressed through its database. One such collaborator, Dr. Elias Karroum, has been assessing the effects of painful RLS on outcomes collected through the Registry and he has submitted an abstract describing his findings to APSS Sleep 2024 in Houston, Texas.

Conclusion

At this time, we are very pleased that the Registry is obtaining the data we had hoped, and participant commitment is high, as demonstrated by low rates of attrition. We aim to accurately answer questions about the efficacy and safety of opioid medications for the treatment of RLS, and in doing so, we are keeping with the RLSF’s mission to improve the lives of those living with RLS.

RLS Foundation and American Academy of Sleep Medicine Foundation Announce Research Grant Opportunity

The Restless Legs Syndrome (RLS) Foundation and the American Academy of Sleep Medicine Foundation (AASM Foundation) today announced a new collaboration to co-fund a $50,000 grant for research on restless legs syndrome (RLS). The funding will be made available through the RLS Foundation’s Research Grant Program, which has awarded over $1.9 million in grants for medical research on RLS causes and treatments since 1997.

“The RLS Foundation’s partnership with the American Academy of Sleep Medicine Foundation signifies our shared commitment to expanding the availability of RLS research funding,” says RLS Foundation Executive Director Karla Dzienkowski.

RLS is a chronic neurological disease characterized by an irresistible urge to move the legs, especially at night. Many people with RLS endure unrelenting symptoms that severely disrupt sleep and can have a devastating impact on their well-being. “For people who live with the daily challenges of RLS, research offers hope for new, durable treatments leading to better treatment outcomes and improved quality of life,” says Dzienkowski. An estimated 7%–8% of adults in the US have RLS, and treatments are limited.

“The AASM Foundation is excited to collaborate with the RLS Foundation on funding a research grant opportunity that will contribute to our understanding of RLS and help optimize treatment options and care delivery for people with RLS,” says R. Nisha Aurora, MD, MHS, President of the AASM Foundation.

Funding priorities for the RLS Foundation’s 2024 grant cycle are:

• Neurobiological interaction that elucidates the points of interaction between RLS-relevant neurotransmitters, neuronal pathways and iron deficiency.
• Pharmacologic treatments elucidating effects of novel pharmacological approaches on RLS.
• Clinical practice that looks to innovations in patient care delivery including, but not limited to, population health programs, technology-enabled healthcare delivery and public health initiatives.
• Other research topics to advance the understanding and treatment of RLS.

To apply, researchers must submit a pre-application (letter of intent) by January 26 February 24. Selected applicants will be invited to submit a full application.

Note: Letter of Intent (LOI) deadline extended to Saturday, February 24 at 11:59 PM. All applicants informed by March 8, 2024 if their proposal will be invited for a full application.

More details and application instructions are available on the RLS Foundation website, www.rls.org.

Founded in 1998, the AASM Foundation is a not-for-profit 501(c)(3) charitable and scientific organization established by the American Academy of Sleep Medicine. The AASM Foundation has invested in the future of sleep medicine by supporting more than 300 grants totaling $25.7 million in funding. The AASM Foundation’s portfolio includes research grants for all career stages, community grants and awards and training programs. For more information, please visit foundation.aasm.org

Call for RLS Research Grant Proposals

The RLS Foundation, a 501(c)(3) nonprofit corporation, aspires to achieve universal awareness of the disease, to support identification of effective treatments, and to find the cure for the millions of men, women, and children who suffer from RLS.

The RLS Foundation calls for grant proposals of a 1 year-duration, with funding levels of up to $50,000 (including 8% for F&A costs), based on the number of funded applications. A renewal or extension of a proposed project may be considered, but this extension would be subject to the regular competitive approval process for year 2.

Spring 2024 Priorities

For this round of funding, the primary research priorities are:

• Neurobiological interaction:Elucidate the points of interaction between RLS-relevant neurotransmitters, neuronal pathways, and iron deficiency.
• Pharmacologic treatments:Elucidate effects of novel pharmacological approaches on RLS.
• Clinical Practice:research based on innovations in patient care delivery including but not limited to population health programs, technology-enabled healthcare delivery (i.e.; telemedicine) and public health initiatives.
• Other topics: Other research areas accepted for funding consideration.

Requirements

• Eligibility: All institutions within the United States, Canada, and other countries where supervision of grant administration is possible are eligible.
• Human Subject Protection: Approval by the institution’s human investigation committee is necessary for all projects that involve human subjects.
• Recombinant DNA Research and Animal Welfare: The RLS Foundation has adopted the regulations pertaining to these areas, as established by the US Public Health Service.
• Multiple Awards: Individual investigators may receive a maximum of one RLSF grant award of any kind in a given year.

Application process

• Submission is a two-step process requiring both preapplication (letter of intent) due no later than January 26, 2024 and full application as indicated below.
• The application title and all information for the Principal Investigator (PI), Business Official(s), Performing Organization, and Contracting Organization must be consistent throughout the entire preapplication and full application submission process.
• If a joint submission by multiple PIs (Partnering PI Option): The Initiating PI must complete the preapplication submission process and submit the contact information for the partnering PI. The Partnering PI(s) will then be notified of the preapplication submission separately by email.
• Fund disbursement for successful applications will be contingent upon documentation of approved institutional review or animal user protocols, as appropriate.

Preapplication (Letter of Intent) Submission Components

The Letter of Intent (LOI) should consist of preproposal narrative with:

• Rationale: State the hypothesis and reasoning on which the proposed research project is based. Briefly describe how preliminary data, scientific rationale, and referenced literature support the research hypothesis. Clearly demonstrate that there is sufficient rationale for the project (Limit: 500 words).
• Focus Area: State the Research Priority that the proposed study seeks to address. Select one or more from the current research priority list.
• Specific Aims and Study Design: Clearly describe the type of research study being proposed. Concisely state the project’s objectives, specific aims, and ultimate endpoints. As applicable, briefly describe the proposed recruitment strategies and methods, how they will accomplish the project’s aims, as well as the outcome measures that will be used. (Limit: 500 words)
• Research Team: Provide a description of the research team that clearly demonstrates the appropriate background and experience to accomplish the proposed work. (Limit: 250 words)
• Impact and Relevance to RLS: Describe how the proposed work will impact healthcare and quality-of-life needs for patients and/or family members or beneficiaries living with RLS. (Limit: 250 words)

In addition, applicants should provide a reference list (one-page limit), list of abbreviations, acronyms, and symbols, and key personnel biographical sketches (NIH format).

Letter of intent (see attached sample application) to be submitted starting December 8, 2023 online here by no later than January 26, 2024.

Applicants will be informed the second week of February if their proposal will be invited for a full application.

Full Application Submission Components

If selected, the full online application consists of a cover page that must be signed by the university or organizational representative(s) and the principal investigator, an abstract with a clearly stated hypothesis, and the proposal that includes:

Project Narrative (no more than 5 pages), with background, hypothesis / objective, specific aim(s) and research strategy. Within the research strategy section, describe the study design, methods, models, and analyses in sufficient detail for assessment of the application. Explain how the research strategy will meet the project’s goals and milestones within the proposed period of performance. Address potential pitfalls and problem areas and present alternative methods and approaches. For studies performing prospective human subject recruitment or observation: Describe the population(s) of interest. Describe how data will be reported.

Budget and budget justification

Biographic sketches of each investigator (NIH format)

Disclosure of previous RLS Foundation support and other sources of funding.

Full Applications to be submitted online, link to be provided in LOI acceptance notification, and the deadline for the full proposal submission is April 5, 2024.

Award Process

Schedule: The RLS Foundation Scientific and Medical Advisory Board (SMAB) and external reviewers strives to review all applications in a timely manner. The goal is to provide the results to the LOI applicants within 2 months of the respective grant deadline and 4 months after submission of the full proposals.

Review: The SMAB will evaluate and rank the full proposals based on scientific merit. Overall impact, significance, approach, innovation (conceptual, technical) and individual criteria will be taken into account for funding consideration.

Award: The RLS Foundation Board of Directors will make final award decisions in accordance with available funds, based on the evaluation provided by the SMAB and other prioritization factors as determined by the Board of Directors.

Recipient Requirements: In order to receive an RLS Foundation research grant, the recipient must:

1. Within one month of the grant award, provide a photo of the grantee and a one-page article for publication in NightWalkers (the Foundation’s quarterly news magazine), describing in layman’s language the importance of the research to the RLS community and the recipient’s intention for future research.
2. Use the terminology restless legs syndrome in all grant-related publications and correspondence.
3. For 1-year awards, agree to submit a progress report after 6 months and 12 months from the starting date of the grant.
4. Acknowledge the RLS Foundation’s support in any published work or audiovisual productions resulting from research that the Foundation has supported. (Provide pdf copies of any reprints to the Executive Director of the RLS Foundation.)
5. Agree, if RLS Foundation funded research is commercialized or generates revenues, to devote a portion of the revenues to repaying the entire amount of the grant received, plus interest at the-prevailing prime rate, to the Foundation. Interest will be calculated semi-annually on the unpaid portion of the amount to be repaid.

Lastly, the intent of the RLS Foundation Research Grant Program is to provide seed monies to support researchers in their research endeavors and help them obtain the data to successfully request large scale funding elsewhere.

Thus, while an application may be also submitted to other organizations or agencies for funding, the applicant may not receive funding from the RLS Foundation, if any of those other projects are awarded or funded prior to the award being granted by the RLS Foundation.

The applicant will notify the RLS Foundation in writing of award funding for the same proposal from another organization and withdraw the application from consideration.

Costs Not Permitted

The following costs are not allowable under the RLS Foundation’s grant programs:

• New construction, alterations, or renovations of existing facilities
• Consultant fees, unless specified in the original grant application
• Travel costs

RLS Research Grant Program

The RLS Grant Program started in 1997 and has funded 50 grants totaling nearly $2 million. Membership giving is the primary funding support of the RLS Foundation Research Grant Program. Help us to continue to fund promising new RLS research and end RLS for future generations.

Your Generosity Can Change Lives: The Power of Giving Tuesday

Among the busyness of the holiday season, don’t forget to pause and reflect on the friends, family and organizations that have positively impacted your 2023 year. Giving Tuesday, which is celebrated on the Tuesday following Thanksgiving, is a global movement that encourages people to contribute to the charitable organizations that largely influence their lives. As you harness compassion and generosity during this season of giving, consider extending it to the Restless Legs Syndrome (RLS) Foundation. Participating in Giving Tuesday at the RLS Foundation is an opportunity to make a difference and support those suffering from this often devastating disease.

The Impact of Giving Tuesday

Your participation in Giving Tuesday is essential for providing the means to fund critical research that aims to improve diagnosis methods, better our understanding of RLS, and develop more effective treatments. You become part of the solution to this complex medical challenge. Further, Giving Tuesday offers a unique opportunity to connect with the RLS community. People from all walks of life come together with a shared purpose – to support those living with RLS. You can become part of a supportive network that provides comfort and encouragement to individuals and families affected by RLS.

Education and Awareness

Another crucial aspect of the RLS Foundation’s mission is enhanced education and awareness. Through Giving Tuesday donations, the Foundation can create and distribute valuable resources, organize awareness campaigns, and promote a better understanding of RLS among healthcare professionals and the public. Our resources include over 30 patient handouts, a monthly webinar series, a quarterly magazine NightWalkers, and a free physician education webinar series. By participating in this annual event, you help dispel the misconceptions and stigmas often associated with the condition.

The Joy of Giving

Your participation in Giving Tuesday at the RLS Foundation extends far beyond just supporting a good cause; it’s also about experiencing the joy of giving. The act of contributing to something greater than oneself can be immensely fulfilling. Knowing that your donation, no matter how small, can make a difference in someone’s life is a powerful motivator and a source of personal satisfaction.

The importance of Giving Tuesday lies in its ability to inspire philanthropy and unity and serves as a powerful reminder of the impact we can collectively achieve as a community. Your participation will further our outreach related to RLS research, advocacy and education. So, mark your calendar for Tuesday, November 28, open your heart, and make a meaningful contribution this Giving Tuesday to help the RLS Foundation in its mission to improve the lives of countless individuals living with RLS.

The Knowledge and Comfort of Knowing You Are Not Alone = Priceless

For 31 years, the RLS Foundation has been dedicated to improving the lives of the men, women and children who live with RLS by increasing awareness, improving treatments, and funding research to find a cure for this often-devastating disease. The RLS Foundation is proud to have the only dedicated RLS Research Grant Program, which funds promising research. We are a patient services organization, committed to ensuring those in the RLS community have access to top-notch resources, support, information and much more. Membership dues from our cherished members are the lifeblood of this organization, and our work can’t be done without you, our members.

FIVE REASONS WHY YOUR MEMBERSHIP IS BENEFICIAL

1. ACCESS TO EXPERT RESOURCES

Members can tap into a wealth of knowledge about RLS, including the latest research, treatment options and management techniques. The Foundation offers comprehensive educational materials, such as educational brochures, open-access articles and webinars, which can empower you with a deeper understanding of your disease. All of our publications are available for immediate download through our Member Portal, as well as an archive of webinars on a variety of topics. Our materials are rigorously reviewed and edited by members of our Scientific and Medical Advisory Board. These RLS experts volunteer their time and expertise to ensure all our materials are up-to-date and scientifically accurate.

2. A CARING AND SUPPORTIVE COMMUNITY

Being an RLS Foundation member means you have access to a support system made up of thousands of individuals living with RLS across the globe who can empathize with what you are going through. You are no longer alone in your RLS journey. An RLS Foundation membership gives you discounted pricing on events such as our upcoming National RLS Patient Symposium, where you will meet individuals from all over the country and foster lifelong connections with those in your same shoes. Sharing personal stories, triumphs and challenges with others who can relate provides a sense of camaraderie and emotional support that can be invaluable for individuals coping with RLS.

3. CREATING YOUR LEGACY THROUGH ADVOCACY

Members of the RLS Foundation have the chance to actively participate in advocacy efforts that aim to raise awareness about RLS and improve the lives of those living with the disease. Through the Foundation’s initiatives, you can contribute to public policy discussions, promote research funding, and collaborate with healthcare professionals to advance the understanding and treatment of RLS. By joining forces with like-minded individuals and making your voice heard, you have the power to affect meaningful change and make a lasting impact on the RLS community for future generations to come.

4. THE ONLY DEDICATED RLS RESEARCH GRANT PROGRAM

As an RLS Foundation member, you contribute to the Foundation’s efforts to fund research and drive advancements in the field of RLS. The financial support from membership fees and donations directly fuels research projects such as small clinical trials to investigate new treatment options, with the end goal of finding a cure. By actively supporting these initiatives, you play an instrumental role in accelerating progress, ultimately benefiting not only yourself but also future generations affected by RLS.

5. EXCLUSIVE MEMBER-ONLY BENEFITS

In addition to the broader benefits of knowledge, community, advocacy and research advancements, RLS Foundation members enjoy exclusive perks. These include discounts on RLS Foundation merchandise in our online store, priority registration for events and conferences, and access to special member-only content in the Member Portal on our website. Four times a year, each member receives our quarterly news magazine, NightWalkers, which is meticulously planned, written and edited to deliver news about the latest happenings at the RLS Foundation and in the RLS realm. Our members also receive our Special Accommodations Card for use when traveling, along with our Medical Alert Card, which outlines medications that often trigger RLS and provides safe alternatives.

From gaining access to expert resources and support from a community of peers, to actively participating in advocacy efforts and contributing to research advancements, an RLS Foundation membership offers a comprehensive range of benefits. By joining or renewing, individuals not only empower themselves with knowledge and support but also contribute to the overall mission of improving the understanding and treatment of RLS to improve the quality of life for those living with the disease. The nominal fee to join or renew your membership is $40, but the benefits that come with it bring peace of mind in knowing that you are a member of an active and supportive community that alone is priceless.

Hope for a Better Future

My RLS started very gradually – I really didn’t think much about it at the time. About 15 minutes into my meditation, I had this creepy-crawly, gnawing feeling in my legs. I found I could tighten my leg muscles, the feeling would subside, and I could then start my day. This feeling would appear intermittently from time to time, with increasing frequency until about 18 years ago. It became such a persistent and growing problem that I had to stop meditating. Then this issue began to interfere with my sleep. Just when I started to dream, I was suddenly awakened by an uncontrollable leg jerk. That’s when I decided it was time to ask my physician about this problem.

My doctor had the vague idea that I might be suffering from restless legs syndrome (RLS). She performed a blood test to check for iron deficiency, then wrote a prescription for quinine. For those who are unfamiliar with quinine*, it really did help with my RLS, though not consistently. However, I soon discovered that quinine has an insidious and horrifying consequence. Quinine kills bacteria. My intestinal flora was now a decimated wasteland (no pun intended). To say I was a difficult person to be around was a noxious understatement. I may not contract malaria, but I was destined to live my life as a hermit, alone and without human contact.

After about six months, my wife decided to schedule another appointment with my doctor. She said she was concerned for my health; I was not convinced that was her motive. My doctor prescribed ropinirole**, a drug many with RLS have been on. Fortunately for me (and my wife) the drug worked like a dream, literally. I could finally fall asleep provided I took the medication several hours before bedtime. My downfall was that in the evening, I would fall asleep on the couch if I sat still for 10 minutes or so. This was embarrassing when went to someone’s house for dinner and would sit for conversation after the meal, and within a short while I was snoring. Eventually, I let go of my embarrassment, as my wife would explain to our hosts the challenges of my medication. I also discovered that this was a great way to escape conversations that didn’t interest me. I would just close my eyes and willfully drift off.

My next pharmaceutical experience came when I changed physicians. My new doctor suggested I try pramipexole (Mirapex). He felt it could have less of a tranquilizing effect yet still provide the RLS relief I needed. He was right. For seven or eight years, this medication was consistent so long as I took it two hours before bedtime.

But it seems all good things must come to an end. For me, augmentation started subtly. I found I needed a little bit more medication to manage my RLS. I also had to adjust my schedule by taking it a half-hour earlier. Soon the augmentation dramatically changed. On bad nights, not only did my arms and legs violently jerk, but also I could feel it in the core of my body. Some nights while trying to fall asleep on the couch, I would be in tears at 2 or 3 o’clock in the morning. “Horrible” doesn’t begin to describe the problem.

Out of desperation, and following an article in NightWalkers about augmentation, I started to search for an RLS specialist. I called the Norman Fixel Institute for Neurological Diseases at Shands in Gainesville, Florida – a three-hour drive from my home. After a thorough review of my medical history, my newest doctor started me on a regimen of 600 mg of gabapentin, increasing it to 900 mg after six months. At the next appointment, we would discuss the reduction of Mirapex. Within three weeks, I decided I needed to be more aggressive with my therapy by reducing the Mirapex sooner. Through constant communication with my neurologist and my own assertive impatience, we were able to move me out of dopaminergic dependency, replacing Mirapex with 600 mg of gabapentin within eight months of my first exam. Needless to say, I am elated. I no longer need medication before boarding a plane or taking a long road trip. I can stay up late again if I want to. Chocolate, caffeine and alcohol no longer make me twitchy. I feel so much freer than I have in decades.

I understand that each of us is unique, and results will vary, but I stand before you as a positive example of what can be accomplished. You have a whole world of RLS sufferers who are behind you, cheerleading you on to success. Don’t give up! There is always hope for a better future.

Dan and his wife, Lara, keep pretty busy with their successful optical office in Port Saint Lucie, Florida. In his spare time, his hobbies include traveling, bookbinding, jewelry making, and numerous other activities (Attention Deficit Disorder is both a blessing and a curse)! They have a five-year- old granddaughter who lives too far away in Connecticut.

*Quinine has no proven effect on RLS except for a placebo effect. Quinine may kill bacteria but there is no real documentation of negative effects on the intestinal flora. The real concern with quinine (which is why it requires prescription and only approved for treating Malaria and not leg cramps) is its rare side effects of cardiac arrhythmia and blood dyscrasias.

**Ropinirole is no longer considered first-line treatment for RLS.