Ben Wipper is a current medical student at Harvard Medical School and lead author of the study Restless legs syndrome severity in the National RLS Opioid Registry during the COVID-19 pandemic.

Wipper graduated from Williams College in 2019, and over the past two years has been a part of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital in Boston. Wipper has co-authored numerous peer-reviewed research articles relating to restless legs syndrome and other sleep disorders.

Learn more about the Sleep Disorders Clinical Research Program.

Podcast Transcript

Sree Roy:
Hello, and welcome. I’M Sree Roy with Sleep Review, and I’m happy to be here today with Ben Wipper.

Sree Roy:
Ben is a current medical student at Harvard Medical School. He graduated from Williams College in 2019, and over the past two years has been a part of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital in Boston. Ben has co-authored numerous peer-reviewed research articles relating to restless leg syndrome and other sleep disorders. Today we’re discussing his investigation into restless leg syndrome severity during the COVID-19 pandemic.

Sree Roy:
Welcome, Ben.

Ben Wipper:
Hi, Sree. Happy to be here.

Sree Roy:
Great. This investigation used data from the RLS National Opioid Registry. What is the RLS National Opioid Registry?

Ben Wipper:
Thanks so much for having me on. Really excited to talk with you today. It is probably best to start off with a bit of background on our team and what the RLS Opioid Registry is.

Ben Wipper:
I work with the Sleep Disorders Clinical Research Program at MGH in Boston, which is led by Dr. John Winkelman. We spent a lot of time studying restless leg syndrome, which as listeners probably know is a neurological disorder that causes an irresistible urge to move the legs. Insufficiently treated RLS symptoms can interfere with sleep and reduce quality of life a great deal. There are several FDA approved medications for RLS treatments, such as ropinirole and gabapentin enacarbil. Although these medications are initially effective in many patients, they do have certain limitations. For example, a portion of patients using dopamine agonists experience a worsening of symptoms known as augmentation. With this in mind, it’s important that we do look for other treatments that might able to help patients.

Ben Wipper:
Low dose opioid medications, such as methadone are frequently prescribed for patients with RLS that’s refractory to other common treatments. Controlled short duration studies have suggested that low dose opioids may be dramatically effective for the treatment of RLS. However, patients and physicians do need more scientific evidence to assess the risks and benefits of treating RLS with opioids. With this in mind, our team created the RLS National Opioid Registry, which I’ll call the RLS Registry moving forward. This is a longitudinal observational study, following 500 patients who use prescribed opioids for treatment refractory RLS.

Ben Wipper:
Most patients participating in the Registry live in the United States, but a handful are living in other countries around the world. We enrolled new participants on a rolling basis from the end of 2020 to about the end of 2019. At baseline, participants were administered a whole series of questionnaires about their RLS medications types and dosages, different side effects, RLS symptoms, other physical and mental health conditions, and many more questions. We then continued to administer follow up surveys online every six months, and on these, we ask many of the same questions that we ask participants at baseline.

Ben Wipper:
The RLS Registry will collect data for at least five years. This database will hopefully give us a better idea of whether opioid medications are safe and effective long term in the treatment of RLS and may help physicians identify which patients might be at risk of dose escalations.

Sree Roy:
Why did you hypothesize that restless leg syndrome severity would increase during the COVID-19 pandemic in people diagnosed with RLS?

Ben Wipper:
Yeah. The initial idea for this project came from our interactions with our RLS Registry participants. As we continued to collect follow up data for this study during the pandemic, we noticed that some of our participants were reporting that their RLS symptoms had worsened since the onset of COVID-19 and the associated lockdowns. We also saw all of the different reports of increased anxiety and depression levels during the pandemic. There is quite a bit of cross-sectional in longitudinal evidence linking RLS to various psychiatric illnesses, and with this in mind, we found it possible that RLS severity could have increased in association with these different mental health conditions.

Ben Wipper:
Our RLS Registry data proved to be quite useful in assessing trends in RLS severity during the pandemic. As mentioned, all participants were enrolled between 2017 and 2019, so we did have pre-pandemic survey values for everybody. And by comparing these pre-pandemics survey values with follow up surveys completed after the onset of the pandemic, we figured that we’d be able to get an idea of how RLS severity changed in this sample during the public health crisis.

Sree Roy:
You found higher RLS symptom severity scores at the outset of the COVID-19 pandemic, and that the scores had returned toward baseline by the spring of 2021. Will you elaborate on the findings?

Ben Wipper:
Yeah, definitely. The primary measure that we looked at was the International Restless Legs Syndrome Study Group Severity Rating Scale. That’s a bit of a mouthful and I’ll call it the IRLS moving forwards. The IRLS is a validated self-administered questionnaire that assesses RLS symptom severity over the past week. It is 10 questions and it’s scored on a scale of zero to 40. A score of zero indicates no RLS symptoms over the past week, and a score of 40 would indicate very severe RLS symptoms.

Ben Wipper:
Initially, we performed a between subjects analysis. We looked did our subset of RLS Registry participants who had completed follow up questionnaires in April and May 2020 directly after the onset of the pandemic. We compared this group’s IRLS scores to participants who had completed surveys in January and February 2020 directly before the onset of the pandemic. We found that the April and May IRLS scores were significantly higher than the January and February scores. The difference between these two groups was roughly three points, and this is generally deemed to be a clinically significant difference on the IRLS. Additionally, we found the of participants who completed surveys in April and May 2020 were about twice as likely to record an IRLS score of 20 or above, which denotes pretty severe RLS.

Ben Wipper:
Of course, this made us ask the question, what if the elevated IRLS score is seen on the April and May 2020 surveys were simply because these individuals had more severe baseline IRLS scores to begin with? To help answer this question, we then performed a within subjects analysis where we compared the April and May 2020 IRLS scores to the same participant scores from before the pandemic. In doing this, we found that during early COVID in April and May 2020, IRLS scores were higher than those same participants’ baseline values from before the onset of the pandemic. Over half of participants had a higher score in the spring of 2020 as compared to their baseline score, and of those who increased the vast majority, about 90% saw a clinically significant increase of three points or more. And continuing the same theme, participants were significantly more likely to have an IRLS score of 20 or above in spring 2020 than they were on their pre-pandemic baseline surveys.

Ben Wipper:
We then looked at the subsequent follow up surveys. Like I said, we administer these every six months. We wanted to see if the increases in RLS symptom severity persisted as the pandemic went on. When we looked at the same groups next iteration of surveys completed mostly in October and November 2020, we saw that IRLS scores were similar to what they were in April and May 2020. Scores were relatively high and significantly higher than baseline scores. However, when looking at the next round of follow up surveys completed mostly in the spring of 2021, RLS symptoms severity scores were no longer significantly higher than baseline scores.

Ben Wipper:
So just to summarize all that, both our between subjects and the within subjects analysis showed evidence of higher RLS severity scores in the two months directly after the onset of the pandemic in the US. And it looked like these elevated RLS symptoms severity scores seemed to persist into the fall of 2020, but did return to lower baseline values come the spring of 2021, which was a time when COVID-19 infections rates dropped and some public health restrictions were loosened.

Ben Wipper:
It is important to note that due to the observational nature of this study, we can’t definitively say that the COVID-19 pandemic and the associated lockdowns caused these elevations in RLS severity. There were other events going on in the US at the time, such as the eventful 2020 presidential race, for example, which conceivably could have had some kind of impact on RLS severity.

Ben Wipper:
Nonetheless, it was pretty eye-opening for us to see these increases in RLS severity. As far as we know, this is the first evidence of increased RLS severity during the COVID-19 pandemic.

Sree Roy:
Doesn’t RLS tend to increase in severity over time even when there’s not a pandemic? Could these elevated scores simply have been a reflection of the passage of time?

Ben Wipper:
Yes, it’s true that RLS symptoms generally do worsen as people get older. However, Registry participants had been in the study just about one to two years at the time of the spring 2020 surveys and we wouldn’t really expect to see significant IRLS increases in a time period that is this short. Come today, all Registry participants they’ve completed their two year surveys, and our analysis has shown that there’s no increase in IRLS scores from baseline to this two year mark. So this suggests that the IRLS increase as seen in the spring of 2020 compared to baseline weren’t due to the passage of time alone.

Ben Wipper:
Furthermore, when we look at the individuals who completed surveys in January and February 2020 who had been in the Registry for a similar amount of time as the participants who completed surveys in April and May, there was no increase in IRLS scores from baseline. So this again suggests that the higher IRLS scores that we saw in the April and May group weren’t solely due to the passage of time since baseline.

Sree Roy:
You found associations between RLS and anxiety, depression, and insomnia. Can you describe these findings in greater detail?

Ben Wipper:
I can do that, yeah. As I mentioned previously, there are a number of studies out there that have linked RLS to various psychiatric illnesses, such as depression and anxiety, and are team actually just recently published a review on this topic. On the recurring RLS Registry surveys we administered the Patient Health Questionnaire, or the PHQ-9, which is a questionnaire that inquires about depressive symptoms. We also administered the Generalized Anxiety Disorder 7 Scale, called the GAD-7, which measures anxiety symptoms, and also the Insomnia Severity Index, which I’ll call the ISI, which asks about sleep disturbance.

Ben Wipper:
We wanted to know if participants who saw elevated IRLS scores in April and May 2020 also saw increases on these other questionnaires relating to depression, anxiety, and sleep disturbance. Generally speaking, this is what we found. We looked at that same group of patients who completed questionnaires in the spring of 2020 and calculated correlations between changes in IRLS scores from baseline and changes in PHQ-9, GAD-7 and ISI scores from baseline.

Ben Wipper:
We found relatively strong and significant positive correlations across the board; that is increases in RLS severity from baseline to spring of 2020 were is significantly associated with increases in depression, anxiety, and sleep disturbance. There was an especially strong relationship between the IRLS and the insomnia severity index. About 60% of participants with elevated RLS severity in the spring of 2020 also saw increases in sleep disturbance. And this is compared to about 23% of other participants seeing increased sleep disturbance. This relationship between RLS severity and sleep disturbance made sense to us knowing just how much RLS symptoms can negatively impact sleep.

Ben Wipper:
Again, with the nature of our observational data set, we are somewhat limited in the interpretations. We can’t really tell whether increases in RLS severity preceded the increases in anxiety, depression, or insomnia or vice versa. Regardless, we did think that these were really interesting findings and they definitely add to the body of research linking RLS to other neuropsychiatric disorders.

Sree Roy:
Did you identify any other factors associated with worsening RLS that may be valuable to predict which patients are more at risk during future lockdowns?

Ben Wipper:
We did. It’s important to note that not all of the RLS Registry participants saw IRLS increases during the pandemic. As I already mentioned, it was only about half of the participants completing surveys in April and May 2020 that saw IRLS increases from baseline. With this in mind, we ran a logistic progression analysis to see which factors were associated with elevated IRLS scores in the spring of 2020. As you say, identifying such factors can help us predict who might be at risk of worsening RLS during future times of lockdown and civil unrest.

Ben Wipper:
This analysis revealed two factors that were associated with IRLS increases from baseline. One was participant employment status. Particularly individuals in the Registry who were unemployed at baseline were more likely to see increases in RLS severity in April and May 2020. We don’t know exactly why this was the case, but it does seem important to mention that the majority of RLS Registry participants are 65 years or older. Thus, many of the patients who reported that they were unemployed at baseline were likely retired.

Ben Wipper:
The second factor we found that was associated with IRLS increases was participant’s state. Becker’s Hospital Review published a list of the 10 states with the most COVID-19 restrictions in the spring of 2020, and we found that the individuals in the Registry living in these 10 states with heavier early COVID restrictions were less likely to see elevated RLS symptom severity scores as compared to those not living in these 10 states.

Ben Wipper:
This is another somewhat difficult one to interpret. We speculated that maybe participants living in the states with more restrictions felt safer with such measures in place and this translated to less increases in RLS less severity. However, there are many potential compounds here, and one could probably think of numerous potential causes for the pattern that we found.

Sree Roy:
Is there anything else you’d like to add such as websites for more information or anything like that?

Ben Wipper:
Yeah. In terms of the study, I think that was pretty comprehensive. We talked about this study provided the first evidence we know of of increased RLS severity during the COVID-19 pandemic. We also found associations, like I said, between elevations and RLS severity and elevations in depression, anxiety, and sleep disturbance scores. All in all, we think that these data suggests that clinicians should be watchful for worsening RLS symptoms during future lockdowns.

Ben Wipper:
Also I just wanted to quickly thank the RLS Registry participants and the funders who have helped us keep this project going. Those include the RLS Foundation, the Baszucki Brain Research Fund, the Florence Petrlik Family Foundation, Diane and Richard Brainerd, Steven Silin, and Jerry Blakeley.

Ben Wipper:
As for our social media, we do have a Facebook page. The best way to find out information about our team is through our website. You can find that by googling the MGH Sleep Disorder Clinical Research Program. There we have information about who’s in our team as well as links to some of our studies.

Sree Roy:
Wonderful. Well I want to thank you, Ben, for joining Sleep Review today for this discussion. Sleep Review Magazine also has more information about RLS research. For anybody who wants to access that, you can visit our website, sleepreviewmag.com. And you can find those links and more in the show notes. Thank you everyone for joining us today on this podcast episode.

Ben Wipper:
Thanks so much for having me on the show, Sree.