Will I Get Addicted to Opioids from My Restless Legs Syndrome (RLS) Treatment?: Part II; A ReLACSing Blog #32

(Note: Part II is… wait for it….dependent on reading A ReLACSing Blog #31 first, or at least watching the full @andyberkowskimd YouTube video summarizing this series)

Last week in Part I, we laid the groundwork for understanding the definitions of the terms related to “addiction” such as dependence and abuse and how it may manifest with opioid use in the treatment of restless legs syndrome (RLS). In this blog, we will focus on the data showing that for RLS, these risks are low.

As a sleep specialist who sees a lot of individuals with RLS, mostly complex cases of RLS, opioid prescribing is something that I commonly am required to do. My guess is that I have ordered opioid therapy to a few hundred patients with RLS in my career. I really cannot recall anyone who started on opioids for RLS having developed opioid use disorder. This is also the experience of some of my RLS-specialized colleagues who may have 5–10X more experience with opioid prescribing over longer careers. The risk is not zero, but it is very low. There have been a few patients with opioid problems in the past or at the time they were treated for RLS, as they were on opioids for other conditions like chronic pain. However, even those seemed to do well once stabilized for RLS, mainly with good monitoring, structure, and the help of safer opioids like buprenorphine and methadone. Sure, my individual experience and those of my buddies do not constitute data, but there are data that suggest that our experience is the standard and not the exception.

Photo by Claudio Schwarz on Unsplash

Opioids, particularly methadone, have been in RLS practice for at least three decades, likely increasing in the mid-2000s with the emergence and boom of dopamine agonists leading to thousands now developing severe RLS from dopaminergic augmentation. For those who are unfamiliar with augmentation, it is an insidious worsening of RLS over time with symptoms occurring earlier in the day, spreading to other areas of the body, increasing in intensity, and lessening the ability to sit or lie down for periods of time. This video summarizes this process, and this previous ReLACSing Blog #4 highlights why these drugs are bad for the condition.

The more intractable, severe cases are immune to many therapies, so opioids, as the most potent, are needed more in RLS with increasing condition severity. The most famous study was from the Johns Hopkins database from Silver et al. that looked back for 10 years comparing patients on methadone with those on either of two dopamine agonists, pramipexole and pergolide. Pergolide was taken off the market in 2015 due to the damage it may cause heart valves in those treated with it. In the first year of use, 5% of those on pramipexole and 3% of those on pergolide discontinued these medications due to augmentation. Methadone, which is a different class of drugs of course–opioid, not dopamine agonist–did not cause discontinuation of treatment from augmentation. Over the 10 years this study reviewed, augmentation led patients to stop pramipexole and pergolide 7% and 5%, respectively, each year they were on the drug. In other words, just because you did not have augmentation in Year 1 or 2, you had an equal chance of developing it in Year 3 and Year 4 and Year 10. Conversely, 15% of patients discontinued methadone in the first year due to short-term adverse effects, which can be expected given the potential adverse effects of opioids, but 0% discontinued the medication over the remaining 9 years. That’s right, everyone who did well with methadone in the first year never had to stop the medication. Of note for clarification, this study looked back ten years, but it did not track each patient for ten years individually, so many were only observed for a few years within the ten year range, depending on when they started. Nevertheless, this tells us a lot about the stability of methadone.

I can already hear some of you say: See! No one was able to get off methadone in 10 years! They were all addicted! I suppose that is one (cynical) way to look at it. Yes, if they were chemically dependent on methadone, maybe they wanted to go off but couldn’t due to drug withdrawal. You can also look at it the other way. After long-term use and augmentation from the dopamine agonists, these individuals may have been chemically dependent on pergolide or pramipexole. They surely would have had dopamine agonist withdrawal to endure, but they nevertheless got off the drug due to augmentation and how bad the RLS was getting. If people in this study were developing opioid use disorder, one would assume that a subset of them would switch treatments or come off the methadone. The positive way of looking at it is that methadone provided significant relief or RLS symptoms and was well tolerated, so people stayed on the effective treatment with no need to go off.

But, Dr. Berkowski, they probably had to keep taking more and more and more methadone to stay on the drug! The authors in the study have a table of methadone dose level increases per year on methadone compared to the baseline dose they were on at six months. It does show some increases to the dose, but the median dose increases were anywhere from 0 to 7.5 mg. There were more dose increases in those on methadone for a longer time, which could suggest some mild tolerance, but overall there was no exponential increase in this drug’s dosing to maintain effectiveness. In fact, the dose increases that were reported are higher than in my own personal experience with methadone. Keep in mind that this is a 2011 study looking at 1997 to 2007. A LOT less was known about RLS in those years. For example, some of the dose increases could have been due to iron deficiency developing before we knew to assess iron regularly and the power of intravenous iron infusion. Maybe the increases were due to other causes making RLS worse and not tolerance developing from methadone. Regardless, this was a very stable treatment for many years even though it encompassed treatment approaches from a quarter century ago.

Fast forward to the present and the ongoing National RLS Opioid Registry run by my colleague Dr. John Winkelman through Massachusetts General Hospital. His 2023 publication may be even more enlightening when it comes to opioids. This publication reviewed the opioid dose strength of those taking these medications over the course of two years in the registry. Overall, there was no change in the severity of RLS in the two years, yet 58.9% of participants were able to maintain the same or reduce their opioid dose in those two years. The average strength of the opioid daily dose was 38.4 morphine equivalents (MME). MME is a rough estimate of the strength of each opioid relative to morphine in order to compare them more easily. The FDA defines > 50 MME as a high dose of opioids and most were stabilized at a low dose. About 12% of the 41.1% who increased their dose over two years, increased by more than 25 MME. These individuals in almost all cases had other factors associated with the increase including switching opioid types, discontinuation of other RLS treatments, mild or worse insomnia, depression, male gender, age < 45, and opioid use for chronic pain. These are all common risk factors for either opioid dose increases or worsening RLS necessitating opioid dose increases. Again, like the previous study, it did not screen for abuse or dependence, though dependence would be hard to assess unless one attempted to go off the opioid. Dependence, as discussed in Part I, is not necessarily a big problem. Abuse and tolerance are greater concerns.

There are other studies of opioids but these two strongly support the contention from RLS experts that opioids are generally safe and effective at low doses, specifically for RLS. What could be the reasons for this?

To find out, you will have to wait for Part III!

-Andy Berkowski, MD, currently misusing and abusing his keyboard with a three-part blog