A ReLACSing Blog #4: Dopamine Agonists are BAD for Restless Legs Syndrome
Enjoying the Seattle skyline this week…
Today, I am in the great city of Seattle, Washington, attending the American Academy of Neurology’s (AAN) Annual Conference. On Tuesday, I will be presenting “The Compulsive Use of Dopamine Agonists for Restless Legs Syndrome: 21st-century RLS Management” at C-94 Clinical Approach to Sleep Disorders at 7 AM PDT.
This is the evolution of a lecture I have been giving a lot since 2015. Unfortunately, little has changed with the underlying premise of the lecture: dopamine agonists are BAD for restless legs syndrome (RLS). It appears that medical professionals are not getting the message. From fall of 2017 to 2018, providers prescribed these medications to 58.8% of patients and 19.1% were above the maximum recommended doses. Finally, however, I get to give this talk to a national audience (and some brave international souls).
Three dopamine agonists (DAs): ropinirole, pramipexole, and rotigotine are actually FDA approved for RLS, when they should now have Black Box Warnings against their use in RLS. These medications work to relieve symptoms of RLS really well initially, and most clinical trials, particularly randomized, placebo-controlled clinical trials, the gold standard for medical research, generally last weeks, months, or a year or two at most. The disturbing effects of these medications may occur after several years of use. Obviously, research groups cannot run randomized trials for many years and have to use retrospective data on regular patients with long term use of any drug to pick up on risks and benefits over extended time.
If they work so well at first, then why do I think they are “BAD” for RLS? The drugs cause scary changes to the dopamine system in the brain. They cause long term dependence of the brain on the medications. Thus, it is very hard to get off them. One will have significant withdrawal if they miss a dose for more than a day or sometimes if they are late by a few hours. Moreover, the changes cause the brain’s dopamine system to become dysfunctional and the brain shuts down some of its natural dopamine function. Also, these drugs may stimulate the systems that actually make the symptoms of RLS more severe as time goes on. This phenomenon is called augmentation. Is that bad enough? No, because impulse control disorders may start to emerge at an alarming rate. Dopamine is a chemical highly involved in the reward system of the brain. Think of the kid getting the rush from a package of gummy worms, or the person hitting all 7s on the slot machine at the casino. The anticipation of the reward of the activity causes the brain to release dopamine. These medications magnify that response. The statistics are alarming. I have personally had some patients compulsively shop away their retirement savings, become so obsessive-compulsive that they have alienated their family, take up substance abuse, etc. In the past 6 months, I have even had a few patients recently who developed alcohol use disorder in their 70s while on dopamine agonists. Why were they OK with alcohol for 50+ years, only then to develop an alcohol use problem? Well, they were started on a drug that altered their behavior, so a pattern that typically develops in young adulthood, develops in their 70s. I shake my head.
What happens to RLS patients who are on dopamine agonists? They may do well for the first few months or years, but the symptoms of augmentation start to emerge. The symptoms spread to other areas of the body, they come on earlier in the day, the same dose is not as effective as before (called tolerance). Then the patient and their clinician begin to think the condition is getting worse so the patient needs more drug….OOOPS! That works for many conditions but not this one. The condition is getting worse due to the drug, not in spite of the drug. Increasing the dose provides a few months of relief and then things will worsen again and the cycle will keep repeating. Unfortunately, the higher the dose and the longer one takes the drug, the more chemical dependence, the worse the augmentation, and the more severe the withdrawal. However, the brain needs one to get off the drug to go through withdrawal to recover from the drug effect. The withdrawal is a miserable process, and that is what I have helped patients do for the past seven years as a sleep physician.
OK, Dr. Berkowski, you have made your point, so why so little movement on the use of dopamine agonists for RLS? Despite these facts, providers are still regularly prescribing these drugs.
There are several reasons (there will be future blogs to expand on these but in summary):
Providers are afraid of the alternatives: gabapentin, gabapentin enacarbil, pregabalin, buprenorphine, methadone, and other opiates are all controlled substances. There is a perception of increased risk that is often beyond the actual risk. There is also an irrational fear of infusions, particularly of iron, which is a first-line, safe and effective treatment for RLS, that does not involve augmentation or impulse control disorders.
Providers do not want to deal with the hassle of the alternatives: controlled substances require repeated monitoring and frequent visits, refills, etc. Patients on opioids require even more prescriptions, generally written monthly, and annual urine drug screens, tight regulations from pharmacists and state regulators, etc.
Non-dopamine agonist treatments may not be covered by insurance: iron infusions are often only covered for a secondary condition (iron deficiency anemia) and not for RLS. Good luck finding an insurance that pays for Horizant or Belbuca. Some insurance companies want the patient to try several DAs before other meds are covered. Perampanel is a drug I’d love to try but have never had a patient on it. It is not even paid for by insurance companies for severe epilepsy most of the time, and it was FDA approved for this condition.
It may take 20 years to change clinical practice, even if the guidelines change: this is a general trend in paradigm shifts, particularly in medicine, but the clinical consensus guidelines began to change in 2016 so we’ve got 13 more years!
Most doctors have too little time with patients and practice reflexive medicine: doctors seeing patients for 10 minutes with 12 conditions don't have time to look up the latest clinical guidelines. They don’t know to check everyone's iron. They only remember DAs from medical school and that’s it.
(a.) Experts have received money from the drug companies that make dopamine agonists AND
(b.) The latest clinical guidelines are thus not as strongly opposing these agents as they should be. Go to the Open Payments website and type in the authors. You can see whether there are financial relationships with the drug industry and specific manufacturers of medications that are in the guidelines. This may have influenced a “second line” recommendation in this paper, when the medications should arguably be off the market. If you type in my name to this open payments website, you won’t find me. Sure, not all industry relationship are bad and many are necessary, and there’s the chance that one day I will collaborate with a company on a treatment. However, there are currently no financial influences on my opinion, so that should mean something and explains why I am free to reject DAs as “second line”.
Thankfully, the tide is starting to change, albeit slowly. I often feel I am a lonely voice out there but many RLS and sleep experts are aware of this as well. The great work of the RLS Foundation has also helped patients, who can become more educated on the condition than their doctors, sadly. Patients with RLS, but really those with any chronic disease in our healthcare system, need to become their own advocates and keep up to date with advances in research so that they know their doctors are on the right track. After all, it is the patient’s health, not the doctor that suffers from poor treatment outcomes.
- Andy Berkowski, MD, non-dopamine prescriber
ReLACS Health
