Reviewed by Sahil Chopra, MD, and Stacey Gunn, MD.

Research by Savit Malhotra and Theresa Do.

Introduction

In our previous crash course article, we explored the dopaminergic mechanisms underlying restless leg syndrome. Building on that foundation, we will now turn our focus to the different dopaminergic therapies available to treat RLS. Interestingly, these medications used to be the frontline treatment when it came to RLS, serving as the standard protocol for many physicians. However, it later became clear that many of these medications were actually making RLS symptoms worse over time, a phenomenon called augmentation. While dopaminergic medications may still be prescribed for some cases of RLS, other treatments have taken the spotlight, which we will discuss in a future article.

Today, we will review the role of dopamine in RLS (especially in terms of the responsible receptors) and go over the different medications in the dopaminergic class. We will then discuss the mechanisms behind these medications and how this can explain augmentation.  

Mechanism of Dopaminergic Medications

Before all else, we will quickly refresh on the role of dopamine in RLS. Dopamine, the brain’s reward chemical, helps control movement and process sensory signals. Dopamine does this through binding to and activating dopamine receptors. The two main receptor families are is mediated by receptors called D1-like receptors and D2-like receptors.[1,2] While D1-like receptors tend to enhance neuronal activity, D2-like receptors dampen neuronal excitability.[3] In RLS, dopamine activity is most important in the spinal cord, where neurons process sensory information for leg movements.[4] When dopamine levels are low, D2-like receptors, particularly D3 receptors, help regulate neuronal excitability and calm overactive sensory pathways in the spinal cord, reducing the uncomfortable sensations and urge to move characteristic of RLS.[2,5,6] Dysregulation of these receptors contributes directly to symptom generation.[2] In contrast, stimulation of D1-like receptors does not alleviate symptoms and may even worsen them in animal models.[2,7] Notably, some evidence suggests that lower medication doses may preferentially act on D2 and D4 receptors, while higher doses activate D3 receptors, which may be associated with augmentation rather than sustained therapeutic benefit.[8]

To target this dysregulation, dopaminergic medications, also called dopamine agonists, mimic the neurotransmitter dopamine in the body. Dopamine agonists exert their effects by binding to and activating dopamine receptors. In a way, the binding acts like a key turning a lock to trigger subsequent responses within the nerve cells of the brain. Specifically, dopaminergic medications used for RLS bind to the D2-like receptor families. These receptors are critically involved in the brain’s sensory-motor pathways implicated in RLS symptoms.[2] By selectively binding to the D2 and D3 receptors, dopamine agonists can enhance these receptors’ activities. 

Types of Dopaminergic Medications

Dopaminergic medications for RLS are sold under a variety of names. The NIH lists three main FDA-approved agents (ropinirole, pramipexole, and rotigotine) sold under the trade names Requip, Mirapex, and Neupro (respectively).[9] Requip, particularly the immediate-release formulation, retains its FDA approval for treating RLS (as well as Parkinson’s disease, which can also be treated by the extended-release formulation).[10] This medication targets the D3 receptor, and clinical studies have shown that patients on the medication experience significant reductions in their subjective RLS symptom severity assessment.[11] Requip is reported as having an augmentation rate of approximately 7-10%.[9] 

Similar results were also found when Mirapex was analyzed. A 2017 meta-analysis found that, of the 3,286 patients included in the study, there was a 50% reduction in the International Restless Leg Syndrome (IRLS) Study Group Rating Scale scores, along with Mirapex demonstrating outcomes significantly better than placebo outcomes in terms of the scores for the Clinical Global Impression of Improvement and Patient Global Impression scales.[12] However, the meta-analysis also found the medication to have an augmentation rate ranging from 7.83%-47.06%, furthering the need for follow-up care in patients who are using Mirapex long-term.[12] 

Finally, Neupro is another effective dopamine agonist for the treatment of RLS. A 2011 clinical study of 295 patients showed that Neupro led to a significant reduction in IRLS scores (from 27.7 to 9.0, a reduction of 18.7 points), with augmentation being reported in 39 (13%) patients.[13] One review notes that, in longer-acting dopamine receptor agonists, most events of augmentation occurred within the first 2 years of a 5 year study.[14] The review also notes that higher dosages of Neupro are more likely to cause augmentation.

Long-term follow-up may be necessary to monitor treatment progression to ensure augmentation does not lead to a worsening of symptoms. The cumulative annual incidence of augmentation for long-term use of all dopamine agonists sits around 7-10%, meaning that regardless of which medication is used, a medical professional should still closely monitor usage.[9,15]

It is important to note that the current American Academy of Sleep Medicine guidelines now conditionally recommend against dopamine agonists as standard daily treatment due to the risk of augmentation. Instead, gabapentinoids are recommended as the first-line therapy. However, there is much debate surrounding whether dopaminergic medications should be used in cases where gabapentinoids are ineffective or not well tolerated. So, while these medications are considered to be effective on paper, general practice guidelines strongly recommend against their use.

Risks of Dopaminergic Medications

Like with the majority of medications, dopaminergic medications can come with adverse side effects and risks. Commonly reported side effects include gastrointestinal distress such as nausea and vomiting, as well as neurological symptoms, such as dizziness, headache, and sudden sleepiness.[14] One more serious risk associated with taking these medications for RLS is augmentation. Dopaminergics initially show efficacy by reducing the symptoms of RLS at low dosages.[2] However, their long-term use, especially at higher dosages, can lead to augmentation.[16] Augmentation generally is described as the worsening of RLS symptoms attributable to the medication itself. Typically, RLS symptoms are more prominent in the evening or at night. When augmentation occurs, this pattern changes. The key manifestations of augmentations include a shift in symptom onset, increased intensity and severity, wider distribution of symptoms, and shorter latency.[16] Symptoms of RLS begin to noticeably shift earlier and earlier in the day.[17] 

An example would be a patient who previously only experienced symptoms at 10 PM starting to feel RLS symptoms at 7 PM, then at 5 PM, and eventually in the early afternoon. The patient may notice that symptoms may appear more quickly upon rest or inactivity. Additionally, this patient may also experience worsening of the symptoms beyond the legs, such as in their arms, requiring higher dosages of medication to provide the same relief. Without treatment adjustments, this causes a vicious cycle of augmentation and leads to negative impacts on quality of life and sleep. Researchers suspect dopamine system dysfunction as one of the underlying causes of augmentation. In mouse models, long-term use of pramipexole can cause a paradoxical effect by desensitizing D3 receptors and reducing the uptake of dopamine.[18] This diminishes the effectiveness of dopamine agonists as the receptors are no longer able to lead to desired effects. Iron deficiency, vitamin D deficiency, circadian rhythm malfunction, and genetic risk factors may also play a role in augmentation, as well as through further dysregulation of the dopamine system.[18]

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Managing Augmentation

There are a couple of clinical strategies and approaches to mitigate the effects of augmentation when taking dopaminergic medications. The first strategy that your provider may discuss is adding an iron supplement to your diet. Iron deficiency is associated with worse RLS and can potentially contribute to augmentation.[18] Therefore, having an iron supplement can improve iron (ferritin) levels to not only reduce symptoms of augmentation, but also RLS as well. Another effective strategy is to discuss with your provider about switching to a different class of medication. Alternatives include non-dopaminergic drug classes, such as alpha-2-delta (α2δ) ligands, benzodiazepines, and opioids, which will be discussed in detail in future articles.[17] Since these medications provide relief through a different mechanism of action, they are not associated with the risk of augmentation. The usual technique is to either slowly and gradually cross-taper (coming down on one medication while going up on another) or to add in another medication until it is effective, then very slowly and gradually come down on the dopaminergic medication.[19] If your provider decides that you should stay on dopaminergic medications (which is less common and often only in specific cases), an alternative strategy would be to adjust the regimen. As augmentation is often dose-dependent and is more severe at higher dosages, lowering the dose of the medication can potentially alleviate the symptoms of augmentation in mild cases. One option is to change from a shorter, acting into a longer-acting dopaminergic. With all these strategies, consulting with a provider, such as a sleep specialist or neurologist, will be crucial.

Conclusion

Dopaminergic medications are said to be highly effective in treating RLS symptoms and have been traditionally considered the first line of treatment for RLS. However, over recent years, they have now been considered the third line of treatment due to their augmentation risk. We advise working with your provider to determine which treatments may be best suited for your condition and your needs. Here at Empower Sleep, our sleep specialists are no strangers to RLS, among other sleep conditions. If you need help getting your sleep back on track, our experts are here to help. Get started by talking to one of our sleep coaches today!

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