Pharmacists Can Contribute to Management of Restless Legs Syndrome Augmentation

Restless legs syndrome (RLS) is a neurological disorder that causes an overwhelming urge to move the legs, often accompanied by discomfort, especially during rest periods. It can significantly interfere with sleep and quality of life. Many individuals with moderate to severe RLS find relief through medication, particularly dopamine agonists. However, long-term use of these medications can lead to a phenomenon known as "augmentation," in which the very treatment for RLS inadvertently worsens the symptoms over time. Understanding augmentation, its causes, symptoms, and management strategies is crucial for those managing chronic RLS.

Woman with restless legs syndrome | Image credit: Andrey Popov | stock.adobe.com

What is Augmentation in RLS?

Augmentation is a condition in which RLS symptoms intensify or change in response to long-term dopamine agonist treatment. Unlike tolerance, which is a diminished response to medication, augmentation specifically means the symptoms appear earlier in the day, become more severe, or spread to other body parts, such as the arms. This phenomenon poses a significant challenge because it limits the effectiveness of one of the most prescribed RLS treatments.

Causes and Risk Factors for Augmentation

The exact cause of augmentation is not entirely understood, but it is believed to be related to the mechanisms by which dopamine agonists function. Dopamine agonists, including pramipexole (Mirapex; Boehringer Ingelheim), ropinirole (Requip; GSK), and rotigotine (Neupro; UCB), work by mimicking dopamine, a neurotransmitter involved in movement and reward pathways. Over time, the brain may become sensitized to these drugs, leading to changes in dopamine receptor regulation, which may contribute to worsening symptoms. The augmentation risk is also connected to carbidopa levodopa.

Updated 2024 guidelines from the American Academy of Sleep Medicine (AASM) for the treatment of RLS advise against use of dopamine agonists and levodopa for RLS because of the augmentation risk.¹ However, these medications are still commonly used in clinical practice.

Several factors increase the risk of augmentation, including the following²:

• Higher doses of dopaminergic medications: The risk of augmentation tends to increase with higher doses of dopamine agonists, carbidopa levodopa, etc.
• Long-term use: Prolonged use over years is a common factor in patients who experience augmentation.
• Severe RLS symptoms: Those with more severe initial symptoms may be more likely to experience augmentation.
• Low iron levels: Iron deficiency has been associated with RLS severity and may also contribute to augmentation. Monitoring and addressing iron levels is often part of RLS management.

Recognizing Augmentation Symptoms

Augmentation symptoms can vary, but several indicators can help differentiate it from typical RLS. These include the following^1-3:

• Earlier symptom onset: A hallmark sign of augmentation is the earlier onset of symptoms. Whereas symptoms may have previously started in the evening, patients may notice discomfort earlier in the day.
• Increased symptom severity: Augmentation often leads to more intense sensations, even with the same dosage of medication.
• Spread to other body parts: Augmentation may cause symptoms to appear in other parts of the body, such as the arms or torso.
• Shorter relief from medication: Patients may find that their usual dose no longer provides lasting relief, leading to a shorter symptom-free period.

If these symptoms occur, it is important to consult a health care provider to assess whether augmentation might be contributing to the changes.

Strategies for Managing Augmentation

Managing augmentation requires a careful approach and, often, adjustments to the treatment plan. The following are common strategies used by health care providers³:

• Reducing or discontinuing dopamine agonists: Gradual reduction of the dopamine agonist may help manage symptoms without causing severe withdrawal effects. In some cases, discontinuation might be necessary. Since stopping these medications suddenly can lead to withdrawal symptoms, any reduction should be done under medical supervision.
• Switching to alternative medications:Medications that do not carry the same risk of augmentation are often considered. These alternatives may include the following³:
  • Alpha-2-Delta Ligands: Gabapentin enacarbil (Horizant; Azurity) and pregabalin (Lyrica; Viatris) are effective for many patients with RLS and are associated with a lower risk of augmentation.
  • Opioids: For severe cases in which other treatments are ineffective, low doses of opioids such as extended-release oxycodone may be considered. Opioids can be highly effective for RLS but require careful monitoring due to risks of dependence and adverse effects.
• Iron supplementation: Because iron deficiency is linked to RLS severity, iron supplementation may be recommended, especially if iron levels are low. Ferritin levels below 75 ng/mL are often considered an indicator for supplementation. Intravenous iron is sometimes used for individuals who do not respond to oral supplements or have absorption issues.
• Non-pharmacological treatments: Several non-drug therapies can help manage RLS symptoms, including augmentation. High-frequency nerve stimulation, such as peroneal nerve stimulation, has shown promising results in reducing RLS symptoms. Lifestyle adjustments, including maintaining a regular sleep schedule, reducing caffeine and alcohol intake, and engaging in regular physical activity, may also provide some symptom relief.
• Close monitoring and regular follow-up: Regular follow-up with a health care provider is essential for managing RLS, especially for those experiencing augmentation. Adjusting medications, assessing symptoms, and monitoring adverse effects require careful, individualized management.

Preventing Augmentation in RLS Treatment

Although augmentation is not entirely preventable, several steps can help reduce its risk, including³:

• Starting with low doses: If a dopamine agonist is recommended for the patient, initiate treatment with the lowest effective dose.
• Periodic reassessment of medications: Regularly reviewing and adjusting medications can help manage risks. Some clinicians may rotate between therapies to reduce the likelihood of augmentation.
• Monitoring iron levels: Proactively monitor iron levels and supplement as needed to help address one of the risk factors for RLS.

Augmentation in RLS presents a unique challenge for patients and health care providers alike. Although dopamine agonists have long been a mainstay of RLS treatment, their long-term use requires careful management to avoid worsening symptoms. For those experiencing augmentation, a tailored treatment plan that may include alternative medications, lifestyle changes, and regular monitoring offers the best approach to managing symptoms. The evolving understanding of augmentation has led to updated treatment guidelines, emphasizing alternatives like alpha-2-delta ligands and iron supplementation, which may provide effective, safer relief for those with RLS. As research progresses, new therapies and approaches will hopefully offer even better options for those affected by this challenging condition.

In managing augmentation of RLS, pharmacists play a crucial role by monitoring patients’ symptoms, medication regimens, and potential adverse effects. Pharmacists can identify early signs of augmentation, such as the worsening or earlier onset of symptoms, and educate patients about this possibility when starting dopamine agonists. Additionally, they can advise on alternative treatments, such as alpha-2-delta ligands or iron supplementation, and provide guidance on lifestyle modifications that may help manage RLS symptoms. By collaborating with other health care providers, pharmacists contribute to optimizing therapy, reducing the risk of augmentation, and improving the quality of life for patients with RLS.

Reference

1. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2024 Sep 26. doi: 10.5664/jcsm.11390. Epub ahead of print. PMID: 39324694

2. Zeng P, Wang T, Zhang L, Guo F. Exploring the causes of augmentation in restless legs syndrome. Front Neurol. 2023 Sep 28;14:1160112. doi: 10.3389/fneur.2023.1160112. PMID: 37840917; PMCID: PMC10571710.

3. Silber MH, Buchfuhrer MJ, Earley CJ, et al. The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clinic Proceedings. 2021;96(7):1921-1937. doi:https://doi.org/10.1016/j.mayocp.2020.12.026