The Risks of Dopamine Agonists for the Treatment of Restless Legs Syndrome
Introduction
In 2005, a significant medical advancement occurred when ropinirole received approval from the Food and Drug Administration (FDA) for the treatment of restless legs syndrome (RLS). This milestone marked the first FDA-approved medication for this debilitating condition, offering patients a highly effective treatment option with minimal side effects. Approaching two decades since this advancement, ropinirole and its related drug pramipexole have become widely prescribed for RLS, establishing their status as a first-line therapy for over a decade.
Restless legs syndrome (RLS) is a neurological disorder characterised by an overwhelming urge to move the legs, holding still often worsens the condition and moving around gradually improves it.
It can affect individuals of all ages, but it is more apparent amongst the middle age group. Those severely affected by RLS may find it challenging to engage in everyday activities that require sitting for extended periods, such as watching a movie or enduring long-distance travel. The introduction of effective treatments like ropinirole and pramipexole has been a miracle for patients with severe RLS symptoms.
Ropinirole and pramipexole are classified as dopamine agonists, which refer to its ability to activate dopamine receptors in the brain. While the potential of dopamine-related drugs mitigating RLS symptoms was recognised prior to 2005, these drugs carried significant risks. The development of these two new dopamine agonists, followed by rotigotine in 2008, meant much safer RLS treatment options.
However, in 2024, there was an unexpected shift in the treatment of RLS when the American Academy of Sleep Medicine (AASM) implemented new clinical practice guidelines. These guidelines not only eliminated dopamine agonists as the first-line treatment for RLS but also conditionally advised against their standard of use for long-term RLS management, as they have likely caused greater suffering to RLS patients.

Dopamine agonists have two major problems:
1. Augmentation
Augmentation occurs when prolonged use of a dopamine agonist leads to worsening of RLS symptoms. This might present as patients having symptoms earlier in the day or as the spread of symptoms to other body parts, such as the arms.
Dopamine agonists are not the RLS saviours they were once thought to be.
Augmentation is believed to result in the brain reducing its own natural dopamine production, increasing reliance on medication to stimulate dopamine receptors.
Hence, patients require higher or more frequent doses to achieve the same degree of relief.
This leads to problematic consequences such as:
- Increased dosage only provides temporary relief.
- Reducing the dose worsens their symptoms.
- Patients develop a dependency on these drugs.
- These drugs will become addictive.
The only way to address augmentation is the discontinuation of the offending medication. The process of weaning off dopamine agonists can be extremely challenging as patients may experience symptoms like: insomnia, intense pain, anxiety, depression, suicidal thoughts and more. However, once patients successfully cease consumption of dopamine agonists, their RLS symptoms will improve drastically.
2. Impulse Control Disorders
Dopamine agonists, when taken in higher doses often lead to a highly destructive condition called impulse control disorders (ICDs). ICDs are a form of compulsive behaviour in which patients find it difficult to resist harmful urges or compulsions. The most common ICDs related to dopamine agonists are eating, shopping, gambling, and pornography consumption. For example, patients with a gambling ICD might spend an entire day at a blackjack table. The financial and social toll on these patients can be immense, and many of them are unaware that their RLS medication is the underlying cause.
After many years of experience, physicians have come to recognise dopamine agonists as a double-edged sword for patients in the treatment of RLS. Since these medications have revealed significant long-term risks, they are no longer recommended to patients for daily use. When prescribed, dopamine agonists should be limited to low doses, and ideally used sparingly for certain situations that may trigger the RLS, such as a long flight.
Alternatives to Dopamine
Thankfully, RLS treatment has evolved substantially, with several effective alternatives available in place of dopamine agonists now.
1. Iron
Without exception, the most critical treatment is iron. Low level of iron in the brain is a common and treatable cause of RLS, making it essential to ensure sufficient levels of brain iron as the foundation of successful treatment.
2. Drug Therapy (e.g. Gabapentin and Opioids)
The first-line drug therapy is gabapentin, a drug initially approved for seizures which is also highly effective for RLS. There are also related medications that are effective options for RLS treatment such as gabapentin enacarbil and pregabalin.
Another highly effective class of medications for RLS includes opioids, such as methadone and buprenorphine. Likewise, dipyridamole, a drug previously used to prevent strokes, is now being explored for RLS treatment.
3. Nerve Stimulator Band
Earlier this year, a nerve stimulator band worn below the knees was introduced to the American market as a drug-free treatment option. Each of these therapies offers viable alternatives for managing RLS.
Conclusion
Understanding the risks associated with dopamine agonists, particularly augmentation and ICDs, is essential for both healthcare providers and patients affected by RLS. Fortunately, there are numerous alternatives available that can provide relief for patients suffering with RLS without the long-term risks of dopamine agonists.
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