The risks of dopamine agonists for the treatment of restless legs syndrome
An extraordinary breakthrough of modern medicine occurred in 2005 when the FDA approved ropinirole for the treatment of restless legs syndrome (RLS). With the first drug ever approved for this misery-inducing condition, patients finally had a highly effective treatment with relatively few side effects. Nearly 20 years later, ropinirole and its cousin pramipexole are among the most prescribed treatments for RLS, and they have been considered first-line therapy for over a decade.
Restless legs syndrome is an unpleasant sensation, typically described as an intense urge to move, that worsens later in the day, is provoked by holding still, and improves while moving. It can affect people of all ages, but it gets more common around middle age. For people with this condition, life can become unbearable. They are unable to sit long enough to enjoy a meal or watch a movie. Taking a flight or a long car ride is torture. Having an effective treatment like ropinirole and pramipexole was beyond a miracle for patients with severe symptoms.
Ropinirole and pramipexole fall under the drug category of dopamine agonists. This means that these drugs stimulate dopamine receptors in the brain. While it was known long before 2005 that dopamine-related drugs could improve RLS symptoms, those drugs had unacceptable risks. The two new dopamine agonists—which were joined in 2008 by a third drug, rotigotine—were considered much safer, and doctors who treated RLS flocked to them. Dopamine agonists were how RLS was treated. Problem solved, apparently.
Another extraordinary event is taking place in 2024, though. Dopamine agonists are not only being removed as first-line treatment for RLS, new guidelines by the American Academy of Sleep Medicine place dopamine agonists on the “do not use” list. This complete about-face is a result of years of observing that dopamine agonists are not the RLS saviors they were once thought to be. In fact, they have almost certainly caused even more suffering.
Dopamine agonists have two major problems: augmentation and impulse control disorders. Augmentation occurs when consistent use of a dopamine agonist starts to make RLS symptoms worse. This might manifest as patients having symptoms earlier in the day or having symptoms in other body parts, such as the arms.
Dopamine agonists are not the RLS saviors they were once thought to be.
Augmentation is thought to be the result of the brain shutting down its own natural dopamine production to rely more and more on the pills to stimulate dopamine receptors. As a result, patients require higher or more frequent doses to achieve the same degree of relief. Eventually, even those doses don’t provide relief, and the suffering starts to spread throughout the day. These drugs are particularly insidious because each time the dose is increased, patients feel better. Temporarily. If they try to decrease their dose, they feel worse. Essentially, patients become dependent on these drugs; they’re addictive.
The only treatment for augmentation is to stop the offending medication. Dopamine agonists must be weaned off, and the process can be brutal: insomnia, severe pain, anxiety, depression, thoughts of suicide, and more. When it’s over, though, the RLS symptoms are inexorably better.
The elevated doses of dopamine agonists that patients with augmentation often take can also cause a highly destructive condition called impulse control disorders (ICDs). ICDs are a form of compulsive behavior in which patients find it difficult or impossible to stop doing things that are harmful to them. The most common ICDs related to dopamine agonists are eating, shopping, gambling, and pornography consumption. Patients with a gambling ICD, for example, might spend 24 straight hours at a blackjack table. Those with a shopping ICD might start buying gifts they can’t afford for all their friends and family members just because an advertisement came on TV. The financial and social losses incurred by these patients can be massive, and many of them have no idea that their RLS medication is the cause.
With decades of experience, it became clear to physicians treating RLS that dopamine agonists were a seductive enemy to RLS patients. Exposing patients to the risks of augmentation and ICDs could no longer be justified, and they are no longer recommended for daily use. If patients do take dopamine agonists, the doses must be kept low, and ideally, used only sparingly for situations likely to trigger the RLS, like a long flight.
Fortunately, there are highly effective alternatives to dopamine agonists now. The most important treatment, bar none, is iron. A low level of iron in the brain is a very common cause of RLS and a very treatable one. Successful treatment of RLS begins with ensuring adequate levels of brain iron. After that, first-line drug therapy is now gabapentin, a drug originally approved for seizures that is highly effective for RLS, along with its related drug gabapentin enacarbil and their counterpart pregabalin. The other highly effective class of medications for RLS is opioids, including methadone and buprenorphine. Dipyridamole, a drug that used to be used to help prevent strokes, is starting to be used for RLS now. And earlier this year, a nerve stimulator band worn below the knees entered the American market for a drug-free treatment option. Each of these therapies can be considered for the treatment of RLS.
It is crucial for doctors and patients to understand the risks of dopamine agonists, including augmentation and ICDs. There are many alternatives to help this long-suffering group of people without the threat of making them worse over time. Patients who suffer with RLS should know they need not suffer forever.
