November 3, 2021

Understanding Augmentation and How to Recover from Dopamine Dependence

by J. Andrew Berkowski, MD, member of the RLS Foundation’s Scientific and Medical Advisory Board

Dopaminergic medications had been the mainstay of first-line pharmacological treatment of RLS for many years, but they have significantly fallen out of favor in the past decade due to high rates of augmentation and, secondarily, impulse-control disorders. Clinical consensus guidelines no longer consider these agents to be first-line treatments, despite the abundance of research demonstrating significant efficacy in the short term (months to a few years). The high rates of augmentation, which is thought to be inevitable with long-term use, begs the question: “Should anyone take dopaminergic agents at all for this chronic, lifelong condition?”

Despite relegation of dopaminergics to second-line status in the more updated clinical guidelines since 2015, many RLS experts only use these medications now in rare circumstances. If these therapies are considered, they should be trialed only after the ineffectiveness or intolerable side effects of the other treatments available for RLS. After initiation for daily use, regular monitoring must be performed for early identification of the stages of effects on the dopaminergic system, including dependence, tolerance, mild augmentation and severe augmentation. Dopamine agonists may have initial side effects, including nausea, vomiting, headache, sleepiness and dizziness.

The most commonly used dopamine agonists are the short-acting pramipexole and ropinirole, and the long-acting transdermal rotigotine patch. Levodopa is reserved for intermittent RLS symptoms, due to extremely rapid onset of augmentation (weeks to months) when taken daily. Though no studies have investigated augmentation with intermittent use, three doses or fewer per week has been considered reasonable. Potential uses include evening dosing for occasional RLS symptoms, dosing prior to sedentary situations (e.g., plane flight, theater presentation), and dosing for patients in whom the diagnosis of RLS is in doubt.

Augmentation

Since dopamine agonists became a first-line treatment for RLS in the early 2000s, two decades of experience have demonstrated high rates of (possibly inevitable) augmentation with long-term use. Augmentation is a worsening of RLS with one or more of the following features: an advance of the typical time of day when symptoms begin, two or more hours earlier than before the start of treatment; a spread of restlessness from the legs to the arms or trunk; a shorter interval before symptoms start after inactivity (sitting or lying); progressive dosage escalation to produce the same effect; and even paradoxical triggering of RLS symptoms immediately after taking the medication.

Augmentation has led to the most dramatic paradigm shift in RLS management, as it causes the majority of refractory RLS cases. This phenomenon poses significant philosophical challenges to the clinician, as a potential worsening of the condition long term in most cases should prohibit the use in the short term, regardless of the significant short-term effectiveness. Because of the increasing prevalence of augmentation, the RLS Foundation’s Scientific and Medical Advisory Board published a guideline outlining the identification and treatment of augmentation. The presence of one or more of the following factors is known to increase the likelihood of augmentation: more frequent RLS symptoms before treatment, greater discomfort with RLS symptoms before treatment, co-morbid asthma, older age, longer treatment duration, lower serum ferritin levels, and greater baseline severity of RLS.

Four screening questions are recommended to identify augmentation:

1. Do RLS symptoms appear earlier than when the drug was first started?
2. Are higher doses of the drug now needed, or does the medication need to be taken earlier in the day, to control the RLS symptoms compared to the original effective dose?
3. Has the intensity of symptoms worsened since starting the medication?
4. Have symptoms spread to other parts of the body (e.g., arms, trunk, face) since starting the medication?

Augmentation is considered mild if all of the following are present: symptoms manifest predominantly as a temporal shift of symptoms to earlier in the day compared to before starting treatment; dopaminergic monotherapy is at a total daily dose at or below maximum recommended levels; symptoms cause only mild distress; and there has been no prior increase in total dose above that which was previously therapeutically effective. In cases of mild augmentation, there is more time to make adjustments to treatment regimen, but the symptoms do represent an early stage of dopaminergic system impairment and dependence. This will progress to more severe symptoms and advanced augmentation if no changes are made or dopamine medication dosage is simply increased.

Augmentation is considered severe if it does not fulfill the criteria for mild augmentation (e.g., the total agonist dose exceeds recommended levels or the symptoms cause more than mild distress) or does not respond to treatment of mild augmentation.

Treating Augmentation

Initially, it is important to identify and eliminate or treat factors that exacerbate RLS. These could include poor sleep hygiene or other untreated sleep disorders, ingestion of drugs/foods that worsen RLS symptoms, or low levels of ferritin or percent transferrin saturation. If the iron stores are low, then iron therapy (oral or intravenous) should be considered.

For mild augmentation, the dopamine agonist medication could be continued and the total dose maintained but given in divided doses, or the medication could be given earlier to precede the onset of RLS symptoms. If symptoms are not managed by splitting the dosage, then the addition of other therapies should be considered, such as iron infusion, alpha-2-delta ligand medications, and possibly opioid medications. Changing to a longer-acting dopaminergic agent such as transdermal rotigotine could be considered, but this will only delay the inevitable augmentation to future months or years. Rotigotine has lower rates of augmentation long term in studies but is thought to mask augmentation due to having a steady level of the drug in the system continuously without time off from the drug. If the second treatment added does not provide symptom relief, then augmentation should be considered severe. Even if augmentation is mild, long-term plans should be discussed for transition to other treatments before more severe augmentation develops. Tapering off the dopamine agonist, with or without a second-line agent added, should be considered long term, to initiate dopaminergic system withdrawal and reconstitution.

For severe augmentation, the goal over several weeks to months is to wean, slowly but completely, off all dopaminergic agents to enable withdrawal, recovery from dopaminergic dependence, and maximal reconstitution of the natural dopaminergic system to as close to previous baseline as possible. One method is to perform a slow wean of the dopaminergic agent, followed by a two-week drug holiday, and then the addition of an alternative agent if still requiring symptomatic treatment. Though this approach is ideal in terms of natural recovery and limiting medication side effects, it is often met with apprehension due to the severity of withdrawal symptoms. The addition of a second medication prior to reduction in the dopaminergic medication is more common. Therapies may include an IV iron infusion (more potent and rapid than oral iron), alpha-2-delta ligands, opioids and, rarely, benzodiazepines. The dopamine agonist weaning process can be highly variable among patients, depending on initial severity of symptoms and strength of dosage. Anecdotal evidence suggests that many patients can go through a mini-withdrawal and recovery process after each dosage decrease in four to seven days, but some may take a few weeks or require increases in the secondary agent if they do not improve. Recovery after complete discontinuation may be the greatest in the first two weeks, though some patients take much longer to recover significantly. Many may have slow improvement beyond the initial few weeks for months or years after discontinuation, though the natural history of dopamine agonist withdrawal and recovery has not been well studied yet.

Dose reduction must be managed by a healthcare provider, and each situation is different; however, there are some management guidelines. Ropinirole may be tapered by 0.25 to 0.5 mg per week as tolerated, pramipexole by 0.125 mg, and rotigotine by 1 mg. However, the initial decreases may be larger, particularly if the patient is on dosages beyond maximum recommended, with progressively smaller decreases as the patient approaches discontinuation. Symptoms of withdrawal are generally a temporary but possibly severe worsening of restless legs symptoms, including more severe breakthrough symptoms, symptoms during the night leading to insomnia, earlier onset of symptoms during daytime with possible spread to other anatomic regions, and even involuntary limb movements while awake. These symptoms generally improve over several days before the patient can begin the next step in the tapering process. If a second agent is used, it may need to be adjusted to balance effectiveness with side effects, to combat the withdrawal symptoms. Other symptoms during dopaminergic withdrawal may include high levels of anxiety, irritability, insomnia, excessive daytime sleepiness and depressed mood.

After at least two weeks from discontinuation, the patient should be reassessed to see if the new symptomatic agent can be gradually tapered as well, or a second medication added in the case of patients who tapered without additional drug treatment. Several weeks to months after complete withdrawal, recovery is frequently seen and further dosage reduction can be made, as the dosage of a second medication is generally higher in the withdrawal period than weeks to months after recovery, due to progressive reconstitution of the dopaminergic system.

Impulse Control Disorders

Impulse control disorders are another side effect of dopamine agonist therapy. Due to long-term effects on the dopaminergic system and behavioral pathways, dopamine agonists are associated with impulse control disorders (e.g., pathologic gambling, excessive shopping, hypersexuality) within nine months of treatment onset. Symptoms of impulse control disorders (and augmentation) should be screened regularly, regardless of duration of use. The consequences of unrecognized impulse control disorders can be devastating, including substantial financial loss, the threat of criminal prosecutions, substance abuse and social disruption. However, complete resolution of the pathologic tendencies is the general rule with discontinuation or dose decrease of the causative agent.

Education and Awareness

Decades of dopamine agonist use have revealed the risk of augmentation and impulse control disorders. Education of healthcare providers is the first step to raise awareness about RLS treatment guidelines and the adverse side effects of dopaminergic medications. Support for RLS research leading to the identification of new medications that address the chronic progressive nature of RLS and its treatment challenges are priorities for the RLS community.