Abstract

Restless Legs Syndrome (RLS) is a common neurological disorder characterised by an uncontrollable urge to move the legs. Dopamine agonists are widely used as first or second-line treatments for RLS due to their efficiency in alleviating the symptoms of RLS and improving sleep quality. Whilst efficacious, dopamine agonists can also cause several side effects which are important to understand and monitor. This article aims to provide a practical overview of when and how to prescribe dopamine agonists together with appropriate monitoring advice for clinicians. 

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What is restless legs syndrome? 

Restless Legs Syndrome (RLS), or Willis-Ekbom disease, is a prevalent neurological disorder characterised by an irresistible urge to move the legs, often accompanied by uncomfortable sensations described as creeping, crawling, tingling, or burning [1]. Symptoms are most pronounced during periods of rest, particularly in the evening or at night, and are temporarily alleviated by movement. 

Diagnosis of RLS is clinical, guided by the International Restless Legs Syndrome Study Group (IRLSSG) criteria [2]. A simple screening question can also be used: “When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement?” This question has a 100% sensitivity and 96.8% specificity for diagnosing RLS [3]. 

What causes RLS? 

RLS affects 5-15% of the population, with prevalence rising with age, peaking in the seventh decade. Women are affected twice as often as men (2:1 ratio) [4]. While most cases are idiopathic, secondary causes such as iron deficiency, pregnancy, and end-stage chronic kidney disease (CKD) are critical to identify, as they can exacerbate symptoms [5]. Neurological disorders like peripheral neuropathy may also increase RLS risk [6]. 

Modifiable risk factors, including poor sleep hygiene, smoking, caffeine, alcohol, and physical inactivity, contribute to the development and severity of RLS. Certain medications – antidepressants, antipsychotics, antiepileptics, dopamine antagonists, beta-blockers, and sedating antihistamines – can worsen RLS symptoms [5,7,8]. 

The pathophysiology of this condition is thought to involve a dopaminergic system dysfunction, as evidenced by the efficacy of dopamine agonists (DA) in treatment [9,10]. 

Initial management 

Dopamine agonists are certainly not first-line treatments for RLS. Screening for iron deficiency is essential, with ferritin levels below 75 µg/L warranting supplementation [11,12]. If oral iron is insufficient or contraindicated, intravenous iron may be considered. 

Non-pharmacological management includes addressing modifiable risk factors of RLS, patient education, sleep hygiene advice, encouraging smoking cessation, minimising caffeine and alcohol intake, and moderate exercise [7]. Signposting patients to resources like the RLS-UK website can also empower them to take an active role in their condition [1]. 

Reviewing the patient’s medications is crucial, some of which may have been obtained over-the-counter; consider switching or discontinuing these medications [5]. Patients with RLS often experience daytime dysfunction, presenting to practitioners with symptoms of insomnia, depression, or anxiety. A common pitfall is to initiate a sleep-enhancing antidepressant, such as mirtazapine, to combat the insomnia and depression caused by RLS, inadvertently exacerbating the symptoms [13]. 

Pharmacological management 

After excluding reversible causes, medications could be considered. For mild cases, low-potency opioids during acute episodes may suffice (Figure 1) [5]. 

For frequent attacks, a regular preventative medication can be utilised. The first-line treatment is alpha2-delta ligands (A2DL), such as pregabalin or gabapentin, although the use for this is currently ‘off-label’ in the UK [14]. These are generally given once or twice daily, approximately 1-2 hours before symptom onset. Initiate at a low dose (100mg gabapentin or 25mg pregabalin), titrating every few days as indicated. 

If A2DLs are contraindicated or ineffective, non-ergot dopamine agonists (DA) may be used [15]. Although DAs have comparable efficacy to A2DLs, they are considered second-line due to the risk of augmentation and impulse control disorders (ICD) [5,16]. Relative contraindications to A2DLs include obesity, moderate to severe depression, gait instability, respiratory failure, and a history of substance misuse [5]. 

Dopamine agonists in RLS 

The non-ergot dopamine agonists pramipexole, ropinirole, and rotigotine are all effective for RLS. Selection is based on administration preference, drug availability, and presence of daytime symptoms (Figure 2) [17]. Balancing symptom control with adverse effects can be challenging, and consulting a specialist pharmacist is advised. 

DAs are contraindicated in pregnant women, those with a history of DA hypersensitivity, and patients on monoamine oxidase inhibitors. Those at high risk of ICDs – patients with OCD, impulsive personality traits, or a history of substance misuse – should be carefully screened and monitored. 

Adverse effects 

The two major adverse effects of DAs are augmentation and ICDs. These are pertinent to warn patients about, as they can be subtle yet have drastic implications on the patient and disease progression. 

Augmentation refers to a paradoxical worsening of RLS symptoms with DA use, including earlier symptom onset, increased severity, and spread to other body parts like the arms or trunk [18]. The risk of augmentation is estimated around 8% per year, with higher doses increasing this risk [19]. Differentiating augmentation from rebound symptoms, tolerance, loss of efficacy, or natural disease progression requires elaborate history taking. When augmentation is suspected, it is essential to recheck the baseline investigations to rule out potential exacerbating factors. For mild cases of augmentation, the DA dose can be split – half taken before symptom onset and the other half at bedtime. For severe cases, consider referral to a specialist. Although it is common to try switching DAs when one proves ineffective, this often fails to achieve satisfactory results [20]. 

ICDs associated with DA use include pathological gambling, binge eating, compulsive shopping, and hypersexuality, with a risk estimated at 17% [21]. Notably, augmentation has been linked to impaired decision-making, even in the absence of overt ICD symptoms [22]. Patients and their families should be informed of these risks before initiating DA therapy – ideally a family member should be present for the initial consultation. If an ICD is suspected, the DA should be down-titrated or discontinued, and a specialist referral considered. 

Other common DA side effects include nausea, headache, dizziness, fatigue, fluid retention, constipation, and nasal congestion, most of which self-resolve within two weeks or after discontinuation [5]. Daytime sleepiness or sudden sleep attacks can occur with higher doses, and patients should be advised not to drive if affected. Rotigotine patches cause skin reactions in 5-10% of patients [5]. 

Monitoring and discontinuation 

Annual monitoring is necessary to assess medication efficacy and adverse effects, with a close scrutiny for subtle signs of ICDs. More frequent follow-ups (e.g. every 3 months) may be needed during dose titration. If symptoms are well-controlled for over a year, a dose reduction could be considered. 

Dopamine agonists should be tapered gradually to avoid withdrawal symptoms, which may include depression, anxiety, irritability, fatigue, nausea, vomiting, generalised pain, and drug cravings [23]. A tapering rate of 20-25% per week is reasonable, with adjustments based on patient response. 

Special populations 

Pregnancy: RLS often begins or worsens in the third trimester, usually resolving post-partum [5]. Most cases can be managed with education, reassurance, iron supplementation, and non-pharmacological strategies. Pharmacological treatment could be considered [24], although DA use is generally avoided due to its potential to inhibit lactation [5]. 

Children: RLS in children may present as sleep or behavioural issues, often linked with neuropsychiatric conditions like ADHD, depression, anxiety, and parasomnias [25,26]. Diagnosing RLS in children can be challenging due to their limited ability to articulate symptoms. Therefore, a low threshold for specialist referral is recommended for accurate diagnosis and treatment. 

Referral to a specialist 

Many general practitioners and neurologists will feel entirely comfortable utilising DA in the treatment of RLS. However, referral to a sleep specialist is recommended if: 

  1. There is a diagnostic uncertainty or possible additional obstructive sleep apnoea 
  2. There is an insufficient response to DA treatment despite adequate dosage and duration 
  3. The side effects are intolerable 
  4. Symptoms are not controlled on maximum dosage 
  5. There are signs of ICD or augmentation, or 
  6. Symptoms are present in children [5] 

References

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