What is the relationship between dopamine and restless leg syndrome (RLS)?

Dopamine's Role in Restless Legs Syndrome

Dopamine dysfunction is central to the pathophysiology of RLS, with brain iron deficiency disrupting dopamine neurotransmission in specific neural circuits, particularly the hypothalamic A11 dopaminergic system, leading to the characteristic sensorimotor symptoms of the disorder. 1

Pathophysiological Mechanisms

Dopaminergic Dysfunction

• The hypothalamic A11 dopaminergic circuit is the primary site of dopamine dysfunction in RLS, explaining why dopamine D2 receptor agonists provide therapeutic benefit by modulating this pathway. 2
• Brain iron deficiency, particularly in specific brain regions, interacts with dopamine systems to produce RLS symptoms, even when serum iron studies appear normal. 1
• The impairment of dopamine transport in the substantia nigra due to reduced intracellular iron plays a critical role in most RLS patients. 1

Peripheral Dopamine Alterations

• Blood plasma dopamine levels are significantly increased in medicated RLS patients compared to unmedicated patients and controls, though norepinephrine and epinephrine levels remain unchanged. 3
• Downregulation of D2-subtype dopamine receptors (D2Rs) occurs in white blood cells of RLS patients, with lymphocytes showing altered D2R expression that differs between medicated, unmedicated, and control subjects. 3
• This peripheral D2R downregulation is not reversed by medication, despite commonly used RLS medications increasing plasma dopamine levels. 3

Striatal Dopamine Transporter Changes

• Dopamine transporter (DAT) density is increased in the caudate, posterior putamen, and entire striatum of moderate to moderately severe RLS patients compared to controls. 4
• This suggests dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission underlies RLS pathogenesis, with decreased dopaminergic neurotransmission potentially causing moderate to moderately severe symptoms. 4

Clinical Implications of Dopamine Dysfunction

Historical Treatment Approach

• Dopamine agonists (ropinirole, pramipexole, rotigotine) were historically FDA-approved first-line treatments for RLS based on their ability to stimulate dopamine D2 receptors. 5
• The precise mechanism by which dopamine agonists relieve RLS symptoms is thought to relate to their ability to stimulate dopamine receptors, though the exact pathway remains incompletely understood. 5

Major Treatment Paradigm Shift

• The American Academy of Sleep Medicine now suggests against the standard use of dopamine agonists due to the major problem of augmentation with long-term use, representing a substantial change in RLS treatment recommendations. 1, 6
• Augmentation is a phenomenon where dopaminergic medication causes worsening of symptom severity above baseline, with earlier onset of symptoms in the evening, increased symptom intensity, and spread to other extremities. 5
• This complication led to downgrading of dopamine agonists despite their constituting the majority of FDA-approved medications for RLS. 1

Current Treatment Recommendations

• Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, pregabalin) are now strongly recommended as first-line therapy instead of dopaminergic agents. 6
• Dopamine agonists may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 6
• Iron therapy (IV ferric carboxymaltose or oral ferrous sulfate) is strongly recommended when ferritin ≤75 ng/mL or transferrin saturation <20%, addressing the underlying iron-dopamine interaction. 6

Dopamine-Related Adverse Effects

Augmentation Risk

• Augmentation has been observed in postmarketing trials of ropinirole, with symptoms including earlier onset in the evening or afternoon, increased symptom severity, and spread to other extremities. 5
• When augmentation occurs, dopamine agonist dosage adjustment or discontinuation should be considered, with gradual dose reduction recommended. 5

Medication-Induced Worsening

• Dopamine antagonists (antipsychotics including lurasidone, typical antipsychotics) can trigger or worsen RLS symptoms through dopamine receptor blockade. 6, 1
• Other medications that exacerbate RLS include tricyclic antidepressants, SSRIs, and lithium. 1

Abuse Potential

• Rare cases of dopamine dysregulation syndrome have been reported, with patients progressively abusing levodopa (up to 4000 mg/day documented), possibly linked to the rewarding effect of dopamine. 7
• This abuse potential can occur even without central dopamine depletion, suggesting physicians treating RLS with dopaminergic agents should monitor for this complication. 7

Common Pitfalls

• Do not assume normal serum iron studies exclude iron deficiency in RLS—brain iron deficiency in specific regions drives dopamine dysfunction even with normal peripheral iron markers. 1
• Avoid long-term dopamine agonist monotherapy without monitoring for augmentation, as this complication can develop insidiously and significantly worsen patient outcomes. 1
• Screen all RLS patients for medications that antagonize dopamine (antipsychotics, antiemetics) or otherwise worsen symptoms (SSRIs, antihistamines), as these can undermine treatment efficacy. 1, 6