Restless legs syndrome (RLS) is a potentially debilitating condition that causes those affected to feel the need to move their legs, and occasionally arms, most commonly while trying to rest. Studies show the neurotransmitter, dopamine, plays an important role in the development of RLS and medications that activate dopamine receptors can help alleviate symptoms.

Introduction

Restless legs syndrome, also known as Willis-Ekbom Disease, is a neurological disorder characterised by an uncontrollable urge to move one’s legs, particularly whilst resting or trying to sleep. In the United States, RLS affects 7-10% of people, being more common in females and after the age of 45. Sufferers often describe experiencing unpleasant sensations such as aching or tingling in the lower limbs which is temporarily alleviated by movement. In some cases, the arms can also be affected. The condition can disrupt sleep, causing daytime fatigue, lack of productivity and overall worse quality of life. RLS has been associated with low iron levels, peripheral neuropathy, psychiatric and neurological illnesses, as well as the use of certain medications such as antipsychotics and antidepressants.¹

Research indicates that reduced availability or deficits in the transmission of the neurochemical dopamine might produce RLS symptoms. RLS is also disproportionately common in those diagnosed with conditions that affect dopamine homeostasis such as Attention Deficit and Hyperactivity Disorder (ADHD) and Parkinson’s Disease. In fact, dopaminergic therapies are the most effective pharmacological intervention for RLS.² Given the potentially profound psychological, lifestyle, and sleep disturbances patients may experience, it is fundamental to understand the neurochemical connection to RLS and how to ameliorate them. In this article, I will focus on dopamine as a target for RLS treatment.

Symptoms and causes of RLS

The main symptom of RLS is an uncontrollable urge to move one’s legs, and occasionally arms or torso, typically preceded by often poorly defined unpleasant sensations. Patients describe these as tingling, pain, electrical shocks, crawling under the skin, “pins and needles”, feeling like someone is pulling their limbs, or simply an exaggerated positional awareness of the area. These are usually worse upon relaxation, particularly when one is trying to sleep, and movement provides short-term relief.³

The causes of RLS are poorly understood, but researchers believe it might be linked to changes in levels of the neurotransmitter, dopamine, in the brain. Accordingly, conditions associated with lower-than-normal dopamine levels such as Parkinson’s Disease and ADHD carry an increased risk of RLS.¹ Iron deficiency, which can have many causes such as poor dietary intake, pregnancy, intestinal disorders, or end-stage kidney disease, has been found to be an important cause of RLS, as it might disturb dopamine neurotransmission.⁴ Genetics have also been implicated with up to 60% of patients having an affected relative.⁵ Other factors that have been associated with the development of RLS include:

• Peripheral neuropathy, most frequently due to Diabetes
• Autoimmune conditions such as Multiple Sclerosis
• Use of certain medications, including some antipsychotics, antidepressants, antihistamines, and antiemetics
• Alcohol and opiate withdrawal
• Lifestyle factors such as deprivation and excessive alcohol and caffeine intake¹

Dopamine as a neurotransmitter

Dopamine is a key neurotransmitter of the catecholamine class that has important signalling functions across the central and peripheral nervous systems. Dopamine has different roles across the body, modulating, for example, gut motility, renal sodium excretion and release of pancreatic hormones.⁶ In the brain, the mesolimbic dopamine pathway is most famously linked to the experience of reward and pleasure, as well as signalling the motivational drive for behaviours perceived as desirable.⁷ Dopamine-secreting neurons in the midbrain relay to brain areas that control movement execution and planning.  Degeneration of these neurons, as seen in Parkinson’s Disease can result in chronic tremors and motor impairment.⁸ By contrast, deficits in dopamine signalling in areas relating to pleasure and motivation may underlie the pathophysiology of many psychiatric conditions such as depression, anhedonia, substance addiction, and ADHD.⁷

The link between RLS and dopamine

Upon being released by neuronal terminals, dopamine activates its receptors on postsynaptic neurons. Studies show that RLS patients have reduced expression of the D2 receptor in the basal ganglia, an area of the brain that controls the planning and execution of movement.⁹ In the spinal cord, mice lacking the dopamine D3 receptor have a faster and more exuberant withdrawal response to pain, a potential mouse model for RLS.10 In accordance, medications that stimulate or block these receptors can treat or worsen RLS, respectively.² Interestingly, studies have also found that individuals with RLS had a compensatory increase in the enzyme that synthesises dopamine in different brain areas, causing it to potentially overstimulate other receptors such as the D1.⁹ Overall, there is extensive evidence linking RLS to different imbalances in dopamine levels and receptor expression, which might occur due to genetic factors, neurological conditions or low availability of iron.

Management and prognosis of RLS

In some cases, RLS can be treated by ensuring adequate iron supply, often through supplementation, dietary changes, or treating underlying renal or intestinal diseases that affect iron absorption and excretion. Sometimes RLS is caused or exacerbated by medications, most notably antipsychotics, in which case changing the medication regime might be necessary.

The first-line treatment for idiopathic RLS is lifestyle modifications such as avoiding alcohol and caffeine and maintaining good sleep hygiene. However, medications are often also necessary for moderate to severe cases. Most commonly, doctors will prescribe dopamine agonists that activate D2 receptors such as pramipexole and ropinirole. Other options include anticonvulsants like gabapentin, which can help with nerve pain and benzodiazepines for their sedative effects.¹

The prognosis for RLS varies. Unfortunately, RLS is often a chronic condition that can worsen over time and put one at risk of several complications such as psychiatric conditions, insomnia, and daytime fatigue.⁸ However, through adequate care - focusing on symptom relief, monitoring sleep quality, and addressing any psychosocial – symptoms, distress and disability can be reduced.

Conclusion

In conclusion, RLS is a distressing condition, affecting 7-10% of people, that causes an uncontrollable urge to move one’s limbs, often accompanied by unpleasant sensory feelings. Symptoms are worse at night during relaxation, often interfering with sleep. As a result, RLS can be very distressing, and affect daytime productivity, and quality of life. Understanding its pathophysiology and treatment options is thus fundamental.

The most popular hypothesis to explain RLS involves the neurotransmitter dopamine and the receptors it activates, which show abnormalities in RLS patients. This is often caused or exacerbated by iron deficiency, medications or lifestyle factors, which can be addressed by dietary changes, improving kidney function, or avoiding alcohol and caffeine. Oftentimes, however, medications that activate dopamine receptors are necessary to fix the chemical imbalance and alleviate symptoms.

FAQs

What is restless legs syndrome (RLS)?

Restless Legs Syndrome (RLS) is a neurological disorder characterised by an uncontrollable urge to move the legs, often accompanied by uncomfortable sensations, typically when one is trying to relax or fall asleep.

Who is at risk of RLS?

RLS can affect anybody, but it is most common in women and those aged 45 or above. Having certain conditions such as kidney disease, peripheral neuropathy, Parkinson’s Disease, and psychiatric disorders, as well as affected relatives can increase one’s risk.

How is dopamine related to RLS?

Dopamine is an important neurochemical that plays various roles across the nervous system and has been implicated in several neurological and psychiatric disorders. Studies have shown that RLS patients may have abnormalities in dopamine neurotransmission in areas of the central nervous system involved with sensorimotor function. Accordingly, drugs that activate dopamine receptors can improve RLS symptoms.

How is RLS diagnosed?

RLS is diagnosed based on patient-reported symptoms and medical history. There are no specific tests for RLS, but doctors may perform tests to rule out other conditions. Diagnostic criteria include: the urge to move the legs, worsening symptoms at rest, and relief with movement.

What are the treatment options for RLS?

If RLS is thought to be due to low iron levels, ensuring adequate supply is the first treatment. Other options include lifestyle changes, such as regular exercise and good sleep hygiene, and medications like dopamine agonists (e.g., pramipexole, ropinirole). Other medications like anticonvulsants and benzodiazepines may also be used.