Restless legs syndrome (RLS/Willis-Ekbom disease): irresistible urge to move the legs + uncomfortable sensations (creeping, crawling, burning) + 4 defining criteria (URGE). Affects 5-15% of Western populations; more common in women; increases with age. Causes significant sleep disruption and daytime fatigue. Frequently misdiagnosed as cramps, anxiety or neuropathy.

What is augmentation?

Augmentation is the paradoxical worsening of RLS from dopamine agonist therapy — the drug makes the condition worse over time. Affects ~30-50% of long-term daily DA users. Features: earlier onset (morning symptoms instead of just evening); spread to arms; more intense; faster onset with rest. Never increase the DA dose — this perpetuates augmentation. Correct management: gradually withdraw DA; switch to alpha-2-delta ligands or low-dose opioids.

Why is iron important in RLS?

Iron deficiency is the most important correctable RLS cause — even when Hb is normal. Brain iron deficiency (substantia nigra) impairs dopamine synthesis → RLS. Check serum ferritin in all RLS patients. If <75 μg/L: supplement. IV iron (ferric carboxymaltose) is substantially more effective than oral iron for RLS — produces dramatic sustained improvement in many patients.

Which medications worsen RLS?

Antihistamines (diphenhydramine — the most potent trigger, in many OTC products); SSRIs, SNRIs, mirtazapine; metoclopramide and prochlorperazine (extremely common antiemetics — major clinical offenders); antipsychotics. Any RLS worsening after a new medication = review the drug list immediately.

How does GMJ News cover RLS?

GMJ News covers URGE criteria, iron deficiency as primary correctable cause, IV iron superiority, augmentation (definition, management — never increase DA), alpha-2-delta as new first-line for chronic RLS, medications that worsen RLS (metoclopramide, antihistamines, SSRIs), RLS in pregnancy, PLMD distinction, and opioids for refractory augmentation.

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Restless Legs Syndrome

Q: Which medications worsen RLS?

Antihistamines (diphenhydramine — the most potent trigger, in many OTC products); SSRIs, SNRIs, mirtazapine; metoclopramide and prochlorperazine (extremely common antiemetics — major clinical offenders); antipsychotics. Any RLS worsening after a new medication = review the drug list immediately.

Q: How does GMJ News cover RLS?

GMJ News covers URGE criteria, iron deficiency as primary correctable cause, IV iron superiority, augmentation (definition, management — never increase DA), alpha-2-delta as new first-line for chronic RLS, medications that worsen RLS (metoclopramide, antihistamines, SSRIs), RLS in pregnancy, PLMD distinction, and opioids for refractory augmentation.

GMJ News knowledge hub · last reviewed August 2026 · Georgian Medical Journal

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Restless legs syndrome (RLS, also called Willis-Ekbom disease) — a neurological sensorimotor disorder characterised by an irresistible urge to move the legs, worse at rest and in the evening, partially or fully relieved by movement, and causing significant sleep disruption — affects approximately 5-15% of Western populations, is frequently underdiagnosed or misdiagnosed as leg cramps, anxiety or peripheral neuropathy, and has a clear iron deficiency link (serum ferritin <50-75 μg/L should trigger iron supplementation as a first-line treatment) even in the absence of anaemia (WHO). The most clinically significant risk with dopamine agonist therapy (pramipexole, ropinirole) — the traditional pharmacological mainstay — is augmentation: the paradoxical worsening and spread of RLS symptoms over time from the very drug prescribed to treat it, now leading major guidelines to recommend first-line alpha-2-delta ligands (gabapentin enacarbil, pregabalin) over dopamine agonists for long-term treatment.

Key messages

URGE — the four diagnostic criteria

URGE mnemonic (IRLSSG criteria — all 4 required): Urge to move the legs; Rest provokes symptoms; Gets better with movement; Evening/night predominance (circadian component). No diagnostic blood test or nerve conduction study required.

Iron deficiency — the most important correctable cause

Serum ferritin <50-75 μg/L triggers iron supplementation — regardless of haemoglobin. Brain iron deficiency (substantia nigra) → reduced dopamine synthesis → disinhibition of sensorimotor pathways → RLS. IV iron (ferric carboxymaltose) is substantially more effective than oral iron for RLS — consider when ferritin <100 μg/L. Can produce dramatic sustained improvement.

Augmentation — the most important complication of dopamine agonist therapy

Augmentation: symptoms appear earlier in the day; spread to arms; more intense; faster onset with rest. Affects approximately 30-50% of patients on long-term daily dopamine agonists (pramipexole, ropinirole). Management: DO NOT increase DA dose (worsens augmentation) → gradually withdraw DA → switch to alpha-2-delta ligands (gabapentin enacarbil, pregabalin) or low-dose opioids.

Alpha-2-delta ligands now preferred first-line for chronic RLS

AASM 2021 and IRLSSG 2022 guidelines: alpha-2-delta calcium channel ligands (gabapentin enacarbil — FDA-approved; pregabalin) are preferred first-line pharmacotherapy for chronic RLS — over dopamine agonists — to reduce augmentation risk. Dopamine agonists remain appropriate for intermittent RLS.

Medications that worsen RLS — check every drug list

Significant RLS aggravators: antihistamines (diphenhydramine — most potent); SSRIs/SNRIs/TCAs; metoclopramide (very commonly prescribed antiemetic — major offender); prochlorperazine; antipsychotics. Any new RLS worsening → review the medication list immediately.

PLMD — periodic limb movement disorder — distinct but associated

PLMS (periodic limb movements during sleep — stereotyped triple flexion every 20-40 seconds): present in 80-90% of RLS patients. PLMD: PLMS causing clinically significant sleep disturbance without RLS or other explanation. Both treated similarly. PLMS ≥15/hour on PSG + symptoms = PLMD.

Key statistics

5-15%

Western population prevalence of RLS

IRLSSG/AASM

Ferritin <75

μg/L triggers iron supplementation — IV iron preferred if <100 μg/L

IRLSSG 2022

30-50%

of long-term DA users develop augmentation

IRLSSG 2022

URGE

mnemonic — the 4 IRLSSG diagnostic criteria for RLS

IRLSSG

Alpha-2-delta

ligands (gabapentin enacarbil, pregabalin) now preferred first-line for chronic RLS

AASM 2021/IRLSSG 2022

Metoclopramide

one of the most common RLS-aggravating drugs — very frequently prescribed

IRLSSG

RLS treatment algorithm — IRLSSG 2022 / AASM 2021

Source: IRLSSG/AASM. Iron first; alpha-2-delta preferred chronic; DA for intermittent; opioids for augmentation.

Glossary of key terms

Augmentation
IRLSSGIatrogenic worsening of RLS from DA therapy: symptoms begin 2+ hours earlier; spread to arms/upper body; onset faster with rest; more intense. Diagnostic: Max Planck Institute augmentation severity scale. Management: confirm augmentation vs disease progression; check iron; gradually reduce and stop DA over weeks-months; bridge with alpha-2-delta or opioids. Never increase DA dose.

Brain iron and dopamine
NeuroscienceSubstantia nigra iron deficiency → reduced tyrosine hydroxylase activity (iron cofactor) → reduced dopamine → impaired spinal dopaminergic inhibition → RLS sensorimotor symptoms. CSF ferritin reduced in RLS regardless of serum ferritin. MRI neuromelanin imaging and 7T MRI can demonstrate substantia nigra iron deficiency. IV iron treats RLS by restoring brain iron, bypassing oral absorption limitations.

Gabapentin enacarbil (Horizant)
FDA 2011Prodrug of gabapentin — active transport absorption; less variable pharmacokinetics than standard gabapentin. FDA-approved for moderate-severe primary RLS (2011). Alpha-2-delta calcium channel subunit binding → reduced neuronal excitability → RLS symptoms and PLMS. Dose: 600mg once daily with evening meal. Also treats associated insomnia. Preferred by AASM 2021 and IRLSSG 2022 for chronic nightly RLS.

Medications worsening RLS
ClinicalAntihistamines: diphenhydramine (most potent — in many OTC sleep aids/allergy products); cetirizine/loratadine lower risk. Antidepressants: SSRIs, SNRIs, TCAs (mirtazapine particularly). Dopamine antagonists: metoclopramide (extremely common in clinical practice); prochlorperazine; domperidone. Antipsychotics (all). Safer alternatives: bupropion (may improve RLS); low-dose trazodone; gabapentin.

RLS in pregnancy
ObstetricsAffects approximately 20-25% of pregnancies (third trimester most common). Mechanisms: iron and folate deficiency + elevated oestrogen + disrupted sleep posture. Resolves within 4 weeks of delivery usually. Management: oral iron (ferritin >75 μg/L target); folate; sleep hygiene; warm baths; walking. Avoid DA in pregnancy (limited safety data).

RLS vs leg cramps
ClinicalRLS: urge to move + relief with movement + rest-provoked + evening predominance — NO muscle tightening. Nocturnal cramps: sudden painful muscle CONTRACTION; brief (seconds-minutes); relief by stretching; not systematically worse at rest or evening. Not treated with DA. RLS also confused with: peripheral neuropathy (no circadian pattern); akathisia (drug-induced restlessness without leg-specific predominance or circadian pattern).

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