Likely Diagnosis: Drug-Induced Restless Legs Syndrome
This patient has developed drug-induced restless legs syndrome (RLS) triggered by tirzepatide (Zepbound), a GLP-1 receptor agonist that may exacerbate or unmask RLS through mechanisms that are not fully understood but likely involve dopaminergic or iron-metabolism pathways. 1
Diagnostic Confirmation
Essential Clinical Features to Assess
- Confirm the four cardinal RLS criteria: (1) urge to move the legs with uncomfortable sensations, (2) symptoms begin or worsen during rest or inactivity, (3) relief with movement, and (4) symptoms worse in the evening or at night 2
- Temporal relationship: Document that symptoms started shortly after tirzepatide initiation, which strongly suggests a causal relationship 1
- Rule out mimics: Perform a thorough neurological examination to exclude peripheral neuropathy, radiculopathy, vascular disease, or arthritides that can present similarly 3, 2
- Distinguish from akathisia: RLS involves uncomfortable leg sensations relieved by movement, whereas akathisia is a generalized urge to move without specific limb discomfort 4
Mandatory Laboratory Work-Up
- Morning fasting serum ferritin and transferrin saturation after withholding iron supplements for ≥24 hours 1, 5
- Complete blood count to screen for anemia 1
- Check transferrin saturation >45% to exclude hemochromatosis before starting iron therapy 1
Treatment Algorithm
Step 1: Discontinue or Modify the Offending Agent
- Strongly consider discontinuing tirzepatide if clinically feasible, as medication-induced RLS typically resolves within days to weeks after stopping the causative drug 1, 2
- If tirzepatide must be continued for diabetes or weight management, proceed directly to pharmacologic RLS treatment while monitoring for symptom progression 1
Step 2: Correct Iron Deficiency (If Present)
- If ferritin ≤75 ng/mL or transferrin saturation <20%:
- Oral iron: Ferrous sulfate 325–650 mg daily or every other day (conditional recommendation, moderate certainty) 1, 5
- IV iron: Ferric carboxymaltose 750–1000 mg in one or two infusions is strongly recommended (strong recommendation, moderate certainty) for patients who cannot tolerate oral iron, fail oral therapy after 3 months, or have ferritin 75–100 ng/mL with persistent symptoms 1, 5
- Iron repletion alone may resolve symptoms if iron deficiency is the primary driver 1
Step 3: First-Line Pharmacologic Therapy (If Symptoms Persist)
- Alpha-2-delta ligands are strongly recommended as first-line treatment (strong recommendation, moderate certainty) 1, 5:
- Gabapentin: Start 300 mg three times daily; titrate by 300 mg/day every 3–7 days to maintenance dose of 1800–2400 mg/day divided TID (maximum 3600 mg/day) 1
- Pregabalin: Start 50 mg TID or 75 mg BID; increase to 300 mg/day after 3–7 days, then by 150 mg every 3–7 days as tolerated (maximum 600 mg/day) 1
- Gabapentin enacarbil: Extended-release formulation with improved bioavailability, allowing once- or twice-daily dosing 1, 3
- Approximately 70% of patients treated with gabapentinoids achieve much or very much improved symptoms vs. 40% with placebo (P <0.001) 5
Step 4: Avoid Dopamine Agonists
- The American Academy of Sleep Medicine conditionally recommends against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to a 7–10% annual risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread 1, 5
- Dopamine agonists may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects, but this is not the standard approach 1
Step 5: Second-Line Options for Refractory Cases
- If symptoms persist despite adequate trials of iron repletion and alpha-2-delta ligands:
- Extended-release oxycodone 5–10 mg at bedtime (conditional recommendation, moderate certainty) 1, 5
- Low-dose methadone 5–10 mg daily or buprenorphine (transdermal or sublingual) for 24-hour symptom coverage 1
- Long-term studies show only modest dose escalation over 2–10 years and relatively low abuse risk in appropriately screened patients 1
- Bilateral high-frequency peroneal nerve stimulation is a non-invasive alternative (conditional recommendation, moderate certainty) for patients who refuse or cannot tolerate opioids 1
Medications to Avoid
- Strongly avoid or discontinue:
- Do not use as RLS therapy:
Lifestyle and Non-Pharmacologic Interventions
- Eliminate exacerbating substances: Alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 1
- Sleep hygiene: Dark, quiet, comfortable temperature; avoid bright light at night; increase daytime bright-light exposure 1
- Exercise: Regular morning or afternoon exercise; avoid vigorous exercise close to bedtime 1
- Treat obstructive sleep apnea if present, as untreated OSA worsens RLS and increases respiratory-depression risk with alpha-2-delta ligands or opioids 1, 6
Monitoring and Follow-Up
- Reassess RLS severity using the International RLS Study Group Rating Scale at 4–6 weeks after treatment initiation 1
- Repeat iron studies every 6–12 months, as brain iron deficiency may persist despite clinical improvement 1
- Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) and opioids (constipation, respiratory depression) 1
- Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life) 1
Critical Pitfalls to Avoid
- Do not assume "normal" ferritin (e.g., 50–75 ng/mL) excludes iron deficiency in RLS—the disease-specific threshold is ≤75 ng/mL 1
- Do not start dopamine agonists as first-line therapy given the high augmentation risk and current guideline shift favoring alpha-2-delta ligands 1, 5
- Do not increase dopamine-agonist doses if symptoms worsen—this likely reflects augmentation and will worsen the problem 1, 6
- Do not use clonazepam as monotherapy—it only treats insomnia, not the underlying RLS pathology 1
- Do not withhold opioids from appropriately screened patients with severe refractory RLS—evidence supports their use with low long-term abuse risk 1