What is the best course of action for a patient with Restless Legs Syndrome (RLS) who is currently on methadone (opioid analgesic) 5mg and still experiencing symptoms?

Management of Persistent RLS Symptoms on Low-Dose Methadone

Increase the methadone dose to 10-20 mg daily, as the current 5 mg dose is below the effective therapeutic range for refractory RLS. 1, 2

Rationale for Dose Escalation

• Methadone 5 mg daily is at the very low end of the effective dose range for RLS—the evidence-based therapeutic window is 5-20 mg daily, with most patients requiring 10-20 mg for adequate symptom control 1, 2
• The 2026 JAMA review explicitly states that patients with refractory RLS "often benefit from low-dose opioids (eg, methadone 5-10 mg daily)," positioning 5 mg as a starting point rather than a maintenance dose 3
• Long-term studies demonstrate that opioids for RLS show only small dose increases over 2-10 years with relatively low risks of abuse and overdose in appropriately screened patients 1, 2

Before Dose Escalation: Critical Assessment Steps

Check iron status immediately if not done recently:

• Obtain morning fasting ferritin and transferrin saturation 1, 4, 5
• Supplement with IV ferric carboxymaltose (1000 mg) if ferritin ≤75 ng/mL or transferrin saturation <20%, as iron deficiency is a treatable cause of persistent symptoms even on opioid therapy 1, 4, 3
• The JAMA review notes that iron supplementation should target ferritin ≤100 ng/mL or transferrin saturation <20%, slightly higher than guideline thresholds 3

Review medication list for RLS-exacerbating agents:

• Discontinue serotonergic antidepressants, dopamine antagonists (antipsychotics), and centrally acting H1 antihistamines (diphenhydramine) if possible 1, 4, 3
• These medications can completely negate the benefits of opioid therapy 1

Screen for untreated obstructive sleep apnea:

• Opioids carry risk of respiratory depression and central sleep apnea, particularly in patients with untreated OSA 1
• This must be addressed before escalating opioid doses 1

Alternative Approach: Add Alpha-2-Delta Ligand

If the patient has not previously tried gabapentinoids, consider adding gabapentin or pregabalin to the methadone rather than immediately escalating the opioid dose:

• Gabapentin should be initiated at 300 mg three times daily and titrated by 300 mg/day every 3-7 days to a maintenance dose of 1800-2400 mg/day divided three times daily 1, 4
• Pregabalin allows twice-daily dosing with potentially superior bioavailability and is strongly recommended as first-line therapy 1, 4
• Approximately 70% of patients treated with gabapentinoids achieve much or very much improved RLS symptoms versus 40% with placebo 3
• Combination therapy (opioid + alpha-2-delta ligand) is explicitly mentioned as a therapeutic option for refractory cases 2

Why Not Switch to a Different Opioid?

• Methadone is specifically recommended alongside oxycodone as one of the most commonly used agents for refractory RLS 2
• The effective dose range for oxycodone is 10-30 mg daily, suggesting that if switching from methadone 5 mg, you would still need to use higher doses of the alternative agent 2
• There is no evidence that switching opioid class improves outcomes—the issue is inadequate dosing, not the wrong medication 2

Monitoring and Safety Considerations

Implement appropriate opioid monitoring:

• Assess opioid risk with standard questionnaires 2
• Use an opioid contract 2
• Perform urine drug screens 2
• Consult state prescription drug monitoring programs 2
• Frequent reevaluation of effectiveness and side effects 2

Recognize that RLS-specific opioid dosing differs from chronic pain:

• Effective doses for RLS are considerably lower than used for chronic pain 2
• The risk of opioid use disorder is relatively low in RLS patients when appropriately monitored 2
• Controlled-release medication should be used for evening dosage, with short-acting drugs if needed during the day 2

Common Pitfalls to Avoid

• Do not assume 5 mg methadone is adequate simply because it is "a dose"—this is below the therapeutic range for most patients 2
• Do not switch to dopamine agonists (pramipexole, ropinirole, rotigotine) as these carry a 7-10% annual incidence of augmentation and are no longer first-line therapy 3, 6
• Do not use clonazepam or other benzodiazepines as monotherapy—these are explicitly recommended against by the American Academy of Sleep Medicine 1
• Do not delay iron supplementation if ferritin is low-normal, as brain iron deficiency may persist despite "normal" serum parameters 1

Expected Outcome

• With appropriate dose escalation to 10-15 mg methadone daily (or addition of gabapentinoid), combined with iron optimization and removal of exacerbating factors, most patients achieve substantial symptom relief 2
• Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio 2
• Quality of life improvements include restored sleep, reduced cardiovascular risk (RLS patients have 29.6% prevalence of coronary artery disease, stroke, or heart failure), and decreased depression (30.4% prevalence in RLS) 3