What is the approach to prescribing methadone for a patient with Restless Legs Syndrome (RLS) in the UK, and how common is its use?

Prescribing Methadone for RLS in the UK

Methadone is a conditionally recommended second-line opioid for refractory RLS when first-line treatments (alpha-2-delta ligands and iron supplementation) have failed, but prescribing in the UK requires navigating significant regulatory barriers as it is not licensed for RLS and requires specialist involvement.

Current Treatment Algorithm Before Considering Methadone

Before prescribing any opioid for RLS, you must exhaust first-line options:

• Check iron status first: Measure morning fasting ferritin and transferrin saturation, and supplement if ferritin ≤75 ng/mL or transferrin saturation <20% using IV ferric carboxymaltose (strong recommendation) or oral ferrous sulfate 1

• Initiate alpha-2-delta ligands as first-line therapy: Gabapentin, gabapentin enacarbil, or pregabalin are strongly recommended with moderate certainty of evidence and should be trialed at adequate doses (gabapentin 1800-2400mg/day divided three times daily, or pregabalin with twice-daily dosing) 1, 2

• Avoid dopamine agonists: The American Academy of Sleep Medicine now recommends against standard use of pramipexole, ropinirole, and rotigotine due to high augmentation risk 1, 3

When to Consider Methadone

Methadone should only be considered for refractory RLS characterized by:

• Inadequate response to alpha-2-delta ligands at therapeutic doses 4
• Intolerable adverse effects from first-line agents 4
• Augmentation from dopaminergic agents that cannot be managed otherwise 1, 2
• Severely impaired quality of life, profound insomnia, or suicidal depression despite optimal first-line treatment 4

Evidence Supporting Methadone Use

Methadone has the strongest long-term efficacy data among opioids for RLS:

• In a 10-year longitudinal study, methadone showed 0% annual augmentation rate compared to 7% for pramipexole and 5% for pergolide, with 0% annual discontinuation rate after the first year 5

• A study of 27 refractory RLS patients who had failed an average of 5.9 different medications (including 2.9 dopaminergics) found that 17 remained on methadone for 23±12 months with at least 75% symptom reduction and no augmentation 6

• The National RLS Opioid Registry found that nearly 50% of 500 patients with refractory RLS were taking methadone, with median total daily dose of 30 morphine milligram equivalents (MME) and good long-term efficacy 7

Practical Prescribing Approach in the UK

Regulatory considerations:

• Methadone is not licensed for RLS in the UK, so prescribing is off-label and requires clear documentation of rationale 4
• Specialist involvement (neurologist or sleep medicine physician) is strongly advisable given the off-label use and controlled drug status 4
• Shared care agreements with primary care may be difficult to establish for this indication 4

Dosing protocol:

• Start with 5mg daily in the evening, as effective doses for RLS are considerably lower than for chronic pain or opioid substitution therapy 4, 6
• Titrate slowly by 5mg increments every 1-2 weeks based on symptom response 4
• Target dose range is typically 5-20mg daily (median 15-16mg in published studies), which is far below methadone maintenance doses 4, 6, 7
• Use controlled-release formulation for evening dosing; short-acting formulations can be added for daytime symptoms if needed 4

Mandatory safety precautions:

• Screen for respiratory depression risk: Methadone causes dose-dependent central sleep apnea and respiratory depression, particularly dangerous in patients with untreated obstructive sleep apnea 2, 3
• Assess opioid misuse risk using validated questionnaires (e.g., Opioid Risk Tool) before initiating therapy 4
• Implement opioid contract/agreement outlining expectations, monitoring requirements, and consequences of misuse 4
• Utilize prescription drug monitoring programs to check for concurrent opioid prescriptions 4
• Perform urine drug screens at baseline and periodically during treatment 4
• Monitor QTc interval: Methadone can prolong QTc, requiring baseline and follow-up ECGs, particularly at doses >100mg (though RLS doses are much lower) 4

How Common is Methadone Use for RLS?

Methadone is relatively uncommon but represents a significant proportion of opioid-treated refractory RLS:

• In the National RLS Opioid Registry of 500 patients, methadone was the most commonly prescribed opioid (nearly 50%), followed by oxycodone formulations (25%) 7
• However, this represents a highly selected population of refractory RLS patients who have already failed multiple treatments 7
• The overall prevalence of opioid use for RLS in the general population is unknown, but given that only a subset of RLS patients are refractory to first-line treatments, methadone use for RLS remains uncommon in absolute terms 4, 7

In the UK specifically, methadone prescribing for RLS is likely even less common due to:

• Stricter controlled drug regulations compared to some other countries 4
• Limited specialist awareness of methadone's role in refractory RLS 4
• Concerns about opioid prescribing in the context of the opioid crisis, despite evidence showing relatively low abuse risk in appropriately screened RLS patients 4, 7

Critical Monitoring and Follow-Up

• Frequent reevaluation of effectiveness and side effects, particularly in the first 6-12 months 4
• Monitor for dose escalation: The National RLS Opioid Registry found that 31.2% of patients increased their dose over 1 year, but median increase was only 10 MME, and larger increases were associated with predictable factors (opioid use for non-RLS pain, <1 year of use, switching to methadone) 7
• Reassess iron status every 6-12 months, as declining iron stores may contribute to symptom recurrence 1
• Evaluate for augmentation: Unlike dopamine agonists, methadone shows no augmentation in long-term studies, but monitor for earlier symptom onset, increased intensity, or spread to other body parts 1, 5

Alternative Opioid Options

If methadone is not feasible due to regulatory or patient factors:

• Extended-release oxycodone (10-30mg daily) is conditionally recommended and may be easier to prescribe in the UK 1, 2, 4
• Buprenorphine has reduced respiratory depression risk compared to other opioids and is increasingly recognized as preferable when opioid therapy is necessary 2, 3
• Tramadol is mentioned in some literature but is not specifically recommended in current American Academy of Sleep Medicine guidelines and carries similar respiratory risks 2

Key Pitfalls to Avoid

• Do not prescribe methadone as first-line therapy: Always optimize iron status and trial alpha-2-delta ligands first 1, 2, 3
• Do not use pain-level doses: RLS requires much lower doses (5-20mg) than chronic pain or addiction treatment 4, 6
• Do not ignore respiratory risk: Screen for and treat obstructive sleep apnea before initiating opioids, as the combination significantly increases respiratory depression risk 2, 3
• Do not assume all refractory RLS needs opioids: Consider combination therapy with alpha-2-delta ligands plus iron, or non-pharmacological options like bilateral high-frequency peroneal nerve stimulation 1
• Do not prescribe without specialist input in the UK: Given off-label use and controlled drug status, involve neurology or sleep medicine specialists 4