What alternative non‑dopaminergic therapies can be used to treat restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) when gabapentin and pregabalin are not tolerated, without risking augmentation?

Alternative Non-Dopaminergic Treatments for RLS and PLMD When Gabapentin and Pregabalin Are Not Tolerated

If you cannot tolerate gabapentin or pregabalin, your best evidence-based options are intravenous iron therapy (if your ferritin is ≤75 ng/mL or transferrin saturation is <20%), followed by low-dose opioids (extended-release oxycodone, methadone, or buprenorphine) for refractory cases, or bilateral high-frequency peroneal nerve stimulation as a non-pharmacological alternative—all of which avoid the augmentation risk associated with dopamine agonists. 1

Iron Therapy: The Critical First Step

Before considering any other medication, you must have your iron status evaluated, as this is a foundational treatment that does not cause augmentation:

• Check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1
• If ferritin ≤75 ng/mL or transferrin saturation <20%, iron supplementation is strongly indicated—note that this threshold is different from general population guidelines and specific to RLS 1
• Oral ferrous sulfate is conditionally recommended for mild iron deficiency (moderate certainty of evidence) 1, 2
• IV ferric carboxymaltose is strongly recommended (moderate certainty of evidence) and can provide rapid correction, especially if oral iron is not tolerated or ineffective after 3 months 1
• IV low molecular weight iron dextran and IV ferumoxytol are also conditionally recommended alternatives 1

Critical pitfall: Many patients and clinicians assume "normal" ferritin levels are adequate, but RLS requires higher brain iron stores—even ferritin levels between 75-100 ng/mL may benefit from IV iron therapy 1

Opioid Therapy: For Refractory Cases

When alpha-2-delta ligands cannot be used and iron therapy is insufficient, opioids represent the next evidence-based option without augmentation risk:

• Extended-release oxycodone and other low-dose opioids (including methadone and buprenorphine) are conditionally recommended for moderate to severe refractory RLS (moderate certainty of evidence) 1
• Long-term studies show relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over extended periods (2-10 years) 1
• Opioids are particularly effective for treating augmentation when transitioning away from dopamine agonists 1

Important safety considerations:

• Screen for risk factors for opioid misuse before initiating therapy 1
• Monitor for respiratory depression and central sleep apnea, especially if you have untreated obstructive sleep apnea 1
• Avoid morphine, codeine, and tramadol if you have stage 4-5 chronic kidney disease (eGFR <30 mL/min); instead use fentanyl or buprenorphine which do not accumulate toxic metabolites 1

Non-Pharmacological Option: Peroneal Nerve Stimulation

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a newer noninvasive treatment option (moderate certainty of evidence) based on initial success in short-term studies 1
• This represents a completely non-pharmacological approach that avoids both medication side effects and augmentation risk 1

Special Population Considerations

End-Stage Renal Disease (ESRD)

If you have ESRD, your options are more limited but still available:

• IV iron sucrose is recommended if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty of evidence) 1
• Vitamin C supplementation is conditionally recommended (low certainty of evidence) 1
• Avoid pregabalin entirely in ESRD due to increased hazard for altered mental status and falls (50-68% higher hazard) 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with a safety profile favoring oral formulations throughout gestation 1
• Non-pharmacological approaches and iron therapy should be prioritized over medications during pregnancy 2

Additional Adjunctive Therapy

• Dipyridamole is conditionally recommended (low certainty of evidence) as a second-line pharmacological option 1

What You Must Avoid

Never use dopamine agonists (pramipexole, ropinirole, rotigotine, levodopa) as they carry a high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to other body parts 1, 2

Specifically avoid:

• Cabergoline (strong recommendation against use) 1
• Bupropion, carbamazepine, clonazepam, valproic acid, and valerian (all conditionally recommended against) 1

Address Exacerbating Factors

Before or alongside any treatment, eliminate substances and medications that worsen RLS:

• Avoid alcohol, caffeine, and nicotine, especially close to bedtime 3, 2
• Discontinue or substitute antihistaminergic medications (including over-the-counter sleep aids and allergy medications) 3, 2
• Review serotonergic medications (certain antidepressants) and antidopaminergic medications (antipsychotics, anti-nausea drugs) with your physician 3, 2
• Treat untreated obstructive sleep apnea if present 3, 2

Practical Treatment Algorithm

1. Measure iron status (ferritin and transferrin saturation) 1, 2
2. If ferritin ≤75 ng/mL or transferrin saturation <20%: Start oral or IV iron supplementation 1, 2
3. If iron therapy alone is insufficient after 3 months or if iron parameters are adequate:
   • Consider low-dose opioids (extended-release oxycodone, methadone, or buprenorphine) with appropriate screening and monitoring 1
   • OR consider bilateral high-frequency peroneal nerve stimulation as a non-pharmacological option 1
4. Monitor response every 6-12 months with repeat iron studies and symptom assessment 1

The evidence strongly supports this stepwise approach, with iron therapy as the foundation and opioids or nerve stimulation as the next tier when alpha-2-delta ligands cannot be used—all while completely avoiding dopamine agonists that cause augmentation 1, 2