What is the best approach to manage nocturnal lower extremity pain in a patient with Restless Legs Syndrome (RLS), Coronary Artery Disease (CAD), and dementia?

Management of Nocturnal Lower Extremity Pain in a Patient with RLS, CAD, and Dementia

Start gabapentin enacarbil or gabapentin as first-line therapy for this patient's restless legs syndrome, which is the most likely cause of their terrible nocturnal lower extremity pain, while checking iron studies and carefully reviewing their medication list for RLS-exacerbating agents. 1

Initial Diagnostic Clarification

This clinical presentation requires distinguishing RLS from other causes of nocturnal leg pain:

• RLS is characterized by an uncomfortable urge to move the legs with dysesthesias, symptoms exacerbated by rest/inactivity, relief with movement, and worsening in the evening or at night 2
• Nocturnal leg cramps present as painful, involuntary muscle contractions (typically calf) with no urge to move, and relief comes from stretching the affected muscle—not from general movement 2
• Peripheral artery disease causes ischemic rest pain that does not improve with movement and may require vascular evaluation 3

Critical consideration: In patients with dementia, RLS often manifests as nighttime agitation or "sundowning" rather than typical sensory complaints, since these patients cannot reliably describe their symptoms 4, 5

Immediate Assessment Steps

Iron Status Evaluation

• Check morning fasting serum ferritin and transferrin saturation before starting any iron-containing supplements 1
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology 1
• Consider IV ferric carboxymaltose for faster repletion if oral iron fails or in severe cases 1

Medication Review

• 79% of dementia patients with RLS receive medications that worsen symptoms 5
• Identify and deprescribe: antihistamines, SSRIs, SNRIs, antipsychotics (dopamine antagonists), tricyclic antidepressants, and lithium 1, 5
• This is particularly important given the patient's dementia, as antipsychotics are commonly prescribed for behavioral symptoms but will dramatically worsen RLS 1

First-Line Pharmacological Treatment

Alpha-2-Delta Ligands (Strongly Recommended)

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy with moderate certainty of evidence 1

Gabapentin enacarbil is particularly advantageous in this patient with dementia:

• A 2025 randomized controlled trial specifically in older adults with dementia, nighttime agitation, and RLS showed gabapentin enacarbil significantly reduced nighttime agitation at 8 weeks (estimate -1.67, P=0.003) and improved total sleep time by 48.45 minutes (P=0.026) 6
• This represents the highest quality, most recent evidence directly addressing this patient population 6

Practical dosing:

• Start gabapentin 300 mg three times daily, titrate to 1800-2400 mg/day divided three times daily over 1-2 weeks 1
• Gabapentin enacarbil: extended-release formulation allowing once-daily dosing, improving adherence in dementia 1
• Pregabalin: allows twice-daily dosing with superior bioavailability 1

Monitor for side effects: dizziness and somnolence, which are typically transient and mild but may increase fall risk in elderly patients with dementia 1

Why NOT Dopamine Agonists

The American Academy of Sleep Medicine suggests against standard use of pramipexole, ropinirole, and rotigotine due to augmentation risk 1, 7

• Augmentation causes paradoxical worsening with earlier symptom onset, increased intensity, and anatomic spread 7, 8
• These agents cause higher rates of dizziness and somnolence, directly increasing fall risk—particularly dangerous in elderly patients with dementia 1
• The FDA label for ropinirole explicitly warns about augmentation and early-morning rebound in RLS 8

Special Considerations for This Patient

Dementia-Specific Issues

• Patients with dementia cannot reliably understand or answer RLS diagnostic interviews 4
• Nighttime agitation behaviors (repetitious mannerisms, general restlessness) are the primary manifestations rather than verbal complaints 4, 5
• Sleep disturbance and low transferrin saturation are negatively associated with nighttime agitation frequency, explaining 20% of variance 5

Coronary Artery Disease Considerations

• RLS patients have impaired vascular endothelial function (FMD 6.6% vs 8.4% in controls, p<0.05) and RLS severity negatively correlates with endothelial function 9
• This suggests shared vascular pathophysiology, but does not change treatment approach 9
• Rule out critical limb ischemia: if pain does not improve with movement or if there are signs of tissue loss, urgent vascular evaluation is needed 3

Treatment Algorithm Summary

1. Check iron studies (ferritin, transferrin saturation) and supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1
2. Review and deprescribe RLS-exacerbating medications (antihistamines, SSRIs, antipsychotics) 1, 5
3. Start gabapentin enacarbil or gabapentin as first-line therapy, with evidence specifically supporting efficacy in dementia patients with nighttime agitation 1, 6
4. Monitor for improvement in nighttime agitation behaviors and sleep quality over 2-8 weeks 6
5. Recheck ferritin every 6-12 months as brain iron deficiency may persist despite symptom improvement 1

Critical Pitfalls to Avoid

• Do not start dopamine agonists in elderly patients with dementia due to augmentation risk and increased fall risk 1, 7
• Do not assume the patient can describe RLS symptoms—look for behavioral manifestations of nighttime agitation 4, 5
• Do not overlook iron deficiency—79% of patients may have low transferrin saturation contributing to symptoms 5
• Do not continue RLS-exacerbating medications without attempting deprescribing first 1, 5
• Do not miss critical limb ischemia—if pain persists despite movement or tissue loss is present, obtain vascular imaging 3