What is the appropriate starting dose and titration schedule of pregabalin for an elderly patient with restless‑leg syndrome, taking renal function into account?

Pregabalin Dosing for Restless Legs Syndrome in Elderly Patients

Critical Recommendation

For elderly patients with RLS, pregabalin 75 mg once daily at bedtime is the appropriate starting dose, with titration by 75 mg increments every 5-7 days to a target of 300 mg daily, but mandatory renal function assessment using Cockcroft-Gault equation must be performed first, as dose reduction of at least 50% is required for creatinine clearance below 60 mL/min. 1, 2, 3

Why Pregabalin Over Dopamine Agonists in 2025

The most recent 2025 American Academy of Sleep Medicine guidelines represent a major paradigm shift from older recommendations:

• The AASM now suggests AGAINST the standard use of all dopamine agonists (pramipexole, ropinirole, rotigotine) for RLS due to long-term augmentation risk, despite short-term efficacy 1
• This directly contradicts the 2009 JAGS guidelines that recommended dopamine agonists as first-line therapy 1
• Pregabalin demonstrated significantly lower augmentation rates (2.1%) compared to pramipexole 0.5 mg (7.7%) over 52 weeks, making it preferable for long-term management 3
• The 2012 European guidelines gave pregabalin a Level A recommendation for short-term RLS treatment 4

Mandatory Renal Assessment Before Initiating Therapy

Do not rely on serum creatinine alone in elderly patients, as this is the most critical pitfall:

• A "normal" creatinine of 1.0 mg/dL in an 80-year-old weighing 60 kg corresponds to a creatinine clearance of approximately 40 mL/min, requiring immediate dose reduction 2
• Calculate creatinine clearance using the Cockcroft-Gault equation before prescribing 2
• Elderly patients have reduced muscle mass, making serum creatinine an unreliable marker of renal function 1, 2
• Renal function declines by 1% per year after age 30-40, meaning a 70-year-old may have 40% reduced renal function 1

Pregabalin Titration Schedule by Renal Function

Normal Renal Function (CrCl ≥60 mL/min):

• Start: 75 mg once daily at bedtime 5, 3
• Week 1-2: Increase to 150 mg daily (75 mg twice daily or 150 mg at bedtime) 3
• Week 2-3: Increase to 225 mg daily (75 mg three times daily) 3
• Week 3-4: Increase to 300 mg daily (target dose) 3
• Use 5-7 day intervals between increases in elderly patients (not the faster 3-day intervals used in younger patients) 6
• Maximum dose: 300 mg daily for RLS (higher doses up to 600 mg were studied but 300 mg is the standard target) 7, 3

Moderate Renal Impairment (CrCl 30-59 mL/min):

• Start: 25-50 mg once daily at bedtime 2
• Titrate by 25-50 mg every 5-7 days 2, 6
• Maximum dose: 150 mg daily (representing at least 50% reduction from standard dosing) 2

Severe Renal Impairment (CrCl 15-29 mL/min):

• Start: 25 mg once daily at bedtime 2
• Titrate by 25 mg every 7 days 2
• Maximum dose: 75 mg daily 2

End-Stage Renal Disease (CrCl <15 mL/min):

• Consider gabapentin instead of pregabalin, as the AASM specifically recommends gabapentin for RLS patients with ESRD 1
• If pregabalin is used: maximum 25-50 mg daily as single dose 2

Duration of Adequate Trial

Allow 6-8 weeks total before declaring treatment failure:

• 3-4 weeks for titration to target dose 6, 5
• Plus 2-4 weeks at stable target dose to assess efficacy 6
• The 2021 study used 4 weeks at stable dose followed by 8 weeks total observation 5
• Efficacy develops gradually; premature discontinuation is a common error 6

Monitoring for Toxicity in Elderly Patients

Watch for these signs of pregabalin toxicity, especially if renal function declines:

• Altered mental status, confusion, or hallucinations 2
• Dizziness and increased fall risk (most common in elderly) 6, 7, 3
• Somnolence and sedation 7, 3
• Myoclonus or tremulousness 2
• If acute kidney injury develops during treatment, temporarily discontinue pregabalin until renal function stabilizes 2

Critical Pitfalls to Avoid

1. Do not rush titration in elderly patients: Use 5-7 day intervals, not 3-day intervals, to minimize dizziness and fall risk 6
2. Do not use serum creatinine alone: Always calculate CrCl using Cockcroft-Gault 2
3. Do not discontinue abruptly: Taper over at least 1 week (preferably 2-4 weeks in elderly) to avoid withdrawal symptoms including headache, nausea, and dizziness 8
4. Do not declare treatment failure prematurely: Allow full 6-8 week trial 6, 5
5. Do not ignore drug interactions: Pregabalin has fewer interactions than dopamine agonists, but monitor for additive CNS depression with other sedating medications 7

Advantages of Pregabalin in Elderly RLS Patients

• Lower augmentation risk (2.1%) compared to dopamine agonists (5.3-7.7%) 3
• Improves comorbid insomnia, which is common in elderly RLS patients 5, 3
• No orthostatic hypotension risk unlike dopamine agonists, which is critical in elderly patients 1
• No compulsive behavior risk unlike dopamine agonists 1
• Effective as add-on therapy if patient already on dopamine agonist 5

When to Consider Alternative Approaches

• If ferritin <75 mcg/L: Correct iron deficiency first before or concurrent with pharmacotherapy 1
• If CrCl <15 mL/min: Consider gabapentin instead, as AASM specifically recommends it for ESRD patients with RLS 1
• If intolerable side effects at low doses: Consider switching to gabapentin with three-times-daily dosing 2, 6