What are the best medications for insomnia in patients with Chronic Kidney Disease (CKD) on Hemodialysis (HD)?

Best Medications for Insomnia in CKD Patients on Hemodialysis

For hemodialysis patients with insomnia, start with basic sleep hygiene measures and nonpharmacologic interventions (exercise, cognitive behavioral therapy), and when pharmacotherapy is needed, use "simple sedatives" with extreme caution, as recent high-quality evidence shows that neither CBT-I nor trazodone outperforms placebo in this population, and trazodone carries significant cardiovascular risk. 1, 2

Critical Evidence Gap and Safety Concerns

The most recent and highest quality evidence—a 2024 multicenter randomized controlled trial in 126 hemodialysis patients—found that neither cognitive behavioral therapy for insomnia (CBT-I) nor trazodone 50mg was more effective than placebo for reducing insomnia severity at 7 or 25 weeks. 2 More concerning, trazodone was associated with significantly higher rates of serious cardiovascular adverse events (annualized cardiovascular SAE incidence: trazodone 0.64 vs placebo 0.21 vs CBT-I 0.05). 2

This directly contradicts older general insomnia guidelines that suggest trazodone as a sedating antidepressant option. 1 The 2017 American Academy of Sleep Medicine guideline for general populations actually recommends against using trazodone for insomnia treatment. 1

Recommended Approach

First-Line: Nonpharmacologic Management

• Sleep hygiene measures should be implemented first, including addressing concurrent symptoms that disrupt sleep (pruritus, restless legs syndrome, pain). 1
• Exercise programs have demonstrated efficacy and should be prescribed. 1
• Cognitive behavioral therapy for insomnia (CBT-I) can be attempted, though its superiority over placebo in hemodialysis patients is not established. 2
• Optimize dialysis timing and adequacy, as dialysis-related factors contribute to sleep disruption. 3, 4

Second-Line: Address Contributing Factors

• Correct iron deficiency and hyperphosphatemia, particularly if restless legs syndrome coexists (present in 10-20% of dialysis patients). 1
• Treat uremic pruritus if present (affects 40% of dialysis patients), using topical capsaicin, emollients, gabapentinoids, or ultraviolet B therapy. 1
• Manage pain that may be disrupting sleep, using acetaminophen (max 3000mg/day), topical agents, or carefully dosed gabapentin/pregabalin. 5, 6

Third-Line: Pharmacologic Options (Use with Extreme Caution)

When pharmacotherapy is absolutely necessary after nonpharmacologic measures fail:

Benzodiazepine Receptor Agonists (BZRAs)

The KDIGO guideline mentions "simple sedatives" without specific recommendations for hemodialysis patients. 1 General insomnia guidelines suggest:

• Short-intermediate acting BZRAs such as:
  • Zolpidem 5-10mg (primarily for sleep onset; short-to-intermediate acting) 1
  • Eszopiclone 1-2mg (for sleep onset and maintenance; no short-term usage restriction) 1
  • Temazepam 7.5-15mg (for sleep onset and maintenance; short-to-intermediate acting) 1

Critical caveat: These recommendations are extrapolated from general populations. There are no studies demonstrating efficacy specifically in hemodialysis patients. 1 Start with the lowest doses given altered pharmacokinetics in kidney failure. 1

Melatonin Receptor Agonists

• Ramelteon 8mg is suggested for sleep onset insomnia in general populations 1, but efficacy in hemodialysis is unknown.

Gabapentinoids (If Neuropathic Component)

• Gabapentin starting at 100-300mg at night with careful titration, particularly if uremic pruritus or restless legs syndrome coexist. 1, 5 Requires significant dose adjustment in hemodialysis. 5

Medications to AVOID

• Trazodone: Despite being commonly used off-label, it showed no benefit over placebo and significantly increased cardiovascular adverse events in hemodialysis patients. 2 General insomnia guidelines also recommend against its use. 1
• Over-the-counter antihistamines (diphenhydramine): Not recommended due to lack of efficacy and safety data. 1
• Melatonin, valerian, L-tryptophan: Not recommended due to insufficient evidence. 1
• Tiagabine: Specifically not recommended. 1

Implementation Principles

When prescribing any sedative-hypnotic in hemodialysis patients:

• Start with the lowest effective dose and uptitrate cautiously given altered pharmacokinetics. 1
• Monitor for QT prolongation and drug interactions, which are particularly problematic in kidney failure. 1
• Follow patients every few weeks initially to assess effectiveness and adverse effects. 1
• Avoid administration during or immediately before dialysis to prevent excessive sedation. 4, 7
• Screen for sleep apnea (present in 40-69% of CKD patients), as sedatives can worsen this condition. 8
• Assess for depression (present in 39% of dialysis patients), which may require specific antidepressant treatment rather than sedatives alone. 1

Common Pitfalls

• Polypharmacy: Hemodialysis patients are already on multiple medications; adding sedatives increases interaction risks. 7
• Assuming efficacy: The evidence base for insomnia treatment specifically in hemodialysis is extremely limited. 1, 4, 7
• Ignoring cardiovascular risk: This population has heightened cardiovascular morbidity and mortality; trazodone's cardiovascular adverse event profile is particularly concerning. 2
• Overlooking treatable causes: Insomnia in hemodialysis is multifactorial (uraemia, medications, mood disorders, concurrent symptoms); addressing underlying causes is more effective than sedatives alone. 3, 4