In an adult palliative‑care patient with refractory pruritus unresponsive to first‑line antihistamines and basic skin care, what off‑label systemic therapy should be started and how should it be dosed?

Management of Refractory Pruritus in Palliative Care

For an adult palliative care patient with refractory pruritus unresponsive to antihistamines and basic skin care, start gabapentin 100-300 mg at bedtime (titrating up to 300 mg three times daily as tolerated) or paroxetine 5-20 mg daily, depending on the underlying etiology. 1, 2

Algorithmic Approach Based on Underlying Etiology

If Pruritus of Unknown or Mixed Origin

• Start paroxetine 5 mg in the evening, which demonstrated strong antipruritic effect in palliative care patients with pruritus of diverse origins (reducing pruritus by 0.78 points on a 0-10 scale). 2, 3
• Paroxetine may be effective at very low doses (5 mg), with full resolution possible within 2 days, and can be titrated up to 20 mg if needed. 3
• Alternative systemic options include mirtazapine, gabapentin, pregabalin, ondansetron, or naltrexone (all off-label). 1

If Uremic Pruritus (Renal Failure/Dialysis Patients)

• First choice: Gabapentin starting at 100-300 mg at bedtime, titrating to 300 mg three times daily as tolerated (strong effect, reducing VAS by 5.91 points on 0-10 scale). 2, 4
• Second choice: Nalfurafine (κ-opioid receptor agonist) if available, which reduces pruritus by 0.95 points on VAS with few adverse events (moderate effect). 2, 4
• Third choice: Cromolyn sodium, reducing pruritus by 2.94 points on VAS (moderate to strong effect). 2, 4
• Fourth choice: Naltrexone, though effects are heterogeneous (weak to strong, with significant side effects including dizziness 0-50% and nausea 0-50%). 2, 4

If Cholestatic/Hepatic Pruritus

• First choice: Rifampin (moderate effect, reducing VAS by 24.64 points on 0-100 scale). 2, 4
• Second choice: Naltrexone (moderate to strong effect, reducing VAS by 2.26 points on 0-10 scale). 2, 4
• Third choice: Flumecinol (weak to moderate effect). 2, 4
• Consider fifth-line options including dronabinol, phenobarbital, or propofol in severe refractory cases. 1

If Opioid-Induced Pruritus

• Naltrexone is the first-choice recommendation if cessation of opioid therapy is impossible (Strength of recommendation B). 1
• Critical caveat: Large doses of opioid antagonists may reduce analgesia in palliative care patients, which is unacceptable when pain control is paramount. 4
• Alternative agents include methylnaltrexone, ondansetron, droperidol, mirtazapine, or gabapentin. 1

If Neuropathic Pruritus

• Gabapentin or pregabalin are the systemic agents of choice for neuropathic itch. 1, 5
• Topical agents with neuropathic efficacy include menthol, pramoxine, or lidocaine, which can be combined with topical steroids. 6
• Capsaicin, local anesthetics, doxepin, or tacrolimus may provide additional benefit topically. 5

Specific Dosing Recommendations

Gabapentin

• Start: 100-300 mg at bedtime 1, 6
• Target: 300 mg three times daily (adjust for renal function in uremic patients) 2, 4

Paroxetine

• Start: 5 mg in the evening 3
• Target: 5-20 mg daily (may be effective at very low doses) 1, 2, 3

Mirtazapine

• Dose: 15-30 mg at bedtime (provides both antipruritic effect and sedation, which may be beneficial in palliative care) 1

Naltrexone

• Start: 12.5-25 mg daily 1
• Target: 50 mg daily (monitor for dizziness and nausea; avoid if opioid analgesia is essential) 2, 4

Pregabalin

• Start: 75 mg at bedtime 1
• Target: 150-300 mg daily in divided doses 6

Critical Pitfalls to Avoid in Palliative Care

• Never use sedating antihistamines long-term, especially in elderly patients (increased falls, confusion, dementia risk). They are only acceptable in short-term or end-of-life palliative settings. 1
• Avoid crotamiton cream (ineffective, Strength of recommendation B). 1
• Avoid topical capsaicin or calamine lotion for generalized pruritus of unknown origin. 1
• Do not use high-dose opioid antagonists if the patient requires opioid analgesia for pain control, as this may precipitate withdrawal or reduce analgesia. 4
• Antihistamines and corticosteroids lack efficacy in neuropathic itch and should not be relied upon as monotherapy. 5

Adjunctive Measures to Continue

• Maintain emollients with high lipid content applied at least twice daily. 1
• Consider topical menthol or clobetasone butyrate for additional symptomatic relief. 1
• In palliative settings, sedative antihistamines like hydroxyzine may be acceptable for short-term use when quality of life and comfort are prioritized over cognitive side effects. 1

When to Reassess or Refer

• If no improvement after 2-4 weeks of systemic therapy, reassess the underlying etiology and consider alternative agents from the same category or combination therapy. 1, 6
• Referral to dermatology or palliative care specialists may be warranted if diagnostic uncertainty exists or if multiple therapeutic trials have failed. 1
• For cholestatic pruritus refractory to medical management, consider phototherapy (BB-UVB or combined UVA/UVB) or transcutaneous electrical nerve stimulation. 1