What is the best course of treatment for a patient with severe, chronic pruritus (itching) all over their body, normal blood reports, and no underlying conditions, considering their age, medical history, and current medications?

Management of Severe Chronic Generalized Pruritus with Normal Blood Work

Start with a 2-week trial of high-lipid emollients applied liberally twice daily combined with topical hydrocortisone 2.5% or triamcinolone 0.1% to the most affected areas, as this addresses both inflammatory and xerotic causes while you complete a focused diagnostic workup. 1, 2, 3

Immediate Diagnostic Priorities

Even with "normal blood reports," you must verify the following specific tests were actually performed, as these are the most common missed systemic causes:

• Ferritin levels (not just hemoglobin) - iron deficiency causes 25% of systemic pruritus cases and ferritin can be falsely elevated as an acute-phase reactant 4, 1
• Liver function tests with bile acids - cholestatic disease may present before LFTs become abnormal 1, 4
• Creatinine and BUN - uremic pruritus from early chronic kidney disease 1, 4
• If ferritin is normal or elevated, check serum iron and total iron binding capacity to exclude true iron deficiency 4

Additional targeted testing based on clinical features:

• JAK2 V617F mutation if aquagenic pruritus (itching triggered by water contact) - this is pathognomonic for polycythemia vera 5
• Medication review for opioids, ACE inhibitors, or recent drug changes - drug-induced pruritus occurs in 12.5% of cases 5, 1
• HIV and hepatitis serologies only if risk factors present (not routine) 5, 1

Treatment Algorithm

First-Line Therapy (Weeks 1-2)

For all patients regardless of suspected cause:

• Emollients with high lipid content applied immediately after bathing and at bedtime 1, 2, 3
• Topical hydrocortisone 2.5% or triamcinolone 0.1% to affected areas 1-2 times daily 2, 3
• Topical menthol preparations (0.5-3%) for neuropathic component 1, 2

Critical pitfall: This initial trial excludes asteatotic eczema (xerotic eczema), which is extremely common in chronic pruritus and often misdiagnosed as "pruritus of unknown origin" 1, 2

Second-Line Therapy (Weeks 3-4)

If inadequate response after 2 weeks:

Add non-sedating antihistamines:

• Fexofenadine 180 mg daily or loratadine 10 mg daily 1, 2
• Cetirizine 10 mg at bedtime if sleep disturbance is prominent (mildly sedating) 2

Important caveat: Antihistamines work primarily for histamine-mediated itch (urticaria, allergic dermatitis). They have limited efficacy in most chronic pruritus cases but are safe to trial 1, 2, 3

Third-Line Therapy (Weeks 5-8)

If still inadequate response, choose based on suspected mechanism:

For suspected neuropathic or mixed etiology (most common in generalized pruritus without rash):

• Gabapentin 300 mg at bedtime, titrate up to 300 mg three times daily over 1-2 weeks 1, 2, 3
• Alternative: Pregabalin 75 mg twice daily 2

For suspected central sensitization or depression/anxiety:

• Paroxetine 10-20 mg daily (SSRI with best evidence) 1, 2, 3
• Alternative: Mirtazapine 7.5-15 mg at bedtime (dual benefit for itch and sleep) 1, 2, 3
• Alternative: Doxepin 10-25 mg at bedtime (tricyclic with antihistamine properties) 3

For refractory cases:

• Naltrexone 25-50 mg daily (opioid receptor antagonist) - start low at 12.5 mg to avoid dysphoria 1, 2

Fourth-Line: Dermatology Referral

Refer if no response after 8 weeks of appropriate therapy for:

• Phototherapy (BB-UVB or NB-UVB) - highly effective with Strength of Recommendation A for multiple etiologies 1, 2
• Consideration of systemic immunomodulators (dupilumab, methotrexate) if inflammatory component suspected 3

Critical Red Flags Requiring Urgent Investigation

Refer immediately or expedite workup if:

• Age >60 years with pruritus <12 months duration - heightened malignancy risk, particularly lymphoma 4, 6
• Constitutional symptoms (fever, night sweats, weight loss) - suggests lymphoma 5
• Aquagenic pruritus - check JAK2 mutation for polycythemia vera 5, 4
• Excoriations with normal-appearing surrounding skin - consider skin biopsy to exclude cutaneous lymphoma 5

Psychosocial Management

Do not dismiss psychological factors, but always exclude physical causes first 5

For patients with significant distress or suspected psychological contribution:

• Behavioral interventions including habit reversal training to break the itch-scratch cycle 5, 2
• Consider referral to psychology/psychiatry if anxiety or depression is prominent 5, 1
• Patient support groups can provide significant benefit 5, 2

Common Pitfalls to Avoid

• Never use long-term sedating antihistamines (diphenhydramine, hydroxyzine) except in palliative care - associated with dementia risk 1, 4
• Avoid gabapentin in hepatic pruritus - it is ineffective and potentially harmful 1, 2
• Do not assume normal ferritin excludes iron deficiency - check serum iron and TIBC if clinical suspicion remains 4
• Do not perform extensive malignancy screening in young patients with acute onset or localized symptoms 7