How should I evaluate and manage an adult with new‑onset generalized pruritus without any rash?

Evaluation and Management of Pruritus Without Rash

Begin with a systematic laboratory workup while simultaneously starting symptomatic treatment with emollients and non-sedating antihistamines, as 25% of cases are due to iron deficiency alone and another 15% have other treatable systemic causes. 1, 2

Initial Laboratory Investigations

Order the following tests immediately for all patients with generalized pruritus without rash: 1, 3

• Complete blood count with differential – to screen for polycythemia vera, lymphoma, and anemia 1, 3
• Ferritin and complete iron studies – iron deficiency causes 25% of cases and responds completely to replacement therapy within days 2, 3, 4
• Liver function tests, total bilirubin, and serum bile acids – cholestatic liver disease is a major cause, with pruritus affecting palms/soles and worsening at night 1, 2
• Urea, electrolytes, and creatinine – uremic pruritus from chronic kidney disease is common 1
• Thyroid function tests – only if clinical features suggest thyroid disease (not routine) 1, 3

Do not order routine endocrine panels, chest X-rays, or extensive malignancy workups unless specific systemic symptoms are present. 1

Critical History Elements to Guide Workup

Focus your history on these specific features that direct further investigation: 1, 2

• Aquagenic pruritus (triggered by water contact) → order JAK2 V617F mutation for polycythemia vera 1
• Pruritus worsening with salt intake → suggests fluid retention from kidney, liver, or heart disease; restrict sodium to <2g daily immediately 2
• Travel history or HIV risk factors → order HIV and hepatitis A, B, C serology 1
• Recent medication changes → drug-induced pruritus occurs in 12.5% of drug reactions; trial cessation if safe 1, 2
• Palms/soles involvement, worse at night → strongly suggests cholestatic liver disease 2

Immediate Symptomatic Management

Start these treatments while awaiting laboratory results: 1, 4

• Emollients applied liberally at least twice daily – universal first-line therapy for all pruritus 1, 2, 4
• Non-sedating antihistamines: fexofenadine 180 mg daily OR loratadine 10 mg daily 1, 4
• Topical menthol or pramoxine (refrigerated) for additional symptomatic relief 2

Avoid sedating antihistamines (hydroxyzine) except in short-term/palliative settings due to dementia risk in elderly patients. 1, 4

Cause-Specific Treatment Algorithms

Iron Deficiency (25% of cases)

• Iron replacement therapy leads to complete cessation of pruritus shortly after starting treatment 1, 2, 4
• This is the most common treatable cause; verify comprehensive iron studies were performed, not just ferritin alone 3

Uremic Pruritus

• Optimize dialysis adequacy first (Kt/V ≥1.6) – relieves pruritus in 40% of patients 2
• Broadband UVB phototherapy is the most effective treatment with Level 1+ evidence 1, 4
• Gabapentin 300-1200 mg daily in divided doses for refractory cases 1, 2

Hepatic/Cholestatic Pruritus

• Rifampin 150 mg twice daily as first-line treatment 1, 2, 4
• Cholestyramine 9 g daily as second-line 1, 2
• Sertraline as third-line 2
• Never use gabapentin for hepatic pruritus – it is specifically contraindicated 4
• Refer to hepatology if significant hepatic impairment or persistent elevation 2

Polycythemia Vera

• Cytoreductive therapy, aspirin, interferon-α, SSRIs, or NB-UVB phototherapy 1
• Order JAK2 V617F mutation if suspected (especially with aquagenic pruritus) 1, 3

Lymphoma-Associated Pruritus

• Cimetidine, carbamazepine, gabapentin, or mirtazapine 1
• Oral corticosteroids for incurable lymphoma 1
• BB-UVB for Hodgkin lymphoma or NB-UVB for non-Hodgkin lymphoma 1

Second-Line Systemic Therapies for Refractory Cases

If initial treatments fail after 2-4 weeks, consider: 1, 2

• Paroxetine, fluvoxamine, or mirtazapine (antidepressants) 1
• Gabapentin or pregabalin (for neuropathic component, except in hepatic disease) 1, 2
• Naltrexone or butorphanol (opioid antagonists) 1
• Ondansetron or aprepitant (antiemetics) 1, 2
• Dupilumab for severe refractory cases 2

When to Consider Additional Investigations

Order these only if initial workup is unrevealing and pruritus persists >2 weeks: 1, 3

• Skin biopsy – to evaluate for cutaneous lymphoma or small fiber neuropathy in persistent unexplained cases 1, 3
• Antimitochondrial antibodies – if cholestatic pattern on LFTs suggests primary biliary cholangitis 1, 2
• Chest X-ray – only if lymphoma suspected based on systemic symptoms (not routine) 1, 5

Critical Pitfalls to Avoid

• Do not accept "normal labs" without verifying comprehensive iron studies were performed – many cases are missed when only ferritin is checked 3
• Do not assume antihistamines alone will work – they are generally ineffective for systemic causes like malignancy 4
• Do not delay medication review – drug-induced pruritus is common and immediately reversible 1, 2
• Do not continue sedating antihistamines long-term – dementia risk in elderly 4
• Do not use gabapentin for hepatic pruritus – specifically contraindicated 4

Referral Indications

Refer to dermatology if: 2

• Diagnosis remains uncertain after initial workup
• No response to first-line therapies after 2-4 weeks
• Considering phototherapy or systemic immunosuppression

Refer to appropriate specialist if: 1, 2

• Hepatology: significant hepatic impairment or persistent LFT elevation
• Nephrology: elevated creatinine requiring dialysis optimization
• Hematology: suspected polycythemia vera (elevated hemoglobin/hematocrit with JAK2 mutation)

Send to emergency department immediately if: 2

• Hypotension, tachycardia, or respiratory distress (anaphylaxis)
• Severe abdominal pain with jaundice
• Altered mental status
• Rash with fever and mucosal involvement