How should I evaluate and manage an adult with chronic (>6 weeks) generalized pruritus of unknown etiology?

Evaluation and Management of Chronic Generalized Pruritus Without Rash

Begin immediate symptomatic treatment with emollients applied at least twice daily and non-sedating antihistamines (fexofenadine 180 mg or loratadine 10 mg daily) while simultaneously ordering a focused laboratory panel to identify treatable systemic causes, particularly iron deficiency and cholestatic liver disease. 1

Mandatory Initial Laboratory Workup (Order for All Patients)

Order these tests immediately for every patient with chronic generalized pruritus without visible dermatosis: 1, 2

• Complete blood count with differential – screens for polycythemia vera, lymphoma, and anemia 1, 2
• Comprehensive iron studies (serum iron, ferritin, transferrin saturation) – iron deficiency causes 25% of cases and responds completely to replacement therapy within days 1, 2
• Liver function tests, total bilirubin, and serum bile acids – cholestatic liver disease accounts for 15% of cases and presents with palm/sole predominance and nocturnal worsening 1, 2
• Renal panel (urea, creatinine, electrolytes) – uremic pruritus is common in chronic kidney disease 1, 2
• Thyroid-stimulating hormone – only if clinical features suggest thyroid dysfunction (do not order routinely) 1, 2

Do not order extensive endocrine panels, chest radiographs, or malignancy screens unless specific systemic symptoms are present. 1, 2

Critical History Elements to Guide Additional Testing

Focus your history on these specific triggers that direct targeted investigations: 1, 2

• Aquagenic pruritus (triggered by water contact) → order JAK2 V617F mutation analysis for polycythemia vera 1, 2
• Recent travel or HIV/hepatitis risk factors → obtain HIV and hepatitis A, B, C serologies 1, 2
• New medication within 6 months → recognize that drug-induced pruritus causes 12.5% of cases; discontinue suspected agent if safe 2, 3
• Salt intake worsening symptoms → immediately restrict dietary sodium to <2 grams daily and investigate for kidney/liver/heart failure 2
• Dietary restrictions (vegetarian/vegan) or gastrointestinal symptoms → increases likelihood of iron deficiency 1

Immediate Symptomatic Management (Start While Awaiting Results)

First-line therapy (initiate in all patients): 1, 2

• Emollients applied liberally at least twice daily – universal treatment for all pruritus 1, 2
• Non-sedating antihistamines: fexofenadine 180 mg daily OR loratadine 10 mg daily OR cetirizine 10 mg daily 1, 2
• Avoid sedating antihistamines (hydroxyzine) except for short-term palliative use due to dementia risk in elderly patients 1, 2

Second-line topical options (if inadequate response after 1 week): 1, 4

• Topical doxepin (limit to 8 days, 10% body surface area, 12 grams daily maximum) 1, 4
• Topical clobetasone butyrate or menthol 1, 4
• Do not use crotamiton cream, capsaicin, or calamine lotion – ineffective per guideline evidence 1

Cause-Specific Treatment Algorithms

Iron Deficiency Pruritus (25% of Cases)

Oral iron replacement leads to complete cessation of pruritus within days of starting therapy. 1, 2 Start ferrous sulfate 325 mg daily and recheck ferritin in 4 weeks. 1

Uremic Pruritus (Chronic Kidney Disease)

Treatment hierarchy based on strength of evidence: 1, 2

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

Hepatic/Cholestatic Pruritus

Treatment algorithm: 1, 2

1. First-line: Rifampin 150 mg twice daily (Strength of Recommendation A) 1, 2
2. Second-line: Cholestyramine 9 g daily 1, 2
3. Discontinue suspected hepatotoxic drugs immediately (statins cause cholestatic hepatitis in 1.1% of patients) 2

Polycythemia Vera (Aquagenic Pruritus)

Management options include: 2

• Cytoreductive therapy, low-dose aspirin, interferon-α, selective serotonin reuptake inhibitors, or narrow-band UVB phototherapy 2

Lymphoma-Associated Pruritus

Pharmacologic options: 2

• Cimetidine, carbamazepine, gabapentin, mirtazapine, oral corticosteroids (for incurable disease) 2
• Phototherapy: broadband UVB for Hodgkin lymphoma; narrow-band UVB for non-Hodgkin lymphoma 2

Refractory Systemic Therapies (If No Improvement After 2-4 Weeks)

Consider these agents in order of preference: 1, 2, 4

• Antidepressants: paroxetine, fluvoxamine, or mirtazapine 1, 4
• Neuropathic agents: gabapentin or pregabalin (avoid pregabalin in hepatic disease) 1, 4
• Opioid antagonists: naltrexone or butorphanol 1, 4
• Anti-emetics: ondansetron or aprepitant 1, 4
• Combined H1 and H2 antagonists: fexofenadine plus cimetidine 1

Referral Criteria and Timing

Refer to dermatology if: 2, 4

• Persistent pruritus >2-4 weeks despite first-line therapy 2, 4
• Diagnostic uncertainty or rash develops 2, 4

Refer to hepatology if: 2

• Significant hepatic impairment or persistent elevation of liver enzymes 2
• Antimitochondrial antibodies positive (suggests primary biliary cholangitis) 2

Refer to hematology if: 2

• Elevated hemoglobin/hematocrit with positive JAK2 V617F mutation 2

Send to emergency department immediately if: 2

• Hypotension, tachycardia, or respiratory distress develops 2
• Severe abdominal pain with jaundice or altered mental status 2
• Rash with fever and mucosal involvement (suggests drug reaction) 2

Additional Investigations for Persistent Unexplained Pruritus

Order these tests only if initial workup is unrevealing after 4-6 weeks: 1, 2

• Skin biopsy – evaluates for cutaneous T-cell lymphoma or small fiber neuropathy 1, 2
• Antimitochondrial antibodies – if cholestatic liver tests suggest primary biliary cholangitis 2
• Chest radiograph – only if systemic features raise suspicion for lymphoma 2

Critical Clinical Pitfalls to Avoid

Common errors that delay diagnosis or worsen outcomes: 1, 2, 3

• Do not rely on ferritin alone – order comprehensive iron studies (serum iron, transferrin saturation) because ferritin is an acute-phase protein and may be falsely normal 1
• Do not assume antihistamines alone will control systemic pruritus – they are generally ineffective for malignancy or organ-specific causes 2
• Always obtain complete medication history including over-the-counter and herbal products – drug-induced pruritus is common and reversible 2, 3
• Consider scabies even with minimal skin signs – especially in immunocompromised or HIV-positive patients 2, 3
• Do not delay bile acid testing if cholestatic disease is suspected – this is the definitive diagnostic test 2, 3
• Do not order routine thyroid panels without clinical indicators of thyroid dysfunction 1, 2

Age-Specific Considerations for Elderly Patients

For patients >65 years with pruritus: 4

• Initially treat with emollients and topical steroids for at least 2 weeks to exclude asteatotic eczema (dry skin) 4
• Use moisturizers with high lipid content applied immediately after bathing 4
• Gabapentin may be beneficial for elderly patients with neuropathic pruritus 4
• Avoid sedating antihistamines due to increased dementia risk 1, 2

Adjunctive and Behavioral Interventions

Consider these approaches for distressed patients or refractory cases: 1, 4

• Psychosocial interventions: education on trigger avoidance, relaxation techniques, cognitive restructuring, habit reversal training 1, 4
• Patient support groups can be beneficial 1
• Acupuncture as monotherapy or combined with Chinese herbal remedies (second-line option) 4