What is the cause and treatment of a pruritic (itchy) rash that appears and worsens at night without an identifiable source?

Generalized Pruritus Without Rash: Diagnostic Approach and Management

This presentation of generalized itching that worsens at night without an identifiable rash most likely represents either scabies infestation, intrahepatic cholestasis (especially in pregnancy), iron deficiency, or drug-induced pruritus—and requires immediate diagnostic workup with specific laboratory tests while initiating symptomatic treatment. 1, 2

Key Diagnostic Features

The nocturnal worsening pattern is highly characteristic of specific conditions:

• Scabies presents with intense nocturnal itching affecting all body regions except the head, often appearing out of proportion to visible skin changes, and typically involves close contacts who are also itching 3
• Intrahepatic cholestasis of pregnancy (ICP) causes generalized itching predominantly affecting palms and soles, worse at night, and is generally not associated with a rash 1
• Iron deficiency causes generalized pruritus without rash and is a common, treatable cause 1, 2

Immediate Diagnostic Workup

Order the following laboratory panel immediately in the outpatient setting 1, 2:

• Complete blood count with differential to assess for polycythemia vera, lymphocytosis, or hematological malignancy 1, 2
• Ferritin levels (iron studies including serum iron and TIBC) as both iron deficiency and overload cause generalized pruritus 1, 2
• Liver function tests, total bilirubin, and serum bile acids as cholestatic liver disease is a major cause of generalized pruritus 1, 2
• Urea and electrolytes as chronic kidney disease and uremia are well-established causes 2
• Thyroid function tests if clinical features suggest thyroid disease 2

Critical History and Physical Examination Elements

Focus your evaluation on these specific details 1:

• Onset timing: New-onset pruritus in second half of pregnancy suggests ICP 1
• Distribution: Palms and soles involvement suggests cholestasis; generalized with close contacts suggests scabies 1, 3
• Medication review: Complete list of all medications, as 12.5% of drug reactions present with pruritus without rash 2
• Skin examination: Look specifically for burrows (pathognomonic for scabies), excoriations from scratching (may be mistaken for primary rash), or prurigo nodularis 1, 3
• Associated symptoms: Dark urine and jaundice suggest hepatic disease beyond ICP 1
• Close contacts: Ask if household members or sexual partners are also itching (scabies) 3

Immediate Symptomatic Treatment

Begin treatment while awaiting diagnostic results 1, 2:

• Emollients and moisturizers as first-line for all pruritus 1, 2
• Refrigerated menthol and pramoxine topical anti-itch remedies 1, 2
• Non-sedating antihistamines (loratadine 10 mg daily) for symptomatic relief 2
• Hydroxyzine 25-50 mg at bedtime may be particularly useful for nocturnal pruritus given its sedating properties 4

Condition-Specific Management

If Scabies is Suspected

• Refer to dermatology or infectious disease if diagnostic doubt exists 3
• Close inspection for burrows (up to 1 cm in length) is essential 3
• Consider empiric treatment if history is highly suggestive (intense nocturnal itch, close contacts affected) 3

If Iron Deficiency is Confirmed

• Iron replacement therapy leads to complete cessation of pruritus shortly after treatment begins 2

If Cholestasis is Confirmed

• Rifampin 150 mg twice daily as first-line treatment for hepatic pruritus 2
• Cholestyramine 9 g daily as second-line treatment 2
• Discontinue suspected hepatotoxic medications immediately (statins, NSAIDs) 2

For Severe Refractory Pruritus

If symptoms persist despite initial management 1, 2:

• Gabapentin 300-1200 mg daily in divided doses 1
• Pregabalin as alternative 1
• Aprepitant or dupilumab for severe cases 1

Critical Pitfalls to Avoid

• Do not dismiss nocturnal worsening as this pattern is highly specific for scabies, cholestasis, or iron deficiency 1, 3
• Do not delay medication review as drug-induced pruritus can occur without visible skin changes and may precede rash development 2
• Do not overlook iron studies as iron deficiency is a common, easily treatable cause that clinicians frequently miss 1, 2
• Do not assume excoriations are primary lesions as intense itching leads to secondary skin changes that may be mistaken for a rash 1
• Do not forget to ask about close contacts as this is the key historical feature distinguishing scabies from other causes 3

When to Escalate Care

Refer to dermatology if 1, 2:

• Rash persists beyond 2 weeks or diagnosis remains uncertain
• Skin biopsy is needed to evaluate for cutaneous lymphoma or small fiber neuropathy
• Autoimmune skin disease is suspected

Refer to hepatology if 2:

• Significant hepatic impairment or persistent elevation of liver enzymes is present

Send to emergency department immediately if 2:

• Hypotension, tachycardia, or respiratory distress develops (anaphylaxis)
• Severe abdominal pain with jaundice occurs
• Altered mental status develops
• Rash with fever and mucosal involvement appears (Stevens-Johnson syndrome)