What is the treatment for pruritus (itching) without a rash?

Treatment of Pruritus Without Rash

Start with non-sedating antihistamines (fexofenadine 180 mg or loratadine 10 mg) combined with emollients as first-line therapy, while simultaneously investigating for underlying systemic causes through targeted laboratory workup. 1

Immediate Symptomatic Management

First-Line Therapies

• Non-sedating antihistamines are the preferred initial oral treatment: fexofenadine 180 mg daily or loratadine 10 mg daily, or mildly sedative cetirizine 10 mg daily before considering sedating agents 1, 2
• Emollients should be applied liberally to maintain skin hydration, particularly important in elderly patients where asteatotic eczema may be the underlying cause 3, 2
• Topical therapies include clobetasone butyrate or menthol preparations for localized relief 3, 2
• Topical doxepin can be used but must be limited to 8 days, covering no more than 10% body surface area, maximum 12g daily 2

Second-Line Therapies (if first-line fails after 2-4 weeks)

• Combination H1 and H2 antagonists: fexofenadine plus cimetidine may provide additive benefit 1
• SSRIs: paroxetine or fluvoxamine 1, 2
• Mirtazapine: particularly useful when depression or sleep disturbance coexists 1, 2
• Gabapentin or pregabalin: effective for neuropathic-type itch, but avoid gabapentin in hepatic pruritus 1, 3, 2
• Naltrexone or butorphanol: opioid antagonists for refractory cases 1, 2
• Ondansetron or aprepitant: serotonin/neurokinin receptor antagonists 1

Sedating Antihistamines: Use With Caution

• Hydroxyzine 25 mg three to four times daily is FDA-approved for pruritus management 4
• However, limit sedating antihistamines to short-term use or palliative settings only due to potential dementia risk with long-term use 3, 2

Mandatory Diagnostic Workup

Every patient with chronic pruritus without rash requires systematic investigation for underlying causes, as 25% of cases are due to iron deficiency alone. 1

Essential Laboratory Tests

• Complete blood count and ferritin: iron deficiency is the most common systemic cause (25% of cases), and iron replacement can resolve pruritus within days of starting therapy 1
• Liver function tests: assess for hepatic causes including cholestasis 3
• Renal function (urea and electrolytes): evaluate for uremic pruritus 3
• Thyroid function tests: screen for endocrine causes 1

Additional Tests Based on Clinical Suspicion

• Bile acids and antimitochondrial antibodies if liver disease suspected 3
• HIV and hepatitis A, B, C serology if risk factors present 3
• JAK2 V617F mutation if polycythemia vera suspected (raised hemoglobin/hematocrit with aquagenic pruritus) 1
• Lactate dehydrogenase, ESR, blood film if hematological malignancy suspected 1
• Tissue transglutaminase antibodies if unexplained iron deficiency (celiac disease screening) 1

Critical Pitfall: Ferritin Interpretation

Ferritin is an acute-phase protein and may appear falsely "normal" in iron deficiency with concurrent inflammation. If ferritin is borderline normal but clinical suspicion remains high, check serum iron and total iron binding capacity. Give a trial of iron replacement if ferritin is below 15-25 μg/L or if unexplained anemia/microcytosis exists. 1

Cause-Specific Treatment Algorithms

Uremic Pruritus (Renal Failure)

• Optimize dialysis parameters first: normalize calcium-phosphate balance, control parathyroid hormone, correct anemia 3, 2
• Broadband UVB (BB-UVB) phototherapy is the most effective treatment with Level 1+ evidence, showing clinical significance in meta-analysis of RCTs 1
• Effect onset occurs at 2 weeks, lasting up to 7 months 1
• Avoid cetirizine and long-term sedative antihistamines in uremic pruritus except palliative settings 3

Hepatic Pruritus (Cholestasis)

• Rifampicin is first-line treatment 3, 2
• Cholestyramine is second-line 3, 2
• Sertraline is third-line 3, 2
• Naltrexone or nalmefene are fourth-line options 3
• Specifically avoid gabapentin in hepatic pruritus 3, 2

Hematologic Causes

Polycythemia Vera:

• Cytoreductive therapy, aspirin, interferon-α, SSRIs, PUVA, UVB phototherapy, cimetidine, or atenolol 1, 3
• Ruxolitinib (JAK1/JAK2 inhibitor) produces rapid reductions in pruritus scores in recent RCT 1

Lymphoma-Associated Pruritus:

• Cimetidine, gabapentin, carbamazepine, or mirtazapine 1, 3
• Oral corticosteroids for incurable lymphoma 1
• BB-UVB for Hodgkin lymphoma, NB-UVB for non-Hodgkin lymphoma (temporary relief) 1, 3

Iron Deficiency:

• Iron replacement therapy can produce complete cessation of pruritus shortly after starting treatment 1, 3

Drug-Induced Pruritus

• Trial of medication cessation if risk-benefit analysis acceptable 3, 2
• Naltrexone for opioid-induced pruritus if cessation not possible; methylnaltrexone is alternative 3, 2
• Diclofenac 100 mg rectally for postoperative pruritus 2

Immune Checkpoint Inhibitor-Related Pruritus

For patients on cancer immunotherapy with pruritus but no rash:

• Topical anti-itch remedies: refrigerated menthol and pramoxine 1
• Gabapentin, pregabalin, aprepitant, or dupilumab for grade 3 severity 1

Phototherapy for Generalized Pruritus

BB-UVB phototherapy has the strongest evidence (Level 1+) for uremic pruritus and should be considered early in treatment algorithm. 1

• Uremic pruritus: BB-UVB is treatment of choice per meta-analysis, only therapy reaching clinical significance 1
• Polycythemia vera: NB-UVB or BB-UVB with 50-80% response rates, though relapses common 1
• Cholestatic pruritus: BB-UVB may be effective per case series 1
• Maintenance phototherapy once weekly can prevent relapse after initial response 1

Special Populations

Elderly Patients

• Exclude asteatotic eczema first with 2-week trial of emollients and topical steroids before extensive workup 3, 2
• Use moisturizers with high lipid content 2
• Avoid long-term sedating antihistamines due to dementia risk 3, 2

Pruritus of Unknown Origin (GPUO)

When comprehensive workup reveals no cause:

• Progress through treatment ladder: emollients → non-sedating antihistamines → SSRIs/mirtazapine → gabapentin/pregabalin → naltrexone → aprepitant 1, 3, 2
• Consider phototherapy (expert opinion suggests benefit despite limited evidence for GPUO specifically) 1
• Behavioral interventions, relaxation techniques, and cognitive restructuring may help when psychological factors contribute 2
• Patient support groups can be beneficial for chronic management 2

Key Clinical Pitfalls to Avoid

• Never assume antihistamines alone will work: they are generally ineffective for pruritus due to solid tumors and many systemic causes 1
• Don't overlook medication review: drug-induced pruritus is common and reversible 3
• Don't use gabapentin in hepatic pruritus: it is specifically contraindicated 3, 2
• Don't continue sedating antihistamines long-term: dementia risk outweighs benefits except in palliative care 3, 2
• Don't skip iron studies: iron deficiency causes 25% of systemic pruritus cases and responds dramatically to replacement 1
• Don't accept "normal" ferritin at face value: check iron studies if clinical suspicion high, as ferritin can be falsely elevated by inflammation 1