What is the role of Selective Serotonin Reuptake Inhibitors (SSRIs) in treating chronic itching?

Role of SSRIs in Chronic Itching

SSRIs have a limited but specific role in chronic pruritus, primarily as second-line therapy for polycythemia vera-associated itch and paraneoplastic pruritus, while other antidepressants (particularly mirtazapine) demonstrate superior efficacy for most chronic itch conditions. 1

Evidence-Based Indications for SSRIs

Polycythemia Vera-Associated Pruritus

• SSRIs are recommended as one treatment option for pruritus associated with polycythemia vera when first-line therapies (cytoreductive therapy, aspirin) have failed 1
• The evidence supporting this use comes from case series and reports, representing Level 3-4 evidence with Strength of Recommendation D 1
• SSRIs should be considered alongside other options including interferon-alpha, PUVA, UVB phototherapy, cimetidine, or atenolol 1

Paraneoplastic Pruritus from Solid Tumors

• Paroxetine specifically is recommended for paraneoplastic pruritus associated with solid malignancies 1
• This represents Strength of Recommendation D based on case reports and small series 1

Generalized Pruritus of Unknown Origin (GPUO)

• Paroxetine and fluvoxamine may be considered as second-line options for GPUO after topical therapies and antihistamines have failed 1
• These are listed alongside multiple other systemic options including mirtazapine, naltrexone, gabapentin, and pregabalin, with no clear hierarchy established 1

Clinical Evidence Supporting SSRI Use

Paroxetine and Fluvoxamine Trial Data

• An open-label study of 72 patients with chronic pruritus showed that 68% experienced weak to very good antipruritic effects with paroxetine or fluvoxamine 2
• Best responses occurred in patients with atopic dermatitis, systemic lymphoma, and solid carcinoma 2
• However, adverse effects occurred in 70.8% of patients, leading to treatment discontinuation in 25% 2
• This study provides proof-of-concept but lacks placebo control, limiting the strength of conclusions 2

Critical Limitations and Caveats

Inferior to Alternative Antidepressants

• Mirtazapine demonstrates superior efficacy for chronic pruritus compared to SSRIs across multiple etiologies 1, 3, 4
• Mirtazapine is specifically recommended for lymphoma-associated pruritus, nocturnal itch, and refractory chronic pruritus 1, 3
• All studies of mirtazapine reported reduction in itch intensity, suggesting more consistent benefit than SSRIs 3

Cholestatic Pruritus Exception

• Sertraline is used empirically for cholestatic pruritus unresponsive to cholestyramine and rifampicin, but evidence is limited to a single small placebo-controlled trial 1
• The mechanism is presumed to involve altering central neurotransmitter concentrations 1
• This represents third- or fourth-line therapy after established treatments have failed 1

Diabetic Neuropathy Context

• The American Society of Anesthesiologists guidelines suggest SSRIs may be considered specifically for diabetic neuropathy-related symptoms, though this applies more to neuropathic pain than pure pruritus 1
• Tricyclic antidepressants and SNRIs are preferred over SSRIs for most neuropathic conditions 1

Practical Prescribing Algorithm

When considering SSRIs for chronic pruritus:

1. First, ensure proper diagnosis and exclude treatable underlying causes (iron deficiency, renal disease, hepatic cholestasis, malignancy) 1

2. Initiate first-line therapies before SSRIs:

   • High-lipid content emollients 1
   • Topical corticosteroids (if inflammatory component) 1
   • Non-sedating antihistamines (fexofenadine 180mg, loratadine 10mg) 1

3. Consider SSRIs as second-line only for specific conditions:

   • Polycythemia vera: After aspirin 300mg daily fails 1
   • Paraneoplastic pruritus: Paroxetine as alternative to mirtazapine or granisetron 1
   • Cholestatic pruritus: Sertraline after rifampicin failure 1

4. Preferred SSRI choices based on evidence:

   • Paroxetine: Most studied for chronic pruritus 1, 2
   • Fluvoxamine: Alternative with similar efficacy profile 1, 2
   • Sertraline: Specific to cholestatic itch 1

5. Strongly consider mirtazapine instead for:

   • Lymphoma-associated pruritus 1
   • Nocturnal itch predominance 4
   • Refractory cases 3
   • When sedation would be beneficial 4

Important Clinical Pitfalls

High Discontinuation Rates

• Expect adverse effects in approximately 70% of patients taking SSRIs for pruritus, with discontinuation rates around 25% 2
• Common side effects include nausea, dry mouth, drowsiness, and reduced libido 2

Avoid in Elderly Without Clear Indication

• Sedative antihistamines are contraindicated long-term in elderly patients (Strength of Recommendation C) due to dementia risk 1
• While this applies to antihistamines, exercise caution with any sedating medication in elderly populations 1

Drug Interactions

• SSRIs are metabolized by cytochrome P450 enzymes and can interact with multiple medications including anticonvulsants, benzodiazepines, tricyclic antidepressants, and warfarin 1
• Screen for potential interactions before prescribing, particularly in elderly patients on multiple medications 1

Not Appropriate for All Visceral Conditions

• SSRIs are not recommended for related visceral pain conditions like irritable bowel syndrome, where they failed to improve symptoms (RR 0.74; 95% CI 0.52-1.06) 5
• The mechanism of increased serotonin at nerve endings could theoretically worsen certain symptoms 5

Strength of Evidence Summary

The evidence supporting SSRIs for chronic pruritus is predominantly Level 3-4 (case series, case reports, open-label studies) with Strength of Recommendation D across all major guidelines 1. This reflects the limited quality of available data and the lack of large-scale randomized controlled trials. The 2018 British Association of Dermatologists guidelines provide the most comprehensive and recent guidance, consistently rating SSRI recommendations as weak 1.