Pain Management in Erythromelalgia: A Systematic Review and Graded Appraisal Across Etiological Subtypes

Erythromelalgia is a rare disorder characterised by burning pain, erythema and increased skin temperature in the extremities. Its pathophysiological heterogeneity, together with variable treatment responses, complicates management in the absence of evidence-based guidelines. This systematic review appraised pain-management strategies across reported aetiological subtypes.

Following PRISMA 2020 guidelines, the review was registered in PROSPERO (CRD420251232074). PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for studies published or registered between 1 January 2000 and 30 April 2026. Randomised controlled trials, non-randomised interventional studies, cohort studies and case series were eligible; non-randomised studies required at least five individuals. Risk of bias was assessed using Joanna Briggs Institute tools and certainty of evidence using GRADE.

Of 3372 records, 25 studies reporting 591 individuals were included. Aetiological subtype was reported for 277 individuals (46.9%). Mechanistic and aetiological characterisation varied substantially across domains, with haematological data available for 72.6% and SCN9A status for 19.0% of the overall population. Moderate-certainty evidence supported aspirin in myeloproliferative neoplasm-associated erythromelalgia. Low-certainty evidence suggested benefit from mexiletine and carbamazepine in primary erythromelalgia, as well as from prostaglandin analogues, corticosteroids, selected topical therapies and sympathetic interventions in specific contexts. Evidence for selective Naᵥ1.7 inhibitors and most other interventions was of very low certainty.

Treatment-response patterns in better-characterised populations suggest that aetiology and underlying mechanisms may be relevant to treatment selection. However, this mechanism-informed approach remains hypothesis-generating and requires prospective validation through systematic aetiological and mechanistic characterisation.

This systematic review provides a comprehensive, graded evaluation of the full spectrum of pain-management strategies in erythromelalgia, including systemic, topical, interventional and non-pharmacological approaches, across reported aetiological subtypes. Integrating risk-of-bias appraisal and GRADE certainty ratings, it identifies moderate-certainty evidence for aspirin in myeloproliferative neoplasm-associated disease and low-certainty evidence for conventional sodium-channel blockers in selected primary forms, while evidence for other interventions remains low or very low. These patterns suggest that aetiology may inform treatment selection, but require prospective validation.