Efficacy, safety, and tolerability of palmitoylethanolamide in the management of diabetic neuropathic pain: a systematic review and meta-analysis.

Despite a substantial body of evidence supporting the analgesic and anti-inflammatory properties of palmitoylethanolamide (PEA) in chronic neuropathic pain (CNP), there is an absence of systematic reviews and meta-analyses (SRMAs) specifically evaluating its efficacy in diabetic neuropathic pain (DNP) and distal sensory polyneuropathy (DSPN). MEDLINE/Pubmed, EMBASE, CINAHL, Web of Science, Clinicaltrials.gov and Herdin were searched for relevant articles using the following terms: (PEA or Pamitoylethanolamide or Palmidrol or Palmitoyl Ethanol Amine or Um-pea or Impulsin) AND [(Diabetes or Diabetes Mellitus or DM) AND (polyneuropathy or sensory polyneuropathy or neuronopathy or neuropathic pain or radiculopathy)]. Titles and abstracts were screened by 2 of the authors independently. The references of included papers were also scanned for possible additional journals not obtained from database search. Three studies involving 188 patients were included. PEA, administered either alone or in combination was consistently associated with significant reductions in neuropathic pain scores compared with control. Moreover, in meta-analysis PEA demonstrated a significant reduction in pain scores (SMD: -5.44; CI: -8.47 to - 0.41, p = 0.0004, I2 = 96%). Improvements were also observed in secondary measures such as sleep quality, depressive symptoms, nerve conduction velocity, and vibration perception threshold. Safety data were limited but indicated a favorable tolerability profile with only mild, self-limited adverse events. PEA shows promise as a safe and potentially effective adjunctive therapy for DNP, improving pain and related clinical outcomes. However, the evidence base is limited by heterogeneity, small sample sizes, and frequent use of combination formulations that obscure PEA's independent effects. Larger, high-quality RCTs directly comparing PEA with established therapies are warranted to define its role in clinical practice.