Cannabinoids in peripheral neuropathic pain: Resolving mechanistic mismatch through CB₂-oriented phenotype...

Peripheral neuropathic pain (PNP) affects approximately 7-10% of the population, yet 40-60% of patients derive inadequate relief from first-line pharmacotherapies. Cannabinoid-based medicines engage the endocannabinoid system and offer a strong biological rationale for analgesia, but randomised trials show only modest, heterogeneous benefits and non-trivial adverse-effect liability. The 2025 Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain meta-analysis (313 trials; 48,789 participants) issued a weak recommendation against routine cannabinoid use, and the 2025 Agency for Healthcare Research and Quality review reported small analgesic effects with increased adverse events. This review argues that limited efficacy reflects translational mismatch rather than biological implausibility. Cannabinoid receptor type 1 (CB₁)-biased, centrally penetrant formulations are misaligned with inflammation-dominant PNP phenotypes, whereas peripheral cannabinoid receptor type 2 (CB₂)-mediated neuroimmune modulation, attenuating cytokine release, macrophage infiltration, and glial activation, represents an aetiology-aligned target. CB₂ is framed as a hypothesis-driven precision target with strong preclinical support but limited clinical validation, the most informative signals emerging from prespecified subgroup analyses (olorinab CAPTIVATE; lenabasum RESOLVE-1 and DETERMINE) rather than primary endpoints. Cannabidiol is repositioned as a tolerability- and symptom-modifying adjunct rather than a primary analgesic. Translation has been further constrained by species-specific CB₂ pharmacology, heterogeneous cohorts, and trial durations misaligned with immunomodulatory time courses. We therefore propose a tiered precision framework integrating sensory phenotyping, inflammatory biomarker profiling, endocannabinoid tone, and pharmacogenomic profiling, coupled with an operational trial template. Its predictive validity remains hypothesis-generating and requires prospective clinical testing.