Cannabinoid Receptor Modulators in Neuropathic Pain: Expanding Therapeutic Horizons Beyond Conventional Analgesics

Abstract

Background: Neuropathic pain (NP) is a chronic and debilitating condition arising from lesions or dysfunction in the somatosensory nervous system. Conventional pharmacological treatments, including antidepressants, anticonvulsants, and opioids, often provide inadequate relief and are associated with significant adverse effects. Cannabinoid receptor modulators targeting the endocannabinoid system (ECS) have emerged as promising alternatives. Objective: This review aims to evaluate the therapeutic potential, mechanisms, and clinical evidence of cannabinoid receptor modulators (CB1 and CB2 agonists/antagonists) in neuropathic pain management. Methods: A comprehensive literature review of preclinical studies, randomized controlled trials, and systematic reviews (2020–2026) was conducted focusing on cannabinoid pharmacology, receptor modulation, and clinical outcomes. Results: Cannabinoids demonstrate analgesic effects through modulation of neurotransmitter release, reduction of neuroinflammation, and activation of descending inhibitory pathways. CB2-selective agonists show significant promise due to reduced central side effects. However, clinical evidence remains inconsistent, with modest efficacy and notable adverse effects reported in some trials. Conclusion: Cannabinoid receptor modulators represent a promising but complex therapeutic strategy in neuropathic pain. Future research should focus on receptor-selective drugs, personalized medicine approaches, and improved clinical trial design.