Therapeutic use of cannabinoids in age-related pain: Current evidence and clinical perspectives

Pain is a frequently reported long lasting symptom among older adults, often associated with age-related conditions such as osteoarthritis, neuropathies, and musculoskeletal degeneration. In a normal inflammatory condition, the release of pro-inflammatory mediators and the concomitant local vasodilation increases capillary permeability leading to the sensation of pain and hyperalgesia. In a physiologically balanced system, removal of the noxious stimulus allows gradual reduction in inflammation and pain. However, in ageing individuals, the inflammatory response is frequently dysregulated due to immunosenescence, leading to impaired resolution mechanisms, sustained production of pro-inflammatory mediators, and chronic low-grade inflammation-commonly referred to as "inflammaging." This persistent inflammatory condition contributes to the development and maintenance of chronic pain states in the elderly. In this context, the present review explores the role of the endocannabinoid system (ECS) in modulating pain and inflammation during ageing. Particular attention is given to the therapeutic potential of phytocannabinoids derived from Cannabis sativa L., including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and their interactions with cannabinoid receptors. The synergistic effects of phytocannabinoids with other bioactive plant constituents, such as terpenes and flavonoids-commonly known as the "entourage effect"-are also discussed as a means to enhance analgesic efficacy. Furthermore, this review examines how advanced drug delivery platforms, particularly nano-carriers, can address the limitations of conventional cannabis-based formulations by improving bioavailability, pharmacokinetic stability, and targeted delivery, ultimately optimizing the therapeutic application of cannabinoids in managing age-related pain.