Patients with sickle cell disease (SCD) suffer from both acute and chronic pain, whose pathophysiology involves not only red blood cell sickling with subsequent vaso-occlusion leading to ischemia-reperfusion injury but also neurogenic inflammation, possibly mediated by mast cell activation.Chronic pain affects approximately 40% of patients with SCD, and its management is often a difficult challenge for clinicians. Indeed, morphine, which has long been considered the reference analgesic for acute pain, may paradoxically worsen chronic pain, by promoting mast cell activation and degranulation, leading to the release of mast cell mediators such as substance P or histamine. Substance P is a pain neurotransmitter and a neuro-modulator found to induce peripheral sensitization and neuroinflammation in an SCD effects in SCD by promoting endothelial P-selectin expression. In patients, high levels of plasma histamine have been reported during vaso-occlusive crisis (VOC) but also at steady state, contrasting with normal or slightly increased tryptase level, which suggests mast celltransgenic mouse model. Histamine may also have deleterious effects in SCD by promoting endothelial P-selectin expression. In patients, high levels of plasma histamine have been reported during vaso-occlusive crisis (VOC) but also at steady state, contrasting with normal or slightly increased tryptase level, which suggests mast celltransgenic mouse model. Histamine may also have deleterious activation rather than an increased number of mast cells.In the last few years, the efficacy of cannabinoids has been increasingly reported in chronic cancer and non-cancer pain, including neuropathic, nociceptive, nociplastic, and spasticity-related pain.