Pain in multiple sclerosis: clinical phenotypes and therapeutic strategies - a narrative review

Introduction: Pain is a frequent and burdensome symptom in multiple sclerosis (MS), yet it remains underrecognized and undertreated. Objective: This review summarizes current knowledge on the prevalence, mechanisms, clinical phenotypes, and therapeutic strategies of MS-related pain, with an emphasis on implications for clinical management. Methods: We conducted a narrative review of the literature, integrating epidemiological, clinical, and mechanistic evidence on pain in MS. Results: Pain is reported by 29% to 86% of people with MS, and up to one-third describe it as their most distressing symptom. Multiple sclerosis-related pain can be classified mechanistically as nociceptive, neuropathic, nociplastic, or mixed. Common clinical syndromes include migraine, tension-type headache, optic neuritis-related pain, trigeminal neuralgia, painful spasticity, and Lhermitte sign. Nociplastic, fibromyalgia-like widespread pain has recently gained attention but remains poorly defined. Evidence for pharmacological interventions - such as anticonvulsants, tricyclic antidepressants, muscle relaxants, corticosteroids for acute optic neuritis, and nabiximols for spasticity - is limited, with few trials addressing specific pain subtypes. Among nonpharmacological strategies, structured exercise shows the most consistent benefits for MS-related pain, whereas evidence for other approaches, including physiotherapy, psychological interventions, and neuromodulation, remains limited. Nevertheless, multimodal strategies addressing co-occurring fatigue, depression, and sleep disturbance appear most effective. Conclusion: Pain is common and disabling across all MS phenotypes but is often insufficiently addressed in clinical practice. A mechanism-based classification combined with individualized, multimodal treatment offers the most promising framework to improve patient outcomes.