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Treatment Options in Phantom Limb Pain Maria Isabel Brazão Lusitano de Freitas, Javier De Andrés Ares. University Hospital Viamed Santa Elena, University Hospital HLA Moncloa, Madrid, Spain Upon completion of this session, attendees will be able to discuss: • The pathophysiology of phantom limb pain (PLP). • Clinical evaluation of PLP and differential diagnosis. • Pharmacological therapies for PLP. • Interventional therapies for PLP. • Surgical and advanced therapies for PLP. 1. Introduction PLP is a neuropathic pain perceived in a limb or part of a limb that has been amputated, representing a form of deafferentation pain. 1 It must be distinguished from non-painful phantom sensations and residual limb (stump) pain, conditions that often coexist and complicate clinical assessment.2 PLP affects 60–85% of amputees and typically begins within days to weeks post-amputation, though it may persist chronically.3 With increasing rates of amputations due to vascular disease, diabetes, trauma, and conflict-related injuries, PLP poses a substantial burden on physical rehabilitation, prosthesis use, mental health, mobility, and quality of life.4 2. Pathophysiology of PLP PLP results from interconnected peripheral, spinal, and supraspinal mechanisms that contribute to pain generation and maintenance.5 2.1 Peripheral Mechanisms and Stump Pain Spontaneous ectopic neural activity near transected nerves has been demonstrated. These contribute to stump pain, which is often closely associated with PLP. Relief through peripheral nerve blocks supports the peripheral origin of some pain components.6 2.2 Spinal Mechanisms Loss of normal input due to amputation leads to reorganization within the spinal dorsal horn. These changes include reduced descending inhibition, abnormal DRG activity, ephaptic transmission, and the formation of perineural fibrosis. Together, these processes promote central sensitization, enhancing the perception and persistence of pain.8 2.3 Central and Supraspinal Mechanisms Functional neuroimaging (fMRI, MEG) has shown significant cortical reorganization involving the primary somatosensory and motor cortices, the thalamus, and brainstem. The degree of cortical remapping has been correlated with the severity and duration of PLP, reinforcing the importance of central plasticity.8 9 3. Clinical Evaluation & Differential Diagnosis Diagnosis is clinical, based on history and examination. Other causes must be excluded, including radicular pain, limb ischemia, neuromas (identified via Tinel’s sign), prosthesis-related issues, local infections, pressure lesions, or dermatologic conditions. Imaging, vascular assessments, and electrodiagnostic testing support diagnostic clarification. 4. Multimodal Management in the Pain Unit Treatment should be individualized and multimodal, combining pharmacological, interventional, surgical, and non-invasive approaches.10 4.1 Pharmacologic Therapies • Tricyclic antidepressants (e.g., amitriptyline, nortriptyline): Enhance serotonergic and noradrenergic transmission, block sodium and NMDA channels, with low NNT in neuropathic pain. • Anticonvulsants (gabapentin, pregabalin): Act on calcium channels to reduce excitatory neurotransmission; modest efficacy in PLP. • SNRIs (e.g., duloxetine): Facilitate descending inhibition; supported by diabetic neuropathy data. • Opioids: μ-receptor agonists; use is cautious due to dependency risks, though short-term benefit on cortical plasticity is suggested. • NMDA antagonists (ketamine, memantine): Ketamine is effective in refractory cases but limited by adverse effects; memantine offers better tolerability. • IV lidocaine: Reduces central and peripheral hyperexcitability. • Adjuvants: Calcitonin, botulinum toxin A, and propranolol used selectively in persistent or refractory cases.11 4.2 Interventional Therapies • Peripheral nerve blocks: Diagnostic and therapeutic role, especially in neuroma-related pain. • Sympathetic blocks: Conflicting evidence; some patients benefit, particularly when sympathetic involvement is suspected.12 • Pulsed radiofrequency (PRF): Minimally invasive method targeting neuromas or DRG.13 • Cryoneurolysis: Disrupts nerve conduction and prevents neuroma formation through localized freezing.11 • Neuromodulation: Spinal cord stimulation, DRG stimulation, and peripheral nerve stimulation for refractory cases.17 • Intrathecal ziconotide: A calcium channel blocker with central effects; use is limited due to neuropsychiatric side effects.14 4.3 Surgical and Advanced Neurosurgical Therapies • Deep brain stimulation (DBS) and thalamic stimulation: Reserved for highly refractory cases due to invasive nature and potential complications.15 4.4 Non-Invasive Therapies • Repetitive transcranial magnetic stimulation (rTMS): Modulates cortical excitability; supported by recent meta-analyses.9 10 • Transcutaneous electrical nerve stimulation (TENS): Safe, cost-effective option, especially for mild to moderate PLP. • Mirror therapy: uses visual feedback to create the illusion of movement and presence of the amputated limb. By reflecting the intact limb’s movements in a mirror, it helps to retrain the brain’s sensorimotor cortex and reduce maladaptive neuroplasticity associated with phantom limb pain. Studies have shown that can decrease pain intensity and improve functional outcomes.16 4.5 Novel Technologies • Virtual Reality (VR), and Augmented Reality (AR) provide visual and sensory feedback to restore sensorimotor integration. Immersive VR has shown benefits in both symptom relief and cortical reorganization.10 16 5 Conclusion Phantom Limb Pain is a complex neuropathic condition resulting from maladaptive changes across the nervous system. Effective management requires a multimodal, multidisciplinary approach that includes pharmacologic, interventional, and technological strategies. Emerging therapies such as rTMS and VR offer exciting opportunities, but further research is required to validate their role in routine care. 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