Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN

Background: Trigeminal neuralgia (TN) is a chronic, often debilitating neuropathic facial pain condition. First-line treatment is medical therapy, with carbamazepine being the gold standard. Surgery, including stereotactic radiosurgery in particular with Gamma Knife (GK-SRS), is usually considered when medical management fails, which occurs in > 50% of participants. While surgery can provide long-term relief, prolonged disease duration before intervention is linked to a reduced response rate. A highly precise type of radiation therapy, GK-SRS is a non-invasive management option in TN, with a low risk of serious complications and fewer bothersome side effects compared to medical therapy. Evidence supports the safety and efficacy of GK-SRS in medically-refractory TN, with published data suggesting that earlier intervention (within 3 years of pain onset) leads to improved long-term outcomes. However, the safety and efficacy of ultra-early GK-SRS—administered soon after TN diagnosis and before medical refractoriness—have not been examined. We hypothesize that ultra-early GK-SRS will yield superior long-term pain relief compared to ongoing medical management while also having a lower incidence of treatment-related adverse events. Methods: We will perform a single-centre, two-arm, randomized, controlled, parallel-group design, pragmatic, noninferiority, phase II trial of ultra-early GK-SRS for TN in participants who will be treated before they have developed a medically-refractory state and within 2 years of diagnosed TN per study neurologist. Eighty participants will be randomized 1:1 to either GK-SRS (intervention arm) or ongoing medical management (non-intervention/control arm). Crossover from the non-intervention/control arm to the intervention arm will be permitted. An intention-to-treat analysis will be conducted. The primary outcome will be the proportion of participants with satisfactory pain control at 2 years by the Barrow Neurological Institute Facial Pain Scale. Discussion: This trial aims to test ultra-early GK-SRS as a first-line option in TN, based on a sound rationale for offering GK-SRS prior to failure of medical therapy. If validated, ultra-early GK-SRS will represent a paradigm shift in TN management leading to improved long-term pain control free from adverse medication-related side effects. Trial Registration: This clinical trial has been registered with ClinicalTrials.gov under the identifier number NCT06949436. Registered on April 28, 2025.