Abstract
Background
Trigeminal neuralgia (TN) is a chronic, often debilitating neuropathic facial pain condition. First-line treatment is medical therapy, with carbamazepine (CBZ) 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 patients. 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 (AEs).
Methods
We will perform a single-center, 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
ClinicalTrials.gov NCT06949436. Registered on April 28, 2025.
Keywords: Trigeminal neuralgia, Gamma Knife, Stereotactic radiosurgery, Surgery, Ultra-early surgery
Administrative information
Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).
| Title {1} | Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia: feasibility and potential benefit URGEnt-TN |
|---|---|
| Trial registration {2a and 2b} |
Trial registry: ClinicalTrials.gov ClinicalTrials.gov ID: NCT06949436 Trial registration date: April 28, 2025 |
| Protocol version {3} | SRS-0301 |
| Funding {4} | This trial is currently unfunded. |
| Author details {5a} |
Amanda Lussoso (1), Samir Patel (2), Wasif Hussain (3), Michael Knash (3), Matt Wheatley (4), Gregory Bowden (4), Ngoc Khanh Vu (5), Tejas Sankar (4) 1 Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada 2 Division of Radiation Oncology, Department of Oncology, University of Alberta, Edmonton, AB, Canada 3 Division of Neurology, University of Alberta, Edmonton, AB, Canada 4 Division of Neurosurgery, University of Alberta, Edmonton, AB, Canada 5 Real World Evidence Unit, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada |
| Name and contact information for the trial sponsor {5b} | Not applicable. This trial is unsponsored. |
| Role of sponsor {5c} | Not applicable. This trial is unsponsored. |
Introduction
Background and rationale {6a}
Trigeminal neuralgia (TN) is a chronic, often severely debilitating, neuropathic facial pain condition characterized by “recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve (cranial nerve five—CNV) and triggered by innocuous stimuli” [1]. TN has an approximate global incidence of 12 cases per 100,000 and a female predominance of 3:2 [2, 3], and occurs predominantly in the sixth decade of life, peaking around 70 years [4–6]. The severe lancinating pain of TN is triggered by common somatosensory stimuli experienced in everyday life, such as chewing, speaking, brushing teeth, temperature changes, or tactile pressure to the face; pain attacks may also occur entirely spontaneously [7].
Given the severity of TN, prompt pain management is critically important. In general, pharmaceutical therapy is the first-line treatment, with carbamazepine (CBZ) being the gold standard. However, CBZ is associated with a high incidence of adverse effects (40%–66%) [8], including somnolence, dizziness, double vision, rash, nausea, headache, vomiting, tremor, ataxia, disturbed sleep, mood changes, lack of concentration, memory loss, and hyponatremia [9–12]. In rare circumstances, severe adverse effects can occur, including myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, elevated liver enzymes, hematologic dyscrasias, thrombocytopenia, aplastic anemia [10], and dosages reaching toxic levels [5]. In addition, the presence of the HLA-B*15:02 allele found almost exclusively in Asian genealogy warrants genetic testing for participants with Asian lineage to determine their potential risk of CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis that may be life-threatening [13]. Oxcarbazepine (OXC) is an enantiomer of CBZ associated with fewer side effects, contraindications, and overall better tolerability [5, 10, 14]; however, similar to CBZ, it can cause sedation, dizziness, poor concentration, diplopia, nausea, headache, somnolence, ataxia, and thrombocytopenia, typically experienced to a lesser degree [10–12, 15]. Of note, the incidence of hyponatremia is dose-dependent and of particular concern [10], so OXC use needs to be monitored carefully to avoid electrolyte imbalance.
A large retrospective study examining the natural history of classical TN demonstrated robust initial responsiveness of 98% for CBZ and 94% for OXC. However, following means of 8.6 (CBZ) and 13 (OXC) months, a significant proportion of participants (27% CBZ, 18% OXC) developed intolerability and required subsequent dosage reduction to inadequate levels for appropriate pain management [10]. Other quantitative examinations of the frequency of adverse effects and overall tolerability of CBZ and OXC for neuralgiform pain have found that dosage increases sufficient for pain management subsequently increase adverse cognitive effects [11]. More specifically, a standard one-unit dosage increase, the dosage necessary to generate a pharmacologically significant effect, results in a 50% increase in the likelihood of worsening side effects and eventual incapacity to reach therapeutic dosage for adequate pain suppression [11]. Taylor et al. [16] examined CBZ treatment for classical TN over a 16-year period and found a significant decline in efficacy by year 4, with an overall 44% failure rate necessitating alternative treatment. Despite the favorable tolerability of OXC, a long-term cohort study comparing OXC and surgical management of intractable TN found that effectiveness was short-term, subsequently necessitating surgical intervention as a rescue therapy [15].
According to the American Academy of Neurology (AAN) and the European Federation of Neurological Societies (EFNS) guidelines on TN management, when medical therapy becomes ineffective due to poor pain control or intolerability, referral for surgery is the next reasonable step [17]. Current surgical options in TN include microvascular decompression (MVD), percutaneous rhizotomy (PR), and Gamma Knife stereotactic radiosurgery (GK-SRS), and are typically reserved for participants deemed “medically refractory” [18]. However, there is no consensus as to the number of failed medical treatments required before surgical referral. Although some guidelines state that up to three groups of medications be trialed [18], some experts suggest that participants failing first-line medical therapy are unlikely to respond to other medications and should be referred for surgery earlier [15, 17]. Furthermore, pain becomes increasingly intractable with disease duration [15], and there is evidence that participants refractory to medical therapy prefer earlier surgery [19]. Accordingly, there is a need for further evaluation of the potential benefits of early surgery.
Developed in 1951, GK-SRS uses radioactive cobalt-60 isotope sources to produce converging radiation beams intersecting a target volume and was ultimately adapted for treating TN [20]. The least invasive neurosurgical approach to TN, GK-SRS is entirely non-invasive other than the use of stereotactic headframe immobilization [21]. In a single session, GK-SRS delivers a highly concentrated dose of ionizing radiation to a precise treatment target along the trigeminal nerve (typically the mid-cisternal segment at 70–90 Gy) with minimal irradiation of surrounding normal healthy tissues beyond the treatment margins [22], and no need to stop anticoagulation in participants requiring it [23].
Tuleasca et al. [3] summarized evidence in support of GK-SRS across 45 studies (5687 participants), by way of a systematic review and meta-analysis reporting freedom from pain (FFP), time to pain relief (TTPR), recurrence rates, time to recurrence, and presence of hypesthesia or other complications. Mean FFP outcome with or without medication adjustment was 84.8% and mean FFP outcome without the need for medication entirely was 53.1%, with TTPR ranging from 15 to 78 days. Mean pain recurrence rate was 24.6%, occurring between 7.5 and 20.4 months. Additionally, the maintenance of pain relief at 7 and 10 years was noteworthy in five studies, ranging between 22% and 59.7% (7 years) and 30% and 45.3% (10 years). Incidence of facial sensory dysfunction (i.e., hypesthesia) is the most significant complication of GK-SRS (21.7%), occurring between 6 and 36 months. However, the development of bothersome or very bothersome hypesthesia occurred in only a tiny proportion of participants (0%–17.3% mean = 3.1%). Other rare side effects included dry eye, deafferentation pain, and keratitis. In 27/45 GK-SRS studies, there were no reported side effects at all [3]. In addition, post GK-SRS associated malignancies are rare, with a cumulative incidence of 0.00045% over 10 years [24]. It is pertinent to consider that the number needed to harm (NNH) for the most significant complication of GK-SRS (hypesthesia) is approximately 4.7 [25], compared to approximately 2.6 for at least one adverse effect of CBZ [8].
There remains a notable gap in the literature exploring very early GK-SRS. Of particular importance, of the 45 studies reviewed by Tuleasca et al. [3], only one retrospective study analyzed GK-SRS when used exclusively as the primary surgical treatment in TN [26]. Mousavi et al. [26] reported initial pain relief in 88% of participants, with earlier GK-SRS treatment within 3 years of pain onset resulting in earlier pain relief (median 1 week) compared to 6 weeks for participants with TN >3 years. Longer duration of adequate pain control was also seen in a larger percentage of participants whose pain history was <3 years (1 year 93%, 10 years 73%) compared to participants with a longer pre-operative pain history (1 year 63%, 10 years 28%). Moreover, a longer interval of pain relief without medication (89% at 3 years) was seen in a greater proportion of participants with a history of pain <3 years compared to those with >3-year history of pain (52% at 3 years). Participants with a history of pain for >3 years prior to GK-SRS had an 8% likelihood of being pain-free without medication by year 5 and 0% at year 10, compared to 73% and 40%, respectively, in participants with pain <3 years [26]. In line with these data, a recent international multicenter study proposed consideration of earlier radiosurgery (within 4 years of diagnosis), finding a shorter interval to pain relief and significant decreases in medication utilization for participants treated within this time frame [27]. Taken together, these findings point to the potential of early GK-SRS to provide faster and more durable medication-free pain relief with a very low rate of adverse side effects.
What is not known is whether ultra-early intervention with GK-SRS—before the actual development of medical refractoriness (however that is defined)—may alter the natural progression of TN, avoiding the need for long-term high-dose medical therapy with its associated side effects. In this study, we aim to evaluate the feasibility and potential benefit of GK-SRS as an ultra-early treatment option for TN. We hypothesize that ultra-early GK-SRS will:
Provide more durable pain relief compared to ongoing best medical management
Reduce or eliminate the need for high-dose medical therapy
Have a lower rate of adverse effects compared to best medical management
Objectives {7}
To assess the efficacy of ultra-early (i.e., prior to medical refractoriness) GK-SRS as a treatment for TN compared to standard best medical management.
Trial design {8}
This is a single-center, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial of ultra-early GK-SRS for TN in participants treated prior to developing a medically refractory state and within 2 years of diagnosed TN per study neurologist. Two parallel cohorts will be studied: (1) participants treated with GK-SRS (intervention arm/treatment group) and (2) participants treated with ongoing best medical management (non-intervention/control group). Crossover will be allowed from the non-intervention arm to the intervention arm. An intention-to-treat analysis will be carried out.
Methods: participants, interventions, and outcomes
Study setting {9}
The primary location of the intervention is the Brown & Scott Families Advanced Imaging and Gamma Knife Centre at the University of Alberta Hospital, Edmonton, Alberta, Canada.
Eligibility criteria {10}
Inclusion criteria
Age ≥ 18 years
Clinical diagnosis of classical or idiopathic TN [1], based on clinical history and MRI scan
Onset of pain within 2 years prior to enrollment
Not deemed medically refractory (defined as suboptimal pain control despite ≥2 medication trials of adequate dose)
If currently on medication, on stable dose for at least 3 months
Exclusion criteria
Secondary TN
Bilateral TN
Any contraindication to GK-SRS
Any prior cranial radiation
Any prior surgical intervention for TN
History of new psychiatric diagnoses within 2 years of study participation, or uncontrolled, concurrent psychiatric illness (e.g., depression with recent suicide attempts)
Females who are pregnant or breastfeeding
Who will take informed consent? {26a}
Investigators will ensure all study aspects are thoroughly discussed with potential participants, including accessing electronic health records (to assess eligibility) and all potential risks and benefits prior to enrollment. Participants will have the opportunity to ask questions at any stage of enrollment. Written informed consent for access to health care records and consent to contact will be obtained by the referring physician. Following the determination of eligibility, written consent will be obtained by a study coordinator or team physician (other than the participant’s treating physician) to ensure that there is no undue pressure on potential participants to agree to the study at the time of enrollment. Participants will state their complete understanding of risks, benefits, intervention details, and ability to withdraw their consent at any time without compromising the quality of their treatment. A written informed consent form (ICF) will be obtained for each participant, signed and dated by the participant and the study team member who conducted the informed consent procedure.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable. The process of collecting biological specimens will not be carried out for this research.
Interventions
Explanation for the choice of comparators {6b}
The intervention group receiving GK-SRS will be compared to a non-intervention/control group treated with current standard of care medical therapy. Among these, CBZ and OXC are the most commonly prescribed due to their established efficacy in managing symptoms of TN.
Intervention description {11a}
Intervention arm
GK-SRS treatment will be carried out to the mid-cisternal segment of the trigeminal nerve ipsilateral to the affected side of the face. Under local anesthesia, a Leksell stereotactic head frame will be fixed to the patient’s head to allow for complete cranial immobilization during treatment. The mid-cisternal segment will be treated using a single 4 mm isocenter. A dose of 40 Gy (maximum point dose 80 Gy) will be administered to the 50% isodose line while limiting the brainstem dose to 12 Gy [3].
Non-intervention/control arm
Participants allocated to the non-intervention/control arm will continue medical management per the judgment of their treating physician (see 11b).
Criteria for discontinuing or modifying allocated interventions {11b}
For the GK-SRS intervention arm, the intervention is a single surgical procedure occurring on a single day. It is possible that the treatment may need to be halted prematurely due to patient discomfort or technical issues, though this would be a very rare event. In the event that GK-SRS treatment needs to be stopped prematurely, it will be allowed to be completed at a later date, per usual practice.
Two neurologist members of the study team (MWH and MK) with expertise in the medical management of TN will manage medication use in all enrolled participants across both groups. Where appropriate, medication dosage will be modified as necessary, depending on whether the patient’s condition improves or worsens. These adjustments will be made at the discretion of the treating neurologist, who will carefully evaluate the patient’s response to the treatment and any request for modifications (including weaning off medications).
Strategies to improve adherence to interventions {11c}
Given GK-SRS is a one-time intervention, “adherence to interventions” applies only to medication management, study visits, and performance surveillance labs in both the intervention arm and the non-intervention/control arm. To improve adherence to the intervention protocol, at each follow-up visit (6, 12, 24 months and 5 years), participants will be asked by the study team of any changes to their medication, additional surgical procedures, or non-surgical treatments for TN. A medication diary will be requested to improve adherence to medical therapy for both the intervention arm and the non-intervention/control arms.
Relevant concomitant care permitted or prohibited during the trial {11d}
Participants allocated to the intervention arm will receive ongoing medical management tailored to their specific needs, as determined by the clinical judgment of the treating neurologist. Participants may receive other medications as required. Crossover will be permitted from the non-intervention/control arm to the intervention arm at any time. Participants in the non-intervention arm will be informed of the standard of care at enrollment. This standard indicates that a referral for surgery (i.e., crossover) will only occur if they experience unsatisfactory pain control despite having undergone two or more trials of medication before the 2-year period.
Provisions for post-trial care {30}
In accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2), if a participant is harmed as a result of participating in this trial, the research team and the University of Alberta will ensure access to appropriate care and support, including follow-up care where warranted. Post-trial access to care or interventions shown to be beneficial during the study may be provided where feasible and ethically appropriate.
At the conclusion of the trial, all enrolled participants will be given the option of continuing ongoing care by the neurologist who managed their medications during the trial.
Outcomes {12}
The primary endpoint is satisfactory pain control at 2 years after GK-SRS treatment (for the intervention arm) or 2 years after enrollment in the non-intervention/control arm, without any period of medically refractory pain prior to 2 years, measured using Barrow Neurological Institute Pain Intensity Score (BNI) (satisfactory pain control = BNI I, II, IIIa) [28].
Secondary endpoints include:
-
I.
Worst incidence of treatment-related adverse events (AEs) by intervention arm. AEs will be determined using the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [29] at 6, 12, 24 months, and 5 years after the day of GK-SRS treatment, for participants in the intervention arm and at 6, 12, 24 months, and 5 years after enrollment, for participants in the non-intervention/control arm.
-
II.
Pain medication equivalent dose measured with the Medication Quantification Scale version III (MQS III) [30]. Intervention arm: baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrollment.
-
III.
Score of BNI I 2 years after the day of GK-SRS treatment.
-
IV.
Proportion of participants with satisfactory pain control at long term: those participants classified as BNI I–IIIa 5 years after day of GK-SRS treatment, or 5 years after enrollment in the non-intervention/control arm.
-
V.
Presence and severity of facial numbness in the intervention arm after GK-SRS treatment measured using the Barrow Neurological Institute Facial Numbness Scale [28] at 6, 12, 24 months, and 5 years after GK-SRS treatment.
-
VI.
Number of participants crossing over from non-intervention/control arm to intervention arm during follow-up period at 6, 12, 24 months, and 5 years after enrollment. Patients crossing over will have been considered to have failed to meet the primary endpoint.
-
VII.
Number of participants in GK-SRS arm referred for repeat surgery at 6, 12, 24 months, and 5 years after GK-SRS treatment.
-
VIII.
Patient-rated pain severity (0–100) measured with the Visual Analogue Scale (VAS) [31]. Intervention arm: baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrollment.
-
IX.
Brief Pain Inventory-Facial (BPI-Facial) [32] to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrollment.
-
X.
Psychological status measured using the Hospital Anxiety and Depression Scale (HADS) [33] and Pain Catastrophizing Scale (PCS) [34]. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrollment.
-
XI.
Quality of life measured using the Short Form Health Survey (SF-36 v2) [35]. Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrollment.
Participant timeline {13}
Participant timelines are summarized in Fig. 1 (SPIRIT figure) and Fig. 2 (flowchart).
Fig. 1.
SPIRIT figure [36]. Participant timeline: schedule of enrollment, intervention, and assessments. BNI, Barrow Neurological Institute Pain Intensity Score; BNI Facial Numbness Scale, Barrow Neurological Institute Facial Numbness Scale; BPI-Facial, Brief Pain Inventory-Facial; VAS, Visual Analogue Scale; MQS-III, Medication Quantification Scale version III; HADS, Hospital Anxiety and Depression Scale; PCS, Pain Catastrophizing Scale; SF-36 v2, Short Form Health Survey, version 2
Fig. 2.
Schematic flowchart representation of study design
Sample size {14}
The sample size is estimated based on the primary outcome over 2 years using a noninferiority design for two proportions, i.e., the proportion of participants with satisfactory pain control at 2 years (BNI I–IIIa). We aim to detect a difference of 10% satisfactory pain control between the 2 groups, i.e., over 2 years the GK-SRS group would have a proportion of satisfactory pain control not lower than the medical therapy by 10%. We aim for 80% power and a 0.05 significance level for detecting the aforementioned difference. Using a 35% failure rate for medical therapy over 2 years, a 7% failure rate for GK-SRS at 1 year, and an 11% failure rate at 3 years for GK-SRS [26, 37], the required sample size ranges from 32 to 47 participants per group, with 40 being a practical recommendation.
Recruitment {15}
Outreach is occurring to the local population of referring physicians. The study team includes individuals who are heavily involved in the surgical treatment and medical management of TN and are aware of other practitioners within the catchment area.
Study information flyers will be distributed via email (e.g., Alberta College of Family Physicians, Alberta Dental Association, Canadian Headache Society, Trigeminal Neuralgia Association of Canada, and TN facial pain groups) to family physicians, neurologists, and dentists/oral pain specialists within the catchment area. The intention of the flyers is to inform potential referring clinicians so that they can identify potentially eligible participants for further evaluation by the study team. Flyers may also be made available via email newsletters and/or social media outlets. Additionally, in-person outreach (flyer distribution) will be carried out in the Urgent Neurology Clinic at the primary institution.
Assignment of interventions: allocation
Sequence generation {16a}
To minimize bias, participants will be allocated by blocked randomization, on a 1:1 basis, to either the non-intervention/control or intervention arm via the National Institutes of Health (NIH) Clinical Trial Randomization Tool [38].
Concealment mechanism {16b}
To ensure allocation concealment, we will implement the following procedures: A study coordinator or team physician will log into the NIH Clinical Trial Randomization Tool to input participant information. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. After inputting all required baseline information, a unique profile for each patient will be generated. Access to these data will be restricted to an authorized third party.
Implementation {16c}
A study coordinator or team physician will enroll eligible participants. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. Per the NIH Clinical Trial Randomization Tool requirements, all essential researchers will not have access to the output. Access to the output sequence will be restricted to a study coordinator who will reveal each successive trial participant allocation, following consent and acceptance into the trial.
Assignment of interventions: blinding
Who will be blinded {17a}
This trial will, by definition, be non-blinded due to the nature of the head frame application in the intervention arm where participants will be treated with GK-SRS, and by administration of medication and performance surveillance labs for the non-intervention/control group. However, team members (i.e., statistician) will remain blinded to the group assignment of individual participants.
Procedure for unblinding if needed {17b}
Not applicable.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Efficacy assessments
Assessment of pain: At each time point, pain-related outcome variables will be assessed by:
Pain relief status (BNI I–IIIa = response, BNI IIIb–V = non-response) using the BNI score (I—no pain, no medication; II—occasional pain, no medication required; III—some pain, adequately controlled with medication; IIIa—no pain, continued medication; IIIb—persistent pain, controlled with medication; IV—some pain, not adequately controlled with medications; V—severe pain or no pain relief).
Patient-rated pain severity (0–100) using the VAS.
BPI-Facial to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities.
Assessment of medication: At each time point, medication-related outcome variables will be quantitatively assessed for drug class, dosage, and detriment (risk) using the MQS III, which provides a single numeric value for all patient’s pain medication profiles.
Safety and other assessments
Assessment of AEs: AEs will be assessed, if necessary, using the CTCAE, version 5.0.
History and physical examination: A routine neurological examination will be performed by a neurologist on our study team at initial screening and on an as-needed basis during follow-up per standard of care in TN management.
Psychological assessments: At each time point, we will assess psychological status using the HADS and PCS. Both measures are widely used in clinical applications, have strong psychometric properties, low patient burden, and have proven valid and reliable.
Other assessments:
Bothersome facial numbness will be assessed using the BNI Facial Numbness Scale (I = no facial numbness; II = mild facial numbness that is not bothersome; III = somewhat bothersome facial numbness; IV = very bothersome facial numbness).
Quality of life will be assessed via the SF-36 v2.
Plans to promote participant retention and complete follow-up {18b}
All consenting and enrolled participants will receive comprehensive information regarding the potential risks and benefits of the study. Investigators will stress the importance of follow-up with each enrolled participant. To simplify this process and facilitate data collection, follow-up assessments can be conducted via telephone if desired.
Participants have the right to withdraw from the study at any time. Additionally, investigators may decide to withdraw participants for reasons related to safety, behavior, or non-compliance. If a participant withdraws their participation or consent, no further assessments will be conducted, and no additional data will be collected.
Data management {19}
The electronic Research Electronic Data Capture system “REDCap” [39] will be used in this trial. Study data will be collected and managed using REDCap electronic data capture tools hosted at the University of Alberta. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources [39].
Independent case report forms (CRFs) will be completed for each eligible and consented participant. Data will be entered and maintained by a study coordinator. Any changes made to CRFs will not obscure the original entry. All changes will be dated, initialed, and explained as necessary.
Confidentiality {27}
Each patient will be assigned a unique sequential identification number upon registration. This identification number will be crucial for tracking each patient throughout the study and will be included on all CRFs used in the trial. To ensure the confidentiality of personal information, no other identifiable data regarding the patient will be included on these CRFs.
To further safeguard sensitive information, the patient’s health care number, which will be linked to their identification number, will be maintained in a secure, password-protected master file. Access to this file will be restricted solely to authorized members of the study team, ensuring that patient privacy is upheld throughout the duration of the trial. This structured approach is designed to prioritize both the integrity of the trial and the confidentiality of patient information.
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable. This trial does not intend to collect, assess, or store biological specimens for the purpose of genetic or molecular analysis.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
General approach
All analyses will follow the intention-to-treat principle. For binary outcomes, chi-square or Fisher’s exact tests will be used as appropriate. If any baseline covariate shows evidence of imbalance between treatment groups (standardized mean difference > 0.1), additional multivariable regression models adjusting for those covariates will be conducted as secondary analyses. For outcomes measured repeatedly over time, longitudinal mixed-effects models will be used.
Missing outcome data will be handled using longitudinal mixed-effects models, which use all available data under the missing-at-random assumption, rather than through explicit imputation. If covariate imbalance is observed and substantial missingness of baseline covariates exists (i.e., >20% of participants are missing one or more key covariates), multiple imputation will be applied to enable adjusted analyses.
Analysis of the primary efficacy endpoint(s)
The primary outcome—satisfactory pain control at 2 years—is binary. A chi-square or Fisher’s exact test will be applied, as appropriate. If covariates are unbalanced between the two groups, a multivariable logistic regression model will be used to adjust for these factors. In the case of substantial loss to follow-up at 2 years that could compromise the intention-to-treat principle, an additional longitudinal logistic mixed-effects model incorporating all time points will be employed.
Analysis of the secondary endpoint(s)
For binary and categorical secondary outcomes (endpoints III and IV), a chi-square or Fisher’s exact test will be used. Longitudinal mixed-effects models will be used for outcomes measured at multiple time points (endpoints I, II, VIII, IX, X, XI). Proportions with 95% confidence intervals will be reported among the intervention group for secondary endpoints V, VI, and VII.
Interim analyses {21b}
An interim analysis is not planned nor required per institutional policy, as the study is considered low risk.
There are no predetermined stopping rules for this trial. The principal investigator or the Research Ethics Board (REB) retains the authority to terminate the trial at any point should safety concerns arise. This decision will be informed by ongoing follow-up assessments and the reporting of any serious adverse events (SAEs) for those in the intervention group.
Methods for additional analyses (e.g., subgroup analyses) {20b}
If there is an imbalance between the two groups regarding the distribution of characteristics associated with the outcomes of interest, multivariable models will be employed to adjust for potential confounding.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Appropriate efforts will be employed to minimize the lost to follow-up rate, especially the measurement of the primary efficacy outcome, i.e., satisfactory pain control at 2 years (BNI I–IIIa).
All study participants including lost to follow-up individuals will be included in analyses to maintain the intention-to-treat principle. When the lost to follow-up rate is substantial, longitudinal data models, generalized estimating equations (GEE), or a mixed-effects model will also be employed.
Plans to give access to the full protocol, participant-level data, and statistical code {31c}
The principal investigator will grant access to the full protocol upon reasonable request.
Oversight and monitoring
Composition of the data monitoring committee, its role and reporting structure {21a}
As this is a single-center trial classified as low risk per University of Alberta’s Health Research Ethics Board, there is no steering committee, coordinating center, or DSMB; all data and adverse events are adjudicated by lead personnel on the study team. In addition, the study is not subject to regulation and does not require auditing procedures.
A study coordinator will maintain comprehensive and accurate source records that serve as the basis of CRFs. These records will include all relevant data and documentation related to the study. A study coordinator will provide direct access to all pertinent documents, enabling thorough oversight and verification of the study’s progress and compliance with regulatory requirements.
Furthermore, the study coordinator will communicate with all potential and enrolled participants to arrange interventions and assessments. The study team will convene on an as-needed basis to meet the demands of the study, to review updates related to the trial, and to ensure the organization of study materials.
Adverse event reporting and harms {22}
AEs and serious adverse events (SAEs) will be evaluated and monitored by the principal investigator until the patient is considered stable based on the resolution of these events. AEs and SAEs that occur following the initiation of the intervention will be reported using the CTCAE, version 5.0 [29], and recorded in the relevant REDCap database. In the case of SAEs, the principal investigator will be informed within 24 h, and the incidents will be reported to the appropriate regulatory bodies and REBs.
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
A member of the study team will submit reports, updates, and other information to the principal investigator and to the REB, such as expedited safety reports, amendments, and administrative letters, in accordance with regulatory requirements and institutional procedures. In addition, they will ensure that all relevant study documentation is up to date and that any amendments to the protocol are duly recorded on ClinicalTrials.gov and in the REB database.
Dissemination plans {31a}
The results of the trial will be documented in a manuscript to be submitted to a peer-reviewed scientific journal in the field of chronic pain, headache neurology, or neurosurgery for publication. The authorship of the resulting manuscript will include the principal investigator as senior author, along with all co-investigators as co-authors. Additional individuals may be added to the co-author list depending on their contributions (e.g., individuals providing additional assistance with data analysis).
Discussion
If GK-SRS, implemented as a first-line treatment for TN, proves safe and effective, then this trial may initiate a paradigm shift in TN management, wherein early surgical treatment with GK-SRS is accepted as a viable alternative to medical therapy. Clinically, these findings will translate to less ambiguity in optimal time to surgical referral and an increased willingness to refer participants for earlier surgery. As a result, TN treatment guidelines may adopt firmer recommendations for earlier surgical treatment, enabling both clinicians and participants with more informed decision-making potential. Importantly, generating evidence in favor of GK-SRS as a viable first-line treatment option may mitigate potentially detrimental repercussions of prolonged disease duration on pain chronification and overall detriment to quality of life with prolonged, inadequate medical management.
Limitations
The proposed study has important limitations. First, due to the necessity of cranial immobilization in GK-SRS, blinding the investigators and participants to treatment allocation is not feasible, which may introduce bias and compromise the validity of our results. However, carrying out a sham surgery could expose patients to unnecessary risk. Second, our study is limited to clinical diagnoses of classical and idiopathic TN, which may affect generalizability to those with secondary TN.
Acknowledgements
Not applicable.
Trial status
Protocol version number: SRS-0301.
Recruitment start date: August 15, 2025.
Estimated recruitment end date: May 1, 2029.
Abbreviations
- AAN
American Academy of Neurology
- AEs
Adverse events
- BNI
Barrow Neurological Institute Pain Intensity Score
- BPI-Facial
Brief Pain Inventory-Facial
- CBZ
Carbamazepine
- CTCAE
Common Terminology Criteria for Adverse Events
- CNV
Cranial nerve five
- CRFs
Case report forms
- DSMB
Data and Safety Monitoring Board
- EFNS
European Federation of Neurological Societies
- FFP
Freedom from pain
- GK-SRS
Gamma Knife stereotactic radiosurgery
- GEE
Generalized estimating equations
- HADS
Hospital Anxiety and Depression Scale
- ICF
Informed consent form
- MQS III
Medication Quantification Scale version III
- MVD
Microvascular decompression
- NIH
National Institutes of Health
- NNH
Number needed to harm
- OXC
Oxcarbazepine
- PCS
Pain Catastrophizing Scale
- PR
Percutaneous rhizotomy
- REDCap
Research Electronic Data Capture
- REB
Research Ethics Board
- SAEs
Serious adverse events
- SF-36 v2
Short Form Health Survey
- TTPR
Time to pain relief
- TN
Trigeminal neuralgia
- VAS
Visual Analogue Scale
Authors’ contributions {31b}
TS is the principal investigator, and conceived the study while contributing to the development of the study protocol and manuscript. AL contributed to the development of the study protocol and wrote the first draft of the manuscript. SP, WH, MW, and GB contributed to the methodology, review, and editing of the study protocol and manuscript. NKV provided statistical and data analysis input and reviewed the manuscript draft. All authors read and approved the final study protocol and manuscript. All authors will also contribute to study execution.
Funding {4}
At this time, this research has not received any specific grant funding from agencies in the public, commercial, or not-for-profit sectors.
Data availability {29}
The final dataset will be accessible only to the research team members listed on the title page of the current protocol, REB officials, and University of Alberta auditors upon request. If third parties request access to the collected data, informed consent must first be obtained from all participants. Only de-identified data will be provided to third parties. Data will be stored for a minimum of 15 years after the study is completed. After 15 years, all paper documents will be securely destroyed in accordance with the University of Alberta’s guidelines.
Declarations
Ethics approval and consent to participate {24}
This study has been approved by the University of Alberta’s Health Research Ethics Board—Biomedical Panel (IRB00000927, FWA00000077). Written, informed consent to participate will be obtained from all participants.
Consent for publication {32}
Not applicable.
Competing interests {28}
All authors declare that they have no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The final dataset will be accessible only to the research team members listed on the title page of the current protocol, REB officials, and University of Alberta auditors upon request. If third parties request access to the collected data, informed consent must first be obtained from all participants. Only de-identified data will be provided to third parties. Data will be stored for a minimum of 15 years after the study is completed. After 15 years, all paper documents will be securely destroyed in accordance with the University of Alberta’s guidelines.