Personalized Treatment by rTMS in Chronic Pain (PersoNINpain)
Personalized Pain Treatment by Transcranial Magnetic Stimulation in Patients With Chronic Pain: a Study on Mechanisms
Study Overview
Status
Conditions
Detailed Description
This project aims to test if the effects of non-pharmacological, non-invasive pain treatment can be enhanced by employing brain connectivity information to guide the application of repetitive transcranial magnetic stimulation (rTMS). Previous efficacy and safety trials have supported that rTMS for pain relief is applied to four main cortical areas: primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and posterosuperior insular (PSI). However, some patients respond to rTMS to one of these targets but not to the others. Since there is no current strategy to know which patient will respond to each treatment target, patients with chronic pain end up undergoing trial and error strategies, which delay their improvement. This is actually not different from challenges related to pharmacological treatment, where each medication only relieves pain in 30-40% of patients, and the choice of each medication is based on "trial-and-error basis".
Several strategies currently aim to provide a more individualized strategy for choosing analgesic interventions based on patient-related information. In order to allow for the design of efficacy trials in the future, the present project is based on a proof-of-concept, mechanistic design. It will employ rTMS stimulation for pain control, but the choice of each of the stimulation targets will be made based on each individual's brain signals as read by EEG recorded before the start of the treatment. Therefore, before receiving a full rTMS treatment, patients will undergo a neurophysiological screening session using single-pulseTMS-EEG. Single-pulseTMS and EEG have been routinely used in the clinic as a part of the neurophysiological assessment of patients for decades but have not yet been used in the association as an attempt to try to guide the choice of treatment. In the screening session, single pulses TMS will be applied to each of the primary network hubs used in therapeutic rTMS: M1, DLPFC, ACC, and PSI. Concomitantly, the EEG oscillatory activity of these four cortical areas will be recorded, and the brain connectivity state will be assessed. By using information derived from a patient´s brain connectivity state using transcranial magnetic stimulation with electroencephalography (TMS-EEG), the most appropriate of the four classic targets will be selected and used in rTMS on an individualized basis. It is hypothesized that the brain regions with low local-to-global connectivity will provide better pain relief compared to non-personalized treatment approaches and compared to targets with optimized local-to-global connectivity status.
A total of 90 subjects with chronic pain will be included in a double-blind, randomized three parallel-arm study comparing the analgesic effect of the therapeutic rTMS target chosen based on TMS-EEG:
- target area presenting the lowest local-to-global connectivity
- target area presenting the highest local-to-global connectivity
- classic M1 stimulation.
The subjects will be allocated in a 1:1:1 ratio to one of three arms (30 subjects per arm). The protocol is designed as an adaptive study, incorporating interim analyses after enrolling 30 and 60 subjects. These evaluations, conducted by a blinded specialist statistician panel, will assess the efficacy of the target selection strategy for each arm, focusing on the primary outcome's progression.
In the initial baseline measurement, the subjects will fill out questionnaires and undergo neurophysiological assessments. After this baseline measurement, the subjects will be assigned to one of the three arms and will receive daily rTMS sessions targeting areas (called induction phase) for 5 consecutive days (Monday to Friday) with either "high connectivity", "low connectivity", or a "classic M1 target". Each of the 5 daily stimulations will last 30 minutes, of which 15 minutes will be under treatment.
The induction phase will be followed by a 6-week maintenance phase, with 1 rTMS session per week (totaling 6 rTMS sessions). At the end of the maintenance phase, primary and secondary outcomes (questionnaires) will be collected to investigate the efficacy of the rTMS treatments. A random subsample of 30 participants (10 from each arm) will be asked if they would like to participate in a second 3-hour neurophysiological assessment to investigate the changes in brain connectivity.
Subjects experiencing significant pain reduction (according to the primary outcome) by the treatment will be asked if they would like to continue maintenance stimulation sessions. Participants accepted to join this part of the study will receive 1 stimulation session every 2 weeks for 4 weeks (total of 2 stimulation sessions). The participants will receive either active stimulation exactly as they received previously or sham stimulation with rTMS in a double-blind, randomized, placebo-controlled, two-group setup. After the extended maintenance phase, primary and secondary outcomes (questionnaires) will be issued, and a random subsample of 20 patients (10 per group) will go through a third, 3-hour-long assessment involving neurophysiological assessment to investigate the changes in connectivity.
When 50% of inclusion is completed, a preplanned interim futility analysis is scheduled to examine safety and the main outcome.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
North Denmark
-
Gistrup, North Denmark, Denmark, 9260
- Aalborg University
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Presence of chronic pain (present most of the days for more than 3 months).
- Pain with a mean pain intensity between 3-9 on a 0-10 pain scale (where 0 means no pain and 10 means the worst pain imaginable).
- Speak and understand English or Danish
Exclusion Criteria:
- Pregnant or breastfeeding
- Current uncontrolled major depression as the main diagnosis
- Current history of substance abuse
- Lack of ability to cooperate, to fully understand the protocol or any difficulty in filling out questionnaires (e.g., due to language or cognitive problems)
- Formal contraindications to TMS application (presence of epilepsy, cranial implanted ferromagnetic devices, e.g., intracranial neurostimulator or cochlear implants, tattoos with metal ink on the face or permanent make up with metal in the face )16
- Unable to answer the "Transcranial Magnetic Stimulation Adult Safety Screen" screening questionnaire.
- Participation in other research protocols within 1 month before the inclusion.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Active Comparator: Classical rTMS to M1x
The patients will receive repetitive transcranial magnetic stimulation (rTMS) to the primary cortex (M1) according to the classical treatment.
|
The rTMS intervention consists of 10-Hz rTMS.
Thirty trains of ten seconds with an interval of twenty seconds between trains will be delivered, as traditionally performed.
Each train includes 100 pulses, and the total number of pulses will be 3,000 given in 15 minutes.
|
|
Experimental: High connectivity target
The patients will receive repetitive transcranial magnetic stimulation (rTMS) to target showing the largest connectivity during the TMS-EEG assessment one week before starting the treatment
|
The rTMS intervention consists of 10-Hz rTMS.
Thirty trains of ten seconds will be delivered with an interval of twenty seconds between trains.
Each train includes 100 pulses, and the total number of pulses will be 3,000 given in 15 minutes.
The rTMS will be delivered to the target, showing the highest connectivity.
|
|
Experimental: Low connectivity target
The patients will receive repetitive transcranial magnetic stimulation (rTMS) to target showing the lowest connectivity during the TMS-EEG assessment one week before starting the treatment
|
The rTMS intervention consists of 10-Hz rTMS.
Thirty trains of ten seconds with an interval of twenty seconds between trains will be delivered.
Each train includes 100 pulses, and the total number of pulses will be 3,000 given in 15 minutes.
The rTMS will be delivered to the target, showing the lowest connectivity.
|
|
Sham Comparator: Sham stimulation
Subjects experiencing significant pain reduction (according to the primary outcome) by the treatment will be asked if they would like to continue maintenance stimulation sessions.
Participants accepted to join this part of the study will receive 1 stimulation session every 2 weeks for 4 weeks (total of 2 stimulation sessions).
The participants will receive either active stimulation exactly as they received previously or sham stimulation with rTMS in a double-blind, randomized, placebo-controlled, two-group setup.
|
Sham stimulation was carried out with a sham coil of identical size, color, and shape, emitting a sound similar to that emitted by the active coil.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Pain intensity (Visual analogue scale)
Time Frame: VAS will be assessed before treatment, after 2 months, and again after 3 months. Responders are those with ≥30% pain reduction at the end of maintenance compared to average pain intensity the week before baseline assessment.
|
The '0' represents 'no pain' at all, and '100' represents the 'worst possible pain' that the individual can imagine.
|
VAS will be assessed before treatment, after 2 months, and again after 3 months. Responders are those with ≥30% pain reduction at the end of maintenance compared to average pain intensity the week before baseline assessment.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Quality of life (EQ-5D)
Time Frame: Quality of life changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
EQ-5D is a standardized measure of health-related quality of life
|
Quality of life changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
|
Patients' Global Impression of Change
Time Frame: Patients' Global Impression of Change will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
The questionnaire assesses the individual's impression of change after an intervention.
|
Patients' Global Impression of Change will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
|
Short Brief Pain Inventory
Time Frame: Short Brief Pain Inventory changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
9 item self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning.
|
Short Brief Pain Inventory changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
|
Short McGill Pain Questionnaire
Time Frame: Short McGill Pain Questionnaire changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
a comprehensive multidimensional tool that assesses the three main aspects of pain: sensory discriminative, affective-motivational, and cognitive-evaluative
|
Short McGill Pain Questionnaire changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
|
Connectivity analysis
Time Frame: Connectivity changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
Electroencephalography (EEG) recorded during single pulses of TMS will be used to evaluate brain connectivity.
|
Connectivity changes will be investigated before the treatment, immediately after 2 months of treatment, and again after 3 months of treatment.
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Enrico De Martino, Dr, Aalborg University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- N-20230076
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.