Towards Individualized Deep Brain Stimulation Treatment of Chronic Neuropathic Pain (DBSforPain)

Chronic neuropathic pain affects millions of individuals worldwide. It causes marked reduction of health, utility and quality of life and represents a considerable economic burden to society due to loss of work capacity and large treatment expenses. The proposed project will explore new and rational methods for deep brain stimulation treatment of patients with severe chronic neuropathic pain, resistant to conventional treatment. Deep brain stimulation is a neurosurgical procedure in which a small stimulating electrode is implanted into deep brain areas. Furthermore, we will utilize new positron emission tomography neuroimaging and a new prototyped technology, called targeted transcranial magnetic stimulation, to predict the outcome of deep brain stimulation and localize brain regions with maximum symptom relief for each patient. This will optimize the selection of patients for deep brain stimulation and provide a rational customized choice of brain target for each patient, without surgical intervention. Novel techniques will be validated on healthy volunteers and at the same time provide new insights into the mechanisms underlying brain stimulation and pain perception. The project has great clinical impact, potential for innovative development and industrial spin-out, facilitates exchange for Danish research talents and senior researchers with Stanford University and California Pacific Medical Research Institute in San Francisco, and unites world leading experts in pain research and clinical treatment to achieve its goals.

Study Overview

• Status: Terminated
• Conditions: Neuralgia
• Intervention / Treatment: Procedure: Deep brain stimulation; Device: Cervel Neurotech, Multi-coil TMS; Drug: 11C-Carfentanil

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Region Midtjylland
    • Aarhus, Region Midtjylland, Denmark, 8000
      • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

General inclusion criteria (case and control):

• No gender criteria
• Age > 25 years.
• Legal competency.
• Ability to comply with the proposed protocol schedule.
• Stability of chronic medical diseases.
• A negative validated pregnancy test for fertile female participants prior to project enrolment.
• Use of validated anti-conception for fertile female participants

Case-specific inclusion criteria:

• Well-defined neuropathic pain [21].
• Chronic and stable pain condition. Numerical Rating Scale score > 5.
• Documented resistance to, or poor tolerance of pharmacological treatments. Unless contraindicated, the treatment must have included opiate derivatives, tri-cyclic antidepressants and anti-epileptic drugs.

Exclusion Criteria:

General exclusion criteria:

• Pregnancy or nursing.
• Cognitive impairment.
• Alcohol or drug abuse
• Severe psychiatric disorders.
• Allergies towards compounds used in the trial, such as PET tracers, Capsaicin, etc. Other significant medical allergies.
• Severe medical disorders
• Neurodegenerative disorders
• Severe cerebrovascular diseases and risk-factors, malignant hypertension, vascular abnormalities.
• Prior intracranial surgery
• Cardiac pacemaker or other implanted electronic medical devices
• Coagulopathy (excl. drug induced)
• Structural brain abnormalities
• Epilepsy or prior isolated seizure.
• Severe obesity
• Severe claustrophobia
• Magnetic metallic implants
• Other conditions that may contraindicate deep brain stimulation surgery, full anesthesia, transcranial magnetic stimulation, PET/CT imaging (specifically the use of carfentanil) or magnetic resonance imaging. This will be evaluated according to specific investigational product specifications and clinical guidelines.

Control specific exclusion criteria:

- Chronic pain syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
SHAM_COMPARATOR: Sham-DBS; Only patients. Inactive deep brain stimulation for the initial three months following implantation.	Procedure: Deep brain stimulation; Implantation of a deep brain stimulation electrode into pain processing brain areas; Device: Cervel Neurotech, Multi-coil TMS; Non-invasive selective stimulation of deep brain areas using magnetic fields.; Other Names: TMS; Drug: 11C-Carfentanil; PET-radioligand for functional brain imaging to assess opioid binding. The compound is a potent synthetic opioid.; Other Names: 11C-Carfentanyl
ACTIVE_COMPARATOR: Active DBS; Only patients. Active deep brain stimulation for the initial three months following surgery.	Procedure: Deep brain stimulation; Implantation of a deep brain stimulation electrode into pain processing brain areas; Device: Cervel Neurotech, Multi-coil TMS; Non-invasive selective stimulation of deep brain areas using magnetic fields.; Other Names: TMS; Drug: 11C-Carfentanil; PET-radioligand for functional brain imaging to assess opioid binding. The compound is a potent synthetic opioid.; Other Names: 11C-Carfentanyl
EXPERIMENTAL: TMS and PET imaging; This experiment includes all participants (cases and controls). Each subject will undergo both active and sham stimulation (cross-over) with Cervel Neurotech Multi-coil TMS and related test/re-test PET imaging with 11C-Carfentanil. Only patients will proceed into deep brain stimulation experiments.	Device: Cervel Neurotech, Multi-coil TMS; Non-invasive selective stimulation of deep brain areas using magnetic fields.; Other Names: TMS; Drug: 11C-Carfentanil; PET-radioligand for functional brain imaging to assess opioid binding. The compound is a potent synthetic opioid.; Other Names: 11C-Carfentanyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain relief upon deep brain stimulation of the dorsal anterior cingulate cortex.	We will measure the changes in pain ratings upon deep brain stimulation of the dorsal anterior cingulate gyrus. Results will be based on the numerical rating scale and validated questionnaires. We will compare active and sham stimulation and changes upon activation of initial sham-stimulation.	Assessment after 3 and 12 months of active stimulation
Predictive values of PET imaging and transcranial magnetic stimulation on deep brain stimulation outcome	Individuals will be classified according to PET activity/no-activity and positive/null-negative outcome of transcranial magnetic stimulation. We will correlate the effect of deep brian stimulation to these categories and evaluate their predictive values.	Assessed upon final evaluation of deep brain stimulation outcome (expected 2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of deep brain stimulation on cingulate opioid binding and blood flow.	We will do test/re-test PET imaging before and after deep brain stimulation surgery to assess the effect of this treatment on cingulate opioid binding and blood flow. We will utilize 11C-Carfentanil and 15O-water PET, respectively.	After 3 and 12 months of active deep brain stimulation
Pain relief upon individualized deep brain stimulation	Patients that derive no benefit from initial deep brain stimulation treatment of the dorsal anterior cingulate, will be offered deep brain stimulation of another expectedly efficacious brain area. The choice of target will be based of PET images and magnetic stimulation testing. Results of deep brain stimulation will be based on the numerical rating scale and validated pain questionnaires.	After 3 and 12 months of active deep brain stimulation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of transcranial magnetic stimulation on pain ratings, cingulate opioid binding and blood flow	We will do test/re-test PET imaging with transcranial magnetic stimulation in between. We will evaluate quantitative effects on 1) pain ratings using the numerical rating scale, 2) cingulate opioid binding using 11C-carfentanil PET and 3) cingulate blood flow using 15O-water PET. Results will be compared for sham stimulation and active stimulation in each individual, and also between cases and controls.	results will be assessed upon final transcranial magnetic stimulation session (last participant/last treatment, average 5 weeks)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Stanford University; California Pacific Medical Center Research Institute
• Investigators: Principal Investigator: Jens Christian H Sørensen, MD,PhD,DMSc, Aarhus University Hospital, Department of Neurosurgery

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2014
• Primary Completion (ACTUAL): August 1, 2019
• Study Completion (ACTUAL): August 1, 2019

Study Registration Dates

• First Submitted: July 3, 2013
• First Submitted That Met QC Criteria: July 10, 2013
• First Posted (ESTIMATE): July 15, 2013

Study Record Updates

• Last Update Posted (ACTUAL): September 14, 2021
• Last Update Submitted That Met QC Criteria: September 13, 2021
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: deep brain stimulation; personalized treatment; multi-coil transcranial magnetic stimulation; PET-imaging
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Carfentanil
• Other Study ID Numbers: 28052013; 2013-002385-39 (EUDRACT_NUMBER)