Developing Brain Stimulation as a Treatment for Chronic Pain in Opiate Dependent

NCT03681769 | Completed Early Phase 1 Results DMC FDA Device

• 3 other identifiers: 00078668UG3DA048506R21DA044503
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Effective control of chronic pain is a top priority in the United States, as approximately 10% of adults have severe chronic pain - most of which is chronic lower back pain (CLBP). However, despite the advances in neuroscience over the past 20 years, chronic pain is still largely treated with opiate narcotics, much as was done in the Civil War. In addition to the high abuse liability and dependence potential, only 30-40% of chronic pain patients declare they receive satisfactory (\>50%) relief from their pain through pharmacological treatment. In these patients a common clinical practice is to escalate the dose of opiates as tolerance develops - which unfortunately has contributed to escalation in opiate overdose deaths, a resurgence of intravenous heroin use, and $55 billion in societal costs. Consequently there is a critical need for new, treatments that can treat pain and reduce reliance on opiates in individuals with chronic pain. Aim 1. Evaluate repetitive Transcranial Magnetic Stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) as a tool to dampen pain and the engagement of the Pain Network. Hypothesis 1: DLPFC TMS will attenuate the baseline brain response to pain (Pain Network activity) and increase activity in the Executive Control Network (ECN) when the patient is given instructions to 'control' the pain. Aim 2. Evaluate Medial Prefrontal Cortex (MPFC) rTMS as a tool to dampen pain and the engagement of the Pain Network. Hypothesis 1: MPFC TMS will also attenuate the baseline brain response to pain (Pain Network activity) but will not effect the ECN or the Salience Network (SN) when the patient is given instructions to 'control' the pain.

Conditions

Chronic Pain; Opiate Dependence; Lower Back Pain

Keywords

Transcranial Magnetic Stimulation; Dorsolateral Prefrontal Cortex; Medial Prefrontal Cortex; Brain Stimulation

Outcome Measures

Primary Outcomes (1)

• Change in Quantitative Pain Testing Following Active TMS Compared to Baseline

  Based on pilot data, the investigators expect an interaction between treatment (DLPFC or MC rTMS) and time (Before vs. After rTMS) on reported painfulness using a quantitative sensory testing technique that determines thermal pain threshold.

  Change from baseline to 16 weeks

Secondary Outcomes (1)

• Change in Patient Reported Pain and Discomfort

  Patient reported pain/discomfort at 16 weeks.

Study Arms (4)

Intermittent Theta Burst Stimulation (iTBS) to the left dlPFC

EXPERIMENTAL

For intermittent theta burst stimulation (iTBS) (Aim 1), participants will receive 20 trains of stimulation over the dlPFC (middle frontal gyrus) (F3) (each train: 3 pulse bursts presented at 5 hertz, 15 pulses/sec for 2 sec, 8 sec rest, 200 pulses/train; 110% resting motor threshold, MagPro; 600 pulses total) using a figure 8 coil (Coil Cool-B65 A/P).

Device: iTBS to the left dlPFC

Sham iTBS to the left dlPFC

SHAM COMPARATOR

The MagVenture MagPro system has an integrated, active sham which passes current through two surface electrodes placed on the scalp. The electrodes will be placed on the left frontalis muscle for all sessions. A patient identification card will randomize participants to receive either real or sham stimulation. This system maintains blinding by a gyroscope in the coil which indicates to the clinical staff whether the coil should be rotated up or down for this participant once the card is entered into the machine. One side of the coil is active, the other is sham. The integrity of the double-blind procedure will be assessed by asking the patients and study personnel rate their confidence regarding whether they thought they received real or sham (scale 1-10).

Device: Sham iTBS to the left dlPFC

cTBS to the mPFC

EXPERIMENTAL

For continuous theta burst stimulation (Aim 2), participants will receive 1 train of stimulation over the left frontal pole (FP1) (each train: 3 pulse bursts presented at 5 hertz, 15 pulses/sec for 40 sec, 600 pulses/train, 110% resting motor threshold, MagPro; 600 pulses total) using a figure 8 coil (Coil Cool-B65 A/P). This protocol has been shown to attenuate the mPFC and striatum in cocaine dependent individuals in the past (61-63) and has been more effective than 1200 or 1800 pulses of cTBS in attenuating depression (The time between the end of the TBS procedures and the beginning of the behavioral assessments, as well as the scalp-to-cortex distance (which effects the actual TMS dose given to the cortex) will be compiled and used as covariates in subsequent analyses.

Device: cTBS to the mPFC

Sham cTBS to the mPFC

SHAM COMPARATOR

The MagVenture MagPro system has an integrated, active sham which passes current through two surface electrodes placed on the scalp. The electrodes will be placed on the left frontalis muscle for all sessions. A patient identification card will randomize participants to receive either real or sham stimulation. This system maintains blinding by a gyroscope in the coil which indicates to the clinical staff whether the coil should be rotated up or down for this participant once the card is entered into the machine. One side of the coil is active, the other is sham. The integrity of the double-blind procedure will be assessed by asking the patients and study personnel rate their confidence regarding whether they thought they received real or sham (scale 1-10).

Device: Sham cTBS to the mPFC

Interventions

iTBS to the left dlPFC DEVICE

This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the Universal Serial Bus (USB) key).

Intermittent Theta Burst Stimulation (iTBS) to the left dlPFC

Sham iTBS to the left dlPFC DEVICE

This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the B60 coil.

Sham iTBS to the left dlPFC

cTBS to the mPFC DEVICE

This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key)

cTBS to the mPFC

Sham cTBS to the mPFC DEVICE

This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the B60 coil.

Sham cTBS to the mPFC

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 75 (to maximize participation)
• Currently using prescription opiates
• Able to read and understand questionnaires and informed consent.
• Is not at elevated risk of seizure (i.e., does not have a history of seizures, is not currently prescribed medications known to lower seizure threshold)
• Does not have metal objects in the head/neck.
• Does not have a history of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage.
• Does not have a history of claustrophobia leading to significant clinical anxiety symptoms.

You may not qualify if:

• Any psychoactive illicit substance use (except marijuana and nicotine) within the last 30 days by self-report and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative (or decreasing) urine Carboxy-Tetrahydrocannabinol levels.
• Meets Diagnostic and Statistical Manual of Mental Disorders IV criteria for current axis I disorders of major depression, panic disorder, obsessive-compulsive disorder, post traumatic stress syndrome, bipolar affective disorder, schizophrenia, dissociate disorders, eating disorders, and any other psychotic disorder or organic mental disorder.
• Has current suicidal ideation or homicidal ideation.
• Has the need for maintenance or acute treatment with any psychoactive medication including anti-seizure medications and medications for Attention Deficit Hyperactivity Disorder.
• Females of childbearing potential who are pregnant (by urine human chorionic gonadotropin level), nursing, or who are not using a reliable form of birth control.
• Has current charges pending for a violent crime (not including driving under the influence related offenses).
• Does not have a stable living situation.
• Suffers from chronic migraines.

Sponsors & Collaborators

• Medical University of South Carolina: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

MeSH Terms

Conditions

Chronic Pain; Opioid-Related Disorders; Low Back Pain

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Back Pain

Results Point of Contact

• Title: Dr. Jeff Borckardt
• Organization: Medical University of South Carolina

borckard@musc.edu

843-792-3295

Study Officials

• Jeffrey Borckardt, PhD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Data for this randomized, double-blind, sham-controlled study (behavioral assessments, functional MRI measurements) will be acquired by the members of the Dr. Hanlon's lab, including graduate students and research specialists. These individuals will also perform data under the guidance of the PI. Manuscript composition will be led by the PI, with the assistance of the research team.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This randomized, double-blind, sham-controlled study will parametrically evaluate the longitudinal effects of 16 days of rTMS to the DLPFC (Aim 1) or the MPFC (Aim 2) on self-reported pain and the brain's response to pain. This will be done in a cohort of patients recruited from Medical University of South Carolina clinics and the outer community with chronic lower back pain that have been using prescription opiates for 3 or more months without adequate pain relief. Participants will be randomized to receive TMS to the DLPFC, MPFC, or sham (50% at each site), using a Latin square randomization. Resting state connectivity will be collected along with data from a standardized thermal pain paradigm wherein individuals are exposed to pain and instructed to try to "control' the pain. Quantitative Pain Testing will be collected 12 times. MRI data will be collected 3 times: before the 1st visit of TMS, before the 12th visit of TMS, and before the 16th visit of TMS.

Study Record Dates

• First Submitted: September 17, 2018
• First Posted: September 24, 2018
• Study Start: February 22, 2019
• Primary Completion: March 19, 2021
• Study Completion: March 19, 2021
• Last Updated: February 10, 2023
• Results First Posted: February 10, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)