Developing Brain Stimulation as a Treatment for Chronic Pain in Opiate Dependent
Condition: Chronic Pain; Opiate Dependence; Lower Back Pain
MeSH terms: Chronic Pain; Low Back Pain; Opioid-Related Disorders
Study type: Interventional
Phase: Early Phase 1

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.
    

Detailed description: 
      The goal of this proposal is to evaluate two novel non-invasive brain stimulation strategies
      to mitigate pain and the brain's response to pain in CLBP patients. Transcranial Magnetic
      Stimulation (TMS), can induce long term potentiation (LTP-like) and long term depression
      (LTD-like) effects on brain activity in a frequency dependent manner. The investigators have
      previously demonstrated that LTP-like TMS to the dorsolateral prefrontal cortex (DLPFC, a
      node in the Executive Control Network (ECN)) can decrease perceived pain and corresponding
      Blood Oxygen Level Dependent (BOLD) signal in the "Pain Network'. The Pain Network is an
      expansion of the Salience Network (SN; insula, dorsal anterior cingulate) which includes the
      thalamus and somatosensory cortex. The analgesic effects of DLPFC TMS can be blocked by
      naloxone - suggesting that the analgesic effects of LTP-like DLPFC TMS are opiate mediated.
      Additionally, DLPFC TMS delivered postoperatively leads to less patient administered morphine
      use (PCA-pump) in the hospital and less opiate use in the outpatient setting. These data all
      suggest that LTP-like DLPFC TMS is a promising candidate for treating pain.

      An alternative strategy is to apply LTD-like stimulation to the medial prefrontal cortex
      (LTD-like mPFC rTMS. This strategy is based on the understanding of functional neural
      architecture, wherein the SN is modulated by two other core networks: the ECN and the default
      mode network (DMN). As stated above, it is possible to attenuate activity in the SN through
      LTP-like TMS to the DLPFC, a node in the ECN. It is also possible to attenuate the SN through
      LTD-like TMS to the ventral medial prefrontal cortex (a node in the DMN). The proposed study
      will be the first to employ a randomized, double-blind, sham-controlled design to
      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 the community as well as Medical University of South
      Carolina clinics with chronic lower back pain that may or may not be using prescription
      opiates for 3 or more months without adequate pain relief. Participants will be randomized to
      receive rTMS to the DLPFC (10Hz), MPFC (cTBS), 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. MRI data will be collected 3 times: before the 1st day of TMS,
      after the 12th day of TMS, and before the 16th day of TMS (the last day administered).
    

Intervention name(s): iTBS to the left dlPFC; Sham iTBS to the left dlPFC; cTBS to the mPFC; Sham cTBS to the mPFC
Intervention type(s): Device; Device; Device; Device
Intervention description(s): 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).; 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.; This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key); 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Transcranial Magnetic Stimulation; Dorsolateral Prefrontal Cortex; Medial Prefrontal Cortex; Brain Stimulation