Project Relief: Developing Brain Stimulation as a Treatment for Chronic Pain
Condition: Chronic Pain; Chronic Lower Back Pain; Back Pain; Opioid Use; Opiate Dependence; Pain, Chronic; Neuropathic Pain; Chemotherapy-induced Peripheral Neuropathy
MeSH terms: Neuralgia; Peripheral Nervous System Diseases; Back Pain; Chronic Pain; Low Back Pain; Opioid-Related Disorders
Study type: Interventional

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 largely
      treated with opiate narcotics, much as was done in the Civil War. In addition to their 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.

      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 Repetitive
      transcranial magnetic stimulation (rTMS) to the primary motor cortex (MC) or the medial
      prefrontal cortex (MPFC) 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 Wake Forest Baptist
      Health (WFBH) clinics with chronic lower back pain that have not been able to find adequate
      pain relief, whether or not they are using prescription opiates for 3 or more months.
      Participants will be randomized to receive rTMS to the MC, MPFC, or sham (50% at each site),
      using a Latin square randomization. Resting state connectivity 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).
    

Detailed description: 
      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 largely
      treated with opiate narcotics, much as was done in the Civil War. In addition to their 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.

      The goal of this proposal is to evaluate 2 novel non-invasive brain stimulation strategies to
      mitigate pain and the brain's response to pain in CLBP patients that are currently taking
      chronic opiates, or that are seeking an alternative treatment for pain. 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. Our group has
      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 our understanding of functional neural
      architecture, wherein the SN is modulated by 2 other core networks: the executive control
      network (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 MC or the MPFC 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 WFBH clinics with
      chronic lower back pain that have not been able to find adequate pain relief, whether or not
      they are using prescription opiates for 3 or more months. Participants will be randomized to
      receive rTMS to the MC, MPFC, or sham (50% at each site), using a Latin square randomization.
      Resting state connectivity 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).

      Aim 1. Evaluate MC rTMS as a tool to dampen pain and the engagement of the Pain Network.
      Hypothesis 1: MC TMS will attenuate the baseline brain response to pain (Pain Network
      activity) and increase activity in the ECN when the patient is given instructions to
      'control' the pain.

      Aim 2. Evaluate 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 SN when the patient is given instructions to
      'control' the pain.

      (Exploratory Aim): The investigator will evaluate if there are rate-dependent effects between
      baseline SN connectivity with the ECN and DMN and the efficacy of each TMS strategy on
      subjective pain. Data will be analyzed by using multivariate pattern analysis (MVPA). While
      the primary outcomes will be magnetic resonance imaging (MRI) Visit 1 versus Visit 2, the
      investigator will also examine the relative 'durability' of the effects on pain by comparing
      the MRI data at the end of all TMS visits between and within groups with factor analysis.

      The relative efficacy of these strategies will directly translate to development of a large
      clinical trial investigating rTMS as an innovative, new treatment option for pain in patients
      with CLBP.
    

Intervention name(s): Real TBS to the mPFC; Sham TBS to the mPFC; Real TBS to the MC; Sham TBS to the MC
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); This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the coil.; This will be delivered with the Magventure Magpro system (double blinded).; This will be delivered with the Magventure Magpro system (double blinded). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the 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 MC (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 Wake Forest University clinics and the outer community 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 TMS to the MC, MPFC,or sham (50% at each site), using a Latin square randomization. Resting state connectivity will be collected. Quantitative Pain Testing will be collected 11 times. MRI data will be collected 3 times: before the 1st visit of TMS, after the 12th visit of TMS, and after the 16th visit of TMS.
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Transcranial Magnetic Stimulation; Brain Stimulation; Treatment; Neuroimaging; Alternative