Role of the Supraspinal Opioidergic Circuit in Prefrontal TMS-Induced Analgesia

Medical University of South Carolina (MUSC)

Status: Completed

Conditions: Pain

Treatments: Procedure: Sham rTMS; Procedure: Real rTMS

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01643798

1F30DA033748-01 (U.S. NIH Grant/Contract)

1F30DA033748

Details and patient eligibility

About

Studies have shown that transcranial magnetic stimulation (TMS), a non-invasive form of brain stimulation, can reduce pain in the laboratory and in the clinic. The purpose of this study is to investigate how TMS relieves pain and affects pain circuitry in the brain. One of the primary study hypotheses is that opioid blockade will significantly reduce the pain relief produced by left prefrontal cortex TMS.

Full description

Non-invasive forms of brain stimulation such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are currently being investigated as alternative or adjunctive therapies for pain. Clinical interest in these techniques continues to grow because of rising opiate abuse and inadequate pain management strategies. Despite this enthusiasm, studies on the efficacy of repetitive TMS (rTMS) for pain have produced mixed results. Some of the most promising and informative research has focused on rTMS for perioperative pain. In two different postoperative studies, a single session of left dorsolateral prefrontal cortex (DLPFC) rTMS after gastric bypass surgery reduced morphine self-administration by 40% when compared to sham stimulation. These data are particularly fascinating given the role of the DLPFC in top-down pain processing.

Centered at the juncture of Brodmann Areas (BAs) 9 and 46, the DLPFC remains a popular therapeutic target for rTMS given its accessible location and presumed role in high-order cognition and emotional valence. Animal and human studies suggest that cingulofrontal regions like DLPFC may modulate pain perception via recruitment of opioidergic midbrain and brainstem structures like the periaqueductal gray (PAG) and the rostroventromedial medulla (RVM), respectively. These data outline the functional circuitry that might be involved in the analgesic effects of DLPFC rTMS.

While many studies aim to evaluate the clinical efficacy of DLPFC rTMS for pain management, few have examined how it affects pain processing. Imaging the cerebral signature of pain before and after left DLPFC rTMS might reveal information about pain circuitry and help to elucidate the mechanism by which prefrontal rTMS may produce analgesia. Previous studies suggest that opioid blockade abolishes left but not right DLPFC rTMS-induced analgesia. In this study, our a priori hypothesis was that left DLPFC rTMS would attenuate blood oxygenation-level dependent (BOLD) signal response to painful stimuli in pain processing regions. More specifically, we anticipated that midbrain and medulla BOLD signal changes induced by left DLPFC rTMS would be abolished by pretreatment with the μ-opioid antagonist naloxone.

Enrollment: 15 patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• healthy volunteers
• no history of depression or pain
• no metal in body
• no medications that lower seizure threshold

Exclusion criteria

• history of depression or pain
• history of seizures or epilepsy
• metal implants in body
• medications that lower seizure threshold
• psychiatric medications

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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15 participants in 2 patient groups, including a placebo group

Saline

Placebo Comparator group

Description:

Participants received intravenous saline immediately prior to sham and real rTMS of the left dorsolateral prefrontal cortex. The parameters of the stimulation paradigm are as follows: 10 Hz, 5 seconds on, 10 seconds off, 20 minutes, 4000 pulses).

Treatment:

Procedure: Real rTMS

Procedure: Sham rTMS

Naloxone

Active Comparator group

Description:

Participants received intravenous naloxone (0.1mg/kg) immediately prior to sham and real rTMS of the left dorsolateral prefrontal cortex. The parameters of the stimulation paradigm are as follows: 10 Hz, 5 seconds on, 10 seconds off, 20 minutes, 4000 pulses).

Treatment:

Procedure: Real rTMS

Procedure: Sham rTMS