Uncovering the Mechanism of Pain Relief by Peripheral Transcutaneous Magnetic Stimulation

Chronic pain (pain lasting ≥3 months) is a debilitating condition associated with depression, dementia, increased risk of suicide, decreased productivity, and substance abuse. Opioids continue to be a crucial part of pain management. However, the misuse of prescription opioids has led to a shift towards injectable opioids such as heroin, with nearly 80% of new heroin users reporting prior use of prescription opioids. Further, co-morbid substance abuse can exacerbate pain symptoms despite pharmaceutical treatment, revealing the limitations of current pain management strategies. Due to tolerance, people with a history of opioid dependence often need higher doses of opioids to treat acute pain and long-term opioid use paradoxically worsens chronic pain. From a public health perspective, there is an increased chance of transmitting and acquiring hepatitis B and C due to opioid use-related engagement in risky behaviors. Moreover, the economic burden of untreated pain in the US is estimated to be more than $100 billion per year. Therefore, there is an urgent need to develop novel therapeutic strategies and reduce reliance on opioids.

Peripheral Transcutaneous Magnetic Stimulation (pTMS) is a non-invasive method of relieving pain by stimulating the target area with magnetic pulses. The magnetic field pulse passing into the body induces a voltage difference between any two points, which creates an electric field and causes electrons to flow between these two points. The magnetic field can penetrate deep tissue, such as spinal nerve roots or muscles. No mechanical contact is necessary, making pTMS applicable to patients with extreme hypersensitivity or allodynia to skin touch. pTMS is FDA-cleared for post-traumatic and post-surgical chronic pain. However, to date, no clear evidence has emerged about pTMS's potential mechanism of pain relief, which has moderated its applicability and acceptability.

The study will require recruiting patients over the phone, followed by an on-site visit, which includes patient interaction, blood collection, pain study, performing pTMS therapy at the site of pain, and patient monitoring. Three more on-site visits on consecutive days will include pTMS therapy. The last (fourth) visit will include specimen collection and a pain study. The first and the fourth visits will take 2.5 hours, while the second and the third visits will require 30 minutes. The participants will be followed over the phone every 30 days till the completion of the study to inquire about their wellness.

Inclusion criteria

• Confirmed diagnosis of chronic peripheral pain secondary to trauma or surgery. Age 19 - 80; the lower end of this age range was chosen to capture young adults with pain, and participants over 80 years are increasingly likely to meet one or more exclusion criteria.

Currently receiving pain medication Chronic pain must self-report peripheral pain, more than once per week, for at least three consecutive months

Exclusion criteria

• Implanted Electronic Devices and / or Conductive Objects in or near the head: Patients who have an implanted device that is activated or controlled in any way by physiological signals (examples: deep brain stimulators, cochlear implants, and vagus nerve stimulators).

Non-Removable Metallic Objects near the coil: Patients who have conductive, ferromagnetic, or other magnetic-sensitive metals implanted in their head or within 30 cm of the treatment coil (examples: cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, and bullet fragments). F NOTE: Standard amalgam dental fillings are not affected by the magnetic field and are acceptable in patients.

Active microbial infections may alter the quantity or quality of blood inflammatory cells such as monocytes and neutrophils.

Positive Urine Drug test: (COC/AMP/OPI/mAMP/PCP/BAR/BZO/MTD/MDMA/OXY/PPX/BUP/TCA) Use of any medication other than pain medications. However, participants will not be excluded or asked to withdraw from medications used for pain management since temporary withdrawal from these medications could affect pain measures (exceptions will be therapies such as methadone or buprenorphine used to treat opioid addiction). Only those who have been stable on these medications for at least 60 days will be included. All patient medications used for at least 60 days prior to participation will be recorded and controlled in statistical analyses as needed.

Systemic rheumatic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). These rheumatologic conditions will be excluded due to their autoimmune characteristic.

Cachexia (wasting syndrome) and severe frailty as determined by the Groningen Frailty Index (score >4). This exclusion is in place to protect against the stress of experimental pain testing.

Uncontrolled hypertension (i.e. SBP/DBP of >140/90) or cardiovascular or peripheral arterial disease. These exclusions are in place primarily for safety reasons because the cold pressor task represents a cardiovascular challenge. However, uncontrolled hypertension can also affect pain perception, which is another reason for excluding these individuals.

Poorly controlled diabetes (HbA1c > 8%) for both safety reasons and because diabetic neuropathy could alter pain perception.

Neurological disease (e.g. Parkinson's, multiple sclerosis). Serious psychiatric disorder requiring hospitalization within the past 12 months or characterized by active suicidal ideation. Any participant deemed to be actively suicidal upon study screening will be escorted to the emergency room and evaluated by the Psychiatry Service.

A diminished cognitive function that would interfere with the understanding of study procedures. The Mini-Mental Status Exam (MMSE) will be administered to ensure that participants are free of cognitive impairment that would compromise study participation. MMSE <18 will be excluded.

Pregnancy