TMS Treatment for Pain in Chronic Pancreatitis
TMS Treatment for Pain in Chronic Pancreatitis
The researchers aim to study the effects of repetitive transcranial magnetic stimulation
 (rTMS) on chronic visceral pain in patients with idiopathic chronic pancreatitis.
The purpose of this protocol is to investigate a possible novel treatment for intractable
 visceral pain in patients with chronic pancreatitis. Pain is a major contributor to the poor
 quality of life in patients with chronic pancreatitis. The refractory nature of this
 condition to medical and surgical procedures prompted us to hypothesize that one mechanism
 leading to pain in these patients is the dysfunction of brain cortical regulation of visceral
 sensation. This notion is particularly supported by findings that patients with chronic
 pancreatitis can continue to experience disabling pain even after total pancreatectomy. This
 suggests that symptoms are sustained by a pancreas-independent, neural-based mechanism.
 Visceral sensation is particularly processed in the secondary somatosensory area - SII.
 Therefore, chronic pancreatitis pain may be sustained by a dysfunction of SII rather than by
 pancreatic inflammation alone. The researchers hypothesize further that the dysfunction of
 SII is one of hyper-excitability. According to this hypothesis, suppression of SII activity
 may help control the pain in patients with chronic pancreatitis. Temporary inhibition of SII
 activity can be obtained by a novel tool, namely transcranial magnetic stimulation (TMS),
 which can suppress brain excitability non-invasively beyond the duration of the TMS if
 appropriate stimulation parameters are employed. In the initial sham controlled, double blind
 pilot trial of 5 subjects with idiopathic chronic pancreatitis, TMS applied to SII resulted
 in significant pain improvement in 3 of the subjects. The researchers will rigorously test
 the hypothesis that chronic pancreatitis pain is sustained by a dysfunction of SII
 characterized by hyperexcitability through two specific aims:

 1. The first aim of this study is to examine whether slow repetitive TMS (rTMS) applied to
 SII in patients with pain and chronic pancreatitis has an analgesic effect as measured
 by changes in the Visual Analogue Scale (VAS) for pain and a decrease in analgesic
 intake, as well as an overall improvement in quality of life. In addition, if this study
 finds a significant effect of rTMS on pain reduction, the duration of this effect will
 be further assessed. TMS will be applied at parameters of stimulation known to decrease
 excitability.

 2. The second aim of the study is to assess the safety of rTMS in this patient population.
 In the pilot study none of the patients experienced any adverse effects of a single
 session of rTMS. However, the extension of the study protocol to a 10-day course of
 daily rTMS requires careful safety assessment. Fifteen-day courses of rTMS have been
 used for treatment of various neuropsychiatric diseases without any complications if
 safety guidelines are carefully followed. The researchers will adhere to the current
 safety recommendations for rTMS endorsed by the International Society for Transcranial
 Stimulation and the International Federation for Clinical Neurophysiology. Therefore,
 the researchers hypothesize that the proposed rTMS protocol will be safe for the patient
 population.

 3. The third aim of the study is to study the physiologic mechanism of action of rTMS in
 these patients using magnetic resonance imaging (MRI). In doing so, the researchers aim
 to contribute to a better understanding of the pathophysiology of chronic pain in
 patients with pancreatitis by investigating the correlation between pain improvement and
 areas of brain activation. This could lead to the development of markers of therapeutic
 response. Magnetic resonance spectroscopy allows a non-invasive measure of GABAergic and
 glutamatergic activity in a defined volume of interest in the brain. The researchers
 hypothesize that the balance of GABA and glutamate will be abnormal in SII in patients
 with pain from chronic pancreatitis, with a relative decrease in GABA and increase in
 glutamate indicating an abnormal, hyperexcitable dysfunction. This abnormality will be
 normalized by rTMS in correlation with its analgesic effect.
Inclusion Criteria:

 Patients will be eligible if:

 They are age 18 years or older They have daily abdominal pain for at least three months
 attributed to their chronic pancreatitis Average pain scores (VAS) in the baseline period
 higher than 4.

 The diagnosis of chronic pancreatitis will be based on the existence of chronic abdominal
 pain and at least one of the four following criteria:

 Calcifications throughout the pancreas on plain abdominal radiograph. Endoscopically
 derived pancreatogram showing ductal changes consistent with chronic pancreatitis.

 Abnormal secretin pancreatic function test with a peak bicarbonate level of less than 70
 mEq/L (normal being >80 mEq/L).

 Tissue diagnosis of chronic pancreatitis from a surgical specimen.

 Exclusion Criteria:

 Other causes of chronic pancreatitis will be excluded as follows:

 Hereditary pancreatitis based on genetic mutations or a family history of pancreatitis;
 Alcohol abuse (the criteria for "at risk" [heavy] drinking established by the National
 Institute on Alcohol Abuse and Alcoholism [NIAAA], which suggest that the person is at risk
 for adverse consequences, are greater than 14 drinks per week or 4 drinks per occasion for
 men, and greater than 7 drinks per week or 3 drinks per occasion for women);

 Medications associated with the development of pancreatitis (e.g. valproic acid,
 metronidazole, tetracycline, sulfonamides, nitrofurantoin, azathioprine, pentamidine),
 trauma, metabolic causes including hyperlipidemia and hypercalcemia, and autoimmune
 pancreatitis.

 Participants will be excluded if there are known complications of chronic pancreatitis
 requiring interventions including pseudocysts or pancreatic duct obstruction or if there is
 the presence of cancer.

 In addition, in order to minimize the risk of TMS, the following exclusion criteria will be
 followed:

 Patients with a clinical diagnosis of severe depression including suicidal ideation; Prior
 neurosurgical procedure; Past history of epilepsy or family history of epilepsy; Previous
 head injury; Metal located in the head, i.e. shrapnel, surgical clips, or fragments from
 welding; Signs of increased intracranial pressure; Stroke; Chronic treatment with
 epileptogenic medications; Abnormal neurological examination other than as signs of the
 condition studied in the present protocol; Implanted pacemaker; Medication pump; Vagal
 stimulator; Deep brain stimulator; Transcutaneous electrical stimulation (TENS) unit and
 ventriculo-peritoneal shunt; Pregnancy; Other chronic medical conditions and history of
 substance abuse; History of medical and surgical therapies for pain within 3 months.