TMS for the Treatment of Pancreatic Cancer Pain
Condition: Pain; Visceral Pain; Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms; Visceral Pain
Study type: Interventional

Summary: 
      This is a phase II study that aims to investigate prospectively a new therapy for a cohort of
      patients with chronic pain attributed to pancreatic cancer. The justification of this study
      is that the pain is the most important factor for the quality of life of these patients and
      rTMS has been shown to be significantly associated with pain improvement in patients with
      abdominal pain due to chronic pancreatitis. This therapeutic trial will be a 10-day,
      randomized, parallel-group design, double-blind, incomplete cross-over, placebo controlled
      clinical trial conducted at Beth Israel Deaconess Medical Center. The principal aim of this
      investigation is the study of pain after a therapeutic intervention. The primary outcome is
      pain reduction indexed by pain reduction and or analgesic intake reduction. The second aim of
      the study is to assess the safety this new treatment in patients with pancreatic cancer. The
      third aim of this study is to investigate whether rTMS treatment is associated with a change
      in the activity of right secondary somatosensory cortex using magnetic resonance
      spectroscopy. Because patients with locally advanced or advanced pancreatic cancer often
      require increasing doses of narcotic pain medications, such as morphine, oxycodone and
      fentanyl, in order to control their pain, adverse side effects are frequent observed in this
      population of patients. Therefore rTMS treatment might represent a new therapeutic approach
      that might be useful not only for pancreatic cancer but also to other types of cancer.
    

Detailed description: 
      The primary aim of this protocol is to investigate a possible novel treatment for visceral
      pain in patients with locally advanced or advanced pancreatic cancer. Pain is a major
      contributor to the poor quality of life in patients with pancreatic cancer. Most patients
      with locally advanced or advanced pancreatic cancer have abdominal pain that requires
      treatment with increasing doses of narcotic pain medication. The refractory nature of
      pancreatic cancer pain to pharmacologic therapy led us to hypothesize that one mechanism
      leading to pain in these patients is dysfunction of brain cortical regulation of visceral
      sensation. This notion is supported by the finding that deep electrical stimulation of the
      brain can produce pain relief in patients with intractable pain due to progressive cancers of
      various types. In addition, patients with pancreatitis, a non-malignant pancreatic condition
      causing chronic pain, can continue to experience disabling pain even after total
      pancreatectomy. These finding suggests that pain symptoms in pancreatic cancer can be
      sustained by a pancreas-independent, neural-based mechanisms in the brain.

      Visceral sensation is processed in the secondary somatosensory area (SII). Therefore,
      pancreatic cancer pain may be sustained by dysfunction of SII rather than by local effects of
      the cancer alone. We hypothesize further, that dysfunction of SII is one of
      hyper-excitability. According to this hypothesis, suppression of SII activity may help
      control the pain in patients with pancreatic cancer and may provide synergy with
      pharmacologic treatment.

      Temporary inhibition of SII activity can be obtained by a novel, non-invasive procedure
      called transcranial magnetic stimulation (TMS). TMS can suppress brain excitability beyond
      the duration of the direct application of TMS if appropriate stimulation parameters are
      utilized. This hypothesis is supported by a sham controlled, double blind pilot trial of 5
      subjects with idiopathic chronic pancreatitis: active rTMS applied to SII resulted in
      significant pain improvement in three of the subjects while sham did not provide any benefit
      in any of these patients. Furthermore, recent evidence suggests that stimulation of other
      brain areas, such as the dorsolateral pre-frontal cortex, can modulate acute, experimentally
      invoked pain (Graff-Guerrero et al 2005).

      We will rigorously test the hypothesis that pain due to pancreatic cancer is sustained by
      dysfunction of SII characterized by hyperexcitability through two specific aims:

        1. The first aim of this study is to examine whether 1Hz repetitive TMS (rTMS) applied to
           SII for ten days during two consecutive weeks in patients with abdominal pain due to
           pancreatic cancer has an analgesic effect.

             1. The primary outcome for this aim is the difference in pain score level on the
                Visual Analogue Scale at Day 11 and at Day 28 compared to the week before rTMS. The
                null hypothesis is that there is no difference in pain score between pre and
                post-treatment.

             2. The secondary outcome for this aim is to assess the difference in the use of
                narcotics for pain control on Day 11 and Day 28 compared to Day 1. The null
                hypothesis is that there is no difference in narcotic use (in IV morphine
                equivalency units) between pre and post-treatment.

        2. The second aim of the study is to assess the safety of rTMS in patients with pancreatic
           cancer.

        3. The third aim of this study is to investigate whether rTMS treatment is associated with
           a change in the activity of right SII using magnetic resonance spectroscopy. Therefore
           we will compare the levels of these substances between the two different time points
           (baseline and post-treatment) and between left and right SII. We expect a decrease in
           the excitatory neurotransmitters levels (Glutamine - Glx) in the stimulated area as a
           result of the inhibitory rTMS.

      SAFETY In a pilot study of chronic pancreatitis patients, no subject experienced adverse
      effects from a single session of rTMS. Subjects in an ongoing study of a 10-day course or
      rTMS in chronic pancreatitis patients also have not experienced adverse events (10 patients
      thus far). Fifteen-day courses of rTMS have been used for the treatment of various
      neuropsychiatric diseases without any complications if safety guidelines are carefully
      followed. We 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, we hypothesize that the proposed rTMS protocol will be
      safe for our patient population.
    

Intervention name(s): Transcranial Magnetic Stimulation
Intervention type(s): Procedure
Intervention description(s): 1Hz repetitive transcranial magnetic stimulation for 10 days 26 minutes each day
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: TMS; Visceral Pain; Analgesia; Pancreatic Cancer; Cancer; Electric stimulation therapy; Electric stimulation; Pain; Safety