Treatment of chronic visceral pain with brain stimulation

Pain secondary to chronic pancreatitis is extremely refractory to medical treatment, frequently requiring large doses of narcotics. Remarkably, a variety of surgical treatments, including (unilateral and bilateral) celiac nerve blocks and even pancreatectomy often fail to control the pain. We believe that this indicates that a pancreas-independent, neurally sustained mechanism must be responsible for the pain. If so, cortical stimulation to modulate activity in suitable brain targets could represent a successful, novel approach to analgesia. Cortical brain stimulation, using either repetitive transcranial magnetic stimulation (rTMS) or epidural cortical stimulation, has been increasingly investigated for the treatment of neuropathic and somatic pain. For this treatment, the target is usually the primary sensorimotor cortex (SM1). However, neuroimaging studies suggest that secondary somatosensory area (SII), rather than SM1, is critically involved in the representation of visceral sensations and pain. Therefore, we conducted a pilot randomized, crossover and controlled trial to (1) investigate whether rTMS treatment results in amelioration of pain in patients with chronic pancreatitis, and (2) determine the optimal parameters of this treatment: frequency (high vs. low frequency rTMS) and site of stimulation (left vs. right secondary somatosensory area [SII]). Five patients (mean age, 44 11 years) with chronic pain due to chronic pancreatitis were investigated after giving written informed consent to a protocol approved by the institutional review board and the Food and Drug Administration. Each patient underwent six different weekly rTMS sessions separated by at least a 1-week washout period. Stimulation was applied over the right or left SII as active 1Hz rTMS, active 20Hz rTMS, or sham rTMS (using a specially designed sham coil). The order of stimulation was randomized and counterbalanced across patients using a Latin square design. Patients were blinded to treatment condition, and a blinded rater evaluated analgesic use, patient’s responses in a Visual Analogue Scale (VAS) of pain, and MiniMental State Examination (MMSE) administered immediately after each session of rTMS. Each weekly rTMS session consisted of 1,600 stimuli applied at an intensity of 90% of the resting motor threshold. SII was defined by anatomical landmarks on each patient’s brain MRI and localized using a frameless stereotactic system (Brainsight frameless, www.rogue-research.com) to assure precise targeting throughout each rTMS session. The statistical analysis was performed using a mixed model of analysis of variance (ANOVA), in which the dependent variable was the sum of the percentage change (between prestimulation and poststimulation) of VAS and medication use. We performed an analysis of variance in which we evaluated the effects of the six different types of stimulation on pain reduction (as defined above). This analysis showed a significant overall effect of stimulation type (F 2.8; df 5,24; p 0.04). Post hoc analysis (using Fisher least significant difference correction for multiple comparisons) showed that only right-1Hz stimulation was associated with a significant pain improvement (p 0.037), with a mean decrease of pain of 62% ( 26%). We then performed another model in which we included two factors (frequency and site of stimulation). This analysis showed a significant main effect of frequency (F 4.3, df 2,26; p 0.02) and site of stimulation (F 4.5, df 1,26; p 0.045). Post hoc analysis showed that whereas 1Hz (of left and right SII) stimulation significantly improved pain by 36% ( 16%), 20Hz stimulation had an opposite effect, worsening the pain (mean of 51%, 35%), and a trend toward a differential hemispheric effect: whereas stimulation of right SII (1 and 20Hz) caused pain reduction (mean reduction of 31%, 21%), left SII stimulation caused pain worsening (mean worsening of 45%, 33%) (p 0.07). Importantly, baseline pain scores were not significantly different across the six conditions of stimulation (F 1.6, df 5,24, p 0.2), speaking against carryover effect. There were no adverse effects and no cognitive impact (MMSE unchanged regardless of TMS parameters and brain target ANOVA, F 1). Our findings support the notion that neural mechanisms are critically involved in sustaining pain in chronic pancreatitis and suggest that chronic visceral pain is a central nervous system disorder associated with a hyperexcitability of right SII. Consistent with this conclusion, low-frequency rTMS that suppresses cortical excitability in most individuals resulted in a reduction of pain. Therefore, suppression of excitability in right SII might be a novel therapeutic strategy for visceral pain. These effects might be enhanced by consecutive daily sessions of rTMS, the use of other forms of rTMS that may suppress cortical excitability more than 1Hz rTMS (eg, primed 1Hz rTMS), combining rTMS with specific medications, or by targeting other brain regions in addition to right SII. For example, inhibitory 1Hz rTMS of the right prefrontal cortex can decrease perception of pain and may potentiate the analgesic effects of rTMS to SII.