S4485 New Kid on the Block: Could Suzetrigine’s Promise of Pain Relief Improve Outcomes in Management of DGBI?

Introduction: Suzetrigine is a first-in-class, selective NaV1.8 sodium channel blocker expressed in peripheral sensory neurons, including dorsal root ganglion (DRG) neurons. Suzetrigine inhibits transmission of pain signals from peripheral sensory neurons to the spinal cord and brain. The U.S. Food and Drug Administration approved it on January 30, 2025, for the treatment of moderate-to-severe acute pain in adults. We describe 2 cases where suzetrigine was used for relief of abdominal pain. Case Description: A 51-year-old man presents with chronic constipation associated with abdominal pain and bloating. Sitz marker study revealed delayed colonic transit. Colonoscopy, computed tomography enterography and anorectal manometry were normal. He tried linaclotide, plecanatide, lubiprostone, prucalopride, and tenapanor. Tenapanor improved constipation and bloating, but he continued to have debilitating, episodic abdominal pain prompting several emergency room (ER) visits over 3 years. Adjunct pharmacological neuromodulators like nortriptyline, duloxetine, and gabapentin were not helpful. A 14-day trial of suzetrigine (100 mg initially, then 50 mg twice daily) led to rapid and clinically meaningful pain relief. A 21-year-old woman with history of anxiety developed recurrent, progressively worsening episodes of epigastric pain with no relation to bowel habits or food 1 year after a COVID-19 infection. Endoscopic evaluation, cross-sectional imaging, and gastric emptying study were normal. She responded partially to duloxetine, buspirone, mirtazapine, and cognitive behavioral therapy. After months of recurring symptoms and ER visits, suzetrigine allowed her to up-titrate augmentive neuromodulator therapy and achieve sustained pain relief. Discussion: Pain-predominant disorders of gut-brain interaction (DGBI) have an unmet need for novel analgesics. There are limitations to the current standard of care with neuromodulators like tricyclic antidepressantand serotonin and norepinephrine reuptake inhibitors due to inadequate pain relief or side effects. Suzetrigine’s inhibition of NaV1.8 reduces pain signals in primary human DRG sensory neurons with no adverse central nervous system, cardiovascular, or behavioral effects and no evidence of addictive potential or dependence based on nonclinical and clinical safety assessments. Studies have directly and indirectly established the importance of NaV1.8 to visceral pain perception. Additional trials are needed to evaluate the impact of this medicine on visceral pain perception especially in conditions associated with acute and/or chronic abdominal pain, including DGBIs.