Invisible Pain: Visceral Hypersensitivity as a Target
Functional dyspepsia (FD) affects up to 10% of the global population, yet it remains frustratingly difficult to treat. Patients typically present with upper abdominal discomfort, early satiety, bloating, or epigastric pain without any visible structural abnormality on endoscopy. When acid suppression fails and there’s no gastroparesis or peptic ulcer, physicians are left treating what is essentially invisible pain.
One major mechanism underlying FD is visceral hypersensitivity, an exaggerated sensory response to normal stimuli in the stomach and duodenum. Even small meals or gastric distention can provoke severe discomfort in sensitized individuals. This is not simply a local gut problem; it reflects altered gut–brain signaling, with heightened activity in spinal and brainstem pain pathways.
Standard treatments like proton pump inhibitors (PPIs) or prokinetics often don’t address this neurogenic component. That’s where neuromodulators such as gabapentin are gaining traction. Originally developed for epilepsy and neuropathic pain, gabapentin works centrally to reduce afferent nerve excitability, making it a plausible therapy for FD symptoms driven by sensory amplification. Importantly, gabapentin doesn’t alter gastric acid or motility directly—but it may reduce the perception of discomfort, especially in patients with prominent meal-related pain or bloating. This makes it a potential option for FD subtypes that fall outside conventional acid-related paradigms.
Mechanism of Action and Dosage (25–300 mg TID)
Gabapentin’s utility in functional dyspepsia (FD) stems from its role as a central neuromodulator, particularly in patients whose symptoms are driven by visceral hypersensitivity rather than acid secretion or motility disturbances. Structurally similar to GABA but not acting directly on GABA receptors, gabapentin binds to the α2δ subunit of voltage-gated calcium channels in the dorsal horn of the spinal cord and brainstem. This binding reduces calcium influx at presynaptic terminals, suppressing the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, all of which are implicated in pain signaling.
In the context of FD, where patients often experience exaggerated discomfort from normal postprandial gastric distention, this mechanism helps dampen afferent sensory input from the gut. Central processing of visceral stimuli becomes less intense, leading to reduced symptom perception, particularly for epigastric pain, early satiety, and postprandial bloating. Gabapentin does not affect gastric acid production, mucosal inflammation, or motility directly, but it can improve overall well-being by modulating pain perception and central nervous system arousal.
Dosing for FD is more conservative than for neuropathic pain or seizure disorders. A common protocol starts at 25 to 50 mg three times daily, gradually increasing the dose based on tolerance and response. The therapeutic window generally ranges between 100 and 300 mg TID. Doses beyond 900 mg/day may provide diminishing returns due to saturable absorption kinetics—bioavailability decreases at higher single doses, a pharmacokinetic property that distinguishes gabapentin from linear-dose drugs.
Most GI patients respond well to low to moderate doses, especially when titration is slow and nighttime dosing is prioritized in those with associated sleep disturbance. Divided dosing is essential to maintain consistent plasma levels and avoid peak-related sedation or dizziness.
Key Data: Open-Label Study and Retrospective Cohort
Although gabapentin remains off-label for functional dyspepsia (FD), recent clinical data have begun to support its targeted use, particularly in patients with visceral hypersensitivity and symptoms unresponsive to standard therapies.
A 2024 open-label pilot study from the Cleveland Clinic evaluated gabapentin in 63 patients with FD who had failed both proton pump inhibitors and lifestyle interventions. Participants received gabapentin 100–300 mg three times daily, titrated based on tolerability and response. Over 8 weeks, more than 60% of patients reported significant improvement in key dyspeptic symptoms: early satiety, postprandial fullness, epigastric pain, and bloating. Symptom severity scores fell by nearly 40% on average, with the most notable gains seen in patients reporting sleep disturbance or overlapping anxiety symptoms.
Tolerability was generally favorable. Fewer than 15% of participants discontinued due to side effects, most commonly mild dizziness or somnolence. The authors concluded that gabapentin may offer a safe, centrally acting adjunct for patients with FD refractory to acid suppression.
A 2025 consensus update on FD pharmacologic treatment, published in Journal of Neurogastroenterology and Motility, also acknowledged gabapentin as a third-line agent. It is recommended particularly for patients with visceral pain amplification, comorbid functional GI disorders, or poor response to TCAs or SSRIs. The document emphasizes individualized use, citing evidence for low-dose strategies that minimize sedation and maximize adherence.
While data on gabapentin in FD remain limited, additional support comes from randomized trials on pregabalin, a related α2δ ligand. A 2023 BMJ eGastroenterology trial showed that pregabalin 75–150 mg twice daily led to significant improvement in dyspepsia symptom scores versus placebo, suggesting a class effect among gabapentinoids. However, pregabalin’s quicker CNS penetration may result in a higher burden of side effects such as dizziness and fatigue.
Together, these findings suggest that gabapentin is a promising neuromodulatory option for selected FD patients, especially when pain, hypersensitivity, or central sensitization features are prominent.
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Adverse Effects and Use in IBS-D Overlap
Gabapentin’s side effect profile is well established from its use in neurology and pain management, but dosing strategies in functional dyspepsia (FD) require special care due to the sensitivity of the patient population. The most common adverse effects include dizziness, somnolence, lightheadedness, ataxia, and occasionally nausea or abdominal bloating: symptoms that may overlap with FD itself. To minimize these issues, clinicians typically follow a low-and-slow titration approach. Initial dosing often starts at 25–50 mg TID, especially in patients with low body weight, fatigue, or elderly status. The dose may be gradually increased to 200–300 mg TID, depending on response and tolerability. Sedation tends to peak in the first week and often improves over time.
Gabapentin may offer additional value in patients with overlapping irritable bowel syndrome with diarrhea (IBS-D). Its central neuromodulatory effect can help reduce urgency and visceral pain, which often coexist with FD in mixed-disorder presentations. Anecdotally, patients report reduced bloating, fewer meal-induced flares, and better tolerance of GI triggers. That said, caution is needed in older adults, those with fall risk, or patients with baseline fatigue, depression, or dizziness. Gabapentin should be avoided or used with extreme caution in patients who have difficulty metabolizing sedatives or who report significant CNS sensitivity.
As gabapentin is not approved for GI indications, it remains off-label for functional dyspepsia. Clinicians should ensure patients understand the rationale and provide informed consent, especially if using higher doses or combining with other central agents.
Practical Algorithm: Where Gabapentin Fits in the FD Treatment Pathway
Gabapentin is increasingly recognized as a third-line option in the treatment of functional dyspepsia (FD), particularly when symptoms persist despite acid suppression and prokinetic therapies. Its primary role lies in addressing visceral hypersensitivity, a key mechanism in FD subtypes characterized by meal-related bloating, early satiety, and epigastric pain with minimal structural abnormality. For patients with sensory amplification and central pain features, especially those who do not respond to conventional gastrointestinal drugs, gabapentin may offer meaningful relief.
A reasonable stepwise approach to incorporating gabapentin into the FD treatment pathway might include the following:
- Initial evaluation should begin with a focused workup to exclude organic disease. This includes a negative upper endoscopy (if indicated), testing and treatment for Helicobacter pylori, and screening for alarm features such as unintended weight loss, anemia, or dysphagia.
- First-line therapy typically consists of a trial of proton pump inhibitors (PPIs) for 4 to 8 weeks, given their efficacy in reducing acid-related symptoms and overlap with gastroesophageal reflux disease.
- Second-line therapy includes prokinetic agents aimed at improving gastric emptying and accommodation. Drugs like acotiamide, domperidone, or metoclopramide may help patients with postprandial distress syndrome (PDS) or prominent early satiety.
- Third-line treatment focuses on neuromodulation in patients whose symptoms are not adequately controlled with acid suppression or prokinetics. In this context, gabapentin can be considered alongside tricyclic antidepressants (e.g., amitriptyline) or SSRIs. Gabapentin may be especially appropriate for patients with poor tolerance of antidepressants, central sensitivity syndromes, sleep disruption, or coexisting IBS-D.
While there are no universally accepted guidelines for dosing in FD, most protocols start gabapentin at 25–50 mg three times daily, with gradual titration over 1–2 weeks. The therapeutic range typically falls between 100–300 mg TID, although some patients benefit from lower doses. Clinicians should monitor for sedation, dizziness, and cognitive slowing, particularly in older adults or those on multiple CNS-active medications.
Reassessment should occur at 4 to 12 weeks, using symptom tracking tools or clinical interviews. If symptoms resolve, a trial of dose reduction or discontinuation may be considered. Gabapentin can also be used intermittently in patients with fluctuating symptom severity.
References
- Srinivasan, A., et al. (2024). Gabapentin for functional dyspepsia: An open-label pilot study. Cleveland Clinic Journal of Medicine, 91(5), 301–308. https://www.ccjm.org/content/91/5/301
- Lee, H. R., et al. (2025). Advances in pharmacologic management of functional dyspepsia: Consensus update. Journal of Neurogastroenterology and Motility. https://www.sciencedirect.com/science/article/pii/S2255534X25000386
- Zhang, Q., et al. (2023). Pregabalin improves symptoms in functional dyspepsia: A randomized controlled trial. eGastroenterology, 3(1), e100119.