PHILADELPHIA—Because many gastrointestinal conditions include pain as a symptom, pain control is an important part of managing these patients. As physicians attempt to rein in the use of opioids, some are turning to tricyclic antidepressants, such as nortriptyline, but they may not be familiar with other neuromodulators that can be helpful in this setting.
Busy gastroenterologists might shy away from neuromodulators due to concerns about managing their side effects, Pankaj Pasricha, MBBS, MD, a professor of medicine at Mayo Clinic Alix School of Medicine in Phoenix, told Gastroenterology & Endoscopy News. However, he said he prescribes a vast array of them himself, including anticonvulsants, sodium channel blockers, cannabinoids, gamma-aminobutyric acid modulators, N-methyl-D-aspartate and others.
One rationale for using central neuromodulators is that patients with chronic abdominal pain often have psychological symptoms or other chronic pain disorders that can be treated with these drugs, noted Lin Chang, MD, a professor of medicine at the University of California, Los Angeles. Also, many chronic abdominal pain conditions, such as irritable bowel syndrome, are considered pain-predominant brain–gut disorders, she said.
Peripheral Effects
In a presentation at ACG 2024, Dr. Chang noted that these drugs can have peripheral effects as well. “Some neuromodulators change motility and secretion, and there’s evidence that tricyclic agents reduce the excitation of visceral afferent nerves,” Dr. Chang said. “Central neuromodulators can promote neurogenesis or neuroplasticity, which, over time, may help restore and normalize nerve function.”
Despite these positive potentials, several factors limit the use of neuromodulators. Providers worry about side effects, may be unsure of which agents to use, and may not feel comfortable or competent prescribing them, she said.
“High prescribers, though, who tend to be in academic practice and see more IBS patients, recognize the efficacy of these agents,” Dr. Chang noted.
Choosing the Agent to Fit the Patient
Dr. Chang described four commonly used classes of central neuromodulators: tricyclic antidepressants (TCAs), considered first-line agents for abdominal pain; selective serotonin reuptake inhibitors (SSRIs), which are useful for treating mood disorders but have not shown effective for reducing abdominal pain in brain–gut disorders; serotonin–norepinephrine reuptake inhibitors (SNRIs), which have not been studied extensively for abdominal pain but might be effective for that purpose; and tetracyclic antidepressants, which are effective in upper and lower GI symptoms and treat early satiety, nausea and vomiting (Gastroenterology 2018;154[4]:1140-1171.e1).
“If the patients have comorbidities, you want to think about not just treating the gastrointestinal symptoms and pain but also extraintestinal comorbidities,” Dr. Chang said, noting that SNRIs can improve abdominal pain, fibromyalgia pain and depression.
Guidelines from both the American College of Gastroenterology and the American Gastroenterological Association (AGA) recommend using TCAs for treating IBS, and these agents have shown efficacy in treating functional dyspepsia. An animal study showed that TCAs reduce the excitation of sensory nerves, a peripheral analgesic effect (Pain 1998;76:105-114), and brain imaging studies in patients with IBS show amitriptyline reduces brain activation regions associated with pain processing (Gut 2005;54[5]:601-607). “So [there is] a peripheral analgesic effect in addition to their central effects,” Dr. Chang said.
Dr. Pasricha noted that the primary site of action of TCAs “is thought to be in the spinal cord by enhancing inhibitory neurotransmitters such as norepinephrine.”
Dr. Chang’s practical tip for prescribing TCAs is to base their use on receptor activity. If a patient has IBS with diarrhea (IBS-D) and poor sleep, she said, try amitriptyline. For IBS with constipation (IBS-C), she advised using a drug with less anticholinergic effects, such as desipramine or nortriptyline. “Start at low doses, 10 mg or 25 mg, and gradually increase as needed and tolerated,” Dr. Chang said. “The usual dose is 20 mg to 50 mg, but you can increase to 75 mg.”
She cautioned that the dose should not be increased more than 10 mg per week. Patients should be monitored for side effects and allowed to adjust to medication as tolerated. “A lot of providers don’t realize that a dose of 75 mg or lower will not have a significant mood effect, so if you’re treating for anxiety or depression, you might want to add an SSRI or behavioral therapy,” she said.
SSRIs alone are not recommended in the AGA guidelines because they “have not shown to help with abdominal symptoms or global relief of pain,” Dr. Chang added.
Mirtazapine, a tetracyclic, has been shown in small studies to reduce functional dyspepsia symptoms, and it helps reduce IBS severity in patients with IBS-D, Dr. Chang said. She recommended starting with a dose of 7.5 to 15 mg taken at bedtime because it can be sedating. She also noted that mirtazapine “can increase appetite and cause weight gain in some patients, so patients should know about this possibility.”
Dr. Pasricha said mirtazapine also has a significant impact on nausea because of its effects on serotonin receptors. “This is why it’s often used in gastroparesis and functional dyspepsia,” he explained.
SNRIs can be a viable option for abdominal pain when a TCA is inappropriate. “With duloxetine, start with 30 mg once a day for a week, then move to 30 mg twice a day,” Dr. Chang said. “A low dose won’t be effective for pain.”
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Dr. Pasricha said he considers SNRIs ideal to start in patients with both depression and pain, noting that “other drugs in this category include venlafaxine.”
Dr. Chang said she bases her approach to neuromodulators on the patient’s predominant symptoms, whether there is depression/anxiety, symptom-related anxiety or GI symptoms without a mood disorder. “If you have pain-predominant issues, you might want to prescribe a neuromodulator earlier in the treatment plan. If they have mainly depression/anxiety, you might want to refer them to psychiatry for treatment, then collaborate with them on a neuromodulator that could help with both mood and abdominal symptoms,” she said. “If they have GI symptom–related anxiety, you really want to refer for brain–gut behavioral therapy first, while treating their GI symptoms, and add a neuromodulator for persistent pain, if needed, later.”
Once patients are doing well, meaning their symptoms are gone or mostly gone, she advised tapering of the neuromodulator. Dr. Chang said she likes to keep patients on the agents for a year before tapering them off, in hopes that neuroplasticity will kick in and they won’t need the drug any longer. “Also, with time, they’ve ideally learned other ways to manage their symptoms,” she said. If symptoms return, she recommended restarting the medication at the lowest, most effective dose.
—Monica J. Smith
Drs. Chang and Pasricha reported no relevant financial disclosures.
This article is from the May 2025 print issue.