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Introduction
This article continues the review of neuromodulators used in clinical practice and their role in the treatment of various disorders of brain-gut interaction (DBGI), particularly those affecting the stomach, intestines, and anus.
Functional Dyspepsia
Upon confirmation of a functional dyspepsia diagnosis1-3, treatment should be initiated with acid secretion inhibitors (proton pump inhibitors [PPIs]), H2 receptor antagonists, potassium-competitive acid blockers (PCABs), and prokinetic agents (acetylcholinesterase inhibitors, dopamine receptor antagonists, and serotonin receptor agonists)1,2. If there is no improvement, the use of neuromodulators should be considered as a second-line treatment2. These are recommended for patients who do not respond to acid suppression and Helicobacter pylori eradication, in accordance with British and American guidelines, due to their pain-modulating properties at various levels of the gut-brain axis4,5. Their effectiveness may be linked to the high correlation between functional dyspepsia and psychiatric conditions such as anxiety and depression, which impact the brain-gut axis.
The efficacy of tricyclic antidepressants (TCAs) has been studied, showing effectiveness as a second-line treatment, particularly for abdominal pain management. However, in cases of anxiety or depression, they may be considered as first-line treatment.
Both TCAs and selective serotonin reuptake inhibitors (SSRIs) modulate serotonin levels, influencing motility and visceral nociception. Neither SSRIs nor serotonin-norepinephrine reuptake inhibitors (SNRIs) have demonstrated benefit in patients with functional dyspepsia6. These medications should be started at low doses, preferably at night, and gradually titrated based on tolerance to avoid side effects that may lead patients to discontinue treatment. The estimated treatment duration is between 6 and 12 months; in some cases, based on clinical progression, they may be continued longer, particularly when there are psychiatric comorbidities. Discontinuing these medications in such cases could result in relapses of these concomitant conditions4.
Tricyclic Antidepressants
Among the TCAs, imipramine, at a dose of 25 mg for two weeks and then 50 mg for up to 12 weeks, has shown satisfactory overall relief of global dyspepsia symptoms compared to placebo (63% vs. 36%), with a number needed to treat (NNT) of four. It also reduces the overall score of epigastric pain, abdominal distension, postprandial fullness, satiety, and vomiting, along with improvement in mood and anxiety6. TCAs should be used with caution due to their side effects, starting with low doses (10 mg/day) and slowly titrating up to a maximum of 30-50 mg/day4,5. The side effects are described in Table 1 6. Amitriptyline at a dose of 50 mg, compared to escitalopram at 10 mg and placebo for 10 weeks, showed better symptom improvement in its group, with a global improvement of symptoms. However, both amitriptyline and escitalopram improved quality of life without significant adverse effects (Table 2)6.
Table 1 Side Effects of Neuromodulators
| Group | Medication | Side Effects |
|---|---|---|
| TCA | Amitriptyline, imipramine, desipramine, nortriptyline | Sedation, constipation, hypotension, dry mouth, nausea, arrhythmias, weight gain, sexual dysfunction, QT prolongation6-9 |
| SSRI | Citalopram, escitalopram, fluoxetine, paroxetine, sertraline | Agitation, diarrhea, insomnia, night sweats, headache, weight loss, sexual dysfunction, drowsiness, dry mouth, headache8,9 |
| SNRI | Duloxetine | Nausea, agitation, dizziness, sleep disturbances, fatigue, liver dysfunction8,9 |
| Atypical Antipsychotics | Quetiapine | Sedation, drowsiness, dry mouth, metabolic syndrome, cardiac arrhythmias, liver dysfunction, weight gain, diabetes8,9 |
| Delta Ligands | Gabapentin, pregabalin | Sedation, headache, dizziness, vertigo, fatigue, weight gain, peripheral edema8,10,11 |
| Tetracyclic Antidepressant | Mirtazapine | Weight gain, increased appetite, dry mouth, nausea, constipation, vomiting6-8 |
| Antipsychotics | Levosulpiride | Mild drowsiness6,7 |
| Anxiolytics | Buspirone | Sedation, headache, diziness6,7 |
Adapted from: Bosman L, and colleagues. 20236; Wauters L, and colleagues. 20207; Drossman DA, and colleagues. 20188; Younger J, and colleagues. 20149; Rao SSC, and colleagues. 201610; Carrington EV, and colleagues. 202011.
Table 2 Summary of Neuromodulator Use for Each Clinical Condition
| Clinical Condition | Medication | Dose | Study Type | Effects |
|---|---|---|---|---|
| Functional Dyspepsia | Tricyclic Antidepressants | |||
| Imipramine | 25 mg for 2 weeks 50 mg for 12 weeks | RCT6,7 | Overall relief of dyspepsia, improvement in anxiety | |
| 50 mg/day for four weeks compared to placebo | Cross-over RCT6,7 | Reduction in IG symptoms in four weeks | ||
| Amitriptyline | Amitriptyline 50 mg Escitalopram 10 mg | RCT6,7 | Relief of 40% with placebo, 53% with amitriptyline, 38% with escitalopram | |
| SNRI | ||||
| Venlafaxine | 75 mg for two weeks, 150 mg for four weeks | Cross-over double-blind RCT with placebo6,7 | No significant difference in symptoms compared to placebo | |
| SSRI | ||||
| Sertraline | 50 mg/day for eight weeks | Double-blind placebo-controlled trial6,7 | Improvement in dyspepsia index, no changes in overall symptoms | |
| Tetracyclic Antidepressant | ||||
| Mirtazapine | 15 mg for eight weeks | Double-blind placebo-controlled trial6,7,12 | Weight gain, better tolerance to nutrients | |
| Antipsychotics | ||||
| Levosulpiride | 25 mg/day | CCT vs. placebo6,7 | Overall symptom relief, improved gastric emptying time | |
| Anxiolytic Agents | ||||
| Buspirone | 20-30 mg/day for four weeks | RCT with placebo6,7,12 | Relief of dyspepsia, postprandial fullness, and distension | |
| IBS | TCA | 25-100 (150) mg | Network meta-analysis19 | Most effective for pain relief between weeks 4 and 12 (RR 0.53; 95% CI: 0.34-0.83) |
| Amitriptyline, imipramine, desipramine, nortriptyline | Systematic review and meta-analysis, 12 TCA-specific studies19 | RR for symptom improvement: 0.65 (CI: 0.55-0.77); NNT: 4.5 | ||
| SSRI | ||||
| Citalopram, escitalopram, fluoxetine, paroxetine, sertraline | Psychiatric dose range: citalopram 10-20 mg, escitalopram 20 mg/day, fluoxetine 20 mg/day, paroxetine 20 mg/day, sertraline 50 mg for eight weeks | Systematic review and meta-analysis, 7 SSRI-specific studies19 | RR for symptom improvement: 0.68 (CI: 0.51-0.91); NNT: 5 | |
| SNRI | Duloxetine 30-90 mg Venlafaxine 225 mg | Case series19 | 40% achieved pain score reduction | |
| Atypical Antipsychotics | Quetiapine 25-100 mg | Case reports19 | Improvement in pain and insomnia | |
| Olanzapine 2.5-10 mg | Case reports19 | Improvement if diarrhea is present | ||
| Centrally Mediated Abdominal Pain | TCA | Amitriptyline, imipramine, desipramine, nortriptyline: 25-100 mg | Systematic review and meta-analysis13,14 | RR for symptom improvement: 1.36 (CI: 1.07-1.71); NNT: 4.5 |
| Duloxetine | 30-60 mg | Cohort studies15 | Pain reduction | |
| Pregabalin | 75-225 mg | CCT10 | Improvement in pain scale and quality of life | |
| Functional Anorectal Pain | TCA | Case series10,11 | Pain reduction | |
| Gabapentin | Case series10,11 | Pain reduction | ||
TCA: tricyclic antidepressants; CM: centrally mediated; RCT: randomized controlled trial; DB: double-blind; SSRI: selective serotonin reuptake inhibitors; SNRI: serotonin-norepinephrine reuptake inhibitors; NNT: number needed to treat; RR: relative risk; SR & M: systematic review and meta-analysis; IBS: irritable bowel syndrome; CBT: cognitive-behavioral therapy. Adapted from: Bosman L, and colleagues. 20236; Wauters L, and colleagues. 20207; Rao SSC, and colleagues. 201610; Carrington EV, and colleagues. 202011; Engsbro AL, and colleagues. 202112; Ford AC, and colleagues. 201913; Kilgallon E, and colleagues. 201914; Yang H, and colleagues. 202115; Black CJ, and colleagues. 202019.
Selective Serotonin Reuptake Inhibitors (SSRIs)
One of these medications is sertraline. In a double-blind, randomized, placebo-controlled study, a dose of 50 mg of sertraline was administered for eight weeks. The results showed a statistically significant improvement in the mean dyspepsia index, but there was no difference in quality of life, subjective global symptom resolution, depression, or anxiety. The reported side effects included constipation and agitation (Table 1)6,16.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine is one such drug. In a double-blind, randomized, placebo-controlled study, venlafaxine was administered at a dose of 75 mg/day for two weeks, followed by 150 mg/day for four weeks, and then 75 mg/day for the final two weeks. The study results showed no improvement compared to placebo, neither in symptom severity nor in the number of symptoms, anxiety, depression, or overall health quality6,16.
Tetracyclic Antidepressant
Mirtazapine has shown effects in relaxing the gastric fundus, reducing early satiety, improving food tolerance, enhancing quality of life, promoting weight gain, and alleviating depressive symptoms and somatization6,7. In a randomized placebo-controlled study, mirtazapine at a dose of 15 mg for eight weeks reduced the severity of dyspepsia symptoms and improved early satiety, but there was no difference in key symptoms of functional dyspepsia such as fullness, weight gain, or tolerance to nutrient volumes, nor did it affect gastric emptying. It did improve quality of life and gastrointestinal anxiety, but it did not significantly impact anxiety or depression6. Side effects included weight gain, increased appetite, nausea, vomiting, dry mouth, and constipation16.
Antipsychotics
Levosulpiride at a dose of 25 mg once daily, compared to placebo, showed significant improvement and greater efficacy in relieving dyspeptic symptoms and motility issues, as well as a reduction in gastric emptying time, though mild drowsiness was reported. The effect of levosulpiride on gastric emptying has been evaluated against placebo, showing a reduction in upper abdominal pain, distension, early satiety, nausea, and vomiting, with no reported side effects. British guidelines for functional dyspepsia recommend providing careful explanations about its use and its side effect profile4.
Anxiolytic Agents
Buspirone, a serotonin 1-A receptor antagonist, relaxes the gastric body and improves gastric accommodation, significantly reducing overall symptoms of functional dyspepsia and postprandial distress syndrome6,7. In a randomized, double-blind, placebo-controlled crossover study, a reduction in the severity of dyspepsia symptoms was observed, along with a significant decrease in postprandial fullness and distension7.
Irritable Bowel Syndrome (IBS)
Treatment for irritable bowel syndrome (IBS) begins with educating patients about the condition, emphasizing its benign nature, and explaining the usefulness and safety of diagnostic tests and treatment options. Treatment should be tailored to the specific symptoms and their severity12,17-20. Management focuses on controlling pain as the predominant symptom and addressing other symptoms, whether constipation, diarrhea, or alternating between the two, as well as additional symptoms like bloating, which is common in all types of IBS. Thus, treatment options include prokinetics, secretagogues, laxatives, antispasmodic analgesics, among others8,18. Pain management often requires a synergistic approach, combining medications that provide peripheral neuromodulation, such as antispasmodics, secretagogues, opioid agonists/antagonists, serotonin receptor antagonists, and centrally acting agents, including the better-known neuromodulators, which are discussed in more detail later19.
First-Line Treatment
For moderate to severe pain, tricyclic antidepressants (TCAs) present the strongest evidence. A recent network meta-analysis ranked TCAs as the most effective for pain relief between weeks 4 and 12 (RR 0.53; 95% confidence interval [CI]: 0.34-0.83)19. Due to their complex mechanism of action, their therapeutic properties can derive from both the intended effects and side effects. For example, sedation can help treat insomnia, or increased intestinal transit can help manage diarrhea8,9. Regarding the medications in this group:
Amitriptyline and imipramine (tertiary amines) more commonly cause side effects due to their stronger antimuscarinic and antihistaminic effects.
Desipramine and nortriptyline (secondary amines) have fewer antihistaminic and antimuscarinic effects than amitriptyline.
Doses range from 10/25 to 150 mg/day, but the final dose is determined by the balance between side effects and therapeutic benefits (therapeutic index)8,9.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) also have evidence of efficacy for conditions that often co-exist with IBS, such as back pain, headaches, and fibromyalgia. They have fewer side effects than TCAs and can be used when TCA side effects are poorly tolerated. This is due to their serotonergic effect and lack of antimuscarinic effects, making this group useful for managing IBS when constipation and depression are part of the clinical picture8,9.
Selective serotonin reuptake inhibitors (SSRIs) are also part of the first-line treatment, especially when anxiety, depression, obsessive, or phobic characteristics are central alongside IBS symptoms. It is important to note that SSRIs do not help with pain management but rather with overall symptom control, and are used in psychiatric dose ranges8.
Second-Line Treatment
Drugs like olanzapine and quetiapine are considered atypical antipsychotics, producing fewer extrapyramidal side effects and used as co-treatment in managing abdominal pain in IBS. Quetiapine has multiple effects on different receptors: D2, 5-HT2A, H1 receptor antagonist, partial 5-HT1A receptor agonist, affinity for α1 and α2 receptors, and inhibition of norepinephrine reuptake through one of its metabolites (N-desalkylquetiapine). It has shown effects on pain associated with fibromyalgia and is used at low doses (25-200 mg/day for gut-brain axis disorders). Olanzapine has been studied more extensively in managing chronic pain associated with fibromyalgia and headaches, with doses ranging from 2.5-10 mg/day. The adverse effects are described in Table 1 8.
Delta ligands are another group of peripheral neuromodulators that block the α2δ subunit of voltage-gated calcium channels in neurons. These include gabapentin and pregabalin, both of which have demonstrated a reduction in visceral hypersensitivity in IBS. The coexistence of IBS with fibromyalgia and parietal abdominal pain could be a scenario where this treatment option is viable8,9.
Lastly, low-dose naltrexone (4.5 mg/day) offers an alternative for chronic pain management, which can be extrapolated to IBS. Its analgesic effect seems to stem not only from opioid antagonism but also from its anti-inflammatory and neuroprotective effects via microglial cells9.
Centrally Mediated Abdominal Pain Syndrome
Managing centrally mediated abdominal pain syndrome (CAPS) requires establishing an effective physician-patient relationship, setting treatment goals, and tailoring treatment based on symptom severity, offering a combination of treatment options, including pharmacological and psychological therapies21-23. Medical treatment is most effective in the context of a strong physician-patient relationship and a comprehensive biopsychosocial treatment plan24. There is limited evidence from studies specifically designed for CAPS treatment, which is why many concepts are general and similar to other pain disorders in brain-gut interaction disorders (DBGI), such as IBS. Therefore, the following insights are mainly based on IBS studies, particularly those addressing severe cases21.
Tricyclic Antidepressants (TCAs)
Twelve randomized clinical trials (RCTs) evaluated the efficacy and safety of TCAs in treating IBS patients. Of those receiving active therapy, 63.8% improved. The number needed to treat (NNT) with TCAs was 4.5 (95% CI: 3.5-7). The latest systematic reviews and meta-analyses assessed the effect of antidepressant therapy on abdominal pain13,19. Antidepressants were more likely to improve abdominal pain symptoms compared to placebo; however, the beneficial effects were due to TCAs, not SSRIs. TCAs also improved global symptoms in IBS patients relative to placebo (relative risk [RR]: 1.36; 95% CI: 1.07-1.71). The number needed to treat (NNT) with TCAs was 4.5 (95% CI: 3.5-7)14. A recent clinical guideline for managing IBS strongly recommends using TCAs for treating global IBS symptoms, with moderate-quality evidence supporting this recommendation25.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
In two cohort studies14,26, specifically targeting patients with CAPS, a favorable response was observed with duloxetine at an initial dose of 30 mg/day for pain improvement, compared to various interventions (TCAs, opioids, gabapentin) (p = 0.003)14,26.
Pregabalin
A CCT with 107 CAPS patients compared quality of life scores (PHQ-15) and pain scale scores (GAD-7). It found that patients tolerated pregabalin at a dose of 75 mg three times a day, or a combined regimen of pregabalin and pinaverium, with a greater reduction in pain compared to pinaverium bromide alone (p = 0.0002 vs. p = 0.0033)27.
Other Agents
A prospective randomized controlled trial (RCT) was conducted to explore the short-term efficacy of the local analgesic (lidocaine) and the opioid analgesic (sufentanil) in 130 CAPS patients. Both treatments showed negative efficacy during short-term observation, with no worsening of symptoms from the opioid receptor blocker (sufentanil)15. Regarding the doses and side effects of the mentioned medications, see Table 3.
Table 3 Side Effects of Neuromodulatory Medications
| Group | Medication | Side Effects |
|---|---|---|
| TCA |
Amitriptyline Imipramine Desipramine Nortriptyline |
Sedation, constipation, hypotension, dry mouth, nausea, arrhythmias, weight gain, sexual dysfunction, QT prolongation6,8,14,15 |
| SSRI |
Citalopram Escitalopram Fluoxetine Paroxetine Sertraline |
Agitation, diarrhea, insomnia, night sweats, headache, weight loss, sexual dysfunction, drowsiness, dry mouth, headache14,15 |
| SNRI | Duloxetine | Nausea, agitation, dizziness, sleep disturbances, fatigue, liver dysfunction14,15 |
| Atypical Antipsychotics | Quetiapine | Sedation, drowsiness, dry mouth, metabolic syndrome, cardiac arrhythmias, liver dysfunction, weight gain, diabetes14,15 |
| Delta ligands | Gabapentin Pregabalin | Sedation, headache, dizziness, vertigo, fatigue, weight gain, peripheral edema11,14,27 |
| Tetracyclic Antidepressant | Mirtazapine | Weight gain, increased appetite, dry mouth, nausea, constipation, vomiting6,8,14 |
| Antipsychotics | Levosulpiride | Mild drowsiness6,8 |
| Anxiolytics | Buspirone | Sedation, headache, diziness6,8 |
TCAs: tricyclic antidepressants; SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibitors. Adapted from: Bosman L, and colleagues. 20236; Drossman DA, and colleagues. 20188; Carrington EV, and colleagues. 202011; Kilgallon E, and colleagues. 201914; Yang H, and colleagues. 202115; Xu R, and colleagues. 202327
Functional Anorectal Pain
Functional anorectal pain is classified into three types of disorders: levator ani syndrome, nonspecific functional pain, and proctalgia fugax. Their clinical differentiation is based on the duration of pain and the presence or absence of anorectal tenderness10.
Treatment
Treatment for levator ani syndrome (LAS) typically includes electrical stimulation, biofeedback therapy (which has been shown to be more than 90% effective in improving defecation effort in the short term), and muscle relaxants such as methocarbamol, diazepam, and cyclobenzaprine. Additionally, therapies like levator ani muscle massage and sitz baths have also proven useful10.
Therapeutic approaches in neuromodulation for levator ani syndrome and nonspecific functional anorectal pain include measures such as low-dose tricyclic antidepressants (TCAs), gabapentin, and cyclobenzaprine. However, there are no controlled clinical studies on these treatments, but TCAs are suggested for patients who also have coexisting anxiety11.
Conclusions
After reviewing the literature for each disorder of brain-gut interaction (DBGI), clinical studies were selected (systematic reviews, CCTs, or the best available evidence in each case) to propose various therapeutic options for pain modulation and to obtain some therapeutic benefits from these types of medications in patients.
In general, it is notable that these medications are initially used in low doses, with the option to gradually increase the dose and to combine certain subgroups of medications or use them simultaneously with psychotherapy targeting gastrointestinal symptoms. However, special attention should be given to the potential side effects and drug interactions.
There is also a clear need for more CCTs in the future to obtain higher-quality evidence to support the recommendation of these medications in each case.
