Disorders of Gut-Brain Interaction and Psychological Comorbidity in Singapore: Insights From the Rome IV Global Epidemiology Study.

In DGBI where pain is dominant, a central neuromodulator is a logical part of the treatment profile. (1) TCAs are first-line when pain dominates: low-to-modest dosages have the most convincing evidence for chronic GI pain. Start low (10 mg/d helps patients get past early side effects), titrate within 4-6 weeks to 25-75 mg/d at night, and increase further to 100-150 mg/d only if no disturbing side effects develop; evidence for analgesic effect at <25 mg/d is lacking. Tertiary amines (amitriptyline, imipramine) are more anticholinergic/antihistaminic and may be chosen when constipating/sedating effects are useful (IBS-D, disturbed sleep); secondary amines (nortriptyline, desipramine) when those effects are unwanted (IBS-C, or pain with constipation). The TCA class is first-line for IBS, especially IBS-D. (2) SNRIs (duloxetine 30-90 mg, venlafaxine 75-225 mg with >225 mg needed for noradrenergic pain effect, milnacipran) 'may have at least equal benefit as TCAs' for chronic GI pain, but this is extrapolated from fibromyalgia, migraine, widespread body pain and neuropathy; they 'have not been adequately tested for chronic GI pain' and have not been adequately studied in IBS. Their advantage is the absence of anticholinergic/antihistaminic effects that preclude adequate TCA dosing; start in the low-dose range for the first week because nausea is common. SNRIs may be favored for IBS-C. (3) SSRIs are for anxiety, depression and phobic features, not pain: 'SSRIs can be considered in IBS if anxiety states, including hypervigilance, somatic symptom disorder, visceral anxiety, and maladaptive cognitions, are present, and the abdominal pain and diarrhea are not the dominant clinical features.' (4) Functional dyspepsia is treated by Rome IV subgroup. For PDS with early satiety, fullness and nausea predominating: buspirone, dosed as for anxiety, 30 mg/d divided 2-3 times daily, increasable to 60 mg/d (a 4-week trial reduced dyspeptic symptoms). Mirtazapine is 'a good treatment option for PDS when there is chronic nausea and vomiting, or weight loss', 15 mg in the evening for 8 weeks was superior to placebo in FD patients with weight loss and without coexisting anxiety or depression; usual range 15-45 mg in the evening. For EPS, studies mainly support TCAs (amitriptyline), either initially or after an unsuccessful PPI trial; the SNRI group 'can also be considered for patients with EPS who do not tolerate TCA treatment, although confirmatory studies are lacking.' (5) Functional heartburn and functional chest pain (after excluding GERD): 'There is insufficient evidence to recommend a particular class of central agent.' SSRIs have shown some benefit for esophageal pain; low-dose imipramine or amitriptyline 'can be considered,' but those studies are small and one was open-label; venlafaxine 75 mg extended-release at night beat placebo in a young cohort (20-29 years). (6) A comorbid dominant psychiatric diagnosis, identified by clinical assessment or questionnaires such as the HADS, 'may need to be a primary consideration when selecting a neuromodulator'; neuromodulators can alternatively be selected for their peripheral effects (disturbed bowel habit, chronic nausea). (7) Augmentation, reducing the dose of the first agent and adding a second, complementary treatment, is recommended when monotherapy is insufficient or dose-limited by side effects: an azapirone (dyspeptic features, prominent anxiety), a delta ligand (abdominal wall pain, comorbid fibromyalgia; pregabalin 150-600 mg/d, effect expected within a month), an SSRI (dominant anxiety/phobic features), an atypical antipsychotic (quetiapine 25-200 mg for pain with disturbed sleep, the psychiatric range of ≥200-400 mg/d is poorly tolerated; olanzapine/sulpiride for anxiety and nausea), bupropion (prominent fatigue/sleepiness), or a psychological treatment. (8) Behavioral therapy is positioned as an adjunct/augmentation, not as a co-equal mandatory arm: CBT where maladaptive cognitions and catastrophizing are present, DBT/EMDR with a history of PTSD or trauma, hypnosis/mindfulness/relaxation as alternatives; many RCTs support behavioral interventions 'as an adjunct to pharmacologic strategies,' and few studies compare behavioral alone against combination. (9) Continue treatment 6-12 months after treatment response to reduce relapse (empiric recommendation, extrapolated from major depression where 4-9 months is advised); consider longer-term treatment where ongoing psychosocial stress, positive family history, multiple prior episodes, or current psychiatric comorbidity exist. (10) Opioids should be avoided: there are no controlled data supporting opioids in chronic visceral pain, and their use carries substantial risk of opioid-induced constipation and narcotic bowel syndrome. (11) Implementation depends on communication: educate, provide a physiological rationale, address the patient's reluctance to take a 'psychiatric' drug, and involve the patient in medication choice, merely recommending the drug leads to refusal, nonadherence, or anxiety-driven side-effect reports.