Functional Nausea

Functional nausea is a chronic, bothersome sensation of nausea (the unpleasant feeling of the need to vomit) that occurs at least 1 day per week for at least 3 months, with onset at least 6 months before diagnosis. It is not usually associated with vomiting. It is not explained by a structural, metabolic, drug induced or systemic disease on appropriate assessment, nor better explained by another functional gastroduodenal disorder (such as functional dyspepsia, gastroparesis or cyclic vomiting syndrome).

• It is a distinct disorder from chronic nausea due to organic conditions. It affects about 1 to 3% of adults, and is more common in women and in young and middle aged adults. It is a common reason for referral to gastroenterology and has a large effect on quality of life.
• Mechanisms are not fully understood. Proposed contributors:
  • visceral hypersensitivity
  • brain gut axis dysregulation (altered central processing of visceral signals, with abnormal activation of the vomiting centre and insula)
  • autonomic dysfunction (vagal tone)
  • delayed gastric emptying or abnormal gastric accommodation and gastric dysrhythmia in a subset
  • psychological factors (anxiety, depression, trauma, stress, and a history of abuse)
  • conditioned responses
  • altered sensitivity to hormones and neurotransmitters (serotonin, dopamine, histamine)
• Associations: functional dyspepsia, irritable bowel syndrome, migraine (with vestibular dysfunction, motion sensitivity), chronic fatigue, fibromyalgia, anxiety and depression, and postural orthostatic tachycardia syndrome.
• Triggers: meals (especially fatty), stress, motion, strong smells, hormonal changes, poor sleep, fasting, and certain medicines.
• The course is chronic, but about 30 to 50% of patients improve over several years.
• Functional nausea is a diagnosis of exclusion, and requires a careful search for organic causes of chronic nausea.

• Persistent or recurrent nausea, often daily or most days, which may be mild to severe, may be worse in the morning or after meals, and is accompanied by loss of appetite, early satiety, bloating, epigastric discomfort, and fatigue. Vomiting is rare (less than once a week), and when it occurs it does not relieve nausea. Weight loss is uncommon.
• Symptoms may be linked to stress, anxiety and psychosocial factors, and patients often have other functional symptoms.
• Examination: normal general and abdominal examination, with normal weight and no signs of dehydration or systemic disease.
• Differential diagnosis (organic causes of chronic nausea):
  • Gastrointestinal: peptic ulcer disease, gastro oesophageal reflux disease, gastroparesis, gastric outlet obstruction, small bowel obstruction, coeliac disease, pancreatitis, biliary disease, hepatitis, inflammatory bowel disease, gastric and pancreatic cancer, intestinal pseudo obstruction, chronic mesenteric ischaemia, and Helicobacter pylori gastritis.
  • Medicines and substances: opioids, NSAIDs, antibiotics, metformin, GLP-1 receptor agonists, SSRIs, iron, digoxin, chemotherapy, levodopa, oestrogen containing contraceptives, theophylline, alcohol, and cannabis (cannabinoid hyperemesis syndrome).
  • Metabolic and endocrine: pregnancy, diabetes (ketoacidosis, gastroparesis), thyroid disease, adrenal insufficiency, hypercalcaemia, hyponatraemia, uraemia, and liver failure.
  • Neurological: raised intracranial pressure, brain tumour, migraine, vestibular disorders, and Chiari malformation.
  • Psychological: anxiety, depression, eating disorders, and somatic symptom disorder.
  • Others: heart failure, myocardial ischaemia (especially in women and people with diabetes), infections, and urinary tract disease.
• Red flags:
  • persistent vomiting, weight loss, haematemesis or melaena, dysphagia, abdominal pain or distension
  • early morning vomiting with headache and visual symptoms, neurological signs
  • jaundice, a palpable mass, age over 50 years with new nausea, unexplained anaemia
  • a family history of gastrointestinal cancer, and nocturnal symptoms
• Complications: poor nutrition, weight loss (uncommon), social and work disability, anxiety and depression, and excess investigations and medicines.

• Clinical diagnosis, made after a systematic and careful exclusion of other causes, based on a detailed history (onset, frequency, triggers, relation to meals, vomiting, medicines, substances, pregnancy possibility, psychological stressors, and weight changes) and examination.
• Initial tests: full blood count, urea and electrolytes, calcium, glucose or HbA1c, liver function tests, thyroid function tests, amylase or lipase, C-reactive protein, coeliac serology (tissue transglutaminase IgA with total IgA), urinalysis, and pregnancy test in women of childbearing age. Consider morning cortisol if adrenal insufficiency is suspected.
• Review medicines and substances systematically, and consider stopping the suspected agent for 2 to 4 weeks.
• Upper endoscopy for alarm features, age over 50 years, or persistent symptoms, with biopsies for Helicobacter pylori and gastritis, and with duodenal biopsies for coeliac disease.
• Helicobacter pylori testing (urea breath test or stool antigen test, 2 weeks off proton pump inhibitors, and 4 weeks off antibiotics).
• Abdominal ultrasound for biliary and pancreatic disease. CT or MR imaging of the abdomen, or enterography, for suspected obstruction, mass, or small bowel disease.
• Gastric emptying scintigraphy (a 4 hour solid meal study, after stopping prokinetics and opioids) for patients with persistent nausea, vomiting, or early satiety, to identify gastroparesis, interpreting results in the clinical context (a delayed result does not exclude a functional disorder).
• Brain imaging (MRI) and neurological or vestibular assessment for neurological signs, headaches, vertigo, or when early morning symptoms occur.
• Screen for anxiety, depression, eating disorders and somatic symptom disorder, and consider a cannabis history.

• A positive diagnosis, reassurance, and explanation of the brain gut mechanism, with agreement on treatment goals (symptom reduction and improved function), a long term relationship with one clinician, and avoidance of repeated tests.
• Lifestyle and diet: small, frequent, low fat meals, cold or room temperature foods (less smell), avoiding trigger foods and strong odours, adequate hydration, regular sleep, avoiding alcohol and cannabis, regular activity, and stress reduction.
• Ginger (capsules 250 mg 3 to 4 times daily, or ginger tea, or 1 g daily) has limited evidence of benefit. Acupressure at the P6 point (on the inner wrist) with wristbands may help some patients.
• Drug treatment (usually started for the symptom, as a 4 to 8 week course, with review of benefit):
  • Antiemetics:
    • Ondansetron 4 to 8 mg orally (or sublingually) 8 to 12 hourly as needed or regularly, with constipation, headache and QT prolongation as adverse effects. Avoid with other QT-prolonging drugs and in congenital long QT syndrome.
    • Metoclopramide 5 to 10 mg orally 3 times daily before meals, for no more than 5 days at a time (risk of tardive dyskinesia and extrapyramidal effects).
    • Domperidone 10 mg orally 3 times daily before meals for the shortest time (maximum 30 mg per day), with attention to the QT interval and interactions (avoid with ketoconazole, clarithromycin, and other CYP3A4 inhibitors).
    • Prochlorperazine 5 mg orally 8 hourly (or 12.5 mg intramuscularly), or promethazine 12.5 to 25 mg orally 8 hourly, for short term use, with sedation and anticholinergic effects.
    • Cyclizine 50 mg orally 8 hourly for motion or vestibular components.
  • Neuromodulators (the main option for persistent functional nausea):
    • Mirtazapine 7.5 mg orally at night, increased to 15 mg after 1 week, and up to 30 mg, for 8 weeks. It increases appetite, improves sleep and reduces nausea (a benefit in about 50 to 60%). Weight gain and sedation are the main adverse effects.
    • Amitriptyline 10 mg orally at night, increased by 10 mg every 1 to 2 weeks to 25 to 50 mg, or nortriptyline 10 to 25 mg at night, with anticholinergic effects (avoid in gastroparesis because it slows gastric emptying, and use caution in older patients).
    • Buspirone 5 mg orally 3 times daily, increased to 10 mg 3 times daily, for patients with early satiety and impaired gastric accommodation.
    • SSRIs (citalopram 10 to 20 mg, sertraline 25 to 100 mg daily) for anxiety and depression, with limited evidence for nausea, and with nausea as an adverse effect early in treatment.
    • Gabapentin 100 mg at night, titrated to 300 mg 3 times daily, for refractory cases in specialist care.
  • Aprepitant 80 mg orally once daily (after 125 mg on day 1), a neurokinin-1 antagonist, in refractory cases in specialist care.
  • Dronabinol and cannabinoids are not advised (risk of cannabinoid hyperemesis and dependence).
  • Treat any comorbid conditions: gastro oesophageal reflux disease (omeprazole 20 mg daily), Helicobacter pylori (eradication), migraine prophylaxis (propranolol 40 to 80 mg twice daily, or amitriptyline 10 to 50 mg at night), and vestibular disorders (vestibular rehabilitation).
• Psychological treatment: cognitive behavioural therapy (6 to 12 sessions), gut directed hypnotherapy, relaxation, and mindfulness based therapy, which reduce symptoms and improve coping and function.
• Gastric electrical stimulation, pyloric botulinum toxin and surgery have no role in functional nausea, and are reserved for confirmed refractory gastroparesis in specialist centres.
• Nutritional support: dietitian review for weight loss or restriction, with oral supplements, and enteral feeding in severe malnutrition.
• Special groups:
  • Pregnancy: nausea in pregnancy is common (nausea and vomiting of pregnancy, affecting up to 70% of pregnancies). Use small meals, ginger, pyridoxine 10 to 25 mg orally 3 to 4 times daily, and doxylamine 10 mg with pyridoxine 10 mg 2 to 4 times daily, or promethazine 12.5 to 25 mg 8 hourly. Avoid mirtazapine and other neuromodulators unless essential.
  • Children and adolescents: exclude organic disease, abdominal migraine and cyclic vomiting, use reassurance and cognitive behavioural therapy, and use cyproheptadine 0.25 mg/kg per day in 2 divided doses in specialist care.
  • Elderly: review polypharmacy (opioids, anticholinergics, SSRIs, digoxin, metformin), investigate for malignancy and cardiac disease, and use lower doses of neuromodulators and caution with metoclopramide (extrapyramidal effects).
  • Diabetes: assess for gastroparesis and ketoacidosis, and optimise glucose control.
  • QT prolongation or cardiac disease: avoid ondansetron, domperidone and citalopram at high doses, and obtain an electrocardiogram.
  • Renal and hepatic impairment: reduce doses (ondansetron maximum 8 mg per day in severe hepatic impairment, and metoclopramide half dose in renal impairment).
• Follow up: review every 4 to 8 weeks to assess response and adverse effects, and reassess the diagnosis for any new or evolving symptoms.
• Refer to a gastroenterologist for refractory symptoms, weight loss, or diagnostic uncertainty, to a psychologist for significant anxiety or somatic symptom disorder, and to neurology when neurological features develop.