Guts and Butts: Treatment Options for IBS and Functional Dyspepsia

7/2/2020

Amy McCracken, DNP, APRN

Learning Objectives:

● Discuss the diagnosis and management of IBS and functional dyspepsia in order to optimize treatment strategies ● Describe pharmacological and alternative treatment approaches of IBS-C, IBS-D, IBS-M, and functional dyspepsia ● Articulate patient-specific treatment options for those with IBS and functional dyspepsia as derived from case studies

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Irritable Bowel Syndrome (IBS)-Definition and Epidemiology

● Comprises a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habits in the absence of an organic disease. ● The prevalence of IBS in North America is estimated at approximately 10-15%. ● More common in women compared to men. ● Second highest cause of work absenteeism ● IBS accounts for approximately 25 to 50% of all referrals to gastroenterologists. ● Important to remember: This is a diagnosis of exclusion!

IBS-Etiology

● Stress ● Visceral hypersensitivity ● Psychosocial factors ● Common-cannot be explained ● Chronic and benign ● High association with stress in the pathophysiology and clinical presentation of IBS

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IBS-Signs and Symptoms

● Chronic abdominal pain-usually a cramping sensation that varies in intensity with periodic exacerbations ● The character and location of pain can vary widely and often times related to defecation ● Abdominal fullness, bloating or swelling ● Diarrhea, constipation or alternating diarrhea and constipation or normal bowel habits alternating with either diarrhea and/or constipation ● Feeling of incomplete evacuation ● Mostly during waking hours

IBS-Atypical Signs and Symptoms

The following atypical signs and symptoms should prompt further evaluation for organic disease:

● Acute onset of symptoms or onset of symptoms after age 50 ● Fever ● Rectal bleeding or anemia ● Weight loss ● Persistent diarrhea ● Severe constipation ● Nocturnal symptoms ● Abnormal colonoscopy ● Family history of GI cancer, IBD, or celiac disease

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IBS-Diagnosis

● IBS is a diagnosis of exclusion ● ROME IV criteria for IBS: Defined as recurrent abdominal pain, on average, at least one day per week in the last three months, associated with two or more of the following: ○ Relieved with defecation; and/or ○ Onset associated with a change in frequency of stool ○ Onset associated with change in the form of stool (appearance)

IBS Subtypes

● IBS with predominant constipation (IBS-C): Abnormal bowel movements are usually constipation ● IBS with predominant diarrhea (IBS-D): Abnormal bowel movements are usually diarrhea ● IBS with mixed bowel habits (IBS-M): Abnormal bowel movements are usually both constipation and diarrhea (at least ¼ of each) ● IBS unclassified: Diagnostic criteria met, but cannot be categorized into one of the other three subtypes

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Differential Diagnosis

● If diarrhea predominant: celiac disease, microscopic colitis, small intestinal bacterial overgrowth, fructose/lactose/sucrose intolerance, inflammatory bowel disease (IBD), bile salt malabsorption ● If constipation predominant: organic disease, dyssynergic defecation ● Always review medication profile as a potential cause for constipation or diarrhea (psychotropic medications, oral hypoglycemic agents, thyroid replacement therapy, iron supplements, narcotics)

Initial Evaluation of IBS

● Detailed H&P: medication exposure; recent acute viral or bacterial gastroenteritis; family history of IBD, colon cancer, celiac disease ● Lab work: ○ CBC to evaluate for anemia ○ In patients with constipation: TSH and calcium (or ionized calcium) ○ In patients with diarrhea: Fecal calprotectin or CRP, stool studies, serologic testing for celiac disease ● Colorectal cancer screening if age appropriate ● Abdominal imaging in patients with constipation ● Anorectal manometry in patients with severe constipation refractory to management with dietary changes and osmotic laxative therapy

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IBS-Treatment

● Initial Therapy ○ Lifestyle and dietary modification in patients with mild and intermittent symptoms that do not impair quality of life ○ Dietary modification: low FODMAP (fermentable oligo-, di-, and monosaccharides and polyols), lactose free diet, gluten free diet ○ Fiber ○ Food allergy testing and breath testing ○ Physical activity

IBS Treatment-Fiber

● Role of fiber is controversial, but no serious side effects, so should be considered in patients with IBS whose predominant symptom is constipation ● Primarily exert their laxative effect by absorbing water and increasing fecal mass ○ Psyllium based fiber: contains 70% soluble fiber, so can cause increased fullness/bloating/gas and slow digestion ■ Examples: Metamucil, Konsyl ○ Insoluble based fiber (Methylcellulose): nonfermentable, so less likely to contribute to bloating and gas ■ Example: Citrucel (gluten free) ○ Calcium Polycarbophil (Fibercon) and Wheat dextrin (benefiber)

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IBS-C Pharmacologic Treatment Options

● Osmotic Laxatives-Polyethylene glycol (PEG), Lactulose, Magnesium Citrate ● Stimulant Laxatives-Bisacodyl, Senna ● Secretagogue- ○ Lubiprostone (Amitiza) ○ Linaclotide (Linzess) ○ Plecanatide (Trulance)

Osmotic Laxatives

● Examples: Polyethylene Glycol (PEG), Lactulose, Milk of Magnesia, Magnesium Citrate ● Mechanism of Action: Cause intestinal water secretion and thus increase stool frequency ● Side Effects: Excessive use may result in electrolyte imbalances and volume overload in patients with renal or cardiac disease ● Polyethylene Glycol (Miralax) ○ Inexpensive, few side effects ○ Improves constipation, but not abdominal pain or severity of bloating ○ Initially start with 17 g of powder dissolved in 8 oz of water (other liquid) daily ○ Titrate up or down to a maximum of 34 g daily ○ Important to educate the patient on proper use and titration

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Osmotic Laxatives, Cont

● Lactulose ○ Synthetic disaccharide-not metabolized by intestinal enzymes, so water and electrolytes remain within the intestinal lumen due to the osmotic effect of the digested sugar ○ Requires 24-48 hours to achieve its effect ○ May cause bloating and flatulence ● Milk of Magnesia/Magnesium Citrate ○ Poorly absorbed and act as hyperosmolar solutions ○ May cause hypermagnesemia, especially in patients with renal impairment

Stimulant Laxatives

● Examples: Bisacodyl (Dulcolax), Senna (Senokot) ● Mechanism of Action: ○ Cause alteration of electrolyte transport by the intestinal mucosa ○ Increase intestinal motor activity ● Side Effects: ○ Prolonged daily ingestion may be associated with hypokalemia, protein losing enteropathy and salt depletion ○ Long term safety has not been established

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Secretagogue

● Examples: Lubiprostone (Amitiza), Linaclotide (Linzess), Plecanatide (Trulance)

Lubiprostone-Amitiza

● Mechanism of Action: ○ Locally acting chloride channel activator that enhances chloride-rich intestinal fluid secretion, thus secreting chloride and water into the gut lumen ● Side Effects: ○ Long term safety has not been established ○ Most common adverse event was nausea; followed by diarrhea and headache ● Used for treatment of IBS-C in women age 18 years and older, but can also be used in men; should discontinue use with pregnancy ● The approved dose for IBS-C is 8 mcg twice daily (the approved dose for treatment of chronic idiopathic constipation is 24 mcg twice daily)

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Linactolide-Linzess

● Mechanism of Action: ○ Guanylate cyclase agonist that stimulates intestinal fluid secretion and transit ○ May decrease visceral pain by reducing pain sensing nerve activity ● Side Effects: ○ The most common side effect is diarrhea (16-22%); Discontinue use if diarrhea is severe ○ Contraindicated in pediatric patients under the age of 6 and safety has not been established in patients younger than 18 ● The approved dose for IBS-C is 290 mcg daily (the approved dose for treatment of chronic idiopathic constipation is 145 mcg daily or 72 mcg daily) ● Administer 30 minutes prior to the first meal of the day on an empty stomach (loose stools and greater stool frequency can occur if taken with a high fat breakfast) ● Can be used with pregnancy

Plecanatide-Trulance

● Mechanism of Action: ○ Guanylate cyclase agonist that stimulates intestinal fluid secretion and transit ● Side Effects: ○ May cause diarrhea during the first month of use (severe diarrhea during the first 3 days of use); discontinue use if diarrhea is severe or dehydration occurs ● The approved dose for IBS-C (and chronic idiopathic constipation) is 3 mg once daily ● Can be taken with or without food ● Can be used with pregnancy

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IBS-D Pharmacologic Treatment Options

● Antidiarrheal agents-Loperamide ● Bile acid sequestrants-Cholestyramine (Questran)/Colestipol (Colestid)/Colesevelam (Welchol) ● 5-hydroxytryptamine (serotonin) 3 receptor antagonists (5HT-3)-Alosetron (Lotronex) ● Eluxadoline (Viberzi)

Antidiarrheal Agents

● Example: Loperamide (Imodium) ● Mechanism of Action: ○ Acts directly on circular and longitudinal intestinal muscles, through the opioid receptor, to inhibit peristalsis and prolong transit time ○ Decreases stool frequency and consistency; increases anal sphinter tone ● Side Effects: ○ Constipation (2-5%), abdominal cramps and nausea (<3%) ● Should be used as the initial treatment of IBS-D ● Typically will not treat symptoms of bloating, abdominal discomfort or global IBS symptoms ● Dosing: 4 mg after first loose stool, followed by 2 mg after each subsequent stool (max 16 mg/day) ● Data is conflicting for use in pregnancy

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Bile Acid Sequestrants

● Examples: Cholestyramine (Questran)/Colestipol (Colestid)/Colesevelam (Welchol) ● Mechanism of Action: ○ Bile acids cause diarrhea by stimulating colonic secretion and motility; thus bile acid sequestrants/binders form a nonabsorbable complex with bile acids in the intestine and release chloride ions in the process ● Side Effects: ○ Constipation, abdominal bloating, flatulence, abdominal discomfort ● Used as a second line therapy for treatment of IBS-D ● Dosing varies based upon agent used (4-8 g/day; 1-4 g/day; 1-6 g/day) ● May interfere with maternal vitamin absorption, so regular prenatal supplementation may not be adequate

5-hydroxytryptamine (serotonin) 4 receptor agonists (5-HT4)

● Examples: Alosetron (Lotronex), Tegaserod (Zelnorm)-no longer available ● Mechanism of Action: ○ Modulates visceral afferent activity from the GI tract, thereby decreasing colonic motility and secretion, and may improve abdominal pain ● Side Effects: ○ Ischemic colitis ○ Severe constipation ● Approved for the treatment of severe IBS-D in female patients who have had symptoms for 6 months and have failed to respond to all other conventional therapy; Can only be prescribed under restricted conditions ● Initial dosing: 0.5 mg bid for 4 weeks, then if tolerated, but response inadequate may increase to a maximum dose of 1 mg bid ● Can be used with pregnancy

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Eluxadoline-Viberzi

● Mechanism of Action: ○ Mixed mu-opioid receptor agonist, delta opioid receptor antagonist and kappa opioid receptor agonist that acts locally to reduce abdominal pain and diarrhea ● Side Effects: ○ Constipation, pancreatitis, sphincter of Oddi spasm ○ Contraindicated in patients without a gallbladder, known or suspected biliary duct obstruction or sphincter of Oddi disease, history of pancreatitis or structural diseases of pancreas, alcohol abuse/addiction, severe hepatic impairment ● Dosing: 100 mg twice daily; may decrease to 75 mg twice daily if unable to tolerate the higher dose; Take with food ● May be used with pregnancy

IBS-M

● Treatment should be directed towards treating the underlying predominant symptom of constipation or diarrhea ● Consider pharmacologic and non-pharmacologic treatment options ● Remember to consider treatment options for associated symptoms: abdominal bloating, gas, abdominal pain, etc

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Alternative Pharmacologic Treatment Options for IBS

● Antispasmodics-Hyoscycamine (Levsin or Levbid), Dicyclomine (Bentyl) ● Antidepressants-Tricyclic antidepressants (TCAs)-Amitriptyline, nortriptyline, imipramine, desipramine ● Antibiotics-Rifaximin (Xifaxan) ● Probiotics

Antispasmodics

● Examples: Hyoscycamine (Levsin or Levbid), Dicyclomine (Bentyl) ● Act via anticholinergic or antimuscarinic properties ● Selective inhibition of gastrointestinal smooth muscle reduce stimulated colonic motor activity ● May be beneficial in patients with postprandial abdominal pain, gas, bloating and fecal urgency ● Should be administered on an as-needed basis and/or in anticipation of stressors with known exacerbating effects ● Typical doses: ○ Hyoscyamine: Levsin: 0.125 mg to 0.25 mg PO/SL tid-qid prn; Levbid: 0.375 to 0.75 mg PO q12h ○ Bentyl: 10-20 mg PO qid prn

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Antidepressants

● Examples: Tricyclic antidepressants (TCAs)-Amitriptyline, nortriptyline, imipramine, desipramine ● Anticholinergic properties which also slow intestinal transit time ● Use cautiously in patients with constipation ● Start at a low dose and adjust based on tolerance and response ○ Amitriptyline/Nortriptyline/Imipramine: start at a dose of 10 to 25 mg at hs ○ Desipramine: start at a dose of 12.5 to 25 mg at hs ● Results of studies with use of SSRIs/SNRIs lack have been inconsistent, however if depression is a cofactor with IBS then these medications can be used

Antibiotics

● Examples: Rifaximin (Xifaxan), Metronidazole (Flagyl), Ciprofloxacin, Doxycycline, Augmentin, Bactrim DS ● Should not be routinely recommended in all patients with IBS ● If patients have moderate to severe IBS without constipation, especially those with bloating, who have failed to respond to other modalities (diet changes, antispasmodics, TCAs), then can try a 2 week course of Rifaximin 550 mg PO tid ● Would limit use of alternative antibiotics unless suspicion is high that there is a component of bacterial overgrowth, but would recommend confirming with a SIBO breath test

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Probiotics

● Not routinely recommended in patients with IBS ● Probiotics have been associated with an improvement in symptoms, but the magnitude of benefit and the most effective strain and species is unknonwn

Nonpharmacologic Treatment Options for IBS

● Stress management ● Cognitive behavioral therapy ● Hypnosis ● Acupuncture ● Pain management programs ● Exercise

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Dyspepsia-Definition and Etiology

● Functional (idiopathic or nonulcer) dyspepsia requires exclusion of other potential organic causes of dyspepsia ● Defined by the presence of one or more of the following: ○ Postprandial fullness ○ Early satiety ○ Epigastric pain or burning ○ And NO evidence of structural disease to explain the symptoms ● Occurs in at least 20% of the population

Dyspepsia Secondary to Organic Disease

● Peptic ulcer disease ● Gastroesophageal reflux disease (GERD) ● Medications (NSAIDs are the most common offender) ● Gastroesophageal malignancy (higher incidence in patients of Asian, Hispanic or Afro-Caribbean descent) ● Biliary pain ● Celiac disease ● Chronic pancreatitis ● Other rare causes: Eosinophilic gastroenteritis, Crohn’s disease, sarcoidosis, lymphoma, amyloidosis, diabetic radiculopathy, metabolic disturbances, hepatoma, steatohepatitis, celiac artery compression syndrome, SMA syndrome, abdominal wall pain, intestinal angina

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Initial Evaluation of Dyspepsia

● Detailed history to determine underlying cause and to identify any potential alarm features ○ Example: dominant heartburn/regurgitation symptoms (GERD); medications/NSAID/Aspirin use; radiation of pain to back/history of pancreatitis; weight loss/anorexia/vomiting/dysphagia/odynophagia/family history of gastroesophageal malignancy; presence of severe pain lasting at least 30 minutes (?cholelithiasis); N/V with or without weight loss associated with abdominal pain (? gastroparesis) ● Physical exam should be normal with functional dyspepsia with the exception of epigastric tenderness ● Lab work: CBC, CMP, amylase, lipase

Diagnosis of Dyspepsia

● In patients age 60 or over: upper endoscopy is recommended with biopsies to rule out H. pylori ● In patients under age 60: evaluate and treat for H. pylori, and upper endoscopy should be performed selectively (significant weight loss, overt GI bleeding, weight loss, dysphagia, odynophagia, iron deficiency anemia, persistent vomiting, palpable mass or lymphadenopathy, FH of upper gastrointestinal cancer)

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Treatment of Dyspepsia

● Treat with antisecretory therapy with once daily proton pump inhibitor (PPI) therapy for 8 weeks ○ PPI’s are likely to be more effective with relieving symptoms compared to H2 receptor antagonists ● If symptoms persist after 8 weeks, then trial a tricyclic antidepressant ● Prokinetics (metoclopramide, domperidone, erythromycin) should only be used in patients who fail tricyclic antidepressant therapy ○ If symptoms improve with prokinetic therapy, then discontinue use and repeat a 4 week course if symptoms recur ○ If symptoms persist on prokinetic therapy, then re-evaluate symptoms and perform an upper endoscopy if not previously done, assess gastric emptying in patients with predominant N/V symptoms ● Trial of psychoterapy in patients who do not respond to PPI’s, TCAs, prokinetic agents

Case Study #1

A 23 year-old female presents with a 5 month history of generalized abdominal discomfort that is relieved by stooling. She typically has diarrhea one day per week and on the other days she has no stools or she passes small, hard pebbles of stool. She denies rectal bleeding or weight loss.

● Physical exam: Abdomen soft and nondistended with no tenderness to palpation ● Lab work: CBC, BMP, CRP/ESR, pregnancy test negative

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Case Study #2

A 21 year-old female presents with a 2 year history of recurrent crampy lower abdominal pain associated with abdominal bloating and frequent loose stools. She denies any fevers, weight loss, anorexia or bloody stools. Her physical exam is unremarkable. Lab work shows a normal CBC and CRP/ESR. Which of the following tests should be performed?

1. Abdominal ultrasound 2. Colonoscopy with biopsies 3. Stool for O&P, enteric pathogens, C. difficile 4. TSH level 5. Tissue transglutaminase antibody IgA, serum IgA

Case Study #3

A 28 year-old female with a history of hypothyroidism presents with increasing abdominal pain and constipation. She complains of daily nausea. She has infrequent and hard stools. She is currently taking Polyethylene glycol 34 grams twice daily without improvement.

● Physical exam: VSS, abdomen soft and mildly distended; hard stool in rectal vault. Weight is 49 kg ● Abdominal X-Ray: Large amount of stool in the colon ● Lab work: CBC/CRP normal, pregnancy test positive

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Case Study #4

A 21 year-old male who attends UNL and is majoring in biology presents with a 2-3 month history of abdominal pain. He describes his pain as a burning pain in the epigastrium that is worsened by spicy foods. He has associated nausea and early satiety, but no vomiting or weight loss. His symptoms come and go throughout the day, but then improve at night. He does not take NSAIDs. He moves his bowels once daily. His mother is concerned as she thinks he has an ulcer.

● Physical exam: abdomen soft and mild tenderness to palpation in the epigastric region ● Lab work: CBC, CRP are normal; H.. Pylori stool antigen is negative

Questions?