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Upper GI motility Functional Dyspepsia: Objectives disorders and functional dyspepsia • Definition • Epidemiology: natural history, and costs Willem J.S. de Villiers,,, MD, PhD • Etiology and pathophysiology Chief, Division of Gastroenterology, University of Kentucky • Cost effective diagnosis Lexington, KY • Evidence-based treatments • Future treatment options

Symptoms of Functional Dyspepsia Dyspepsia • Persistent or recurrent abdominal pain • Epigastric pain/discomfort – 90% or discomfort centered in the upper • Post-prandial fullness – 75% abdomen • – 75% • Uninvestigated dyspepsia following • Post-prandial – 50% endoscopy • Early satiation – 50% – Organic: 30% • Belching – 45% – Functional: 70% • Weight loss – 30% • Nausea and – 20%

Dyspepsia: Epidemiology and Burden of The Economics of Dyspepsia Illness • Annual US prevalence = 20-25% • It is estimated that 10% of all healthcare • Incidence is estimated at 1% per year expenditures in the go • Less than 50% of those with symptoms of towards treating dyspepsia dikdildyspepsia seek medical care. • In the USA, direct costs (diagnostic studies, • Dyspepsia – 5% of all family practice ER visits, medications) and indirect costs consultations (absenteeism, presenteeism) for dyspepsia • Dyspepsia significantly reduces quality of life amount to more than $2 billion/year • Significant misconceptions abound – 20% • FD patients spend an average of $698/year believe their symptoms will turn into treating their condition ($20 billion/year)

1 Functional Dyspepsia: Diagnosis Functional Dyspepsia: Rome III Criteria Unclear Natural History • Presence of one or more of the following • 80% of patients have symptoms 18 to symptoms, thought to originate in the gastroduodenal region 24 months after diagnosis – Epigastric pain syndrome (EPS) • 74% of ppypatients have symptoms 12 to • Epigastric pain • EiEpigas tibtric burn ing 24 months later – Postprandial distress syndrome (PDS): Meal-related FD • In contrast, some studies have shown • Bothersome postprandial fullness after ordinary sized meals 30-50% of patients experience • Early satiety that prevents finishing a regular sized meal • No evidence of structural disease to explain the resolution of symptoms over the course symptoms and symptoms present for the past 3 of 12 to 24 months months, with onset at least 6 months before diagnosis. • Heartburn should be excluded

Functional Dyspepsia: Diagnosis Overlap of GI motor and sensory disorders • Thorough history and physical examination

• Evaluation for warning signs/features Belching Bloating – Unintentional weight loss, anemia or dysphagia Dyspepsia – History of NSAID use; recurrent vomiting Discomfort Chronic GERD – Previous GI bleeding or ulcer disease Constipation – Abnormal physical examination other than Heartburn (CC) epigastric pain/discomfort • High-prevalence or low-prevalence IBS Helicobacter pylori area? Regurgitation Abdominal pain • Evaluation of the upper GI tract (EGD) Diagnosis can shift from one disorder to another over time

FD: Etiology and Pathophysiology Putative mechanisms linked to functional dyspepsia

Failure Gastric Small bowel of fundic Gastric hyper- hyper- relaxation dysrhythmias sensitivity sensitivity to a meal

Delayed Vagal gastric Functional dyspepsia neuropathy emptying / antral hypomotility

H. pylori Acid Small bowel Psychological sensitivity dysmotility distress / CNS disturbances

Talley et al. In: Rome II: Functional Gastrointestinal Disorders, Drossman et al. 2000: 306

2 Environmental Genetic influences Candidate genotypes: FD Stress Predisposition • GNB3 (825 CC genotype) Helicobacter pylori • GNB3 (TT homozygous) Other factors Inflammation FD Symptoms • GNB3 (825T allele) (Mild) • SNPs (single nucleotide polymorphism) –HTR2A Stress – MAGI2 Somatization –IL-9 Poor coping skills FD Symptoms Depression – IL-4R (Severe)

Range of treatment options in FD Current issues with treating functional dyspepsia

Lifestyle modification y reassurance and Avoidance of • The range of treatment options reflects the explanation NSAIDs y y dietary modification y SSRIs uncertain pathogenesis of functional Antisecretories y Antacids dyspepsia, the diversity of symptoms and y H2RAs the lack of satisfactory treatment1 Antinauseants Functional y PPIs y dyspepsia treatment H. pylori • There is a significant placebo response: options eradication 2 Antispasmodics 40–60% y Dicyclomine Prokinetics y Metoclopromide Fundic relaxants y y 5HT y agonists 1 1 y Sumatryptan Visceral analgesics y (withdrawn) Rome II: Functional Gastrointestinal Disorders, Sen Ed. DA Drossman; 2000: 306 y y Fedotazine y 2 Van Zanten et al, Am J Gastroenterol 1996; 91: 660 y 55--HTHT3 antagonists

Dr. Drossman’s Ten Dr. Drossman’s Ten Commandments Commandments 1. Obtain the history through a non- 4. Provide a thorough explanation of the directive, non-judgmental patient- disorder that takes into consideration centered interview the patient’s beliefs 2. Conduct a careful examination and 5. Identify and respond realistically to the cost-efficient investigation patient’s expectations for improvement 3. Determine how much the patient 6. When possible, provide a link between understands about the illness and stressors and symptoms that are his/her concerns consistent with the patient’s beliefs

Drossman DA. Gastroenterology 2006: 130: 1377-1390

3 Current Management of Dr. Drossman’s Ten Functional Dyspepsia Commandments • Test & Treat for H. pylori or EGD? 7. Set consistent limits. • Dietary changes 8. Involve the patient in treatment. • Historical treatments 9. Make recommendations consistent with • H. pylori eradication the patient’s interests. • Antisecretory therapy 10. Establish a long-term relationship with • Prokinetics a primary care provider. • agents • Antinociceptive agents • Psychological therapies

Treatment Strategy: Test & Treat, Prompt Endoscopy, or Empiric FD & Diet

Acid Suppression • Intraduodenal infusion of fat induces • Test & Treat for H. pylori: for younger symptoms in FD patients but not health patients, those without warning signs, and volunteers those in a high prevalence H. pylori area • Small amounts of fat added to meals induces FD symptoms of bloating, fullness and • Prompt endoscopy: for older patients, those nausea with warning signs; and those in a low • A high fat meal induces more symptoms than prevalence H. pylori area an isocaloric high carbohydrate meal • Empiric PPI: safe for younger patients • Upper abdominal fullness and bloating was without warning signs, may decrease need directly related to the amount of fat ingested for EGD, may treat patients with occult reflux

Cochrane Collaboration Meta- Treatment of Dyspepsia (circa 1892) Analysis of H. pylori Cure for Functional Dyspepsia • “Replace digestive juices that are • 12 RCTs (2903 patients) lacking • Mean response rate – Placebo: 29% (range, 7%-51%) • Infusions of hydrochloric acid and – HpyloriH. pylori cure: 37% (range, 21%-62%) ferments • Relative risk of symptoms remaining – 0.91 (95% CI: 0.86-0.95) • 90-100 drops at intervals of 15 minutes • NNT = 15 (95% CI: 10-28) after meals” • Second meta-analysis of 10 RCTs in patients with FD followed for 1 year after treatment of H.pylori did not show any benefit in resolution of dyspepsia symptoms compared with placebo

4 Cochrane systematic review updated Are the H. pylori “responders” Moayyedi et al. Cochrane Database Syst Rev 2003;(1):CD001960 forme fruste ulcer patients? NNT = 15 (95% CI 10 to 28) Risk ratio Study (95% CI) % Weight z Hypothetical Blum/Talley0.92 (0.81,1.03) 13.2 McColl0.85 (0.77,0.93) 14.5 z No convincing evidence that symptom Koelz0.95 (0.81,1.11) 7.3 Talley(Orchid) 0.97 ()(0.85,1.11) 10.9 subgroups or H. pylori virulence Talley(USA)1.07 (0.86,1.34) 7.5 Miwa0.91 (0.70,1.18) 3.2 factors will identify responders Malfertheiner0.88 (0.77,0.99) 19.8 Varannes0.83 (0.68,1.00) 8.9 Froehlich0.86 (0.60,1.24) 3.6 z Past/future ulcer patients? Koskenpato0.91 (0.78,1.07) 6.3 Gisbert0.76 (0.40,1.46) 1.1 Hsu0.93 (0.66,1.33) 3.7 z Duodenitis?

Overall (95% CI) 0.91 (0.86,0.95) p<0.0001 Heterogeneity χ2=7.4 (df=11) Xia et al. Aliment Pharmacol Ther 2003; 17; 1-9 .40 1 2.5 p=0.77 Favours eradication Favours placebo

H2RA therapy Forest plot H2RAs for Functional Dyspepsia Moayyedi et al. Cochrane Database Syst Rev 2003;(1):CD001960 • Meta-analysis (2001) NNT = 8 (95% CI = 5 to 24) Risk ratio • 22 RCTs in patients with nonulcer dyspepsia Study (95% CI) % Weight Delattre 19850.53 (0.40,0.69) 11.0 • 14 studies: parallel groups; 8 studies: Gotthard 19880.74 (0.53,1.04) 9.6 Hadi 19890.03 (0.00,0.43) 0.4 crossover Hansen 19981.20 (0.88,1.64) 10.1 Kelbaek 19851.19 (0.62,2.29) 5.1 • 15 of 22 studies found H2RA superior to Nesland 19850.75 (0.53,1.06) 9.6 Saunders 19860.50 (0.32,0.78) 7.8 placebo at relieving epigastric pain but not Singal 19890.57 (0.32,0.99) 6.1 Olubuyide 19861.00 (0.88,1.14) 13.5 global symptoms of dyspepsia Muller 19940.78 (0.67,0.91) 13.0 Blum 20000.89 (0.80,0.98) 13.8 • Significant design flaws in many studies, including crossover design and inclusion of Overall (95% CI) 0.78 (0.65,0.93) GERD-predominant patients .1 1 10 Favours H2RA Favours placebo Heterogeneity χ2 =54.6 (df=10), p<0.0001

Cochrane Collaboration Meta- PPI therapy in Functional Dyspepsia Analysis of PPI Therapy for n=1262 Functional Dyspepsia % patients Omeprazole 20 mg 80 Omeprazole 10 mg Placebo • 7 RCTs (3031 patients) * p<0.05 vs placebo • PPI for 2 to 8 weeks was superior to placebo in 60 * reliev ing symp toms o f non-uldlcer dyspeps ia 54 * * • Relative risk of symptoms remaining 40 * 45 40 38 – 0.86 (95% CI: 0.80-0.93) 35 37 32 31 30 27 • NNT = 9 (95% CI: 6-26) 20 23 25 – Six RCTs (2032 patients) found no difference between low-dose and standard-dose PPI for FD 0 Ulcer-like Reflux-like Dysmotility-like Other

Talley et al. Aliment Pharmacol Ther 1998; 12:1055-65

5 PPI therapy Forest plot Gastric emptying Moayyedi et al. Cochrane Database Syst Rev 2003;(1):CD001960 Delayed in 440%0% of NUD cases NNT = 9 (95% CI 6 to 26) - target prokinetic therapy to Risk ratio Study (95% CI) % Weight this subset?

Bond 0.78 (0.68,0.89) 13.9 Opera 0.99 ((,)0.85,1.14) 13.6 Blum 0.82 (0.75,0.90) 16.5 PeuraM96 0.80 (0.70,0.90) 14.5 PeuraM97 0.80 (0.71,0.91) 14.9 Wong 1.09 (0.97,1.23) 14.8 Lauritsen0.75 (0.63,0.90) 11.9

Overall (95% CI) 0.86 (0.77,0.95)

.63 1 1.58 Pooled OR=1.46 (times slower in NUD control) Favours PPI Favours placebo Quartero et al Dig Dis Sci 1998;43:2028-33 Heterogeneity χ2 = 26.3 (df=6), p<0.0001

Prokinetic Agents for the Treatment of Functional Dyspepsia Evidence for Prokinetic Physiological effects Therapies Agent Primary mode Gastric Visceral Gastric Gastric fundic • Cisapride – 17 studies. Earlier apparent of action Emptying sensitivity antral accommodation motility favorable response might have been

Metoclopramide attributed to publication bias. Recent review – antagonist 5- √ ↑ ↓ ↑ HT4 no sign ifican t b ene fit compared w ith p lace bo.

Domperidone Dopamine • – The most commonly used antagonist √↑↓ prokinetic in FD treatment. Recent meta-

Tegaserod 5-HT4 agonist analysis failed to show any significant benefit ↑↓↑ ↑ above placebo.

Levosulpiride 5- √↑↓↑ HT4 agonist

Prokinetic therapy Forest plot Evidence for Prokinetic Therapies Moayyedi et al. Cochrane Database Syst Rev 2003;(1):CD001960 NNT = 4 (95% CI 3 to 7) Risk ratio • Domperidone – 8 studies were evaluated. Study (95% CI) % Weight

Many had severe design flaws. Recent meta- Al-Quorain 0.19 (0.09,0.41) 7.6 Champion 200.75 (0.48,1.18) 9.7 analysis showed a slight benefit at improving Champion 10 0.84 (0.55,1.29) 9.9 Chung 0.36 (0.15,0.85) 6.9 symptdithlbtoms compared with placebo. De Nutte 0.33 (0.11,1.03) 5.4 Francois0.30 (0.10,0.90) 5.6 Hannon 0.33 (0.12,0.91) 6.1 • – Dopamine antagonist not Hansen0.99 (0.70,1.38) 10.4 Kellow 0.50 (0.20,1.28) 6.5 available in the USA. Recent study showed Rosch0.27 (0.15,0.48) 8.8 Yeoh0.89 (0.56,1.44) 9.5 benefit compared with cisapride, though no Wood 0.42 (0.05,3.36) 2.4 Holtmann 1.01 (0.88,1.17) 11.2 placebo group was included. Overall (95% CI) 0.53 (0.37,0.77)

.05 1 19 Favours prokinetic Favours placebo Heterogeneity = χ2 =72.0 (df=12), p<0.0001

6 CNS Dysfunction in FD Therapy in functional dyspepsia? • Exaggerated response to buspirone in NUD • Targets wrong? • Differences most significant at 90 min following the Acid suppression challenge. • Female subjects, both patients and healthy HpyloriH. pylori volunteers, showed a greater response to • Requires altering multiple buspirone than male subjects targets e.g. acid and – ? Hypersensitivity of central receptors motility/sensation or secondary to chronic pain • Target the brain to get the gain? Chua et al. BMJ 1992:305:280-282 Dinan et al. Aliment Pharmacol Ther 2001;15:1613-8

Cerebral regions activated during gastric distention Effects on the CNS- ACC, ant cingulate cortex; Pain BS,brain stem; Cortex CA, caudate Perception nucleus; Spinal Cord Pharmacological CBL, cerebellum; Descending inhibitory fibers Options INS, insula; µ opiates, tricyclics OC, occipital cortex - ANS input 5HT3 antittagonists (including fusiform 2nd order neurons & lingual gyri, and cuneus); Dorsal horn nucleus κ opiates PFC, prefrontal 5HT3 antagonists cortex THL, thalamus; Dorsal root ganglion Substance P VM, cerebellar CGRP antagonists vermis NSAIDs Sensory nerve endings in gut κ opiates

Ladabaum et al Gastreonterology 2001;120:3692001;120:369--376376 5HT3 antagonists

Functional Dyspepsia: Functional Dyspepsia: TCAs SSRIs/SNRIs • antidepressants (TCAs) • Selective serotonin reuptake – Visceral and somatic perception are inhibitors (SSRIs) improved – enhanced gastric accommodidation i ihn hea lhlthy vo lunteers – Amitryptiline improved symptoms but did not alter sensation of gastric distention – was no better than placebo – or mirtazepine may be better – Meta-analysis in patients with FGID found choices improvement of global symptoms (OR=4.2; – NIH Functional Dyspepsia Trial in progress NNT=3.2) and pain (TCA vs. SSRI vs. placebo)

7 Meta-Analysis of Antidepressants for IBS/NUD Emerging Therapies for Favours Placebo Favours Treatment Functional Dyspepsia Greenbaum (1987) Heffner (1978) • agents Loldrup (1989) • Serotonergic agents Loldrup (1989) Mertz (1998) • Kappa- agents Myren (1984) • Antidepressants Rajagopalan (1998) • Ghrelin Steinhart (1981) • Behavioral therapy Tanum (1996) •CAM – Capsaicin Overall (95% CI) 0.9 (0.6-1.2) – Herbals Effects of medications on 0 1 234 abdominal pain scores Standardized mean difference Jackson et al Am J Med 2000;108:65-72

Is the glass half-empty or half- Glass Half-empty full? • Dopamine antagonists – • Serotonergic agents – 5-HT4 recep tor agon is ts (tegasero d) – 5-HT3 receptor antagonists () • Kappa-opioid agonists – • Antidepressants – Venlafaxine

Glass Half-full FD: 5-HT1A agonists

• TCAs & SSRI/SNRIs • • 5-HT1 agonists – DB, R, Placebo-controlled: Rome II criteria • – N=144; 4 weeks: 10mg tid vs. placebo • CAM – Tandospirone improved symptoms of upper – Iberogast abdominal pain (p=0.02) and discomfort (p=0.002) – Capsaicin more than placebo – Acupuncture • R-137696 • Behavioral therapy – DB, R, Placebo-controlled: Rome II criteria –CBT – N=53; 4 weeks: 2mg tid vs. placebo – Hypnotherapy – No difference between drug and placebo

8 FD: Acotiamide FD: Herbal remedies

• Enhances ACh release – blocks M1 & M2 • 17 RCTs were included in a systematic review (8 trials had a Jadad score >3) receptors • and caraway oil were the best-studied • Inhibits AChE activity herbal remedies – 4 RCTs showed their benefits • Phase IIa, R, DB; placebo-controlled trial • Most studies were conducted with combinations • N=71 – Effective ingredient and quality control were unclear • Iberogast®, a combination of 9 herbs, relieved • 100-300mg tid symptoms compared with placebo in several European studies • Significantly improved gastric accommodation • Capsaicin – beneficial in small DB, R, placebo- and bloating controlled study; N=30.

Hypnotherapy in functional FD: Acupuncture dyspepsia

100 Hypnotherapy • 68 patients with FD (Rome II criteria); Medical randomized Supportive 80 • Mean age 35; 79% women 73 59 provement provement • 6-point acupuncture vs. nondefined point score 60 • 3 sessions/week for 2 weeks 41 43 • Nepean Dyspepsia Index pre- and post-Tx 40 33 34

• Results: Both groups showed significant symptom in improvement in QOL and symptom scores 20 Percentage of im Percentage of (p<0.001), but no difference between the 0 groups Short (16 weeks) Long (56 weeks)

Calvert et al. Gastroenterology 2002;123:1778–85

FD: Potential Future Therapies Functional Dyspepsia: Summary

• Mianserin (tetracyclic antidepressants) • Antisecretory therapy is effective in a • (Remeron) small subset of patients • Ghrelin • The benefits of H . pylori cure are small • Neurokinin antagonists • Small, frequent low-fat meals improve • Corticotrophin-releasing factor (CRF) symptoms antagonists • Effective pro-kinetic therapy is eagerly • Opioid antagonists awaited

9 Functional Dyspepsia: Summary

• Agents that improve accommodation (i.e. tandospirone) and nociception are needed • Treat co-existing anxiety • Psyc ho log ica l therap ies (TCAs an d SSRIs ) appear effective in a subset of FD patients • Consider behavioral therapy (CBT) and/or hypnotherapy • Complementary strategies require further study

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