Gastroparesis: Why do we do what we do

1. Gastroparesis: Why do we do what we do? Nicholas Netherland, M.D. UAB Gastroenterology Grand Rounds September 8, 2008

2. Gastroparesis Epidemiology Clinical Manifestations Etiology Differential Diagnosis Diagnosis Treatment

3. Epidemiology Estimated to affect up to 4% of US population. 34 y/o – average age of onset 82% female

4. Clinical Manifestations Nausea 92% Vomiting 84% Bloating 75% Early Satiety 60%

5. Clinical Manifestations Mild Intermittent mild symptoms No weight loss or nutritional deficiencies Easily controlled with diet/avoiding meds that slow emptying

6. Clinical Manifestations Moderate Moderately severe symptoms Controlled with prokinetics/antiemetics Infrequent hospitalizations

7. Clinical Manifestations Severe Fail to maintain nutrition/hydration Frequent hospital visits/admissions Unresponsive to prokinetics/antiemetics How do we define these groups if we want to do a clinical trial? Until recently no standardized method

8. Clinical Manifestations Validated Patient-assessed Gastroparesis symptom severity measure Gastroparesis Cardinal Symptom Index (GCSI) Revicki DA, et al. Aliment Pharmacol Ther 2003

9. GCSI N = 169 7 US University Hospitals 3 subscales of PAGI-SYN for upper GI symptoms

10. GCSI Each parameter scored on 0-5 scale 1. Nausea 2. Retching 3. Vomiting 4. Stomach Fullness 5. Not able to finish normal-sized meal 6. Feeling excessively full after meals 7. Loss of appetite 8. Bloating (feeling like you need to loosen your clothes) 9.Stomach or belly visibly larger

11. GCSI Baseline and 8 weeks GCSI SF-36 Disability days Clinician assessment GCSI was significantly related to all 3 comparitors

12. Etiology Diabetic Idiopathic Post-surgical Other

13. Diabetic Delayed Gastric emptying DM-1 – 27-58% DM-2 – 30%

14. Etiology - Diabetic Impared antral contractions Altered intragastric distribution Prolonged liquid retention in fundus Prolonged solid food retention in both proximal and distal stomach

15. Etiology - Diabetic Neuropathic Gastric acid output reduced Vagus nerve histology shows myelin degeneration Non-neuropathic Decreased Interstitial Cells of Cajal (ICCs)

16. Etiology - Diabetic Non-neuropathic Hyperglycemia (as low as 140 mg/dL) Blounts antral contractions healthy humans In diabetics, hyperglycemia delays solid emptying that improves with euglycemia

17. Etiology - Idiopathic Not well understood Up to 25% with acute onset after viral illness Symptoms may resolve over several years No underlying neuropathy Normal pH after sham feedings Can have decreased ICCs

18. Etiology – Post-Surgical Vagotomy for ulcer disease Nissen Fundoplication Roux - en - Y gastrojejunostomy Roux stasis syndrome Spastic/retroperistaltic Roux limb contractions Esophagectomy/Gastric pull through Whipple (pylorus preserving)

19. Differential Diagnosis Chronic Intestinal Pseudo-Obstruction Scleroderma Polymyositis/dermatomyositis SLE Myotonic dystrophy/muscular dystrophy Amyloidosis Paraneoplastic Chaga’s

20. Evaluation PE Evaluate Volume Status Skin turgor, dry mucous membranes Tachycardia, orthostasis Abdominal distention, Succussion splash Clues to other etiologies Malar rash, sclerodactyly Cachexia, lymphadenopathy

21. Evaluation Lab Electrolytes Protein/albumin Glucose Thyroid/parathyroid If suspected, autoantibodies for scleroderma, SLE, polymyositis

22. Evaluation EGD or Barium study Rule out gastric outlet obstruction

23. Evaluation Gastric Emptying Scintigraphy Gold standard 99M Tc Sulfur colloid bound to solid food Traditionally lack of standard criteria between institutions T1/2 or time intervals Different diagnostic criteria determined at each institution Delay of 2 SD vs. 1.5 SD vs. 1 SD Different Meals Different patient positions

24. Evaluation Gastric Scintigraphy Tougas et al, AJG 2000 Define normal gastric emptying 123 healthy volunteers 60 female, 63 male No illnesses, surgeries, medications 102 Whites; 21 Asian, African-American, Hispanic 72 USA, 37 Canada,14 Europe Standard meal EggBeaters (equiv. to 2 large eggs) 1 mCi 99Tc labeled sulfur colloid 2 slices of bread Strawberry jam 120ml Water

25. Gastric Scintigraphy Tougas et al, AJG 2000 Images at 0, 60, 120, 240 minutes Data was not normally distributed, using SD may be unreliable Retention of >10% at 4hr (95% percentile) is abnormal

26. Gastric Scintigraphy Consensus Statement American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine Abell TL et al. AJG 2008

27. Gastric Scintigraphy Eggbeaters meal as described by Tougas et al. 0, 1, 2, 4 hr images standing 1 min anterior and 1 min posterior image Percent remaining in stomach reported 1h (37-90%) 2h (30-60%) 4h (0-10%)

28. Diagnosis Antro-Duodenal Manometry Ultrasonography Electrogastrography (EGG) 13C-breath testing

29. Therapy Dietary/Non-medical Medications Antiemetics Pro-motility Endoscopic Surgical

30. Dietary/Non-medical No evidence from controlled trials Multiple small meals Liquid instead of solid meals Low fat Reduce indigestible fiber Discontinue medications that slow emptying if possible Place jejunal feeding tube if unable to maintain nutritional needs

31. Antiemetics No evidence from controlled trials Phenothiazines Prochlorperazine Promethazine Serotonin 5-HT3 antagonists Odansetron Muscarinic antagonisits scopolamine

32. Prokinetics Metoclopramide Only FDA approved drug for gastroparesis Erythromycin Domperidone Not FDA approved in US Cisapride Removed from US market 2000 Cardiac toxicity

33. Prokinetics Data limited Small Very few RCTs Heterogeneous Etiology of gastroparesis Outcomes Symptoms or improved emptying?

34. Prokinetics Data limited Most studies lack validated symptom score Lack standardized gastric emptying study Poor long-term data Dose in erythromycin studies varies widely

35. Prokinetics Metoclopramide Substituted benzamide Promotility effect in upper GI tract 5-HT4 receptor agonist Increase LES pressure/fundic tone Increase antral contractions Dopamine receptor antagonist Weak 5-HT3 receptor antagonist

36. Prokinetics Metoclopramide Side effects – up to 30% Crosses blood-brain barrier Dizziness, drowsiness, hyperprolactinemia Dystonic reactions Facial spasm Trismus Torticollis Oculogyric crisis

37. Prokinetics Metoclopramide Perkel Dig Dis Sci 1979 n=26 Idiopathic = 19 Diabetic = 5 Post-surgical = 4 Abnormal barium “burger” test (>6hr) 3 week, double blind, placebo controlled Metoclopramide 10mg QID vs placebo QID

38. Metoclopramide Perkel Dig Dis Sci 1979 Composite symptom score – graded 0-4 1. Meal intolerance 2. Epigastric pain 3. Post-prandial bloating 4. Heartburn 5. Belching & regurgitation 6. Nausea 7. Vomiting 8. Anorexia 9. Early satiety

39. Metoclopramide Perkel Dig Dis Sci 1979 Mean Symptom Score

40. Metoclopramide McCallum RW, et al. Diabetes Care 1983 Double blind, randomized, placebo 3 weeks N = 44 All DM Metoclopramide 10mg QID vs. placebo QID

41. Metoclopramide McCallum RW, et al. Diabetes Care 1983 Symptom Score for each area graded 0-4 Fullness Nausea Vomiting Anorexia Early satiety Intolerance of meals

42. Metoclopramide Evaluated improvement in patients reporting at least moderate (2) symptoms pre-treatment

43. Metoclopramide

44. Metoclopramide

45. Metoclopramide McCallum RW, et al. Diabetes Care 1983 Adverse Effects Metoclopramide = 9 8 CNS (restlessness, drowsyness, anxiety, depression) Placebo = 4 3 CNS (drowsyness, headache)

46. Prokinetics Erythromycin Macrolide antibiotic Motilin receptor agonist Increase antral peristalsis Trigger MMC Tachyphylaxis possibly avoided by using low doses (50-100mg/d)

47. Prokinetics Erythromycin Adverse effects Skin rash Nausea Abdominal cramping Torsades de pointes Antibiotic resistance

48. Erythromycin Janssens J et al. NEJM 1990 N = 10 All DM Series of 3 radionucleotide gastric emptying studies 1. Pre-treatment 2. Initial dose of erythromycin 200mg IV at time of test 3. After 4 weeks of po erythromycin 250mg TID

49. Erythromycin Janssens J et al. NEJM 1990

50. Erythromycin Richards RD, et al. AJG 1993 N = 14 Idiopathic = 10 DM = 4 All had prior abnormal gastric emptying study Initial IV dose of erythromycin (6mg/kg) Then oral erythromycin 500mg QID May dose reduce if adverse affects 4 weeks

51. Erythromycin Richards RD, et al. AJG 1993 Gastric emptying studies at time of IV erythromycin and at completion Composite symptom score Calculated at baseline and completion 5 symptoms on a 0-10 scale At least 15 points for enrollment

52. Erythromycin Richards RD, et al. AJG 1993 Significant improvement in both on-treatment gastric emptying studies vs. pre-treatment study Significant improvement in “global score” Though the global score wasn’t defined No significant improvement in composite symptom score. Only 10 completed study several dose-reduced secondary to side effects.

53. Erythromycin Dhir R, Richter JE. J Clin Gastroenterol 2004 n = 25 DM = 2 Scleroderma = 1 Hypothyroidism = 3 Initial gastric emptying study 235 +/- 124.5 min (T1/2) Erythromycin 50-100mg TID

54. Erythromycin Dhir R, Richter JE. J Clin Gastroenterol 2004 Clinical Outcomes Worsened Unchanged Improved (but <50% improvement) Dramatically improved (>50% improvement)

55. Erythromycin Dhir R, Richter JE. J Clin Gastroenterol 2004 6-8 week follow-up 15/18 (83%) improved 12/18 (66%) with dramatic (>50%) improvement 3/18 (17%) no improvement or worsening Long term follow-up (telephone) Mean duration of use -11 months 12/18 (67%) symptom improvement 6/18 (33%) no improvement or worsening 15/18 (83%) discontinued treatment by time of contact

56. Prokinetics Domperidone Benzimidazole derivative Dopamine 2 antagonist Promotility effect in upper GI tract Not FDA approved in US Doesn’t cross blood-brain barrier Fewer central side effects Hyperprolactimemia, breast engorgement, galactorrhea

57. Prokinetics Domperidone Horowitz M et al. Dig Dis Sci 1985 Open label, 6 month follow-up N = 12 Insulin dependent diabetics Domperidone 20mg TID

58. Domperidone Horowitz M et al. Dig Dis Sci 1985 Composite score – each symptom 0-3 scale Anorexia/nausea Early satiety Epigastric fullness/upper abdominal discomfort Post-prandial vomiting Gastric emptying study Pre-treatment, 7-days after starting therapy, 35-51 days after starting therapy

59. Domperidone Horowitz M et al. Dig Dis Sci 1985 Composite score Pre-treatment - mean 4.5 Post-treatment - mean 1.5 (p<0.001) Gastric emptying study Significantly improved acutely After chronic use, solid phase emptying not significanty different than pre-treatment No adverse effects reported during study

60. Domperidone Patterson D. et al. AJG 1999 4 week, multicenter, double-blind, randomized Insulin Dependent Diabetics Domperidone 20mg QID vs. Metoclopramide 10mg QID (no placebo group) N=93 Domperidone = 48 Metoclopramide = 45 Composite symptom score – each 0-4 scale Nausea, vomiting, bloating/distention, early satiety

61. Domperidone Patterson D. et al. AJG 1999 Treatment Efficacy (composite score) Domperidone Pre treatment 8.0 +/- 0.3 End treatment 4.7 +/- 0.5 (41% reduction) Metoclopramide Pre-treatment 8.3 +/- 0.3 End treatment 5.1 +/- 0.5 (39% reduction) Effect in 2 groups not significantly different

62. Domperidone Patterson D. et al. AJG 1999 Side Effects CNS (somnolence, akathisia, anxiety, depression, mental acuity) Significantly greater with metoclopromide (~22-52%) than domperidone (15-30%)

63. Endoscopic Pyloric injection of Botulinum Toxin A Case reports and case series have reported favorable results 2 small unpublished RCTs with negative results 1 published RCT

64. BoTox Double blind, placebo, crossover N=12 (DM =2, idiopathic =10) 25u BoTox in 4 quads vs. Saline 2 EGDs 4 weeks wash-out between Symptom score and scintigraphy Before treatment 4 weeks after each above treatment

65. BoTox Scintigraphy (T1/2) Symptom score – no significant change

66. BoTox Double blind, placebo controlled, randomized, crossover N=18 (DM=8, post-nissen=10) 25u BoTox in 4 quads vs. Saline Scintigraphy and GCSI

67. BoTox Scintigraphy (t1/2) GCSI

68. Friedenberg et al. First published RCT 34 patients randomized 200 units BoTox n=16 vs. Saline n=16 1 month follow-up Primary end point – symptomatic improvement (>9 pt improvement in GCSI) Secondary end point – improvement in Gastric emptying study

70. Friedenberg et al.

71. Endoscopic Pyloric Balloon Dilation No published evidence

72. Endoscopic Venting PEG Only 1 published case series in gastroparesis 8 patients All idiopathic gastroparesis All females with “severe” symptoms 15 – 51 y/o 20f PEG placed for venting

73. Endoscopic Venting PEG Follow-up 18-41 months (mean 29) Symptomatic improvement in all patients Defined by 18 point symptom scale All patients gained weight after PEG 4-41 month duration fo PEG use

74. Endoscopic

75. Jejunal Feeding tube No controlled studies in adults

76. Surgical Gastric Electrical Stimulation High-energy/low-frequency Produces gastric contraction Entrains gastric rhythm External generator required Low-energy/High-frequency Generator small enough to be implantable doesn’t produce gastric contractions

77. Surgical Gastric Electrical Stimulation Enterra System (Medtronic) FDA Humanitarian Device Exemption Must be implanted in an institution where IRB has approved

79. Surgical Gastric Electrical Stimulation (GES) Only controlled study published N=33 12 month study, 2 phases 2 month randomized cross over double blind 1 month on then 1 month off or vice versa 10 month open label All on Remained on prokinetics/antiemetics Low-energy/high-frequency

80. Surgical Monitored parameters Vomiting frequency Composite score (total symptom score - TSS) 6 symptoms rated on 0-5 scale Gastric scintigraphy Baseline, 6mo, 12 mo SF-36 Baseline, 1mo, 2mo, 6mo, 12mo

81. GES

82. GES

83. GES Phase II Statistically significant improvement in all measured parameters Vomiting TSS Gastric scintigraphy SF-36

84. GES Complications – 5/33 (15%) required surgery 2 infected generator pockets 1 gastric perforation by lead 1 generator erosion through skin 1 pain from generator migration

85. Summary Strong data doesn’t exist Need more, larger, better designed studies GCSI Standardized gastric emptying scintigraphy

86. Summary Step-wise approach depending on severity of symptoms Dietary modification Antiemetics Prokinetics In proper clinical situations Jejunal feeding tube placement TPN

87. Summary No evidence to support Botox Pyloric balloon dilation Venting PEG Maybe future studies could identify subgroups that may benefit In the future Gastric electrical stimulation

88. References Soykan I, Sivri B, Saroseik I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 1998;43:2398–2404 Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. Arch Intern Med. 2001;161:1989–1996 Merio R, Festa A, Bergmann H, et al. Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose, and glycemic control. Diabetes Care. 1997;20:419–423. Forster J, Damjanov I, Lin Z, et al. Absence of interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointest Surg. 2005;9:102–108. Tougas G, Eaker EY, Abell TL, et al. Assessment of Gastric Emptying using a Low Fat Meal: establishment of international control values. Am J Gastroenterol. 2000;95:1456-1462. Abell TL, Camilleri M, Donohoe K, et al. Consensus Recommendations for Gastric Emptying Scintigraphy: A Joint Report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol. 2008;103:753-763. Perkel MS, Moore C, Hersh T, et al. Metoclopramide therapy in patients with delayed gastric emptying: a randomized, double-blind study. Dig Dis Sci. 1979;24:662-666. McCallum RW, Ricci DA, Rakatansky H, et al. A Mutlicenter placebo-controlled trial of oral metoclopramide in diabetic gastroparesis. Diabetes Care. 1983;6:463-467.

89. References Janssens J, Peeters TL, Vantrappen G, et al. Improvement of Gastric Emptying in Diabetic Gastroparesis by Erythromycin. Prelimanary Studies. NEJM. 1990:322;1078-1079. Richards RD, Davenport K, McCallum RW. The Treatment of Idiopathic and Diabetic Gastroparesis with Acute Intravenous and Chronic Oral Erythromycin. Am J Gastroenterol. 1993:88;203-207. Dhir R, Richter JE. Erythromycin in the Short and Long-Term Control of Dyspepsia Symptoms in Patients with Gastroparesis. J Clin Gastroenterol. 2004;38:237-242. HorowitzM, Harding PE, Chatterton BE, et al. Acute and Chronic Effects of Domperidone on Gastric Emptying in Diabetic Autonomic Neuropathy. Dig Dis Sci. 1985;30:1-9. Patterson D, Abell T, Rothstein R, et al. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol. 1999;94:1230-1234. Arts J, Caeaenepeel P, Degreef T, et al. Radomised double-blind cross-over study evaluating the effect of intrapyloric injection of botulinum toxin in gastric emptying and sypmtoms in patients with gastroparesis. Gastroenterology 2005;128:A544 Arts J, Bisschops R, Caenepeel P, et al. A placebo-controlled crossover study of intrapyloric injection of botulinum toxin in diabetic or postsurgical gastroparesis. Gastroenterology 2007;132:A779. Friedenberg et al. Botulinum Toxin A for the Treatment of Delayed Gastric Emptying. Am J Gastroenterol 2008;103:424-426 Kim et al. Venting Percutaneous gastrostomy in the treatment of refractory idiopathic gastroparesis. Gastrointest Endosc 1998;47:67-70. Abell et al. Gastric Electrical Stimulation for Medically Refractory Gastroparesis. Gastroenterology 2003;125:421-428