Medical Therapy of GI Motility Disorders

1
Medical Therapy of GI Motility Disorders

• Joel M. Wittles, MDAssociate Professor of
  Clinical Medicine
• Department of MedicineDivision of
  Gastroenterology
• Indiana University School of Medicine

2
Medical Therapy of GI Motility Disorders

• Gastroparesis
• Functional Dyspepsia
• Rapid Gastric Emptying
• Irritable Bowel Syndrome
• Cyclic vomiting
• Functional nausea, emesis

3
Goal Evidence Based Medicine

• Limitations of the studies that form the basis of
  therapy of GI motility disorders
• Few symptoms ? multiple pathogenesis
• e.g. bloat
• Limited number of drugs, modalities
• Side effects
• Variable responses
• Studies sub optimal
• uncontrolled placebo effect
• Small number of patients, short duration
• Mixed populations e.g. FD GERD
• Meta analyses limitations
• Opposing effects e.g. tricyclics for gp ? ? ge

Gp FD IBS
Rapid ge Slow ge dysaccommodation
4
Limitations of studies (cont)

• Limited availability of tests to define
  abnormalities in motility, several available,
  many not proven to alter patient care e.g. EGG,
  accommodation tests (limited proven RXs)
• University or complex patients skew results,
  different population
• Limited understanding
• interplay end target
• ENS (enteric nervous system)
• CNS
• Recommendations often by consensus

5
Strategy Goals of Therapy

• Relieve symptoms
• Improve QOL minimize side effects
• Temper treatment based on symptom severity
• Multiple levels of interaction lead to symptoms
• Lots of Overlap- eg gastroparesis, functional
  dyp.
• Only limited repertoire of medical treatments
• Multifaceted, team approach for complex cases
• How can we best help our patients with what is
  available

6
FGID Conceptual Model

• Depression
• Anxiety
• Somatization
• Catastrophizing
• Not required

• Early Life
• Genetics
• Environment
• History of abuse

• Psychosocial
• Factors
• Life stress
• Psychological state
• Coping
• Social support

Behavioral Rx
Central Filter-amplification-suppression
Brain Gut CNS ENS

• Physiology
• Motility
• Sensation
• Inflammation
• Altered bacterial

• Outcome
• Medications
• MD visits
• Daily function
• Quality of life

• FGID
• Symptoms
• Behavior

Levy, Drossman et al Gastro 20061301447-58 Dross
man Gastro 2006 1301377-90
7
Gastroparesis

• Chronic condition with delayed gastric emptying
  of solids in the absence of mechanical
  obstruction symptoms. Gastric pump failure
• Primary symptoms 3
  groups
  
• nausea 92.
• post prandial emesis 84 N/V
• early satiety 60
  Dyspeptic
• bloating 75
  Reflux
• abdominal pressure
• pain 46-89

8
(Diagram etiology)
Dig Dis Sci 43(11) Nov 1998. Soykan, McCallum et
al.
9
Pathophysiology

• CNS N/V center, psychological factors, signal
  processing
• ENS abnormal antral duodenal coordination, ?
  gut sensitivity fat, acid
• Sensory abnormal accommodation
• abnormal sensation (hypersensitivity)
• vagal nerve damage
• Electrical slow wave pacemaker disorder/
  propagation defects, (ICCs)
• Myopathic hypo motility
• pylorospasm
• Other factors contribute to symptoms visceral
  hyperalgesia
• bacterial OG

10
Diagnosis Scintigraphy- global measure of pump
function- transit

• Update since study 2000- a standardized exam
• Johns Hopkins study follow up of the Tougas
  protocol
• Confirms benefit of 4 hour study
• Normal 1 20 abnormal at 4
• Abnormal 1 22 normal at 4
• Normal 2 13 abnormal at 4
• Abnormal 2 24 normal at 4

Ziessman, et al. J of Nuclear Med V48 4 April
2007568-72
11

• Standardization of nuclear medicine gastric
  emptying test.
• AJG 2000 95(6) 1456. updated AJG
  2008103753-63- position paper
• Low fat egg substitute based
• Results reported retained. ANMS and
  SNM
• 95th percentile for abnormality
• Time Median 95th percentile
• 60 --
  lt30
• 120 24 gt60
• 240 1.2 gt10
• Utilized retained as measure rather than
  calculated t1/2
• Note poor correlation severity of symptoms and
  degree of gastric stasis, no outcomes analysis,
  day to day variability, influence on patient
  management questioned (Gut 199334916-9).

12
Optimize Results of GE Scintigraphy

• 8o fast, off TPN 12
• Euglycemia in diabetics
• check sugar prior to test and record in
  report, consider cancel lt 75, gt 275.
• Medications Hold 48
• Consider outpatient test
• avoid in hospital multiple medications
• severity of illness

13
Medications that alter GI Motility and Transit
Tests

• Delay
• Anticholinergics
• Tricyclic antidepressants
• Narcotic analgesics
• Phenothiazines (5HT-3
  antagonists ok)
• Adrenergic agents
• Tetrahydrocannabinol
• Others Lithium, L-dopa, ETOH, Omeprazole, Al OH3
  Antacids, Calcitonin, progesterone, tobacco, ca
  channel blockers, clonidine, exantide(Byetta)
• Accelerate
• Prokinetics
• DC meds that affect ge study 48

14
General Principles of Treatment

• Treatment diet prokinetics antiemetics
• Diabetics optimize treatment,
• Hyperglycemia ? gastric motor abnormalities
• Role of antidepressants symptom and or pain
  relief
• Ancillary measures Chinese herbs, ginger,
  acupuncture (J Trad Chin Med 2004241633-5

15
Proposed classification of gastroparesis severity
Grade 1 Mild gastroparesis Symptoms
relatively easily controlled Able to maintain
weight and nutrition on a regular diet or
minor dietary modifications Grade 2 Compensated
gastroparesis Moderate symptoms with partial
control with pharmacological agents Able
to maintain nutrition with dietary and lifestyle
adjustments Rare hospital admissions Grade
3 Gastroparesis with gastric failure
Refractory symptoms despite medical therapy
Inability to maintain nutrition via oral route
Frequent emergency room visits or hospitalizations
The American Motility Society Task Force on
Gastroparesis Neurogastenterol Motil (2007) 18,
273-83
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Nutrition

• Low fat, low residue, more frequent and smaller
  meals
• Liquid supplements for Kcal 0-6gm fat, (avoid
  diabetic supplements 2o high fat- 12-13gm) Low
  fat30-45gm very low25
• Feeding jejunostomy ideal, g-tube
  difficulty GES
• TPN- rarely needed long term, jejunum normally
  functional
• Methodist nutritionists-free service, 962-8341
  Laura Dean, Sonia Jurado http//www.healthsystem.v
  irginia.edu/internet/digestive-health/nutrition/ga
  stroparesis-diet.pdf Caroll Parrish RD, MS

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Criteria for enteral nutrition

• Severe weight loss gt5-10 usual body wt. over
  3-6mo. unresponsive dietary adjustments
• Repeated hospitalizations for IV/med Rx
• Inability to meet goals set by physician,
  dietician, and patient

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Criteria for enteral nutrition

• Severe weight loss gt5-10 usual body wt. over
  3-6mo. unresponsive dietary adjustments
• Repeated hospitalizations for IV/med Rx
• Inability to meet goals set by physician,
  dietician, and patient

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Metoclopramide

• Prokinetic Antiemetic
• Prokinetic effect ? over time unlike antiemetic
  effect
• D2 5HT3 antagonist, 5HT4 agonist
• Several studies all short term symptom
  improvement and gastric emptying increase
  compared to placebo.
• CNS SE up to 40
• Poor correlation gastric emptying and symptom
  changes.

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Metoclopramide

• Dose range 5 20 mg IV or po ac hs, reduce
  as able.
• Liquid form always preferred
• Drowsiness, fatigue, restlessness,
  irritability, intolerance doses gt
  10-15 mg
• Dystonia
• Tardive Dyskinesia 1 10, minimum use 3
  months
• Document this discussion in the chart for
  patients on chronic therapy.

21
Domperidone

• Prokinetic, antiemetic
• D2 Rec. antagonist, doesnt cross BBB.
• Increased solid and liquid emptying.
• Largest study 260 patients 1998, 80 responders
  (gt 30 symptom reduction)
• Vs Metoclopramide equally effective, ? side
  effects AJG, 1999
• Increased prolactin (same as MCP)
• Can be used in Parkinson's Disease
• Check QT interval baseline, serum K, repeat
  yearly

22
Domperidone

• Dosage
• start 10 mg ac hs x 3days, then ? 20 mg, max
  120mg/day
• need 1 month to assess
• No IV form rare reports fatal cardiac
  arrhythmia
• Need IRB OK for institution, IND (Investigational
  New Drug), approval FDA to prescribe
• FDA 2004 No Compounding.
• Available internet from other countries, e.g.,
  Canada, New Zealand

Reddymasu, et al. AJG 20071022036-45
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Erythromycin

• Most potent prokinetic acutely- useful IV
• Motilin agonist - induces phase III MMCs ?
  antralduod contractions.
• IV and oral forms improve emptying
• Reviewed ? symptomatic relief AJG (2003) 98,
  259-263
• Examined 35 trials, only 5 using symptoms as
  end point
• DM, idiopathic, post surgical, PSS
• Overall gt 25 improvement symptoms in 48 of
  patients.
• Problem outlined with these studies open
  label, small size, treatment lt 4 weeks. Authors
  conclude all weak, subject to bias.

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Erythromycin

• Dosage lower dosages recommended
• tachyphylaxis down regulation of the motilin
  receptor 3 weeks on, 1 week off proposed
• Range 50-250 mg 2-4 x daily. Trial 2 weeks
• Liquid syrup form absorbed better
• Side effects abdominal cramp and nausea,
  antibiotic effects. ? accommodation
• Use with MCP ? No data
• Important precaution increase in sudden
  cardiac death, 2 fold
• Concurrent use with strong inhibitors CYP3A
  enymes should be avoided
• e.g. calcium channel blockers, verapamil,
  diltiazem (NEJM 20046511089)

25
Other prokinetics

• Cisapride- consensus risk not outweigh benefit
• Tegaserod- FDA restricted only emergency IND

26
Antiemetics
No studies specifically for gastroparesis Class
of agent Examples Dopamine D2-receptor
antagonists With prokinetic activity
Metoclopramide, domperidone Without prokinetic
activity Prochlorperazine,
trimethobenzamide, thiethylperazine Seroton
in 5-HT3-receptor Ondansetron, granisetron,
dolasetron, antagonists tropisetron
Tricyclic antidepressants Desipramine,
nortriptyline, amitriptyline Muscarinic
M1-receptor antagonists Scopolamine,
hyoscyamine, clinidium Histamine H1-receptor
antagonists Dimenhydrinate, meclizine,
Promethazine Cannabinoids
Tetrahydrocannabinol as Dronabinol Benzodiazepine
s Lorazepam Neurokinin NK1-receptor
antagonists Aprepitant The H1, D2 and M1
receptor antagonists have overlap. The
classification reflects the predominant activity.
Neurogastroenterol Motil (2006) 18, 269
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Common Antiemetics

• Prochlorperazine
• Trimethobenzamide
• Ondansetron
• Scopolamine
• Dimenhydrinate
• Meclizine
• Promethazine
• Tetrahydrocannabinol

28
Tricylics in DM with NV
Sawhney, Clouse, et al. Dig Dis Sci
200752418-24 Possible role - ?
anxiety/depression Type 1 2 DM -
Benefit in FGID in non diabetics/includes funct.
emesis - Multivariate analysis
stronger predictor UGI c/o
Clouse, et al 1989 AJG84868-72 Retrosepctive
review - 24 pt, unsatisfactory
response prokinetics, 7 ? gastr emptying


- Likert scale of improvement
- 42 CVS
type symptoms/ 58 persistent - 38
anxiety or depression (no RX listed) (Diabetic
Gastropathy Talley, AJG 200398264-71-exellent
review)
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Results - Moderate response 88 - Near
resolution 33 - Most effective therapy 68
- Response not related to gastric emptying time
or psychological dx - Side effects 46,
discontinued lt 20 - CVS type less
benefit SUM Retrospective open label,
chart review study role TCA DM chronic
N/V refractory conventional therapy.
Psychological dx not required for response
30
Medications Dosages Used

• Amitriptyline, Nortriptyline, Desimpramine
• Median dose 50 mg day (10-75 mg)
• Starting dose 10-25 mg/d
• Minimize side effects
• Start low dose
• Change dose
• Alternate TCA
• Secondary vs tertiary amines

31
Mirtazapine (Remeron) DM GastroparesisKim et
al. Psychosomatics 45, Sept-Oct 2006

• 1 Case report
• 27 yo F DM, abn ge study, depression. 6
  hospitalizations over 4 months, failed
  Metoclopramide, Erythro, Domperidone, Botulinum
  toxin
• 15 mg/d orally disintegrating tablet
• Marked ?symptoms x 3 months

32
Mirtazapine Drug has 5HT3 antagonist
effect Reports of results N/V in hyperemesis
cancer chemotherapy
gastric
bypass Potential use patients with poorly
responsive, intractable nausea/emesis when
considering an antidepressant. -
gastroparesis - functional dyspepsia -
functional N/V Note SSRI/SNRI common SE
nausea
33
Botulinum Toxin for Gastroparesis
2 Abstracts last year Gastro PC trials -
Arts, et al - Parkman, et al 1 Published
Parkman AJG 2008 103417-23 Open label
trials to date Conclusion Injection 200U ? ge
1 mo Not superior to placebo Symptom
improvement Not superior to placebo Sum
further studies needed before can advocate use
for gastroparesis
34
The Gastric Electrical Stimulator

• What is currently known about its efficacy?
• What patients are candidates?
• What are the complications?
• How is it done?
• How Does It Work?

35
Take Home Points of GES

• Primary Benefit Strong Anti-emetic
• Modest, inconsistent effect on gastric emptying
• Other symptoms seen with gp (early satiety,
  fullness, anorexia, pain) no predictable response

36
The Initial StudiesPatient selection

• gt 7 episodes emesis/week
• Delay gastric emptying gt 60 2, gt 10 4
• Symptoms gastroparesis gt 12 months
• Refractory or intolerant, 2/3 classes prokinetics
  and antiemetics
• Diabetic or Idiopathic

37
WAVES Study With a randomized crossover phase
33 patients, Multicenter, Female 24 DM-17
Idiopathic 16 Phase 1 - 1 mo. on, 1 mo. Off
post implantation. Phase 2 - on x 10
months Measured - vomiting frequency Preferen
ce on/off TSS 0-4, N,V, early satiety,
bloating, post prandial bloating, epigastric
pain HQOL Gastric emptying Adverse events
38
Results

• Phase 1
• Decrease Vf, Mean ? 50 p lt .05
• Preference for GES on 21 vs. 7, (NP5) p lt .05
  
• Phase 2
• 6 and 12 months ?Vf, TSS, ?QOL p lt .05
• Gastric emptying modest increase
• 5 device removed due to complications
• However

39

• When analyze phase 1 by subgroups
• No significant difference vomiting for either
  (trend for each p.16)
• No significant difference DM on or off p.08
• As a result of the somewhat disappointing results
  in the randomized portion of the study, FDA
  approval was limited and remains so at present.

40
Humanitarian Use Device HUD ? 1999 Device 4000
patients/year rare disorder Safe/Probable benefit
to patient outweighs risk of injury and/or
illness from its use Requires IRB approval 3035
since 2001/ 685 last 1 year/ new RC data in DM
Humanitarian Device Exemption HDE ?
2000 Authorizes marketing of a HUD Applied for by
maker of device
41
Summary of open label studies to date

• Improvements reported in
• TSS - BMI - Weight gain
• QOL
• HbAIC
• Decreased need JTube/TPN
• Decreased prokinetic medication
• Decreased hospital days
• Benefits for post surgical etiologies

42
GES vs Intensive Medical Therapy
Patients 16 Medical Versus GES over 3
years Measure Symptoms, HRU, Hospital
Costs Concluded GES more effective ?symptoms,
reducing costs, and decreasing utilization of
health care resources.
Neurogastroenterology Motil 20051735
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Candidates for GES
Best candidates DM
Note Benefit can take
months No narcotics
May need adjust power Absence of
diffuse motility disorder Failed antiemetic
prokinetic therapy Not a candidate Severe
psychiatric disorder/eating disorder CVS Ruminat
ion Negative factors Chronic
pain, esp. chronic abdominal pain
Idiopathic etiology Lin, McCallum et al,
Gastro 20061304supp2A-601
46
Complications

• Infection, irrigate site Ab periop use? ?
  infection
• Overall 4-5 implanted devices removed
• Pain, migration of pulse generator, erosion site
• Loss of function, communication with device
• Detachment or penetration of electrodes
• Volvulus 1 case, obstruction 2o to wires

47
Current studies involving the GES

• Temporary stimulator placed PEG or EGD
• Dr. Abells group
• Functional N/V- abstract
• CIIP- abstract

48
Guides to TherapyConsensus- not published
Mirtazapine Nausea 5HT3 antagonist
Depression Duloxetine Anxiety, depression
Pain Bloating 24/d nausea TCA If
need pain med, Tramadol TCA,
duloxetine, other pain modulators
Methadone addiction, but less effect gastric
motility Fentanyl
patch Control glucose level , Insulin pump
personal rec Dr. Abell, before GES