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The American College of Osteopathic Family Physicians is accredited by the American Osteopathic Association Council to sponsor continuing medical education for osteopathic physicians.
The American College of Osteopathic Family Physicians designates the lectures and workshops for Category 1-A credits on an hour-for-hour basis, pending approval by the AOA CCME, ACOFP is not responsible for the content.
ACOFP / AOA’s 122nd Annual Osteopathic Medical Conference & Exposition
OCTOBER 7 - 10PHILADELPHIA, PENNSYLVANIA29.5 Category 1-A CME credits anticipated
OMED 17®
Joint Session with ACOFP and Cleveland Clinic: Managing Chronic Disease
Constipation and Opioid-Induced Constipation
Scott Gabbard, MD
10/5/2017
1
Constipation and OIC
Scott Gabbard, M.D.Staff, Department of GastroenterologyDigestive Disease & Surgery Institute
Assistant Professor of MedicineLerner College of Medicine
Cleveland Clinic
Agenda
• Epidemiology
• Pathogenesis
• Diagnosis/testing
• Treatment
• OIC
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Why is constipation important?
How common is this?
Physician visits due to constipation each year in the US ( most non-specialist)
US annual direct medical costs
Barucha AE et al. Gastroenterology 2013;144:218-238
8 million
>$230 million
• Prevalence: ~ 28%, Female predominance
10/5/2017
3
What is constipation?
• Excessive straining
• Hard stools
• Unproductive urge
• Infrequent stools
• Feeling of incomplete evacuation
Heaton, Gut 1992;33:818
10/5/2017
4
Why do patients get constipation?
Constipation: Etiology
• Primary: - Normal transit (IBS-C)- Defecatory disorders (pelvic floor dysfunction)- Slow transit constipation (colonic inertia)
• Secondary: Drugs, Metabolic, Hormonal, Neurological, Obstructive, Malignant, rectocele
• Almost all studies on pathophysiology emanate from tertiary centers
Barucha AE et al. Gastroenterology 2013
10/5/2017
5
Constipation: Primary Causes
• Retrospective review of >1000 patients with intractable constipation (by colonic transit and anorectal studies)
- Slow transit constipation – 11 percent
- Dysynergic defecation – 13 percent
• Combination of the two – 5 percent
- Irritable bowel syndrome/functional constipation – 71 percent
Nyam, Dis Colon Rectum 1997
Constipation – Diagnostic testing
• Labs:
- CBC, TSH, glucose, calcium, BMP
• Colonoscopy
- >age 50 (if no previous screening)
- Alarm symptoms (anemia, rectal bleeding, weight loss)
- New onset disease
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IBS - Definition
• Definition – Rome IV
- Recurrent abdominal pain (1 day/wk) in the previous 3 months, with a duration of at least 6 months
• Two or more:
• Related to defecation
• Change in frequency of stool
• Change in form of stool
• Prevalence = 12%
Lacy et al. Gastroenterology, 2016
Lacy et al. Gastroenterology, 2016
IBS-Subtypes
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IBS Treatment – Step 1
• Make a confident diagnosis!!- Use Rome IV criteria
- Give the Rome IV papers to your patient (show diagnostic criteria)
• “This is you!”• What not to do
- “We don’t know what you have”
- “It’s probably just IBS, here’s the door”
IBS Treatment – Step 2
• Patient: “Why did I get IBS?”
- “We think that many factors are at play”
• Genetics
• Inflammatory/post-infectious event
• Sensitization of the visceral nerves
• Central sensitization
- Show this figure to your patients (from NEJM 2017)
Lacy et al. NEJM, 2017
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Step 3 - ReassuranceDiagnosis 6 months–6 years after original diagnosis of IBS :
• Unchanged IBS symptoms:30–50%
• Symptom free: 12–38 %
• Worsened IBS symptoms: 2–18%
• Alternative diagnosis: 2–5%
Long term follow up
• 112 patients, mean FU 29 years
• Organic GI disease <10%, 15 yr. after diagnosis of IBS
• No impact on expected survival
El-Serag HB, et al. Aliment Pharmacol Ther. 2004
Owens DM et al. Ann Intern Med. 1995
Step 4 - Fiber
• Dietary or commercial
• Start at 4-6 g/day and increase slowly to 20-30 grams
- Soluble fiber preferred (psyllium/ispaghula husk)
• 1 tsp = 4-6g of fiber
- Prunes (6-12 BID)
- Hemp seed extract (7.5g BID)
• Bloating/flatulence/abdominal distension main side effects
• Less effective in severe constipation and pelvic floor dyssynergia
Bharucha et al. Gastroenterology 2013Lacy et al. Gastroenterology, 2016
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Prunes
• 50g prunes (12 prunes) BID vs. 2 teaspoons of psyllium BID
• Significant increase in spontaneous BMs (SBM) from baseline in both groups
• Prunes resulted in significantly increased SBMs compared to psyllium
• No difference in adverse events
Attaluri et al. APT 2011
Hemp Seed Extract
• Functional constipation
• 7.5 grams BID
• Responders
- HS = 43.3%
- Placebo 8.3%
- NNT = 2.8
• Adverse Events
- Abdominal pain/bloating (13%; 3.4% for placebo)
- Nausea (6.7% for HS and placebo)
Cheng et al, AJG. 2011
10/5/2017
10
Probiotics
• Certain strains may increase frequency, improve consistency
- Bifidobacterium lactis DN-173
- Lactobacillus casei Shirota
- Escherichia coli Nissle 1917
Lacy et al. Gastroenterology, 2016
Step 5 - Laxatives
Poorly Absorbed Ions
• Magnesium: hypermagnesemia
• Phosphate: hyperphosphatemia
Poorly Absorbed sugars
• Disaccharides (Lactulose): bloating
• Sorbitol: bloating
Polyethylene glycol: Best data for osmotic laxatives
• Increases stool frequency
• Improves stool consistency
• Does not improve pain/bloating
Barucha AE et al. Gastroenterology 2013
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Laxatives
Stimulants
• Anthraquinones (senna): melanosis coli
• Ricinoleic acid (castor oil) : cramps
• Bisacodyl: Increases frequency, but SE of pain
Emollients
• Mineral oil: fat malabsorption, anal seepage
• Stool softeners (docusate): No data
Lacy et al. Gastroenterology, 2016
Step 6 - Secretagogues
• Lubiprostone- Activates Chloride-2 channels
- Enhances GI fluid secretion
• Phase III trials
- Response rate = 17% vs. 10% for placebo
• NNT = 14- SEs = Nausea (8%),
diarrhea (6%)
• Dosing
- IBS-C: 8mcg BID
- CIC: 24mcg BID
Drossman et al. APT 2009
10/5/2017
12
Secretagogues - Linaclotide
• Linaclotide
- GC-agonist, upregulates CFTR channels
- Enhances GI fluid secretion
• Phase III data
- Response rate 33.7% vs. 13.9% for placebo
- NNT = 5- Most common SE = diarrhea
(19%)
• Dosing
- IBS-C: 290mcg daily
- CIC: 72mcg or 145mcg daily
Chey et al, AJG. 2012
Secretagogues - Plecanatide
• Plecanatide
- GC-agonist
• Phase III data
- Response rate 21% vs. 10% for placebo (durable CSBM)
- 36% weekly responder vs. 16% with placebo
- NNT 5-10- AEs: Diarrhea (6%),
sinusitis (2%)
• Dosing: 3mg daily (CIC)
Miner et al. AJG 2017
10/5/2017
13
Step ?? - Antidepressants
• SSRIs- Numerous serotonin
receptors involved in IBS
- Promote GI motility
• RCT – fluoxetine 20mg daily
- 85% symptom improvement (4.6 -> 0.7) vs. 35% with placebo (4.5 -> 2.9)
• Meta-analysis
- NNT (SSRI) = 4• Cost!!
Vahedi et al. APT. 2005
What if my patient fails laxatives?????
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Pelvic Floor Dysfunction
• Impaired rectal evacuation • Prevalence = 26%• Common symptoms
- Difficult evacuation- Excessive straining - Manual disimpaction
• Physiology:- Contraction of anal sphincter during
attempted defecation- Impaired evacuation (balloon, imaging)
Kepenekci et al. Dis Colon Rectum. 2011
Anorectal Physiology: Anorectal Angle
Lembo A, et al. N Engl J Med. 2003;349:1360
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Ano-rectal Manometry
• Detect features of dyssynergia
• Assess rectal sensation
- Hypersensitivity = IBS
• Identify candidates for biofeedback
• Hirschsprung´sdisease
Anorectal Manometry
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16
Balloon expulsion
• Test not standardized
• 50-60 ml, water- filledballoon. Expulsion in <1min
• An adjunct test for the diagnosis of dyssynergia
0
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RectalSensors
Simulated Defecation
Baseline sphincter pressure
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RectalSensors
Simulated Defecation
Balloon expulsion
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mmHg
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Sensor P
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RectalSensors
Simulated Defecation - Normal
Sphincter relaxation
10/5/2017
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0
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40
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Sensor P
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RectalSensors
10 sec
SimulatedDefecation
Dyssynergic Defecation
Balloon expulsion
No sphincter relaxation
Pelvic Floor Dysfunction - Treatment
• Biofeedback
- Biweekly 1 hour sessions
- 86% of patients with improvement in symptoms
Rao et al. Clin Gastroenterol Hepatol. 2007
10/5/2017
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Slow Transit Constipation – Colonic Inertia
• Symptoms of constipation (infrequent BM’s, hard stool), absence of systemic disorders
• Most common in young women
• Reduction of colonic nerve fibers and ICC’s
• May coexist with dyssynergia
Colon Transit - Radio-opaque Markers: Qualitative
• Single capsule, with 24 markers
• 1 capsule on day 0
• Abdominal x-ray day 5 (no laxatives)
• Normal = < 20% markers retained
Hinton et al. Gut 1969;10:842-847
10/5/2017
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Colonic Inertia - Treatment
• Laxatives
• Secretagogue
- Linaclotide, lubiprostone, plecanatide
• Colectomy
- Not for patients with
• Pelvic floor dysfunction
• Pain as predominant symptom
Opiod-Induced Constipation
• Definition
- A change from baseline bowel habits upon initiation of opioids that is characterized by any of the following symptoms:
(1) reduced bowel movement (BM) frequency
(2) development or worsening of straining to pass stool
(3) a sense of incomplete rectal evacuation
(4) harder stool consistency
• Up to 47% of patients on chronic opiates
• Highest prevalence in women and increasing age
Argoff et al, Pain Med. 2015
10/5/2017
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OIC - Diagnosis
• Bowel Function Index
- Validated scale for assessing OIC
- Mean of 3 variables
- Change of >12 points is clinically significant
- BFI > 30 should prompt consideration of prescription medication
Argoff et al, Pain Med. 2015Ueberall et al. J Int Med Res. 2011
OIC - Prevention
• Lifestyle changes
- Fiber
• Laxatives
- Senna
- Docusate
- PEG
10/5/2017
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OIC – Lubiprostone
• Lubiprostone
- 24mcg BID
- NNT = ~12- Adverse events (AEs)
• Diarrhea – 11%
• Nausea – 10%
• Vomiting – 4%
• abdominal pain – 7%
Jamal MM, et al. AJG. 2015
OIC - Methynaltrexone
• Methylnaltrexone
- Peripherally-acting μ-opioid antagonist
- SC: 8mg (up to 61kg); 12mg (>61kg)
- Every 2-3 days
- NNT = 3
- Adverse events
• Abdominal pain, nausea, vomiting similar to placebo
Thomas J, et al. NEJM. 2009
10/5/2017
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OIC - Naloxegol
• Naloxegol
- Peripheral opioid antagonist
- 25mg PO daily
• NNT = ~8
- Adverse events
• Diarrhea (3%)
• Abdominal pain (4%)
Chey et al, NEJM. 2014
OIC - Naldemedine
• Naldemedine
- Peripherally acting mu-opioid receptor antagonist
- 0.2mg PO daily
- NNT = 5
- Adverse events
• Abdominal pain (6%)
• Diarrhea (7%)
• Nausea (5%)
Hale et al. Lancet Gastroenterol Hepatol. 2017;2:555-564.
10/5/2017
24
OIC - Alvimopan
• Peripherally acting μ-opioid antagonist
• FDA approved for post-surgical ileus
- Short term use only
• Increased risk of myocardial infarction with use > 1 month
- Not FDA approved for OIC!!
Main Points - Constipation
• Diagnosis
- Most often IBS/Functional Constipation
• Make a confident diagnosis!
- Low threshold to refer patients to a center that performs anorectalmanometry
• Treatment
- Fiber
• Prunes or hemp seed extract may be preferred to psyllium
- Laxatives
- Secretagogues
- Antidepressants
- PT/Biofeedback