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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

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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

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What is constipation?

• Excessive straining

• Hard stools

• Unproductive urge

• Infrequent stools

• Feeling of incomplete evacuation

Heaton, Gut 1992;33:818

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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

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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

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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

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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

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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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Balloon expulsion

• Test not standardized

• 50-60 ml, water- filledballoon. Expulsion in <1min

• An adjunct test for the diagnosis of dyssynergia

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Simulated Defecation

Baseline sphincter pressure

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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

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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

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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

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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

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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

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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.

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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