Refractory Constipation

Jack A. Di Palma, MD, FACG

University of South Alabama
Mobile, Alabama

Prescription Products
Lactulose
Synthetic disaccharide
Metabolized by bacteria
Increased volume,
frequency

Lubiprostone
Bicyclic fatty acid PG E1
derivative
Chloride 2 channel
activator
Cl ion enters, Na and
water follows
Increased motility and
frequency

Prescription Products
Additional agents- Diarrhea side effects
Colchicine
Misoprostol
Discontinued agents
Tegarerod
Cisapride
Promising agents in development
Linaclotide
Prucalopride
Alvimopan

REFRACTORY

Refractory Constipation
Severe
Dissatisfied
Ineffective
Multiple symptoms
Lack of predictability
Ineffective against bloating
of surveyed
40% of Medicare patients have chronic
constipation

Criteria for Severe or Refractory

Peng, WJG 2006

1. Difficult defecation for a year

2. Frequency <3 times a week for >3 months
3. Difficult defecation accompanied by
abdominal pain and distension
4. Digital exam showing stenosis, hemorrhoids
and rectal prolapse
5. Slow transit, rectocele and long-winded
sigmoid colon

DISCLOSURE
Lecture Honoraria
Takeda, Braintree Laboratories
Advisory Boards
Takeda, Ironwood, Braintree
Consultant Directorship
Braintree Labs
Research Support
Braintree Labs, Takeda

Typical Approach
Increase dose
PEG 3350 data on up to 84g
Lubiprostone to 48mcg/d limited by nausea
Combinations (layering of products)
Rescue
MOM, bisacodyl, PEG 3350, senna

 A 65-year-old man has rectal pain with

defecation
Chronic constipation -infrequent bowel
movements and difficulty in passage
ASHD- furosemide, calcium channel blocker
Parkinsons disease- anti-Parkinsonian meds
Which intervention has FDA approval for
non-narcotic medication constipation?
A. Methylnaltrexone
B. Lubiprostone
C. Linaclotide
D. PEG 3305
E. None

Medications
PDR lists over 900 drugs to cause
constipation;
Over 100 more than 3%
40% screened subjects meeting Rome II
criteria used constipating medications
Adeniji 2001, Rutland 2004

PEG 3350 Constipating Medications

Di Palma, Am J Gastroenterol 2000

Design:
Randomized, placebo-controlled, multicenter,
parallel trial
Study subjects:
100 with ROME criteria and constipating medication
Results:
Relief of ROME:
PEG 78.3%, control 39.1%, p<0.001
Effective by patient and investigator
Similar findings in elderly
No adverse experiences or abnormal lab

Methylnaltrexone
Thomas, N Engl J Med 2008

Peripherally-acting mu-opioid antagonist

Reverses the constipation and post-operative
side-effects of opioid drugs
Without affecting analgesia or precipitating
withdrawal

Lubiprostone
Takeda/ Sucampo Pharmaceuticals

Conflicting data on success in medication

constipation
Methadone but not morphine inhibits
stimulation of chloride-2 channel
Several studies in progress for narcotic
constipation and non-narcotic medication
constipation

A 65-year-old man has rectal pain with

defecation
Chronic constipation -infrequent bowel
movements and difficulty in passage
ASHD- furosemide, calcium channel blocker
Parkinsons disease -anti-Parkinsonian meds
Which intervention has FDA approval for
non-narcotic medication constipation?
A. Methylnaltrexone
B. Lubiprostone
C. Linaclotide
D. PEG 3305
E. None

 A 23-year-old-patient with significant

discomfort from chronic constipation
finds that she is pregnant
Which of the following laxatives
is/are acceptable?
A. Misoprostol
B. Methylcellulose
C. Colchicine
D. Saline osmotic laxatives such as
magnesium or phosphates
E. Castor oil

Issues in Pregnancy

Saline laxatives Stimulate uterine contractions

Misoprostol Contraindicated (Category X)
Colchicine Should not be used (Category D)
Sodium phosphate Fluid overload and electrolyte
disturbances
Castor oil Premature labor, rupture (Category X)
Lubiprostone Fetal loss in experimental animals
(Category C)
Mineral oil Hypoprothrombinemia, neonatal
bleeding (Category C)

Ob/GYN Advised Products

Magnesium citrate Hypermagnesemia,
hyperphosphatemia (Category B)
Senna Low risk short term (Category C); excreted
in breast milk
Bisacodyl Low risk short term use (Category C)
PEG 3350 Inert, minimal absorption (Category C)
Sorbitol, lactulose Not absorbed (Category B)
Methylnaltrexone (Category B)
Fiber, methylcellulose

 A 23-year-old-patient with significant

discomfort from chronic constipation
finds that she is pregnant
Which of the following laxatives
is/are acceptable?
A. Misoprostol
B. Methylcellulose
C. Colchicine
D. Saline osmotic laxatives such as
magnesium or phosphates
E. Castor oil

Bristol Stool Scale

Colon (Sitz) Marker

Evacuated

Inertia

Obstructed
Defecation

Colonic inertia
Effective in some
PEG 3350
Lubiprostone
Combination therapy
Generally ineffective
Metoclopramide
Erythromycin
Cholinergics
Colchicine
A. Wald

The accompanying photograph is taken

from a colonoscopy in a 35-year-old
woman who has been taking senna
laxatives daily for several years
Proper management advice would be to:
A. Discontinue senna
B. Continue senna without regard to the
finding
C. Recommend annual dysplasia
screening biopsies
D. Reduce senna dose to weekly
administration
E. Add cascara sagrada

Melanosis coli

Marker of anthraquinone laxative use

Brown pigment, lipofuscin, in macrophages
No correlation with disease
No enteric injury
No indication to discontinue or screen for
dysplasia

 The accompanying photograph is taken

from a colonoscopy in a 35-year-old
woman who has been taking senna
laxatives daily for several years
Proper management advice would be to:
A. Discontinue senna
B. Continue senna without regard to the
finding
C. Recommend annual dysplasia
screening biopsies
D. Reduce senna dose to weekly
administration
E. Add cascara sagrada

Clues to Pelvic Floor Dysfunction

Prolonged and excessive straining, even with
soft stool
Dyschezia
Digital manipulation: Need for vaginal or
perineal pressure to pass a bowel movement
Failure to respond to standard laxative
treatment

Biofeedback is superior to laxatives for

dyssynergia
Chiaroni, Gastroenterology 2006

6m treatment outcomes:

Long-term Efficacy of Biofeedback

Rao, Am J Gastroenterol 2010

Design:
Prospective, 1y, randomized, controlled trial
Methods:
Stool diaries, visual analog scales, transit,
anorectal manometry and balloon expulsion
Results:
Biofeedback subjects had increased CSBMs,
normalized dyssynergy and transit

Megacolon

Megacolon
At risk
Children with retentive soiling
Institutionalized elderly
Psychotic disorders
Neurologic disorders, Parkinsons
Chagas
Treatment
Low fiber
Water enemas
PEG 3350
Surgery

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Surgical Indications for Megacolon

Intractable and disabling symptoms

Colonic inertia
No pseudo-obstruction
Normal anorectal function

Chronic Fecal Retention

Hard stool
Voluntary stool withholding
Painful defecation
Encopresis
Overflow incontinence

Chronic Fecal Retention

Medications
Polypharmacy
Constipation
Fecaloma
Incontinence
Overflow?

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The Young and the Old

Treatment Approach
1. Education and behavior modification
2. Evacuation and disimpaction
Enemas, magnesium citrate, gut lavage
washout, PEG 3350
3. A regular regimen
Saline laxatives, lactulose, fiber,
PEG 3350

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