Management of chronic idiopathic constipation

1. Demystifying the spectrum of Constipation Disorder:
What's new in the Medical Management

2. Definition of constipation
According to the Rome IV criteria for constipation-
A patient must have experienced at least two of the following
criteria over the preceding 3 months:
 Fewer than three spontaneous bowel movements per week
 Straining
 Lumpy or hard stools
 Sensation of anorectal obstruction or blockage
 Sensation of incomplete defecation
 Manual maneuvering required to defecate
For at least 25% of
defecation attempts
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114

3. of global population suffers from
Chronic Constipation
28%
In Bangladesh, the prevalence is
11.8%
2-3 times more common
in women
Epidemiology
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114

4. 40%
35%
23%
2%
IBS-D
IBS-C
IBS-M
IBS-U
The Burden of CIC
Almost 85% of physician visit
for constipation results in a
prescription for laxative
Adults over the age of 35
years has a higher
prevalence(84%)
35% of IBS patients are
suffering from IBS-C subtype
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114

5. Type I-II
is constipation predominant
stool.
But , for Asian countries Type III
is also considered constipation
defining stool.
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome
Foundation Global Study, Gastroenterology 2021;160:99–114

6. ROME IV
Classification
Constipation
Functional
Constipation
Opioid induced
constipation
IBS-C
Evacuation disorder
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study, Gastroenterology 2021;160:99–114

7. Irritable bowel syndrome (IBS)
Irritable bowel syndrome (IBS) is a chronic, often debilitating, and highly
prevalent disorder of gut-brain interaction.
Rome IV diagnostic criteria for irritable bowel syndrome-
• Recurrent abdominal pain on average at least 1 day/week in the last 3
months, associated with 2 or more of the following criteria-
• Related to defecation.
• Associated with a change in the frequency of stool.
• Associated with a change in the form (appearance) of stool.
These criteria should be fulfilled for the last 3 months with symptoms onset at
least 6 months before diagnosis.
Ref:
1. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study,
Gastroenterology 2021;160:99–114

8. Difference between CIC & IBS-C
Traits CIC IBS-C
Cause Idiopathic or
secondary causes
Altered GI motility,
GI hypersensitivity,
Psychosocial factors.
Primary symptom Constipation Abdominal pain
Secondary symptom Abdominal pain,
bloating, itching,
bleeding
Constipation,
bloating

9. Overlapping between CIC And IBS-C
• According to Rome IV definition, IBS-C patients are more likely to predominantly have
abdominal pain in comparison with CIC patients.
• But in (real-world) clinical practice was found that approximately 90% of patients
with IBS-C also met criteria for CC and 44% of the CC patients also met criteria for
IBS-C.
• In approximately 1/3rd of patients, symptoms shift over time between FC and IBS-C.
• So, sometimes it is difficult to distinguish between IBS-C & CIC and determine the
appropriate therapy.

10. Diagnosis
Red flags

11. History
Taking
Alarm
features
 ROME IV criteria
 Stool consistency
( Bristol Stool form scale)
 H/O Laxative use
 Secondary causes
 Change in stool caliber
 Heme-positive stool
 Iron-deficiency anemia
 Obstructive symptoms
 Patients > 50 years with no
previous colon cancer
screening
 Recent onset of constipation
 Rectal bleeding
 Rectal prolapse
 Weight loss

12. Physical
examinations
Investigations
 Gastrointestinal mass &
lymphadenopathy
 Anorectal inspection by
DRE
- Fecal impaction
- Rectal mass
- Stricture
- Prolapse
- Rectocele
 Blood tests
 Colonoscopy & sigmoidoscopy
 Anorectal Manometry
 Balloon expulsion test
 Colonic transit study
 Defecography

13. Treatment options for Constipation
Bulk forming
laxative
Osmotic
Laxative
Stimulant
Laxative
Lubricants/Stool
softeners
Increasing the
"bulk" or weight of
stool, which in
turn stimulates
your bowel.
Osmotic laxatives
draw water from
the rest of the
body into bowel to
soften stool and
make it easier to
pass.
stimulate the gut
muscles helping
the stool to pass.
Works by reducing
surface tension
between lipid and
water
interface.(check the
language)
Ex- Psyllium Ex- Lactulose,
polyethylene glycol
Ex- Bisacodyl ,
senna ,
sodium picosulfate
Docusate
Laxatives

14. CLC-2 agonist GC-C agonist 5HT4-agonist
Activation of CLC-2
channel increases
intestinal secretion and
peristalsis.
Activation of GC-C
receptors, increases
intestinal fluid secretion &
peristalsis, reduces
activation of visceral
pain sensitive neurons.
Increases secretion of
fluid in intestines and
speed up the rate at
which food passes
through the colon.
Lubiprostone Linaclotide Prucalopride
Non- Laxatives/

15. Challenges in treatment of
Constipation
Association of multiple
pathophysiology
makes the treatment
approach difficult.
Requires Multiple
drugs to alleviate
individual symptom.
Altered
GUT
Motility
Altered
GUT
Sensitivity
Altered brain
gut axis
Multiple
symptoms
Constipation
Abdominal pain
Bloating
Distension
Repeated & long-term
use of Laxatives
causes adverse effects
& makes the intestine
insensitive
Lack of patient
compliances &
hampers the
quality of life.

16. Linaclotide
A novel therapy for constipation
A single intervention to treat-
 Constipation
 Abdominal pain
 Bloating/Distension
Reduces disease burden,
Improves quality of life

17. Linaclotide binds to guanylate cyclase-C (GC-C) act
locally on the luminal surface of the intestinal
epithelium(Luminally acting agent)
Both intracellular and extracellular concentrations
of cyclic guanosine monophosphate (cGMP) rises
Elevation in intracellular cGMP stimulates secretion
of chloride and bicarbonate into the intestinal
lumen, resulting inincreased intestinal fluid and
accelerated transit.
Linaclotide has been also shown to reduces
activationof visceral nociceptive neurons and
reduce intestinal pain.
Mechanism
of
action

18. Linaclotide was also evaluated in 3 CIC clinical trials of more
than 2400 patients.
Results: Patients had increased no of CSBMs, greater improvements
in stool consistency & straining over the treatment period.
Linaclotide Placebo
Therapeutic efficacy Trials of Linaclotide in CIC

19. Therapeutic efficacy Trials of
Linaclotide in IBS-C
Linaclotide was evaluated in 2 IBS-C clinical trials of more than 1600 patients. Trials evaluated
abdominal pain responders, CSBM(Complete spontaneous bowel movements) responders, and
combined responders.
Study population
Linaclotide
group
Placebo
Group
Trial 1 405 395
Trial 2 401 403

20. Complete Spontaneous Bowel Movements
responders
0
5
10
15
20
25
Trial 1 Trial 2
6 out of 12 weeks
Linaclotide Placebo
0
10
20
30
40
50
60
Trial 1 Trial 2
9 out of 12 weeks
Linaclotide Placebo
Reference:
1.LINZESS (linaclotide) [prescribing information]. Madison, NJ: AbbVie Inc.; 2018.
2.Data on file. Forest Laboratories, LLC.
Early response Sustained response

21. Abdominal pain responders
0
5
10
15
20
25
30
35
40
45
Trial 1 Trial 2
6 out of 12 weeks
Linaclotide Placebo
0
10
20
30
40
50
60
Trial 1 Trial 2
9 out of 12 weeks
Linaclotide Placebo
Patients had significant improvement in both abdominal pain and frequency
of CSBMs.
Reference:
1.LINZESS (linaclotide) [prescribing information]. Madison, NJ: AbbVie Inc.; 2018.
2.Data on file. Forest Laboratories, LLC.

22. Combined responders
0
2
4
6
8
10
12
14
Trial 1 Trial 2
6 out of 12 weeks
Linaclotide Placebo
0
5
10
15
20
25
30
35
40
Trial 1 Trial 2
9 out of 12 weeks
Linaclotide Placebo
Significant responder rates in abdominal pain and in CSBMs vs placebo.
Reference:
1.LINZESS (linaclotide) [prescribing information]. Madison, NJ: AbbVie Inc.; 2018.
2.Data on file. Forest Laboratories, LLC.

23. Mean abdominal pain score & percent reduction
0
1
2
3
4
5
6
Trial 1 Trial 2
Baseline
Linaclotide Placebo
0
1
2
3
4
5
6
Trial 1 Trial 2
At week 12
Linaclotide Placebo
Relief from abdominal pain was maintained in Linaclotide group over the treatment period.
-44% -30% -46% -27%

24. Improvement in overall abdominal symptoms was observed
at Week 1 and continued to improve through 12 weeks
34% of patients in the
Linaclotide arm experienced
a clinically meaningful
reduction in overall
abdominal symptoms vs
18.5% in the placebo arm.

25. Comparison between laxatives & Linaclotide
in the treatment of Constipation
Traits Laxatives Linaclotide
Benefit Relieves only constipation. Relieves the entire symptoms complex
as constipation, abdominal pain,
bloating etc.
Role in IBS-C Low efficacy, so not
recommended except for
bulk forming agents( soluble
fibers)
High efficacy, so strongly
recommended by all the renowned
guidelines.
Effect on visceral
hypersensitivity
Poor, so no effect on pain
relief.
Reduce visceral hypersensitivity, thus
relieves abdominal pain and bloating.
Adverse effects Long term uses result in
dehydration, electrolyte
imbalance, persistent
bloating & abdominal
cramps, colonic insensitivity.
Insignificant systemic absorption (
<1%). So, less chances of adverse
effects. Occasional diarrhea is the
commonest adverse effects.

26. Traits Linaclotide Lubiprostone
Therapeutic group Guanylate cyclase
activators
Chloride channel
activators
Mechanism of action Activation of GC-C
receptors, increases
intestinal fluid secretion
& peristalsis, reduces
activation of
visceral nociceptive
neurons.
Activation of CLC-2
channel increases
intestinal secretion and
peristalsis.
Therapeutic response Quick & sustained Delayed & improves
over time.
Dosing Once daily Twice daily
Most common AE Diarrhea(discontinuation
rate is very low)
Nausea(dose
dependent)
Quality of evidence
In favor
High Moderate
Recommendation quality Strongly recommended
by all the guidelines.
Recommended/
suggested
Therapeutic
benefits of Linaclotide
over Lubiprostone

27. Adverse Effects
Linaclotide may cause diarrhea as its most frequent side effect, but has a very low risk of
major systemic adverse responses due to its local action in the intestinal lumen and low
bioavailability(less than 1%).

28. Most of the renowned guidelines has recommended Linaclotide as a novel
& effective therapy for CIC and IBS-C with quotation of strong quality of
evidences .

29. In clinical practice, Chronic Idiopathic Constipation(CIC) and IBS- C
symptoms may overlap and require individual drugs for individual
symptom.
But in both cases the entire symptom complex can be treated by a single
solution.
It has high efficacy and excellent tolerability.
The ultimate therapy for constipation
Linaclotide
CONCLUSION