CHRONIC Western management perspective 2015

J. TACK, M.D., Ph.D. TARGID University of Leuven Leuven, Belgium

www.targid.eu CHRONIC CONSTIPATION Epidemiology in Europe

Epidemiology of constipation in Europe in the general population1 • The mean European prevalence is 17.1%1 Sweden SR (female) (n=1,610) 19.8 – Median 16.6% Sweden SR (male) (n=1,610) 8.3 – Range 5–35% Norway SR (n=62,651) 20.2 • Same range as: Italy* (n=533) 9.2 – Most US estimates 2 Spain Rome II (n=349) 14 (2–27%) – Hong Kong (14.3%)3 Spain Rome I (n=349) 19.2 – Korea (16.5%)4 Spain SR (n=349) 29.5 • Self-reported rates France SR 35 >Rome I>Rome II1 France SR (n=7,196) 22.4

0 5 10 15 20 25 30 35 40

Percentage (%)

1Peppas et al. BMC Gastroenterol 2008;8:5; 2Higgins & Johanson. Am J Gastroenterol 2004;99:750-9 3Cheng et al. Aliment Pharmacol Ther 2003;18:319-26; 4Jun et al. Dig Dis Sci 2006 51:1471-7 CHRONIC CONSTIPATION Role of age and gender

Percentage of men and women reporting • Prevalence increases with constipation by age group6 age1‒3 85≥ 54.5 54.7 – Odds ratio for elderly (≥60 80-84 52.2 44 years) compared to 75-79 47.3 36.4 younger individuals (≤29 70-74 42.1 31.1 years) was 1.54 65-69 38.6 25.2 • As a consequence, the 60-64 36.2 21.3 elderly use more laxatives2,3

55-59 35.4 17.8 Age Age (years) 50-54 34.1 15.9 • Age-related increase in the

45-49 30.3 14.5 rate of physician visits for 5 40-44 27.8 13.6 constipation 35-39 27.3 12.8 – 1.3% between 60–64 years 30-34 27.9 12.5 – 4.1% >65 years 0 20 40 60 80 100 120 Responders (%)

Women Men US Survey of 877.645 subjects

1Hammond. Am J Pub Health 1964;54:11; 2 Harari et al. Arch Intern Med 1996;156:315; 3Everhart et al. Dig Dis Sci 1989;34:1153; 4Wald et al. Aliment Pharmacol Ther 2008;28:917; 5Sonnenberg & Koch. Dig Dis Sci 1989;34:606 %patients 100 20 40 60 80 0 Straining Symptomsin self ● ● ● Hard or Hard stools lumpy CHRONIC CONSTIPATIONCHRONIC 16.7 27.2 1149 % and % self% participants Incomplete emptying - 14.9 reportedconstipation within the past - % constipation constipation %according toRomeIand II reported constipation cannot be cannot passed Stool Pare et al ., ., Am. J. or bloatingor Abdominal fullness Gastroenterol definition definition and Physician’s < 3 focus: week BM per BM per . 2001 press on press ; 3 Need to 96 anus months : 3130 - 7 CHRONIC FUNCTIONAL CONSTIPATION Rome III Definition

● Must include 2 or more of the following: a. Straining during at least 25% of defecations b. Lumpy or hard stools in at least 25% of defecations c. Sensation of incomplete evacuation for at least 25% of defecations d. Sensation of anorectal obstruction for at least 25% of defecations e. Manual maneuvers to facilitate at least 25% of defecations f. Fewer than 3 defecations per week

● Loose stools are rarely present without the use of ● There are insufficient criteria for IBS Longstreth et al., Gastroenterology. 2006 ;130:1480-91 CHRONIC CONSTIPATION Causes of constipation

Primary Secondary

Intrinsic Normal diameter colon •Colorectal cancer • •Diverticular Disease •Idiopathic slow transit constipation •Defaecation disorder Metabolic / Endocrine •Diabetes •Hypercalcaemia Dilated colon •Hirschsprung’s disease •Hypothyroidism •Idiopathic megacolon Neurological •Chronic intestinal pseudo-obstruction •Spinal injury •Parkinson’s •Multiple Sclerosis Iatrogenic •Drugs •Postsurgical Psychological •Depression •Anorexia nervosa Anorectal •Anal fissure •Stricture 1Schiller Aliment Pharmacol Ther 2001; 15: 749 2Rao. Gastroenterol Clin N Am 2003; 32: 659 CHRONIC CONSTIPATION Clinical evaluation

Medical Rectal history examination • Nature of symptoms • Perianal excoriation – Duration of • Skin tags/ constipation haemorrhoids – Description of stool movements • Anocutaneous • Frequency reflex • Consistency • Anal fissure • Current • Prolapse – Including OTC • Rectocoele laxatives • Sphincter resting – Prescription agents tone • Concomitant conditions • Sphincter relaxation during straining CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation (infrequent or hard stools or difficult to pass stools)

History and physical examination

No No Alarm Constipating features? drugs?

Yes Yes

Technical examinations as Stop drugs if possible indicated

Tack et al. Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Clinical evaluation

Medical Rectal Diagnostic history examination testing • Nature of symptoms • Perianal excoriation • Laboratory testing – Duration of • Skin tags/ • Colonoscopy constipation haemorrhoids – Description of stool movements • Anocutaneous • Frequency reflex • Consistency • Anal fissure • Current medications • Prolapse – Including OTC • Rectocoele laxatives • Sphincter resting – Prescription agents tone • Concomitant conditions • Sphincter relaxation during straining CHRONIC CONSTIPATION Clinical evaluation

• Diagnostic studies are only indicated in patients with alarm symptoms/signs

• Specific diagnostic testing may be performed to identify organic disorders, systemic or metabolic disorders (e.g. hypothyroidism) CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation (infrequent or hard stools or difficult to pass stools)

History and physical examination

No No Alarm Constipating Chronical functional features? drugs? constipation

Yes Yes

Technical examinations as Stop drugs if possible indicated

No Adequate relief?

Yes

Drug-induced constipation

No Abnormality identified?

Yes

Organic disease with constipation, treat Tack et al. accordingly Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Clinical evaluation

Medical Rectal Diagnostic Advanced history examination testing tests • Nature of symptoms • Perianal excoriation • Laboratory testing • Colonic transit – Duration of • Skin tags/ • Colonoscopy • Balloon expulsion constipation haemorrhoids • Anorectal – Description of stool manometry movements • Anocutaneous • Frequency reflex • Defecography • Consistency • Anal fissure • Dynamic pelvic • Current medications • Prolapse magnetic resonance – Including OTC • Rectocoele imaging laxatives • Sphincter resting – Prescription agents tone • Concomitant conditions • Sphincter relaxation during straining CHRONIC CONSTIPATION Primary constipation syndromes

DefecationDefecation disorderdisorder ((dyssynergiadyssynergia))

SlowSlow NormalNormal transittransit transittransit

Schiller LR., Aliment Pharmacol Ther. 2001; 15(6):749 Mertz H, et al., Am J Gastroenterol. 1999; 94(3):609 CHRONIC CONSTIPATION Radiopaque marker study

• Ingest 24 radiopaque markers on R L 3 successive days

• No laxatives, , or medicines that affect bowel function

• Days 4&7: abdominal plain film

• Colonic transit = markers (on day 4 and 7), normal <70 markers

Metcalf, AM et al., Gastroenterology 1987; 92:40 CHRONIC CONSTIPATION Bristol stool form scale

Slower Type 1 Less

Type 2

Type 3

Type 4 Water Transit Type 5 content

Type 6

Faster Type 7 More

Lewis SJ, Heaton KW. Scand J Gastroenterol 1997; 32:920 Heaton KW, O’Donnell LJ. J Clin Gastroenterol 1994; 19:28 CHRONIC CONSTIPATION Colonic propulsion

Normal Constipated

Rao et al., Am J Gastroenterol. 2004 Bassotti et al., Arch. Surg. 2003 CHRONIC CONSTIPATION High resolution colonic manometry CHRONIC CONSTIPATION High amplitude propagated contr. CHRONIC CONSTIPATION Balloon expulsion test

Normal < 60 seconds Balloon filled with 50 cc water

Patient sits on toilet Anal Patient tries to canal expel balloon closed Polyethylene 3-way catheter stopcock to pressure transducers CHRONIC CONSTIPATION Anorectal pressure profiles

Rectoanal Pressure Profiles

Dyssynergic Dyssynergic Inadequate Normal Type I Type II expulsion

Rectal

50 mmH g 0

50 mmH g 0 Anal CHRONIC CONSTIPATION Pathophysiology-based subtypes

Tack et al. Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Physiological testing

• Advanced tests have limited availability

• Advanced tests do not necessary determine treatment choices

• The diagnostic accuracy of some advanced tests has been challenged CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation Education; lifestyle (infrequent or hard stools and dietary measures or difficult to pass stools)

History and physical examination

No No Alarm Constipating Chronical functional features? drugs? constipation

Yes Yes

Technical examinations as Stop drugs if possible indicated

No Adequate relief?

Yes

Drug-induced constipation

No Abnormality identified?

Yes

Organic disease with constipation, treat Tack et al. accordingly Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Lifestyle measures

•Fibre-rich foods (e.g. fruit and vegetables) and dietary fibre supplements1 •Low-fibre diets associated with Increased fluid intake1 constipation •Not supported by limited clinical •High-fibre diet increases stool evidence weight and accelerates colonic transit time •May only benefit patients without an underlying motility disorder2

Increased physical activity1 Ritualised bowel habit1 •Evidence of effectiveness is •Most subjects with normal bowel limited and inconclusive habits usually empty their bowels •Limited evidence to suggest that around the same time each day non-strenuous exercise (e.g. •Optimal time for BM around 2 hours walking) improves BMs as after waking sedentary individuals are 3 times •Suggest patients attempt BM twice more likely to report constipation daily 30 minutes after meals •Limited evidence of effectiveness CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation Education; lifestyle Initial or subsequent (infrequent or hard stools and dietary measures addition of laxatives or difficult to pass stools)

History and physical examination

No No Alarm Constipating Chronical functional features? drugs? constipation

Yes Yes

Technical examinations as Stop drugs if possible indicated

No Adequate relief?

Yes

Drug-induced constipation

No Abnormality identified?

Yes

Organic disease with constipation, treat Tack et al. accordingly Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Diversity of laxatives

Class1,2 Main mode of action Example of Bulking Retain water inside stool, facilitating •Methylcellulose and * agents peristalsis (indigestible organic polysaccharides) Stool Decrease absorption of water from stool, • (surfactant) softeners making it softer and facilitating transit •* (lubricant) Osmotic Increase fluid content of stool (and help • (non-absorbable sugar) agents soften stool) by retaining water in bowel •* (PEG; synthetic polyether) •Magnesium or compounds (non-absorbable salts) •Glycerine suppositories Stimulants Hydrolysed in gut and induce peristalsis •Sennoside (naturally occurring by stimulating enteric nerve endings directly anthraquinone) and inhibiting water absorption • ( analogue) •Bisacodyl suppositories Suppositories are shown in italics; enemas may also used. CHRONIC CONSTIPATION Polyethylene glycol

Effects of PEG (PMF-100) on stool frequency at Week 12 PEG: ACG Grade A 15 *** recommendation for CC 10 4.8 2.8 • 5 placebo-controlled RCTs, BM/week 5

Stoolfrequency 5 days to 20 weeks duration: 0 – Increased stool frequency PMF-100 Placebo – Decreased stool consistency Effects of PEG (PMF-100) on straining and stool – Decreased straining consistency – AEs were not adequately 80 ** * reported in most trials 60 – Incidence of diarrhoea ranged from 2‒40%

40 • Can be used during pregnancy Patients% 20 * ** ** * 0 Absent Slight Marked Soft Firm Hard Straining Consistency Placebo PMF-100

1Corazziari et al. Dig Dis Sci 1996;41:1636 2Brandt et al. Am J Gastroenterol 2005;100:S5; 3Drost & Harris. JAAPA 2006;19:24 CHRONIC CONSTIPATION Bisacodyl

CSBM

4 –week trial 247 bisacodyl 10 mg and 112 placebo q.d.

Kamm et al., CGH 2011 CHRONIC CONSTIPATION Bisacodyl

Kamm et al., CGH 2011 CHRONIC CONSTIPATION Laxatives – ACG guideline

How I use laxatives:

- Daily PEG is first choice; replace by a paraffin olil preparation if bloating is an issue

- If necessary, add twice weekly stimulant agent in the event

- Rectal administration of bisacodyl in case of defecatory dysfunction Ford et al., AJG 2014 CHRONIC CONSTIPATION Laxative use - Europe

Muller-Lissner et al., APT 2013 CHRONIC CONSTIPATION Laxative use - Europe

Muller-Lissner et al., APT 2013 CHRONIC CONSTIPATION Traditional treatments

GUT WALL Salts, Sugars and Osmotic agents Water binding in stool

Fibre and Bulking agents Stool softening & lowers surface tension of stool Docusate and Stool softeners

Peristalsis Senna and Stimulant agents

1Tack & Müller-Lissner. Clin Gastroenterol Hepatol 2009;7:502 CHRONIC CONSTIPATION European algorithm: advanced care

Patient with chronic constipation Education; lifestyle Initial or subsequent (infrequent or hard stools and dietary measures addition of laxatives or difficult to pass stools)

Yes History and physical Adequate Long-term examination relief?* management

No No No Alarm Constipating Chronical functional Yes Long-term Add/switch laxative features? drugs? constipation management

Yes Yes

Technical Refer for additional examinations as Stop drugs if possible testing indicated (anorectal function, colonic transit, etc.)

No Normal- Adequate Slow-transit Pelvic floor transit relief? constipation dysfunction constipation

Yes

Drug-induced constipation

No Abnormality identified?

Yes

Organic disease with constipation, treat Adapted from Tack et accordingly al. Neurogastroenterol Motil 2011 CHRONIC CONSTIPATION Primary constipation syndromes

DefecationDefecation disorderdisorder ((dyssynergiadyssynergia)) BIOFEEDBACK

NormalNormal transittransit Slow transit

IBS THERAPY LAXATIVES PROKINETICS

Schiller LR., Aliment Pharmacol Ther. 2001; 15(6):749 Mertz H, et al., Am J Gastroenterol. 1999; 94(3):609 BIOFEEDBACK FOR DYSSYNERGIC DEFECATION

Rao et al., 2007 BIOFEEDBACK FOR DYSSYNERGIC DEFECATION

Rao et al., 2007 BIOFEEDBACK FOR DYSSYNERGIC DEFECATION

Problems: 1. Not known to non-gastroenterologists 2. Insufficiently assessed by gastroenterologists with no specific interest in constipation 3. Lack of a gold standard for diagnosis 4. Access to anal function testing limited 5. Often very limited availability of skilled biofeedback physiotherapitsts or nurses 6. In many countries no reimbursement CHRONIC CONSTIPATION Diagnostic utility of anorectal manometry

Grossi et al. Gut 2015; early online CHRONIC CONSTIPATION Diagnostic utility of anorectal manometry

Grossi et al. Gut 2015; early online CHRONIC CONSTIPATION Diagnostic utility of anorectal manometry

Grossi et al. Gut 2015; early online CHRONIC CONSTIPATION European algorithm: general care

Patient with chronic constipation Education; lifestyle Initial or subsequent (infrequent or hard stools and dietary measures addition of laxatives or difficult to pass stools)

Yes History and physical Adequate Long-term examination relief?* management

No No No Alarm Constipating Chronical functional Yes Long-term Add/switch laxative features? drugs? constipation management

Yes Yes No

Technical Stop laxative and start second-line examinations as Stop drugs if possible therapy (, , indicated )

No Adequate relief?

Yes

Drug-induced constipation

No Abnormality identified?

Yes

Organic disease with constipation, treat Adapted from Tack et accordingly al. Neurogastroenterol Motil 2011 GI MOTOR AND SENSORY DISORDERS Chloride secretion as a therapeutic target

Guanylin or E. Coli or Yersinia uroguanylin enterotoxin LUMEN Cl- Cl- Lubiprostone GC CFTR CCl2 “prostones” : GTP cGMP PKG II Bicyclic fatty acids, EC cell derived from K+ prostaglandin E1

ATP

K+ Na+ Na+ K+ 2Cl- Cl- Cl- CHRONIC CONSTIPATION Effect of lubiprostone

8 Weekly Number of SBM (Ph III) Lubiprostone efficacy not influenced by: 7 • Gender 6 • Race • Age 5 *** * ** ** Associated improvement: 4 * • Stool consistency 3 • Straining • Constipation severity 2 Adverse events: Mean weekly SBM weekly Mean Placebo (n = 122) 1 Lubiprostone (n = 120) • Nausea 31.7% (DR 5%)

0 • Headache 11.7% Baseline 1 2 3 4

Time, weeks

Johanson et al, 2008 CHRONIC CONSTIPATION Lubiprostone – long-term efficacy

Lembo et al, Dig. Dis. Sci. 2011 CHRONIC CONSTIPATION Chloride secretion as a therapeutic target

Linaclotide

Lubiprostone

Guanylin or E. Coli or Yersinia uroguanylin enterotoxin LUMEN Cl- Cl-

GC CFTR CCl2

GTP cGMP PKG II EC cell

K+

ATP

K+ Na+ Na+ K+ 2Cl- Cl- Cl- CHRONIC CONSTIPATION Phase 3 study with linaclotide

STUDY 01 & STUDY 303 ONLY STUDY 303

Linaclotide 145 ug Linaclotide 145 ug (01: n=217; 303: n=213) Placebo Linaclotide 145 ug Linaclotide 290 ug (01: n=216; 303: n=202) Placebo

Placebo (01: n=209; 303: n=215) Linaclotide 290 ug

2 weeks 12 weeks 4 weeks

Randomized Baseline Treatment period withdrawal Randomized study population: CC patients, <3 SBM/week, 1 out of 3 additional criteria, ≥6 SBM/week and <3CSBM/week during baseline Lembo et al., 2011 CHRONIC CONSTIPATION Phase 3 study with linaclotide

Placebo Linaclotide 145 ug Linaclotide 290 ug 25

21.3 ) ** **21.2 20 **19.4

16* patients

15 (% of (%

10

6 5

3.3 Prevalence

0 Study 01 Study 303

Baseline Treatment Period RW Period

CSBMs

weekly No of No

Week Lembo et al., 2011 CHRONIC CONSTIPATION Colonic propulsion - effect of prucalopride

Transverse colon

Left colon

Sigmoid colon

Rectum

Anal Sphincter

Corsetti et al., UEGW 2014 CHRONIC CONSTIPATION Prucalopride Phase 3 studies

Placebo, once daily R Prucalopride 2 mg, once daily Prucalopride 4 mg, once daily Run-in (2 wks) Double-blind treatment period (12 weeks)

0 2 4 8 12

• Daily diaries Screening • Assessments at 2, 4, 8, and 12 weeks • Patient global assessment, PAC-SYM, PAC-QoL, AE, vital signs Randomisation • Assessments at 4 and 12 weeks Endpoint • ECG, clinical laboratory parameters, physical exam Inclusion Criteria – add on slide 1Camilleri et al. N Engl J Med 2008;358:2344. 2Tack et al. Gut 2009;58:357 3Quigley et al. Aliment Pharmacol Ther 2008;29:315 CHRONIC CONSTIPATION Prucalopride Phase 3 studies

% subjects with an average of ≥3 SCBM per week over 12 weeks (normalisation)

35% 28.9*** 28.9*** 30% 24.7*** 23.6*** 23.6*** 23.9** 23.5** 25% 19.5** 20%

15% 13.0 11.3 12.1 9.6 10%

5% n=240 n=236 n=237 n=212 n=214 n=215 n=193 n=190 n=187 0% Pooled data INT-6 USA-13 USA-11

Placebo PRU 2 mg PRU 4 mg **p<0.01 vs. placebo ***p<0.001 vs. placebo Baseline SCBM = 0.46

Camilleri et al. Poster, DDW 2008 [Gastroenterology 2008;134(4):A548]; Tack et al. Gut 2008;Nov 5 [epub]; Quigley et al. Aliment Pharmacol Ther 2009;29:315-328; Camilleri et al. N Engl J Med 2008;358:2344–54. CHRONIC CONSTIPATION Prucalopride; effect on symptoms

Women failing to respond to laxatives in the phase 3 studies Including only those with symptom present at baseline Tack et al., NMO 2013 CHRONIC CONSTIPATION Prucalopride Phase 3 studies

Most common drug-related adverse events 30

Placebo (N=661) 25 Prucalopride 2 mg (N=659)

20 Prucalopride 4 mg (N=657)

15

Patients (%) Patients 10

5

0 Headache Nausea Diarrhoea Abdominal Headache Nausea Diarrhoea Abdominal pain pain

Events during treatment period Events excluding Day 1

Tack et al. Poster, DDW 2008 [Gastroenterology 2008; 134(4):A530] CHRONIC CONSTIPATION Prucalopride Phase 3 studies

Most common drug-related adverse events 30

Placebo (N=661) 25 Prucalopride 2 mg (N=659)

20 Prucalopride 4 mg (N=657)

15

Patients (%) Patients 10

5

0 Headache Nausea Diarrhoea Abdominal Headache Nausea Diarrhoea Abdominal pain pain

Events during treatment period Events excluding Day 1

Tack et al. Poster, DDW 2008 [Gastroenterology 2008; 134(4):A530] CHRONIC CONSTIPATION Prucalopride male study

Prucalopride 2 mgb Run-in

a Period Placebob

Screening Baseline Week 2 Week 4 Week 8 Week 12

(Visit 1) (Visit 2) (Visit 3) (Visit 4) (Visit 5) (Visit 6) a2–4 weeks bElderly patients ( 65 years old) started at a 1 mg dose (or matching placebo) that could be increased to 2 mg (or matching placebo) at the Week 2 or Week 4 Visit in case of insufficient efficacy

Yannakou et al., AJG 2015 CHRONIC CONSTIPATION Prucalopride meta-analysis

Table 1: Proportion of Subjects with an Average of ≥3 Spontaneous Complete Bowel Movements per Week Over 12 Weeks – Key Phase 3/4 Efficacy and Safety Studies in Chronic Constipation (Full Analysis Set)

Placebo Prucalopride ≤2mg Difference in p-value a N=1247 N=1237 Proportion (95% CI) Weeks 1-12 165 (13.2) 344 (27.8) a 14.6 (11.5; 17.7) <0.001 a p-value based on a Cochran-Mantel Haenszel test, performed on the proportion of subjects with an average weekly frequency of ≥3 SCBMs/week over Week 1-12 in the placebo and prucalopride treatment groups controlling for stratification factors study, sex, country, and number of CBMs/week (0 or >0) at baseline CI=confidence interval; CBM=complete bowel movement; SCBM=spontaneous complete bowel movement Source: Table EFF.B.04 Gatta et al, DDW 2013

CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation Education; lifestyle Initial or subsequent (infrequent or hard stools and dietary measures addition of laxatives or difficult to pass stools)

Yes History and physical Adequate Long-term examination relief?* management

No No No Alarm Constipating Chronical functional Yes Long-term Add/switch laxative features? drugs? constipation management

Yes Yes No

Technical Stop laxative and start second-line examinations as Stop drugs if possible therapy (prucalopride, lubiprostone, indicated linaclotide)

No Yes Adequate Adequate Long-term relief? relief?* management

Yes No

Drug-induced Refractory constipation constipation

No Abnormality identified? Refer for additional testing Yes (anorectal function, colonic transit, etc.) Organic disease with constipation, treat Tack et al. Normal- accordingly Slow-transit transit Pelvic floor Neurogastroenterol constipatio constipatio dysfunction n Motil 2011 n EMERGING TREATMENTS FOR FGIDS Constipaiton

• New drugs for IBS-C/CC:

– GCC agonist () – Ileal bile acid transport inhibitor (Elobixibat) – Sodium exchange inhibitor (Tenapanor)

• New drugs for OIC:

– Lubiprostone, prucalopride, linaclotide – Peripherally acting mu opioid receptor antagonistis (, oral , , TD-1211, , Nalcol, …) TARGID Methusalem research group

Human Animal GA, Esophagus Mucosal Enteric GI PET/FMRI human , visceral permeability nervous hormone studies food intake sensitivity system studies

PD

PhD

TP www.targid.eu CHRONIC CONSTIPATION European algorithm

Patient with chronic constipation Education; lifestyle Initial or subsequent (infrequent or hard stools and dietary measures addition of laxatives or difficult to pass stools)

Yes History and physical Adequate Long-term examination relief?* management

No No No Alarm Constipating Chronical functional Yes Long-term Add/switch laxative features? drugs? constipation management

Yes Yes No

Technical Stop laxative and start second-line examinations as Stop drugs if possible therapy (prucalopride, lubiprostone, indicated linaclotide)

No Yes Adequate Adequate Long-term relief? relief?* management

Yes No

Drug-induced Refractory constipation constipation

No Abnormality identified? Refer for additional testing Yes (anorectal function, colonic transit, etc.) Organic disease with constipation, treat Tack et al. Normal- accordingly Slow-transit transit Pelvic floor Neurogastroenterol constipatio constipatio dysfunction n Motil 2011 n