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Obstipatie en laxeermiddelen onder de loep




      Marc Benninga, kinderarts maag-darm-leverziekten
          Emmakinderziekenhuis/AMC, Amsterdam
Objectives

• What is constipation
• Pathophysiology
• Treatment
Functional Constipation

At least a 2 month history of at least two of the following 6 criteria:
1) 2 or fewer defecations/wk, developmental age of at least 4 yrs;
2) At least one episode of fecal incontinence/wk;
3) Retentive posturing or excessive volitional stool retention;
4) History of painful or hard bowel movements;
5) History of large diameter stools which may obstruct the toilet;
6) Presence of a large fecal mass in the rectum


                                       Rasquin et al. Gastroenterology 2006
Prevalence of constipation
0-10%

>10-20%

>20-30%

>30-40%

          Mugie et al. Best Pract & Res Clin Gastroenterol 2011
Childhood functional constipation is a common
                       disease….


•   Occurs in 0.3-8% of the pediatric population and in 5-10% of
    school age children
•   Represents 3% of visits to pediatricians and 25% of visits to
    pediatric gastroenterologists
•   Age: 40% of children with constipation develop symptoms
    during the first year of life
•   Gender boys > girls
Childhood functional constipation represents a
     significant burden on the health care system


•   1.7 (1.1%) million constipated children
•   More outpatients visits and ED visits
•   More days of school missed
•   Children with constipation: $ 3074 / yr
•   Children without:             $ 1096 / yr

            Total extra burden of childhood constipation
                    4 billion dollar/yr in the US!!!



                                        Liem et al. J Pediatr 2009
Symptoms of Functional Constipation
                                       (%)
 Defecation frequency < 3/wk           34
 Fecal incontinence                    69
 Retentive posturing                   58
 Painful defecation                    69
 Large diameter stools                 62

 Presence of a large fecal mass        41


                               Boccia et al. J Pediatr 2007
Knmp congres 4okt-1500u-marc benninga
Fecal incontinence

     Organic (10%)                             Functional (90%)


• Neurologic damage
• Anal sphincter anomalies




• functional constipation 80% • non-retentive fecal incontinence 20%


                                                       JPGN 2005
behavior
                  colon




                                      rectum

                          sphincter



           food
Withholding behavior
                           Fissure
                     Painful defecation

Hard stools

                               Fear
                     Withholding
   Life events???:
   • Divorce
   • Death
   • Sexual abuse
Knmp congres 4okt-1500u-marc benninga
Treatment

• Education / demystification / toilet training
• Disimpaction
• Maintenance
• Follow-up




                             NASPGHAN JPGN 2006
Chronic constipation: Medical and surgical management

                                                                                              Colectomy
                                                                                                   or
                                                                                             Stoma (inc.
                                                                              Pelvic floor   anterograde
                                                                               surgery        irrigation)
                                                                 Nurse-led
% patients




                                                                   Bowel      Sacral nerve
                                                                 retraining    stimulation
                                                Oral                 +/-
                                              and / or          biofeedback
                               Lifestyle       rectal
                             modifications   laxatives
                              Diet, fluid,
              Diagnosis        exercise
             (exclusion of
                organic
              pathology)



                                                         time
Arch Dis Child. 2009;94:117-31
Knmp congres 4okt-1500u-marc benninga
Effect of Glucomannan in the treatment
               of childhood constipation
             14
             14

             12
             12
                                   n=80
             10
             10
                                              Baseline
              8
              8
Median number                                 4 weeks later
    / week    6
                        p = NS
              6

             4
             4

             2
             2
                   *               *
             0
             0
                  Defecation     Defecation
                    Gluc          Placebo


                                               Chmielewska A, et al. Clin Nutr 2011
Rate of success

                   P=NS
            80
            70
            60
Success %




            50
            40                       95% CI 38%-72%
            30
                                     95% CI 41%-74%
            20   56%      58%
            10
            0

                 Gluco   Placebo

                                     Chmielewska A, et al. Clin Nutr 2011
Knmp congres 4okt-1500u-marc benninga
RCT: plums(prunes) vs. psyllium for
          constipation


                          The laxative effects a
                            combination:
                          • sorbitol (14.7 g ⁄ 100 g)
                          • dietary fibre (6 g ⁄ 100
                          • polyphenols (184 mg⁄ 100 g)
                          • exact mechanism has not
                            been established




                 Attalauri et al. Aliment Pharmacol Ther 2011
Background

Probiotics & effects on constipation symptoms:
• Enhance peristalsis of the colon and consequently decrease
  colonic transit time
• Soften stools by stimulating water and electrolyte secretion




                   Moro et al. JPGN 2002, Picard. Aliment Pharmacol Ther 2005, Bouvier
                   M. Bioscience and microflora 2001, Marteau et al. Aliment Pharmacol
                   Ther 2002
Knmp congres 4okt-1500u-marc benninga
Knmp congres 4okt-1500u-marc benninga
Methods (1)

• Double-blind, placebo-controlled randomised multicentre, two
  nation (the Netherlands and Poland) trial

• 160 children, age 3-16 years, with a defecation frequency
   < 3/week

AND

  Fulfilling ≥ 1 of the other Rome-III criteria:
  fecal incontinence > 1/week, large amount of stools which
  clog the toilet, painful defecation, withholding behavior,
  abdominal or rectal fecal impaction
Primary outcome
                          The stool frequency change from baseline
                             to 3 weeks of product consumption


                        2.9 in probiotic group vs 2.6 in placebo, P=0.35

                    7
Defecation / week




                    6
                    5                                             Baseline
                    4                                             3 weeks
                    3
                    2
                    1
                    0
                        Probiotics     Placebo
Rate of success

                     P=0.06
            40
            35
            30
                                      RR 1.61, 95% CI 0.98
Success %




            25
            20                        to 2.69
            15
                   24%     38%        Number needed to
            10
            5
                                      treat of 7
            0

                 Placebo Probiotics

                                        Tabbers et al. Pediatrics 2011
`Until more data are available, we
 believe the use of probiotics for
  the treatment of constipation
 condition should be considered
          investigational`
                                     2010
Knmp congres 4okt-1500u-marc benninga
Baseline characteristics

                                    Enema          PEG           p-value
Number                              46             44
Male                                29             31
Age in years                        7.9±2.9        7.2±2.6
Defecation/wk                       1.9±1.9        1.5±1.2       0.46
Symptom duration (years)            5.2±3.3        4.7±2.8       0.29
Daytime fecal incontinence/wk       15.7±13.1      16.6±12.4     0.13
Night time fecal incontinence       28%            34%           0.70
Abdominal pain                      48%            64%           0.37
Watery stools                       4%             9%            0.18



                                         Bekkali et al, J Pediatr 2009
Results


                           Enemas                           PEG
                            n=46                            n=44




Drop-outs          Successful disimpaction         Successful disimpaction   Drop-outs
   n=5                      n=37                            n=30                n=5
                            80%                             68%




*chi2 statistics p=0.28 (ITT)
Defecation
                                   *
                                                          Enema
Defecation frequency/




                         ns                    ns         PEG
wk (±SE)




                        Intake             Disimpaction
Fecal incontinence
                                   *
Fecal incontinence / wk



                                                        Enema

                           ns                  *        PEG




                          Intake         Disimpaction
Adverse events


    70
    60
                  ns
%                             Enema
    50
    40                        PEG
    30
    20
    10


             Abdominal pain
Adverse events

    90           ns
    80
    70
                          Enema
    60
%   50                    PEG
    40
    30
    20
    10


               Anxiety
Maintenance therapy
PEG and childhood constipation
Authors Journal Year       Pts    Drugs
Pashankar      J Pediatr   2001           24    PEG
Loening        JPGN        2002           49    PEG vs MoM
Gremse         Clin Ped    2002           37    PEG vs lactulose
Pashankar      APAM        2003           83    PEG
Pashankar      Clin Ped    2003           73    PEG
Michail        JPGN        2004           28    PEG
Loening        JPGN        2004           74    PEG
Voskuijl       Gut         2004           90    PEG vs lactulose
Dupont         JPGN        2005/2006      96    PEG vs lactulose
Rendelli       APT         2006           76    PEG vs lactulose
Loening        Pediatr     2006           79    PEG vs MOM
Thomson        JPGN        2007           47    PEG vs placebo!
Nurko          J Pediatr   2008           103   Peg vs placebo
Motility center
Knmp congres 4okt-1500u-marc benninga
Effect of PEG 3350 With Electrolytes vs Lactulose

           14
                           *p<0.05              Baseline
           12
                            n=91                8 weeks later
           10

 Median    8
number /   6
  week     4     *           *             *                 *
           2
           0
                  Def         Def       FI              FI
                PEG 3350   Lactulose PEG 3350       Lactulose
                                       Voskuijl WP, et al. Gut 2004; 53:1590
Knmp congres 4okt-1500u-marc benninga
Side effects after 8 weeks
     % patients with side effects

                                    80                   * p<0.05

                                    60
                                                                                  Transipeg
                                    40      *        *                  *         Lactulose
                                    20                         *
                                    0
                                         Abdominal Straining   Pain   Bad taste
                                           pain

 No difference: diarrhea, stool consistency, nausea, bloating, flatulence
     difference: diarrhea, stool consistency,
PEG 3350 for constipation in children
               younger than 18 months old

75 Infants 0 – 17 months


• Initial           0,9 g/kg/day (0,26-2,14)
• Maintenance       0.8 g/kg/day (0,26-1,26)


• Duration of therapy (3 wks – 21 months)
• Relieve of constipation 97,6% ??????



                                  Loening-Baucke et al. JPGN 2004
Effective dose PEG 4000 per age group


 Age category         Dosage    Range
 6 – 12 months        4g        (2.5-5g)
 13 m – 3 years       6g         (4-7,4g)
 4 – 7 years          12g       (7-16g)
 8 – 15 years         16g       (16-24g)

                  0.5 g/kg!
                               Dupont et al. JPGN 2006
Efficacy per age group
        after 3 months of treatment

Age category       Efficacy
6 – 12 months      100%        (15/15)
13 m – 3 years     90%         (27/30)
4 – 7 years        93%         (26/28)
8 – 15 years       91%         (21/23)


                              Dupont et al. JPGN 2006
PEG 4000 versus Lactulose
              Safety in children


 Laboratory results:
   - HCO3-- , Na+, K+, Cl--
          3
                +   +

   - Creatinin, Osmolality, Albumin, Total protein, Iron, Vita
                                                             a
     Folates, Vitdd
   - Hb, Ht

 No changes after 3 or 12 months of therapy




      Pashankar et al. Arch Pediatr Adolesc Med 2003, Dupont et al. JPGN 2005
Safety of high-dose PEG+E
                   case report


 33 month child ingested 160mg/kg iron
 Whole bowel lavage with PEG+E performed over 5 days
 Total volume administered: 44.3 litres
 No clinical adverse events and no electrolyte abnormalities
  detected
 Child made full recovery




                     Kaczorowski JM et al. Ann Emerg Med 1996
PEG intestinal lavage and aspiration in a
7-year old boy with severe constipation


                      • Vomiting results in
                        migration of the ng-tube
                      • Recheck ng-position




                      Wong et al. Arch Dis Child 2002
                      Liangthanasarn et al. JPGN 2003
Adults
                                                  Bisacodyl



                                        Children
         Price KJ Elliot TM Cochrane Database Syst Rev 2001;3,


         What is the Role of Stimulant Laxatives in the Management of
         Childhood Constipation and Soiling?

         SELECTION CRITERIA: All identified randomised controlled
         trials (RCTs) which compare the administering of stimulant
         laxatives to children with either placebo or alternative treatment.
         DATA COLLECTION AND ANALYSIS: No trials were found that
         met the selection criteria.
Knmp congres 4okt-1500u-marc benninga
Protocol

• Randomization stratified by age and gender

• 1 year:   1) conventional treatment (CT):
                  - education
                  - 0.5 – 1.5 g/kg polyethylene glycol
                  - behavioral modification

            2) Additional treatment with rectal enemas:
                  - 3/week first 3 months;
                  reduced by 1 enema/week every 3 months
Intake Characteristics

                               CT (n=50)      ATE (n=50)

Boys %                            66             64

Age at baseline, y               11.0            10.5
median

Duration of symptoms, y           7.0            6.5
median

Def. freq / week                  1.0            1.5
median

FI freq / week                    7.0            7.5
median
Defecation frequency

                                              NS

                 25         P= <.001*              P= <.001*
times per week




                 20

                 15

                 10

                  5

                  0
                       baseline    one year   baseline   one year
                              CT                     ATE
Fecal incontinence

                                             NS

                            P= <.001*             P= <.001*
                 45
times per week




                 40
                 35
                 30
                 25
                 20
                 15
                 10
                  5
                  0
                      baseline    one year   baseline    one year
                                 CT                     ATE
Success during one year

             80                NS               ATE

             60                                 CT
Percentage




             40

             20

             0
                    3     6            9   12

                              Months
Conclusions

• No additional effect of rectal enemas in treatment of
  functional constipation

• Rectal enemas have no role in maintenance therapy

• Development of new treatment compounds for childhood
  constipation is needed
Side effects of enemas


• Related to water and electrolyte disturbances
  resulting from:
   − Hyperphosphataemia
   − Hypocalcaemia
   − Hypernatraemia
   − Metabolic acidosis

• Absorptive effect of enema components and to
  their inadequate elimination in patients with co-
  morbidities


                      Mendoza J et al. Aliment Pharmacol Ther 2007
Problem???
Are constipation drugs effective and safe to be used in
           children?: a review of the literature

• Lack of large well-designed placebo controlled trials in
  childhood constipation

• Any interpretation with regards to the evidence for the
  effectiveness or safety of laxatives used in children is
  difficult

• Serious side effects of laxatives in children are rarely
  reported; however, evidence for the safety of short- and
  long-term use of laxatives in children with constipation
  is limited

                            Van Wering et al. Expert Opin Drug Saf 2011
NEW DRUGS in the pipeline!
5-HT4 RECEPTOR AGONISTS
                              Selectivity of agonists


                                    Receptor binding profile at therapeutic concentrations

Class         Drug                5-HT4         5-HT3     5-HT2     5-HT1        D2      hERG

              Cisapride            +              +         +                                +

              Renzapride           +              +

Benzamide     Clebopride           +              +                              +

              Mosapride            +              +

              Naronapride          +

              Tegaserod            +                        +          +
Carbazimide
              Velusetrag           +

Benzofurane   Prucalopride         +
Knmp congres 4okt-1500u-marc benninga
Pooled data: Response maintained over
     the 12 week treatment period
50%

45%
                                                                     placebo            pru 2mg          pru 4mg
40%

35%

30%

25%

20%

15%

10%

5%

0%
      run-in   Week 1   Week 2   Week 3   Week 4   Week 5   Week 6    Week 7   Week 8   Week 9 Week 10 Week 11 Week 12




         % subjects with ≥3 SCMB/week
PRUCALOPRIDE
                                  Safety and tolerability: adverse events

           Most common drug-related adverse events
           30
                                  Placebo (n=661)             Prucalopride 2 mg (n=659)             Prucalopride 4 mg (n=657)0
           25

           20
Patients
     (%)




           15

           10

           5

           0
                        e




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                                                                         ch
                                          oe




                                                                                             oe
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                                                 Ab




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                 Events during treatment period                          Events excluding Day 1


                                                                                         Tack et al. Gastroenterology 2008
Efficacy and tolerability of velusetrag, a selective 5-HT4 agonist
      with high intrinsic activity, in chronic idiopathic constipation




Goldberg M et al. Aliment Pharmacol Ther 2010
The Role of Chloride Channels in Intestinal Transport


•    Lubiprostone is a bicyclic
     functional fatty acid
•    Selectively activates
     chloride channel-2 (CIC-2)
      – Enhance intestinal fluid
        secretion
      – Facilitate increased
        motility

•    FDA approved in January
     2006

                                   Lubiprostone
Effects of Lubiprostone on Number of
            Spontaneous Bowel Movements
          7
                         p = 0.0001   p = 0.0017    p = 0.0002   p = 0.0002
          6

          5
                               24 µg lubiprostone BID
  Bowel   4
movements
 per week 3
                                      Placebo
          2

          1                           n = 242
                              Intent-to-treat population
          0
              Baseline   Week 1        Week 2       Week 3       Week 4


                                      Johanson et al. Am J Gastroenterol 2008
Long-Term Safety and Effectiveness of Lubiprostone, in Patients
            with Chronic Idiopathic Constipation




                                     Parkman et al. Dig Dis Sci 2011
Linaclotide
Two Randomized Trials of Linaclotide
     for Chronic Constipation




                                    Primary end point:
        N = 1276                    >3 CSBMs per week




                         Lembo et al. New Eng J Med 2011
Adverse effects of Linaclotide
in patients with Chronic Constipation




                          Lembo et al. New Eng J Med 2011
Long-term follow-up of
functional constipation
Primary care physicians


• After 2 months of treatment 40% remains
  symptomatic

• Primary care physicians tend to undertreat

• Colonic evacuation with laxatives were more
  likely to respond



                              Borowitz et al. Pediatrics 2005
Clinical outcome at follow up
                                                      N = 47, median age 3,5 months
                                    100
Cumulative success percentage (%)



                                     80




                                     60
                                                                     *= p 0.002
                                     40




                                     20

                                                                    < 3 months symptoms

                                          0
                                                                    > 3 months symptoms
                                              0   6      12    18    24   30    36



                                                      Time until first success (months)
                                                                                          Vanden Berg et al. J Pediatr 2006
Results
                               Outcome with and without laxatives

                   190   190   188   187   183   188    186 174 165   154 137   126   115   76   24   1   Number included
                    3     2     3     3     6     0      0   5   3     3   3     2     1    0    0    0   Number missing
             100


             80                                                                                             No succes lax+
                                                                                                            No succes lax-
Percentage




             60
                                                                                                           Succes lax+
                                                                                                            Succes lax-
             40


             20


              0
                   0,5    1     2     3     4     5      6   7   8    9    10 11 12 13 14 15

                                                       Time of follow-up (years)
Summary and
                     Conclusions


• Constipation is a common entity in childhood constipation

• Early and long-lasting treatment with oral laxatives is
  necessary in the majority of children with constipation

• Serious side effects of oral and rectal laxatives are rarely
  reported

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Knmp congres 4okt-1500u-marc benninga

  • 1. Obstipatie en laxeermiddelen onder de loep Marc Benninga, kinderarts maag-darm-leverziekten Emmakinderziekenhuis/AMC, Amsterdam
  • 2. Objectives • What is constipation • Pathophysiology • Treatment
  • 3. Functional Constipation At least a 2 month history of at least two of the following 6 criteria: 1) 2 or fewer defecations/wk, developmental age of at least 4 yrs; 2) At least one episode of fecal incontinence/wk; 3) Retentive posturing or excessive volitional stool retention; 4) History of painful or hard bowel movements; 5) History of large diameter stools which may obstruct the toilet; 6) Presence of a large fecal mass in the rectum Rasquin et al. Gastroenterology 2006
  • 5. 0-10% >10-20% >20-30% >30-40% Mugie et al. Best Pract & Res Clin Gastroenterol 2011
  • 6. Childhood functional constipation is a common disease…. • Occurs in 0.3-8% of the pediatric population and in 5-10% of school age children • Represents 3% of visits to pediatricians and 25% of visits to pediatric gastroenterologists • Age: 40% of children with constipation develop symptoms during the first year of life • Gender boys > girls
  • 7. Childhood functional constipation represents a significant burden on the health care system • 1.7 (1.1%) million constipated children • More outpatients visits and ED visits • More days of school missed • Children with constipation: $ 3074 / yr • Children without: $ 1096 / yr Total extra burden of childhood constipation 4 billion dollar/yr in the US!!! Liem et al. J Pediatr 2009
  • 8. Symptoms of Functional Constipation (%) Defecation frequency < 3/wk 34 Fecal incontinence 69 Retentive posturing 58 Painful defecation 69 Large diameter stools 62 Presence of a large fecal mass 41 Boccia et al. J Pediatr 2007
  • 10. Fecal incontinence Organic (10%) Functional (90%) • Neurologic damage • Anal sphincter anomalies • functional constipation 80% • non-retentive fecal incontinence 20% JPGN 2005
  • 11. behavior colon rectum sphincter food
  • 12. Withholding behavior Fissure Painful defecation Hard stools Fear Withholding Life events???: • Divorce • Death • Sexual abuse
  • 14. Treatment • Education / demystification / toilet training • Disimpaction • Maintenance • Follow-up NASPGHAN JPGN 2006
  • 15. Chronic constipation: Medical and surgical management Colectomy or Stoma (inc. Pelvic floor anterograde surgery irrigation) Nurse-led % patients Bowel Sacral nerve retraining stimulation Oral +/- and / or biofeedback Lifestyle rectal modifications laxatives Diet, fluid, Diagnosis exercise (exclusion of organic pathology) time
  • 16. Arch Dis Child. 2009;94:117-31
  • 18. Effect of Glucomannan in the treatment of childhood constipation 14 14 12 12 n=80 10 10 Baseline 8 8 Median number 4 weeks later / week 6 p = NS 6 4 4 2 2 * * 0 0 Defecation Defecation Gluc Placebo Chmielewska A, et al. Clin Nutr 2011
  • 19. Rate of success P=NS 80 70 60 Success % 50 40 95% CI 38%-72% 30 95% CI 41%-74% 20 56% 58% 10 0 Gluco Placebo Chmielewska A, et al. Clin Nutr 2011
  • 21. RCT: plums(prunes) vs. psyllium for constipation The laxative effects a combination: • sorbitol (14.7 g ⁄ 100 g) • dietary fibre (6 g ⁄ 100 • polyphenols (184 mg⁄ 100 g) • exact mechanism has not been established Attalauri et al. Aliment Pharmacol Ther 2011
  • 22. Background Probiotics & effects on constipation symptoms: • Enhance peristalsis of the colon and consequently decrease colonic transit time • Soften stools by stimulating water and electrolyte secretion Moro et al. JPGN 2002, Picard. Aliment Pharmacol Ther 2005, Bouvier M. Bioscience and microflora 2001, Marteau et al. Aliment Pharmacol Ther 2002
  • 25. Methods (1) • Double-blind, placebo-controlled randomised multicentre, two nation (the Netherlands and Poland) trial • 160 children, age 3-16 years, with a defecation frequency < 3/week AND Fulfilling ≥ 1 of the other Rome-III criteria: fecal incontinence > 1/week, large amount of stools which clog the toilet, painful defecation, withholding behavior, abdominal or rectal fecal impaction
  • 26. Primary outcome The stool frequency change from baseline to 3 weeks of product consumption 2.9 in probiotic group vs 2.6 in placebo, P=0.35 7 Defecation / week 6 5 Baseline 4 3 weeks 3 2 1 0 Probiotics Placebo
  • 27. Rate of success P=0.06 40 35 30 RR 1.61, 95% CI 0.98 Success % 25 20 to 2.69 15 24% 38% Number needed to 10 5 treat of 7 0 Placebo Probiotics Tabbers et al. Pediatrics 2011
  • 28. `Until more data are available, we believe the use of probiotics for the treatment of constipation condition should be considered investigational` 2010
  • 30. Baseline characteristics Enema PEG p-value Number 46 44 Male 29 31 Age in years 7.9±2.9 7.2±2.6 Defecation/wk 1.9±1.9 1.5±1.2 0.46 Symptom duration (years) 5.2±3.3 4.7±2.8 0.29 Daytime fecal incontinence/wk 15.7±13.1 16.6±12.4 0.13 Night time fecal incontinence 28% 34% 0.70 Abdominal pain 48% 64% 0.37 Watery stools 4% 9% 0.18 Bekkali et al, J Pediatr 2009
  • 31. Results Enemas PEG n=46 n=44 Drop-outs Successful disimpaction Successful disimpaction Drop-outs n=5 n=37 n=30 n=5 80% 68% *chi2 statistics p=0.28 (ITT)
  • 32. Defecation * Enema Defecation frequency/ ns ns PEG wk (±SE) Intake Disimpaction
  • 33. Fecal incontinence * Fecal incontinence / wk Enema ns * PEG Intake Disimpaction
  • 34. Adverse events 70 60 ns % Enema 50 40 PEG 30 20 10 Abdominal pain
  • 35. Adverse events 90 ns 80 70 Enema 60 % 50 PEG 40 30 20 10 Anxiety
  • 37. PEG and childhood constipation Authors Journal Year Pts Drugs Pashankar J Pediatr 2001 24 PEG Loening JPGN 2002 49 PEG vs MoM Gremse Clin Ped 2002 37 PEG vs lactulose Pashankar APAM 2003 83 PEG Pashankar Clin Ped 2003 73 PEG Michail JPGN 2004 28 PEG Loening JPGN 2004 74 PEG Voskuijl Gut 2004 90 PEG vs lactulose Dupont JPGN 2005/2006 96 PEG vs lactulose Rendelli APT 2006 76 PEG vs lactulose Loening Pediatr 2006 79 PEG vs MOM Thomson JPGN 2007 47 PEG vs placebo! Nurko J Pediatr 2008 103 Peg vs placebo
  • 40. Effect of PEG 3350 With Electrolytes vs Lactulose 14 *p<0.05 Baseline 12 n=91 8 weeks later 10 Median 8 number / 6 week 4 * * * * 2 0 Def Def FI FI PEG 3350 Lactulose PEG 3350 Lactulose Voskuijl WP, et al. Gut 2004; 53:1590
  • 42. Side effects after 8 weeks % patients with side effects 80 * p<0.05 60 Transipeg 40 * * * Lactulose 20 * 0 Abdominal Straining Pain Bad taste pain  No difference: diarrhea, stool consistency, nausea, bloating, flatulence difference: diarrhea, stool consistency,
  • 43. PEG 3350 for constipation in children younger than 18 months old 75 Infants 0 – 17 months • Initial 0,9 g/kg/day (0,26-2,14) • Maintenance 0.8 g/kg/day (0,26-1,26) • Duration of therapy (3 wks – 21 months) • Relieve of constipation 97,6% ?????? Loening-Baucke et al. JPGN 2004
  • 44. Effective dose PEG 4000 per age group Age category Dosage Range 6 – 12 months 4g (2.5-5g) 13 m – 3 years 6g (4-7,4g) 4 – 7 years 12g (7-16g) 8 – 15 years 16g (16-24g) 0.5 g/kg! Dupont et al. JPGN 2006
  • 45. Efficacy per age group after 3 months of treatment Age category Efficacy 6 – 12 months 100% (15/15) 13 m – 3 years 90% (27/30) 4 – 7 years 93% (26/28) 8 – 15 years 91% (21/23) Dupont et al. JPGN 2006
  • 46. PEG 4000 versus Lactulose Safety in children  Laboratory results: - HCO3-- , Na+, K+, Cl-- 3 + + - Creatinin, Osmolality, Albumin, Total protein, Iron, Vita a Folates, Vitdd - Hb, Ht  No changes after 3 or 12 months of therapy Pashankar et al. Arch Pediatr Adolesc Med 2003, Dupont et al. JPGN 2005
  • 47. Safety of high-dose PEG+E case report  33 month child ingested 160mg/kg iron  Whole bowel lavage with PEG+E performed over 5 days  Total volume administered: 44.3 litres  No clinical adverse events and no electrolyte abnormalities detected  Child made full recovery Kaczorowski JM et al. Ann Emerg Med 1996
  • 48. PEG intestinal lavage and aspiration in a 7-year old boy with severe constipation • Vomiting results in migration of the ng-tube • Recheck ng-position Wong et al. Arch Dis Child 2002 Liangthanasarn et al. JPGN 2003
  • 49. Adults Bisacodyl Children Price KJ Elliot TM Cochrane Database Syst Rev 2001;3, What is the Role of Stimulant Laxatives in the Management of Childhood Constipation and Soiling? SELECTION CRITERIA: All identified randomised controlled trials (RCTs) which compare the administering of stimulant laxatives to children with either placebo or alternative treatment. DATA COLLECTION AND ANALYSIS: No trials were found that met the selection criteria.
  • 51. Protocol • Randomization stratified by age and gender • 1 year: 1) conventional treatment (CT): - education - 0.5 – 1.5 g/kg polyethylene glycol - behavioral modification 2) Additional treatment with rectal enemas: - 3/week first 3 months; reduced by 1 enema/week every 3 months
  • 52. Intake Characteristics CT (n=50) ATE (n=50) Boys % 66 64 Age at baseline, y 11.0 10.5 median Duration of symptoms, y 7.0 6.5 median Def. freq / week 1.0 1.5 median FI freq / week 7.0 7.5 median
  • 53. Defecation frequency NS 25 P= <.001* P= <.001* times per week 20 15 10 5 0 baseline one year baseline one year CT ATE
  • 54. Fecal incontinence NS P= <.001* P= <.001* 45 times per week 40 35 30 25 20 15 10 5 0 baseline one year baseline one year CT ATE
  • 55. Success during one year 80 NS ATE 60 CT Percentage 40 20 0 3 6 9 12 Months
  • 56. Conclusions • No additional effect of rectal enemas in treatment of functional constipation • Rectal enemas have no role in maintenance therapy • Development of new treatment compounds for childhood constipation is needed
  • 57. Side effects of enemas • Related to water and electrolyte disturbances resulting from: − Hyperphosphataemia − Hypocalcaemia − Hypernatraemia − Metabolic acidosis • Absorptive effect of enema components and to their inadequate elimination in patients with co- morbidities Mendoza J et al. Aliment Pharmacol Ther 2007
  • 59. Are constipation drugs effective and safe to be used in children?: a review of the literature • Lack of large well-designed placebo controlled trials in childhood constipation • Any interpretation with regards to the evidence for the effectiveness or safety of laxatives used in children is difficult • Serious side effects of laxatives in children are rarely reported; however, evidence for the safety of short- and long-term use of laxatives in children with constipation is limited Van Wering et al. Expert Opin Drug Saf 2011
  • 60. NEW DRUGS in the pipeline!
  • 61. 5-HT4 RECEPTOR AGONISTS Selectivity of agonists Receptor binding profile at therapeutic concentrations Class Drug 5-HT4 5-HT3 5-HT2 5-HT1 D2 hERG Cisapride + + + + Renzapride + + Benzamide Clebopride + + + Mosapride + + Naronapride + Tegaserod + + + Carbazimide Velusetrag + Benzofurane Prucalopride +
  • 63. Pooled data: Response maintained over the 12 week treatment period 50% 45% placebo pru 2mg pru 4mg 40% 35% 30% 25% 20% 15% 10% 5% 0% run-in Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 % subjects with ≥3 SCMB/week
  • 64. PRUCALOPRIDE Safety and tolerability: adverse events Most common drug-related adverse events 30 Placebo (n=661) Prucalopride 2 mg (n=659) Prucalopride 4 mg (n=657)0 25 20 Patients (%) 15 10 5 0 e e l l a a in na in na a a ch ch oe oe se se pa mi pa mi da da rrh rrh au au do do ea ea ia ia N N Ab Ab D D H H Events during treatment period Events excluding Day 1 Tack et al. Gastroenterology 2008
  • 65. Efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation Goldberg M et al. Aliment Pharmacol Ther 2010
  • 66. The Role of Chloride Channels in Intestinal Transport • Lubiprostone is a bicyclic functional fatty acid • Selectively activates chloride channel-2 (CIC-2) – Enhance intestinal fluid secretion – Facilitate increased motility • FDA approved in January 2006 Lubiprostone
  • 67. Effects of Lubiprostone on Number of Spontaneous Bowel Movements 7 p = 0.0001 p = 0.0017 p = 0.0002 p = 0.0002 6 5 24 µg lubiprostone BID Bowel 4 movements per week 3 Placebo 2 1 n = 242 Intent-to-treat population 0 Baseline Week 1 Week 2 Week 3 Week 4 Johanson et al. Am J Gastroenterol 2008
  • 68. Long-Term Safety and Effectiveness of Lubiprostone, in Patients with Chronic Idiopathic Constipation Parkman et al. Dig Dis Sci 2011
  • 70. Two Randomized Trials of Linaclotide for Chronic Constipation Primary end point: N = 1276 >3 CSBMs per week Lembo et al. New Eng J Med 2011
  • 71. Adverse effects of Linaclotide in patients with Chronic Constipation Lembo et al. New Eng J Med 2011
  • 73. Primary care physicians • After 2 months of treatment 40% remains symptomatic • Primary care physicians tend to undertreat • Colonic evacuation with laxatives were more likely to respond Borowitz et al. Pediatrics 2005
  • 74. Clinical outcome at follow up N = 47, median age 3,5 months 100 Cumulative success percentage (%) 80 60 *= p 0.002 40 20 < 3 months symptoms 0 > 3 months symptoms 0 6 12 18 24 30 36 Time until first success (months) Vanden Berg et al. J Pediatr 2006
  • 75. Results Outcome with and without laxatives 190 190 188 187 183 188 186 174 165 154 137 126 115 76 24 1 Number included 3 2 3 3 6 0 0 5 3 3 3 2 1 0 0 0 Number missing 100 80 No succes lax+ No succes lax- Percentage 60 Succes lax+ Succes lax- 40 20 0 0,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time of follow-up (years)
  • 76. Summary and Conclusions • Constipation is a common entity in childhood constipation • Early and long-lasting treatment with oral laxatives is necessary in the majority of children with constipation • Serious side effects of oral and rectal laxatives are rarely reported