Medikamentell behandling ved IBS – symptomstyrt behandling

Jan G. Hatlebakk Nasjonal kompetansetjeneste for

funksjonell mage-tarmsykdom Helse Bergen HF

Diagnosis and explanation Reassurance

Precipitating factors - Life style Assessment of symptom profile and severity

Dietary advice including probiotics

Pharmacotherapy – dominant symptom Constipation – Diarrhea – Gas/bloating – Psychological - Multiple

Psychological treatment options CBT – Hypnotherapy – Psychotherapy

Multidisciplinary approach Patient centered – Physician continuity

IBS – Sequencing the treatments

Törnblom & Simrén 2013

• Behandling som er rettet mot årsak

• Behandling som er rettet mot patogenetiske mekanismer – Gallesyreabsorsjon

– Antibiotica

– Pancreasenzymer

– Antiinflammatoriske medikamenter

• Behandling som er egnet til å lindre symptomer

Bile acid diarrhea – IBS Effect of a bile acid binding agent

Bajor et al Gut 2015

n=137

18% abnormal SeHCAT test

Colestipol treatment (n=27)

IBS

Symptom

Severity

Bile acid diarrhea in IBS-D

Slattery et al Aliment Pharmacol Ther 2015

28%

25%

IBS-D – Rome I, II & III IBS-D – Rome III

Treatment Bile Acid Diarrhea

Cholestyramine (Questran) 4 g daily initially, increased by 4 g at weekly intervals

(in 1–4 divided doses) to max. 36 g daily.

Other drugs should be taken 1 h before or 4–6 h after.

Cholesevelam (WellChol) 3.75 g daily in 1–2 divided doses; max. 4.375 g daily

Anti-diarrhoeals

Dietary treatment

Wilcox et al APT 2014

Antibiotica ved mistanke om bakteriell overvekst

• Metronidazole /Flagyl

• Ciprofloxacin

• Trimetoprim-sulfa /Bactrim

• Tetracycliner

• Rifaximin / Xifaxan

Rifaximin – IBS (non-IBS-C)

Pimentel et al NEJM 2011

Rifaximin – IBS - retreatment

Lembo et al ACG 2014

Pancreasenzymer ved mistanke om eksokrin insuffisiens

• Finnes hos 2-6% av pasienter diagnostisert med IBS

• Basert på lav f-elastase

• Bare 1-2% har sikker kronisk pancreatitt med rtg. / CT /EUS-funn.

Talley NJ et al. J Gastroenterol Hepatol 2017

Antiinflammatoriske medikamenter

• 5-ASA eller steroider ved mistanke om mikroskopisk colitt eller lavgradig colitt

• Prednisolon / budesonid

• Mesalazin

• Na-chromoglykat?

Mesalazin - Satisfactory relief of the overall IBS

symptoms).

Giovanni Barbara et al. Gut doi:10.1136/gutjnl-2014-308188

Primary efficacy analysis (satisfactory relief of abdominal pain or discomfort).

Giovanni Barbara et al. Gut doi:10.1136/gutjnl-2014-308188

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

• Behandling som er rettet mot årsak

• Behandling som er rettet mot patogenetiske mekanismer

– Gallesyreabsorsjon

– Antibiotica

– Pancreasenzymer

• Behandling som er egnet til å lindre symptomer

Meta-analyses – effective pharmacological treatment in IBS

• Soluble fibre (RR=0.83; 95% CI 0.73-0.94; NNT=7)

• Probiotics (RR=0.79; 95% CI 0.70-0.89; NNT=7)

• Antispasmodics (RR=0.68; 95% CI 0.57-0.81; NNT=5)

• Peppermint Oil (RR=0.43; 95% CI 0.32-0.59; NNT=2.5)

• 5HT3 antagonists (RR=0.78; 95% CI 0.71.0.86; NNT=7) (Cilansetron=Alosetron)

• Tegaserod (RR=0.85; 95% CI 0.80-0.90; NNT=10)

Ford et al Am J Gastroenterol 2014 x 2 Ford Am J Gastroenterol 2009 Ford et al BMJ 2008

Bloating

Pain

Distension

IBS M

C

D

FC

FDr

FC: Functional constipation FDr: Functional diarrhea IBS-C: Irritable bowel syndrome with predominant constipation IBS-D: Irritable bowel syndrome with predominant diarrhea IBS-M: Irritable bowel syndrome with mixed bowel habits (D and C)

Type 1

Type 2

Type 3

Type 7

Type 5

Type 6

Type 4

Functional Bowel Disorders: Rome IV

Lacy et al Gastroenterology 2016

Behandlingsprinsipper:

• Probiotica – Symprove® m.fl.

• Antibiotica – rifaximin

• Clorid-kanal aktivatorer (CIC-2) – Lubiprostone (Amitiza®)

• Guanylat cyclase 2c agonist – Linaclotide (Constella®)

• Opiatagonister og –antagonister – Asimadoline (kappa-agonist) – Eluxadoline (u-agonist, delta-antagonist)

• Serotonerge agonister og –antagonister – Prucaloprid (Resolor®) – Ondansetron (Zofran®)

• Mastcelle stabilisatorer – Na-chromoglycat

Avdeling / enhet

Edoxadoline

Probiotica

Simren M Gut 2013

IBS - Probiotics

McFarland et al WJG 2008

Behandling ved hard avføring

• Toleranse for fiber ofte lav

– Løselig fiber

– Uløselig fiber

• En kombinasjon av laxantia kan fungere

– Movicol

– Vi-Siblin

– Laxoberal

– …

Macrogol / PEG 3350 + Electrolytes for IBS-C

Chapman et al Am J Gastroenterol 2013

Linaclotide – IBS-C

Chey et al Am J Gastroenterol 2012

Rao et al Am J Gastroenterol 2012

Drugs in the pipeline

• Lubiprostone – CIC-2 activator

– approved for IBS-C, constipation, opiate-induced constipation

Avdeling / enhet

4/4 weeks with ≥ “moderately relieved” OR

≥ 2/4 weeks with “significantly relieved”

Not meeting any restriction criteria

Drossman et al Aliment Pharmacol Ther 2009

Lubiprostone - IBS-C

p=0.078

p=0.003

p=0.003

Crowell Nat Rev Gastroenterol Hepatol 2009

Loperamid

• For lite brukt

• Åpne kapsler eller mikstur

Ondansetron – IBS-D

Stool consistency

Ondansetron vs. Placebo: p<0.001

• n=120 IBS-D • 4mg Ondansteron • Dose titration allowed • 5 weeks; cross-over

Garsed et al Gut 2014

FDA responder criteria

Eluxadoline – IBS-D

Percentage of Patients Who Met the Daily Composite Response Criteria over Time.

Primary Efficacy End Point

Lembo et al NEJM 2016

Antidepressants IBS

Antidepressant receptor site effects

Norepinephrine Serotonin Histamine Acetylcholine

TCA

Amitriptyline +++ +++ ++++ ++++

Doxepine ++ +++ ++++ ++

Desipramine +++ +++ + +

Nortriptyline +++ + ++ ++

SSRI

Citalopram 0 ++++ 0 0

Escitalopram 0 ++++ 0 0

Fluoxetine 0 ++++ 0 0

Paroxetine 0 ++++ 0 0

Sertraline 0 ++++ 0 0

SNRI

Venlafaxine ++ ++ 0 0

Duloxetine ++++ +++ 0 0

Milnacipran ++++ ++ 0 0

TCA, Tricyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; SNRI, Serotonin-norepinephrine reuptake inhibitors; 0→++++ = None →Strong

Törnblom & Drossman Neurogastroenterol Motil 2015

Antidepressant drug classes – treatment of abdominal pain

TCA SSRI SNRI

Potential benefit Pain reduction Depression

Depression Panic Anxiety (Pain reduction)

Pain reduction Depression

Side effects Sedation Constipation Hypotension Xerostoma Arrhythmias Weight gain Sexual dysfunction

Agitation Diarrhea Insomnia Night sweats Headache Weight loss Sexual dysfunction

Nausea Agitation Dizziness Sleep disturbance Fatigue Liver dysfunction

TCA, Tricyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; SNRI, Serotonin-norepinephrine reuptake inhibitors;

Törnblom & Drossman Neurogastroenterol Motil 2015

Antidepressants - IBS

Ford et al Am J Gastroenterol 2014

RR=relative risk; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant

RR=0.66 (95% CI: 0.56-0.79)

RR=0.68 (95% CI: 0.51-0.91)

NNT=4 NNT=4

Verd å ta med:

• Varierende effekt av eldre preparater – trolig underforbruk av flere grupper inklusive TCA

• Effekt av nyere preparater ved IBS-C og IBS-D er lovende

• EMA og FDA har definert endpoints som nok underestimerer reell behandlingseffekt