medikamentell behandling ved ibs – symptomstyrt behandling · pancreasenzymer ved mistanke om...
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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