Management of Constipation - Bowel Cancer UK

Constipation: new options for acommon problemAnton EmmanuelMarch 2013National Hospitalfor Neurology& Neurosurgery

Constipation is a common problem8-25% community prevalenceFemale preponderance (2 to 8 times)>500,000 physician visits/year£60m /year on OTC laxatives1.2m laxative prescriptions / year

Auto-intoxicationConstipation: the “disease of diseases”In his lifetime, accepted as nonsenseZero evidence to support in 100 years(Ernst, J Clin Gastro 1997)(Muller-Lissner & Kamm, Gut2007)Arbuthnot-Lane1856-1943

Bowel opening is complexChronic constipationGot to be fullHave to know that it is fullGot to squeeze itGot to take the lid off and putit back on

Effect of dietary fibre & exerciseNurses Health Study: 62,036 women aged 36-61 years3327 (5.4%) constipated ( 7.7gm/dayNot a trialPossible confoundingby co-morbiditiesDukas et al Am J Gastroenterol 2003;98(8):1790-6

Benefit and limitations of exerciseSeveral other studies link exercise with reduced riskCommunity survey of 1,699 Japanese>4h /day walking reduces risk OR 0.46(0.2-1.0)Nakaji et al Eur J Nutr 2002;41(6):244-8One RCT of exercise in IBS-C56 IBS randomised to usual care or 12 weeks exercise programmeRecruitment low (18%)Primary endpoint : QOL showed no changeSignificant improvement in constipationDaley et al Int J Sports Med 2008;29(9):778-82

Role of fluid intake?7% develop constipation in 3 months following admission to nursinghomeRisk factors: race, decreased fluid intake, pneumonia and Parkinson’sdiseaseRobson et al Dis Colon Rectum 2000;43(7):940-3Severe water restriction reduces stool weight• RCT in healthy volunteers reducing fluid intake from 2500ml to

Effect of fibreChemical effect manifests physicallyPhysical effect maximised outFermentabilityFermentationBiliary salts and fattrapped within thematrixEdges of particlesStoolbulkingGasSCFAStimulation ofpropulsion andsecretionExcitation ofsub-mucosalmechanoreceptorsWalldistensionColonic contractileactivityDecrease of segmentationIncrease of propulsionAcceleration of transit time

Bulking agentsDecreased total gut transit time after 1 month ofpsyllium in patients with dyssynergic defaecation 1P

Stool softenersDocusate appears less effective than psyllium in improving bowel movementsand stool output after 2 weeks in patients with normal transit constipation 4P

Osmotic agents: LactuloseSlow transit success (needing ≤1 additionallaxative during 3-week treatment period) withlactulose 1Reduced faecal impaction after 2 monthsof lactulose 1P

Osmotic agents: polyethylene glycolHigher stool frequency with PEG vslactulose after 1 month: elderly 1P

StimulantsMore frequent bowel movements with bisacodylvs placebo in patients with “occasional misseddays” 3 *More frequent bowel movements with sennoside plusbulk laxative vs lactulose in elderly patients (n=30) 4P

Are current laxative options effective?16–40% of those with constipation use laxativesSymptoms persist despite laxative use10080Patients with ongoing constipation symptoms (%)Use laxativeDo not use laxative6040200 US UK FR GE IT BR SKCountryApproximately 2000 adults each from: United States, US; United Kingdom, UK;France, FR; Germany, GE; Italy, IT; Brazil, BR; South Korea, SKWald et al. Aliment Pharmacol Ther 2008;28:917

Patients requirements of constipation treatments?Speed of effect• Ideally within 1 hour of taking pill• This gives patient predictabilityDuration of action• Want the effectiveness to last for a longer period of timeUsage frequency & Type• Desire a product that can be taken on a “as needed” acute basis ratherthan ones that need to be taken chronically (e.g. once daily dosing)• Prefer OTC products to Rx therapies• Prefer pill to other formulationsSide effect profileGentleness of treatment• Besides fast onset, the absence of side effects is of major importance.Compatibility is absolutely key and it is very important that side effectsdon’t occur outside the stomach region (e.g. headaches or dizziness)• There is a strong desire for gentle, but effective treatments, (i.e.homeopathic or herbal products). This is based on negative feelingstowards chemicals and the fear to damage the body by chemical drugsInformation and education• There is a high and unmet need for information and education17

Laxatives for chronic constipation:Luminal mechanism of actionGUT WALLWaterbindingin stoolStoolsoftening &lowers surfacetension of stoolSalts, Sugars and Osmotic agentsFibre and Bulking agentsDocusate and Stool softenersPeristalsisSenna and Stimulant agentsTack & Müller-Lissner. Clin Gastroenterol Hepatol 2009;7:502

Chronic constipation:Symptoms in self-reported constipation● 1149 participants● 27.2% self-reported constipation within the past 3 months● 16.7% and 14.9% constipation according to Rome I and IISelf-reported responders (%)100806040200StrainingHard/lumpystoolsIncompleteemptyingStool cannot bepassedAbdominalfullness/bloating

To be asbrave as 21

Dispel mythsIs chronic constipation best treated byincreasing the intake of dietary fibre?Will increasing fluid intake improve chronicconstipation?Is increasing physical activity beneficial foralleviating chronic constipation?Does a long residence of stools in the colonlead to autointoxication?Can the long-term use of laxatives causeneuronal or muscular damage to the colon?

Dispel mythsIs chronic constipation best treated byincreasing the intake of dietary fibre?Will increasing fluid intake improve chronicconstipation?Is increasing physical activity beneficial foralleviating chronic constipation?Does a long residence of stools in the colonlead to autointoxication?Can the long-term use of laxatives causeneuronal or muscular damage to the colon?NotalwaysNotalwaysUnlikelyNoUnlikely

MythsDoes long-term use of laxatives increasethe risk of colorectal cancer?Can laxatives lead to tolerance,dependence and addiction?Can laxatives be used in combination witheach other?Is it abnormal to have a stool that is toohard or too loose?Is it abnormal to have less than one bowelmovement per day?

MythsDoes long-term use of laxatives increasethe risk of colorectal cancer?Can laxatives lead to tolerance,dependence and addiction?Can laxatives be used in combination witheach other?Is it abnormal to have a stool that is toohard or too loose?Is it abnormal to have less than one bowelmovement per day?HighlyunlikelyRarelyYesNotnecessarilyNotnecessarily

Emerging treatments“Prokinetics”Gut flora in colon lumen5-HT 4 receptorBasolateral membraneTight junctionApical membraneLumenEpithelial cell layerChloridechannelMucosaCl –Enteric nervous systemMuscularis mucosaSubmucosaCircular muscle layerMyenteric nerve plexusGuanylatecyclasereceptorLongitudinal muscle layer+Cl –Prucalopride▼Alvimopan*Lubiprostone*MethylnaltrexoneLinaclotide*Probioticsμ-opioid receptor* Not licensed within UK (February 2012)

Probiotics in chronic constipation1 pot b.d.Bifidobacterium lactis1.25 × 10 10 cfuStreptococcus thermophilus1.2 × 10 9 cfuLactobacillus bulgaricus1.2 × 10 9 cfuAgrawal et al Aliment Pharmacol Ther 2008

Emerging treatments: Medical probioticsRCT details•Lactobacillus caseiShirota vs placebo 1•70 adults; 4-weeks•Lactobacillus caseirhamnosus vs MgOvs placebo 2•45 children; 4-weeks•Lactobacillus reuterivs placebo 3•44 infants; 12-monthsKey findings•Probiotic improved self-reported severity of constipation and stoolconsistency from Week 2 (P

Prokinetics vs. laxatives:laxativeprokineticlaxatives: act in the gut lumenprokinetics: act in the gut wallafter systemic absorption

Colonic 5-HT receptorsExtrinsicafferentExcitatorymotorneuron AChSPSensoryneuron+ + + – – –NOVIPInhibitorymotorneuronACh = acetylcholine; SP = substance P;NO = nitric oxide; VIP = vasoactive intestinal peptide5-HT5-HT 4 receptor5-HT3 receptor

% over 12 weeksEfficacy in chronic constipation:≥3 SCBM/week (primary endpoint)3530252023.6***24.7***19.5**23.6***23.9**23.5**30.9***28.4***151011.39.612.1 12.050Camilleri 11(n=1924)Tack 2(n=713) (91% F)Quigley 3(n=641) (87% F)Camilleri 4(n=620) (88% F)SCBM = spontaneous complete bowel movementsPlacebo Prucalopride 2 mg Prucalopride 4 mg**p≤0.01 vs. placebo***p≤0.001 vs. placebo1Camilleri et al. Gastroenterology 2008;134:A548. 2 Tack et al. Gut 2009;58:3573Quigley et al. Aliment Pharmacol Ther 2008;29:315. 4 Camilleri et al. N Engl J Med 2008;358:2344The 4 mg dose has not been licensed since no incremental benefit wasdemonstrated versus the 2 mg dose

PrucaloprideEffect on symptoms associated with chronic constipation 1PRPRUI1. Kerstens et al.Gut 2010;59(Suppl III):A360

Oral MethylNaltrexone*not licensed in UK/EUEvidence primarily inopioid constipationChappell et al. NEJM 2008;Diego L et al. Expert Rev Gastroenterol Hepatol 2009

LinaclotideLembo et al NEJM 2011

eforeSphincterRectumSphincterafterRectum

Optimal timing for attempted defaecationNarducci et al Gut 1987;28(1):17-25

Importance of synchronising defaecatory effort withcolonic mass movementsDinning et al Gastroenterology 2004;127(1):49-56

Is biofeedback better than stimulantlaxatives?% improvementbiofeedbackbisacodylRCT BF vs bisacodyl(Rao et al AJG 2007)need to strain51 patients, all with dyssinergia1. Rao et al. Clin Gastroenterol Hepatol. 2007;5:331-8

75Biofeedback: Long Term BenefitsPre biofeedbackPost biofeedbackSymptom Scores50250

75Biofeedback: Long Term BenefitsPre BFPost BFfollow-up (median 4yrs)Symptom Scores50250

Transanal irrigationTechnique• Introduction of fluid (e.g.,lukewarm water) into the colonvia the anus, to evacuate faecesfrom the bowel 1Indications• Patients with constipation(and/or faecal incontinence)caused by neurogenic boweldysfunction due to spinal cordinjury (SCI) 1,2Contraindications• Acute active inflammatory boweldisease, and obstructing rectalor colonic mass 3411. Coggrave. Nurs Times 2007;103(26):472. Christensen et al. Gastroenterology. 2006;131(3):738-473. Coggrave. Nursing Times 2007;103(47):44-6[Image developed for ACT programme]

Transanal irrigationEvidence• Clinical trial data show success oftransanal irrigation in 65% SCIpatients with constipation 1-3– Improved symptoms andquality of life vs conservativemanagement 1,2Potential adverse effects• Estimated risk of bowel perforationin patients using transanalirrigation is ≤0.002% (1 in ~80,000irrigations) 4Outcomes of transanal irrigation in patients(n=79) with chronic idiopathic constipationafter mean follow-up of 21 months 3Idiopathicconstipation*Success, n(%)Slow transit (n=43) 14 (32.6)Obstructeddefaecation,but normal transit(n=30)13 (43.3)Undetermined (n=6) 0 (0)*According to the Rome criteria1. Christensen et al. Gastroenterology. 2006;131(3):738-472. Christensen et al. J Spinal Cord Med. 2008;31:560–73. Christensen et al. Dis Colon Rectum. 2009;52(2)286-924. Emmanuel, Spinal Cord 2010:48:664-73