Constipation in the Older Patient: When the Going gets Tough

1. Constipation in the Older Patient: When the Going gets Tough Karen Hall, M.D, Ph.D. Associate Professor Division of Geriatric Medicine University of Michigan

2. Objectives • Define “constipation” • Risk factors • Potential complications • Choices to treat constipation • Different management options • When to refer?

3. Burden of the problem Constipation: 2 % - 27 % in Western countries • US: > 2.5 million visits, 92,000 hospitalizations Compared to adults: more prevalent in women, nonwhites, children, and the elderly “Severe constipation” requiring hospitalization or surgery: young women and the elderly Stewart WF et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94:3530-3540. Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci 1989;34:606-611 Pare P et al. An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;96:3130-3137. Heaton KW et al. Defecation frequency and timing, and stool form in the general population: a prospective study. Gut 1992;33:818-824.

5. Definition • Research criteria vs “patient’s impression” • Patients describe: • Hard stools, infrequentstools, excessivestraining, a sense of incomplete bowel evacuation, and excessivetime spent on the toilet or in unsuccessful defecation • Rome II describes: • Inability to evacuate stool completely and spontaneouslythree or more times per week • Rome III (published April 2006): • Symptoms currently active 3 months • Use Bristol stool classification to define “constipation” Stewart WF et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94:3530-3540. Sandler RS, Drossman DA. Bowel habits in young adults not seeking health care. Dig Dis Sci 1987;32:841-845. Koch A et al. Symptoms in chronic constipation. Dis Colon Rectum 1997;40:902-906. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterol 2006 130:1377-90.

6. Used in Clinical Trials Correlates with symptoms of straining and difficult evacuation Also correlates with colonic transit (Type 1 or Type 7 stool is correlated with slow or rapidcolonic transit Degen LP, Phillips SF. How well does stool form reflect colonic transit? Gut 1996;39:109-113. Majority of “constipated” patients have stools that are Type 1-3 University of Bristol, Scand J Gastroenterol, 1997

7. Risk factors for Constipation • Inherited or aquired neuromuscular disorders • Metabolic disease • Pathophysiologic changes with aging • Medications • Gender: female (hormonal and structural causes) • Physicalinactivity • Low income • Limited education • History of sexualabuse • Symptoms of depression • Low dietary fiber Everhart JE et al A longitudinal survey of self-reported bowel habits in the United States. Dig Dis Sci 1989;34:1153-1162.

8. Risk Factors: Disease • Neurologic: Parkinson’s disease; Multiple sclerosis, CVA • Collagen vascular: scleroderma, mixed connective tissue disease • Metabolic: diabetes mellitus, hypercalcemia, hypothyroidism • Intestinal pseudoobstruction • Structural: tumors, strictures, diverticula

9. Constipating MedicationsOTC • Sympathomimetics • NSAIDS • Antacids: aluminum, calcium • Ca supplements • Iron supplements • Antidiarrheals: loperamide; bismuth

10. Prescription Medications • Narcotics - codeine,morphine • Anticholinergics - benztropine, trihexyphenedyl • Antipsychotics - chlorpromazine • Antidepressants - tricyclics • Antiparkinson - levodopa • Antispasmodics - dicyclomine • Antihistamines - diphenhydramine • Ca blockers - verapamil • Diuretics - furosemide

11. Pathophysiolgic changes in colon with age • 37% decrease in myenteric and submucous plexus neurons in rats and humans primarily in the colon (CGRP, ACh) • Decreased cholinergic myenteric activitiy (fewer, smaller contractions) • Loss of NO containing neurons (NADPH-diaphorase levels aged > fetal > Crohn’s > adult • Impaired relaxation and increased segmental contractions (impaired peristalsis) • Decreased neurotrophin production and release • Decreased calcium influx into neurons, less calcium released in smooth muscle • smaller contractions, impaired peristalsis • Increased connective tissue • Increased intraluminal pressure and formation of diverticula Belai and Burnstock Dig Dis Sci 1999; Santer and Baker J Auton Nerv 1988; Belai et al. Cell Tissue Res 1995; Gomes et al Gerontol 1997; Wade, AGA 2002 Phillips and Powley J Comp Neurol 2001Sheng et al J Neurophysiol 2001, Roberts et al. J Pharm Exp Ther 1994

12. Is gut transit slow in constipated patients? • Studies measuring rate of transit through the bowel and anorectal function in constipated patients without structural disease: • Normal-transit (59 %) • Slow-transit (13%) • Impaired rectal evacuation (25%) • Mixed (3%) • Primarily based on studies in young adults • Select populations (LTC patients) may have higher rates of slow transit (Prather 2000).

13. Slow-Transit Constipation • Measured using Sitz markers (radio-opaque) or scintigraphy (technicium-labeled egg) • Total gut transit and transit through stomach, ileum and colon measured by sequential studies at 2,4,6,24,48,72 hours < 50% gastric emptying in 2 hours < 40% to terminal ileum in 6 hours < 50% expulsion of marker in 72 hours • Patients with slow transit may benefit from stimulant laxatives if neuromuscular function is intact • If neuromuscular function severely impaired: may need surgery Mertz H, Naliboff B, Mayer E. Physiology of refractory chronic constipation. Am J Gastroenterol 1999;94:609-615.

14. Normal-Transit Constipation • “Functional" • Stool transit is normal, frequency is normal, yet patientsbelieve they are constipated • Perceived difficulty with evacuationor the presence of hard stools • Bloating,abdominal pain or discomfort,increased psychosocial distress • Increased rectalcompliance, reduced rectal sensation, or both • Symptoms ofconstipation usually respond to therapy with dietary fiberalone or with the addition of a laxative (older patients may need laxative) Ashraf W et al. An examination of the reliability of reported stool frequency in the diagnosis of idiopathic constipation. Am J Gastroenterol 1996;91:26-32. Mertz H et al. Physiology of refractory chronic constipation. Am J Gastroenterol 1999;94:609-615. Voderholzer WA et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997;92:95-98.

15. Impaired Rectal Evacuation • Important to identify because treatment is different – laxatives may not be effective • Dysfunction ofthe pelvic floor or anal sphincter • May be associated with structural problems • Anal fissure • Rectocele

16. NEJM

17. Impaired Rectal Evacuation • Impaired relaxation of the puborectalis muscle • inability to coordinate the abdominal,rectoanal, and pelvic-floor muscles during defecation • “learned”: prolonged avoidance of the pain associated with either the passageof a large, hard stool or an anal fissure or hemorrhoid mayresult in defecatory disorders • Biofeedback training can improve puborectalis coordination • Abnormal rectal morphology • Rectocele: caused by contraction and straining against a “closed outlet”; rectal muscle gets thinner with age, anal sphincter injury during childbirth Klauser AG, Voderholzer WA, Heinrich CA, Schindlbeck NE, Muller-Lissner SA. Behavioral modification of colonic function: can constipation be learned? Dig Dis Sci 1990;35:1271-1275. Loening-Baucke V. Encopresis and soiling. Pediatr Clin North Am 1996;43:279-298. Camilleri M, Thompson WG, Fleshman JW, Pemberton JH. Clinical management of intractable constipation. Ann Intern Med 1994;121:520-528. Rao SS, Welcher KD, Leistikow JS. Obstructive defecation: a failure of rectoanal coordination. Am J Gastroenterol 1998;93:1042-1050

18. Defecatory Disorders • Identified clinically and with use of defecography: reduced descent of the perineum during simulation of straining to defecate

19. Back to the clinic: History • Screen for risk factors and secondary causes • Medication use • Stool frequency (<3/week) • Stool form using the Bristol stool scale • very loose or hard stools are correlated with rapidor slow colonic transit • Prolonged straining, unusual postures, support of perineum, digitation of rectum, posterior vaginal pressure, inability to expel enema fluid and constipation after subtotal colectomy • Suggests anorectal dysfunction

20. Physical Examination “Intelligent Rectal Exam” (Mike Camilleiri, Mayo clinic) • Inspection • Anal pathology: hemorrhoids, prolapse • Check for sensation • Ask patient to strain: anus moves laterally, ballooning of perineum (rectocele) • Palpation • Increased anal tone & pressure, anal fissure • tenderness of puborectalis muscle • mucosal prolapse or anterior rectal wall defect • Ask to strain: perineum descends on finger <1.0 or > 3.5cm

21. Laboratory Tests • Thyroid function tests • Electrolytes • Calcium • CBC • Urine analysis • Screen for colorectal cancer if none in last 5 years

22. Indications for Endoscopy • New onset constipation: • Weight loss,macroscopic or microscopic blood, family h/o colon Ca, anemia, undiagnosed abdominal pain • Chronic constipation: • Anemia, weight loss, change in stool pattern, undiagnosed abdominal pain • Failure of multiple laxatives • Undiagnosed fecal incontinence

23. Additional Examination • Anoscopy • If you feel comfortable doing this • fissure, fistula, stricture, carcinoma in rectum • If you suspect defecatory disorder: refer to anorectal investigatory group (GI Functional Bowel Disorders; Gynecology: Dr. Dee Fenner; General Surgery) • Anorectal manometry & balloon expulsion • Defecography if above equivocal or suspect structural abnormality • If patient fails trial of fiber and laxatives: refer to specialist (GI, General Surgery) • Colonic transit time

24. Management • Toilet training • Fiber • Laxatives • Prokinetic Drugs For anorectal dysfunction: • Biofeedback Therapy • Botulinum Type A Toxin • Surgery

25. Treat impaction first • Patients with fecal impaction should have the impacted fecesremoved manually or, if necessary, with enemas before starting laxatives • Tap water • Milk and molasses (1 liter; ½ cup) • Mineral oil (less effective) • Not soapsuds (increased risk of colitis) • May take several attempts Wrenn K. Fecal impaction. N Engl J Med 1989;321:658-662

26. Anorectal dysfunction • Biofeedback Therapy • Visual and auditory feedback while contracting anal sphincter and pelvic floor • Anorectal electromyographyor a manometry catheter can be used • Simulated evacuation with a balloonor silicon-filled artificial stool, called "fecom," may be used to train patients to achieve normal coordination Pelsang RE, Rao SS, Welcher K. FECOM: a new artificial stool for evaluating defecation. Am J Gastroenterol 1999;94:183-186.

27. Biofeedback • Patient education and rapport betweentherapist and patient are key to successful biofeedback • Success rate is up to ~70 percent • The benefits appear to be long-lasting. • May be less effective for patients with descendingperineum syndrome than for patients with other defecatory disorders Harewood GC, Coulie B, Camilleri M, Koutsomanis D, Lennard-Jones JE, Roy AJ, Kamm MA. Controlled randomised trial of visual biofeedback versus muscle training without a visual display for intractable constipation. Gut 1995;37:95-99. Enck P. Biofeedback training in disordered defecation: a critical review. Dig Dis Sci 1993;38:1953-1960. Rath-Harvey D, Pemberton JH. Descending perineum syndrome: audit of clinical and laboratory features and outcome of pelvic floor retraining. Am J Gastroenterol 1999;94:126-130.

28. Anorectal dysfunction • Botulinum Type A Toxin • Injection into puborectalis muscle has been effective in thetreatment of defecatory disorders involving spastic pelvic-floormuscles Ron Y, Avni Y, Lukovetski A, et al. Botulinum toxin type-A in therapy of patients with anismus. Dis Colon Rectum 2001;44:1821-1826.

29. Back to the basics • Non pharmacologic • Bowel training (go to bathroom after breakfast) • High fiber diet > 20g/day • Exercise and increased fluid intake (beneficial for patients who aredehydrated) • Most patients without defectatory impairment respond to dietary fiberalone or with the addition of an osmotic or stimulant laxative

30. Is there evidence for laxative selection? • Recent review indicated “good evidence (Grade A) was found to support the use of polyethylene glycol (PEG) and tegaserod. Moderate evidence (Grade B) was found to support the use of psyllium, and lactulose. There was a paucity of quality data regarding many commonly used agents including milk of magnesia, senna, bisacodyl, and stool softeners. “ Ramkumar D, Rao SS.Efficacy and safety of traditional medical therapies for chronic constipation: systematic review.Am J Gastroenterol. 2005 Apr;100(4):936-71

31. Fiber Increases colonic residue,stimulating peristalsis • Psyllium (Metamucil-natural fiber) • Methyl cellulose (Citrucel-semi synthetic) • Polycarbophil (Fibercon-synthetic fiber) • Side effects: flatulence, distention,bloating, and unpleasant taste • In normal-transit or slow-transit type: fiber intake increased to 20 to 25g per day over a period of one to twoweeks

32. Management • If fiber doesn’t work, or patient is “very constipated” - use an osmotic laxative • Increase dose gradually over several days until loose stools are formed

33. Osmotic laxatives • Osmotic laxatives • Poorly absorbed or nonabsorbed • Draws water along osmotic gradient • In patients with renal insufficiency orcardiac dysfunction, may cause electrolyteand volume overload from absorption of sodium, magnesium, orphosphorus. • Overuse can cause dehydration

34. Osmotic laxatives • Magnesium (MOM) • Poorly absorbed sugars • Lactulose - synthetic disaccharide (10-30 g/day) $20/500 ml • Sugar alcohols • Sorbitol & Mannitol $8/month • Polyethylene glycol & Electrolytes GoLYTELY, NuLYTELY $25 • Polyethylene glycol 3350 (Miralax) (17g/day) $41.69

35. Stimulant laxatives Increase intestinal motility and secretion Effective within hours and may cause abdominal cramps Concern about long term use causing cathartic colon (loss of haustrationand dilatation of the colon) –phenolphthalein (old formulation of Exlax) and cascara Melanosis coli may develop in patients who take stimulantlaxatives containing anthraquinones, but this is not a risk for development of colon cancer Badiali D, Marcheggiano A, Pallone F, et al. Melanosis of the rectum in patients with chronic constipation. Dis Colon Rectum 1985;28:241-245. van Gorkom BA, de Vries EG, Karrenbeld A, Kleibeuker JH. Anthranoid laxatives and their potential carcinogenic effects. Aliment Pharmacol Ther 1999;13:443-452.

36. Stimulant Laxatives Useful in multifactorial refractory constipation without obstruction • Anthraquinones • cascara • senna (recent trials indicate safe for long term use but only Grade C evidence that it is effective) • Sennakot up to 4-6 per day ($6.00/100 tablets) • Diphenylmethane derivatives • Bisacodyl $20/100 tablets • “Stool softener” • Docusate sodium (not as effective as psyllium) • McRorie et al. Aliment Pharmacol Ther 1998 12:491-7 • Mineral oil (avoid – risk of aspiration pneumonia) • Castor oil - Ricinoleic acid(avoid may cause cathartic colon)

37. Other treatments Cholinergic agents • Bethanechol • Likely to cause cramps, may cause confusion in older patients with underlying cognitive disorders • Miscellaneous • Misoprostol 200-400 mcg/day • Colchicine

38. “Prokinetic Drugs” • Cisapride - substituted benzamide • Stimulates peristalsis by increasing acetylcholine release from myenteric plexus • Increased risk of cardiac arrhythmias • 5-hydroxytryptamine receptor agonists • Tegaserod - partial 5-HT4 receptor agonist • Improves stoolconsistency and frequency in women with irritable bowel syndrome + constipation (IBS-C) Muller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001;15:1655-1666.

39. Tegaserod • Recent review of therapy (Rao 2003): only PEG and tegaserod received grade A recommendation (2 or more >12 week randomized Level I trials showing benefit without conflicting evidence from Level 1 trials) • Increased # spontaneous BM, decreased straining • Accelerated cecal transit (Prather 2000, Foxx-Orenstein 2005) • Only powered to detect effect in patients < 65 years (age range 18-88 but mean age 47 +/- • Safety data indicates older patients have small increase in plasma levels, prolongation of half life (13 hours vs 11) • No dose adjustment for mild-moderate renal or hepatic impairment. Cannot be dialysed.

40. Novartis Tegaserod Study William Chey, M.D., University of Michigan, Henry Parkman, I Bottoli, D. Joseph, Lina Nahlawi (administrator), Karen Hall, M.D. • RDBPC parallel group multicenter study • Primary outcome: orocecal transit by scintigraphy (S) • Secondary outcomes: total gut transit, gastric emptying, symptoms per diaries After screening, subjects will have two week baseline then will be randomized to Tegaserod 6 mg bid or placebo. Daily diaries of stool frequency, consistency and symptoms reviewed weekly Screening - Baseline - Treatment 4 weeks 2 weeks 2 weeks Day -42 to -15 Day -14 Day 15-17 Balloon expulsion 1st S 2nd S Rescue medication: bisacodyl if no BM x 72 hours

41. Novartis Tegaserod Study Inclusion criteria: • Age > 65 years • Less than 3 spontaneous BM/week • At least 25% very hard or hard stools (Type 1 and 2 on Bristol stool scale) • Straining on at least 25% of defecation • Willing to avoid change in lifestyle or diet during study • Able to adhere to restrictions re: meds • Structural exam of colon within past 5 years • No evidence of dyssynergic defecation • Able to comply with assessments and diary

42. Novartis Tegaserod Study Exclusion criteria: • Uncontrolled disease (CVS,Resp,renal,psych,thyroid) • Loose stools at least once per week (Type 6 or 7) • Abdominal pain relieved by defecation (IBS) • Constipation secondary to medications • Malabsorbtion of study medication • Use of investigational drug within 30 days of screening • History of cathartic colon or laxative abuse • History of fecal impaction requiring surgery or manual intervention • History of using manual maneuvers to obtain a BM • Allergy to eggs • Unwilling or unable to comply

43. Lubiprostone (Amitza) • Selectively activates type 2 chloride channels (ClC-2) in apical membrane of the gastrointestinal tract Cuppoletti J. Malinowska DH. Tewari KP. Li QJ. Sherry AM. Patchen ML. Ueno R.. SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. American Journal of Physiology - Cell Physiology. 287(5):C1173-83, 2004. • Increased fluid secretion into lumen • No significant systemic absorption

44. Lubiprostone • Two RDBPC multicenter phase III studies in patients with chronic idiopathic constipation (1-2 spontaneous bowel movements per week) • Significant increase in stool frequency at 24 mcg/day, higher doses similar

45. Lubiprostone: Geriatric patients • Similar results in DBRPC trial with 479 patients aged 20-81 (~10% over age 65) • Baseline 1.4 +/- 1.3 bowel movements • Lubiprostone increased bowel movements to 5.9 per week compared with 4.0 per week in the placebo group (p < 0.0001) • Significant improvement in straining, stool consistency and constipation severity by self report • No serious adverse events but nausea common - up to 31% of patients receiving lubiprostone • Open label trials: 871 patients (18.4% > age 65) treated 6-12 months had decreased abdominal bloating, discomfort • No data on efficacy and safety in nursing home setting, or patients with significant co-morbidities

46. Surgery For refractory constipation • Total colonic resection and ileorectostomy • Patient does not have defecatorydisorder • After medical therapies have failed • Colonicresection is generally reserved for patients with slow-transitconstipation • A review of 32 studies showed that between 39 percent and 100percent of patients were satisfied after colectomy • Very little data in older patients (>95% of studies patients are young (25-45 years) and female • Knowles CH, Scott M, Lunniss PJ. Outcome of colectomy for slow transit constipation. Ann Surg 1999;230:627-638.[

47. Surgery • Complications of surgery: obstruction of the smallbowel, diarrhea, and incontinence • Diarrhea andincontinence improved after the first year • Patients withupper-gut dysmotility (gastroparesis or pseudo-obstruction)or psychological disturbances have poorer outcomes • Laparoscopic subtotal colectomy is as effectiveas laparotomy • Rectal surgery: only in patients with functionally significant rectocele whose constipation is relieved with application of digital vaginal pressure to facilitate defecation.