Use of Macrogol 4000 in Chronic Constipation

European Review for Medical and Pharmacological Sciences 2011; 15: 960-966 Use of macrogol 4000 in chronic constipation

R. DE GIORGIO1, R. CESTARI2, R. CORINALDESI1, V. STANGHELLINI1, G. BARBARA1, C. FELICANI1, G. DI NARDO3, S. CUCCHIARA3

1Department of Clinical Medicine, School of Medicine, Alma Mater Studiorum University, Bologna (Italy) 2Digestive Endoscopy, Department of General Surgery, School of Medicine, University of Brescia – Spedali Civili, Brescia (Italy) 3Department of Pediatrics, School of Medicine, University “La Sapienza”, Rome (Italy)

Abstract. – Background: Chronic consti- feces and difficult, infrequent evacuations in the pation is a common functional disorder of the absence of detectable abnormalities. This condi- gastrointestinal tract, affecting up to 35% of the tion is very common in the general population, general population, and especially the elderly. However, its definition as perceived by the pa- with a prevalence ranging from 2% to 35%. Fe- tient can vary, making it difficult to understand males (female-to-male ratio of 2-3:1), the elderly the problem and find appropriate therapeutic (>65 years of age), people of non-European de- measures. The approach to chronic constipa- scent and those with a lower socioeconomic sta- tion, thus, needs a thorough understanding of tus are more likely to be affected1,2. Only a frac- the patient’s complaint and the main pathophysi- tion (approximately 25%) of patients consults a ological mechanism requiring treatment. doctor, while most seek alternative solutions such Lifestyle changes do not usually meet with complete patient satisfaction. Other treatments in- as the advice of pharmacists or practitioners of clude different types of laxatives. Of these, os- herbal medicine. As with other functional bowel motic laxatives appear one of the most effective diseases (e.g. irritable bowel syndrome and dys- and are, therefore, frequently prescribed. pepsia), the quality of life of patients with chron- Design: This review will cover the topic of os- ic constipation can suffer as much as patients motic laxatives, specifically focusing on polyeth- with organic diseases such as chronic obstructive ylene glycol (PEG/macrogol 4000) in chronic 3,4 constipation and as a key agent for bowel pulmonary disease or diabetes . cleansing prior to colonoscopy. PEG formula- There is no consensus on the definition of tions, including macrogol 4000, are safe, effec- constipation, making it difficult to understand tive treatments for constipation, even in children the problem and find appropriate therapeutic and elderly patients. Macrogol 4000 may well be measures. The classic criterion used by some more palatable than combined formulations patients is a limited number of evacuations per (macrogol 3350 with electrolytes), which could week5, while others consider themselves consti- help improve adherence to the long-term treatment required for chronic constipation. pated if they have hard stools or must strain ex- Conclusions: PEG/macrogol is also recom- cessively during defecation. Although epidemi- mended as an effective option for bowel cleans- ological studies confirm that 2-3% of the popu- ing prior to colonoscopy. The improved cost-ef- lation have few (less than three) bowel move- fectiveness of macrogol over other commonly ments per week, this number is only an approx- prescribed laxatives, such as lactulose, should imate criterion for defining constipation and be taken into consideration. may cause the real number of affected patients Key Words: to be underestimated considerably. Internation- al groups of experts have, thus, developed Chronic constipation, Polyethylene glycol, Osmotic symptom-based criteria (the best known of laxatives, Colonoscopy which being the Rome criteria) for an appropriate definition. According to the most recently accepted Rome III criteria2, a patient is defined as consti- Introduction pated if he or she has suffered two or more of the following symptoms for at least 3 months Chronic constipation is a functional disorder with symptom onset at least 6 months prior to of the gastrointestinal tract characterized by dry diagnosis:

960 Corresponding Author: Roberto De Giorgio, MD, Ph.D.; e-mail: [email protected] Use of macrogol 4000 in chronic constipation

• Straining during at least 25% of defecations; Nonetheless, it should be stressed that at least in • Lumpy or hard (“nut-like”) stools in at least a minority of patients, constipation may be the 25% of defecations; first alarm symptom of disease, such as cancer, • Sensation of incomplete evacuation for at least or a symptom of metabolic abnormalities (e.g. 25% of defecations; hypothyroidism or hypercalcemia) or neurologi- • Sensation of anorectal obstruction for at least cal diseases (e.g. Parkinson’s disease) (Table I)6. 25% of defecations; Figure 1 illustrates a simple diagnostic algorithm • Manual maneuvers to facilitate defecation in at with different tests which can be applied to better least 25% of defecations; standardize the approach to patients with chronic • Fewer than 3 defecations/week; constipation. • Loose stools rarely present without use of lax- A thorough history taking and clinical evalua- atives; tion are extremely important in order to rule out • Insufficient criteria to justify a diagnosis of ir- any organic or systemic disease. It is useful to ritable bowel syndrome (IBS). evaluate the clinical presentation of the illness (chronic vs. recent constipation), drug use, with Chronic constipation may be associated with a special attention to medicines capable of slowing further degree of disability, if patients have im- down gastrointestinal motility and transit (such pacted feces in the rectum or in more proximal as opiates, analgesics, tricyclic antidepressants, segments of the colon. This may lead to paradox- diuretics, calcium channel blockers, nitrates, an- ical diarrhea (“overflow”) or incontinence (“soil- tihistamines, anti-psychotic and antiparkinsonian ing”), which further worsens the patient’s quality agents – see also Table I), alarm signs and symp- of life1-3. toms (e.g. weight loss, rectal bleeding, palpable abdominal masses, increased erythrocyte sedi- Diagnostic Approach mentation rate), and the coexistence of neurolog- In most patients constipation is an expression ical illnesses. Perineal inspection and rectal ex- of an underlying abnormal colorectal function amination are essential to exclude the presence of that is not associated with organic (inflammatory, anal fissures, fistulas, abscesses or neoplasms. neoplastic) disorders of the gastrointestinal tract. Further examinations, including a complete

Table I. Causes of chronic constipation.

Mechanical Endocrine • Stenosing neoplasms • Hypothyroidism • Extrinsic compression (e.g. pelvic tumors) • Pheochromocytoma • Painful hypertonicity of the anal canal • Addison’s disease (idiopathic anal fissure) • Stenosis/fibrosis of the anal canal Neurological and Psychiatric • Hirschsprung’s disease Pharmacological • Diabetic neuropathy • Anticholinergics • Multiple sclerosis • Antihistamines • Parkinson’s disease • Calcium-channel blockers • Autonomic neuropathies • NSAIDs • Guillain-Barre Syndrome • Dopaminergics • Spinal lesions • Tricylic antidepressants • Damage to the sacral parasympathetic nerves • Antipsychotics • Anorexia nervosa • Opiates • Depression • Iron therapy • Dementia • Aluminum salts (antacids) • Cholestyramine Pregnancy • Diuretics • Antidiarrheals Dehydration

Surgical • Abdominal–pelvic surgery (adhesions) • Colon surgery (anastomosis of insufficient size) • Anorectal surgery (postoperative stenosis)

961 R. De Giorgio, R. Cestari, R. Corinaldesi, V. Stanghellini, G. Barbara, et al.

The relative impact of each of these forms is Patient with chronic constipation approximately 59%, 13% and 25% of cases7,8. Patients with overlapping slow transit and obstructed defecation may also be observed in the clinical setting. Clinical history / physical examination; Colonoscopy / barium enema Irritable bowel syndrome with constipation (IBS-C) is a common condition in which chronic or recurrent constipation is associated with normal gut transit. IBS-C can be differentiated from Normal colon normal transit constipation by the presence of abdominal pain, predominant in IBS with respect to functional constipation2,9. Proctological examination; In this short review, we will focus on the two GI transit time major forms of constipation, slow transit and obstructed defecation. Colonic motor activity is mainly under the control of the enteric nervous system, while defecation is the result of pelvic Disorders of the Altered motility 6 pelvic floor reflexes and voluntary control . Before looking at the pathophysiology, it is important to point out that colonic motor activity is mainly irregular, in- creasing after meals and upon awakening and de- Anorectal manometry creasing during sleep. Colonic motility generally Colonic manometry Defecography consists of non-propagated waves which facili- GI manometry Colonic scintigraphy tate the mixing of endoluminal contents in order Colonic scintigraphy Anal endosonography to maximize water and electrolyte absorption. Propulsive waves include low- and high-ampli- NB: GI = gastrointestinal; EMG = electromyography tude propagated contractions (LAPCs and HAPCs, respectively)6,7,9. HAPCs are capable of Figure 1. Diagnostic algorithm of chronic constipation. rapid movement of the endoluminal contents and often precede defecation. Patients with chronic constipation have a significantly reduced number blood screening along with radiological (double of HAPCs (<5/day) compared to non-constipated contrast barium enema) and endoscopic subjects6,7,9. Furthermore, the so-called gastro- (colonoscopy) examinations, are advisable in se- colonic reflex, which exerts an important control lected cases, based on clinical history and pres- on colonic peristalsis, is reduced in patients with ence of alarm signs/symptoms. Functional tests chronic constipation11. Taken together, these aimed at assessing intestinal motility/transit and findings support the concept that impaired anorectal impairment may be useful to establish colonic motility has an important role in delaying the mechanisms underlying idiopathic chronic transit in a subset of patients with chronic consti- constipation and tailor appropriate therapeutic pation (i.e. those with slow transit [or propulsive] options1,6. constipation). This type may occur in the absence of major systemic or gastrointestinal disorders, although it can also be associated with neurologi- Main Pathophysiological Mechanisms cal impairment (e.g. supraspinal causes, spinal In the absence of reliable biomarkers, chronic lesions, diseases of the autonomic nervous sys- constipation is considered a functional bowel dis- tem, whether extrinsic or intrinsic – the latter is order to which different mechanisms contribute. also referred to as the enteric nervous system, or From a pathophysiological standpoint, there are the “brain-in-the-gut”, due to its independence three main subtypes: from the central nervous system in controlling virtually all gut functions) or with endocrine and 1. Normal transit (“functional constipation”); metabolic disorders (hypothyroidism, hypercal- 2. Slow transit; cemia, porphyria, diabetes mellitus)6-10. 3. “Obstructed” defecation (or dyssynergic defe- The total intestinal transit time can be evaluat- cation when purely functional). ed by giving the patient radiopaque markers oral-

962 Use of macrogol 4000 in chronic constipation ly and assessing their location along the alimen- Non-pharmacologic strategies are the first tary tract by direct standard abdominal radiogra- step and include educating the patient on the phy. On average, in normal subjects 80% of physiologic basis of defecation, the role of diet markers are evacuated within 4 days. In patients and adequate daily fluid intake, and physical ex- with slow transit constipation, expulsion is re- ercise (a sedentary lifestyle causes a threefold duced, and the markers will be distributed increase in the risk of constipation). Patients through the different segments of the colon11. should also be instructed to attempt defecation Obstructed defecation is caused by a pelvic in the morning (within two hours of awakening) floor disorder. This condition is also referred to as and following meals, when colonic motor activi- dyssynergic defecation when it is purely function- ty is at its highest1,6,8. al and not associated with hemorrhoids, genital Increased dietary fiber (20-30 g/day) is known prolapse, anismus (paradoxical contraction of the to reduce colonic transit time. However, not all pubo-rectalis muscle), solitary rectal ulcer syn- patients will respond to this treatment and it may drome, idiopathic perineal pain syndrome, or an- even exacerbate the symptoms of some (patients terior or complete rectal mucosal prolapse. It is with slow transit constipation). It is, thus, impor- caused by either paradoxical contrac- tant to establish the predominant form of the con- tion/inadequate relaxation of the pelvic floor stipation and the underlying pathophysiologic muscle or inadequate propulsion during defeca- mechanism before suggesting dietary fiber sup- tion. Diagnostic examinations such as anorectal plementation to any patient1,6,8. manometry (which assesses internal anal sphinc- In addition to lifestyle changes, which, as not- ter relaxation following rectal distension), rectal ed, are not always fully effective, different types balloon expulsion test, defecography (videoradi- of laxatives can be prescribed by doctors. Laxa- ographic recording of defecation using a contrast tives are agents that stimulate defecation or mod- medium in the rectum), and electromyography of ify stool consistency and ease of passage. Al- the anal muscles and pelvic floor can be useful to though they are generally recommended for determine the type and degree of dysfunction in short-term treatment, current evidence suggests patients with obstructed/dyssynergic defecation12. that they are the first-line remedy for constipa- The challenge for clinicians dealing with patients tion13,14. There are at least three major categories with chronic constipation is to appreciate the na- of laxatives based on their mechanism of action ture of the patient’s complaint, understand the (Table II): bulk-forming, osmotic and stimulants predominant underlying pathophysiological (also referred to as “irritants”). In some countries mechanism (slow transit vs. obstructed /dyssyner- (e.g. United States), a fourth category is avail- gic defecation), and select treatment strategies to able, i.e. stool softeners, such as docusate13,14. improve symptoms and quality of life. In this review, we will focus on osmotic laxatives, and particularly polyethylene glycol (PEG, Treatment also referred as macrogol). This compound has Patients with chronic constipation often self- medicate by changing their diet (increased dietary fiber intake) and, above all, using irritant laxatives. Table II. Classification of major laxatives based on mecha- In the United States, about $400 million is spent nisms of action. on over-the-counter laxatives and roughly 5 million medical prescriptions are written for the treat- Bulk-forming agents • Psyllium ment of constipation every year (8). Nonetheless, • Methylcellulose around 50% of constipated patients are still dissat- isfied with their treatment. Remedies for constipa- Osmotic agents tion are generally unsatisfactory because although • Poorly absorbable disaccharides (lactulose) they may ensure regular bowel movements, they • Polyethylene glycol 3350/4000 do not always resolve (and may even worsen) the • Poorly absorbed ions (magnesium hydroxide) signs and symptoms (e.g. pain and abdominal Stimulant laxatives bloating, flatulence, and straining) which are actu- • Diphenylmethane derivatives (Bisacodyl) ally responsible for the negative impact on the pa- • Anthraquinones (cascara, senna, frangula) tient’s quality of life. Tailoring an effective treat- Stool softeners ment for chronic idiopathic constipation is, thus, a • Docusate challenge for clinicians1,6,8.

963 R. De Giorgio, R. Cestari, R. Corinaldesi, V. Stanghellini, G. Barbara, et al. gained grade A recommendation for the treat- combined with electrolytes, making it slightly ment of chronic constipation in different studies more palatable than other PEG compounds16-18. and meta-analyses14-16. We will examine the clini- This is particularly true for constipated children cal efficacy of PEG/macrogol in chronic consti- and the elderly, whose adherence to long-term pation and as a key agent for bowel cleansing be- treatment could be improved by using more fore colonoscopy. palatable PEG formulations, such as macrogol Osmotic laxatives are normally small ions (e.g. 4000, which is tasteless, odorless and can be magnesium sulfate or phosphate salts) which exert mixed with different beverages to facilitate its their osmotic effect in proportion to the number of use16,19,20. PEG/macrogol 4000 does not cause molecules present in the intestinal lumen. Large fluid or electrolyte imbalance even in prolonged molecules are not normally particularly effective in treatment18-20. Moreover, like other PEG formula- generating significant osmotic pressure, due to tions it does not induce tolerance, as it continues their molecular weight. However, some organic to be effective in the long term, without necessi- polymers, including PEG/macrogol, are an excep- tating dose increase over time. There is no clear tion and do have a powerful osmotic effect. The os- difference in the efficacy of various PEG/macro- motic activity of PEG/macrogol is related to its gol formulations. In a study comparing the effi- ability to sequester water in the intestinal lumen. cacy of PEG/macrogol with and without elec- PEG with molecular weights <1500 are absorbed trolytes in constipated patients, both PEG formu- by the intestinal mucosa and are, thus, unsuitable lations were well tolerated and equally effective as osmotic compounds17. In contrast, those with in improving bowel frequency at any of the doses higher molecular weights (e.g. 3350 or 4000) are tested21. only minimally absorbed, thereby sequestering wa- PEG/macrogol treatment is usually safe and ter in the bowel. Since PEG/macrogol is an inert not associated with severe side effects. However, molecule which cannot be metabolized by the in- diarrhea and bloating may be experienced by a testinal microflora, it should be delivered from the subset of patients. Bloating may result from small intestine to the colon, where it evokes its os- faster transit, occurring when large doses of motic activity17. This causes the volume of the fe- PEG/macrogol are administered after meals. In cal mass to increase (due to a higher water con- these circumstances, nutrients enter the colon tent), which in turn triggers propulsive motor and activate fermentation, producing excessive processes, such as peristalsis, via distension of the gas. This problem can be alleviated by taking colonic wall. The increased hydration also softens PEG/macrogol before going to bed. the feces and eases defecation. Finally, in comparison with other laxatives, es- There is consistent evidence that a relatively pecially irritants (anthraquinones), PEG/macrogol low dose of PEG/macrogol (17 g/day) improves does not alter the normal morphology and archi- stool frequency and consistency in patients with tecture of the gastrointestinal mucosa, as demon- chronic constipation, as clearly shown in recent strated by histological studies18. meta-analyses14-16. In one metanalysis with more The effective dose of macrogol 4000 ranges stringent criteria for study evaluation, the relative from 0.7 to 1.5 g/Kg/day in constipated patients risk ratio in terms of mean number of stools per of any age (Table III). When clinically necessary, week in 573 patients (included in 4 eligible studies) was significantly in favor of PEG/macrogol treatment14. PEG/macrogol, which is usually effective within 48 hours, improves quality of life Table III. Age-related recommended dosages. even in the elderly, a particular subgroup more prone to severe constipation that is often refrac- Body weight Daily Age (Kg) dose tory to various treatment options, including irritant laxatives18. Children 2-8 years old* 6-9 5 g There are at least two pharmaceutical formula- 10-12 7.5 g tions of PEG/macrogol, based on its molecular 13-16 10 g weight: 3350 and 4000. PEG/macrogol 3350 is 17-20 12.5 g Adults and children > 20 10-20 g** commonly combined with variable amounts of > 8 years old electrolytes (e.g. sodium sulfate), believed to combat possible electrolyte depletion over time, *Usual initial dose is 0.7 g/Kg/die. **Never exceed daily whereas PEG/macrogol 4000 is generally not maximum dose (20 g of macrogol).

964 Use of macrogol 4000 in chronic constipation the standard dose may be taken two or three References times per day, provided that patients consume sufficient water to avoid removal of fluids from 1) BRANDT LJ, PRATHER CM, QUIGLEY EM, SCHILLER LR, SCHOENFELD P, T ALLEY NJ. Systematic review on the the body. PEG/macrogol treatment may be of management of chronic constipation in North 16,18 19,20 most benefit to the elderly and children . America. Am J Gastroenterol 2005; 100(Suppl 1): Another group which may benefit is pregnant S5-S21. women, given the need to adhere to strict safety 2) LONGSTRETH GF, THOMPSON WG, CHEY WD, factors for any treatment during pregnancy. In HOUGHTON LA, MEARIN F, S PILLER RC. Functional this respect PEG/macrogol 3350 or 4000 should bowel disorders. Gastroenterology 2006; 130: be considered a first-line option, due to its mini- 1480-1491. mal absorption (1-4%) and elimination in the 3) GLIA A, LINDBERG G. Quality of life in patients with urine without being metabolized22,23. different types of functional constipation. Scand J PEG/macrogol formulations have proven ef- Gastroenterol 1997; 32: 1083-1089. fective for bowel cleansing before colonoscopy 4) WALD A, SCARPIGNATO C, KAMM MA, MUELLER-LISSNER when taken appropriately and under ideal con- S, HELFRICH I, SCHUIJT C, BUBECK J, LIMONI C, PETRINI ditions24-26. Solutions of PEG/macrogol in water O. The burden of constipation on quality of life: re- are isotonic and poorly absorbed, and when in- sults of a multinational survey. Aliment Pharmacol Ther 2007; 26: 227-236. troduced quickly (>1800 mL/h) they can exert a substantial osmotic effect in the colon, leading 5) AICHBICHLER BW, WENZL HH, SANTA ANA CA, PORTER to bowel cleansing. This mechanism also pre- JL, SCHILLER LR, FORDTRAN JS. A comparison of stool characteristics from normal and constipated peo- vents major fluid exchange across the colonic ple. Dig Dis Sci 1998; 43: 2353-2362. mucosa, thus limiting the risk of dehydration or electrolyte depletion. Several studies have indi- 6) LEMBO A, CAMILLERI M. Chronic constipation. N Engl J Med 2003; 349: 1360-1368. cated that PEG/macrogol is a valid option for colonoscopic preparation. However, its efficacy 7) COOK IJ, TALLEY NJ, BENNINGA MA, RAO SS, SCOTT SM. Chronic constipation: overview and chal- may be hampered by poor patient adherence, lenges. Neurogastroenterol Motil 2009; 21(Suppl mainly related to the need for a high fluid in- 2): 1-8. take (at least 4 L), which many patients find 25 8) CASH BD, CHANG L, SABESIN SM, VITAT P. Update on unpleasant and difficult to tolerate . This is the management of adults with chronic idiopathic certainly the case for macrogol 3350 with elec- constipation. J Fam Pract 2007; 56(6 Suppl Up- trolytes; data for macrogol 4000 are not yet date): S13-19. available. 9) RAO SS. Constipation: evaluation and treatment of Finally, the osmotic properties of PEG/macrogol colonic and anorectal motility disorders. Gas- 4000 (in 1-2 L of water) could be exploited to troenterol Clin North Am 2007; 36: 687-711. improve endoscopic investigation, e.g. video cap- 10) MCCREA GL, MIASKOWSKI C, STOTTS NA, MACERA L, sule endoscopy of the small bowel, as suggested VARMA MG. Pathophysiology of constipation in the by international guidelines27. The purpose would older adult. World J Gastroenterol 2008; 14: be to enhance bowel loop distension in order to op- 2631-2638. timize resolution. Using the same principle, 11) RAO SS, CAMILLERI M, HASLER WL, MAURER AH, PARK- PEG/macrogol has already been used to improve MAN HP, SAAD R, SCOTT MS, SIMREN M, SOFFER E, assessment of the bowel wall during ultrasound SZARKA L. Evaluation of gastrointestinal transit in scans28. clinical practice: position paper of the American and European Neurogastroenterology and Motili- In conclusion, the evidence to date indicates ty Societies. Neurogastroenterol Motil 2011; 23: that like other PEG formulations, macrogol 4000 8-23. is a safe, effective treatment for chronic constipa- 9 12) RAO SS. Advances in diagnostic assessment of fe- tion in any age group . It is more palatable than cal incontinence and dyssynergic defecation. Clin combined formulations (macrogol 3350 incorpo- Gastroenterol Hepatol 2010; 8: 910-919. rating electrolytes), which might help improve 13) SCHILLER LR. Review article: the therapy of consti- adherence to the long-term treatment necessary pation. Aliment Pharmacol Ther 2001; 15: 749- for patients with chronic constipation. The im- 763. proved cost-effectiveness of macrogol over other 14) FORD AC, SUARES NC. Effect of laxatives and phar- commonly prescribed laxatives such as lactulose, macological therapies in chronic idiopathic consti- 15 as demonstrated by a recent meta-analysis , pation: systematic review and meta-analysis. Gut should also be taken into consideration. 2011; 60: 209-218.

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