J Clin Gastroenterol 2003;36(5):386389.

2003 Lippincott Williams & Wilkins, Inc.

Clinical Reviews The Colon, Inflammatory Bowel Disease & Infectious Diseases

Is Chronic Use of Stimulant Laxatives Harmful to the Colon?

Arnold Wald, M.D.
Abstract
Although stimulant laxatives cause structural damage to surface epithelial cells that is of uncertain functional significance, there is no convincing evidence that their chronic use causes structural or functional impairment of enteric nerves or intestinal smooth muscle. Nor are there reliable data to link chronic use of stimulant laxatives to colorectal cancer and other tumors. The risks of laxative abuse have been overemphasized, and this has minimized their rational use by physicians. Stimulant laxatives may be used chronically when patients fail to respond adequately to bulk or osmotic laxatives alone. These can be combined with bulk or osmotic laxatives in sufficient amounts to soften the stool, or they can be used alone, according to clinical circumstances. The dose of such agents should be titrated to effect. Bisacodyl may be used if anthraquinone laxatives are unsatisfactory. Key Words: LaxativesStimulant laxativesLaxative abuse Cathartic colonConstipation.

systemically rather than by mucosal contact.4 These admonitions have resulted in a generation of physicians who are reluctant to use stimulant laxatives, except for the short term, and advise their patients that such laxatives may cause dependence and damage to the colon. The aim of this review is to define stimulant laxatives and their mechanisms of action. The following issues are addressed. 1. Do stimulant laxatives cause structural changes in the colon that can lead to intestinal dysmotility and associated colonic dysfunction? 2. Does chronic use or abuse of stimulant laxatives cause cathartic colon? 3. Does chronic use of stimulant laxatives increase the risk of developing colorectal or other cancers? 4. What are safe and effective strategies for the long-term use of stimulant laxatives? MECHANISMS OF ACTION OF STIMULANT LAXATIVES The three groups of stimulant laxatives are the diphenylmethanes, castor oil, and anthraquinones (Table 1). All stimulant laxatives act by altering fluid and electrolyte transport and/or motility in the small and/or large intestines.5 The diphenylmethane laxatives alter net fluid and electrolyte transport after undergoing absorption and excretion via an enterohepatic circulation.57 These agents also have direct effects on colonic motility, as demonstrated when bisacodyl is administered intrarectally as a suppository.8 Phenolphthalein is no longer available as an over-thecounter product, having been withdrawn because of concerns about increased risks of colorectal and other cancer, concerns that have not been substantiated in humans (see below). Castor oil (ricinoleic acid) acts mainly as a secretogogue on both small and large intestines,9 similar to the actions of unabsorbed fatty acids in malabsorption/maldigestion disorders other than pancreatic insufficiency. The parent compound is hydrolyzed from its triglyceride form to glycerol and ricinoleic acid. The latter is an unsaturated fatty acid that decreases absorption of glucose and amino acids, im386

he use of laxatives is deeply rooted in medical and social traditions. Vast amounts of laxatives are consumed in Western societies, and most are available to patients in nonprescription forms. Laxatives are classified into four major groups on the basis of their presumed mode of action. These include bulk-forming agents, emollients, osmotic laxatives, and stimulant laxatives. The first three groups are considered safe and effective for long-term use, and all except the hyperosmolar laxatives are available without prescription. In contrast, stimulant laxatives are traditionally advocated for short-term use only, as the longterm use of these laxatives is claimed by many to impair normal colonic function, produce laxative dependency, cause damage to the enteric nervous system and/or intestinal smooth muscle that governs colonic motility, and increase the risk of colorectal and perhaps other cancers.1,2 In the most extreme case, abuse of stimulant laxatives has been claimed to result in cathartic colon.3 Similar concerns have been highlighted in articles that support the development of enterokinetic compounds, which stimulate colonic motility

From the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address correspondence and reprint requests to Dr. Arnold Wald, Professor of Medicine, University of Pittsburgh Medical Center, PUH, Mezzanine Level, C-wing, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail: walda@msx.upmc.edu.

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TABLE 1. Some commonly available stimulant laxatives

Laxative Castor oil (Ricinoleic acid) Diphenylmethanes Bisacodyl Anthraquinones Aloe (casanthranol) Cascara sagrada Senna Usual adult dose* 1560 mL 30 mg or 10 mg suppository 3060 mg 25 mL 1734 mg

changes of surface epithelial cells that may explain some of the changes in absorption of certain solutes and alterations of electrolyte and fluid movement.11 No morphologic changes of enteric neural elements or intestinal smooth muscle have been reported. Castor oil is rarely used today because of excessive cramping and passage of diarrheal stools.13 Anthraquinones The greatest concern about the possibility that stimulant laxatives can induce permanent enteric nerve or muscle damage has been expressed about the use of anthraquinone laxatives. In part, this may be due to the development of melanosis coli, an easily visible brown pigment of the colonic muscoa that can occur within several months of regular use and can last for nearly 1 year after discontinuing laxative use. This pigmentation is related to lipofuscin, which is released during cellular apoptosis and is contained in mucosal macrophages. However, its functional significance is unknown, it does not extend to the muscle layers or enteric plexuses, and it is completely reversible when the use such laxatives is stopped. The argument that chronic use of stimulant laxatives damages the colonic myenteric system is largely derived from uncontrolled observations in humans and from conflicting data obtained in prospective studies of animals. The original study of humans17 included 12 purgative addicts who underwent examination of their colons that had been removed in an attempt to obtain relief of severe constipation. Although damage to enteric nerves as well as smooth muscle atrophy was demonstrated, it is not possible to determine if it was due to a primary motility disorder, to laxatives no longer currently in use, or to chronic laxative ingestion. Similar arguments refuting causality of structural changes in the colon may be advanced for subsequent descriptions of patients with chronic laxative abuse.16,18,19 Efforts of addressing this issue in laboratory animals have yielded conflicting data. For example, in studies in which senna was orally administered to mice, axonal and dendritic damage occurred after 4 months of continual use, but the quantity and quality of the senna were not specified.19 Subsequent studies in which glycosylated senna was given orally to mice and rats demonstrated no such changes,20 so that it has been speculated that nonglycosylated senna may have been used in the original study and caused changes following small intestinal absorption.13 Such a hypothesis was supported in more recent studies of humans.21 The preponderance of the evidence suggests that long-term use of anthraquinone laxatives is not associated with morphologic changes of colonic muscle or enteric neuronal structures. The recent demonstration that patients with severe colonic inertia have decreased volume or numbers of interstitial cells of Cajal and enteric neurons22,23 suggests

*Oral except where indicated otherwise.

pairs intracellular mechanisms, and increases intestinal secretion.10 The latter effect may be mediated by cyclic AMP.9 Mucosal damage has been demonstrated by both light microscopy and electron microscopy and may be a primary mechanism by which water and electrolyte secretion occurs.11 In addition, alteration in colon motor activity has been demonstrated in animals.12 All anthraquinones appear to work exclusively in the colon to alter electrolyte and fluid transport and/or colonic motility. Some are glycosylated, whereas some are not, leading to some differences in pharmacokinetics. For example, the active molecules of senna are sennosides A and B. Colonic bacteria split the glucose molecules, activating rhein-9-anthrone in the colon.13 These laxatives stimulate the intestinal formation of prostaglandins, serotonin, and histamine to increase mass movements and increase colonic net secretion.14 Of these, prostaglandins are believed to be the most important as inhibition of prostaglandins by indomethacin and similar compounds partially arrests colonic secretion of electrolytes and fluids.15 DO STIMULANT LAXATIVES CAUSE STRUCTURAL CHANGES TO THE COLON THAT PRODUCE COLONIC DYSFUNCTION? Diphenylmethanes Bisacodyl has been shown to cause morphologic changes in surface absorptive cells in both animals and humans, whereas phenolphthalein, a less potent secretogogue, has not.6,7 No prospective studies have demonstrated morphologic changes of enteric neural elements or intestinal smooth muscle by diphenylmethane laxatives. In contrast, ultrastructural changes of colonic submucosal nerves were reported in a retrospective study of 35 patients who chronically abused anthraquinone laxatives or bisacodyl.16 It is unclear from these uncontrolled studies whether such changes were due to an underlying primary motility disorder or caused by chronic use of laxatives or whether such changes are even of functional significance. Ricinoleic Acid Several animal studies have demonstrated that ricinoleic acid and other dihydroxy bile acids produce morphologic

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that previous abnormalities may have been misattributed to the chronic use of stimulant laxatives. CAN CHRONIC USE OR ABUSE OF STIMULANT LAXATIVES CAUSE CATHARTIC COLON? This question was recently addressed in a scholarly review by Mller-Lissner3 who pointed out that the diagnosis of cathartic colon is based upon radiologic findings, including loss of haustrations, a dilated colon and often terminal ileum, gaping of the ileocecal valve, and colonic pseudostrictures. He cited a published review of 240 cases of laxative abuse by Leng-Peschlow24; in this review, no cases of cathartic colon were reported, nor could the author identify a published case of cathartic colon in which laxative intake started after 1960. Mller-Lissner speculated that podophyllin, a neurotoxin when taken orally, may have caused a number of cases of cathartic colon. For example, podophyllin was used medicinally, as in some broths used as traditional Chinese medicine.25 Whatever the cause, cases of cathartic colon must be very rare in recent years. The conclusions of Mller-Lissner3 were challenged subsequently by a report that reviewed barium enemas in patients with chronic constipation who used or did not use stimulant laxatives.26 Loss of haustral markings was described in approximately one quarter of patients using stimulant laxatives versus none of those who did not. This part of the study was retrospective, and no data were provided to compare the severity of constipation in each group. Subsequently, cases of 18 patients who used stimulant laxatives were studied prospectively, and 39% of cases demonstrated loss of haustral folds. As there was no comparative group, the potential for bias cannot be excluded, nor was the clinical significance of the radiologic findings demonstrated. DOES THE CHRONIC USE OF STIMULANT LAXATIVES INCREASE THE RISKS OF DEVELOPING COLORECTAL CANCERS? Diphenylmethanes Although the U.S. Food and Drug Administration had previously classified phenolphthalein as safe and effective, they proposed that it be reclassified as not generally safe and effective after a 2-year study of rodents found increased incidences of ovarian, adrenal, renal, and hematopoietic neoplasms among treated animals.27 In addition, this laxative was found to be genotoxic27 and to bind to estrogen receptors in animal studies. As a result, most phenolphthalein-containing laxatives were voluntarily withdrawn from the market in the United States. Subsequently, a large case-controlled study showed that chronic use of such laxatives does not increase the risk of any cancer types implicated in animal studies.28 It was pointed out that experimental animals were given much higher doses of laxa-

tives than are commonly used in humans. There are no such studies of bisacodyl. Anthraquinones It has been suggested that chronic use of anthraquinone laxatives may be associated with an increased risk of colorectal cancer2; however, the evidence is not consistent, and reliable data are lacking. One study consisted of both retrospective and prospective analyses.29 In the retrospective cohort, the incidence of melanosis coli was increased among patients with colorectal adenomas but not among those with carcinomas, whereas in the prospective study, it was increased among patients with carcinoma but not among those with adenomas. To support such an association, it has been pointed out that certain anthraquinones appear to initiate or promote tumorigenesis in both in vitro and animal studies, where exposures typically greatly exceed those in humans.2,28 However, such findings are not universal in all animal studies,30,31 and many have failed to find a relationship between colorectal cancer and chronic anthraquinone laxative use in humans.3234 Moreover, chronic constipation itself has been hypothesized to be a risk factor for colorectal cancers. Thus, speculation about a possible association of chronic anthraquinone laxative use and colorectal or other cancers is unproven. THE SPECTRUM OF LAXATIVE ABUSE It has long been known that stimulant laxatives can be used inappropriately or abused. Laxative abuse typically occurs in four clinical settings: eating disorders such as anorexia and bulimia, malingering, Munchausen syndrome, and Munchausen syndrome by proxy (Polle syndrome). In eating disorders, laxatives are abused in an effort to lose weight. The malingerer has obvious motives for feigning illness of which he or she is fully aware. The patient with Munchausen syndrome has no other motive than to assume the role of a patient, whereas Polle syndrome induces a factitious illness upon a child by their caregiver as a form of child abuse.35 Laxative abuse often presents as watery high volume diarrhea frequently associated with crampy abdominal pain. Weight loss is common and may result in malnutrition. Lethargy, generalized weakness, and muscle weakness are prominent symptoms of laxative abuse. Malnutrition, dehydration, and hypokalemia can all contribute to this problem.36 Fluid and electrolyte disorders are often seen in affected patients. These include volume depletion that can lead to orthostatic hypotension due to sodium and water loss in the stool, hypokalemia, and metabolic alkalosis, which is in contrast to metabolic acidosis as is usually seen in severe acute diarrhea. The alkalosis may be due in part to hypokalemia impairing the intestinal reabsorption of chloride, thereby diminishing bicarbonate secretion into the intestinal

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lumen via chloridebicarbonate exchange. Loss of a highchloride, low-bicarbonate solution can raise the plasma bicarbonate concentration, and both volume depletion and hypokalemia prevent excretion of the excess bicarbonate in the urine.34 These disorders occur in a setting of psychosocial pathology, and recognition of these disorders is important in clinical medicine. However, the problem is not with laxatives but the emotionally disturbed individuals who misuse them. CONCLUSION Stimulant laxatives do cause structural damage to surface epithelial cells that appears to be reversible and of uncertain functional significance. There is no convincing evidence that chronic use of stimulant laxatives causes structural or functional impairment of enteric nerves or intestinal smooth muscle. Although there are no reliable data to link chronic use of stimulant laxatives to colorectal cancer and other tumors, it is reasonable to exercise reasonable caution when using them on a chronic basis. The risks of laxative abuse have been overemphasized, and this has minimized their rational use by physicians. Stimulant laxatives may be used chronically when patients fail to respond adequately to bulk or osmotic laxatives. A reasonable regimen is to attempt anthraquinone laxatives when no spontaneous bowel movement occurs after 48 hours (thrice weekly) or 72 hours (twice weekly). These laxatives can be combined with bulk or osmotic laxatives in sufficient amounts to soften the stool, or they can be used alone, according to clinical circumstances. The dose of such agents should be titrated to effect. Bisacodyl may be used if anthraquinone laxatives are unsatisfactory. It is counterproductive to advise elderly patients to use nonstimulant laxatives when they have used stimulant laxatives successfully for many years or even decades. Most patients will continue to use them, perhaps inappropriately. A better strategy is to educate such patients to use stimulant laxatives in a more rational way, by limiting their use to twice or thrice weekly in conjunction with nonstimulant laxatives on a daily basis. REFERENCES
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