Laxative Use and Abuse in the Older Adult: Part II

At the conclusion of this activity, participants should be able to:
1. Identify the different classes of laxative therapy that are currently available.
2. Describe the advantages and disadvantages of the different forms of pharmacologic therapy available for the management and treatment of constipation.
3. Recognize the potential for laxative abuse in order to prevent the misuse of these agents.
4. Emphasize the need for further research in order to establish guidelines for the clinical use of laxatives.
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In this two-part article, the authors review the current state of knowledge concerning available laxatives and their use in the older patient. Part I (Clinical Geriatrics 2007;15[4]:37-42) addressed the approach to constipation, opioid-induced constipation, and natural laxatives. Part II discusses the pharmacologic agents used to maintain bowel regularity, the potential for abuse, and future implications.

PHARMACOLOGIC THERAPY

There is a wide availability of pharmacologic agents for maintaining bowel regularity.^1-7  Laxatives are generally classified according to their mode of action. The evidence surrounding the effectiveness of the various classes of laxatives is limited, and as mentioned previously, at present there are no set guidelines to determine choice of treatment. Overall, laxatives can be divided into the following categories (Tables I and II):

(For purposes of classification, some of the natural laxatives discussed in Part I have been included in this section.) 

Bulk-forming laxatives
Dietary fiber (bran), Sterculia, psyllium (Plantago species), Rhamnus frangula, methylcellulose, polycarbophil, malt soup extract 

Bulk laxatives are hydrophilic agents that absorb water from the intestinal lumen, thereby softening the consistency of stools and decreasing bowel transit time. These agents are ideal for patients with functional normal transit constipation, especially for people on low-fiber diets. Bulk laxatives may take several days to be effective, and are therefore not suitable for acute relief. Potential side effects of this class of laxatives include diarrhea, abdominal cramps, and flatulence. In severe cases, their use may lead to bowel obstruction, especially if there is insufficient fluid intake. In fact, the use of bulk-forming laxatives is contraindicated in the management of opioid-induced constipation because of this potential to cause bowel obstruction. Psyllium has been reported to potentially cause bronchospasm and anaphylaxis in susceptible individuals. These agents should be taken with adequate amounts of water to be effective, and are therefore not suitable for patients on water restriction. Patients with dysphagia should also avoid bulk laxatives, as they may expand and become lodged in the esophagus, causing obstruction. Absolute contraindications to this class of drugs include hypersensitivity to these agents, fecal impaction, and gastrointestinal obstruction. The bulk laxatives, particularly psyllium and polycarbophil, have been shown to decrease the effect of drugs such as warfarin, digitalis, salicylates, tetracyclines, ciprofloxacin, and nitrofurantoin.

Emollients (stool softeners)
Docusate sodium, docusate calcium

Emollient laxatives, or stool softeners, act as surfactants by lowering surface tension and facilitating the mixing of aqueous and fatty substances in the intestinal lumen. These agents are particularly useful for patients with structural causes of constipation, such as anal fissures or hemorrhoids that cause painful defecation. Stool softeners are not appropriate as the only treatment for constipation in individuals with intestinal motility problems, as the soft stool may accumulate and lead to intestinal obstruction. Emollients are generally well tolerated; however, common side effects may include diarrhea, abdominal cramping, and abdominal obstruction. The docusates have also been associated with hepatotoxicity in some cases. Hypersensitivity to docusate or any component of the formulation, acute abdominal pain, and intestinal obstruction are absolute contraindications to the use of these agents.

Lubricant laxatives
Mineral oil (liquid paraffin, arachis oil)

Lubricant laxatives act by preventing the reabsorption of water from the colon, thereby coating the feces and lubricating the intestinal wall. This action facilitates the passage of stool through the gastrointestinal tract. These agents are typically used for the temporary relief of occasional constipation, for relief of acute fecal impaction, and for removal of barium sulfate residues after administration of contrast. This class of laxatives is becoming obsolete because of associated severe abdominal cramping and risk of developing lipoid pneumonitis from aspiration of the oil. If lubricant laxatives are to be used, they should be taken at least 30 minutes prior to bedtime to reduce the risk of aspiration. Absolute contraindications to the use of these agents include patients with ulcerative colitis, appendicitis, and presence of a colostomy or ileostomy. This class of laxatives may inhibit the absorption of warfarin, oral contraceptives, and sulfonamides. While prolonged use of these agents may decrease the absorption of fat-soluble vitamins leading to significant deficiencies, coadministration with docusates may increase their absorption and potential systemic toxicity.

Osmotic laxatives
Lactulose, polyethylene glycol, magnesium salts (magnesium citrate, magnesium hydroxide [ie, milk of magnesia], magnesium sulfate [ie, epsom salt]), sugar alcohols (sorbitol, mannitol, lactitol), sodium phosphates

Saline or osmotic laxatives are nonabsorbable, hyperosmolar substances that draw fluid into the intestinal lumen by osmotic action and increase the intraluminal pressure, thus stimulating gut motility. The most commonly used agents in this class are magnesium hydroxide (milk of magnesia), magnesium citrate, and sodium phosphate. These agents are commonly used for bowel clearance prior to surgery and diagnostic procedures, and for the short-term treatment of constipation. Polyethylene glycol, for example, is commonly used in high doses for bowel preparation prior to colonoscopy. These agents are generally well tolerated; however, potential side effects include nausea, vomiting, and diarrhea. Magnesium compounds may cause respiratory depression, muscle weakness, and hypotension. Elderly patients with reduced renal function are particularly at increased risk for developing hypermagnesemia with use of these agents. Sugar alcohols may precipitate hyperglycemia, electrolyte imbalances, and lactic acidosis. The use of sodium phosphate may be associated with acute renal failure (nephrocalcinosis) and hyperphosphatemia. These agents may also lead to fluid and salt overload because of their osmotic properties, and therefore should be used carefully in patients with renal insufficiency and congestive heart failure. The potential for these agents to interact with other medications is a significant problem. The magnesium compounds are known to decrease the effect of tetracyclines and digoxin, for example, and lactulose may decrease the effect of oral neomycin. Phosphates should not be co-administered with angiotensinconverting enzyme (ACE) inhibitors as the combination may increase the risk of nephrocalcinosis and electrolyte imbalances.

Stimulant laxatives
Castor oil (ricinoleic acid), diphenylmethanes (bisacodyl), anthraquinones (senna, cascara sagrada [sacred bark], aloe vera)

These agents act by stimulating the nerve plexus in the intestine, thereby causing increased peristalsis and increased secretion of fluid and electrolytes into the colonic lumen. Bisacodyl directly stimulates the mucosal nerve plexus, causing increased peristalsis. Castor oil, on the other hand, is hydrolyzed to ricinoleic acid which then stimulates secretion of fluid and electrolytes into the small intestine. Like the osmotic laxatives, these agents are used for bowel clearance prior to surgery and diagnostic procedures, and for the short-term treatment of constipation. While they generally produce bowel movements within hours, they may cause abdominal cramping as a result of the increased peristalsis. Chronic use of bisacodyl may cause hypocalcemia, metabolic acidosis or alkalosis, and severe nausea and vomiting. Use of senna may cause a benign condition called melanosis coli, in which dark brown lesions appear on the colonic mucosa. These lesions usually disappear once the laxative is discontinued. Castor oil has been known to cause dizziness, hypotension, and electrolyte imbalances, and is rarely used because of shown that chronic use of this class of agents may lead to colonic inertia or atony, in which the resting colonic motility is normal but there is little or no increase in motility upon stimulation. Stimulant laxatives should be avoided in patients with suspected intestinal obstruction, inflammatory bowel disease, during pregnancy, and in patients with abdominal pain of unclear etiology. These agents are known to decrease the effect of warfarin and should not be taken with dairy products or antacids, which may decrease their laxative effect.

Prokinetic agents
Metoclopramide, erythromycin

Note: Despite having a beneficial effect on intestinal function, tegaserod has been removed from the market by the FDA due to its negative side-effect profile.

Prokinetic agents are used as second-line therapy in the treatment of slow-transit constipation in the absence of an organic cause for obstruction. The mechanisms of action differ slightly among the agents in this class. Metoclopramide inhibits dopamine (D2) receptors, thereby enhancing cholinergic activity in the gastrointestinal smooth muscle, resulting in accelerated intestinal transit. Erythromycin, on the other hand, binds to intestinal motilin receptors enhancing smooth muscle contraction and peristalsis. The use of erythromycin may cause abdominal pain, diarrhea, cholestatic jaundice, and some serious ventricular arrhythmias (eg, torsades de pointes). Being a macrolide antibiotic, erythromycin has the potential to develop resistance if frequently used. However, as of yet, this has not proven to be of concern, as this agent is rarely used. Use of metoclopramide has been associated with extrapyramidal effects, agranulocytosis, AV blocks, and bradycardia. These agents are contraindicated in patients with hypersensitivity to the individual agents and in patients with suspected bowel obstruction. Erythromycin should be avoided in patients with hepatic dysfunction; patients with prolonged QT intervals or a history of arrhythmias should not be given erythromycin. Metoclopramide should not be used in patients with pheochromocytoma and seizure disorder. Several drug interactions have also been noted with this class of laxatives, and caution should be taken when using prokinetic agents with other medications. The anticholinergic agents are known to antagonize the action of metoclopramide and should not be administered together. The combination of metoclopramide and antipsychotic agents may increase the risk of extrapyramidal symptoms. Erythromycin is known to interact with numerous drugs which are hepatically cleared (eg, benzodiazepines, calcium channel blockers, carbamazepine, digoxin, buspirone,) and may increase or decrease their levels in the blood.

New locally acting agent
Lubiprostone

This is a new agent recently approved by the Food and Drug Administration in January 2006 for the treatment of chronic, idiopathic constipation. Lubiprostone acts locally in the small intestine by selectively activating the ClC-2 chloride channel, a normal constituent of the apical portion of the gastrointestinal epithelium. This activation results in an increase in chloride-rich intestinal fluid secretion, without affecting serum sodium and potassium concentrations. This increase in luminal fluid secretion promotes intestinal motility and peristalsis, allowing for the easy passage of stool through the intestinal lumen. Studies indicate that lubiprostone is metabolized locally in the stomach and jejunum by carbonyl reductase without being systemically absorbed. The recommended dosage for lubiprostone is 24 mcg taken orally twice per day. The most common side effects of this agent include nausea, diarrhea, headache, and abdominal bloating. This agent should be avoided in patients with known hypersensitivity to the drug or any of its components, and in patients with a history of mechanical gastrointestinal obstruction. Based on the available information, no significant drug–drug interactions have been identified.

THE POTENTIAL FOR LAXATIVE ABUSE

The widespread availability of laxatives, combined with their relatively low cost, increases their potential for abuse and misuse. Chronic laxative use can result in a variety of life-threatening complications and often occurs in the setting of psychosocial pathology. For this reason, it is essential for physicians to have a clear understanding of the long-term effects of laxative therapy and to be aware of the clinical situations in which this type of abuse may be seen. 

Laxative abuse can occur in a wide spectrum of settings, ranging from false perceptions of normal bowel habits to psychiatric conditions such anorexia nervosa and bulimia. Although all forms of laxatives theoretically have the potential for abuse, the stimulant laxatives have been traditionally implicated. Most patients on chronic laxative therapy are elderly patients who become unintentionally established in a cycle of laxative use. These patients may have been placed on laxatives in the past and never told to discontinue them, they may have the mistaken belief that it is necessary to have at least 1 bowel movement every day, or they may be attempting to cope with the side effects of other prescription medications. Whatever the reason, this pattern of laxative use is frequently overlooked by healthcare providers which in itself contributes to the cycle of abuse.

Chronic abuse of laxatives is very commonly associated with underlying psychiatric conditions. In eating disorders such as anorexia nervosa and bulimia nervosa, laxatives are abused in an effort to lose weight. In the initial phases of these disorders, patients are under the false perception that they can use laxatives to purge their bodies before calories are properly absorbed. As these conditions progress, these patients will continue to use laxatives, despite the realization that there are no long-term weight loss benefits.⁷ Laxatives become a way of coping and a psychological safety net for these patients to fall back on. Those seeking anti-aging remedies may similarly abuse laxatives in an effort to rid their bodies of toxins. Other related conditions in which laxatives are inappropriately used include Munchausen syndrome and Munchausen syndrome by proxy, malingering in which there is a primary gain for the patient (ie, missing work, and in athletes, such as weight lifters or jockeys who have to fulfill specific weight requirements for competition).^8,9 Therefore, in order to properly care for this patient population, it is important to recognize the psychosocial components of this form of abuse.

Patients who suffer from the chronic use of laxatives tend to present with persistent large-volume watery diarrhea frequently associated with abdominal pain and cramps. Constitutional symptoms such as generalized malaise, lethargy, and weakness are common symptoms of this form of abuse.¹⁰  The mostcommonly seen adverse effects of long-term laxative use are fluid and electrolyte disturbances. Metabolic derangements are especially seen with the chronic use of osmotic laxatives, and can include profound hyperphosphatemia, hypernatremia, and hypokalemia, among others. The long-term use of lubricant laxatives has been known to interfere with the absorption of fat-soluble vitamins and may result in significant deficiencies.¹¹The most concerning effects of chronic laxative therapy have been associated anthraquinones such as senna and cascara sagrada. Some studies have demonstrated potential damage to the enteric nervous system as well as the intestinal smooth muscle from chronic use of these laxatives. This damage is believed to be the result of morphologic changes to surface epithelial cells and to structural changes of submucosal nerves along the gastrointestinal tract.¹²  In the most severe cases, the chronic use of stimulant laxatives has been implicated in what is known as “cathartic colon,” a condition associated with the loss of haustrations, dilatation of the terminal ileum and colon, and gaping of the ileocecal valve.¹³  Another associated condition is melanosis coli, in which the sigmoid and rectal mucosa acquire a brown pigmentation whose functional significance is unknown, yet may persist for up to 1 year after discontinuation of laxative use.¹⁴ Furthermore, many studies have attempted to determine whether there is a relationship between laxative abuse and colorectal cancer, with yet no clear association. Chronic constipation, however, has been hypothesized to be an independent risk factor for colorectal cancer.

At present, however, the above-mentioned complications of long-term laxative use remain controversial. Conflicting evidence and limited studies make it difficult to make any definite conclusions about the long-term effects of chronic therapy. Furthermore, laxatives have not been shown to cross the bloodbrain barrier, and therefore there is presently no clear pharmacologic basis for addiction. Laxatives are more than likely being chronically misused rather than medically “abused.” Until further studies are done to clarify this distinction, it is reasonable to exercise caution when using laxatives on a chronic basis.

FUTURE IMPLICATIONS

As long as laxatives remain widely available and inexpensive, they will continue to be commonly used. For this reason, it is necessary for physicians to become familiar not only with the available forms of these agents, but also with their known side effects and their potential for misuse. Although laxatives are generally safe, complications of therapy do exist and can be potentially life-threatening. Furthermore, there are still many unproven beliefs about the longterm effects of chronic laxative therapy, and until more research is undertaken, laxatives should be used with caution and their long-term use avoided whenever possible. More research is needed to help establish standardized guidelines for the clinical use of laxatives. Currently, there is no conclusive evidence that one form of laxative is more effective than another, and, therefore, until further research is available, the choice of agent should be based on cost effectiveness and on the individual patient’s circumstances. However, despite the limited evidence, it is reasonable to initiate therapy with natural laxatives and to move on to pharmacologic methods once the former have proven ineffective.