Medical Treatment of Constipation

Constipation is commonly defined as the paucity of bowel movements. However, patients may have constipation regardless of the number of bowel movements in a unit of time. The inability to satisfactorily evacuate one’s colon and rectum can be manifested by different degrees of abdominal discomfort associated with “normal” bowel habits, infrequent stools, or even overflow diarrhea. In addition, many other abdominal complaints are related to constipation, including pain syndromes, bloating, fullness, and even heartburn and dyspepsia.

It is not unusual for patients referred for constipation to present to the specialist having had at least one (and possibly multiple) full anatomic evaluation(s) of the bowel, including computed tomography (CT) scans, contrast studies, and colonoscopies. The reported results of these studies are usually normal, except for varying degrees of diverticulosis coli. Usually, a careful history suffices to reveal the underlying problem.

Issues to be addressed in the history include bowel habits, frequency of bowel movements, ease or difficulty with evacuation, chronicity, childhood bowel habits, medications, and surgery. Careful attention to the use of pain medicines is required, because narcotic use is an often-overlooked cause of constipation-related problems. Physical examination is typically unremarkable, but occasional patients can have palpable ascending or sigmoid colons secondary to stool accumulation. Rectal examination is often normal, but the presence of a large amount of firm stool at the distal rectum can occasionally help to direct therapy.

Interestingly, even patients who move their bowels every day or complain of diarrhea can be constipated, so a plain x-ray of the abdomen can be helpful in patients with vague complaints. The standard radiology report does not include a comment on colonic stool content; therefore, the requesting physician should review the film.

Although routine labs such as complete blood count (CBC), comprehensive metabolic panel, and erythrocyte sedimentation rate (ESR) can be helpful, other tests such as thyroid-stimulating hormone are typically normal. New-onset constipation without an obvious predisposing factor, abnormal rectal exam with hemoccult positive stools, the presence of microcytic anemia on CBC, and an elevated ESR require further investigation, and if a colonoscopy has not been done relatively recently, it should be performed.

Anatomic and Physiologic Considerations

Three important functions of the colon are absorbing water once chyme is delivered from the small intestine and fecal storage and evacuation. The evacuation function has both voluntary and involuntary elements; when evacuation is hindered, constipation results.

Normal bowel function requires the coordination of motility, mucosal transport of water, as well as involuntary and voluntary defecation reflexes. Gastrointestinal motility is dependent on the electrophysiologic activity of smooth muscle cells, neural input from the intrinsic and autonomic nervous systems, hormonal interactions, and coordinated smooth muscle contraction.

The gut exhibits two types of movement: propulsion and mixing. The basic propulsive movement is peristalsis, in which coordinated contractions of the circular as well as longitudinal muscles cause gastrointestinal contents to be pushed forward. The stimulus for peristalsis is distention of the intestine, which causes stretching of the bowel wall smooth muscle. As a result, the intestinal nervous system reacts by stimulating a contraction proximal to the food bolus, thus pushing it distally In the colon the proximal segment functions in both a mixing and absorptive capacity: segmental mixing movements maximize the surface exposure and fluid absorption, whereas slow contractions distally propel the luminal contents. The distal colon functions primarily in a storage capacity

The intestinal smooth muscle is organized in two layers: a longitudinal outer layer and a circular inner layer. In the colon the longitudinal layer forms three bands, the taeniae that eventually form the external anal sphincter distally; the internal circular layer extends distally and eventually becomes the internal anal sphincter. The smooth muscle of the intestine generates intrinsic electrical signals that are translated into contractions. This mechanism is true in the stomach and small intestine, but due to the lack of gap junctions between muscle fibers in the colon, such intrinsic electrical signals usually fail to generate a synchronized contraction. Thus the motility of the colon is regulated by and dependent mainly on external stimuli. As in the rest of the gut, stretching the muscle fibers and cholinergic stimulation via extrinsic neural influences cause an excitatory effect, while noradrenaline and sympathetic stimulation are inhibitory

The intrinsic enteric nervous system lies entirely within the wall of the gut from the esophagus to the anus: the outer myenteric (Auerbach’s) plexus and the inner submucosal (Meissner’s) plexus. The myenteric plexus lies between the longitudinal and circular layers of the entire gut; its main function is control over motor activity. Stimulation increases the tone of the gastrointestinal (GI) wall, intensity and rhythm of contractions, and conduction velocity. The submucosal plexus controls local secretory and absorptive activity. More than a dozen neu-rotransmitters are released from nerve endings of enteric neurons.

In addition to acetylcholine having an excitatory influence and norepinephrine a relaxing one, other neurotransmitters such as dopamine, serotonin, vasoactive intestinal peptide (VIP), substance P, and the endogenous opioid peptides leuenkephalin and metenkephalin have excitatory or inhibitory activity. Other substances, including nitric oxide (NO), carbon monoxide (CO), amines, and purines also have inhibitory influence on GI motility. Gastrointestinal hormones such as gastrin, cholecystokinin (CCK) and motilin stimulate smooth muscle; somatostatin, gluca-gon, and gastric inhibitory peptide have inhibitory effects.

Extrinsic autonomic control of the gut is mediated through the vagus nerve for parasym-pathetic control from the esophagus to the proximal half of the colon, and the pelvic nerves via the sacral parasympathetics for control of the distal colon. Sympathetic fibers located in the thoracic and lumbar regions of the spinal cord reach the gut through the splanchnic nerves. Both the excitatory parasympathetics and inhibitory sympathetics synapse with neurons in the myenteric plexus and submucosal plexus.

Treatment of Constipation

The medical treatment of constipation is usually empiric and based on the experience of both the physician and patient. Patients who are chronically constipated usually bring to the doctor’s office a history of various over-the-counter remedies that they have tried. Currently, more frequently, a patient presenting to a specialist for constipation has often been evaluated with colonoscopy or other visualization studies of the colon. This chapter reviews the pharmacophysiology of a few medical therapies for constipation and previews some pharmaceuticals due out in the near future.

In a community practice it is appropriate to empirically treat patients with chronic constipation according to one’s clinical judgment, assess the results, and if failure occurs, then decide on whether evaluation with physiologic studies or referral is indicated.

If the patient clearly is constipated (as determined by history or by x-ray), and cannot produce a spontaneous, moderate-sized movement, the treating physician should prescribe a cathartic-type laxative to clean out the colon before more conservative means are started. Once a patient has had a satisfactory evacuation or if the patient is already having bowel movements at least every day or so, bulking agents should be instituted as foundational therapy.

Behavioral Considerations

Common causes of constipation include long-term voluntary restraint of evacuation, eventually leading to involuntary problems, highly efficient colonic dehydration of stools, and the inability to initiate defecation. There is strong evidence from the literature as well as everyday experience in the practice of medicine that many patients’ problems with constipation and related symptoms originate from chronic voluntary restraint of evacuation. The exact profiles and underlying psychological stimuli for this behavior is beyond the scope of this chapter. However, treatment of constipation should include “reteaching” the patient proper bowel habits.

The concept of reteaching the colon should not be ignored. Patients who can achieve at least one evacuatory bowel movement every day or so will have significantly fewer symptoms, despite often years or even decades of problems with constipation-related complaints.

Reeducation of the colon often begins at the time of the first office visit, when the physician should discontinue some, if not all, of the pharmaceuticals, over-the-counter preparations, herbals, and other remedies that other practitioners have previously prescribed for the patient’s abdominal symptoms. Over time, many patients accumulate a long list of various remedies that often counteract one another or are frankly counterproductive. Good examples include antispasmodies, which are frequently prescribed for the cramps of constipation. Unfortunately, all of the commonly prescribed antispasmodies have strong anticholinergic effects and are thus constipating.

Additionally, close examination of nongastrointestinal medications needs to be done so that if one or more drugs have a constipating effect, a substitute can be considered. The calcium channel blockers are a good example of a class of drugs used for hypertension that usually can be easily replaced by a less constipating agent.

The patient often benefits from a brief description of the normal physiology of evacuation. The colon is most active from a propulsive standpoint early in the morning (diurnal influences), and after meals. Having the patient choose one of those times to sit quietly on the commode and not straining but taking advantage of the increased activity is usually at least marginally helpful for the constipated patient.

Suppository and Enema Therapy

Patients who complain of pressure in the rectum or feel that they need help in initiating defecation often benefit from local therapy with water-or oil-based enemas or glycerin suppositories. These agents not only provide some lubrication to the area, but also cause reflexive contraction and evacuation of the distal colon and rectum from local mechanical effects. Patients often need reassurance about the safety and non-habit-forming aspects of this type of therapy.

Bulking Agents

Fiber supplementation should be foundational therapy for most if not all constipated patients. A constipated patient should be started at a relatively low dose and slowly increased to a typical daily dose over several days to 1 week. Starting low will help to decrease bloating. After 2 to 4 weeks on therapy, if the patient is still having symptoms, the dose should be doubled in a split dose. Many patients have relief with fiber alone. Continued problems thereafter can be treated with occasional, mild laxatives. The nonresponders may need the addition of treatment for lactose intolerance, or evaluation to assess for colonic inertia, pelvic floor disorders, or postoperative causes.

Numerous bulk-forming laxatives are available as commercial, nonprescription preparations. Some agents may contain stimulant laxatives in conjunction with fiber. There are many sources for bulking agents such as Plantago seeds — psyllium, plant gums, guar, malt soup extract, and synthetic agents such as methylcellulose and polycarbophil. Table Commercial bulk-forming agents lists some of these commercial agents. These agents are generally effective within 12 to 24 hours, but depending on individual transit time, they may require several days.

Fiber intake should be accompanied by an adequate intake of fluids (at least 2L daily), since constipation might worsen if water intake is insufficient. The amount of bulking agent and water intake should be individually tailored for the patient, depending on the effect. If diarrhea results after a single dose, less fiber and less fluid should be ingested initially. The patient can easily monitor the response and adjust the doses after a brief educational encounter with the physician at the office.

Table Commercial bulk-forming agents

Active ingredient	Trade Name*	Comments
Psyllium	Konsyl	Highest fiber content
	Perdiem
	Metamucil	Contains phenylalanine
	Fiberall
	Syllact
	Effer-syllium
	Hydrocil
Methylcellulose	Citrucel
	Cologel
	Hydrolose
Plant gum	Kondremul	Contains mineral oil
	Genlax-S	Contains senna
Polycarbophil	Mitrolan
	Equalactin
	Fibercon
* Konsyl® — Konsyl Pharmaceuticals Inc., Easton, MD (6 g fiber per dose).
Perdiem® — Novartis Consumer Health, Basel, Switzerland.
Metamucil® — Procter & Gamble, Cincinnati, OH (3.4 g fiber per dose).
Fiberall® — Heritage Consumer products, Brookfield, CT.
Syllact™
Effer-syllium™
Hydrocil® — Numark Laboratories, Inc., Edison, NJ.
Citrucel® — Merrell Pharmaceuticals Inc., Kansas City, MO (2 g fiber per dose).
Cologel™
Hydrolose™
Kondremul® — Barre-National, Inc., Baltimore, MD.
Genlax-S™
Mitrolan® — Wyeth Pharmaceuticals, Collegeville, PA.
Equalactin® — Numark Laboratories, Inc., Edison, NJ.
Fibercon® — Wyeth Pharmaceuticals, Collegeville, PA.

Although there is an array of fiber products on the market, psyllium has been a mainstay of fiber therapy for decades. Usually, one can avoid the bloating associated with psyllium introduction by slowly increasing the dose over days or weeks, and starting therapy on a relatively empty colon. The end point of fiber therapy should be resolution of symptoms. This typically requires enough fiber for the patient to have softer, bulkier stools at least once every day or so. If patients reach the maximum recommended dose without success, then either a different type of fiber preparation can be substituted or a mild laxative can be taken on the days that they do not move their bowels.

Magnesium

An example of a safe, mild laxative is the class of agents with magnesium as the active ingredient. Magnesium-based therapy can often provide a nonprescription aid for constipated patients. Magnesium promotes bowel evacuation by causing osmotic retention of fluid and distension of the colon, thus stimulating increased peristaltic activity. Patients with renal failure should generally avoid magnesium products.

Therapy — Past Present and Future

When bulking agents with or without a mild laxative do not provide relief for the constipated patient, the treating physician has a myriad of treatments, prescription and over-the-counter, to turn to. If the patient’s complaints do not suggest anatomic problems or such problems are excluded by other investigations, then continued medical therapy is warranted. Even for patients with pelvic floor disorders or structural bowel problems likely related to chronic constipation and straining, often conservative measures with medications is warranted, since surgical repair is typically seen as a last resort and is frequently not 100% successful at relieving symptoms.

Below are a few examples of second-line medications for the treatment of constipation. Practitioners should always be ready to use treatments empirically for lactose intolerance when patients continue to complain of cramps or pain even when first-line therapies help the patient to have more frequent bowel movements. In a referral practice, up to 50% of referred patients have lasting relief from sometimes decades of discomfort with the use of daily psyllium supplementation and a commercial lactase preparation with meals.

Therapies of the Past

Senna

The most popular herbal medicines in the health food industry are those agents that are used to correct bowel irregularities and relieve constipation. Senna is a herb that has been used for medicinal purposes for millennia. It is a shrub of the plant family Leguminosae.

The active ingredients of senna were first isolated and characterized in the early 1940s. These were two glycosides that were attributed to the anthraquinone family and named sennosides A and B. They are essentially prodrugs. When ingested, they travel through the alimentary tract chemically unchanged until they reach the colon. In the colon they undergo hydrolysis through the action of bacterial β-glycosidases and a further reduction to the final active substances rhein-anthrone and rhein. Their precise mode of action is unknown, although a dual effect has been observed: an increase in the colonic motility with a net reduction in water absorption.

Oral administration of senna pod extract dose-dependently reversed net absorption of water, sodium, and chloride to net secretion, and also increased potassium secretion in a rat model. It also stimulated the output of prostaglandin E₂ into the colonic lumen as well. Both effects were significantly inhibited by pre-treatment with indomethacin. Later it was shown that the addition of calcium channel blockers to indomethacin completely blocked the diarrhea caused by rhein anthrone. These observations imply that the laxative effect of senna may be attributed, at least in part, to secretion of water and electrolytes into the colonic lumen, and that this secretion is mediated by calcium ions and prostaglandin E₂.

More recently it was suggested that the above-mentioned effects might be mediated by the inhibitory action of senna on nitric oxide synthase. In physiologic conditions, endogenous nitric oxide is a proabsorptive molecule that exerts its effect on the enteric nervous system, the suppression of prostaglandin formation, and the opening of K⁺ channels. Thus, the inhibition of nitric oxide formation produces the opposite effect that results in diarrhea.

Since the administered product must reach the colon to be activated, the effect is limited to the large intestine and usually occurs 6 to 12 hours following oral administration.

Contrary to the common belief that natural or herbal medicines are universally harmless and safe, some herbal products may cause serious, even fatal complications.

Anthraquinone laxatives may produce excessive diarrhea accompanied by severe abdominal pain. The urinary excretion of the compounds may cause abnormal discoloration of the urine (light brown turning red with increasing pH), usually without impairment of the renal function. Prolonged use of anthraquinone laxatives causes a melanotic pigmentation of the colonic mucosa called melanosis coli. The mechanism of this phenomenon is deposition of lipofuscin and ceroid products of apoptosis in macrophages of the colonic mucosa.

This pigmentation is reversible 4 to 12 months after cessation of laxative use. There is a general consensus that melanosis coli is a harmless condition. It does not correlate with higher rates of colorectal cancer, although a higher detection rate of adenomatous polyps was demonstrated in one study This maybe due to the fact that even tiny adenomas (that do not usually contain the pigment) are easier to visualize when the dark colonic mucosa serves as a background.

Cathartic colon is a historic, radiologic term for the anatomic changes in the colon secondary to prolonged use of stimulant laxatives. These alterations are characterized by loss of haustral folds, a finding that might suggest neuronal injury or damage to colonic longitudinal musculature caused by these agents. Furthermore, the gradual adaptation and tolerance to senna, as demonstrated by the need for larger doses to produce the same effect after prolonged use, may be attributed to these changes. Those findings are reversible as well.

Current Therapies

More recent additions to the formulary for the treatment of constipation include osmotic agents and drugs active in neuroendocrine modification at the level of the intrinsic neural pathways of the colon.

Polyethylene Glycol

Polyethylene glycol electrolyte lavage solutions (PEG-ELS) have been used for cleansing the GI tract before diagnostic and surgical procedures. The effect produced by those solutions prompted clinicians to use them for treating constipation; however, it was shown that while ingesting a large volume of solution for bowel cleansing, there was no net absorption of water or electrolytes. The ingestion of smaller volume might result in absorption of the salt component of the solution — a situation that may be hazardous for patients with congestive heart disease and chronic renal failure.

In the late 1990s a new laxative was introduced into clinical practice. MiraLax™ PEG 3350, National Formulary powder for solution (Braintree Laboratories, Braintree, MA) is a tasteless, osmotic laxative, and unlike the above-mentioned lavage solutions, it does not contain salt. It has been gaining increasing popularity, and was subjected to many clinical trials with promising results. It is remarkably nontoxic, and large quantities can be ingested without deleterious side effects. It has no effect on active absorption or secretion of glucose or electrolytes and there is no evidence of tachyphylaxis. The usual dose is 17 g of powder in 8 ounces of liquid per day for adults, with an expected bowel movement occurring after 2 to 4 days of use.

Serotonin and the Gastrointestinal Tract

Serotonin (5-hydroxytryptamine, 5-HT) has long been known to play an integral role in gastrointestinal neurotransmission. Serotonin is formed by the hydroxylation and decarboxyla-tion of tryptophan and is converted to its active form in the nerve terminals.

The GI tract contains approximately 95% of the total body serotonin. Although 5-HT is found in a subpopulation of myenteric interneurons, the vast majority is located in subcellular granules located in the enterochromaffin (EC) cells. The EC cells are located in the epithelial layer of the mucosa in close contact to the enteric nerve endings. The serotonin in the EC cells is released when the cells are stimulated by chemical or mechanical stimuli such as increased intraluminal pressure or vagal stimulation. This in turn activates nerve endings in the enteric nervous system and initiates the peristaltic reflex.

Serotonin has a wide array of effects on the GI tract largely due to the presence of multiple subtypes, which appear to be present on several classes of myenteric neurons, smooth muscle cells, and enterocytes. In general, the release of 5-HT has been found to be directly modulated by ligand-gated and G-protein-coupled receptors, which have at least 15 serotonin receptor subtypes that mediate its effect.

The selective, partial 5-HT4 agonist Tegaserod is one of a new class of compounds called the aminoguanidine indoles. Structurally, Tegaserod is very similar to serotonin and stimulates the release of calcitonin generelated peptide from enteric neurons. This augments the peristaltic reflex, enhances intestinal secretion, and reduces visceral hypersensitivity Tegaserod interacts with enteric 5-HT4 receptors, resulting in amplification of this process.

In an industry-sponsored, multinational randomized trial, researchers assessed the efficacy of Tegaserod in 1348 adults of whom 90% were females. These subjects had complaints of chronic constipation, which was defined as a weekly average of fewer than three spontaneous bowel movements. These patients received 2mg, 6mg, or placebo twice a day for 12 weeks. The study showed that Zelnorm* (Tegaserod) caused a statistically significant improvement and increased the frequency of spontaneous bowel movements and relieved symptoms including straining, hard stool, incomplete evacuation, and abdominal discomfort.

Recently Tegaserod has been approved for chronic constipation in men.

Therapies of the Future

In the not-too-distant future, patients and their physicians may be spared the sometimes tremendously difficult problem of narcotic-induced constipation. To date, the narcotic antagonists have been effective peripherally, but have been unhelpful because they reverse the intended, central effect of the analgesic.

Narcotic administration is perhaps the most common cause of iatrogenic constipation. Three types of receptors for opioid peptides have been identified as having effects on human gastrointestinal function: µ, κ, and λ receptors. They all belong to the family of G-protein-coupled receptors, and reduce intracellular cyclic adenosine monophosphate (cAMP) by inhibiting adenylate cyclase.

At the membrane level, they reduce neuronal excitability by hyperpolarization resulting from increased potassium permeability of the membrane, and neurotransmitter release by inhibition of voltage-gated calcium channels. The overall effect is inhibitory. These actions result in a reduction in acetylcholine release, with an overall inhibitory effect on the neuron.

Opioid receptors are widely distributed in the central and peripheral nervous system, the intestinal musculature, and other tissues. They are found in high concentrations in the dorsal horn of the spinal cord where they process and relay afferent nociceptive signals to the central nervous system. In the brain, they are mainly in areas involved in pain transmission. µ–Receptors are the principal mediators of the analgesic action of endogenous and exogenous opioids, as well as the major side effects of sedation, bowel dysfunction, respiratory depression, and dependence. Localization studies of the human gut have shown that µ-receptor activity is localized to myenteric and submucosal neurons and to immune cells of the lamina propria.

Generally, opioids interfere with normal GI motility by delaying transit, by stimulating non-propulsive motility, segmentation and tone, and by stimulation of sphincters such as the pylorus. These effects are mainly mediated by κ and µ receptors. Delay in colonic transit contributes significantly to the constipating effect of opioids, prolonging content-mucosa contact time and enhancing absorption.

Alvimopan is a new selective, competitive, peripherally acting µ-receptor antagonist, with limited oral bioavailability It can reduce opioid-induced bowel symptoms without antagonizing centrally mediated opioid effects. Its action is against peripheral receptors, and it has a negligible central effect. Gonenne et al have recently shown that Alvimopan blocks the effects of the opioid analgesic codeine on small-bowel and colonic transit in humans. Furthermore, Alvimopan alone significantly accelerates colonic transit in healthy volunteers when compared to placebo.

Conclusion

In a community practice, uncomplicated constipation should be approached in a stepwise manner. Although most patients may have their own methods to deal with acute problems, they occasionally need a one-time oral cathartic or large-volume enema in the beginning of treatment, to start with a “clean slate.” In these situations, prior to treatment, confirmation of constipation is usually easily accomplished by reviewing an abdominal x-ray.

Most patients’ symptoms of constipation can be treated with daily fiber supplements and behavior modification. Of the remaining patients, many respond to rectally administered glycerin suppositories, enemas, or the judicious use of an oral stimulant, such as magnesium or senna.

For those continuing with symptoms despite conservative management, the practitioner will have to decide whether to proceed with prescription therapy such as polyethylene glycol or Tegaserod, or refer the patient for physiologic-anatomic testing with marker studies and defecography

In the near future, effective therapy for narcotic-induced constipation will likely be available. Until then, aggressive, nonspecific therapy accompanied by minimization or elimination of the offending substance is warranted.