48
Constipation
Amanda Metcalf and Howard Michael Ross
678
One of the most common complaints voiced to internists, gas- troenterologists, and colon and rectal surgeons alike is that of constipation. Patient definitions of constipation are so vari- able that the term itself is meaningless and focused question- ing regarding the patient’s actual bowel habits is mandatory.
To facilitate research into and treatment of constipation and other functional bowel disorders, a multinational panel of experts was convened in Rome, Italy. The Rome criteria for the diagnosis of constipation requires two or more of the following for at least 3 months:
●Straining more than 25% of the time
●Hard stools more than 25% of the time
●Incomplete evacuation more than 25% of the time
●Two or fewer bowel movements per week
Sonnenberg and Koch1 described the enormity of the problem in the United States in 1989. These authors estimated that four million people in the United States complain of frequent con- stipation, a prevalence rate of 2%. Complaints of constipation are two to three times more common in women than men and complaints increase with increasing age. The incidence of con- stipation is also higher in nonwhites than whites, in people from a lower socioeconomic and educational status, and in the southern United States. A more recent study in elderly residents of Olmstead County in Minnesota further underscored the enormity of the problem.2 Talley et al. found that nearly one in two women and one in three men over the age of 65 either had complaints of constipation or took laxatives. The magnitude of the problem requires the colon and rectal surgeon to understand the causation of constipation, be facile with the tests used in the evaluation of the constipated patient, and be able to recommend both medical and surgical therapies when appropriate.
Etiology
Constipation can be secondary to a long list of conditions and medications (see Table 48-1). Physiologically, a number of complex interactions are necessary for the development of
formed stool, the passage of stool through the colon, and the elimination of the stool bolus. Evaluation of the constipated patient must include investigation into all of the factors poten- tially responsible for constipation.
Diet affects the size, consistency, and frequency of bowel movements. Dietary intake of fiber is highly correlated with stool bulk. Inhabitants of countries with higher fiber intake pass more voluminous stool than those in countries with a lower intake of dietary fiber. Inhabitants of Western countries typically ingest inadequate amounts of fiber, secondary to reliance on processed grains. Because colonic distension triggers peristalsis, bulkier stools are a stronger and more effi- cient stimulus for colonic propulsion than smaller stools.
As noted, female gender is associated with a higher preva- lence of constipation. Knowles et al.3 reported that of 2004 patients evaluated by transit study at three European tertiary referral centers for intractable constipation, 92% were women. No definitive explanations exist for the gender differ- ence seen, although hormonal influences and pelvic anatomy have been suggested.
Many medical conditions are recognized to affect bowel function. Hypothyroidism and diabetes, lupus and sclero- derma, neurologic illness, immobilization, and psychiatric disease are but a few of a long list of medical maladies associated with increased rates of constipation and should be considered as a source of constipation during evaluation.
Mechanisms of dysfunction include alteration in motor func- tion of the gut and autonomic neuropathy as seen in hypothy- roidism and diabetes mellitus, respectively. Hirschsprung’s disease and Chagas’ disease alter the function of the colon through damage to the enteric nervous system. Connective tissue disorders alter the functionality of intestinal smooth muscle. Colonic stricture secondary to carcinoma, inflamma- tory bowel disease, radiation, or endometriosis can cause colonic obstruction. Medications for the management of com- mon disorders such as hypertension promote the development of constipation. Opiate and anticholinergic use, as well as laxative abuse, is associated with constipation. Opiates decrease the propulsive activity of the colon through
activation of mu-opiate receptors found on neurons of the enteric nervous system.
Evaluation
The evaluation of the patient complaining of constipation begins with a detailed history. Specific details of the patient’s complaints—stool size, frequency, consistency, ease and effi- cacy of evacuation—should be noted. Also important to note are the age at onset of symptoms, diet and exercise details, medical history, surgical history, and medication. Query into psychiatric illness and sexual and physical abuse must be per- formed, because they are associated with defecation difficul- ties. Symptoms of pelvic floor dysfunction involving the urinary tract should be ascertained. A patient diary of dietary intake, defecation frequency, stool consistency, and any asso- ciated symptoms can be very helpful to both the patient and the medical provider.
Physical examination will likely be unremarkable.
Abdominal distension or the presence of a mass may be noted. Rectal examination should involve a clinical evaluation of resting tone and the ability to voluntarily contract and relax the anal sphincter. Evaluation for pelvic floor dysfunction such as perineal descent with straining, the presence of a rec- tocele or cystocele, and the volume and consistency of stool in the rectal vault should be noted.
The evaluation of the patient with symptoms of constipa- tion that do not respond to a trial of diet and medical therapy begins with the elimination of a structural bowel obstruction via colonoscopy or barium enema. Once obstruction has been eliminated as the cause of constipation symptoms, colonic transit time should then be assessed.
The purpose of the radiographic evaluation of the patient with constipation complaints is to identify conditions that may require treatment paradigms other than diet and medication therapy. Specifically, slow-transit constipation (colonic inertia) and pelvic floor outlet obstruction are entities that may be bet- ter treated with surgery and biofeedback, respectively.
Evaluation of upper gastrointestinal motility, colon motility, and the mechanism of defecation is currently possible. When combined with anal manometry, a picture of a patient’s ability to propel and eliminate stool can be generated.
Colonic transit time can be estimated via marker studies or through scintigraphy. The precise technique chosen depends on availability and whether one desires a global or more pre- cise measurement of transit. The most widely available tech- nique for determining colonic transit uses radiopaque markers and radiographs of the abdomen. The concept of assessing transit using markers was first developed by Hinton et al.,4 modified by Martelli et al.,5 and further simplified by Metcalf et al.6
To obtain a global assessment of whether or not patients have slow-transit constipation, the technique requires the patient to refrain from all enemas, laxatives, and most med- ications for 2 days before the ingestion of 24 radiopaque markers. The patient is required to ingest 30 g of fiber daily during the test and must continue to refrain from taking med- ication and laxatives. An abdominal radiograph is obtained on the fifth day. The distribution and the number of markers present in the colon are noted. Eighty percent of normal patients will have passed all the markers by 5 days. If the markers are found to have accumulated in the rectum, outlet obstruction is suggested. If the markers remain scattered throughout the colon and more than 20% of the markers remain in the colon after the fifth day after ingestion, colonic inertia can be diagnosed.
A more precise assessment of transit delay can be obtained by having the patient ingest radiopaque markers on three sequential days while following the same instructions and obtaining a radiograph on the fourth and seventh day (see Figure 48-1). The number and distribution of the markers are tabulated and totaled. The resultant numeric values can then be compared with the established value for normal controls.
TABLE48-1. Factors associated with constipation Lifestyle
Inadequate fluid intake Inadequate fiber intake Inactivity
Laxative abuse Medications
Anticholinergics Antidepressants
Calcium channel blocker anti-HTN Iron
Opiates Medical illness
Neurologic
Spinal cord dysfunction/damage Parkinson’s disease
Multiple sclerosis
Endocrine/metabolic dysfunction Diabetes mellitus
Hypothyroidism Electrolyte abnormalities Uremia
Hypercalcemia Porphyria Psychological
Depression Anorexia Psychiatric illness Sexual abuse Colonic structure/function
Cancer Crohn’s disease Irradiation Endometriosis Hirschsprung’s disease Chagas’ disease Pelvic floor abnormality
Nonrelaxing puborectalis Anal stenosis
Rectocele/enterocele
The mean colon transit time through the entire colon in men has been shown to be 31 hours in males and 39 hours in women. Patients with normal transit constipation will have a colon transit time that is in the normal range (< 65 hours in 95% of men, < 75 hours in 95% of women).
Scintigraphic evaluation of colonic transit has been described, and although not as widely available, is useful in the assessment of transit in the colon and proximal gut.7 Transit times obtained through scintigraphy are generated by following the passage of a radiolabeled meal. Small bowel and gastric emptying rates can also be estimated with this one examination. Normal small bowel transit is between 90 and 120 minutes.
Outlet obstruction suggested on a marker study can be fur- ther characterized through defecography. Defecography facil- itates visualization of the mechanism of defecation.
Nonrelaxing puborectalis or a large rectocele can both be identified on a defecogram.8
Anal manometry reveals the absence of the rectoanal inhibitory reflex and therefore suggests the presence of Hirschsprung’s disease. Balloon expulsion testing performed during manometry can add to the reliability of the diagnosis of pelvic floor outlet obstruction caused by nonrelaxation of the puborectalis muscle.9Anal electromyography is performed
in conjunction with manometry. The recruitment of puborec- talis muscle fibers during defecation simulation indicates the entity of nonrelaxing puborectalis outlet obstruction.
Assessment of upper gastrointestinal motility is appropriate in patients who are demonstrated to have slow-transit consti- pation. Patients with generalized motility disturbances and colonic inertia have less favorable results after surgical inter- vention than patients with colonic inertia alone.10 Small bowel transit time may be measured scintigraphically as men- tioned above or with a lactulose hydrogen breath test. The principle of this examination is that hydrogen produced through lactulose fermentation only occurs in the colon. If one records the time from ingestion of lactulose to hydrogen production, small bowel transit time can be inferred.
Medical Treatment of Constipation
Therapy of the constipated patient should begin with patient counsel. It is sage advice to help the patient understand that a daily bowel movement is not requisite to good health. All providers should strive to decrease patient anxiety over the act of defecation. The elimination of malignancy and mechanical causes of symptomatology, performed for the evaluation of constipation, often goes far in this regard.
Simple measures that can influence the passage of colonic content are increasing physical activity and fluid intake.
Exercise, even gentle walking, can facilitate the elimination of stool. Fluid intake can cause the stool to be softer and easier to pass. Medications that promote constipation should be elimi- nated or substituted with alternatives that are less constipating.
Lack of dietary fiber intake is a major factor in the develop- ment of constipation symptoms. Bulk-forming agents are a first-line therapy in the prevention and treatment of constipa- tion. Bulk-forming agents facilitate an increase in the size of the stool bolus as well as make the stool softer. Bulking agents facilitate these changes by delivering a mass of nondigestible substrate to the colon and, because of their hydrophilic nature, facilitate the absorption and retention of fluid. Bulk laxatives are derived from the nondigestible components of plants or are synthetic methylcellulose derivatives. Common bulk agents are psyllium (Metamucil, Konsyl), methylcellulose (Citrucel), and calcium polycarbophil (FiberCon). Side effects of fiber therapy include bloating and flatulence. A dietary intake of 20–30 g of nonstarch polysaccharide is generally recom- mended to minimize symptoms of constipation.
Osmotic laxatives are a class of medications that promote the accumulation of large volumes of fluid in the colon lumen through the delivery of osmotically active molecules into the small and large bowel. The osmotically active particles can be derived from sugars or salts. Sorbitol and lactulose are exam- ples of sugar-based osmotic agents. Lactulose is broken down in the colon yielding the production of fatty acids, hydrogen, and carbon dioxide. Cautery in the presence of these gases can cause an explosion.
FIGURE48-1. Marker study revealing colonic inertia.
Osmotic laxatives can also be based on nonabsorbable ions, frequently derived from magnesium or phosphate. Examples are magnesium hydroxide (milk of magnesia) or sodium phosphate (Fleets Phospho-soda). Caution must be exercised in patients with renal insufficiency because hypermagnesemia can result. Polyethylene glycol–based products are used in many bowel-cleansing regimes. Chronic use can lead to elec- trolyte disturbances and dehydration.
Colonic irritants are a class of agents that diminish consti- pation through stimulation of colonic motility. Anthracene derivatives include senna and cascara and are found in Senokot and Peri-Colace. Long-term anthracene intake can generate a characteristic brown discoloration of the mucosa called pseudomelanosis coli. There is some debate whether long-term intake of anthracene laxatives increases the risk of colon cancer. Bisacodyl is another irritant and can be found in the agent Dulcolax. Long-term use of anthracene irritants may lead to poor colon function and such use is therefore discouraged. However, there is little objective evidence to support this belief.
Mineral oil and docusate sodium (Colace) are laxatives that act through the manipulation of the composition of stool.
Mineral oil coats the stool bolus, preventing fluid absorption from it. Docusate sodium lowers the surface tension at the stool water interface, allowing greater penetration of the stool with fluid.
Enemas and suppositories are used to stimulate a bowel movement. Strategies include promotion of defeca- tion through distension (saline enema), rectal irritation (soap- suds, bisacodyl), or physical softening of the stool (glycerine).
Colonic Inertia
Colonic inertia, also called slow-transit constipation, repre- sents a severe functional disturbance of colonic motility, which results in significant disability to the patient. Patients with colonic inertia, similar to patients with normal transit consti- pation and patients with outlet obstruction, exhibit infrequent defecation and may experience abdominal pain, bloating, nau- sea, difficulty with and incomplete evacuation of stool. Only a very small percentage of patients with constipation actually have colonic inertia. The diagnosis of colonic inertia requires the documentation of abnormal colonic transit (> 20% of ingested markers present and scattered throughout the colon on day 5 of colonic transit time testing). Patients with consti- pation are often highly motivated to relieve their symptoms.
Many are very willing to undergo surgery. Total abdominal colectomy (TAC) for colonic inertia is only appropriate for patients with documented abnormalities in colonic transit.
TAC entails the risk of abdominal operation and intestinal anastomosis. Persistent or recurrent constipation, progression to small bowel inertia, and fecal incontinence may occur after TAC with ileorectal anastomosis and must be explained to the patient. Precise evaluation of colonic motility and pelvic floor
function is critical in the identification of patients that truly exhibit colonic inertia and have the highest probability to ben- efit from surgical intervention. A review of the outcomes of surgical intervention for colonic inertia follows.
Lane11reported the results of surgical intervention for the elimination of constipation in 1908, and described the resolu- tion of constipation symptoms through the removal of the abdominal colon in two-thirds of patients. Lane performed his series of operations without the benefit of manometry, transit studies, or defecography. Remarkably, he was able to state that if the abdominal colon was not removed, symptoms could recur.
Dr. Lane’s words speak volumes. “In the earliest cases in which I removed the greater part of the large bowel the symp- tom demanding it was pain, usually in the caecum, splenic flexure, or sigmoid. Though I was aware of the associated symptoms of autointoxication I did not operate for their removal, nor was I aware that the excision of the large bowel would result in their complete disappearance. I only became conscious of this result after the removal of the large bowel.
And the comparatively abrupt change which ensued during the few days following the operation was almost startling. The recognition of the immense advantages which these miserable people obtained from the removal of the large bowel then induced me to operate also in cases where pain was not nec- essarily such a marked feature, but where life was becoming a burden through the misery and distress induced by the autointoxication and its result . . . . At first I was satisfied in most cases to remove the large bowel as far as the splenic flexure, as I believed that the risk of the operation was reduced by leaving the descending colon and sigmoid, for these structures being vertically placed I did not expect that material would accumulate in them above the junction of the ileum and rectum. I found, however, that many of those in whom I left them complained, after a lapse of time, of symp- toms which I was able to attribute to distension of the descending colon and sigmoid with gas. Therefore I excised the residual bowel in many such cases of incomplete resection and took away the entire large bowel with the exception of the rectum in all primary operations.”
Multiple trials have recently reported the long-term results of TAC for colonic inertia. Pikarsky et al.12 from the Cleveland Clinic Florida identified 50 patients that had under- gone TAC for colonic inertia between 1988 and 1993. Thirty were available for telephone interview designed to assess bowel function, concomitant use of any antidiarrheal medica- tions, postoperative complications, persistence or develop- ment of preoperative symptoms such as pain or bloating, and overall satisfaction. The mean follow-up was 106 months (range, 61–122 months). Remarkably, all 30 patients reported the outcome of surgery as “excellent.” The average number of bowel movements per day was 2.5 (1–6). Twenty percent of patients required admission for small bowel obstruction and half of these patients required laparotomy for obstruction (10%). Two patients (6%) required assistance with bowel
movements despite operation. Two patients (6%) needed antidiarrheal medication to reduce bowel frequency.
Long-term follow-up has also recently been reported by Webster and Dayton13from the University of Utah. Their ret- rospective review identified 55 patients who underwent TAC for colonic inertia. Eighty-seven percent were female and the average age was 40. Postoperatively, 8% experienced a bowel obstruction. “Good” or “excellent” results were reported by 89% of patients. “Poor” results were reported by 11% of patients. The mean stool frequency per day was three at 12 months from surgery. Verne et al.14from the University of Florida identified 13 patients who underwent TAC for colonic inertia between 1983 and 1987. Seven patients had an ileosig- moid anastomosis and six an ileorectal anastomosis. The overall number of bowel movements per week increased from 0.5 to 15 ± 4.5 postoperatively.
The Mayo Clinic reported their long-term results of TAC for colonic inertia in 1997.15Seventy-four patients were iden- tified as having had a TAC. Fifty-two had slow-transit consti- pation alone and twenty-two had colonic inertia and pelvic floor dysfunction. These twenty-two underwent pelvic floor retraining followed by surgery. Similar to most other studies, 90% of patients had a “good” or improved quality of life. All patients could pass stool spontaneously. Nine percent of patients developed a small bowel obstruction. There was no difference in the surgical outcome of patients who required pelvic floor retraining and surgery when compared with the group that required surgery alone.
FitzHarris et al.16 from the University of Minnesota addressed the question of whether the increase in bowel movements experienced by patients with colonic inertia that undergo TAC resulted in an improved quality of life. Patients were sent a survey that inquired about bowel function and included a gastrointestinal quality-of-life index. Gastro- intestinal quality-of-life index scores were correlated with specific functional outcomes. Eighty-one percent of patients were at least “somewhat” pleased with their bowel movement frequency, but 41% cited abdominal pain, 21% incontinence, and 46% had diarrhea at least some of the time. Five percent of patients had recurrent or persistent constipation and 17%
underwent lysis of adhesions for small bowel obstruction. No correlation was found between frequency of bowel move- ments and quality-of-life scores. If offered subtotal colectomy again, 93% of patients stated they would accept. These authors concluded that although the vast majority of patients were no longer constipated, a significant number had persistent or new adverse symptoms.
Knowles et al.17in 1999 published a thorough review of the outcome of colectomy for slow-transit constipation. All series published in the English language through 1999 including 10 or more patients treated with colectomy for colonic inertia were included in the review. Thirty-two studies between 1981 and 1998 met entry criteria. The authors noted that the median rate of success in these studies was 86% with a range between 39%–100%. The authors of the review revealed that no study
was controlled with respect to the outcome from other surgical or medical interventions. Although not every study in the review commented on each potential functional outcome variable, many patterns of postoperative problems were identified. Fecal incontinence was reported in 16 series with a median incidence of 14% (range, 0%–52%). Persistent abdominal pain was reported in 14 series. A 41% median incidence of abdominal pain was identified, with a range between 0%–90%. Recurrent constipation was reported in 15 series with a median incidence of 9% (range, 0%–33%).
A permanent ileostomy was created in 5% of patients because of poor functional outcome (0%–28%).
Despite consistently increasing stool frequency, TAC to treat colonic inertia does not guarantee a successful functional outcome. Furthermore, even extensive preoperative work-up does not ensure patient satisfaction. In their study of 21 patients diagnosed with slow-transit constipation via colon transit studies, anal manometry, defecography, pelvic floor electromyography, and determination of small bowel transit time, Mollen et al.18 found a satisfaction rate of 52% after 1 year. They appropriately caution against the promiscuous use of colectomy to treat functional constipation. Operations other than TAC with ileorectal anastomosis have been pro- posed in the treatment of colonic inertia. Segmental resection has the theoretic advantage of reducing diarrhea and fecal incontinence. In a consecutive series of 28 patients with slow- transit constipation as determined by scintigraphic transit study that were subsequently treated with segmental colec- tomy, 23 patients were pleased with the outcome.19 The median follow-up in this study was 50 months. The median stool frequency increased from one to seven per week.
Incontinence was unchanged. Similarly in a study from China using right or left colectomy to treat transit abnormalities of either the right or left colon, 37 of 40 patients followed for 2 years had improvement of their symptoms without diarrhea or incontinence.20Three of the 40 patients experienced recur- rent constipation that ultimately required TAC with ileorectal anastomosis. Because the follow-up time of these studies is short and the ability to define segmental colonic transit inex- act, TAC remains the most widely accepted surgical treatment option in the treatment of colonic inertia. Historically, patients having segmental colectomy have had poor results.21 Proctocolectomy with ileoanal pouch reconstruction has been described as a salvage operation for patients with recur- rent constipation after subtotal colectomy with ileorectal anastomosis for slow-transit constipation. The number of patients that have had pouch reconstruction for salvage after subtotal colectomy has been quite small. Keighley et al.22 reported the results of eight patients who underwent such rad- ical surgery. Four of these eight ultimately required pouch excision for recurrent constipation. Proctocolectomy as initial treatment for slow-transit constipation and rectal inertia has recently been explored.23Two of 15 patients required pouch excision within 18 months because of intractable pelvic pain.
Significant improvement in lifestyle scores were recorded in
the categories of physical function, social function, pain, and general health for the group during the follow-up period.
A difficult subgroup of patients with slow-transit constipa- tion to treat is those with concomitant pelvic floor dysfunction.
Bernini et al.24 from the University of Minnesota evaluated 16 patients who had a combination of colonic inertia and non- relaxing pelvic floor as diagnosed by transit marker study, electromyography, and defecography. All patients completed preoperative biofeedback training and could demonstrate relaxation of the pelvic floor musculature. Despite biofeed- back training, difficult evacuation persisted. Postoperatively, 43% of patients had complete resolution of symptoms of con- stipation or difficult evacuation. Eighteen percent complained of diarrhea and incontinence of liquid stools. Six of the 16 patients complained of incomplete evacuation. The authors concluded that subtotal colectomy could improve some symp- toms in patients with colonic inertia and nonrelaxing pelvic floor, however, incomplete evacuation persisted in a signifi- cant number of patients. Almost half were dissatisfied with their surgery.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a disorder in which patients have abdominal discomfort and altered bowel habits that defy explanation by identifiable organic pathology. Although there is overlap between patients in this category and those described in the previous section, this diagnosis is more inclu- sive because patients can have constipation or diarrhea. There are no specific tests to identify this disorder. Rather, it is a diagnosis of exclusion, and remains a clinical diagnosis. The most recent consensus of the clinical features of IBS is known as the Rome criteria and was reached at the conference described earlier. These criteria were reached to standardize the diagnosis of this disorder for both research purposes and clinical practice.25 The Rome criteria for a clinical diagnosis of IBS are listed in Table 48-2. In essence, patients must have chronic symptoms that include abdominal pain relieved by defecation and or associated with a change in the consistency or frequency of stools. These symptoms are variably associ- ated with mucorrhea and/or abdominal bloating.
Population-based studies in Western countries report an overall prevalence of IBS of 10%–20%.26With the exception of Hispanics in Texas and Asians in California, who may have a lower rate, the prevalence is similar in Western minority populations.27,28Some studies suggest that the incidence may be lower in Asian countries and Africa. In Western countries, women are 2–3 times more likely to develop IBS than men; in India, this phenomenon is reversed.29The prevalence seems to be lower in the elderly. Retrospectively, many patients report childhood symptoms, and 50% of patients have symptoms before age 35.30 The incidence in Western countries is 1%–2% per year.
It has been recognized for many years that there are a vari- ety of disorders associated with a clinical diagnosis of IBS.
These include nonulcer dyspepsia, fibromyalgia, chronic fatigue syndrome, dysmenorrhea, urinary tract symptoms, and psychiatric disorders. Patients who undergo physician evaluation for IBS tend to have increased scores for depres- sion, anxiety, somatization, and neuroticism on standardized tests, although no specific pattern of personality traits in patients has been identified. Patients with IBS who present for evaluation are at least twice as likely to meet criteria for psy- chiatric disorders as patients with organic disease. The most frequent of these disorders are depression and generalized anxiety. Interestingly, individuals with clinical symptoms of IBS who do not seek medical care have a similar prevalence of psychiatric disorders as the general population.31This sug- gests that the psychiatric disorder may be more important in healthcare-seeking behavior than as an etiologic agent of the syndrome.
It has been estimated that only 10% of patients with IBS symptoms consult a physician for evaluation or treatment of their symptoms. With the exception of Indians, women are more likely than men to present for physician evaluation. The socioeconomic impact of this disorder is significant. There are estimated to be 3.5 million physician visits in the United States, and IBS is the most common diagnosis in gastro- enterologist practice. Patients with IBS have more work absenteeism, more physician visits, and report a lower quality of life.32
The current theories regarding the pathophysiology of IBS are of a complex interaction between altered gut motility and or visceral hyperalgesia and neuropsychopathology. Many studies measuring myoelectric activity in the colon have demonstrated abnormalities in patients with IBS. Normal colonic myoelectric activity consists of background slow waves with superimposed spike potentials. Bueno et al.33 demonstrated increased long spike bursts in patients with constipation and irregular short spike bursts in patients with diarrhea. Myoelectric studies in the small bowel have demon- strated shorter intervals between the migrating motor com- plex, which is, of course, the predominant interdigestive small bowel motor pattern.34 Patients with IBS have variations in the colonic slow wave frequency and a blunted late peaking postprandial response of spike potentials in the colon. Transit TABLE48-2. Rome criteria for IBS
Abdominal pain or discomfort characterized by the following:
Relieved by defecation
Associated with a change in stool frequency Associated with a change in stool consistency
Two or more of the following characteristics at least 25% of the time:
Altered stool frequency Altered stool form Altered stool passage Mucorrhea
Abdominal bloating or subjective distension
studies in the small bowel have demonstrated delayed meal transit in patients with constipation-predominant IBS and accelerated meal transit in patients with diarrhea-predominant IBS.35,36These studies and others suggest an underlying gen- eralized hyperresponsiveness of smooth muscle in patients with IBS.
Visceral hyperalgesia seems to be another component of this disorder. Studies measuring the perception of gut disten- sion using various techniques have demonstrated abnormally low sensitivity in both the small and large bowel.37,38It seems that patients with a diagnosis of IBS have both an increased awareness of gut distension, and experience such distension as painful at lower volumes and pressures as normal subjects.
This is especially in response to rapid distension.39Although there has been some argument regarding a reporting bias in patients with IBS (i.e., routinely reporting pain at lower sub- jective intensities than normal controls), such differences do not account for all of the sensory abnormalities seen.40 Furthermore, patients with IBS have widened dermatomal referral pain patterns than normal controls from gut disten- sion.41This visceral hypersensitivity is not associated with a somatic hypersensitivity.42It is thought that patients with IBS may have sensitization of the intestinal afferent nociceptive pathways in the spinal cord.
The central nervous system modulates gut function for optimal digestive function. The limbic system, medial pre- frontal cortex, amygdala, and hypothalamus communicate emotional changes to the gut via the autonomic nervous sys- tem. In turn, signals from the gut to the brain can effect reflex regulation and mood states.43Recent studies have suggested that patients with IBS may process visceral afferent input in the central nervous system in an abnormal way and this response may be modified by attentional factors such that stress, anxiety, and prior unpleasant life events increase the perception of painful events.44–46 On a biochemical level, patients with IBS have been demonstrated to have increased hypothalamic corticotropin-releasing factor in response to stress, as well as an exaggerated colonic motility response.47
The relationship between psychopathology and IBS is not clear. As noted previously, patients with IBS have a higher incidence of panic disorder, major depression, anxiety disor- der, and hypochondriasis than normal populations.48In addi- tion, they report a higher prevalence of physical or sexual abuse.49Two-thirds of patients with IBS report the onset of gastrointestinal complaints with an axis 1 disorder.50
In summary, patients with IBS have been demonstrated to have abnormal gut motility, visceral hyperalgesia, and neu- ropsychologic abnormalities. In a particular patient, any of these factors may predominate, but all may be involved and they are not mutually exclusive. An understanding of these abnormalities has led to the emergence of new possibilities in the pharmaceutical treatment of this syndrome.
The altered stool habits reported by patients with IBS can be constipation, diarrhea, or alternating constipation and diar- rhea. Constipation can be described as hard and/or infrequent
stools, or painful defecation requiring laxative use. Diarrhea is usually described as small volume, frequent, urgent, and watery stool. Diarrhea when present is often postprandial in nature. Usually patients have either constipation or diarrhea alone, however, alternation between each can be present.
Abdominal pain is usually perceived as diffuse, and is most common in the lower abdomen, especially on the left. Sharp pain may be superimposed on a more chronic duller compo- nent. Pain may be precipitated by meals and is often relieved by defecation. Patients often report increasing bloating and gas through the daytime hours, which may or may not be associated with objective evidence. Mucorrhea, either white or clear, is often reported. Patients with IBS are more likely to report upper gastrointestinal symptoms of nausea, vomiting, and heartburn. Overall symptoms may be worse in times of stress. Symptoms that are not typical of IBS that should alert the clinician to organic disease include: onset in middle age or older, progressive or nocturnal symptoms, anorexia, weight loss, fever, hematochezia, painless diarrhea, or steatorrhea.
Although there are emerging novel medications for IBS that may prove useful, much current medical therapy depends heavily on reassurance. Explanation and patient education have an important role in the management of this chronic dis- order. Treatment strategies depend not only on the type of symptoms present but their severity and chronicity.
Fiber supplementation may improve symptoms of either constipation or diarrhea, although studies are inconclusive because of a strong placebo effect. Many physicians believe that polycarbophil-based bulking agents may be tolerated bet- ter than psyllium-based compounds because of an exacerba- tion of bloating symptoms in some patients with the latter.
Similarly, ingesting more water, avoiding caffeine and legumes are all reasonable patient advice.
As noted above, treatment strategies are symptom directed.
Currently available and widely used pharmacologic agents for patients with diarrhea-predominant IBS include anticholin- ergic medications, nonabsorbable synthetic opioids, and tricyclic antidepressants.
Anticholinergics inhibit intestinal smooth muscle depolar- ization at the muscarinic receptor. These include dicyclomine hydrochloride (Bentyl) and hyoscyamine sulfate (Levsin).
Either has been shown to decrease fecal urgency and pain.
Nonabsorbable synthetic opioids, which are frequently used as antidiarrheals act via peripheral mu-opiate receptors.
Diphenoxylate hydrochloride with atropine (Lomotil) or lop- eramide (Imodium) inhibit intestinal motility and prolong transit through the gut. They also reduce visceral nociception via afferent pathway inhibition. They improve stool fre- quency, urgency, and consistency. Tricyclic antidepressants such as amitriptyline (Elavil) and imipramine (Tofranil) have also been evaluated in off-label use in very low doses for a visceral analgesic effect. Either medication increases orocecal transit time, reduces abdominal pain, mucorrhea, and stool frequency. These results are at subtherapeutic doses for the treatment of depression.
Novel treatments that have been introduced more recently for patients with diarrhea-predominant IBS include the sero- tonin (5-HT3) agonist Alosetron (Lotronex). This drug inhibits activation of nonselective cation channels that modu- late the enteric nervous system. It has been approved only for women with severe diarrhea-predominant symptoms of IBS who have not responded to conventional medication. It has been demonstrated to improve abdominal pain and decrease diarrhea in such patients.51 Alosetron was temporarily removed from the market by the Food and Drug Administration because of serious and unpredictable side effects including colonic ischemia and toxic megacolon.
Cilansetron is another 5-HT3 antagonist currently undergoing testing. This medication shows promise for relief of symp- toms in both male and female patients with diarrhea-predom- inant IBS.52
For patients with constipation-predominant IBS who do not respond to fiber supplementation (20 g/day) or do not tolerate it, osmotic laxatives such as milk of magnesia, sorbitol, or polyethylene glycol may be tried.
A novel pharmacologic agent that is currently available is the serotonin (5-HT4) agonist, Tegaserod. Tegaserod is a par- tial 5-HT4 agonist and accelerates transit in the small bowel and colon. It has been demonstrated to be useful in improving constipation and improving global IBS symptoms in women with constipation-predominant IBS.53
Other novel agents undergoing evaluation primarily for symptoms of pain include clonidine (alpha-adrenergic ago- nist), fedotozine (kappa opioid agonist), and ammonium derivatives (antimuscarinic and neurokinin-receptor antago- nist). Of these, fedotozine is clinically available for this indi- cation and has shown to be helpful in reducing symptoms of pain in patients with IBS.54
An adjunctive therapy to medication is psychological treat- ment. This is appropriate when there is evidence that stress or psychologic factors are contributing to an exacerbation of symptoms, or patients have failed to respond to medical treat- ment. A clear explanation of the rationale for such treatment is important in patient acceptance of such therapy.
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