AGA technical review on irritable bowel syndrome☆☆☆

Article Outline

• Abstract
• Definition and classification
• Epidemiology
  • Prevalence
  • Symptom features
  • Health care utilization and the health care burden
• Pathophysiology of IBS symptoms
  • Abnormal motility in patients with IBS
  • Visceral hypersensitivity in IBS
  • Inflammation
  • Autonomic activity
  • Central nervous system modulation
• Role of psychosocial factors in IBS
  • IBS can lead to impaired HRQL
• Diagnosis
  • Symptom-based criteria
  • Evaluation
• Treatment
  • General treatment approach
    • The therapeutic relationship
    • Education and reassurance
    • Dietary modification
    • Symptom monitoring
  • Pharmacotherapy targeted at specific symptoms
  • Investigational compounds
  • Complementary/alternative therapies in IBS
  • Psychological treatment
  • Centrally targeted (psychotropic) medications
    • Antidepressants
    • Address patient perceptions and expectations for taking antidepressants
    • Provide a rationale for medication use that is consistent with the patient's expectations
    • Negotiate a treatment plan
    • Continue phone contact with the patient to assess compliance and side effects
    • Consider alternates if treatment response is suboptimal
• Conclusions
• Acknowledgements
• References
• Copyright

Abstract 

The irritable bowel syndrome (IBS) is part of the larger group of functional gastrointestinal (GI) disorders that, despite differences in location and symptom patterns, share common features with regard to their motor and sensory physiology, central nervous system (CNS) relationships, and the approach to patient care.¹ IBS is a functional bowel disorder characterized by symptoms of abdominal pain or discomfort that is associated with disturbed defecation.² This disorder is highly prevalent and can be associated with significant emotional distress, impaired health-related quality of life (HRQL), disability, and high health care costs. Psychosocial factors, although not part of IBS per se, have an important role in modulating the illness experience and its clinical outcome.³

GASTROENTEROLOGY 2002;123:2108-2131

Abbreviations:  FDA , Food and Drug Administration, GI , gastrointestinal, HRQL , health-related quality of life, IBS , irritable bowel syndrome, PI-IBS , postinfectious irritable bowel syndrome, SSRI , selective serotonin reuptake inhibitor, TCA , tricyclic antidepressant

Knowledge of the pathophysiology of IBS and the diagnosis and management of patients has previously been hampered by few well-designed investigations, a lack of diagnostic precision, and an absence of specific treatments. In the last 5 years, since publication of the previous AGA Technical Review on IBS,⁴ there has been a notable increase in basic, mechanistic, and clinical investigations that has improved our understanding of this disorder and its physiological and psychosocial determinants. The adoption of multinational symptom-based criteria,¹ particularly for clinical research studies, has increased diagnostic precision, and within clinical practice, may lead to a reduction in unneeded diagnostic studies. Finally, treatment methods have evolved toward use of more integrated multicomponent pharmacological and behavioral strategies based on the severity of, and psychosocial factors, influencing the patient's symptom pattern.

This technical review updates our previous report.⁴ Based on a critical review and analysis of the existing literature, we address: (1) the epidemiology and impact of the disorder, (2) its pathophysiological determinants, (3) the role of psychosocial factors in symptom experience and behavior, (4) the diagnostic approach, and (5) recommendations for treatment.

Back to Article Outline

Definition and classification 

The Rome classification system¹ characterizes the IBS in terms of multiple physiological determinants contributing to a common set of symptoms rather than a single disease entity. It is defined as a “group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecation.”², ³ Table 1 lists the recently revised Rome II diagnostic criteria for IBS.¹

Table 1. Rome II diagnostic criteria for irritable bowel syndrome³

NOTE. The diagnosis of a functional bowel disorder always presumes the absence of a structural or biochemical explanation for the symptoms.

Back to Article Outline

Epidemiology 

Prevalence 

Table 2 gives the prevalence estimates for IBS from population surveys among American, European, and Australia/New Zealand adults. These prevalence estimates vary due to the diversity of definitional criteria and to differences in the specific questions used to elicit the information. There is also evidence that survey recall rates for reporting bowel symptoms are frequently inaccurate⁵ and are strongly influenced by anxiety.⁶

Table 2. Epidemiological studies of IBS in Western countries using symptom criteria

The data from Table 2 may be summarized as follows: (1) the prevalence of IBS is greater in women; (2) the first presentation of patients to a physician is between the ages of 30 and 50 years, and there is a decrease in reporting frequency among older subjects; and (3) the prevalence seems to be similar in whites and blacks, but may be lower in Hispanics. Sandler's analysis of the NHANES data²⁷ shows a 5-fold greater prevalence of IBS in whites than blacks. However, this was based on self-report rather than symptom criteria or may have been influenced by limited access to health care by blacks. The overall prevalence was 2.9%. However, epidemiological studies of non-European American and non-Western ethnic groups are limited and may be confounded by cultural influences. Available studies suggest that IBS seems to be as common in Japan, China, South America, and the Indian subcontinent as it is in Western countries.³ There are limited data to address incidence rates.

Symptom features 

In the short term (weeks to months), the symptoms of IBS occur frequently. In a study of 59 patients in the United States, England, and the Netherlands, the majority reported at least one GI symptom on over one half of the days, and pain was reported one third of the time.⁷ Symptom episodes (defined as a period of symptoms bounded by symptom-free days) occurred 12.4 times during the 12 weeks of observation and averaged 5 days/episode.

Over a longer period of time (years), the symptoms of IBS wax and wane. When the prevalence of IBS is examined in the same population at 2 time points separated by 12 months⁸ or 5 years,⁹ the point prevalence remains almost unchanged. However, up to 40% of subjects reporting symptoms at time 1 lose them at time 2, only to be replaced by new cases at time 2.

Health care utilization and the health care burden 

In the United States, up to 70% of persons with IBS symptoms do not seek medical attention.¹⁰, ¹¹ This may relate to cultural factors,¹² the presence and degree of pain,¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷ and psychological disturbance.¹⁴, ¹⁸ However, these rates are also influenced by access to health care. In the United States, where up to 40% of patients do not have easy access to health care, the consulting rate is 46%,¹⁷ whereas in Australia, where health care access is close to 100%, the consulting rate is 73%.¹⁹ IBS accounts for 12% of patients seen in primary care practice and is the largest diagnostic group seen in GI practice. Two surveys of AGA members²⁰, ²¹ undertaken 10 years apart show that functional GI disorders comprised respectively 41% and 35% of symptomatic outpatients' diagnoses, and IBS was the most frequent of the functional GI diagnoses.

Patients with IBS, when compared with persons with IBS not seeking health care or persons without bowel symptoms, have more non-GI complaints and consult physicians more for these symptoms.¹³, ²², ²³ Female patients with IBS are 3 times as likely to receive a hysterectomy²⁴ and report more surgical procedures such as appendectomies.²⁵ In the U.S. Householder Study,¹⁷ persons with IBS visited physicians 1.64 times in the year before the survey for GI and 3.88 times for non-GI complaints, compared with 0.09 and 1.77 times, respectively, for persons without bowel symptoms.

Although most persons with IBS do not consult physicians, the cost to society in terms of direct medical expenses and indirect costs, such as work absenteeism, is considerable: (1) they miss 3 times as many work days as those without bowel symptoms (13.4 days vs. 4.9 days) and are more likely to report that they are too sick to work (11.3 % vs. 4.2)¹⁷; (2) there are between 2.4 and 3.5 million physician visits annually for IBS in the United States,²⁶, ²⁷ during which 2.2 million prescriptions are written²⁷; and (3) they incur health care costs of $4044 (1995 dollars), compared with $2719 for those without IBS over the previous year.²³ In a comprehensive assessment of burden of illness for GI illnesses in the United States, IBS was second only to esophageal reflux disease in its prevalence (15.4 million people) and was associated with $1.6 billion in direct and $19.2 billion in indirect costs.²⁸ By adding 3.5 million people suffering from chronic diarrhea, the prevalence for lower functional bowel disorders nears that of gastroesophageal reflux disease.²⁸ These data have important implications with regard to the need to identify treatments that can help improve HRQL and associated costs to society among a very large clinical population.

Back to Article Outline

Pathophysiology of IBS symptoms 

The physiological mechanisms responsible for abdominal pain and altered bowel habits occur in healthy control subjects and in persons with IBS. Symptoms can occur in response to a disruption of functioning of the GI tract from an infection, dietary indiscretions (e.g., increased fat or alcohol intake), lifestyle changes (e.g., traveling or vigorous physical activity), or psychologic stress. Among college students and hospital employees, 71% reported that stresses affected their bowel pattern, and 54% reported that stress led to abdominal pain or discomfort.¹⁰

Abnormal motility in patients with IBS 

Table 3 details the studies of altered GI motility in IBS and is summarized below. The differences between IBS patients and healthy controls are quantitative rather than qualitative.

Table 3. Studies of altered GI motility in IBS

DCC, discrete clustered contractions; CRH, corticotropin-releasing hormone; CCK, cholecystokinin; HAPC, high-amplitude propagated contractions; IBS-C, constipation predominant IBS; IBS-D, diarrhea-predominant IBS; MMC, migrating myoelectric complex; PPC, prolonged propagated contractions.

Motility observations in the stomach, small intestine, colon, and rectum are qualitatively similar to those in healthy controls. Moreover, only 25%–75% of IBS patients exhibit the motility “abnormalities” listed in Table 3, which are considered to differentiate IBS from healthy controls. These motility parameters cannot be used as diagnostic markers.

In the ileum, colon, and rectum, IBS patients show an exaggerated response to a variety of provocative stimuli including meals, distention, stress, cholecystokinin, neostigmine, and corticotropin-releasing hormone injection. No corresponding pattern of hyper-reactivity has been shown in the proximal small intestine and stomach, where the response to stress (inhibition of contractions) differs from the response to meals (increase in contractions).

There is no consensus on the patterns of motility responsible for diarrhea and constipation, although accelerated transit is seen in diarrhea and slowed transit is seen in constipation. Among IBS patients exhibiting diarrhea and abdominal pain, there are significantly more high-amplitude propagating contractions, which are of higher amplitude than those observed in healthy controls, and these high-amplitude propagating contractions are more likely to be associated with a sensation of pain.

Motility abnormalities may interact with low sensory thresholds to produce symptoms: delayed transit of gas causes greater abdominal perception in IBS,²⁹ and IBS patients are more likely than healthy controls to perceive the occurrence of normal migrating motor complexes.³⁰

Visceral hypersensitivity in IBS 

In 1973, Ritchie first reported that IBS patients have pain at lower volumes and pressures when a balloon is inflated in the bowel.³¹ This seminal observation has been replicated by a number of research laboratories,³¹, ³², ³³, ³⁴, ³⁵, ³⁶ and the threshold to report pain is below the normal range in 50%–70% of IBS patients. Consistent with the concept of enhanced perception of visceral events are observations that IBS patients are more likely than controls to notice intestinal contractions³⁷ and gas,²⁹ and their pain thresholds are correlated, albeit weakly, with the amount of clinical pain they experience.³², ³⁸, ³⁹

Enhanced perception of visceral events is documented throughout the GI tract, including the esophagus,⁴⁰ stomach,⁴¹ duodenum,⁴², ⁴³, ⁴⁴ and ileum.⁴⁵ However, IBS patients do not show somatic hypersensitivity to pain⁴², ⁴⁶, ⁴⁷ and may have elevated⁴⁸, ⁴⁹ somatic pain thresholds.

One study³² noted that when combining other measures of pain sensitivity, such as the intensity with which the pain sensation is described and the location and size of the somatic referral area, up to 95% of patients show evidence of visceral hypersensitivity. The investigators concluded that visceral hypersensitivity might be a biological marker for IBS, although this interpretation has been challenged.³⁸

Inflammation 

Preliminary evidence for a possible alteration in gut immune function in IBS comes from both unselected and so-called postinfectious IBS (PI-IBS) patients. In unselected patients, increased numbers of mast cells in the muscularis externa of the colon⁵⁰ and the ileal and colonic mucosa⁵¹, ⁵² have been reported. Increased cellularity of the colonic mucosa and lamina propria has also been described in unselected IBS patients using semiquantitative microscopy.⁵³ In patients with intractable IBS, lymphocytic infiltrates of the myenteric plexus were reported,⁵⁴ and most recently, preliminary evidence for increased iNOS (nitric oxide synthetase) expression was described.⁵⁵ For subgroups of IBS, these findings suggest there is an up-regulation of gut immune function. However, methodological deficiencies exist, including the influence of the bowel preparation, the classification of the patients, and the nonquantitative analysis of gut cells. Further studies are needed to explore these intriguing findings.

Further support for a possible role of altered gut immune function in IBS comes from recent studies in PI-IBS patients.⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹ A subset of IBS patients associate the development of IBS symptoms with the onset of gastroenteritis.⁶⁰, ⁶¹, ⁶² In recent prospective studies, IBS-like symptoms were found in 7%–30% of patients who recovered from a proven bacterial gastroenteritis.⁵⁹ Reported risk factors included: female gender, duration of the acute diarrheal illness, and the presence of significant life stressor occurring around the time of the infection. Patients with PI-IBS were found to have a variety of functional alterations, including changes in gut motility,⁶³, ⁶⁴ epithelial function,⁶⁵, ⁶⁶ and an increase in colonic enterochromaffin cells.⁶⁶ In addition, evidence for increased expression of interleukin 1β messenger RNA, increased cellularity of lamina propria, and an increase in CD3⁺ lymphocytes were reported from mucosal biopsy specimens.⁶⁶ The correlation of IBS symptoms with these observed changes has not been established. Furthermore, because the majority of patients do not develop postinfectious diarrhea and the prevalence of IBS is not higher in countries with high rates of enteric infections, further studies are required to determine if vulnerability factors (such as altered neuroimmune system responsiveness) play a role in the development of PI-IBS in a subset of patients. In addition, psychological distress seems to be an important cofactor in determining who retains symptoms after an enteric infection.⁶⁷

Autonomic activity 

Abnormalities in extrinsic autonomic innervation of the viscera occur in approximately one fourth of patients with functional bowel disorders.⁶⁸, ⁶⁹ Aggarwal et al. showed that cardiovagal dysfunction is specifically associated with a constipation-predominant subgroup of patients with IBS, whereas patients with diarrhea-predominant symptoms had evidence of sympathetic adrenergic dysfunction.⁷⁰ The role of autonomic dysfunction in IBS requires further evaluation.

Central nervous system modulation 

In general, brain-gut interactions play a prominent role in the modulation of gut function in health and disease.⁷¹, ⁷², ⁷³, ⁷⁴ Signals from the brain to the gut assure that digestive function is optimized for the overall state of the organism (e.g., sleep vs. wake, stress vs. relaxation).⁷⁵ Conversely, signals from the gut to the brain play a role primarily in reflex regulation⁷⁶ as well as in modulation of mood states.⁷⁷ In addition, certain vagal afferent pathways can influence pain perception.⁷⁸

The CNS modulates motility, secretion, immune function, and blood flow.⁷⁹ The emotional motor system in the brain⁸⁰ is a revised name for the limbic system and some paralimbic structures (including the medial prefrontal cortex, amygdala, and hypothalamus) communicate emotional changes via the autonomic nervous system to the gut. The CNS is also essential in the perception of events occurring within the gut. This brain-gut bidirectional communication is largely not perceived consciously. In effect, the CNS functions as a “filter” with regard to the perception of peripheral afferent signals, and the threshold for perception can vary depending on the individual's emotional and cognitive state. Most visceral afferent signals reach the brainstem and thalamus, and only a very few are consciously perceived in the cortex.⁸¹ However, one recent study⁸² suggests that low intensity signals are subliminally registered.

Modulation of visceral afferent information occurs at multiple levels from the periphery to cortical regions, as shown in Table 4.

Table 4. CNS modulation of gut sensations

ICCs, interstitial cells of Cajal.

The activation of these modulatory systems is dependent on peripheral as well as central events, even though the latter seem to be dominant. For example, although acute gut inflammation results in sensitization of peripheral, spinal, and central transmission,⁸³ it is hypothesized that chronic inflammation may adaptively down-regulate perceptual sensitivity.⁴⁹, ⁸⁴, ⁸⁵ Stress, anxiety, or recall of aversive memories all can enhance perception of painful events,⁸⁶ whereas distraction, hypnosis, and relaxation can decrease perceptual sensitivity.⁸⁷, ⁸⁸ Stress-induced visceral hyperalgesia⁸⁹ may be an important mediator of visceral hypersensitivity in IBS patients. Therapeutic approaches aimed at attenuating stress responsiveness may effectively prevent the development of stress-induced visceral hypersensitivity, as well as attenuate autonomic gut responses to stress.⁹⁰, ⁹¹

Evidence for the alterations in the way the brain responds to visceral stimuli, and how this response may be altered in IBS patients, comes from recent studies using functional brain imaging techniques.⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶ Two of the studies, using distal colonic stimulation, have shown a greater activation in IBS patients of the midcingulate cortex, a brain region concerned with attentional processes and response selection.⁹⁷, ⁹⁸ Modulation of this region by hypnotic suggestion was associated with changes in the subjective unpleasantness of a somatic pain stimulus in another study.⁸⁸ The extent of abnormal visceral afferent processing by the brain in IBS patients needs to be established because they may be plausible mediators of various therapeutic approaches: cognitive therapies are likely mediated via networks involving the lateral prefrontal cortex, which in turn enhance the restraining effect of the medial prefrontal cortex on the emotional motor system.⁷⁷ Hypnosis is likely to modulate attentional mechanisms (including the midcingulate cortex),⁸⁸, ⁹⁹ and relaxation exercises involving deep breathing techniques may alter vagal afferent input to the brain. Centrally targeted medications such as anxiolytics, low dose tricyclic antidepressants (TCAs), NK-1R antagonists, and CRF1R (corticotropin releasing factor 1R) antagonists all involve inhibitory effects on the responsiveness of the emotional motor system and provide options for future therapeutic investigations.

Back to Article Outline

Role of psychosocial factors in IBS 

Research on the psychosocial aspects of patients with IBS has yielded 4 general observations.¹⁰⁰

1. Psychologic stress exacerbates GI symptoms. Although stressful experiences produce GI symptoms in most individuals, patients with IBS are particularly susceptible.¹⁰ Studies of the effects of stressful life events on IBS patients are shown in Table 5.

Table 5. Effects of stress on IBS symptoms

LES, life event survey; RAP, recurrent abdominal pain.

With one exception,¹⁰¹ these studies suggest IBS patients report more lifetime and daily stressful events,¹⁰, ¹⁴, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷ including severe abuse history,¹⁰⁸, ¹⁰⁹ than medical comparison groups or healthy controls. Furthermore, in IBS patients, stress is strongly associated with symptom onset¹⁰⁵, ¹⁰⁷, ¹¹⁰ and symptom severity.¹⁰⁹ Even though the effects of stress on gut function are universal, patients with IBS seem to have greater reactivity to stress.⁷², ¹¹¹ The identification of specific psychological stressors associated with exacerbation of symptoms may help in planning treatment through psychological or psychopharmacological interventions.

2. Psychological and psychiatric comorbidity is common among patients with IBS. A large proportion of patients with IBS and other functional bowel disorders have concurrent psychological disturbances. As shown in Table 6, when using standardized research interviews, the prevalence of a psychiatric disorder ranges from 40% to over 90% among patients with IBS/functional bowel disorders in tertiary care centers.

Table 6. Prevalence of psychiatric disorder in functional bowel disorder/IBS using standardized research psychiatric interviews

FBD, functional bowel disorder (e.g., consecutive nonorganic gastrointestinal disorders in the clinic); CIS, clinical interview schedule; PSE, present state examination; DIS, diagnostic interview schedule for diagnostic statistical manual (DSM-IIIR and DSM-IV); SCID, structured clinical interview for DSM-IIIR and DSM-IV.

Other psychological features identified to be greater in IBS include personality style,¹⁴, ¹⁰⁶, ¹¹² psychological distress,¹⁸, ¹⁰⁹, ¹¹³ and altered health beliefs, cognitions, and coping style.¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷ As indicated below, these findings are not associated with the disorder per se, but their prevalence is over-represented within the health care–seeking subset of patients.

3. Psychosocial factors affect health status and clinical outcome. Psychological and sociocultural factors, when present in patients with IBS, will also influence the illness experience and treatment outcome. Psychosocial factors that adversely affect health status and clinical outcome include: (1) a history of emotional, sexual, or physical abuse¹⁰⁹, ¹¹⁸, ¹¹⁹, ¹²⁰, ¹²¹; (2) stressful life events¹⁰⁴, ¹¹⁰; (3) chronic social stress¹²² or anxiety disorder¹²³, ¹²⁴; and (4) maladaptive coping style.¹¹⁹ Some of these psychosocial influences may occur early in life. For example, increased attention by family to a child's illness complaints seems to result in delayed symptom reporting, health care seeking, and health care costs.¹²⁵, ¹²⁶, ¹²⁷, ¹²⁸, ¹²⁹

4. Psychosocial factors influence which patients consult physicians. This tends to overestimate the true prevalence of psychosocial disturbance when evaluating patients in referral clinical settings. In fact, persons with IBS who do not see physicians are psychologically similar to subjects without bowel complaints.¹⁴, ¹⁸, ¹³⁰

IBS can lead to impaired HRQL 

HRQL addresses the psychological and social consequences of having IBS. It incorporates the patient's perceptions, illness experience, and functional status.¹³¹ Several self-administered questionnaires to study HRQL now exist for GI disorders¹³² and IBS.¹³³ To date, 2 IBS-specific instruments have been shown to be responsive to change.¹³⁴, ¹³⁵

The data show that patients with functional GI disorders have poorer functional status (Sickness Impact Profile) than those with organic GI diagnoses.¹⁰⁹ In addition, patients with IBS have significantly poorer HRQL (SF-36) than the general population or of patients with gastroesophageal reflux disease, and have selected impairments in HRQL relative to patients with diabetes and end-stage renal disease.¹³⁶ However, the degree of impairment also relates to the population being studied: nonpatients with IBS have HRQL scores (SF-36) that are intermediate between referred IBS patients (who were similar to patients with congestive heart failure) and normal controls.¹³⁷ When using IBS-specific questionnaires, patients show the lowest scores related to interference with activity, food avoidance, and health worry concern (IBS quality of life).¹³⁸ Moreover, quality of life improves in relation to changes in pain severity and daily function after psychological or antidepressant treatment.¹³⁴ When compared with patients having other GI conditions, physical, emotional, and social role functions and energy (IBS quality of life) were poorer.¹³⁹

Figure 1 provides a conceptual model on the role of psychosocial factors on illness and outcome in IBS.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1. 

  A conceptual model depicting the relationship between early life, psychosocial factors, physiology, symptom experience, and behavior and outcome. See text for details.

Early life factors influence later psychosocial experiences, physiologic functioning, and susceptibility to developing IBS. Therefore, a psychosocial stressor, interpreted from previous experiences, may produce symptoms primarily through changes in intestinal function, central amplification of normal gut signals, or a combination of these factors. The combined and integrated effects of altered physiology and the person's psychosocial status via the brain-gut axis affects how the symptom is experienced, the individual's illness behavior, and ultimately the outcome. Furthermore, the clinical outcome will, in turn, affect the severity of the disorder. Therefore, while psychosocial factors are not etiologic to IBS, they are relevant to understanding the patient's adjustment to IBS, the clinical outcome, and the plan of treatment.

Back to Article Outline

Diagnosis 

Symptom-based criteria 

A diagnosis is based on identifying positive symptoms (e.g., Rome criteria) consistent with the condition (Table 1), and excluding, in a cost-effective manner, other conditions with similar clinical presentations, which may include organic or other functional (e.g., functional diarrhea or bloating, pelvic floor disorders, or slow transit constipation with associated abdominal discomfort relieved with defecation) disorders.³, ¹⁴⁰ Any needed tests, as suggested by “alarm features,” should be discussed with the patient and set up at the first encounter. When “alarm features” such as weight loss, refractory diarrhea, and family history of colon cancer are excluded, the specificity of the symptom-based Rome I criteria for IBS exceeds 98% and hence, the risk of missing organic disease is low.¹⁴¹

Evaluation 

A physical examination should be performed on the first visit and on subsequent visits as needed. This is done to exclude findings not consistent with IBS (e.g., enlarged liver, abdominal mass, signs of bowel obstruction) and to meet the patient's expectations of a thorough evaluation. A pelvic examination is often indicated for lower abdominal/pelvic symptoms and/or if there is a change in menstrual pattern. A rectal examination, particularly for patients reporting symptoms of incontinence or dyschezia, can help to identify a lax sphincter or paradoxical pelvic floor muscle contraction. This may require anorectal testing of pelvic floor muscle function.

Two algorithms applicable to the evaluation of patients with IBS seen in primary care settings have recently been presented.¹⁴² Figures 2 and 3, as summarized below, provide an algorithm for patients presenting to gastroenterologists.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2. 

  Initial evaluation by the gastroenterologist for patients with IBS.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 3. 

  Diagnostic evaluation based on symptom subtype after initial treatments are insufficient to control patient's symptoms.

In general, if Rome criteria are fulfilled, “alarm signs” or “red flags” are not present, and screening studies from the referring physician are negative, further testing is not needed. Screening studies are recommended when certain historical information is present¹⁴³: (1) short symptom duration or worsening severity and trajectory of symptoms, (2) demographic features (e.g., onset in an older patient), (3) family history (e.g., colon cancer or inflammatory bowel disease), and (4) no concurrent psychosocial difficulties or symptom behaviors (particularly the absence of comorbid psychosocial features or health care seeking). We recommend a complete blood count and a stool hemoccult for screening purposes. A sedimentation rate (particularly in a younger patient), serum chemistries, thyroid-stimulating hormone (TSH), and stool for ova and parasites can be ordered based on symptom pattern, geographic area, and relevant clinical features (e.g., predominant diarrhea, areas of endemic infection). However, studies do not generally support a role for these tests without supportive clinical features.¹⁴⁴ A colonoscopy is recommended for patients over age 50 (due to higher pretest probability of colon cancer), but in younger patients, performing a colonoscopy or sigmoidoscopy is determined by clinical features suggestive of disease (e.g, if there is significant diarrhea) and may not be indicated. There has been growing interest in the use of antiendomysial (ema) and antigliadin (aga) antibodies to diagnose celiac sprue.¹⁴⁵, ¹⁴⁶, ¹⁴⁷ However, such testing must be put into a clinical perspective as determined by presence of symptom pattern, ethnicity, and other clinical features suggestive of the disease.¹⁴³

In many cases, the therapeutic trial can be undertaken before further diagnostic studies are done and will depend on the symptom subtype and its severity (Figure 2): for constipation, fiber, or an osmotic laxative; for diarrhea, loperamide, or diphenoxylate-atropine and possibly cholestyramine; and for pain/gas/bloating, an anticholinergic, or, if more severe, antidepressant or psychologic treatment may be considered. It needs to be emphasized that patients presenting with typical symptoms and no “alarm” signs are rarely found to have another diagnosis,¹⁴⁴, ¹⁴⁸ supporting the benefit of ongoing care and symptomatic management rather than continued diagnostic evaluation.

If initial treatment fails, or certain clinical features emerge requiring further evaluation, we recommend the algorithm indicated in Figure 3. Many of these studies are performed by gastroenterologists in specialty centers.

In patients with infrequent bowel movements, whole gut transit study by Sitzmark technique or a plain radiography (to evaluate for obstructive signs or fecal retention) is indicated. When symptoms of dyschezia or incomplete evacuation are prominent, suggesting obstruction to defecation, or when the physical examination discloses poor pelvic floor relaxation with straining, further anorectal testing is indicated. This includes anorectal motility testing with balloon expulsion (to evaluate for pelvic floor dyssynergia) or defecography (to evaluate for enterocele or rectocele).

If diarrhea is persistent, other tests to consider include: 24-hour stool volume and fat; if increased (>400 mL/day), electrolytes and laxative screen; and small bowel biopsy for giardia lamblia or sprue and colonic biopsy for microscopic colitis. On occasion, transit tests of the small bowel and colon can help evaluate the severity of the motility component of the diarrhea. A therapeutic trial of cholestyramine may also be considered, particularly if symptoms developed or worsened after a cholecystectomy. A jejunal biopsy and aspirate can be done to obtain samples to assess malabsorption (e.g., sprue), or to obtain an aspirate for giardia or for bacterial overgrowth. Colonic biopsies can be considered to evaluate for collagenous or lymphocytic colitis, although the findings may not lead to instituting more effective treatments. Finally, when postprandial symptoms of bloating and gaseousness accompany the diarrhea, a breath H₂ study to exclude bacterial overgrowth can be considered.¹⁴⁹

The persistence of pain-predominant symptoms or severe bloating usually requires plain abdominal radiography during an acute episode to exclude bowel obstruction, an increased gastric air bubble from aerophagia, and/or other abdominal pathology. If negative, additional imaging studies (e.g., small bowel radiography, computerized tomography scan, pelvic ultrasonography) may be recommended, particularly when there are other symptoms or signs present (e.g., vomiting, weight loss, abdominal mass, irregular menses, abnormal chemistries). A balloon distention test may confirm rectal or colonic visceral hypersensitivity, although this test is usually done for investigative purposes.

Back to Article Outline

Treatment 

The treatment strategy is based on the nature and severity of the symptoms, the correlation of IBS symptoms with food intake and/or defecation, the degree of functional impairment, and the presence of psychosocial difficulties and psychiatric comorbidity affecting the course of the illness. Table 7 provides a practical framework, supported by recent empiric evidence¹⁵⁰ for differentiating patients into subgroups of severity based primarily on patient pain reports and behaviors.²², ¹⁵¹, ¹⁵²

Table 7. Spectrum of clinical features among patients with IBS

0, Generally absent; +, mild; ++, moderate; +++, marked. Data from Drossman.²⁶⁵

In general, milder symptoms relate primarily to visceral hyperactivity and/or hypersensitivity and are commonly treated symptomatically with pharmacological agents directed at the gut, whereas more severe symptoms are associated with greater levels of psychosocial difficulties and illness behaviors and often require psychological/behavioral and antidepressant medications.

The most frequently seen group of IBS patients have mild symptoms. They are usually cared for in primary care practices, usually maintain normal daily activities, have little or no psychosocial difficulties (although they may experience symptom exacerbations with stress), and are not high health care users. Treatment involves education, reassurance, and dietary/lifestyle changes. A smaller proportion of patients have moderate symptoms that are usually intermittent, although at times disabling. Symptoms may be associated with considerable symptom-related distress, and historical symptoms are associated with greater physiological gut reactivity (e.g., worse with eating, relieved by defecation). Treatments involve gut-acting pharmacological agents (e.g., anticholinergics, antidiarrheals, newer GI treatments, etc.), and if more persistent, possibly low-dose TCAs and/or psychological treatments. Finally, only a very small proportion of patients with IBS have severe and sometimes refractory symptoms. These symptoms predominate among patients seen in referral centers; these patients frequently have more severe, often constant pain symptoms, psychiatric comorbidity (e.g., depression, anxiety disorders), and psychosocial difficulties (history of sexual/physical abuse, poor coping) associated with high health care use rates. These patients require antidepressant medication and possibly mental health or pain center referral, along with an ongoing relationship with the primary care physician to provide psychosocial support through brief, regular visits.¹⁵³

General treatment approach 

The therapeutic relationship 

An effective physician-patient relationship is the cornerstone of effective treatment. Here, the physician must: (1) listen actively to determine the patient's understanding of the illness and his or her concerns, (2) provide a thorough explanation of the disorder, (3) identify and respond to the patient's concerns and expectations, (4) set realistic and consistent limits, (5) involve the patient in the treatment, and (6) establish a long-term relationship with a primary care provider.¹⁵³, ¹⁵⁴ This type of approach is associated with a reduction in health care visits¹⁵⁵ and improved patient satisfaction. Patients who do not feel properly informed have more health care visits.¹⁵⁶ Furthermore, when diagnostic and prognostic information is provided, there is also a reduction in symptoms.¹⁵⁷

As with any chronic illness, it helps to determine the immediate reasons for the patient's visit. These may include: (1) everyday environmental stressors (e.g., difficulty meeting deadlines, financial or relationship problems, daily “hassles”), (2) new exacerbating factors (e.g., dietary change, concurrent medical disorder, side effects of new medication), (3) personal concern about a serious disease (e.g., recent family death), (4) psychiatric comorbidity (e.g., depression, anxiety), (5) major life events or difficulty adjusting to them (e.g., family death, abuse history), (6) impairment in daily function (e.g., recent inability to work or socialize) or (7) a “hidden agenda” (e.g., narcotic or laxative abuse, pending disability or litigation).

Education and reassurance 

Education involves an iterative process in which the physician assesses the patient's level of knowledge about the disorder and provides information, verbally or in print, to enhance the patient's understanding. Patients frequently want to understand the basis for their symptoms, and, at times, seek validation that their symptoms are “real.” In practice, useful statements include: “You have a common disorder where the intestine overreacts to a variety of stimuli such as food, hormonal changes, medication, and stress. These stimuli can produce spasm or stretching of the gut, enhanced sensitivity of nerves, or both. This is experienced as pain, diarrhea, constipation, bloating, or any combination anywhere in the abdomen.” or “IBS is a disorder where communication between the brain and gut is not in order, so bowel disturbance may trigger symptoms of anxiety or distress, which in turn, makes your symptoms worse. We need to understand both your physical symptoms and the associated emotional distress related to it.”

Reassurance should follow after the physician elicits the patient's worries and concerns, and after an adequate and generally conservative diagnostic evaluation. If reassurance is communicated in a perfunctory manner before evaluation, the patient will reject it.

Dietary modification 

Although many patients may attribute their symptoms to specific food substances, the type of food does not generally contribute to symptoms. Patients are more likely to experience symptoms as a generalized effect of eating, and at times may even become conditioned to reduce eating to avoid postprandial discomfort. However, certain dietary substances may aggravate symptoms in some individuals. This might include fatty foods, beans, and gas-producing foods, alcohol, caffeine, lactose in lactose-deficient individuals, and, in some cases, excess fiber. Care should be taken to avoid an unnecessarily restrictive diet.

Although fiber has an established role in treating constipation, its value for IBS for the relief of diarrhea is controversial and not helpful for pain. In 2 randomized crossover studies of IBS patients,¹⁵⁸, ¹⁵⁹ the groups receiving increased fiber (15 g bran and 20 g corn fiber, respectively) and the control groups had similar degrees of symptomatic improvement.

Symptom monitoring 

It helps to have the patient use a diary to monitor symptoms for 2–3 weeks to assess the time and severity of symptoms, the presence of possible aggravating factors, and the emotional and cognitive impact of the symptoms on the individual.¹⁵³, ¹⁶⁰ The diary may identify dietary indiscretions or specific stressors not previously considered, and may also give the patient a sense of participation in the planning of care. The physician can then review and consider diet, lifestyle, or behavioral modifications with the patient. In addition, identification of maladaptive coping styles (e.g., “catastrophizing”)¹¹⁹ may lead to referral for psychological treatment.

Pharmacotherapy targeted at specific symptoms 

For pain and bloating, antispasmodic (anticholinergic) medication, particularly when symptoms are exacerbated by meals, should be considered. Meta-analyses of available studies suggest that some of these agents may be effective, although the trial methodology was inadequate by modern standards.¹⁶¹ In one meta-analysis of smooth muscle relaxants in IBS,¹⁶² 5 drugs showed efficacy over placebo: (1) cimetropium bromide (an antimuscarinic compound), (2) pinaverium bromide and (3) octylonium bromide (quaternary ammonium derivatives with calcium-antagonist properties), (4) trimebutine (a peripheral opiate antagonist), and (5) mebeverine (a derivative of beta-phenyl-ethylamine that has antimuscarinic cholinergic activity). None of these drugs underwent extensive trials in North America or received approval from the Food and Drug Administration (FDA). Notably, the commonly prescribed dicyclomine and hyosyamine were not effective in the meta-analysis. Other meta-analyses have been published with similar conclusions.¹⁶³, ¹⁶⁴, ¹⁶⁵ Eight trials with peppermint oil for IBS, including a meta-analysis of 5 placebo-controlled, double-blind trials, have not established a role for this treatment in IBS.¹⁶⁶ There are also meta-analyses on the effect of tricyclic antidepressants, which will be reviewed later.

In clinical practice, antispasmodics and anticholinergic agents are best used on an as-needed basis up to 3 times per day for acute attacks of pain or before meals when postprandial symptoms are present. Agents such as dicyclomine or mebeverine seem to retain efficacy when used on an as-needed basis, but become less effective with chronic use. Low-dose TCAs may be considered when the pain is more constant and/or disabling.

For constipation, increased dietary fiber (25 g/day) is recommended for simple constipation, although its effectiveness, based on several studies, in reducing pain in constipation-predominant IBS is mixed (see dietary modification section). If fiber is not helpful, osmotic laxatives such as milk of magnesia, sorbitol, or polyethylene glycol may be used. For diarrhea, loperamide (2–4 mg up to 4 times daily) or diphenoxylate (2.5 mg and .025 mg atropine up to 3–4 times a day) can reduce loose stools, urgency, and fecal soiling,¹⁶⁷ and in low doses, does not seem to affect the CNS. Cholestyramine may be considered for a subgroup of patients with cholecystectomy or bile acid malabsorption.⁶⁵

Investigational compounds 

A novel approach to the treatment of diarrhea and pain/discomfort of IBS is based on antagonism of the 5-HT₃ receptors. 5-HT₃ receptors are extensively distributed on enteric motor neurons, on peripheral terminals of visceral afferent nerves, and on central locations such as the vomiting center. Antagonism of these receptors reduces visceral pain, colonic transit, and small intestinal secretion.¹⁶⁸ Alosetron hydrochloride, a selective 5-HT₃ antagonist, is effective in relieving pain and normalizing bowel frequency, and reducing urgency in diarrhea-predominant female patients with IBS (effect size 12%–15%).¹⁶⁹ It was more effective than placebo in inducing adequate relief of pain and discomfort and improved bowel frequency, consistency, and urgency¹⁷⁰, ¹⁷¹, ¹⁷² in women with diarrhea-predominant IBS. The most common adverse event was constipation, affecting 28% of patients in clinical trials; only 10% withdrew from these studies for this symptom. A significant adverse event with an unclear relationship to alosetron is acute ischemic colitis, estimated to occur in 0.1%–1% (risk factors were not identified). The drug was withdrawn from the market in November 2000 because of these side effects, but after further evaluation was reapproved by the FDA in the spring of 2002 under restrictive guidelines to be developed for its use.

Another 5-HT₃ antagonist, cilansetron, has demonstrated similar efficacy to that of alosetron in 2 phase II trials¹⁷³ and was effective in male patients (possibly because of a larger number of male patients studied). This drug is currently in phase III trials.

For constipation, new partial or full 5-HT₄ agonists seem promising in the treatment of constipation or constipation-predominant IBS. The partial agonist, tegaserod, is an aminoguanidine indole, which was shown to result in global relief of IBS symptoms and constipation in females with constipation-predominant IBS.¹⁷⁴ The effective dose of tegaserod is 12 mg per day in 2 divided doses (6 mg twice daily). Pooled analysis of the trials to date suggests that the drug is significantly effective, with approximately a 10% advantage over placebo in the intent to treat population and up to a 14% advantage over placebo in females and those with documented constipation during the baseline run-in period. Tegaserod appears safe, with no serious adverse events reported in the clinical trials program or in open evaluation for over 6 months. An effect of tegaserod on the delayed rectifier potassium current that rarely leads to cardiac dysrhythmias has been carefully excluded; this appears to differentiate the drug from other 5-HT₄ agonists such as the substituted benzamide, cisapride. The drug was approved by the FDA in July 2002 for females with constipation-predominant IBS symptoms.

The full 5-HT₄ agonist, prucalopride, is a benzofuran that induces strong contractions in the proximal colon in vivo in dogs¹⁷⁵ and accelerates colonic transit in healthy participants¹⁷⁶, ¹⁷⁷ and in patients with functional constipation.⁷⁴ The drug induced a significant increase in the number of spontaneous and complete bowel movements in 2 trials of patients with functional constipation.¹⁷⁸, ¹⁷⁹ The effects of prucalopride on abdominal pain have not been thoroughly assessed. Clinical trials have been discontinued because of carcinogenicity in animals.

Other new approaches being explored in phase II studies include: newer type 3 antimuscarinic agents, NK1 and NK3 receptor antagonists, cholecystokinin antagonists, the alpha₂ adrenergic agonists, clonidine,¹⁸⁰ a 5-HT₁ agonist (buspirone),¹⁸¹ and a selective serotonin reuptake inhibitor (SSRI) (citalopram).¹⁸², ¹⁸³ Recommendations on the use of these newer receptor-active agents with regard to being first- or second-line treatments need to be determined based on issues of efficacy, safety, and cost.

Complementary/alternative therapies in IBS 

Several reports indicate that the public holds some skepticism toward conventional medicine and are using complementary or alternative medicine therapies more frequently in IBS than with “organic” diseases.¹⁸⁴, ¹⁸⁵, ¹⁸⁶, ¹⁸⁷ However, the efficacy of alternative therapies has not been established in controlled trials.¹⁸⁸ One exception is a placebo-controlled 16-week trial of Chinese herbal medicines that showed improved bowel symptom scores, global symptoms, and reduced IBS-related interference with life relative to placebo.¹⁸⁹ Notably, patients receiving individualized Chinese herbal medicine continued to report benefit beyond the actual treatment period.¹⁸⁹ Many herbs were used, so it is not possible to make specific recommendations.

Psychological treatment 

Psychological treatment can be considered when IBS symptoms are moderate to severe, when patients have failed to respond to medical treatments, or when there is evidence that stress or psychological factors are contributing to GI symptom exacerbations. The patient's understanding of the rationale for psychological treatment and their motivation to undertake such treatment is critical to a successful outcome. Therefore, the physician has an important role in clearly communicating why referral for psychological treatment is recommended. If this is not done properly, patients may not accept the referral and may even feel abandoned by their physicians. Table 8 indicates that psychological treatments are frequently helpful both at reducing bowel symptoms and improving psychological symptoms.

Table 8. Randomized controlled studies of psychological treatments with at least 20 subjects and follow-up at least 3 months

EOT, end of treatment; FU, follow-up; SMT, standard medical treatment; CBT, cognitive behavior therapy.

Psychological treatment trials have methodological limitations because of the inability to blind patients or the investigators as to treatment assignment, and the difficulty of coming up with a placebo treatment that is credible, but also not effective, to patients. There are 14 randomized controlled trials (Table 8), but only 5 included placebo arms; 2 of these placebo-controlled trials were positive,¹⁹⁰, ¹⁹¹, ¹⁹² 1 showed a trend for greater bowel symptom reduction in the active treatment group,¹⁹³ and 2 showed equivalence between active and placebo arms.¹⁹⁴, ¹⁹⁵ Many trials have compared the active psychological intervention to continuation of standard medical therapy or merely to symptom monitoring while waiting to start therapy. However, it is probable that both these control groups are associated with a negative expectancy. Patients are only referred to these trials if they have failed medical therapy, and they are not expected to improve while they are waiting to be treated. Thus, despite a number of positive trials, there is room for doubt.

Currently, no studies indicate that one psychological intervention technique is superior to another. The symptoms associated with a favorable response are abdominal pain, diarrhea, and psychological distress.¹⁹⁶ Predictors of a positive response to psychological treatment¹²⁴, ¹⁹⁶ are: (1) awareness that stress exacerbates their bowel symptoms, (2) at least mild anxiety or depression, (3) the predominant bowel symptom is abdominal pain or diarrhea and not constipation, (4) the abdominal pain waxes and wanes (rather than being constant) in response to eating, defecation, or stress, and (5) the symptoms are of relatively short duration. Also, it has been proposed that patients who exhibit maladaptive coping styles or cognitions (e.g., “catastrophizing”) relating to their symptoms, or perceive an inability to decrease them, may be particularly responsive to cognitive-behavioral treatment.¹¹⁹, ¹⁹⁷

Psychological treatment is initially expensive because it requires multiple, long sessions. However, its benefits persist or even increase over time,¹⁹⁶ and in the long run there may be a net reduction in clinic visits and health care costs,¹⁹⁸ which offsets the initial cost of psychological treatment.

Centrally targeted (psychotropic) medications 

Antidepressants and anxiolytic agents are commonly prescribed by medical physicians, whereas antipsychotics and mood stabilizers (for which there is little evidence for benefit in IBS) may be prescribed by psychiatrists consulting on patients with IBS.

Antidepressants 

Several antidepressants are prescribed in IBS: TCAs (e.g., amitriptyline, desipramine, imipramine, doxepin), SSRIs (e.g., fluoxetine, sertraline, paroxetine, citalopram), or less frequently, novel antidepressants (e.g., venlaxafine, mirtazapine). The rationale includes: (1) treatment of psychiatric comorbidity (e.g., major depression, anxiety disorders usually using full therapeutic doses) associated with IBS,¹⁹⁹, ²⁰⁰, ²⁰¹ (2) alteration of GI physiology (e.g., visceral sensitivity, motility, and secretion),²⁰², ²⁰³, ²⁰⁴, ²⁰⁵, ²⁰⁶ or (3) reduction of central pain perception arising from afferent signals in the gut.²⁰⁷, ²⁰⁸, ²⁰⁹ There is also some evidence that antidepressants may be synergistic with psychological treatment for medical²¹⁰ and psychiatric²¹¹ disorders. They may improve the motivation for psychologic treatments, which may increase compliance with the medication. Although full antidepressant doses of TCAs are used less frequently today for the treatment of psychiatric conditions (mainly because of their high side effect rates), they are commonly prescribed in smaller doses for the treatment of a variety of chronic pain conditions and functional disorders, including IBS.²¹²

Several randomized controlled trials of TCA medications in IBS have been published¹⁰⁰ and were evaluated in a meta-analysis.²¹² Improvement in global GI symptoms against placebo was highly significant (odds ratio, 4.2; 95% confidence interval, 2.3–7.9), and there was also improvement in standardized pain scores by 0.9 SD (95% confidence interval, 0.6–1.2). Furthermore, only 3.2 patients needed to be treated to improve symptoms in 1 patient. In general, even though a wide range of doses were used in these studies, TCA dosages were lower than that used to treat major depression, suggesting that the therapeutic effect was largely unrelated to the TCA's antidepressant effects. The study limitations (e.g., small sample sizes, short study lengths, variable study design quality, use of outcome measures and medication dosages, large losses to follow-up, failure to assess effectiveness of blinding, whether the benefits relate to improvement in comorbid psychiatric disorders) indicate that better-designed studies are needed to determine the mechanism of benefit and the subpopulations most amenable to treatment.

Table 9 compares the TCAs and provides prescribing recommendations.

Table 9. Comparison of tricyclic and SSRI antidepressants

OCD, obsessive-compulsive disorder.

In general, TCAs have more established benefit over SSRIs. Because antidepressants are used on a continual, rather than an “as needed” basis, they are usually prescribed for patients having chronic or frequently recurring symptoms. Low doses of TCAs (e.g., 10–50 mg/day) are recommended for treatment of pain and sleep difficulties associated with IBS, presumably because of their multiple receptor blocking effects (anticholinergic, antihistaminergic, antiadrenergic) in addition to their nonselective monoamine uptake inhibition (serotonin, noradrenaline).²¹³ Low doses of TCAs also lead to a more rapid onset of action than full doses used for treating major depression. They are also inexpensive and do not carry the potentially serious cardiovascular side effects associated with full antidepressant doses. However, there is some evidence²⁰³ that full dosages of TCAs may also provide benefits when lower dosages are not effective. Notable side effects to the use of high-dose TCAs include sedation, hypotension, and constipation, among others (particularly for amitriptyline, doxepin, and imipramine, over desipramine or nortriptyline), and there is a greater need for dosage adjustments and a greater risk for overdose. If used in higher doses, physicians should be aware of these risks and monitor their patient expectantly.

There are no published controlled studies on the use of SSRIs or novel antidepressants for IBS. However, studies of patients with other painful medical conditions suggest clinical benefits even in the absence of depression,²¹⁴, ²¹⁵ and these agents may have an advantage over TCAs for treating other comorbid psychiatric disorders (e.g., obsessive-compulsive disorder, anxiety disorders, and phobias). Furthermore, physiological studies suggest that they accelerate intestinal transit,²⁰⁶ although the therapeutic value of such peripheral effects remains to be determined.

SSRIs are often prescribed particularly for older patients because of their lower side effect profile. They also are superior in treating associated emotional symptoms of anxiety, panic, obsessional behaviors, and constipation-predominant IBS. Specific agents may be considered: fluoxetine has a long half life and may be selected when poor compliance is an issue, citalopram has a low side effect profile and may prove beneficial because of peripheral effects on colonic tone and sensitivity in IBS,¹⁸³ and paroxetine, because of its greater anticholinergic effect, may be selected for patients with diarrhea.

In addition, there are other, novel antidepressants, such as mirtazapine, which has the potentially beneficial 5-HT₃ receptor blocking effect and is particularly indicated in the patient with poor sleep and inability to gain weight. Venlaxafine produces combined serotonin and norepinephrine uptake inhibition and has been shown to increase stimulated pain thresholds²¹⁶; it has been suggested for treatment of certain chronic painful disorders.²¹⁷

Anxiolytic medications (benzodiazepines or azapirones) have sometimes been prescribed for patients with IBS because of the frequent comorbidity of anxiety disorders with IBS²¹⁸ and many recognize that acute psychological distress can make bowel symptoms worse. Two small studies support the efficacy of benzodiazepines for IBS,²¹⁹, ²²⁰ but the drug-placebo difference was relatively small. In view of weak treatment effects and a potential for physical dependence and interaction with other drugs, caution should be used when prescribing benzodiazepine anxiolytics, and when prescribed, it should be for a self-limited period of 1–3 weeks. More recently, there is preliminary evidence suggesting that 5-HT₁ agonists like buspirone may have a role in decreasing GI symptoms because of their effects on relaxing visceral organs.¹⁸¹, ²²¹ However, it is not clear if central or peripheral effects mediate the therapeutic effects in IBS, and further studies are needed to confirm these initial impressions.

It is important to communicate the value of centrally acting drugs in treating symptoms of IBS within the context of an effective physician-patient relationship. Several guidelines are recommended.¹⁰⁰, ¹⁵³

Address patient perceptions and expectations for taking antidepressants 

Some patients may refuse to take an antidepressant or may be noncompliant²²² because they perceive: (1) that they are being treated for a psychiatric problem, (2) that the medication may be addicting or “mind altering,” or (3) they do not think the doctor accepts the symptoms as “real.” These issues need to be properly addressed and clarified when they occur.

Provide a rationale for medication use that is consistent with the patient's expectations 

The patient can be informed that for IBS, antidepressants act as central analgesics that work sooner, and in lower dosages, than when they are used to treat major depression.²²³ The medication reduces visceral afferent activity directly or by facilitating descending inhibitory pathways that control pain; however, it can also help to treat depressive symptoms induced by the illness.¹⁵³

Negotiate a treatment plan 

The choice of a particular drug is based on: (1) the target symptoms to be treated, (2) the medication's side effect profile, (3) cost, and (4) the patient's previous experiences and preferences. The patient should be involved in making the selection of a particular medication. The patient should also be informed that benefit may occur no sooner than 3–4 weeks (although benefit can occur sooner), and that side effects, if they occur, tend to diminish in 1–2 weeks. TCAs start with lower dosages (e.g., 25–50 mg) and work up to full therapeutic (150 mg) dosages over several weeks. With SSRIs, only one pill is all that is usually required. Treatment is continued for 6–12 months before tapering, and dosage adjustments are usually mutually determined.

Continue phone contact with the patient to assess compliance and side effects 

Because the benefit of the medication will not occur for several weeks, and because side effects occur immediately, it helps to have an initial phone contact with the patient during the first week of treatment (and possibly repeat the phone call 2–3 weeks later). This is done to make decisions about possible dose or medication changes, and if needed, to help motivate the patient to continue the medication. The response to the treatment is not based only on symptom reduction, but also by improvement in daily function, quality of life, and emotional state. If side effects occur, it is best to hold the same dosage or reduce it, and only if required, to switch to another medication (preferably within the same class).²²⁴

Consider alternates if treatment response is suboptimal 

When symptoms are refractory, switching to a different class of antidepressant may be considered. Occasionally, a low-dose TCA can be combined with an SSRI²¹³; there is evidence to suggest an augmenting effect of combining psychological treatment with an antidepressant.²¹¹

Back to Article Outline

Conclusions 

There is sufficient evidence to conclude that IBS is an important medical disorder with significant impact on those afflicted with regard to symptom severity, disability, and impaired quality of life. Furthermore, the burden to society in terms of direct health care costs and indirect effects including work absenteeism exceeds that of most GI disorders. The authors believe that a compelling need exists for investigations that address the mechanisms for these effects through basic studies, as well as pharmacological and behavioral treatment trials to help ameliorate the suffering of patients so afflicted. Meanwhile, there is some empiric evidence for a diagnostic and hierarchical treatment approach based on predominant symptom type, its severity, and associated clinical and psychosocial features.

Back to Article Outline

Acknowledgements 

The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the authors: James E. Allison, M.D., Lisa Gangarosa, M.D., Richard G. Locke III, M.D., George F. Longstreth, M.D., Howard R. Mertz, M.D., and Amy Foxx-Orenstein, D.O.

The authors thank Carlar Blackman and Cathy Coleman for their invaluable assistance in the preparation of this manuscript.

Back to Article Outline

References 

1. Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, Rome . The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus. 2nd ed. McLean, VA: Degnon Associates; 2000;
   • View In Article
2. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut. 1999;45:II43–II46
   • View In Article
   • CrossRef
3. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SAC. Functional bowel disorders and D. Functional abdominal pain. In: 2nd ed.  Drossman DA,  Talley NJ,  Thompson WG,  Whitehead WE,  Corazziari E editor. Rome II: functional gastrointestinal disorders: diagnosis, pathophysiology, and treatment. McLean, VA: Degnon Associates, Inc; 2000;p. 351–432
   • View In Article
4. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997;112:2120–2137
   • View In Article
   • Abstract
   • Full-Text PDF (376 KB)
   • CrossRef
5. Manning AP, Wyman JB, Heaton KW. How trustworthy are bowel histories? Comparison of recalled and recorded information. BMJ. 1976;2:213–214
   • View In Article
   • CrossRef
6. Heaton KW. Epidemiology of irritable bowel syndrome. Eur J Gastroenterol Hepatol. 1994;6:465–469
   • View In Article
   • CrossRef
7. Hahn B, Watson M, Yan S, Gunput D, Heuijerjans J. Irritable bowel syndrome symptom patterns: frequency, duration, and severity. Dig Dis Sci. 1998;43:2715–2718
   • View In Article
   • MEDLINE
   • CrossRef
8. Talley NJ, Weaver AL, Zinsmeister AR, Melton LJ. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am J Epidemiol. 1992;136:165–177
   • View In Article
   • MEDLINE
9. Kay L, Jorgensen T, Jensen KH. The epidemiology of irritable bowel syndrome in a random population: prevalence, incidence, natural history and risk factors. J Intern Med. 1994;236:23–30
   • View In Article
   • MEDLINE
   • CrossRef
10. Drossman DA, Sandler RS, McKee DC, Lovitz AJ. Bowel patterns among subjects not seeking health care. Use of a questionnaire to identify a population with bowel dysfunction. Gastroenterology. 1982;83:529–534
    • View In Article
    • Abstract
11. Thompson WG, Heaton KW. Functional bowel disorders in apparently healthy people. Gastroenterology. 1980;79:283–288
    • View In Article
    • Abstract
    • Full-Text PDF (663 KB)
12. Jain AP, Gupta OP, Jajoo UN, Sidhwa HK. Clinical profile of irritable bowel syndrome at a rural based teaching hospital in central India. J Assoc Physicians India. 1991;39:385–386
    • View In Article
    • MEDLINE
13. Sandler RS, Drossman DA, Nathan HP, McKee DC. Symptom complaints and health care seeking behavior in subjects with bowel dysfunction. Gastroenterology. 1984;87:314–318
    • View In Article
    • Abstract
    • Full-Text PDF (519 KB)
14. Drossman DA, McKee DC, Sandler RS, Mitchell CM, Cramer EM, Lowman BC, et al. Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology. 1988;95:701–708
    • View In Article
    • Abstract
15. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology. 1991;101:927–934
    • View In Article
    • Abstract
    • Full-Text PDF (794 KB)
16. Heaton KW, O'Donnell LJD, Braddon FEM, Mountford RA, Hughes AO, Cripps PJ. Symptoms of irritable bowel syndrome in a British urban community: consulters and nonconsulters. Gastroenterology. 1992;102:1962–1967
    • View In Article
    • Abstract
    • Full-Text PDF (563 KB)
17. Drossman DA, Li Z, Andruzzi E, Temple R, Talley NJ, Thompson WG, et al. Householder Survey of functional gastrointestinal disorders: prevalence, sociodemography and health impact. Dig Dis Sci. 1993;38:1569–1580
    • View In Article
    • MEDLINE
    • CrossRef
18. Whitehead WE, Bosmajian L, Zonderman AB, Costa PT, Schuster MM. Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples. Gastroenterology. 1988;95:709–714
    • View In Article
    • Abstract
19. Talley NJ, Boyce PM, Jones M. Predictors of health care seeking for irritable bowel syndrome: a population based study. Gut. 1997;41:394–398
    • View In Article
    • MEDLINE
    • CrossRef
20. Mitchell CM, Drossman DA. Survey of the AGA membership relating to patients with functional gastrointestinal disorders. Gastroenterology. 1987;92:1282–1284
    • View In Article
    • MEDLINE
21. Russo MW, Gaynes BN, Drossman DA. A national survey of practice patterns of gastroenterologists with comparison to the past two decades. J Clin Gastroenterol. 1999;29:339–343
    • View In Article
    • MEDLINE
    • CrossRef
22. Sperber AD, Carmel S, Atzmon Y, Weisberg I, Shalit Y, Neumann L, et al. Use of the functional bowel disorder severity index (FBDSI) in a study of patients with the irritable bowel syndrome and fibromyalgia. Am J Gastroenterol. 2000;95:995–998
    • View In Article
    • MEDLINE
    • CrossRef
23. Levy RL, Von Korff M, Whitehead WE, Stang P, Saunders K, Jhingran P, et al. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastoenterol. 2001;96:3122–3129
    • View In Article
24. Whitehead WE, Cheskin LJ, Heller BR, Robinson JC, Crowell MD, Benjamin C, et al. Evidence for exacerbation of irritable bowel syndrome during menses. Gastroenterology. 1990;98:1485–1489
    • View In Article
    • Abstract
    • Full-Text PDF (622 KB)
25. Burns DG. The risk of abdominal surgery in irritable bowel syndrome. South Afr Med J. 1986;70:91; (abstr)
    • View In Article
26. Everhart JE, Renault PF. Irritable bowel syndrome in office-based practice in the United States. Gastroenterology. 1991;100:998–1005
    • View In Article
    • Abstract
27. Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology. 1990;99:409–415
    • View In Article
    • Abstract
    • Full-Text PDF (782 KB)
28. Sandler RS, Everhart JE, Donwitz M, Adams E, Cronin K, Goodman C, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500–1511
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (128 KB)
    • CrossRef
29. Serra J, Azpiroz F, Malagelada JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut. 2001;48:14–19
    • View In Article
    • MEDLINE
    • CrossRef
30. Kellow JE, Eckersley GM, Jones MP. Enhanced perception of physiological intestinal motility in the irritable bowel syndrome. Gastroenterology. 1991;101:1621–1627
    • View In Article
    • Abstract
    • Full-Text PDF (692 KB)
31. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut. 1973;6:105–112
    • View In Article
    • MEDLINE
    • CrossRef
32. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109:40–52
    • View In Article
    • Abstract
    • Full-Text PDF (1360 KB)
    • CrossRef
33. Bradette M, Delvaux M, Staumont G, Fioramonti J, Bueno L, Frexinos J. Evaluation of colonic sensory thresholds in IBS patients using a barostat.. Definition of optimal conditions and comparison with healthy subjects. Dig Dis Sci. 1994;39:449–457
    • View In Article
    • MEDLINE
    • CrossRef
34. Naliboff BD, Munakata J, Fullerton S, Gracely RH, Kodner A, Harraf F, et al. Evidence for two distinct perceptual alterations in irritable bowel syndrome. Gut. 1997;41:505–512
    • View In Article
    • MEDLINE
    • CrossRef
35. Sun WM, Read NW, Prior A, Daly JA, Cheah SK, Grundy D. Sensory and motor responses to rectal distension vary according to rate and pattern of balloon inflation. Gastroenterology. 1990;99:1008–1015
    • View In Article
    • Abstract
    • Full-Text PDF (939 KB)
36. Prior A, Sorial E, Sun WM, Read NW. Irritable bowel syndrome: differences between patients who show rectal sensitivity and those who do not. Eur J Gastroenterol Hepatol. 1993;5:343–349
    • View In Article
    • CrossRef
37. Kellow JE, Eckersley GM, Jones MP. Enhanced perception of physiological intestinal motility in the irritable bowel syndrome. Gastroenterology. 1991;101:1621–1627
    • View In Article
    • Abstract
    • Full-Text PDF (692 KB)
38. Whitehead WE, Palsson OS. Is rectal pain sensitivity a biological marker for irritable bowel syndrome: psychological influences on pain perception. Gastroenterology. 1998;115:1–10
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (46 KB)
    • CrossRef
39. Whitehead WE, Drossman DA, Diamant N, Toner BB, Bangdiwala SI, Hu Y, et al. Correlation of changes in clinical pain and abnormal stools with changes in visceral pain thresholds following treatment (abstr). Gastroenterology. 2000;118(suppl.2):A128
    • View In Article
    • CrossRef
40. Trimble KC, Farouk R, Pryde A, Douglas S, Heading RC. Heightened visceral sensation in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity. Dig Dis Sci. 1995;40:1607–1613
    • View In Article
    • MEDLINE
    • CrossRef
41. Zighelboim J, Talley NJ, Phillips SF, Harmsen WS, Zinsmeister AR. Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism. Dig Dis Sci. 1995;40:819–827
    • View In Article
    • MEDLINE
    • CrossRef
42. Accarino AM, Azpiroz F, Malagelada JR. Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome. Gastroenterology. 1995;108:636–643
    • View In Article
    • Abstract
    • Full-Text PDF (781 KB)
    • CrossRef
43. Evans PR, Bennett EJ, Bak Y-T, Tennant CC, Kellow JE. Jejunal sensorimotor dysfunction in irritable bowel syndrome: Clinical and psychosocial features. Gastroenterology. 1996;110:393–404
    • View In Article
    • Abstract
    • Full-Text PDF (193 KB)
    • CrossRef
44. Holtmann G, Goebell H, Talley NJ. Functional dyspepsia and irritable bowel syndrome: is there a common pathophysiological basis?. Am J Gastroenterol. 1997;92:954–959
    • View In Article
    • MEDLINE
45. Kellow JE, Phillips SF, Miller LJ, Zinsmeister AR. Dysmotility of the small intestine in irritable bowel syndrome. Gut. 1988;29:1236–1243
    • View In Article
    • MEDLINE
    • CrossRef
46. Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98:1187–1192
    • View In Article
    • Abstract
    • Full-Text PDF (711 KB)
47. Rossel P, Drewes AM, Petersen P, Nielsen J, Arendt-Nielsen L. Pain produced by electric stimulation of the rectum in patients with irritable bowel syndrome: further evidence of visceral hyperalgesia. Scand J Gastroenterol. 1999;34:1001–1006
    • View In Article
    • MEDLINE
    • CrossRef
48. Cook IJ, van Eeden A, Collins SM. Patients with irritable bowel syndrome have greater pain tolerance than normal subjects. Gastroenterology. 1987;93:727–733
    • View In Article
    • Abstract
    • Full-Text PDF (794 KB)
49. Chang L, Mayer EA, Johnson T, Fitzgerald LZ, Naliboff B. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain. 2000;84:297–307
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (218 KB)
    • CrossRef
50. Hiatt RB, Katz L. Mast cells in inflammatory conditions of the gastrointestinal tract. Am J Gastroenterol. 1962;37:541–545
    • View In Article
    • MEDLINE
51. Weston AP, Biddle WL, Bhatia PS, Miner PB. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig Dis Sci. 1993;38:1590–1595
    • View In Article
    • MEDLINE
    • CrossRef
52. O'Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12:449–457
    • View In Article
    • MEDLINE
    • CrossRef
53. Salzmann JL, Peltier-Koch F, Bloch F, Petite JP, Camilleri JP. Methods in laboratory investigation: morphometric study of colonic biopsies: a new method of estimating inflammatory diseases. Lab Invest. 1990;60:847–851
    • View In Article
    • MEDLINE
54. Tornblom H, Lindberg G, Nyberg B, Veress B, Inst K. Histopathological findings in the jejunum of patients with severe irritable bowel syndrome. Gastroenterology. 2000;118:A140; (abstr)
    • View In Article
    • CrossRef
55. O'Sullivan MA, Clayton N, Wong T, Bountra C, Buckley MM, O'Morain CA. Increased inos and nitrotyrosine expression in irritable bowel syndrome (IBS). Gastroenterology. 2000;118:A702; (abstr)
    • View In Article
    • CrossRef
56. Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, Walters SJ, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet. 1996;347:150–153
    • View In Article
    • Abstract
    • CrossRef
57. McKendrick MW, Read NW. Irritable bowel syndrome—post salmonella infection. J Infect. 1994;29:1–3
    • View In Article
    • MEDLINE
    • CrossRef
58. McKendrick MW. Post Salmonella irritable bowel syndrome—5 year review. J Infect. 1996;32:170–171
    • View In Article
    • MEDLINE
    • CrossRef
59. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ. 1997;7083:779–782
    • View In Article
60. Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med. 1962;31:307–322
    • View In Article
    • MEDLINE
61. Longstreth GF, Hawkey CJ, Mayer EA, Jones RH, Naesdal J, Wilson IK, et al. Characteristics of patients with irritable bowel syndrome recruited from three sources: implications for clinical trials. Aliment Pharmacol Ther. 2001;15:959–964
    • View In Article
    • MEDLINE
    • CrossRef
62. Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ. 1999;318:565–566
    • View In Article
    • MEDLINE
    • CrossRef
63. Bergin AJ, Donnelly TC, McKendrick MW, Read NW. Changes in anorectal function in persistent bowel disturbance following salmonella gastroenteritis. Eur J Gastroenterol Hepatol. 1993;5:617–620
    • View In Article
    • CrossRef
64. Gwee KA, Collins SM, Marshall JS, Underwood JE, Moochala SM, Read NW. Evidence of inflammatory pathogenesis in post-infectious irritable bowel syndrome (abstr). Gastroenterology. 2001;114:758
    • View In Article
65. Niaz SK, Sandrasegaran K, Renny FH, Jones BJ. Postinfective diarrhoea and bile acid malabsorption. J R Coll Physicians Lond. 1997;31:53–56
    • View In Article
    • MEDLINE
66. Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–811
    • View In Article
    • MEDLINE
    • CrossRef
67. Drossman DA. Mind over matter in the postinfective irritable bowel. Gut. 1999;44:306–307
    • View In Article
    • MEDLINE
    • CrossRef
68. Ogilvie AL, James PD, Atkinson M. Impairment of vagal function in reflux oesophagitis. Q J Med. 1985;54:61–74
    • View In Article
    • MEDLINE
69. Smart HL, Atkinson M. Abnormal vagal function in irritable bowel syndrome. Lancet. 1987;2:475–478
    • View In Article
    • MEDLINE
70. Aggarwal A, Cutts TF, Abell TL, Cardoso S, Familoni B, Bremer J, et al. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology. 1994;106:945–950
    • View In Article
    • Abstract
    • Full-Text PDF (650 KB)
71. Tache Y, Martinez V, Million M, Wang L. Stress and the gastrointestinal tract: III. Stress-related alterations of gut motor function: role of brain-corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol. 2001;280:G173–G177
    • View In Article
    • MEDLINE
72. Mayer EA, Naliboff BD, Chang L, Coutinho SV. Stress and the gastrointestinal tract vs. stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001;280:G519–G524
    • View In Article
    • MEDLINE
73. Thompson JJ, Elsenbruch S, Harnish MJ, Orr WC. Autonomic functioning during REM sleep differentiates IBS symptom subgroups. Gastroenterology. 2001;120:A639; (abstr)
    • View In Article
    • Full-Text PDF (193 KB)
    • CrossRef
74. Bouras EP, Camilleri M, Burton DD, Thomforde G, McKinzie S, Zinsmeister AR. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology. 2001;120:354–360
    • View In Article
    • Abstract
    • Full-Text PDF (1734 KB)
    • CrossRef
75. Mayer EA. The physiology of gastric storage and emptying. In: 3rd ed.  Johnson LR editors. Physiology of the gastrointestinal tract. New York: Raven; 1994;p. 929–976
    • View In Article
76. Rogers RC, McTigue DM, Hermann GE. Vagovagal reflex control of digestion: afferent modulation by neural and “endoneurocrine” factors. Am J Physiol. 1995;268:G1–G10
    • View In Article
    • MEDLINE
77. LeDoux JE. The emotional brain: the mysterious underpinnings of emotional life. In: New York: Simon & Schuster; 1996;p. 1–384
    • View In Article
78. Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res Rev. 1992;17:77–99
    • View In Article
    • MEDLINE
    • CrossRef
79. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861–869
    • View In Article
    • MEDLINE
    • CrossRef
80. Nieuwenheuys R. The greater limbic system, the emotional motor system and the brain. In:  Hostege G,  Bandler R,  Saper CB editor. The emotional motor system. Amsterdam: Elsevier; 1996;p. 627
    • View In Article
81. Rosen SD, Paulesu E, Nihoyannopoulos P, Tousoulis D, Frackowiak RSJ, Frith CD, et al. Silent ischemia as a central problem: regional brain activation compared in silent and painful myocardial ischemia. Ann Intern Med. 1996;124:939–949
    • View In Article
    • MEDLINE
82. Kern MK, Shaker R. Cerebral cortical registration of subliminal visceral stimulation. Gastroenterology. 2002;122:290–298
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (366 KB)
    • CrossRef
83. Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271–293
    • View In Article
    • Abstract
    • Full-Text PDF (2836 KB)
84. Bernstein CN, Niazi N, Robert M, Mertz H, Kodner A, Munakata J, et al. Rectal afferent function in patients with inflammatory and functional intestinal disorders. Pain. 1996;66:151–161
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (2619 KB)
    • CrossRef
85. Bernstein CN, Rollandelli R, Niazi N, Robert M, Hirsh T, Munakata J, et al. Characterization of afferent mechanisms in ileoanal pouches. Am J Gastroenterol. 1997;92:103–108
    • View In Article
    • MEDLINE
86. Keogh E, Ellery D, Hunt C, Hannent I. Selective attentional bias for pain-related stimuli amongst pain fearful individuals. Pain. 2001;91:91–100
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (117 KB)
    • CrossRef
87. Accarino AM, Azpiroz F, Malagelada JR. Attention and distraction: effects on gut perception. Gastroenterology. 1997;113:415–422
    • View In Article
    • Abstract
    • Full-Text PDF (267 KB)
    • CrossRef
88. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science. 1997;277:968–971
    • View In Article
    • MEDLINE
    • CrossRef
89. Coutinho SV, Plotsky P, Sablad M, Miller JC, Zhou H, Bayati AI, et al. Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am J Physiol Gastrointest Liver Physiol. 2002;282:G307–G316
    • View In Article
    • MEDLINE
90. Heinrichs SC, Tache Y. Therapeutic potential of CRF receptor antagonists: a gut-brain perspective. Expert Opin Investig Drugs. 2001;10:647–659
    • View In Article
    • MEDLINE
    • CrossRef
91. Tache Y, Martinez V, Million M, Maillot C. Role of corticotropin releasing factor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome. Eur J Surg (in press).
    • View In Article
92. Silverman DHS, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathologic perception of visceral pain. Gastroenterology. 1997;112:64–72
    • View In Article
    • Abstract
    • Full-Text PDF (516 KB)
    • CrossRef
93. Naliboff BD, Derbyshire SWG, Munakata J, Berman S, Mandelkern M, Chang L, et al. Cerebral activation in irritable bowel syndrome patients and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63:365–375
    • View In Article
    • MEDLINE
94. Mertz H, Tanner G, Morgan V, Pickens D, Price R, Kessler D. Functional MRI detects activation of anterior cingulate and prefrontal cortex in IBS patients and control subjects during rectosigmoid stimulation. Gastroenterology. 1999;116:A1041; (abstr)
    • View In Article
95. Baciu MV, Bonaz BL, Papillon E, Bost RA, Le Bas JF, Fournet J, et al. Central processing of rectal pain: a functional MRI study. AJNR Am J Neuroradiol. 1999;20:1920–1924
    • View In Article
    • MEDLINE
96. Hobday DI, Aziz Q, Thacker N, Hollander I, Jackson A, Thompson DG. A study of the cortical processing of ano-rectal sensation using functional MRI. Brain. 2001;124:361–368
    • View In Article
    • MEDLINE
    • CrossRef
97. Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol. 1995;359:490–506
    • View In Article
    • MEDLINE
    • CrossRef
98. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4:215–222
    • View In Article
    • CrossRef
99. Rainville P, Hofbauer RK, Paus T, Duncan GH, Bushnell MC, Price DD. Cerebral mechanisms of hypnotic induction and suggestion. J Cogn Neurosci. 1999;11:110–125
    • View In Article
    • MEDLINE
    • CrossRef
100. Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE. Psychosocial aspects of the functional gastrointestinal disorders. In: 2nd ed.  Drossman DA,  Corazziari E,  Talley NJ,  Thompson WG,  Whitehead WE editor. Rome II. The functional gastrointestinal disorders: diagnosis, pathophysiology and treatment; a multinational consensus. 2000;p. 157–245 Degnon and Associates
     • View In Article
101. Ford MJ, Miller PM, Eastwood J, Eastwood MA. Life events, psychiatric illness and the irritable bowel syndrome. Gut. 1987;28:160–165
     • View In Article
     • MEDLINE
     • CrossRef
102. Mendeloff AI, Monk M, Siegel CI, Lilienfeld A. Illness experience and life stresses in patients with irritable colon and with ulcerative colitis. An epidemiologic study of ulcerative colitis and regional enteritis in Baltimore, 1960–1964. N Engl J Med. 1970;282:14–17
     • View In Article
     • MEDLINE
     • CrossRef
103. Fava GA, Pavan L. Large bowel disorders. I. Illness configuration and life events. Psychother Psychosom. 1976;27:93
     • View In Article
     • MEDLINE
     • CrossRef
104. Whitehead WE, Crowell MD, Robinson JC, Heller BR, Schuster MM. Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared to subjects without bowel dysfunction. Gut. 1992;33:825–830
     • View In Article
     • MEDLINE
     • CrossRef
105. Walker LS, Garber J, Smith CA, Van Slyke DA, Claar RL. The relation of daily stressors to somatic and emotional symptoms in children with and without recurrent abdominal pain. J Consult Clin Psychol. 2001;69:85–91
     • View In Article
     • MEDLINE
     • CrossRef
106. Dinan TG, O'Keane V, O'Boyle C, Chua A, Keeling PW. A comparison of the mental status, personality profiles and life events of patients with irritable bowel syndrome and peptic ulcer disease. Acta Psychiatr Scand. 1991;84:26–28
     • View In Article
     • MEDLINE
     • CrossRef
107. Levy RL, Cain KC, Jarrett M, Heitkemper MM. The relationship between daily life stress and gastrointestinal symptoms in women with irritable bowel syndrome. J Behav Med. 1997;20:177–193
     • View In Article
     • MEDLINE
     • CrossRef
108. Drossman DA, Leserman J, Nachman G, Li Z, Gluck H, Toomey TC, et al. Sexual and physical abuse in women with functional or organic gastrointestinal disorders. Ann Intern Med. 1990;113:828–833
     • View In Article
     • MEDLINE
109. Drossman DA, Li Z, Leserman J, Toomey TC, Hu Y. Health status by gastrointestinal diagnosis and abuse history. Gastroenterology. 1996;110:999–1007
     • View In Article
     • Abstract
     • Full-Text PDF (97 KB)
     • CrossRef
110. Creed FH, Craig T, Farmer RG. Functional abdominal pain, psychiatric illness and life events. Gut. 1988;29:235–242
     • View In Article
     • MEDLINE
     • CrossRef
111. Welgan P, Meshkinpour H, Beeler M. Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome. Gastroenterology. 1988;94:1150–1156
     • View In Article
     • Abstract
     • Full-Text PDF (786 KB)
112. Talley NJ, Phillips SF, Bruce B, Twomey CK, Zinsmeister AR, Melton LJ. Relation among personality and symptoms in non-ulcer dyspepsia and the irritable bowel syndrome. Gastroenterology. 1990;99:327–333
     • View In Article
     • Abstract
     • Full-Text PDF (780 KB)
113. Blanchard EB, Radnitz CL, Evans DD, Schwartz SP, Neff DF, Gerardi MA. Psychological comparisons of irritable bowel syndrome to chronic tension and migraine headache and nonpatient controls. Biofeedback Self Reg. 1986;11:221–230
     • View In Article
114. Ali A, Toner BB. Sexual abuse and self-blame in women with irritable bowel syndrome. Psychosom Med. 1996;58:66; (abstr)
     • View In Article
115. Toner BB, Garfinkel PE, Jeejeebhoy KN, Scher H, Shulhan D, Gasbarro ID. Self-schema in irritable bowel syndrome and depression. Psychosom Med. 1990;52:149–155
     • View In Article
     • MEDLINE
116. Toner BB, Koyama E, Garfinkel PE, Jeejeebhoy KN, Gasbarro I. Social desirability and irritable bowel syndrome. Int J Psychiatr Med. 1992;22:99–103
     • View In Article
117. Sperber AD, Carmel S, Atzmon Y, Weisberg I, Shalit Y, Neumann L, et al. The sense of coherence index and the irritable bowel syndrome: a cross-sectional comparison among IBS patients with and without coexisiting fibromyalgia, IBS non-patient and controls. Scand J Gastroenterol. 1999;34:259–263
     • View In Article
     • MEDLINE
     • CrossRef
118. Ali A, Toner BB, Stuckless N, Gallop R, Diamant NE, Gould M, et al. Emotional abuse, self-blame and self-silencing in women with irritable bowel syndrome. Psychosom Med. 2000;62:76–82
     • View In Article
     • MEDLINE
119. Drossman DA, Li Z, Leserman J, Keefe FJ, Hu YJ, Toomey TC. Effects of coping on health outcome among female patients with gastrointestinal disorders. Psychosom Med. 2000;62:309–317
     • View In Article
     • MEDLINE
120. Longstreth GF, Wolde-Tsadik G. Irritable bowel-type symptoms in HMO examinees. Prevalence, demographics, and clinical correlates. Dig Dis Sci. 1993;38:1581–1589
     • View In Article
     • MEDLINE
     • CrossRef
121. Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. Gastrointestinal tract symptoms and self-reported abuse: a population-based study. Gastroenterology. 1994;107:1040–1049
     • View In Article
     • Abstract
     • Full-Text PDF (966 KB)
122. Bennett EJ, Tennant CC, Piesse C, Badcock CA, Kellow JE. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut. 1998;43:256–261
     • View In Article
     • MEDLINE
     • CrossRef
123. Fowlie S, Eastwood MA, Ford MJ. Irritable bowel syndrome: the influence of psychological factors on the symptom complex. J Psychosom Res. 1992;36:169–173
     • View In Article
     • MEDLINE
     • CrossRef
124. Blanchard EB, Schwartz SP, Neff DF, Gerardi MA. Prediction of outcome from the self-regulatory treatment of irritable bowel syndrome. Behav Res Ther. 1988;26:187–190
     • View In Article
     • MEDLINE
     • CrossRef
125. Levy RL, Whitehead WE, Von Korff MR, Saunders KW, Feld AD. Intergenerational transmission of GI illness behavior. Am J Gastroenterol. 1998;95:451–456
     • View In Article
     • MEDLINE
     • CrossRef
126. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799–804
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (187 KB)
     • CrossRef
127. Whitehead WE, Crowell MD, Heller BR, Robinson JC, Schuster MM, Horn S. Modeling and reinforcement of the sick role during childhood predicts adult illness behavior. Psychosom Med. 1994;56:541–550
     • View In Article
     • MEDLINE
128. Whitehead WE, Winget C, Fedoravicius AS, Wooley S, Blackwell B. Learned illness behavior in patients with irritable bowel syndrome and peptic ulcer. Dig Dis Sci. 1982;27:202–208
     • View In Article
     • MEDLINE
     • CrossRef
129. Lowman BC, Drossman DA, Cramer EM, McKee DC. Recollection of childhood events in adults with irritable bowel syndrome. J Clin Gastroenterol. 1987;9:324–330
     • View In Article
     • MEDLINE
     • CrossRef
130. Koloski NA, Talley NJ, Boyce PM. The impact of functional gastrointestinal disorders on quality of life. Am J Gastroenterol. 2000;95:67–71
     • View In Article
     • MEDLINE
     • CrossRef
131. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med. 1993;118:622–629
     • View In Article
     • MEDLINE
132. Yacavone RF, Locke GR, Provenzale DT, Eisen GM. Quality of life measurement in gastroenterology: what is available?. Am J Gastroenterol. 2001;96:285–297
     • View In Article
     • MEDLINE
     • CrossRef
133. Luscombe FA. Health-related quality of life and associated psychosocial factors in irritable bowel syndrome: a review. Qual Life Res. 2000;9:161–176
     • View In Article
     • MEDLINE
     • CrossRef
134. Drossman DA, Patrick DL, Whitehead WE, Toner BB, Diamant NE, Hu YJB, et al. Further validation of the IBS-QOL: a disease specific quality of life questionnaire. Am J Gastoenterol. 2000;95:999–1007
     • View In Article
135. Groll D, Vanner SJ, Depew WT, DaCosta LR, Simon JB, Groll A, et al. The IBS-36: a new quality of life measure for irritable bowl syndrome. Am J Gastroenterol. 2002;97:962–971
     • View In Article
     • MEDLINE
     • CrossRef
136. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer E. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119:655–660
     • View In Article
137. Whitehead WE, Burnett CK, Cook E, Taub E. Impact of irritable bowel syndrome on quality of life. Dig Dis Sci. 1996;41:2248–2253
     • View In Article
     • MEDLINE
     • CrossRef
138. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development of a new measure. Dig Dis Sci. 1998;43:400–411
     • View In Article
     • MEDLINE
     • CrossRef
139. Hahn BA, Kirchdoerfer LJ, Fullerton S, Mayer E. Evaluation of a new quality of life questionnaire for patients with irritable bowel syndrome. Aliment Pharmacol Ther. 1997;11:547–552
     • View In Article
     • MEDLINE
140. Whitehead WE, Wald A, Diamant N, Enck P, Pemberton J, Rao SSC. Functional disorders of the anus and rectum. In: 2nd ed.  Drossman DA,  Corazziari E,  Talley NJ,  Thompson WG,  Whitehead WE editor. Rome II. Functional gastrointestinal disorders: diagnosis, pathophysiology and treatment: a multinational consensus. McLean, VA: Degnon Associates; 2000;p. 483–532
     • View In Article
141. Vanner SJ, Depew WT, Paterson W, DaCosta LR, Groll AG, Simon JB, et al. Predictive value of the Rome Criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol. 1999;94:2912–2917
     • View In Article
     • MEDLINE
     • CrossRef
142. Fass R, Longstreth G, Pimentel M, Fullerton S, Russak SM, Chiou CF, et al. Evidence- and consensus-based practice guidelines for the diagnosis of irritable bowel syndrome. Arch Intern Med. 2001;161:2081–2088
     • View In Article
     • MEDLINE
     • CrossRef
143. Drossman DA. Irritable bowel syndrome: How far do you go in the workup?. Gastroenterology. 2001;121:1512–1515
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (150 KB)
     • CrossRef
144. Hamm LR, Sorrells SC, Harding JP, Northcutt AR, Heath A, Kapke GF, et al. Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria. Am J Gastroenterol. 1999;94:1279–1282
     • View In Article
     • MEDLINE
     • CrossRef
145. Ciclitira PJ. American Gastroenterological Association medical position statement: celiac sprue. Gastroenterology. 2001;120:1522–1525
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (113 KB)
     • CrossRef
146. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease–like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001;121:1329–1338
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (231 KB)
     • CrossRef
147. Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet. 2001;358:1504–1508
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (84 KB)
     • CrossRef
148. Tolliver BA, Herrera JL, DiPalma JA. Evaluation of patients who meet clinical criteria for irritable bowel syndrome. Am J Gastroenterol. 1994;89:176–178
     • View In Article
     • MEDLINE
149. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503–3506
     • View In Article
     • MEDLINE
     • CrossRef
150. Drossman DA, Whitehead WE, Toner BB, Diamant NE, Hu YJB, Bangdiwala SI, et al. What determines severity among patients with painful functional bowel disorders?. Am J Gastroenterol. 2000;95:974–980
     • View In Article
     • MEDLINE
     • CrossRef
151. Drossman DA, Li Z, Toner BB, Diamant NE, Creed FH, Thompson DG, et al. Functional bowel disorders: a multicenter comparison of health status, and development of illness severity index. Dig Dis Sci. 1995;40:986–995
     • View In Article
     • MEDLINE
     • CrossRef
152. Shapiro MS, Olden KW. Symptom expression in pain-predominant functional bowel syndrome: is visceral hyperalgesia the whole truth?. Am J Gastroenterol. 2000;95:862–863
     • View In Article
     • MEDLINE
     • CrossRef
153. Drossman DA. Diagnosing and treating patients with refractory functional gastrointestinal disorders. Ann Intern Med. 1995;123:688–697
     • View In Article
     • MEDLINE
154. Drossman DA, Thompson WG. The irritable bowel syndrome: review and a graduated, multicomponent treatment approach. Ann Intern Med. 1992;116:1009–1016
     • View In Article
     • MEDLINE
155. Owens DM, Nelson DK, Talley NJ. The irritable bowel syndrome: long term prognosis and the physician-patient interaction. Ann Intern Med. 1995;122:107–112
     • View In Article
     • MEDLINE
156. O'Sullivan MA, Mahmud N, Kelleher DP, Lovett E, O'Morain CA. Patient knowledge and educational needs in irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2000;12:39–43
     • View In Article
     • MEDLINE
     • CrossRef
157. Jackson JL, Kroenke K. The effect of unmet expectations among adults presenting with physical symptoms. Ann Intern Med. 2001;134:889–897
     • View In Article
     • MEDLINE
158. Lucey MR, Clark ML, Lowndes J, Dawson AM. Is bran efficacious in irritable bowel syndrome? A double-blind placebo-controlled crossover study. Gut. 1987;28:221–225
     • View In Article
     • MEDLINE
     • CrossRef
159. Cook IJ, Irvine EJ, Campbell D, Shannon S, Reddy SN, Collins SM. Effect of dietary fiber on symptoms and rectosigmoid motility in patients with irritable bowel syndrome. Gastroenterology. 1990;98:66–72
     • View In Article
     • Abstract
     • Full-Text PDF (871 KB)
160. Shimberg EF. Relief from IBS. In: 1st ed. New York: M. Evans and Company; 1988;p. 258
     • View In Article
161. Klein KB. Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology. 1988;95:232–241
     • View In Article
     • Abstract
     • Full-Text PDF (1188 KB)
162. Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis of smooth muscle relaxers in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8:499–510
     • View In Article
     • MEDLINE
     • CrossRef
163. Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med. 2000;133:136–147
     • View In Article
     • MEDLINE
164. Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2001;15:355–361
     • View In Article
     • MEDLINE
     • CrossRef
165. Akehurst R, Kaltenthaler E. Treatment of irritable bowel syndrome: a review of randomised controlled trials. Gut. 2001;48:272–282
     • View In Article
     • MEDLINE
     • CrossRef
166. Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. Am J Gastroenterol. 1998;93:1131–1135
     • View In Article
     • MEDLINE
     • CrossRef
167. Read M, Read NW, Barber DC, Duthie HL. Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci. 1982;27:807–814
     • View In Article
     • MEDLINE
     • CrossRef
168. Kozlowski CM, Green A, Grundy D, Boissonade FM, Bountra C. The 5-HT₃ receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetized rat. Gut. 2000;46:474–480
     • View In Article
     • MEDLINE
     • CrossRef
169. Camilleri M, Mayer EA, Drossman DA, Heath AT, Dukes GE, McSorley D, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT₃ receptor antagonist. Aliment Pharmacol Ther. 1999;13:1149–1159
     • View In Article
     • MEDLINE
     • CrossRef
170. Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mill JG, et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2000;14:23–34
     • View In Article
     • MEDLINE
     • CrossRef
171. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet. 2000;355:1035–1040
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (104 KB)
     • CrossRef
172. Mangel AW, Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath AT, et al. Alosetron, a 5-HT₃ receptor antagonist, in the treatment of non-constipated female IBS patients. Am J Gastroenterol. 1999;94:2677; (abstr)
     • View In Article
173. Caras S, Krause G, Biesheuvel E, Steinborn C. Cilansetron shows efficacy in male and female non-constipated patients with irritable bowel syndrome in a United States study (abstr). Gastroenterology. 2001;120:A217
     • View In Article
     • Full-Text PDF (176 KB)
     • CrossRef
174. Mueller-Lissner S, Fumagalli I, Bardhan KD, Pace F, Nault B, Pecher EC, et al. Tegaserod, a 5-HT₄ receptor partial agonist, relieves key symptoms of irritable bowel syndrome. Gastroenterology. 2000;118:A175; (abstr)
     • View In Article
     • CrossRef
175. Briejer E, Ghoos E, Eelen J, Schuurkes JAJ. Serotonin 5-HT₄ receptors mediate the R093877-induced changes in contractile patterns in the canine colon (abstr). Gastroenterology. 1997;112:A705
     • View In Article
176. Emmanuel AV, Kamm MA, Roy AJ, Antonelli K. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut. 1998;42:511–516
     • View In Article
     • MEDLINE
     • CrossRef
177. Bouras EP, Camilleri M, Burton DD, McKinzie S. Selective stimulation of colonic transit by the benzofuran 5-HT₄ agonist, prucalopride, in healthy humans. Gut. 1999;44:682–686
     • View In Article
     • MEDLINE
     • CrossRef
178. Johanson J, Miner PB, Parkman HP, Wojcik MA, Lambert R, Karcher K, et al. Prucalopride improves bowel movement frequency and symptoms in patients with chronic constipation: results of two double-blind, placebo-controlled trials (abstr). Gastroenterology. 2000;118:A175
     • View In Article
     • CrossRef
179. Miner PB, Nichols T, Silvers DR, Joslyn A, Woods M. The efficacy and safety of prucalopride in patients with chronic constipation. Gastroenterology. 1999;116:A1043; (abstr)
     • View In Article
180. Bharucha AE, Camilleri M, Zinsmeister AR, Hanson RB. Adrenergic modulation of human colonic motor and sensory function. Am J Physiol. 1997;273:G997–G1006
     • View In Article
     • MEDLINE
181. Tack J, Piessevaux H, Coulie B, Fischler B, De Gucht V, Janssens J. A placebo-controlled trial of buspirone, a fundus-relaxing drug, in functional dyspepsia: effect on symptoms and gastric sensory and motor function. Gastroenterology. 1999;116:A325; (abstr)
     • View In Article
182. Tack JF, Vos R, Broekaert D, Fischler B, Janssens J. Influence of citalopram, a selective serotonin reuptake inhibitor, on colonic tone and sensitivity in man. Gastroenterology. 2000;118:A175; (abstr)
     • View In Article
     • CrossRef
183. Broekaert D, Vos R, Gevers AM, Janssens J, Vandenberghe J, Fischler B, et al. A double-blind randomised placebo-controlled crossover trial of citalopram, a selective 5-hydroxytryptamine reuptake inhibitor, in irritable bowel syndrome (abstr). Gastroenterology. 2001;120:A641
     • View In Article
     • Full-Text PDF (187 KB)
     • CrossRef
184. Smart HL, Mayberry JF, Atkinson M. Alternative medicine consultations and remedies in patients with the irritable bowel syndrome. Gut. 1986;27:826–828
     • View In Article
     • MEDLINE
     • CrossRef
185. Sloth H, Mortensen NH, Bisgard C. Irritable colon and ulcerative colitis. Alternative treatment is used frequently. Ugeskr Laeger. 1991;153:3304–3306
     • View In Article
     • MEDLINE
186. Verhoef MJ, Sutherland LR, Brkich L. Use of alternative medicine by patients attending a gastroenterology clinic. Can Med Assoc J. 1990;142:121–125
     • View In Article
187. Sutherland LR, Verhoef MJ. Why do patients seek a second opinion or alternative medicine?. J Clin Gastroenterol. 1994;19:194–197
     • View In Article
     • MEDLINE
     • CrossRef
188. Bittinger M, Barnert J, Wienbeck M. Alternative therapy methods in functional disorders of the gastrointestinal system. Zeitschrift fur Gastroenterologie. 1998;36:519–524
     • View In Article
     • MEDLINE
189. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA. 1998;280:1585–1589
     • View In Article
     • MEDLINE
     • CrossRef
190. Payne A, Blanchard EB. A controlled comparison of cognitive therapy and self-help support groups in the treatment of irritable bowel syndrome. J Consult Clin Psychol. 1995;63:779–786
     • View In Article
     • MEDLINE
     • CrossRef
191. Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable bowel syndrome. Lancet. 1984;2:1232–1233
     • View In Article
     • MEDLINE
192. Whorwell PJ, Prior A, Colgan SM. Hypnotherapy in severe irritable bowel syndrome: further experience. Gut. 1987;28:423–425
     • View In Article
     • MEDLINE
     • CrossRef
193. Toner BB, Segal ZV, Emmott S, Myran D, Ali A, DiGasbarro I, et al. Cognitive behavior group therapy for patients with irritable bowel syndrome. Int J Group Psychother. 1998;48:215–243
     • View In Article
     • MEDLINE
194. Blanchard EB, Schwarz SP, Suls JM, Gerardi MA, Scharff L, Greene B, et al. Two controlled evaluations of multicomponent psychological treatment of irritable bowel syndrome. Behav Res Ther. 1992;30:175–189
     • View In Article
     • MEDLINE
     • CrossRef
195. Boyce PM, Talley NJ, Koloski NA, Balaam B, Nandurkar S. A randomized controlled trial of cognitive behavioural therapy, relaxation therapy and routine medical care for irritable bowel syndrome (IBS). Gastroenterology. 2001;120:A115; (abstr)
     • View In Article
     • Full-Text PDF (178 KB)
     • CrossRef
196. Guthrie E, Creed F, Dawson D, Tomenson B. A controlled trial of psychological treatment for the irritable bowel syndrome. Gastroenterology. 1991;100:450–457
     • View In Article
     • Abstract
197. Toner BB, Segal ZV, Emmott SD, Myran D. Cognitive-behavioral treatment of irritable bowel syndrome: The brain-gut connection. In: New York: Guilford Press; 2000;p. 188
     • View In Article
198. Creed F, Ratcliffe J, Fernandez L, Tomenson B, Palmer S, Rigby C, et al. Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome. Ann Intern Med. 2001;134:860–868
     • View In Article
     • MEDLINE
199. Heefner JD, Wilder RM, Wilson JD. Irritable colon and depression. Psychosomatics. 1978;19:540–547
     • View In Article
     • Abstract
     • Full-Text PDF (846 KB)
200. Hislop IG. Psychological significance of the irritable colon syndrome. Gut. 1971;12:452–457
     • View In Article
     • MEDLINE
     • CrossRef
201. Lancaster-Smith MJ, Prout BJ, Pinto T, Anderson JA, Schiff AA. Influence of drug treatment on the irritable bowel syndrome and its interaction with psychoneurotic morbidity. Acta Psychiatr Scand. 1982;66:33–41
     • View In Article
     • MEDLINE
     • CrossRef
202. Su X, Gebhart GF. Effects of tricyclic antidepressants on mechanosensitive pelvic nerve afferent fibers innervating the rat colon. Pain. 1998;76:105–114
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (343 KB)
     • CrossRef
203. Greenbaum DS, Mayle JE, Vanegeren LE, Jerome JA, Mayor JW, Greenbaum RB, et al. The effects of desipramine on IBS compared with atropine and placebo. Dig Dis Sci. 1987;32:257–266
     • View In Article
     • MEDLINE
     • CrossRef
204. Dapoigny M, Abitbol JL, Scherrer B, Fraitag B. “Kapping” visceral pain in patients with irritable bowel syndrome: does it work?. Gastroenterology. 1996;111:531–533
     • View In Article
     • Abstract
     • Full-Text PDF (52 KB)
     • CrossRef
205. Gorard DA, Libby GW, Farthing MJG. Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome. Dig Dis Sci. 1995;40:86–95
     • View In Article
     • MEDLINE
     • CrossRef
206. Gorard DA, Libby GW, Farthing MJG. Influence of antidepressants on whole gut orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8:159–166
     • View In Article
     • MEDLINE
     • CrossRef
207. Onghena P, Houdenhove BV. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992;49:205–219
     • View In Article
     • Abstract
     • Full-Text PDF (1818 KB)
     • CrossRef
208. Clouse RE. Antidepressants for functional gastrointestinal syndromes. Dig Dis Sci. 1994;39:2352–2363
     • View In Article
     • MEDLINE
     • CrossRef
209. Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of amitryptiline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol. 1998;93:160–165
     • View In Article
     • MEDLINE
     • CrossRef
210. Holroyd KA, O'Donnell FJ, Stensland J, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination. JAMA. 2001;285:2208–2215
     • View In Article
     • MEDLINE
     • CrossRef
211. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342:1462–1470
     • View In Article
     • MEDLINE
     • CrossRef
212. Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with anti-depressants: A meta-analysis. Am J Med. 2000;108:65–72
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (116 KB)
     • CrossRef
213. Richelson E. Pharmacology of antidepressants. Mayo Clin Proc. 2001;76:511–527
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (342 KB)
     • CrossRef
214. Finley PR. Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother. 1994;28:1359–1369
     • View In Article
     • MEDLINE
215. Boyer WF. Potential indications for the selective serotonin reuptake inhibitors. Int Clin Psychopharmacol. 1992;6(suppl 5):5–12
     • View In Article
     • CrossRef
216. Enggaard TP, Klitgaard NA, Gram LF, Arendt-Nielsen L, Sindrup SH. Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans. Clin Pharmacol Ther. 2001;69:245–251
     • View In Article
     • MEDLINE
     • CrossRef
217. Pernia A, Micó JA, Calderón E, Torres LM. Venlafaxine for the treatment of neuropathic pain. J Pain Symptom Manage. 2000;19:408–410
     • View In Article
     • Full Text
     • Full-Text PDF (98 KB)
     • CrossRef
218. Lydiard RB, Falsetti SA. Experience with anxiety and depression treatment studies: implications for designing irritable bowel syndrome clinical trials. Am J Med. 1999;107:65S–73S
     • View In Article
     • MEDLINE
219. Ritchie JA, Truelove SC. Comparison of various treatments for irritable bowel syndrome. BMJ. 1980;281:1317–1319
     • View In Article
     • CrossRef
220. Baume P, Cuthbert J. The effect of medazepam in relieving symptoms of functional gastrointestinal distress. Aust N Z J Med. 1973;3:457–460
     • View In Article
     • MEDLINE
     • CrossRef
221. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology. 1998;115:1346–1352
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (123 KB)
     • CrossRef
222. Cakkues AL, Popkin MK. Antidepressant treatment of medical-surgical inpatients by nonpsychiatric physicians. Arch Gen Psychiatry. 1987;44:157–160
     • View In Article
     • MEDLINE
223. Clouse RE, Lustman P, Geisman RA. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther. 1994;8:409–416
     • View In Article
     • MEDLINE
     • CrossRef
224. Brown WA, Harrison W. Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to another?. J Clin Psychiatry. 1995;56:30–34
     • View In Article
     • MEDLINE
225. Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ. 1992;304:87–90
     • View In Article
     • MEDLINE
     • CrossRef
226. Zuckerman MJ, Guerra LG, Drossman DA, Foland JA, Gregory GG. Comparison of bowel patterns in Hispanics and non-Hispanic whites. Dig Dis Sci. 1995;40:1761–1769
     • View In Article
227. Taub E, Cuevas JL, Cook EW, Crowell M, Whitehead WE. Irritable bowel syndrome defined by factor analysis: gender and race comparisons. Dig Dis Sci. 1995;40:2647–2655
     • View In Article
     • MEDLINE
     • CrossRef
228. Osterberg E, Blomquist L, Krakau I, Weinryb RM, Asberg M, Hultcrantz R. A population study on irritable bowel syndrome and mental health. Scand J Gastroenterol. 2000;35:264–268
     • View In Article
     • MEDLINE
     • CrossRef
229. Boyce PM, Koloski NA, Talley NJ. Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice?. Am J Gastroenterology. 2000;95:3176–3182
     • View In Article
230. Talley NJ, Howell S, Poulton R. The irritable bowel syndrome and psychiatric disorders in the community: is there a link?. Am J Gastroenterol. 2001;96:1072–1079
     • View In Article
     • MEDLINE
     • CrossRef
231. Thompson WG, Irvine EJ, Pare P, Ferrazzi S, Rance L. Functional gastrointestinal disorders in Canada: first population based survey using Rome II criteria with suggestions for improving the questionnaire. Dig Dis Sci. 2002;47:225–235
     • View In Article
     • MEDLINE
     • CrossRef
232. Van Wijk HJ, Smout AJPM, Akkermans LMA, Roelofs JMM, ten Thije OJ. Gastric emptying and dyspeptic symptoms in the irritable bowel syndrome. Scand J Gastroenterol. 1992;27:99–102
     • View In Article
     • MEDLINE
     • CrossRef
233. Evans PR, Bak YT, Shuter B, Hoschl R, Kellow JE. Gastroparesis and small bowel dysmotility in irritable bowel syndrome. Dig Dis Sci. 1997;42:2087–2093
     • View In Article
     • MEDLINE
     • CrossRef
234. Caballero-Plasencia AM, Valenzuela-Barranco M, Herrerias-Gutierez JM, Esteban-Carretero JM. Altered gastric emptying in patients with irritable bowel syndrome. Eur J Nucl Med. 1999;26:404–409
     • View In Article
     • MEDLINE
     • CrossRef
235. Welgan P, Meshkinpour H, Ma J. Role of anger in antral motor activity in irritable bowel syndrome. Dig Dis Sci. 2000;45:248–251
     • View In Article
     • MEDLINE
     • CrossRef
236. Leahy A, Besherdas K, Clayman C, Mason I, Epstein O. Abnormalities of the electrogastrogram in functional gastrointestinal disorders. Am J Gastoenterol. 1999;94:1023–1028
     • View In Article
237. Kumar D, Wingate DL. The irritable bowel syndrome: a paraxysmal motor disorder. Lancet. 1985;2:973–977
     • View In Article
     • MEDLINE
238. Kellow JE, Gill RC, Wingate DL. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology. 1990;98:1208–1218
     • View In Article
     • Abstract
     • Full-Text PDF (1209 KB)
239. Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H. Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 1996;31:581–589
     • View In Article
     • MEDLINE
     • CrossRef
240. Simren M, Castedal M, Svedlund J, Abrahamsson H, Bjornsson E. Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS). Dig Dis Sci. 2000;45:2151–2161
     • View In Article
     • MEDLINE
     • CrossRef
241. Gorard DA, Libby GW, Farthing MJG. Ambulatory small intestinal motility in ‘diarrhoea’ predominant irritable bowel syndrome. Gut. 1994;35:203–210
     • View In Article
     • MEDLINE
     • CrossRef
242. Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut. 1998;42:845–849
     • View In Article
     • MEDLINE
     • CrossRef
243. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology. 1987;92:1885–1893
     • View In Article
     • Abstract
     • Full-Text PDF (1109 KB)
244. Kellow JE, Langeluddecke PM, Eckersley GM, Jones MP, Tennant CC. Effects of acute psychologic stress on small-intestinal motility in health and the irritable bowel syndrome. Scand J Gastroenterol. 1992;27:53–58
     • View In Article
     • MEDLINE
     • CrossRef
245. Cann PA, Read NW, Brown C, Hobson N, Holdsworth CG. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut. 1983;24:405–411
     • View In Article
     • MEDLINE
     • CrossRef
246. Lu CL, Chen CY, Chang FY, Lee SD. Characteristics of small bowel motility in patients with irritable bowel syndrome and normal humans: an Oriental study. Chinese Science. 1998;95:165–169
     • View In Article
247. Vassallo MJ, Camilleri M, Phillips SF, Steadman CJ, Talley NJ, Hanson RB, et al. Colonic tone and motility in patients with irritable bowel syndrome. Mayo Clin Proc. 1992;67:725–731
     • View In Article
     • MEDLINE
248. Whitehead WE, Drescher VM. Perception of gastric contractions and self-control of gastric motility. Psychophysiology. 1980;17:552–558
     • View In Article
     • MEDLINE
     • CrossRef
249. Rogers J, Henry MM, Misiewicz JJ. Increased segmental activity and intraluminal pressures in the sigmoid colon of patients with the irritable bowel syndrome. Gut. 1989;30:634–641
     • View In Article
     • MEDLINE
     • CrossRef
250. Fukudo S, Suzuki J. Colonic motility, autonomic function, and gastrointestinal hormones under psychological stress on IBS. Tohoku J Exp Med. 1987;151:373–385
     • View In Article
     • MEDLINE
     • CrossRef
251. Ladabaum U, Minoshima S, Hasler WL, Cross D, Chey WD, Owyang C. Gastric distention correlated with activation of multiple cortical and subcortical regions. Gastroenterology. 2001;120:369–376
     • View In Article
     • Abstract
     • Full-Text PDF (3819 KB)
     • CrossRef
252. Bueno L, Fioramonti J, Ruckebusch Y, Frexinos J, Coulom P. Evaluation of colonic myoelectrical activity in health and functional disorders. Gut. 1980;21:480–485
     • View In Article
     • MEDLINE
     • CrossRef
253. Vassallo M, Camilleri M, Phillips SF, Brown ML, Chapman NJ, Thomforde GM. Transit through the proximal colon influences stool weight in the irritable bowel syndrome. Gastroenterology. 1992;102:102–108
     • View In Article
     • Abstract
     • Full-Text PDF (657 KB)
254. Whitehead WE, Crowell MD, Davidoff AL, Palsson OS, Schuster MM. Pain from rectal distension in women with irritable bowel syndrome: relationship to sexual abuse. Dig Dis Sci. 1997;42:796–804
     • View In Article
     • MEDLINE
     • CrossRef
255. Blomhoff S, Jacobsen MB, Spetalen S, Vatn M, Malt UF. Rectal tone and brain information processing in irritable bowel syndrome. Dig Dis Sci. 2000;45:1153–1159
     • View In Article
     • MEDLINE
     • CrossRef
256. Horikawa Y, Mieno H, Inoue M, Kajiyama G. Gastrointestinal motility in patients with irritable bowel syndrome studied by using radiopaque markers. Scand J Gastroenterol. 1999;34:1190–1195
     • View In Article
     • MEDLINE
     • CrossRef
257. MacDonald AJ, Bouchier IAD. Non-organic gastrointestinal illness: a medical and psychiatric study. Br J Psychiatry. 1980;136:276–283
     • View In Article
     • MEDLINE
     • CrossRef
258. Craig TKJ, Brown GW. Goal frustration and life events in the aetiology of painful gastrointestinal disorder. J Psychosom Res. 1984;28:411–421
     • View In Article
     • MEDLINE
     • CrossRef
259. Colgan S, Creed FH, Klass SH. Psychiatric disorder and abnormal illness behaviour in patients with upper abdominal pain. Psychol Med. 1988;18:887–892
     • View In Article
     • MEDLINE
     • CrossRef
260. Corney RH, Stanton R. Physical symptom severity, psychological and social dysfunction in a series of outpatients with irritable bowel syndrome. J Psychosom Res. 1990;34:483–491
     • View In Article
     • MEDLINE
     • CrossRef
261. Toner BB, Garfinkel PE, Jeejeebhoy KN. Psychological factors in irritable bowel syndrome. Can J Psychiatry. 1990;35:158–161
     • View In Article
     • MEDLINE
262. Blanchard EB, Scharff L, Schwartz SP, Suls JM, Barlow DH. The role of anxiety and depression in the irritable bowel syndrome. Behav Res Ther. 1990;28:401–405
     • View In Article
     • MEDLINE
     • CrossRef
263. Walker EA, Gelfand AN, Gelfand MD, Katon WJ. Psychiatric diagnoses, sexual and physical victimization, and disability in patients with irritable bowel syndrome or inflammatory bowel disease. Psychol Med. 1995;25:1259–1267
     • View In Article
     • MEDLINE
     • CrossRef
264. Irwin C, Falsetti SA, Lydiard RB, Ballenger JC, Brock CD, Brener W. Comorbidity of posttraumatic stress disorder and irritable bowel syndrome. J Clin Psychiatry. 1996;57:576–578
     • View In Article
     • MEDLINE
     • CrossRef
265. Drossman DA. Review article: an integrated approach to the irritable bowel syndrome. Aliment Pharmacol Ther. 1999;13(suppl 2):3–14
     • View In Article
     • CrossRef
266. Svedlund J. Psychotherapy in irritable bowel syndrome: a controlled outcome study. Acta Psychiatr Scand. 1983;67(suppl 306):1–86
     • View In Article
     • MEDLINE
     • CrossRef
267. Creed FH, Fernandes L, Guthrie E, Palmer S, Ratcliffe J, Read N, et al. The cost-effectiveness of psychotherapy and SSRI antidepressants for severe irritable bowel syndrome. Gastroenterology. 2001;120:A115; (abstr)
     • View In Article
     • Full-Text PDF (178 KB)
     • CrossRef
268. Bennett P, Wilkinson S. A comparison of psychological and medical treatment of the irritable bowel syndrome. Br J Clin Psychol. 1985;24:215–216
     • View In Article
     • CrossRef
269. Greene B, Blanchard EB. Cognitive therapy for irritable bowel syndrome. J Consult Clin Psychol. 1994;62:576–582
     • View In Article
     • MEDLINE
     • CrossRef
270. van Dulmen AM, Fennis JFM, Bleijenberg G. Cognitive-behavioral group therapy for irritable bowel syndrome: effects and long-term follow-up. Psychosom Med. 1996;58:508–514
     • View In Article
     • MEDLINE
271. Heymann-Mönnikes I, Arnold R, Florin I, Herda C, Melfsen S, Mönnikes H. The combination of medical treatment plus multicomponent behavioral therapy is superior to medical treatment alone in the therapy of irritable bowel syndrome. Am J Gastroenterol. 2000;95:981–994
     • View In Article
     • MEDLINE
     • CrossRef
272. Voirol MW, Hipolito J. Anthropo-analytical relaxation in irritable bowel syndrome: results 40 months later. Schweiz Med Wochenschr. 1987;117:1117–1119
     • View In Article
     • MEDLINE
273. Shaw G, Srivastava ED, Sadlier M, Swann P, James JY, Rhodes J. Stress management for irritable bowel syndrome: a controlled trial. Digestion. 1991;50:36–42
     • View In Article
     • MEDLINE