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Common Functional Gastroenterological Disorders Associated With Abdominal Pain

      Abstract

      Although abdominal pain is a symptom of several structural gastrointestinal disorders (eg, peptic ulcer disease), this comprehensive review will focus on the 4 most common nonstructural, or functional, disorders associated with abdominal pain: functional dyspepsia, constipation-predominant and diarrhea-predominant irritable bowel syndrome, and functional abdominal pain syndrome. Together, these conditions affect approximately 1 in 4 people in the United States. They are associated with comorbid conditions (eg, fibromyalgia and depression), impaired quality of life, and increased health care utilization. Symptoms are explained by disordered gastrointestinal motility and sensation, which are implicated in various peripheral (eg, postinfectious inflammation and luminal irritants) and/or central (eg, stress and anxiety) factors. These disorders are defined and can generally be diagnosed by symptoms alone. Often prompted by alarm features, selected testing is useful to exclude structural disease. Identifying the specific diagnosis (eg, differentiating between functional abdominal pain and irritable bowel syndrome) and establishing an effective patient-physician relationship are the cornerstones of therapy. Many patients with mild symptoms can be effectively managed with limited tests, sensible dietary modifications, and over-the-counter medications tailored to symptoms. If these measures are not sufficient, pharmacotherapy should be considered for bowel symptoms (constipation or diarrhea) and/or abdominal pain; opioids should not be used. Behavioral and psychological approaches (eg, cognitive behavioral therapy) can be helpful, particularly in patients with chronic abdominal pain who require a multidisciplinary pain management program without opioids.

      Abbreviations and Acronyms:

      DD (defecatory disorder), GI (gastrointestinal), 5-HT (5-hydroxytryptamine), IBS (irritable bowel syndrome), NBS (narcotic bowel syndrome), OBD (opioid bowel dysfunction), OIC (opioid-induced constipation), SNRI (serotonin and norepinephrine reuptake inhibitor), SSRI (selective serotonin reuptake inhibitor), TCA (tricyclic antidepressant)
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      Learning Objectives: On completion of this article, you should be able to: (1) recall the epidemiology of gastroenterological disorders associated with abdominal pain; (2) evaluate clinical features to make a precise clinical diagnosis; and (3) select appropriate diagnostic tests and therapeutic options.
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      Questions? Contact [email protected] .
      This review will focus on nonstructural, or functional, rather than structural (eg, peptic ulcer disease and ulcerative colitis) gastrointestinal (GI) disorders associated with abdominal pain.
      • Drossman D.A.
      Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV.
      Symptoms provide the basis for classifying the functional disorders, which affect the entire GI tract (Figure 1). Many physicians refer to these conditions with the umbrella term irritable bowel syndrome (IBS). It is critical to recognize that although these conditions share several features, they can and should be distinguished from each other primarily on the basis of the nature of symptoms (Figure 2). These specific diagnoses are not only more precise but also facilitate management, which is tailored to the specific symptoms. This review will focus on the 4 most common functional disorders associated with abdominal pain: functional dyspepsia, constipation-predominant and diarrhea-predominant IBS, and functional abdominal pain syndrome.
      Figure thumbnail gr1
      Figure 1Common functional gastrointestinal disorders. These disorders are defined by specific criteria but often coexist. Conditions associated with pain are marked with an asterisk.
      Figure thumbnail gr2
      Figure 2Diagnostic criteria and algorithm for common functional gastrointestinal disorders associated with abdominal pain. This algorithm applies the Rome criteria, which are widely used in research studies. Irritable bowel syndrome (IBS) is defined by abdominal pain accompanied by 2 of these 3 criteria: relief with defecation, altered stool consistency (loose or hard stools), or altered frequency (less or more frequent). The other syndromes are defined by the listed criteria. The criteria also specify the duration and frequency of symptoms: in general, a duration of 6 months and a frequency of 2 days every week or more often.

      Methods

      We searched MEDLINE on the PubMed and Ovid platforms, as well as the Cochrane Database of Systematic Reviews, using the keywords abdominal pain, chronic abdominal pain, abdominal wall pain, visceral pain, narcotic bowel, and functional abdominal pain for English-language articles with no date restrictions. Search terms were cross-referenced with review articles, and additional articles were identified by manually searching reference lists.

      Epidemiology and Natural Course

      In North America, approximately 20% of adults have symptoms of dyspepsia and 10% to 15% have symptoms of IBS.
      • Saito Y.A.
      • Schoenfeld P.
      • Locke III, G.R.
      The epidemiology of irritable bowel syndrome in North America: a systematic review.
      • Talley N.J.
      • Ford A.C.
      Functional dyspepsia.
      Among the latter, approximately 5% each have diarrhea- and constipation-predominant IBS, which are more common in men and women, respectively.
      • Saito Y.A.
      • Schoenfeld P.
      • Locke III, G.R.
      The epidemiology of irritable bowel syndrome in North America: a systematic review.
      By comparison, the prevalence of functional abdominal pain is much lower (0.5%-1.7%).
      • Clouse R.E.
      • Mayer E.A.
      • Aziz Q.
      • et al.
      Functional abdominal pain syndrome.
      Even this figure is probably an overestimate, because the definition of functional abdominal pain in these studies did not incorporate all the criteria for functional abdominal pain syndrome, such as the loss of daily function associated with the pain. Most cases of IBS are diagnosed by primary care specialists.
      • Locke III, G.R.
      • Yawn B.P.
      • Wollan P.C.
      • Melton III, L.J.
      • Lydick E.
      • Talley N.J.
      Incidence of a clinical diagnosis of the irritable bowel syndrome in a United States population.
      It is not uncommon for patients to simultaneously have symptoms of 2 or more disorders (eg, dyspepsia and constipation).
      • Locke III, G.R.
      • Zinsmeister A.R.
      • Fett S.L.
      • Melton III, L.J.
      • Talley N.J.
      Overlap of gastrointestinal symptom complexes in a US community.
      The severity and nature of symptoms vary with time. Over the long term, symptoms were unchanged in 50%, worse in approximately 20%, and improved in 30% of patients with IBS seen in clinics.
      • El-Serag H.B.
      • Pilgrim P.
      • Schoenfeld P.
      Systemic review: natural history of irritable bowel syndrome.
      In the general population, approximately 20% of patients with IBS had the same symptoms, 40% had no symptoms, and 40% had different symptoms at follow-up 12 years later.
      • Halder S.L.
      • Locke III, G.R.
      • Schleck C.D.
      • Zinsmeister A.R.
      • Melton III, L.J.
      • Talley N.J.
      Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study.
      The nature of symptoms may change over time, most frequently from constipation- or diarrhea-predominant IBS to mixed type or vice versa.
      • Garrigues V.
      • Mearin F.
      • Badia X.
      • et al.
      RITMO Group
      Change over time of bowel habit in irritable bowel syndrome: a prospective, observational, 1-year follow-up study (RITMO study).
      In postinfectious IBS, the prognosis is better; symptoms resolve in approximately 50% of patients after 6 to 8 years.
      • Spiller R.
      • Lam C.
      An update on post-infectious irritable bowel syndrome: role of genetics, immune activation, serotonin and altered microbiome.

      Relevant Anatomy, Physiology, and Pathophysiology

      Clinically Oriented Introduction to GI Motor and Sensory Functions

      Motility is regulated by coordinated neurohormonal mechanisms that affect smooth muscle contractility.
      • Camilleri M.
      Integrated upper gastrointestinal response to food intake.
      Gut motor activity is primarily controlled by the intrinsic or enteric nervous system. The central nervous system modulates gut motor activity via the extrinsic sympathetic and parasympathetic pathways, whereas descending pathways in the spinal cord modulate transmission of sensory input from the dorsal horn to supraspinal centers. Visceral sensation is conveyed via afferents that travel to the spinal cord and ultimately to the cerebral cortex, as well as through the vagus to the brainstem. There is a 10:1 ratio of afferent to efferent fibers in the vagus at the level of the diaphragm. The vagus primarily conveys subnoxious messages, whereas the spinal afferents convey nonnoxious and noxious input
      • Sengupta J.N.
      • Kauvar D.
      • Goyal R.K.
      Characteristics of vagal esophageal tension-sensitive afferent fibers in the opossum.
      to the dorsal horn of the spinal cord. Thereafter, information is conveyed via the spinothalamic tract to the medial and posterior thalamus and subsequently to the primary somatosensory cortex, which localizes and discriminates somatic and visceral sensations.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      The spinoreticular and spinomesencephalic tracts project to the brainstem reticular formation and medulla from which information is conveyed to the medial thalamus and the anterior cingulate cortex and insula. These areas process the affective-motivational aspects of pain.
      Descending inhibitory fibers from the anterior cingulate cortex to the dorsal horn of the spinal cord use endogenous opioids, serotonin, and noradrenaline to modulate or gate visceral sensation, including pain, such that only some messages from the viscera are conveyed to higher centers (Figure 3).
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      Figure thumbnail gr3
      Figure 3Pathogenesis of common functional gastrointestinal (GI) disorders. Left panel shows that genetic predisposition and psychological factors contribute to various GI sensory and motor dysfunctions that contribute to symptoms. Center panel shows some factors (eg, bile acids and postinfectious inflammation) that alter mucosal permeability, stimulate enterochromaffin cells, and activate immune mechanisms to stimulate afferent nerves. Right panel shows central sensitization may result from this peripheral sensitization and/or reduced descending inhibition, which normally gates visceral sensation in the spinal cord. ? = controversial.

      Pathogenesis of Symptoms

      Current concepts suggest that the functional GI disorders result from the combined effect of biological, psychological, and social factors (ie, the biopsychosocial model). Exemplifying this model, postinfectious IBS, which occurs after the infection resolves in 4% to 40% of patients with infectious gastroenteritis,
      • Spiller R.
      • Lam C.
      An update on post-infectious irritable bowel syndrome: role of genetics, immune activation, serotonin and altered microbiome.
      is more likely to occur after severe or prolonged gastroenteritis in women older than 60 years, smokers, and patients with anxiety, depression, hypochondriasis, or an adverse life event in the preceding 3 months.
      • Spiller R.
      • Lam C.
      An update on post-infectious irritable bowel syndrome: role of genetics, immune activation, serotonin and altered microbiome.
      The following factors have been implicated in the pathogenesis of functional GI disorders.

      Luminal Irritants

      Luminal irritants primarily include bile acids, nonabsorbed complex carbohydrates, and the products of their bacterial metabolism (ie, short chain fatty acids).
      • Camilleri M.
      Peripheral mechanisms in irritable bowel syndrome.
      Bile acids
      • Bampton P.A.
      • Dinning P.G.
      • Kennedy M.L.
      • Lubowski D.Z.
      • Cook I.J.
      The proximal colonic motor response to rectal mechanical and chemical stimulation.
      and short chain fatty acids activate secretion of enteroendocrine cell products (eg, 5-hydroxytryptamine [5-HT]) and stimulate colonic motility and defecation. Enteric microbiota, including both commensal and pathogenic organisms, also communicates with the host.
      • Rhee S.H.
      • Pothoulakis C.
      • Mayer E.A.
      Principles and clinical implications of the brain-gut-enteric microbiota axis.

      Increased Visceral Sensitivity

      Increased visceral sensitivity is documented with increased perception of GI (eg, rectal) balloon distention. Healthy people have little awareness of GI physiological processes except for the sensation of postprandial fullness after a satiating meal or the desire to defecate. Increased sensitivity refers to an exaggerated awareness of normal events and differs from hyperalgesia, in which painful stimuli evoke more pain than usual, or allodynia, which refers to perception of nonnoxious stimuli as being painful. Increased sensitivity may be due to sensitization of peripheral afferent receptors or spinal dorsal horn neurons, alterations in descending modulation, or central amplification.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      Sensitization of peripheral receptors may be secondary to low-grade inflammation, which activates silent nociceptors and increases the sensitivity and field of peripheral receptors. Peripheral sensitization may increase afferent input to the dorsal horn, causing central sensitization. Exemplifying this phenomenon, acid infusion in the distal esophagus causes hyperalgesia not only in the acid-exposed distal esophagus but also in the unexposed proximal esophagus.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      Repeated distention of the sigmoid colon causes rectal hyperalgesia.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      Central amplification or sensitization is the hallmark of fibromyalgia.
      • Clauw D.J.
      Fibromyalgia and Related Conditions.
      The central mechanisms (eg, reduced descending modulation or central amplification) (Figure 3) that may explain increased visceral sensitivity have been evaluated in fibromyalgia and IBS.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      • Clauw D.J.
      Fibromyalgia and Related Conditions.

      Normal and Disordered GI Motility

      Disordered GI motility may contribute to symptoms. Normally, the stomach relaxes or accommodates after a meal, providing room for food to be digested into smaller particles. Impaired gastric accommodation may explain postprandial symptoms (eg, early fullness or satiety) in functional dyspepsia.
      • Camilleri M.
      Integrated upper gastrointestinal response to food intake.
      The colonic response to feeding, or gastrocolonic response, refers to reflex contraction of the distal small intestine and colon in response to nutrients in the stomach and small intestine. This reflex, which is mediated by afferent vagal pathways and efferent sacral parasympathetic pathways, explains why healthy people experience the desire to defecate after eating. An exaggerated response may explain postprandial discomfort and diarrhea in patients with diarrhea-predominant IBS. The contractile response to colonic distention may also evoke abdominal discomfort. Indeed, the perception of distention may be due to the contractile response to distention rather than distention per se.
      Decreased motility may affect the stomach, small intestine, and/or colon; delay GI transit; and explain symptoms.
      • Bharucha A.E.
      • Pemberton J.H.
      • Locke III, G.R.
      American Gastroenterological Association technical review on constipation.
      For example, opioids markedly delay colonic transit and may predispose to colonic retention of stool, colonic distention, and abdominal distention. Pelvic floor dysfunction (ie, a disturbance in the normal rectoanal coordination during defecation) may impair rectal evacuation of stool, which also predisposes to rectal and colonic distention with stool and similar symptoms.

      Hormonal and Other Chemical Mediators

      Serotonin, which is released from enterochromaffin cells, initiates the peristaltic reflex and activation of extrinsic vagal and spinal afferents that activate extrinsic reflexes and sensation.
      • Camilleri M.
      Integrated upper gastrointestinal response to food intake.
      This reflex involves excitatory (eg, acetylcholine and tachykinins) and inhibitory (primarily vasoactive intestinal pepide and nitric oxide) neurotransmitters. Irritable bowel syndrome is associated with serotonergic disturbances.
      • Mawe G.M.
      • Hoffman J.M.
      Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets.
      Ingestion of calories stimulates the release of hormones such as cholecystokinin and glucagon-like peptide-1, which stimulate vagal afferents and mediate postprandial symptoms such as nausea and satiety.
      • Camilleri M.
      Integrated upper gastrointestinal response to food intake.

      Abdominal Wall Accommodation

      Normally, meal ingestion is accompanied by relaxation of the diaphragm (ie, diaphragmatic ascent), which provides extra space in the upper abdominal cavity, and compensatory contraction of the upper anterior abdominal wall, which prevents abdominal distention in the upright position.
      • Burri E.
      • Cisternas D.
      • Villoria A.
      • et al.
      Abdominal accommodation induced by meal ingestion: differential responses to gastric and colonic volume loads.
      In contrast, patients with dyspepsia have aberrant abdominal accommodation characterized by paradoxical contraction of the diaphragm (ie, diaphragmatic descent) and relaxation of the upper anterior abdominal wall, which increases abdominal girth.
      • Accarino A.
      • Perez F.
      • Azpiroz F.
      • Quiroga S.
      • Malagelada J.R.
      Abdominal distention results from caudo-ventral redistribution of contents.
      Similar disturbances (ie, diaphragmatic contraction and relaxation of the lower rectus and internal oblique) have been observed during intestinal gas infusion in IBS and functional bloating.
      • Barba E.
      • Burri E.
      • Accarino A.
      • et al.
      Abdominothoracic mechanisms of functional abdominal distension and correction by biofeedback.

      Psychosocial Factors

      Early life experiences (eg, verbal, sexual, or physical abuse), adult stressors (eg, divorce or bereavement), lack of social support, and other social learning experiences can affect an individual's physiological and psychological responses. The changes in these responses can lead to maladaptive earned-illness behaviors
      • Chitkara D.K.
      • van Tilburg M.A.
      • Blois-Martin N.
      • Whitehead W.E.
      Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review.
      and predispose to functional GI and psychiatric disorders.
      • Choung R.S.
      • Locke III, G.R.
      • Zinsmeister A.R.
      • Schleck C.D.
      • Talley N.J.
      Psychosocial distress and somatic symptoms in community subjects with irritable bowel syndrome: a psychological component is the rule.
      Women with IBS are more likely to have experienced abuse.
      • Drossman D.A.
      Abuse, trauma, and GI illness: is there a link?.
      These experiences may affect the brain-gut axis and lead to increased visceral sensitivity. Earlier studies suggested that psychosocial factors affect illness behavior (ie, the decision to seek care and excessive expressions of suffering) rather than symptoms per se. More recent studies suggest that psychological disturbances are common even among people with IBS in the community, many of whom have not sought medical attention.
      • Choung R.S.
      • Locke III, G.R.
      • Zinsmeister A.R.
      • Schleck C.D.
      • Talley N.J.
      Psychosocial distress and somatic symptoms in community subjects with irritable bowel syndrome: a psychological component is the rule.
      Whether psychological and somatic symptoms (eg, chronic fatigue and fibromyalgia) reflect the shared expression of a common substrate or whether they cause each other is unknown. Somatization, hypervigilance, and catastrophizing amplify GI and non-GI symptoms in patients with IBS.
      • Keefer L.
      • Mandal S.
      The potential role of behavioral therapies in the management of centrally mediated abdominal pain.

      Clinical Features

      Characteristics of Pain, Physical Examination, and Associated Conditions

      The location of pain may suggest its origin; for example, postprandial epigastric pain likely originates from the stomach. The pattern of pain, particularly its relationship to meals, and associated symptoms are also useful. Patients with dyspepsia, which is derived from the Greek word for indigestion, have pain that occurs shortly (eg, within 60 minutes) after meals, often associated with upper GI symptoms such as nausea, bloating, early satiety, or heartburn (Figure 2). However, dyspepsia is not associated with disordered bowel habits. In contrast, patients with IBS have intermittent abdominal pain, often related to meals. Moreover, the abdominal pain is associated with 2 of these 3 features: improvement with defecation, harder and/or less frequent stools in constipation-predominant IBS, and the opposite in diarrhea-predominant IBS. Some patients with functional constipation and diarrhea also have abdominal pain; however, the pain is not temporally associated with bowel symptoms.
      On physical examination, patients may have tenderness to abdominal palpation, but not guarding or rigidity. The absence of features of autonomic arousal (eg, tachycardia) when patients report severe pain suggests a functional rather than a structural disorder. When the abdomen is palpated, patients with functional pain might wince with their eyes closed (closed eyes sign) whereas patients with an acute abdominal pain episode usually keep their eyes open in anxious anticipation. When the abdomen is palpated with a stethoscope, the behavioral response to pain decreases in functional but increases in acute causes of abdominal pain (stethoscope sign).
      • Sperber A.D.
      • Drossman D.A.
      Review article: the functional abdominal pain syndrome.
      In patients with constipation, stool may be palpable in the colon.
      Somatic symptoms (eg, chronic fatigue, fibromyalgia, and cardiopulmonary symptoms) that are not due to an organic disorder and psychiatric disorders (major depression, anxiety, and somatization) are also common in patients with IBS.
      • Choung R.S.
      • Locke III, G.R.
      • Zinsmeister A.R.
      • Schleck C.D.
      • Talley N.J.
      Psychosocial distress and somatic symptoms in community subjects with irritable bowel syndrome: a psychological component is the rule.
      • Chey W.D.
      • Kurlander J.
      • Eswaran S.
      Irritable bowel syndrome: a clinical review.
      • Drossman D.A.
      • Camilleri M.
      • Mayer E.A.
      • Whitehead W.E.
      AGA technical review on irritable bowel syndrome.
      In patients with chronic abdominal pain, the prevalence of depression and impaired overall functioning is comparable with that in patients with chronic back pain.
      • Townsend C.O.
      • Sletten C.D.
      • Bruce B.K.
      • Rome J.D.
      • Luedtke C.A.
      • Hodgson J.E.
      Physical and emotional functioning of adult patients with chronic abdominal pain: comparison with patients with chronic back pain.
      Hence, all patients with moderate or severe symptoms should be screened for psychiatric symptoms and illness-related disability either during the interview or, perhaps more efficiently, with a screening questionnaire (eg, Generalized Anxiety Disorder-7 or Patient Health Questionnaire-9, Health Anxiety Inventory, and Sheehan Disability Scale). Physicians should also inquire about the relationship of stressors to symptoms; a history of sexual and/or physical abuse, which often is not volunteered by patients; and the presence of social support networks, which are often limited, resulting in maladaptive strategies (eg, catastrophizing thoughts and frustration) to cope with symptoms. The physical and mental quality of life in patients with severe IBS is comparable to or worse than that in patients with severe chronic obstructive lung disease or congestive heart failure.
      • Creed F.
      • Ratcliffe J.
      • Fernandez L.
      • et al.
      Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome.
      • Smith B.
      • Forkner E.
      • Zaslow B.
      • et al.
      Disease management produces limited quality-of-life improvements in patients with congestive heart failure: evidence from a randomized trial in community-dwelling patients.
      • Ståhl E.
      • Lindberg A.
      • Jansson S.A.
      • et al.
      Health-related quality of life is related to COPD disease severity.
      The mental distress is less severe than in patients with severe depression but worse than in patients with cancer.
      • Coulehan J.L.
      • Schulberg H.C.
      • Block M.R.
      • Madonia M.J.
      • Rodriguez E.
      Treating depressed primary care patients improves their physical, mental, and social functioning.
      • Aaronson N.K.
      • Muller M.
      • Cohen P.D.
      • et al.
      Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations.

      Other Conditions

      Musculoskeletal Abdominal Pain

      In contrast to visceral abdominal pain, musculoskeletal abdominal pain is sharp, localized to an area of the abdominal wall usually smaller than 2 cm, and associated with Carnett sign.
      • Costanza C.D.
      • Longstreth G.F.
      • Liu A.L.
      Chronic abdominal wall pain: clinical features, health care costs, and long-term outcome.
      Patients with abdominal wall pain are likely to be women, are often obese, and have painful comorbid conditions (eg, IBS and functional dyspepsia). Carnett sign is elicited by palpating the abdomen before and during contraction of the abdominal muscles (eg, by raising the head from the bed without using the arms); abdominal wall pain and visceral abdominal pain are characterized by more and less pain, respectively, during than before contraction. A positive Carnett sign has a diagnostic accuracy of 97% for abdominal wall pain.
      • Greenbaum D.S.
      • Greenbaum R.B.
      • Joseph J.G.
      • Natale J.E.
      Chronic abdominal wall pain. Diagnostic validity and costs.
      Conversely, less than 10% of patients with visceral pain had a positive Carnett sign.
      • Gray D.W.
      • Dixon J.M.
      • Seabrook G.
      • Collin J.
      Is abdominal wall tenderness a useful sign in the diagnosis of non-specific abdominal pain?.

      Opioid Bowel Dysfunction, Opioid-Induced Constipation, and Narcotic Bowel Syndrome

      These conditions can occur with opioid use for any intra-abdominal or extra-abdominal disease.
      • Kurlander J.E.
      • Drossman D.A.
      Diagnosis and treatment of narcotic bowel syndrome.
      Opioid bowel dysfunction (OBD) comprises the full spectrum of peripheral, μ-opioid receptor–mediated GI adverse effects, including anorexia, nausea, vomiting, gastroparesis, biliary pain, gastroesophageal reflux, constipation (ie, opioid-induced constipation [OIC]), ileus, pseudo-obstruction, abdominal bloating, and straining. In contrast, narcotic bowel syndrome (NBS) is characterized by incompletely controlled abdominal pain that cannot be explained by another known or previous diagnosis in patients receiving steady or increasing doses of opioids. In contrast to OBD, NBS is mediated by centrally mediated visceral hyperalgesia rather than GI dysmotility. Approximately 50% to 60% of patients on opioid therapy have OBD, 40% have OIC, and 5% have NBS. Narcotic bowel syndrome may coexist with OBD and OIC.

      Structural Diseases

      Functional and structural diseases may coexist. For example, persistent abdominal pain in patients with quiescent inflammatory bowel disease likely reflects a coexistent functional GI disorder. Alarm features (ie, symptom onset after age 50 years; severe or progressive symptoms; unexplained weight loss; nocturnal pain or diarrhea; family history of organic GI diseases, including colon cancer, celiac disease, or inflammatory bowel disease; rectal bleeding or anemia; and unexplained iron deficiency anemia) should increase the index of suspicion for structural diseases. However, many patients with structural disease do not have alarm symptoms.

      Diagnostic Testing

      Diagnostic testing should be limited and tailored to the clinical features, alarm symptoms, symptom severity, and response to previous therapy (Figure 4). Absent alarm features, symptoms generally suffice to diagnose functional GI disorders.
      • Chey W.D.
      • Kurlander J.
      • Eswaran S.
      Irritable bowel syndrome: a clinical review.
      Although alarm features may prompt additional testing, most patients with alarm features will have negative test results. After a negative evaluation for structural lesions, the risk is less than 5% that a patient with diagnosed IBS will have a structural disease diagnosed in the future.
      • El-Serag H.B.
      • Pilgrim P.
      • Schoenfeld P.
      Systemic review: natural history of irritable bowel syndrome.
      A complete blood cell count should be checked in all patients. Some guidelines recommend consideration of a blood test (eg, tissue transglutaminase antibodies) or duodenal mucosal biopsies to diagnose celiac disease, given the potential long-term consequences of missing this diagnosis.
      • Chey W.D.
      • Kurlander J.
      • Eswaran S.
      Irritable bowel syndrome: a clinical review.
      Contradicting this recommendation, the prevalence of celiac disease was lower in patients with IBS than in patients without IBS in a US population.
      • Choung R.S.
      • Rubio-Tapia A.
      • Lahr B.D.
      • et al.
      Evidence against routine testing of patients with functional gastrointestinal disorders for celiac disease: a population-based study.
      Abdominal pain and diarrhea occur in inflammatory bowel disease as well as in IBS, but rectal bleeding and systemic symptoms are much more common in inflammatory bowel disease. In a prospective study,
      • Chey W.D.
      • Nojkov B.
      • Rubenstein J.H.
      • Dobhan R.R.
      • Greenson J.K.
      • Cash B.D.
      The yield of colonoscopy in patients with non-constipated irritable bowel syndrome: results from a prospective, controlled US trial.
      inflammatory bowel disease was later diagnosed in less than 1% of patients with IBS symptoms and in no controls. Noninvasive biomarker testing is a cost-effective approach to screen for inflammatory bowel disease. When the C-reactive protein level is less than 5 mg/L or the fecal calprotectin level is less than 40 μg/g, the risk of inflammatory bowel disease is less than 1% in patients with typical IBS symptoms.
      • Chey W.D.
      • Kurlander J.
      • Eswaran S.
      Irritable bowel syndrome: a clinical review.
      A minority of patients with diarrhea-predominant IBS have microscopic colitis, especially patients older than 50 years or those who have nocturnal stools, weight loss, shorter duration of diarrhea, recent introduction of new drugs, or comorbid autoimmune diseases.
      • Macaigne G.
      • Lahmek P.
      • Locher C.
      • et al.
      Microscopic colitis or functional bowel disease with diarrhea: a French prospective multicenter study.
      Figure thumbnail gr4
      Figure 4Multidisciplinary management of functional gastrointestinal (GI) disorders. After a meticulous clinical assessment, many patients with mild symptoms can be effectively managed with limited tests, sensible dietary modifications, and over-the-counter (OTC) medications tailored to symptoms. Gastrointestinal endoscopy and imaging should be performed only when indicated. Behavioral and psychological approaches can be helpful, particularly in patients with chronic abdominal pain who require a multidisciplinary pain management program without opioids. CBC = complete blood cell count; TCA = tricyclic antidepressant.
      In patients with constipation, colorectal cancer and, more importantly, pelvic floor dysfunction (ie, defecatory disorders [DDs]) should be considered. Absent concerning features, less than 1% of patients with typical constipated IBS have colorectal cancer, which is not greater than in asymptomatic controls. Hence, only age-appropriate colorectal cancer screening is required.
      • Nørgaard M.
      • Farkas D.K.
      • Pedersen L.
      • et al.
      Irritable bowel syndrome and risk of colorectal cancer: a Danish nationwide cohort study.
      • Hsiao C.W.
      • Huang W.Y.
      • Ke T.W.
      • et al.
      Association between irritable bowel syndrome and colorectal cancer: a nationwide population-based study.
      Defecatory disorders, which are attributed to the dyscoordination among the abdominal wall, anal sphincter, and pelvic floor muscles during defecation, are a common but underrecognized cause of constipation and abdominal symptoms such as pain, discomfort, and bloating.
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      • Wald A.
      • Bharucha A.E.
      • Cosman B.C.
      • Whitehead W.E.
      ACG clinical guideline: management of benign anorectal disorders.
      Although selected symptoms (eg, the need for digital maneuvers to facilitate defecation) and a meticulous rectal examination may suggest DDs, anorectal testing is necessary to diagnose DDs, which are appropriately managed with pelvic floor retraining through biofeedback therapy rather than with laxatives. Hence, patients with constipation unresponsive to laxatives should be referred for evaluation of rectoanal dysfunction with a digital rectal examination, anorectal manometry, balloon expulsion testing, or anorectal imaging.
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      • Wald A.
      • Bharucha A.E.
      • Cosman B.C.
      • Whitehead W.E.
      ACG clinical guideline: management of benign anorectal disorders.
      Mechanical small bowel obstruction generally presents with acute or recurrent acute symptoms rather than constant abdominal pain. Although adhesions and chronic abdominal pain may occur concurrently after surgery, whether adhesions cause pain is debatable.
      • ten Broek R.P.
      • Bakkum E.A.
      • Laarhoven C.J.
      • van Goor H.
      Epidemiology and prevention of postsurgical adhesions revisited.
      Rare causes of intermittent or chronic abdominal pain include hereditary angioedema, acute intermittent porphyria, and endometriosis.
      • Zuraw B.L.
      Clinical practice: hereditary angioedema.
      • Besur S.
      • Hou W.
      • Schmeltzer P.
      • Bonkovsky H.L.
      Clinically important features of porphyrin and heme metabolism and the porphyrias.
      Endometriosis is identified in up to 80% of women presenting with chronic pelvic pain (defined as noncyclic lower abdominal pain lasting for at least 6 months). It typically presents with perimenstrual lower abdominal pain and dyspareunia; dysuria, urgency, and hematuria are other symptoms. The diagnosis is confirmed by laparoscopy-guided biopsy.
      • Butrick C.W.
      Patients with chronic pelvic pain: endometriosis or interstitial cystitis/painful bladder syndrome?.

      Management

      Establishing an Effective Patient-Physician Relationship

      Many patients with functional GI disorders feel abandoned and undertreated and seek care from multiple doctors with limited success. Physicians caring for these patients may feel frustrated because of the lack of specific diagnostic tests and/or patient dissatisfaction. Therefore, it is essential to establish an effective patient-physician relationship by approaching patients' symptoms with empathy, reassuring patients that life-threatening medical conditions have been excluded after reasonable testing, educating them about the disease, setting reasonable expectations for treatment, and involving them in the management.

      Empathy

      Empathy involves an acknowledgment by the physician that the patient's symptoms and the disability are real (Table 1). Empathy increases patient satisfaction and adherence to recommendations.
      • Drossman D.A.
      Functional abdominal pain syndrome.
      Table 1Suggested Approaches When Caring for Patients With Chronic Abdominal Pain and Other Functional Gastrointestinal Disorders
      GoalPreferAvoid
      Express empathyAcknowledge patient suffering (eg, “I am sorry you feel this way…I can see that the pain has really affected your life. I will do my best to help you.”)Dismissing symptoms (eg, “There is nothing wrong with you.”)
      Assess the patient's insight into the functional nature of the painAsk open-ended questions (eg, “Can you tell me what you think is causing your symptoms?” or “Tell me about what concerns you the most about your symptoms.”)Closed-ended questions (eg, “Do you think your pain is caused by eating?”)
      Understand the patient's expectation from the physicianAsk open-ended questions (eg, “Tell me a little about what you were expecting from this consultation” or “I see that you have been suffering from pain for many years. Could you tell me a little bit about what made you come to see me today?”)Judgmental statements (eg, “I am not sure I can help you. You have been to so many doctors already.”)
      Understand the patient's expectations from treatment(s)Ask probing, open-ended questions (eg, “If I asked you what would be a reasonably tolerable pain level that we can try to achieve, what would you say?”)Imposing a treatment plan (eg, “My plan is to refer you to the psychiatrist and the pain specialist.”)
      Assess the patient's understanding of education provided by the physician“I provided you with quite a bit of information today and want to make sure you understood what I said. Can you tell me what you have understood so far?”Unilateral flow of information (eg, “I hope you understood all the things we discussed today and implement the suggestions I gave you.”)
      Help the patient take responsibility for the illnessSuggest that the patient keep a diary of symptoms for 3-4 wkPrescribing treatments in which the patient is a passive recipient

      Education

      Education entails assessing and increasing patients' understanding of the cause of their symptoms, explaining the benign nature of the disease, and addressing unrealistic expectations (Table 1). Providing analogies to other diseases (eg, arthritis and back pain) is useful to convey that chronic abdominal pain is unlikely to be “cured” but can often be improved. A brief explanation of the role of central sensitization may be helpful. This broader framework (ie, the biopsychosocial model) is more readily accepted by patients than the psychosomatic model, in which physical symptoms are attributed to mental or emotional problems rather than a physical illness. Education provided by a trained nurse in an individual or group setting is as effective as longer education programs or those involving specialists.
      • Ringström G.
      • Störsrud S.
      • Simrén M.
      A comparison of a short nurse-based and a long multidisciplinary version of structured patient education in irritable bowel syndrome.
      Interactive patient education was superior to self-education obtained from an IBS guidebook.
      • Ringström G.
      • Störsrud S.
      • Posserud I.
      • Lundqvist S.
      • Westman B.
      • Simrén M.
      Structured patient education is superior to written information in the management of patients with irritable bowel syndrome: a randomized controlled study.

      Helping the Patient Take Responsibility

      Engaging patients in their treatment increases the likelihood of success and improves patient and physician satisfaction.
      • Drossman D.A.
      Functional abdominal pain syndrome.
      A 2-week symptom diary may identify precipitating and alleviating factors and point to appropriate behavioral treatment strategies. This task should be done with the explicit understanding that it is intended for implementing change and not for uncovering some, as yet, undiscovered pathway of disease.

      Designing a Treatment Strategy on the Basis of Severity of Symptoms

      The approaches include dietary modification, pharmacotherapy, and behavioral or psychological therapy. These should be tailored to the symptoms and individual patient preferences and integrated whenever necessary.
      • Drossman D.A.
      Functional abdominal pain syndrome.
      For instance, lifestyle changes (eg, dietary advice) and psychological therapy may suffice for patients with mild symptoms related to dietary triggers or other stressors. Patients with severe, disabling symptoms will also typically require prescription medications and behavioral and/or psychological therapy (Figure 4).

      Dietary Measures

      Food triggers symptoms in most patients with IBS,
      • Lacy B.E.
      • Chey W.D.
      • Lembo A.J.
      New and emerging treatment options for irritable bowel syndrome.
      underscoring the importance of dietary modification. Although reducing fat intake seems sensible, fat has not been selectively eliminated in controlled clinical trials. Other food intolerances have been implicated, for example, to sugar alcohols (eg, mannitol, sorbitol, xylitol, maltitol, and erythritol), caffeine, and nonceliac gluten sensitivity. Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diets contain reduced content of these, and other ingredients may improve symptoms and have adverse effects.
      • Halmos E.P.
      • Christophersen C.T.
      • Bird A.R.
      • Shepherd S.J.
      • Gibson P.R.
      • Muir J.G.
      Diets that differ in their FODMAP content alter the colonic luminal microenvironment.
      A recent controlled trial
      • Böhn L.
      • Störsrud S.
      • Liljebo T.
      • et al.
      Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.
      observed that a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet was as effective as a sensible, frequently recommended diet for IBS; the latter is characterized by regular meals, avoidance of large meals, and reduced intake of fat, insoluble fiber, caffeine, and gas-producing foods, such as beans, cabbage, and onions.
      Dietary fiber supplementation with a soluble (eg, psyllium) but not an insoluble (eg, bran) fiber preparation is effective, and often the initial approach, for managing constipation (Table 2).
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      The dose should be increased gradually, and patients should be reminded that the effect may not be evident for up to 12 weeks. Probiotics (eg, VSL#3 and Bifidobacterium infantis) improve bloating and flatulence in IBS
      • Kim H.J.
      • Camilleri M.
      • McKinzie S.
      • et al.
      A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome.
      • Kim H.J.
      • Vazquez Roque M.I.
      • Camilleri M.
      • et al.
      A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating.
      • O'Mahony L.
      • McCarthy J.
      • Kelly P.
      • et al.
      Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.
      ; B infantis also improved abdominal pain and the ease of defecation, but not stool frequency or consistency.
      • O'Mahony L.
      • McCarthy J.
      • Kelly P.
      • et al.
      Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.
      Table 2Over-the-Counter and Prescription Treatments of Functional Bowel Disorders
      CC = chronic constipation; IBS = irritable bowel syndrome; IBS-C = irritable bowel syndrome of constipation type; IBS-D = irritable bowel syndrome of diarrhea type; NA = not available; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
      TreatmentNNT (95% CI)
      NNT indicates number needed to treat for IBS unless specified otherwise.
      Benefits and suggestions for use
      Over-the-counter agents
       Fiber: psyllium4.5, NA
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      ,
      NNT for IBS-C, chronic constipation.
      Begin with low dose and increase gradually. Effects are not as pronounced as for laxatives and manifest over time
       Laxatives: polyethylene glycolNA, 3 (2-4)
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      ,
      NNT for IBS-C, chronic constipation.
      More evidence for CC than IBS-C. Improved bowel symptoms but not abdominal pain in IBS-C
      • Chapman R.W.
      • Stanghellini V.
      • Geraint M.
      • Halphen M.
      Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome.
       Antidiarrheals: loperamideNABeneficial for diarrhea, but not abdominal pain in IBS-D
       Probiotics7 (4-12.5)
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      Studies used different species, strains, preparations, and doses in various patient populations; therefore, results are challenging to interpret. Possibly beneficial for bloating and flatulence
       Antispasmodics: peppermint oil3 (2-4)
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      Improves abdominal pain and global symptom relief
      Prescription medications
       Antidepressants: TCAs, SSRIs, and SNRIs4 (3-6)
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      Use TCAs for IBS-D and SSRIs for IBS-C
       Linaclotide7 (5-8), 6 (5-8)
      • Bharucha A.E.
      • Locke G.R.
      • Pemberton J.H.
      AGA practice guideline on constipation: technical review.
      • Videlock E.J.
      • Cheng V.
      • Cremonini F.
      Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.
      • Atluri D.K.
      • Chandar A.K.
      • Bharucha A.E.
      • Falck-Ytter Y.
      Effect of linaclotide in irritable bowel syndrome with constipation (IBS-C): a systematic review and meta-analysis.
      Improves abdominal pain, bloating, and global IBS symptoms in IBS-C
       Lubiprostone13, 4 (3-7)
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      Improves abdominal bloating, discomfort, constipation severity in opioid-induced constipation

      Spierings EL, Rauck R, Brewer R, Marcuard S, Vallejo R. Long-term safety and efficacy of lubiprostone in opioid-induced constipation in patients with chronic noncancer pain [published online ahead of print August 29, 2015]. Pain Pract doi:10.1111/papr.12347.

       PrucaloprideNA, 6 (5-9)
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      Not approved for use in the United States
       Antibiotics: rifaximin9 (6-12.5)
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      Improves global symptoms, bloating, and abdominal pain in IBS
       ClonidineNA
      • Camilleri M.
      • Kim D.Y.
      • McKinzie S.
      • et al.
      A randomized, controlled exploratory study of clonidine in diarrhea-predominant irritable bowel syndrome.
      Improves bowel symptoms in IBS-D
      Other therapies
       Psychological and behavioral therapies4 (35)
      • Ford A.C.
      • Talley N.J.
      • Schoenfeld P.S.
      • Quigley E.M.
      • Moayyedi P.
      Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.
      Cognitive behavioral therapy, hypnotherapy, dynamic psychotherapy, relaxation training, and multicomponent psychological therapy all improved global symptoms in IBS
      a CC = chronic constipation; IBS = irritable bowel syndrome; IBS-C = irritable bowel syndrome of constipation type; IBS-D = irritable bowel syndrome of diarrhea type; NA = not available; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
      b NNT indicates number needed to treat for IBS unless specified otherwise.
      c NNT for IBS-C, chronic constipation.

      Pharmacotherapy for Symptoms

      Visceral Pain

      Except for select indications (eg, managing intractable diarrhea when all other options have failed), opioids should not be used to manage functional GI symptoms because of the likelihood of abuse, dependency, and addiction and the adverse effects of opioids, particularly NBS.
      The pharmacotherapy of pain is often guided by associated symptoms (Table 2). Antidepressants enhance the sense of general well-being; may remedy the psychological comorbidity (eg, anxiety), which can amplify the pain experience; and facilitate central pain modulation, perhaps by increasing descending inhibition.
      • Törnblom H.
      • Drossman D.A.
      Centrally targeted pharmacotherapy for chronic abdominal pain.
      In addition, tricyclic antidepressants (TCAs) prolong and many selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) accelerate intestinal transit, which may be beneficial. A Cochrane meta-analysis
      • Ruepert L.
      • Quartero A.O.
      • de Wit N.J.
      • van der Heijden G.J.
      • Rubin G.
      • Muris J.W.
      Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome.
      observed that 59% of patients treated with antidepressants improved as compared with 39% of patients receiving placebo; the number needed to treat was 5. Tricyclic antidepressants are the first choice for patients with chronic abdominal pain. The initial dose is 10 to 50 mg/d, titrated to effectiveness and adverse effects up to a range of 25 to 150 mg/d. The dose should be increased only if necessary and as tolerated. In the largest controlled trial,
      • Drossman D.A.
      • Toner B.B.
      • Whitehead W.E.
      • et al.
      Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.
      desipramine (150 mg/d) was not significantly different (P=.16) from placebo for patients with moderate or severe functional bowel disorders. However, after the 25% of patients who had dropped out were excluded, desipramine was superior to placebo. Patients should be reassured that as in other painful medical conditions (eg, migraine and diabetic neuropathy), antidepressants are not being used for a psychiatric condition, but as central analgesic agents. Although adverse effects occur early, beneficial effects may take 4 to 6 weeks to appear. In addition, many symptoms attributed to adverse effects of desipramine often predated treatment, which suggests that they were not related to drug per se.
      • Thiwan S.
      • Drossman D.A.
      • Morris C.B.
      • et al.
      Not all side effects associated with tricyclic antidepressant therapy are true side effects.
      Selective serotonin reuptake inhibitors can reduce anxiety and depression and improve the sense of overall well-being. However, there are limited data to suggest that these drugs reduce abdominal pain, perhaps because, in contrast to TCAs and SNRIs, they do not have much noradrenergic effect. Adverse effects (eg, diarrhea, sexual dysfunction, and nightmares) are less common with SSRIs than with TCAs, which can be beneficial for patients who have a low threshold for adverse effects.
      Serotonin and norepinephrine reuptake inhibitors block norepinephrine and serotonin reuptake, which should reduce pain sensation.
      • Farmer A.D.
      • Aziz Q.
      Mechanisms and management of functional abdominal pain.
      They also have other beneficial effects; for example, venlafaxine reduced the colonic contractile response to a meal and also colonic perception of balloon distention.
      • Chial H.J.
      • Camilleri M.
      • Burton D.
      • Thomforde G.
      • Olden K.W.
      • Stephens D.
      Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health.
      Duloxetine is effective for treating peripheral diabetic neuropathic pain and fibromyalgia.
      • Lunn M.P.
      • Hughes R.A.
      • Wiffen P.J.
      Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.
      Despite a lack of evidence, SNRIs may be considered for patients with severe refractory abdominal pain. Because they lack anticholinergic and antihistamine adverse effects, SNRIs are mostly better tolerated than TCAs. When a single antidepressant is not helpful, augmentation therapy, such as multiple antidepressants, or combining an antidepressant with psychological treatment may be tried.
      • Sperber A.D.
      • Drossman D.A.
      Review article: the functional abdominal pain syndrome.
      Excess sedation can be reduced by lowering the dose of the tricyclic agent and/or by supplementing with an SSRI. A benzodiazepine agent or a low-dose TCA at bedtime can reduce “jitteriness” from an SSRI. For patients with dyspepsia and anxiety, the 5-HT1 agonist buspirone, an anxiolytic agent that improved gastric accommodation and reduced postprandial fullness and bloating, should be considered.
      • Chial H.J.
      • Camilleri M.
      • Burton D.
      • Thomforde G.
      • Olden K.W.
      • Stephens D.
      Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health.
      Pregabalin may be considered in patients with a general anxiety disorder or fibromyalgia and abdominal wall pain.
      • Sperber A.D.
      • Drossman D.A.
      Review article: the functional abdominal pain syndrome.

      Constipation

      In patients who do not have a DD, a stepwise approach beginning with dietary fiber supplementation and escalating as necessary to simple osmotic laxatives (eg, polyethylene glycol and milk of magnesia) and stimulant laxatives (eg, bisacodyl and senna) and then to a secretory agent (linaclotide or lubiprostone) is recommended (Table 2).
      • Bharucha A.E.
      • Dorn S.D.
      • Lembo A.
      • Pressman A.
      American Gastroenterological Association
      American Gastroenterological Association medical position statement on constipation.
      In each class, the alternative agent should be considered if one fails. Both lubiprostone and linaclotide increase intestinal secretion of fluids and electrolytes; linaclotide may also have antihyperalgesic effects.
      • Rao S.S.C.
      • Quigley E.M.M.
      • Shiff S.J.
      • et al.
      Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation.
      Among patients with constipation with severe abdominal symptoms (eg, bloating, fullness, discomfort, and pain), approximately 60% treated with linaclotide vs 30% treated with placebo reported adequate relief of IBS symptoms at week 12 of therapy.
      • Rao S.S.C.
      • Quigley E.M.M.
      • Shiff S.J.
      • et al.
      Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation.

      Diarrhea

      The initial options are loperamide, taken regularly or on demand (eg, 2 to 4 mg 30 minutes before meals, up to a maximum of 8 tablets daily), and anticholinergic agents such as diphenoxylate and amitriptyline; amitriptyline may also reduce rectal urgency.
      • Nee J.
      • Zakari M.
      • Lembo A.J.
      Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome.
      Up to 30% of patients with idiopathic diarrhea have idiopathic bile salt malabsorption, suggesting a role for bile acid–binding resins.
      • Nee J.
      • Zakari M.
      • Lembo A.J.
      Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome.
      • Bajor A.
      • Törnblom H.
      • Rudling M.
      • Ung K.A.
      • Simrén M.
      Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS.
      However, these drugs have not been evaluated in controlled clinical trials. Cholestyramine is inexpensive but often associated with bloating, which is not a common adverse effect with colesevelam. Eluxadoline, rifaximin, and alosetron are approved by the US Food and Drug Administration for treating diarrhea-predominant IBS.
      • Lembo A.J.
      • Lacy B.E.
      • Zuckerman M.J.
      • et al.
      Eluxadoline for irritable bowel syndrome with diarrhea.
      Alosetron is available under a restricted-use program.
      • Lembo A.J.
      • Lacy B.E.
      • Zuckerman M.J.
      • et al.
      Eluxadoline for irritable bowel syndrome with diarrhea.
      Clonidine, an α2-adrenergic agonist, improves fluid and electrolyte absorption and improved symptoms in a phase II study in diarrhea-predominant IBS
      • Camilleri M.
      • Kim D.Y.
      • McKinzie S.
      • et al.
      A randomized, controlled exploratory study of clonidine in diarrhea-predominant irritable bowel syndrome.
      ; clonidine also reduces the perception of colonic distention.
      • Bharucha A.E.
      • Camilleri M.
      • Zinsmeister A.R.
      • Hanson R.B.
      Adrenergic modulation of human colonic motor and sensory function.
      At a dose of 0.1 mg tablet twice daily, it is well tolerated, and adverse effects (eg, dry mouth, sedation, and hypotension) are uncommon.

      Abdominal Wall Pain

      Injection of a local anesthetic (eg, lidocaine and bupivacaine) with or without a corticosteroid (eg, methylprednisolone acetate) at the site of maximal tenderness is both diagnostic and therapeutic.
      • Boelens O.B.
      • Scheltinga M.R.
      • Houterman S.
      • Roumen R.M.
      Randomized clinical trial of trigger point infiltration with lidocaine to diagnose anterior cutaneous nerve entrapment syndrome.
      Other options, supported by limited evidence, include lidocaine patches,
      • Saber A.A.
      • Elgamal M.H.
      • Rao A.J.
      • Itawi E.A.
      • Martinez R.L.
      Early experience with lidocaine patch for postoperative pain control after laparoscopic ventral hernia repair.
      local application of heat, low-dose TCAs, and gabapentin.
      • Costanza C.D.
      • Longstreth G.F.
      • Liu A.L.
      Chronic abdominal wall pain: clinical features, health care costs, and long-term outcome.
      In a series,
      • Costanza C.D.
      • Longstreth G.F.
      • Liu A.L.
      Chronic abdominal wall pain: clinical features, health care costs, and long-term outcome.
      various approaches eased the pain in 47% of patients.

      Narcotic Bowel Syndrome

      Treatment requires withdrawal of narcotics, often in combination with medications to control withdrawal symptoms (eg, clonidine and lorazepam), and use of antidepressants (eg, paroxetine, desipramine, duloxetine, and cyclobenzaprine) to control visceral pain and decrease anxiety.
      • Grunkemeier D.M.
      • Cassara J.E.
      • Dalton C.B.
      • Drossman D.A.
      The narcotic bowel syndrome: clinical features, pathophysiology, and management.
      • Berna C.
      • Kulich R.J.
      • Rathmell J.P.
      Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice.

      Nausea and Vomiting

      Phenothiazines (eg, prochlorperazine) and antihistamine agents (including promethazine), which can be administered as a suspension or suppositories, should be tried initially,
      • Camilleri M.
      Peripheral mechanisms in irritable bowel syndrome.
      followed, when necessary, by serotonin 5-HT3 receptor antagonists (eg, ondansetron), which are more expensive. The neurokinin 1 receptor antagonist aprepitant is approved for treating emesis due to chemotherapy.

      Psychological and Behavioral Interventions

      These interventions are tailored to the symptoms, functional impairment, psychological distress, and symptom expression. Patients should be reassured that the goals are to manage pain, improve daily function, and relieve psychological distress.
      Cognitive behavioral therapy, which is the most effective psychological therapy for functional abdominal pain, is generally imparted by therapists, but can be self-administered by patients, with similar efficacy.
      • Lackner J.M.
      • Jaccard J.
      • Krasner S.S.
      • Katz L.A.
      • Gudleski G.D.
      • Holroyd K.
      Self-administered cognitive behavior therapy for moderate to severe irritable bowel syndrome: clinical efficacy, tolerability, feasibility.
      Cognitive behavioral therapy helps patients identify maladaptive thoughts, perceptions, and behaviors. Thereafter, they are taught to develop new approaches to increase control over their reactions and functioning, including an emphasis on stress management, decreasing illness behaviors, increasing social support, and more effective problem solving. Any intervention that enhances the ability to relax will give the patient a sense of control over symptoms and induce more parasympathetic activity. A recent meta-analysis
      • Laird K.T.
      • Tanner-Smith E.E.
      • Russell A.C.
      • Hollon S.D.
      • Walker L.S.
      Short-term and long-term efficacy of psychological therapies for irritable bowel syndrome: a systematic review and meta-analysis.
      of 41 trials involving 2290 patients observed that psychological therapy is moderately effective for improving IBS symptoms for up to 1 year after therapy. Cognitive behavioral therapy was effective whether it was administered in person or online, individually or in a group. The number, duration, and frequency of sessions did not affect its efficacy.
      Behavioral interventions targeted to specific symptoms can be useful. By activating the diaphragm, diaphragmatic breathing is a form of habit reversal training that serves as a competing response and thereby prevents belching, regurgitation, and vomiting.
      • Halland M.
      • Parthasarathy G.
      • Bharucha A.E.
      • Katzka D.A.
      Diaphragmatic breathing for rumination syndrome: efficacy and mechanisms of action.
      • Chitkara D.K.
      • Van Tilburg M.
      • Whitehead W.E.
      • Talley N.J.
      Teaching diaphragmatic breathing for rumination syndrome.
      Patients should begin diaphragmatic breathing at the onset of cues of belching and continue to engage the technique until the cues subside. Measures to prevent aerophagia (eg, cease drinking through a straw) should be emphasized in patients with belching.

      Multidisciplinary Pain Treatment Centers

      Comprehensive pain rehabilitation involves physical therapy, occupational therapy, and cognitive behavioral therapy in an intensive interdisciplinary outpatient setting. Most pain rehabilitation centers offer daily treatment for 2 to 4 weeks. The emphasis is on physical reconditioning and elimination of medications for pain and other symptoms (eg, benzodiazepines), along with activity management and behavior therapy.
      • Rome J.D.
      • Sletten C.D.
      • Bruce B.K.
      A rehabilitation approach to chronic pain in rheumatologic practice.
      Patients who benefit from this approach do so because of a change in their behavior, beliefs, and physical status. These programs are successful. In a study
      • Rome J.D.
      • Townsend C.O.
      • Bruce B.K.
      • Sletten C.D.
      • Luedtke C.A.
      • Hodgson J.E.
      Chronic noncancer pain rehabilitation with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission.
      of 356 patients with chronic pain (abdominal pain in 8%), 132 of 135 patients receiving opioids discontinued them after a pain rehabilitation program.

      Conclusion

      Identifying the precise phenotype, which is predominantly based on clinical features, is essential for appropriate and cost-effective diagnosis and treatment of nonstructural, or functional, GI disorders associated with abdominal pain. The need for and choice of diagnostic tests are guided by the clinical features and alarm symptoms. Testing should evaluate for conditions that are not widely recognized and are amenable to therapy (eg, pelvic floor dysfunction). Multidisciplinary treatment approaches that integrate dietary modification, pharmacotherapy, and behavioral or psychological therapy and are tailored to the symptoms should be considered. The focus is on improving symptoms and restoring quality of life.

      Supplemental Online Material

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      Linked Article

      • Misdiagnosis of Diverticulitis in Patients With Irritable Bowel Syndrome
        Mayo Clinic ProceedingsVol. 91Issue 11
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          Two articles published recently in Mayo Clinic Proceedings1,2 are relevant to an important clinical issue: the misdiagnosis of acute colonic diverticulitis in patients with irritable bowel syndrome (IBS). As clearly described in these articles, abdominal pain and disordered bowel habits are common to both disorders, and symptom severity varies in both. Furthermore, patients with either of these disorders typically have tenderness on examination, most often in the lower abdomen. Computed tomography (CT) of the abdomen and pelvis, the most commonly used diagnostic test for diverticulitis,2 is often not urgently available for clinic patients, and some patients with CT-documented diverticulitis have no fever or leukocytosis.
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