2019 ESNM指南：成人功能性便秘

指南消化内科· 胃肠疾病 · 2019

Authors

# Conclusions and Inferences:

Conclusions and Inferences:

Abstract

Introduction: Chronic constipation is a common disorder with a reported prevalence ranging from 3% to 27% in the general population. Several management strategies, including diagnostic tests, empiric treatments, and specific treatments, have been developed. Our aim was to develop European guidelines for the clinical management of constipation.

Design: After a thorough review of the literature by experts in relevant fields, including gastroenterologists, surgeons, general practitioners, radiologists, and experts in gastrointestinal motility testing from various European countries, a Delphi consensus process was used to produce statements and practical algorithms for the management of chronic constipation.

Key Results: Seventy-three final statements were agreed upon after the Delphi process. The level of evidence for most statements was low or very low. A high level of evidence was agreed only for anorectal manometry as a comprehensive evaluation of anorectal function and for treatment with osmotic laxatives, especially polyethylene glycol, the prokinetic drug prucalopride, secretagogues, such as linaclotide and lubiprostone and PAMORAs for the treatment of opioid-induced constipation. However, the level of agreement between the authors was good for most statements (80% or more of the authors). The greatest disagreement was related to the surgical management of constipation.

European guidelines on chronic constipation, with recommendations and algorithms, were developed by experts. Despite the high level of agreement between the different experts, the level of scientific evidence for most recommendations was low, highlighting the need for future research to increase the evidence and improve treatment outcomes in these patients. K E Y W O R D S chronic constipation, guidelines, Delphi process, management of constipation Key Points • Chronic constipation is a common disorder with a reported prevalence ranging from 3% to 27% in the general population. Multiple management strategies, including diagnostic tests, empiric treatments, and specific treatments, are known to be used. • The aim of the present manuscript was to create European guidelines for the clinical management of constipation, developed by experts in different fields related to constipation across Europe. • After a full review of the literature, relevant statements, final recommendations, and management algorithms were produced using a Delphi consensus process O RCI D

1 | INTRODUC TI ON

Chronic constipation is a common disorder with a reported prevalence ranging from 3% to 27% in the general population. 1, 2 Its prevalence increases with age 3, 4 and consequently is expected to rise over the next few years, 5 in parallel with the predicted increase in longevity of the European population. Constipation is a symptom that may have diverse etiologies, and for this reason, several diagnostic approaches and treatment options are available, ranging from simple lifestyle changes and general measures to sophisticated pharmacological treatments and surgical interventions. 6 In an attempt to unify the health care received by the population across Europe, the European Society of Neurogastroenterology and Motility (ESNM) decided to develop European guidelines to help physicians to take the best decisions to improve the quality of health in patients suffering from common functional and motor disorders. In this document, we present the ESNM guidelines for chronic constipation, which are intended to be a useful tool for the management of this condition in the general population in Europe. In order to produce comprehensive guidelines addressing the different aspects related with constipation, experts from European countries working in related fields developed relevant statements after a thorough review of the available literature, and final recommendations and management algorithms were produced following a Delphi consensus process.

2 | ME THODS

2.1 | Participants

A chair (Jordi Serra) and co-chair (Daniel Pohl) were commissioned by the ESNM Steering Committee to develop the guidelines. A panel of 12 experts from different European countries, constituted by gastroenterologists, surgeons, general practitioners, radiologists, and experts in gastrointestinal (GI) motility testing, was invited by the chairs to participate in the development of the guidelines. Each expert was assigned to develop a specific area of the document (see below) and to establish a team with one or two co-workers to complete the assigned task. The final ESNM guidelines working group was composed of 13 experts and 9 co-authors. biofeedback therapy; alternative treatments; probiotics; and surgical treatment. Based on the results of the search, several statements with specific recommendations were produced by each expert and rated according to the level of evidence. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to rate the level of evidence and recommendation. In parallel, an algorithm for the management of constipation was developed by the chair. When all the statements had been received from all the authors, a Delphi consensus process was initiated by sending all the statements and algorithms to all the experts for anonymous voting, with progressive refinement and revoting of the reformulated statements.

2.2 | The Delphi consensus

Finally, each expert wrote the final statements corresponding to the assigned section, including comments, unmet needs, and the literature supporting the evidence of the recommendations, and three algorithms for the management of constipation were produced. The level of agreement between authors for each statement is shown in Figure 1 .

Algorithms for the management of constipation are in Fugures 2-4.

3 | RE SULTS

3.1 | Definition

3.1.1 | Statement 1: Constipation is defined as difficult, unsatisfactory, or infrequent defecation

• Level of evidence: Not applicable • Recommendation: Not applicable • Level of agreement: 100% (Figure 1 ). This definition is consistent with the definitions of chronic constipation used in recent guidelines and in the Rome consensus for functional constipation (FC). 7, 8 The term unsatisfactory evacuation has been chosen as a general and comprehensive term that includes, among others, feeling of incomplete evacuation. The term difficult evacuation includes straining, sensation of anorectal obstruction, and need for manual maneuvers to facilitate evacuation.

3.2 | Pathophysiology

3.2.1 | Causes and predisposing factors

Statement 2: The prevalence of constipation is higher in women • Level of evidence: High

• Recommendation: Not applicable

• Level of agreement: 100%

Current evidence and literature. The available evidence points toward a clear sex preponderance in women. Most of the studies in a systematic review 9 reported a predominance of females in the prevalence of constipation. The mean female/male ratio was 1.78 (median 1.58), but differed according to the definition of constipation (1.7 for Rome I, 1.8 for Rome II, and 2.3 for selfreporting of constipation).

Female predominance was also shown in a recent epidemiological study in FC patients based on Rome III Criteria, with a higher prevalence in female (17.4%) compared to male students (12.5%). 10 univariate logistic regression analysis, FC was significantly associated with sex (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.06-2.06). In a different population of 7251 constipated patients and 7103 controls, Talley et al 3 showed an OR of 1.62 (95% CI F I G U R E 1 Final agreement between the authors for each of the statements produced after the Delphi consensus process 1.49-1.76) in females. This predominance of females has been attributed to hormonal factors, such as a higher risk of constipation during the luteal phase of the menstrual cycle and the effect of progesterone, most notably in pregnancy, and damage to the pelvic floor muscles that may occur in women during childbirth or gynecological surgery. This effect of additional progesterone on colonic transit could also be confirmed in a prospective study by Gonenne et al 11 in 49 postmenopausal women.

Additionally, premenopausal women (age 25-49) were shown to have longer transit times than older women (64.0 vs 59.5 hours; difference 4.6 hours, 95% CI 1.1-8.1 hours). 12 This leads to less pronounced gender differences in constipation prevalence in the older population.

Future

research/unmet needs. Investigations on further pathophysiological differences except for the hormonal situation between men and women should be done.

Statement 3: The prevalence of constipation increases with age

• Level of evidence: High

Current evidence and literature. It is generally perceived that the prevalence of constipation increases with age. In a postal health survey in 41 724 Australian women, 4 the prevalence of constipation was 14.1% (CI 13.5-14.7) in young women (18-23 years), 26.6% (CI 25.9-27.4) in middle-aged women (45-50 years), and 27.7% (CI 26.9-28.5) in older women (70-75 years). In data analyses from the General Practice Research Database (GPRD) in the United Kingdom, Talley et al 3 showed a higher OR of constipation in patients > 75 years compared to controls (OR 1.96, 95% CI 1. 71-2.24).

Future research/unmet needs. The effects of aging on intestinal connective tissue, influence of hormonal status in relation to gut motility, and age-related changes in the microbiome should be evaluated to analyze functional, intestinal, and external structures as underlying causes of constipation and defecation disorders. were seen in patients with a positive family history of FC. Another study by Ostwani et al 14 demonstrated significantly higher rates of constipation in siblings or parents of children with functional, habitual constipation than in controls (30% vs 7% and 42% vs 9%, respectively; P = .001).

Future research/unmet needs. Genetic and epigenetic studies are needed.

Statement 5: Lower social, economic, and educational levels are associated with a higher prevalence of constipation Current evidence and literature. 8] [29] [30] A US survey showed that the most frequent symptoms of chronic constipation were straining, hard stools, abdominal discomfort, bloating, infrequent bowel movements, and feeling of incomplete evacuation after bowel movement. 31 Hence, the guidelines underscore the importance of a careful history assessing the presence of these symptoms and their duration and progression.

3.3 | Diagnostic approach

3.3.1 | Clinical approach and basic explorations

Specific validated questionnaires, like the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire or the Bristol stool scale, can be used for the clinical evaluation of the patient with constipation. 32 Objective testing is recommended when the physician considers it necessary to rule out organic disease, that is, if alarm symptoms are present, or in refractory cases to identify underlying pathophysiology that may help guide treatment. Current evidence and literature. [30] [33] [34] [35] [36] [37] [38] Despite differences in the prevalence of each individual symptom, the authors chose to maintain the 25% rule (symptom present in 25% of stool movements) for all symptoms to facilitate the use of the criteria in the clinical setting. 28, 30, 37, 39 Most patients will respond adequately to these first-line therapeutic measures, and therefore, specialized diagnostic evaluation should only be offered to patients in whom these measures fail to improve symptoms. 48 Advanced functional testing is not available in all settings; however, procedures such as the balloon expulsion test (BET) and whole gut transit evaluation using radiopaque markers may be performed even when resources are limited. The rectoanal inhibitory reflex (RAIR) depends on the intrinsic innervation of the gut. An abnormal RAIR is typically found in Hirschsprung's disease but may also be detected in other visceral neuropathies such as Chagas disease. 60 Technical aspects are important when evaluating the RAIR. A common pitfall is insufficient rectal distension in patients with megarectum, which may be overcome by using a barostat to obtain sufficient pressure. 61 ture research/unmet needs. There is significant discrepancy between methods in data acquisition, analysis, and interpretation of ARM; there is a need for expert international cooperation to standardize ARM. Current evidence and literature. High-resolution manometry obtains circumferential pressure measurements of the anal canal and distal rectum. Unlike conventional manometry, it may detect asymmetry of the anal pressures at rest or during squeeze. 63 In addition, topographical color-contour plots may facilitate interpretation of the defecatory maneuver compared to conventional manometry. 64 wever, no significant differences in the diagnosis of DD have been detected when directly compared. Current evidence and literature. The BET measures the capacity and time to evacuate an air-or water-filled balloon from the rectum.

This test has been shown to be abnormal in a high proportion of patients with an evacuation disorder, 68 but as mentioned previously, is not diagnostic as a single test. In fact, agreement with disordered defecation measured with ARM is relatively low. Indeed, the BET may be normal in patients with DD who are able to compensate by excessive straining. The BET has been shown to predict response to biofeedback therapy, 69, 70 although this finding is not uniform in all studies. 71 ture research/unmet needs. There is considerable disagreement between the tests of evacuatory function; diagnostic criteria for impaired defecatory function should be established. 72 Current evidence and literature. Rectal compliance may be measured by evaluating the pressure/volume relationship during progressive rectal distension with a balloon. For this purpose, the use of a barostat is useful because it allows direct measurement of rectal capacity at fixed pressure levels. 73 Increased rectal compliance may be associated with chronic constipation, particularly in children with megarectum. 74 Nevertheless, in pediatric constipation, increased rectal compliance has not been shown to increase treatment failure. 75, 76 atement 24: Oro-anal transit is most commonly measured by radiopaque markers; interpretation of slow colonic transit is not reliable in the case of functional or organic outlet obstruction STC is characterized by a delayed colonic transit time. 9] [80] In patients with FC, transit times have been shown to correlate well with stool consistency/form but poorly with stool frequency and associated symptoms. 47, 81 ture research/unmet needs. The procedure should be standardized. Current evidence and literature. The terminology is far from being universally accepted, given the numerous technical variations and the plethora of synonyms for defecography employed since its conception 82 : "cineradiographic defecography," 83 "cinedefecography," 84 "evacuating" 85 or "evacuation proctography," 21 "defecation" 86 or "defecating proctography," 87 "videodefecography," 88 and "videoproctography." 89 However, the term "defecography" has been most commonly reported (~60% of all published articles); it was initially proposed by Mahieu 90 to more clearly imply that the physiological act of defecation is examined in dynamic conditions analogous to the investigation of deglutition or micturition.

3.3.3 | Radiological studies

Future research/unmet needs. One of the principle challenges will be to promote standardization of the language and the technique so that results are transferrable between institutions. Current evidence and literature. A total of only four studies have been conducted in ≥40 healthy subjects, two using barium [X-ray] defecography (BD) 91, 92 and two using MR defecography (MRD). 93, 94 gardless of the technique, a consistent criticism of defecography is the acknowledged overlap between health and disease, 91 hampered by a paucity of normative data, which challenges our ability to define 'true' (pathologic) abnormalities.

Future research/unmet needs. The optimal technique for BD and MRD remains to be defined and should be subject to a Working Group initiative. Normative values are only applicable to specific protocols and are mostly derived from female patients (for MRD, data existing for males are derived from a cohort of only 25 subjects in one study 93 ).

Additional comments. Normative data sets have provided evidence of truly pathologic findings (ie, those not seen in health), such as large rectoceles, high-grade intussuscepta, and enteroceles (whole gut or oro-anal). Current evidence and literature. The prevalence of structural and functional abnormalities detected by defecography is high, but varies considerably across studies, with high heterogeneity depending on technical protocol variations and diagnostic criteria used.

For example, several different cutoffs have been used to define (a) dynamic perineal descent (ranging from 2 to 6 cm) 96, 97 ; (b) the magnitude of the infolding for rectal intussuscepta (any fold "more than a wrinkling of the mucosa" 98 ; ≥3 mm 99 ; > 4 mm 84, 100 ; or > 1 cm 97, 101 ); and (c) severity of rectocele based on maximum depth: 2 cm 93,99,102-107 ; 2.5 cm 108 ; 3 cm 84, 89, 109, 110 ; or 4 cm. 72, 111, 112 ture research/unmet needs. As above, standardization of protocols is a prerequisite for obtaining results that are robust, reproducible, and easily transferable between institutions. Current evidence and literature. BD is considered the gold standard for the assessment of posterior compartment disorders, given its capability to dynamically evaluate the rectum during simulated defecation. 108 Its particular advantage over BET and manometry is that it enables characterization of structural abnormalities. 72, 91 BET and manometry are, de facto, unable to provide such information. A total of four studies (including ≥ 40 subjects) have used BD as the reference standard to assess the diagnostic yield of other imaging modalities (ie, echodefecography 113, 114 and dynamic transperineal ultrasound 115, 116 ) in diagnosing posterior pelvic floor compartment disorders. 'a + b' (n = 4) 96, 108, 111, 137 ; 'a + c' (n = 7) 84, 85, 113, 116, [138] [139] [140] ; 'b + c'

Future research/unmet

(n = 1) 112 ; or 'a + b+c' (n = 4). 72, 114, 141, 142 Current evidence and literature. The literature does not delineate between functional constipation, chronic constipation, or constipation per se. The data are conflicting but largely against benefit from exercise alone for constipation. One study of secondary school pupils (hence, largely normal subjects), which used bowel evacuations less than every two days as the criterion, concluded that constipation was associated with "insufficient" exercise or sedentary behavior, and that this was dose-related to the amount of exercise taken. 147 Similarly, in an education-led program in 35 women with chronic constipation, there was an improvement in their Bristol Stool scores and symptoms. 148 wever, the intervention was multilayered, consisting of advice on diet, fluids, and counseling. Conversely, in a study of healthy men over 35 days, intervention with experimentally controlled bed rest, stool consistency, and bowel symptoms was not influenced by physical inactivity. 149 In another study conducted over six weeks in patients with idiopathic constipation, exercise levels and constipation were assessed. The level of exercise did not correlate with constipation indices and the conclusion was that physical activity to the extent considered "regular exercise" did not play a role in the management of idiopathic constipation. 150 While data do indicate that GI transit times may be accelerated by exercise, this does not translate into outcomes in constipation. Although subjects with the slowest resting transit rates may show the largest exercise effects in mouth-to-cecum transit time, this is not necessarily reflected in constipation symptoms. 151, 152 review in 2011, which included two small randomized placebo-controlled trials and two cohort studies concluded that lifestyle modification to prevent or treat constipation, was not substantiated by evidence. 153 No systematic reviews exist for exercise and constipation, but exercise appears to be associated with a range of health benefits for people of all ages. 150, 152, 154 A further review in 2011 confirmed conflicting evidence, again largely against the effect of exercise for constipation, with studies showing inconsistent effects. 155 However, physical activity was noted to improve quality of life (QoL) in some subjects in some studies and was associated with improved QoL and a decrease in symptom severity. 156 ture research/unmet needs. Evaluation of the level of exercise needed to maintain good general health and gastrointestinal health in individual people (Figures 2 3 4 ). in people with constipation. While there may be an association between "inadequate" fluid intake or dehydration and constipation, there is a lack of evidence to support that increased fluids alone are of benefit. 148, 154, 156 In a study of 833 elderly patients with a mean age of 74 years, it was noted that 71% already drank six or more glasses of water daily and that there was no difference between them in terms of bowel symptoms and the 29% who drank less fluids. 157 In a 2011 review, only one RCT and one observational study was noted, with the RCT showing benefit from fluids only in the presence of additional fiber. 153 Thus, the evidence in relation to increased fluid intake alone, as being positive for the management of constipation, is sparse.

Future research/unmet needs. Larger, well-defined interventional studies should be done to provide data on appropriate intake for patients with constipation.

Statement 37. Dietary fiber alone within the normal (regular) diet helps functional constipation

• Level of evidence: Low

• Recommendation: Weak

• Level of agreement 92%

Current evidence and literature. This section relates to normal or regular intake of dietary components, essentially fiber, and does not relate to therapeutic supplements. However, much of the literature relates to fiber supplements and laxatives, and there is a paucity of data about lifestyle dietary measures geared to FC.

A 2011 review concluded that, while increasing dietary fiber may help constipation caused by fiber deficiency, it should not be assumed that fiber deficiency is the main source of the problem. 148 nsuming a high fiber diet alone may not be as effective as combining it with increased fluid intake. The overall evidence for increased dietary fiber (as opposed to recommended or prescribed fiber) is weak, although the effect may be enhanced if increased fluids are included. 148, 153, 156, 158 ture research/unmet needs. Interventional and observational studies in patients are needed. intake, physical activity, and the use of laxatives. 159 There was no control group, but the lifestyle modification education significantly reduced the severity of the FC and recorded improvements in QoL. Combined with data from other studies, this suggests that there is overall benefit from a combination of lifestyle measures, both in constipation and in the QoL measures. 156, 158 To this can be added the benefits from a more active lifestyle in terms of general health. While the data are not robust, this would seem a reasonable approach in the practical management of patients.

Future research/unmet needs. More studies are needed on overall lifestyle and gastrointestinal health.

3.4.2 | Bulking agents and osmotic laxatives

F I G U R E 2 Algorithm 1.

Management of constipation. First-line management of patients presenting with constipation at any level of the healthcare system. 1 Defined as difficult, unsatisfactory, or infrequent defecation for at least the previous 3 mo. 2 Rescue therapy may include suppositories or rectal enemas, if accepted by the patient, or the use of fiber or osmotic laxatives on demand. Level of evidence very low. Recommendation strong. 3 Use of probiotics seems promising; however, no strong evidence yet. 4 When available, anorectal function testing may be indicated at this stage when there is clinical suspicion of an evacuation disorder (manual maneuvers, hemorrhoids, prolapse or rectocele, painful evacuation, etc). 5 Alternatively, other treatments like prokinetics or secretagogues could be tried influenced by the safety and low cost of this approach, and some efficacy data from trials, together with long-standing clinical experience with these agents. In a systematic review evaluating the effects of fiber in the management of chronic idiopathic constipation, only six RCTs were found to be eligible: four used soluble fiber (three psyllium, one inulin, and maltodextrin) and two used insoluble fiber (one bran and one fiber-rich rye bread).

Soluble fiber led to improvements in global symptoms (86.5% vs.

47.4%), straining (55.6% vs. 28.6%), pain on defecation, and stool consistency, an increase in the mean number of stools per week (3.8 stools per week after therapy compared with 2.9 stools per week at baseline), and a reduction in the number of days between stools. In particular, the effect of psyllium was convincing with a Number-Needed-to-Treat (NNT) of 2 (95% CI 1.6-3), and with no statistically significant heterogeneity between the three psyllium studies. 160 Evidence for any benefit of insoluble fiber was conflicting, mainly based on small patient numbers and few eligible studies. As a follow-up of this systematic review, the American College of Gastroenterology (ACG) recommended, based on these six trials, that fiber and soluble fiber in particular are effective in the management of chronic constipation. 8 8] [169] This leads to increased small bowel water and increased colonic volumes. 170 These effects can explain both the positive effects of bulking agents, that is, increased stool frequency, and potential side effects. Adverse events, particularly bloating, distension, flatulence, 3 Before considering any surgical correction, evaluate the feasibility of biofeedback treatment as the option with the least side effects. 4 Evaluation of colonic transit time can be useful in patients without evacuation disorders, and in patients with persistent constipation after treated evacuation disorders. 5 This means according to Rome IV: Chronic constipation due to "Disease-related," "Medication-induced" or "IBS-C." At this stage, further investigation or symptomatic treatment will be considered and cramping, may limit the use of insoluble fiber, especially if increases in fiber intake are not introduced gradually. but suggest a positive effect of lactulose versus placebo in chronic constipation with a NNT of 4 (95% CI 2-7). 8, 172, 181, 182 Moreover, side effects such as abdominal cramping and bloating limit their clinical usefulness. Also dried plums, which contain sorbitol, but also dietary fibers and polyphenols, may be useful for constipation. This was demonstrated in a randomized controlled trial, where dried plums were found to be safe, palatable and more effective than psyllium for the treatment of mild-to-moderate constipation. 183 At least part of the effect on constipation may be explained by the sorbitol content, which act as an osmotic laxative.

Future research/unmet needs. High-quality trials assessing the effects of the unabsorbed mono/disaccharides and sugar alcohols lactulose, lactitol, mannitol, and sorbitol are needed, including comparisons with newer agents for the treatment of constipation. The first choice will depend on the patient's characteristics, like coexistence of abdominal pain or distension, cost/efficacy evaluation, and local preferences. 2 As rescue therapy, stimulant laxatives may be used, as well as suppositories, rectal enemas, or rectal irrigation propagative contractions of the colon and stimulates intestinal secretion. 184 It is usually given orally at a dose of 5-10 mg daily in a coated tablet that dissolves in the colon to ensure a local effect, or as a suppository given at a dose of 10 mg daily. In healthy volunteers, bisacodyl significantly accelerated emptying of the ascending colon, although overall transit was not modified. 185 In 2005, a systematic review of the literature found that stimulant laxatives, including bisacodyl, had a level III of evidence and were rated as a grade C recommendation, 186 while the American College of Gastroenterology Chronic Constipation Task Force underlined that high-quality data were lacking to make a recommendation about the efficacy of stimulant laxatives for the management of chronic constipation. 187 nce then, only one randomized, double-blind placebo-controlled study comparing the efficacy of daily use of bisacodyl in chronic constipation has been conducted. In this study, performed in 368 patients with chronic constipation defined by Rome III criteria, oral bisacodyl at 10 mg once daily increased the frequency of both bowel movements and complete spontaneous bowel movements over a 4week period. Current evidence and literature. Constipation-related QoL was also improved in the bisacodyl group compared with placebo. 188 Of note, six adverse events leading to drug discontinuation were recorded in the placebo-treated group, versus 44 in the bisacodyl-treated group, the most frequent being diarrhea and abdominal pain. However, the occurrence of serious adverse events was similar ( < 2%) in both groups. A second randomized-double-blind placebo-controlled study showed the efficacy of bisacodyl (10 mg once daily for 3 days) to acutely relieve chronic constipation by increasing the frequency of bowel movements and softening stool consistency. 188 An open-label RCT conducted in two groups of patients with chronic constipation treated with either pyridostigmine or bisacodyl showed that both treatments achieved an increase in bowel movements per week compared to baseline, with greater efficacy with pyridostigmine compared to bisacodyl. 189 ture research/unmet needs. Controlled studies evaluating the efficacy of bisacodyl in FC over 4 weeks of treatment are lacking and should be conducted. Whether the association of bisacodyl with an osmotic laxative is superior to bisacodyl alone or an osmotic laxative alone has yet to be investigated. by the colonic microbiota into active components 192 They cannot be absorbed and are not excreted in breastmilk. Clinical trials are sparse and have often been conducted in the geriatric population or in patients with OIC. In these trials, the objective was often to demonstrate the additional benefit of combining senna to a bulk or osmotic laxative. The available trials prove their efficacy for increasing the number of stools or improving stool consistency. Senna provided more improvement than bulk or osmotic laxatives [193] [194] [195] and obtained similar results to magnesium hydroxide, 196 sodium picosulfate, 197 and even lubiprostone. 198 ture research/unmet needs. Blinded controlled studies evaluating the efficacy of anthraquinones are still lacking and should be performed. Current evidence and literature. Anthraquinones have been linked with the development of melanosis coli, which is a brown pigmentation of the colonic mucosa due to collections of lipofuscin-containing macrophages. 199, 200 It is now established that this pigmentation has no clinical significance. 199 An increased risk of colorectal cancer has also been discussed. In a prospective study of 84 577 females, no association between laxative use and colorectal cancer was found. 201 seudoobstruction, postoperative ileus, etc. 208 On an individual basis, they may be useful in selected cases of CC refractory to other established treatments. Indeed, a small trial reported similar efficacy as bisacodyl. 189 Overall, they have limited use in chronic constipation. This is also due to their low specificity, with effects on both muscarinic and nicotinic receptors, and because they have been associated with multiple systemic, secretory, and serious cardiologic side effects. 209, 210 Acotiamide is a new acetylcholinesterase inhibitor with additional antimuscarinic effects, available in Japan and currently being evaluated in Europe and the United States for functional dyspepsia 211 ; there are no data for chronic constipation.

3.4.3 | Stimulant laxatives

3.4.4 | Prokinetics and secretagogues

Future research/unmet needs. Their therapeutic potential in defined subtypes of constipation disorders is not well defined and thus they are possibly under-utilized. 6] [217] [218] [219] [220] [221] [222] [223] [224] [225] The systemic opioid antagonist naloxone if administered as slow release formula may also inhibit intestinal opioid effects with little/no systemic action due to the high first pass effect in the liver, it is available as a fixed combination tablet with oxycodone. 226, 227 uture research/unmet needs. As there are limited data on combination treatments, further studies should be done. pain 229, 230 due to decreasing effects on visceral hypersensitivity. 229, 230 naclotide may cause diarrhea as its most frequent side effect, but has a very low risk of major systemic adverse responses due to its local action in the intestinal lumen and low bioavailability. Current evidence and literature. Lubiprostone is a chloride channel activator and induces intra-intestinal water and chloride secretion, and accelerates transit. In RCTs in patients with chronic constipation and IBS-C, lubiprostone was associated with significantly improved symptoms 213, [232] [233] [234] [235] [236] with a therapeutic benefit of 7.8%, and a NNT of 12.8. 237 [234] [235] [236] Hence, it is mostly used as reserve medication and has not been approved in most European countries so far.

Future research/unmet needs. The optimal target group and side effects should be defined more clearly. Limited or no availability in most European countries. treatment where information about a physiological process is converted to a simple signal to enable the patient to learn to control the disordered function. 238 Recently, instrumented biofeedback has been reported to ameliorate symptoms and accelerate bowel transit by improved defecation effort in over 70% of STC due to DD, while isolated STC did not benefit. 78 0] [241] These pivotal trials were adequately sized and included only severe, refractory constipation due to DD diagnosed by physiology testing, regardless of abnormal colon transit in most of them. Biofeedback therapy has been consistently reported to be superior to controlled treatment modalities, including sham biofeedback, placebo pill, muscle relaxant drugs (diazepam), and osmotic laxatives. 239, 240 Improved anorectal physiology correlated with successful outcomes, supporting a specific mechanism of action of biofeedback that differed from psychotherapy interventions and simple education. Biofeedback was effective in the long term and devoid of side effects, as confirmed by a recent open-label trial with a follow-up interval extended up to 4 years. 239, 240, 242, 243 In the pivotal trials, a complex protocol addressing the defecation effort as a whole using dedicated instruments was employed [239] [240] [241] ; this seems relevant to the successful outcome of biofeedback therapy, as simpler protocols were less effective than alternative treatments in FDDs. 146 In addition, constipation symptoms associated with isolated anatomical disruption of the pelvic floor seem to benefit little from retraining. 244 Factors that may predict successful outcome of biofeedback therapy are: baseline harder stool consistency, digital maneuvers to facilitate defecation, shorter duration of laxative use, higher resting anal sphincter pressure, and failure to expel a rectal balloon. 69, 245 Comorbid slow colonic transit is not a contraindication to retraining, as it has been repeatedly shown that improved defecation effort is effective on normalizing bowel transit in the vast majority of DD patients. 78, 245 Finally, the patient's willingness to participate, motivation and therapist's skill are all considered relevant to a successful outcome, although these are generally not specifically addressed. 246 ture research/unmet needs. Other RCTs of biofeedback for according to a standardized protocol and is mostly a nurse-led treatment option. 247, 248 It involves dietary advice to improve stool consistency and to maximize the gastro-colic response in order to ease defecation. 247, 248 Patients can be given basic gut anatomy and function training to gain an appreciation of how psychological and social stresses may influence gut functioning, as well as advice about the frequency and length of toilet visits and posture. Simple pelvic floor exercises and abdominal muscular coordination training to improve the pushing effort are relevant treatment components in all protocols. 247, 248 However, habit training is not like biofeedback, where information about a physiological process is presented to enable mastering of a disordered function. 246 Some centers provide this treatment approach in all resistant chronic constipation, regardless of etiology. 248 However, a pelvic floor retraining protocol was prescribed as sole treatment for 22% of constipated Italian patients consulting specialized care. 239 The recently published St Mark's experience has shed some light on habit training given to constipated patients non-responsive to conservative care. 249 A retrospective analysis of data from 347 mostly female constipated subjects (median age, 50 years) showed an improvement in symptoms in 62.5% and in the QoL score in 40.2% of the patients at the end of treatment. Multivariate analysis demonstrated that increasing age, the number of sessions attended, and non-irrigation constipation were independent predictors of treatment satisfaction. 248 No side effects were reported. The same group undertook an historical RCT comparing electromyography (EMG) on straining and rectal balloon biofeedback to abdomino-pelvic muscular coordination training and balloon feedback in a series of 60 adults with functional constipation unresponsive to conservative management. 250 After only two unsatisfactory sessions, patients who were judged unable to respond were switched to the alternative treatment, thus biasing the results. At the end of treatment, approximately 50% of patients in both groups rated their symptoms as significantly improved. The outcome did not correlate with colon transit time, the presence of FDD, or other functional and clinical variables. 250 No other RCTs have attempted to duplicate the results in the adult population.

3.4.5 | Biofeedback therapy

In conclusion, habit training is an appealing treatment option for chronic constipation, regardless of etiology. It is a safe and affordable treatment option. Dedicated expertise is essential to perform it, but costly pretreatment testing is apparently not required.

It comprises a non-drug, non-instrumental, holistic approach that is likely to appeal to patients with functional gastrointestinal disorders.

However, it is not an evidence-based treatment and results from RCTs are pending before consistently endorsing it for all refractory constipation patients. 251 ture research/unmet needs.

3.4.6 | Alternative treatments

Statement 57: Chinese herbal medicine improves bowel function in functional constipation, but it is not known which formulation is best

• Level of evidence: Low • Recommendation: Weak • Level of agreement: 100%

Current evidence and literature. A large proportion of patients with constipation have tried alternative remedies, 252, 253 partly because of the misconception that laxatives damage the bowel in some way or make it lazy. In addition, many patients like to think that they are treating their constipation in a more 'natural' way and, therefore, food or plant extracts that are thought to have a laxative effect are very popular.

[256] This raises the possibility of using data derived from IBS-C patients. However, the outcome measures used in these studies on alternative treatments in IBS tend to be more global, rather than reporting the actual effect on bowel function. Furthermore, even in those studies that divide patients into different bowel function subtypes, the outcomes are also usually global, rather than necessarily reporting specifically on change in stool form or frequency. Despite these drawbacks, where there is a lack of data with respect to the effect of alternative treatments in chronic constipation, it seems reasonable to consider extrapolating results from studies reporting results from IBS-C to chronic constipation.

In contrast to most other alternative approaches to treating constipation, Chinese herbal medicines have been the subject of more recent research in reasonably well-designed controlled trials. 8] [259] [260] [261] [262] However, the formulation of these products can vary, making it difficult to create specific recommendations on their use.

Future research/unmet needs. Many of the alternative remedies for the treatment of constipation have been available for many years, but very few have been subjected to the scrutiny of a modern clinical trial. This situation is unlikely to change in the future, as it is doubtful that funding for research of these established, but largely unproven approaches, will be forthcoming. Many of these preparations contain multiple components, and it would be useful to know whether all of the components are necessary for a clinical effect.

Statement 58: There is insufficient evidence to recommend acupuncture for the treatment of functional constipation

• Level of evidence: Very low

Current evidence and literature. Studies on acupuncture in any disorder are always criticized because of the difficulty in finding an appropriate control group. A systematic review of IBS acupuncture studies was inconclusive, 263 and there have been too few studies on constipation in the English literature to draw any firm conclusions. 258, 264 However, a systematic review of the Chinese literature suggests that acupuncture may be beneficial in constipation, although the authors commented that the studies had methodological flaws. 265 ture research/unmet needs. Better designed trials are necessary before a final decision can be made about the utility of acupuncture in constipation. Current evidence and literature. It has been suggested that Iberogast (STW 5) may be beneficial in IBS, 268 but there are no data on its use in constipation. [271] [272] [273] Future research/unmet needs. Better designed trials are necessary and in particular emphasis should be placed on determining the relative contribution of the multiple constituents of these preparations to the clinical effect. Current evidence and literature. Abdominal massage would appear to be an attractive approach to managing constipation, as it should be a safe and cheap option in which the patient can engage. Trials show some effect, although the methodology of the older trials is questionable. [276] [277] Future research/unmet needs. More uniform and confirmatory studies using a standardized approach should be performed before abdominal massage can be recommended. Current evidence and literature. Behavioral treatments such as psychotherapy, cognitive behavioral therapy, and hypnotherapy have all been shown to be effective in IBS. 278 It therefore seems reasonable to assume that, at the very least, they might improve coping and QoL in patients with FC.

Future research/unmet needs. The specific effect of behavioral treatments on constipation has not been investigated, and there are no studies on the use of any these behavioral approaches in FC. Current evidence and literature. Glycerin or bisacodyl suppositories are frequently used as over-the-counter remedies for FC. However, there has been no good quality research on the subject, although studies that have been undertaken suggest an effect. 154, 279 ture research/unmet needs. Further trials on assessing the utility of these well-used remedies would be welcome. especially with phosphate enemas. 154, 279, 280 ture research/unmet needs. Further well-designed trials on assessing the utility of enemas would be welcome. Current evidence and literature. Transanal irrigation using commercially available kits is being increasingly used for the management of bowel dysfunction, including FC. A systematic review and meta-analysis of the available uncontrolled studies in FC suggested a 50% response rate, which is comparable to that obtained with pharmacological agents. 281 Theoretically, this technique could lead to perforation, but a separate study addressing this possibility has suggested this risk is very low. 282 tive or suspected diverticulitis are contraindications and previous rectal or pelvic surgery increases the chances of perforation.

Good instruction on how to use the technique is essential. 283 lonic irrigation using large volumes of fluid is very popular as a private service but is not offered within healthcare systems. It is not recommended as there is no clinical or research evidence to support its use and it is potentially dangerous.

Future research/unmet needs. Controlled trials of transanal irrigation in chronic constipation are needed. again hard to draw solid conclusions. 287 Zhang and co-workers performed another uncontrolled trial on FMT in 29 patients. 288 After 6 FMTs per patient, they reported clinical remission at week 4 in 69.0% of patients. After one year 48.3% of the patients continued to have at least three complete spontaneous bowel movements per week. Again, the lack of a control group makes it hard to interpret these results.

3.4.7 | Modulation of microbiota

Interestingly, the consumption of milk resulted in an improvement in constipation symptoms, regardless of the probiotic culture. 289 In a well-designed RCT, Spiller et al reported a positive effect of Saccharomyces cerevisiae in patients with IBS-C. 290 The study included 379 patients who received either 1000 mg of the probiotic or placebo for 12 weeks. While there was no overall benefit of S cerevisiae on IBS symptoms and well-being in the total study population, a significant improvement was observed in the IBS-C subjects with respect to abdominal pain/discomfort and bloating. 290 However, this subgroup analysis had not been planned initially. Mezzasalma et al, in a randomized, double-blind, three-arm parallel-group trial in 150 IBS-C patients who received either a daily oral dose of two probiotic mixtures or placebo (for 60 days) found a higher response rate in the two treatment groups. 291 An increase in bowel movement frequency, improvement in stool consistency, and reduction in abdominal bloating were reported in 70%, 60%, and 47%

of patients in a study with the probiotic preparation VSL#3, which contains 8 different bacterial strains. 292 der studies have been summarized in a 2014 meta-analysis by Ford, Quigley, and co-authors, who selected 43 RCTs. 293 In their analysis, probiotics had beneficial effects on abdominal pain, bloating, and flatulence scores in general. 293 In only two RCTs that focused on constipation, limited beneficial effects were described (mean increase in number of stools per week = 1.49; 95% CI = 1.02-1.96). 294, 295 e RCTs studied different bacterial preparations for different treatment periods, with or without PEG, with different endpoints.

This obvious high heterogeneity of even the well-designed clinical trials prevents a recommendation on a specific probiotic preparation/strain for the treatment of FC.

Future research/unmet needs. RCTs need to be performed for well characterized probiotic preparations that focus selectively either on IBS-C or FC patients. Too many post hoc subgroup analyses have been performed that had no primary focus on constipation.

Additional microbiota analyses should be required to evaluate whether an impact on microbiota composition is associated with symptom relief. Current evidence and literature. The surgical method is chosen depending on the pathology. In the case of intussusception, rectocele or prolapse, a STARR or internal Delorme procedure can be done.

3.4.8 | Surgical treatment

Patients show a decrease in the Longo's Obstructed defecation Score (ODS). [310] Future research/unmet needs. At present, there are mostly observational studies and the evidence level is low.

4 | D ISCUSS I ON

This document presents guidelines created by the ESNM for the management of chronic constipation. Following a careful Delphi process, 73 statements were produced and graded according to the level of evidence and the strength of recommendation using the GRADE method. Three algorithms were also developed for the management of constipation. The first algorithm is for first-line management of chronic constipation (Figure 2 ); the second for further investigation of patients with an unsatisfactory response to first-line management (Figure 3 ); and the third is for the treatment of constipation not caused by an evacuation disorder and which is refractory to first-line management (Figure 4 ). In addition to recommendations for the practical management of constipation, unmet needs were identified and future research lines proposed.

In order to develop these comprehensive guidelines that we hope will be useful across Europe, we included experts in different fields who manage constipation, including general practitioners, gastroenterologists, experts in neurophysiology and motility, radiologists, and surgeons, originally from eight European countries. In general, the authors discovered only moderate or low levels of evidence for most of the evaluated items (Table 1 ). 0] [61] Among the therapeutic alternatives, only treatment with saline laxatives, especially polyethylene glycol, 8, 172, 181, 182 the prokinetic drug prucalopride, [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] secretagogues like linaclotide and lubiprostone, 48, 69, 78, [238] [239] [240] [241] [242] [243] [244] [245] [246] [247] [248] [249] [250] [251] [311] [312] [313] [314] [315] and PAMORAs for the treatment of opioid-induced constipation 172, [229] [230] [231] showed high levels of evidence. Despite the different backgrounds of the panel members and the lack of studies with high levels of evidence, an excellent level of agreement between the experts was obtained for most items, as observed in Figure 1 . All but four statements were completely agreed/ agreed upon by 70% or more of the authors (Figure 1 ). These four items were related to the surgical management of constipation, with the greatest disagreement on the use of continuous direct nerve stimulation (SNS/SNM) for the treatment of this condition. Three newly published RCTs have shown no benefit for SNS/SNM on stool frequency in patients with chronic constipation, [303] [304] [305] [306] and several of the panel considered that there was no place for this treatment modality. Nonetheless other authors proposed a trial of SNS/SNM before more aggressive surgical treatment is considered, mainly due to the low rate of side effects of the technique.

In contrast to prokinetics and secretagogues, the evidence for the efficacy of alternative treatments and probiotics was "low" or "very low" in all cases. Consequently, the strength of the recommendation to use these treatments is generally "weak." 2] [273] [274] [275] [276] [277] [278] [279] [280] For the remaining treatment modalities, the authors found at least moderate evidence of their efficacy. However, the need for studies is great in most areas, and the final recommen- Of note, and despite some minor differences, the present guidelines are largely consistent with previous publications. 8, 48, 54, 316, 317 The Guideline of the American College of Gastroenterology published in 2014 8 also recommends bulking agents, osmotic and stimulant laxatives, prokinetics and secretagogues, despite different levels of evidence between the treatments, but with a weak degree of recommendation for non-pharmacological treatments like biofeedback therapy or probiotics. However, these European guidelines give a strong recommendation for biofeedback as the preferred treatment strategy for constipation in functional defecation disorders whenever dedicated expertise is available, regardless of abnormal bowel transit. The World Gastroenterology Organization Guideline published in 2010 54 differentiated between countries with high and low technical resources. For that reason, the colonic transit time test with radiopaque markers, which is cheap and easy to perform, was considered a first-line option. 9] [80] The American Gastroenterological Association (AGA)

guidelines released 2013 48 considered that radiological examinations for evacuation disorders (defecography) should be performed when anorectal manometry and the balloon expulsion test are inconclusive. However, considering different levels of access to motility and sophisticated radiological explorations in European countries, we decided to put the various radiological and manometric investigations for evacuation disorders at the same level in the algorithm.

In the present guideline, the authors reached the consensus that when an evacuation disorder is suspected in patients non-responding to first-line therapy with bulking agents/osmotic laxatives, evaluation of an evacuation disorder with functional studies could help to discriminate patients that could benefit from biofeedback therapy, before a costly chronic treatment with prokinetics and/or secretagogues is started. However, we acknowledge that this recommendation may be controversial, and treatment with secretagogues or prokinetics at this stage could also be considered before future studies comparing the cost-effectiveness of these strategies are available.

An important issue on which all authors agreed was the lack of consistent terminology in this area, resulting in considerable confusion in the medical community. Hence, the terms functional constipation, chronic constipation, defecation disorder, evacuation disorder, outlet obstructed evacuation, dyssynergic defecation, etc, have been used in the literature to describe sometimes the same and, at other times, completely different phenomena. After discussion, the authors of these guidelines reached the consensus that the term chronic constipation be used for all types of constipation with a duration greater than 3 months, and the terms slow-transit constipation or normal transit constipation only when objective evidence has been obtained from transit studies. In relation to evacuation disorders, the generic term "evacuation disorder," which encompasses both structural and functional causes is used, and the specific terms "functional defecation disorder," as defined by the Rome IV consensus, and "structural defecation disorder" are used to differentiate between both types of evacuation disorders.

The aim of the guidelines is to provide a practical tool for physicians all over Europe for the management of patients with chronic constipation. These guidelines have addressed mainly the general adult population with chronic idiopathic constipation. Specific groups such as those with constipation secondary to neurological disorders or to spinal cord injury, or constipation associated with special conditions like pregnancy have not been addressed in the present document. Likewise, the treatment of specific complications like fecaloma, disimpaction, or incontinence secondary to constipation has not been covered here either.

In conclusion, these ESNM guidelines for the management of chronic constipation are presented as a practical tool for the management of adult patients with constipation. They provide sequential algorithms for a progressive diagnostic and management process. This starts with initial first-line assessment and management using general measures and bulking or saline laxatives, followed by more comprehensive diagnostic procedures and more intensive treatment modalities in those patients who fail to respond to first-line treatments.

|0%|10%|20%|30%|40%|50%|60%|70%|80%|90%|100%| |---|---|---|---|---|---|---|---|---|---|---|

|• Pathophysiology|||||||||||

|• Clinical appraoch|||||||||||

|• Functional study|||||||||||

|• Radiological study|||||||||||

|• General measures|||||||||||

|• Bulking/osmotic|||||||||||

|• Stimulant laxatives|||||||||||

|• Prokinetics/|||||||||||

|Secretagogues|||||||||||

|• Biofeedback|||||||||||

|• Alternative|||||||||||

|• Probiotics|||||||||||

|• Surgical|||||||||||

|||Completely agree|Completely agree|Completely agree|Completely agree|Agree|Agree|Agree|Agree|Agree|

|influence stool form, the authors agree that the BSFS is a useful|Statement 14: In constipated patients on opioid medication, opioid-| |---|---|

|but underused tool for clinical practice.|induced constipation (OIC) should be considered as a differential|

||diagnosis|

|Statement 17: Physical examination in patients with FC should always|• Level of evidence: Moderate|

|include digital rectal examination (DRE)|• Recommendation: Strong|

|• Level of evidence: Moderate|• Level of agreement: 92%|

|• Recommendation: Strong||

|• Level of agreement: 100%|Current evidence and literature. Constipation is a common side effect|

||of opioid use that can affect up to 81% of patients, even with the|

|Current evidence and literature. Digital rectal examination (DRE) is|concomitant use of laxatives. 43 Due to the increasing use of opioids|

|a very important physical examination in the diagnosis of a patient|in Western countries, there is a strong need to rule out the use of|

|with constipation. DRE can detect stool in the rectal vault, anorectal|opioids in patients with constipation, especially considering that|

|masses, hemorrhoids, anal fissures, rectal prolapse, and rectoceles|opioid consumption is not always reported by patients. 6,28,37,43-45|

|that may cause constipation. DRE should be performed at rest, and|However, in these patients, other aspects related to the illness|

|asking the patient to strain, to identify alterations such as dyssynergic|requiring opiates such as anorexia, immobility, and concomitant treat-|

|anal contraction, excessive or defective anal descent, or other|ments have also to be considered. Owing to receptor downregulation,|

|structural abnormalities that are not apparent at rest. 48-53 However,|the opiate effect on both pain and the bowel declines over time, and|

|due to the non-physiological conditions of the DRE, the final diagnosis|finally, the best test of whether opiates are truly responsible is an|

|of an evacuation disorder needs confirmation with functional studies.|improvement on discontinuing therapy or response to naloxegol.|

||Statement 15: A simple blood test should be performed in the evaluation|

||of patients with constipation to identify secondary causes|

|Statement 18: Functional testing in chronic constipation is|• Level of evidence: Very low|

|recommended (where available) when first-line therapeutic measures|• Recommendation: Strong|

|have failed to improve symptoms|• Level of agreement: 100%.|

|• Level of evidence: Very low||

|• Recommendation: Strong|Current evidence and literature. Observational studies have identified|

|• Level of agreement: 100%|thyroid-and calcium-related disorders as potential causes of|

||constipation. Consequently, several consensus reports 6,28,29,33-36|

|Current evidence and literature. Patients consulting for constipation|emphasize the relevance of a simple blood test including glucose,|

|should initially be empirically managed with lifestyle and dietary|calcium, and thyroid-stimulating hormone (TSH) in the evaluation of|

|modifications, withdrawal (or reduction) of constipating medications,|patients with constipation. 46|

|primary symptom and fiber supplementation.||

|• Level of evidence: Low|Future research/unmet needs. Cost-effectiveness analysis on the|

|• Recommendation: Weak|value of blood test in patients without other symptoms suggestive|

|• Level of agreement: 92%|of endocrine or metabolic disorders.|

|Current evidence and literature. The differentiation between IBS-C|Statement 16: The Bristol Stool Form Scale (BSFS) can be used to record|

|and FC is an area of major controversy. Most authors consider|stool consistency in patients with constipation|

|that the presence of abdominal pain is the cornerstone for|• Level of evidence: Moderate|

|differentiating between both disorders. However, as recognized in|• Recommendation: Strong|

|the Rome IV criteria, functional bowel disorders are a spectrum|• Level of agreement: 100%|

|of disorders with great overlap and no clear or definite borders||

|that differentiate them in clinical practice. Hence, bloating and|Current evidence and literature. The usefulness of the BSFS in|

|abdominal pain are often seen in patients with constipation. In|assessing constipation has been demonstrated in different studies.|

|line with recent recommendations, we believe that the diagnosis|Lewis at al 26 showed concordance between the whole gut transit|

|of IBS should be considered only when abdominal pain is the main|time objectively measured with radiopaque markers and the stool|

|symptom in a patient with constipation, but not when it is just a|form score. The BSFS has been proposed as a reliable indicator|

|secondary accompanying symptom. 6,27,40-42|of FC that may be particularly useful in assessing patients with|

||some discrepancy between the frequency of bowel movements|

|Future research/unmet needs. There is a lack of objective biological|and stool hardness. 32,46,47 Even though other aspects related to|

|markers that can differentiate between FC and IBS-C.|individual motor patterns or efficiency of water absorption could|

|• Level of evidence: Moderate| |---|

|• Recommendation: Strong|

|• Level of agreement: 91%|

Level of evidence Recommendation

ACK N OWLED G M ENTS

Current evidence and literature. The radiopaque marker (ROM) test is the current standard test for the evaluation of oro-anal transit, with the advantages of low cost, simplicity, and wide availability.

Funding information

References

引用 / 出处

2019 ESNM指南：成人功能性便秘. 2019.