Management of Chronic Constipation in Patients with Diabetes Mellitus

Indian J Gastroenterol DOI 10.1007/s12664-016-0724-2

REVIEW ARTICLE

Management of chronic constipation in patients with diabetes mellitus

V. G. M. Prasad1 & Philip Abraham2

Received: 26 July 2016 /Accepted: 27 November 2016 # Indian Society of Gastroenterology 2016

Abstract are indicated if osmotic laxatives are not effective. Newer Aim The aim of this review is to provide an overview of the agents such as chloride-channel activators and 5-HT4 agonist clinical assessment and evidence-based treatment options for can be considered for severe or resistant cases. managing diabetes-associated chronic constipation. Conclusion The primary aim of intervention in diabetic pa- Methods A literature search of published medical reports in tients with chronic constipation is to better manage the diabe- English language was performed using the OVID Portal, from tes along with management of constipation. The physician PUBMED and the Cochrane Database of Systematic should explain the rationale for prescribing laxatives and ed- Reviews, from inception to October 2015. A total of 145 ab- ucate patients about the potential drawbacks of long-term use stracts were identified; duplicate publications were removed of laxatives. They should contact their physician if short-term and 95 relevant full-text articles were retrieved for potential use of prescribed laxative fails to provide relief. inclusion. Results Chronic constipation is one of the most common gas- Keywords Chronic constipation . Diabetes mellitus . trointestinal symptoms in patients with diabetes, and occurs Laxatives more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based Introduction on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be The prevalence of diabetes mellitus has reached epidemic pro- the first step in management. For patients recalcitrant to these portions in both developed and developing countries, affect- changes, laxatives should be the next step of treatment. ing more than 366 million people worldwide [1]. This number Treatment should begin with bulking agents such as psyllium, is likely to increase in the coming years as a result of an ageing bran or methylcellulose followed by osmotic laxatives if re- global population, urbanization, rising prevalence of obesity sponse is poor. Lactulose, polyethylene glycol and lactitol are and sedentary lifestyles [2]. Diabetes is on the verge of gaining the most frequently prescribed osmotic agents. Lactulose has a the status of an epidemic in India. As per the 2011 estimate, prebiotic effect and a carry-over effect (continued laxative India is home to 62 million diabetics, with an increase of effect for at least 6 to 7 days, post cessation of treatment). nearly two million each year. India is expected to cross the Stimulants such as bisacodyl, sodium picosulphate and senna 100 million mark by 2030 [3]. Several gastrointestinal (GI) symptoms such as diarrhea, chronic constipation and fecal incontinence are often observed * V. G. M. Prasad in patients with diabetes mellitus [4–6]; among these, chronic [email protected] constipation is the most commonly reported [7]. The preva- lence of chronic constipation in the general population is re- 1 VGM Hospital, 2100, Trichy Road, Coimbatore 641 005, India ported as around 14% [8]. A recent cross-sectional study with 2 P D Hinduja National Hospital and Medical Research Centre, Veer 372 diabetic patients treated at an outpatient clinic reported Savarkar Marg, Mahim, Mumbai 400 016, India that about 31% of patients had chronic constipation. Indian J Gastroenterol

Prevalence studies conducted in the US, Europe and Hong Table 1 Rome IV diagnostic criteria for functional constipation Kong report the rate of chronic constipation in diabetic pa- Following criteria should be present for at least 3 months with symptom tients to be 10%, 13% to 22% and 27.5%, respectively, indi- onset at least 6 months prior to diagnosis cating that chronic constipation is a very common GI symp- a tom in diabetics [9–12]. In another cross-sectional study, 1 Presence of ≥2 of the following symptoms : •Lumpyorhardstools(Bristolstoolformscale1–2) in >25% of 13.9% of 224 Indian patients with functional constipation defecations had diabetes [13]. •Straining during >25% of defecations Poor dietary habits, less fluid intake and low physical ac- •Sensation of incomplete evacuation for >25% of defecations tivity are significant factors leading to chronic constipation. •Sensation of anorectal obstruction/blockage for >25% of defecations •Manual maneuvers to facilitate >25% of defecations (digital The prevalence of chronic constipation has been reported to be manipulations, pelvic floor support) higher in women than in men, in older patients (≥50 years), in •<3 spontaneous bowel movements per week those with longer (≥10 years) duration of diabetes mellitus and 2 Loose stools rarely present without the use of laxatives in those who take concomitant medications such as calcium- 3 Insufficient criteria for irritable bowel syndrome channel blockers that promote chronic constipation [14]. The occurrence of chronic constipation is significantly higher in a In research studies, the patients with symptoms of opioid-induced con- diabetic patients with autonomic neuropathy compared to stipation should not be diagnosed as FC, since it is difficult to distinguish between opioid side-effects and other causes of constipation. However, those without neuropathy (22% vs. 9.2%, p <0.04)[15]. clinicians recognize that symptoms of the two conditions might overlap Measures of general health, social functioning and mental health are significantly impaired in patients suffering from chronic constipation and are comparable with those in other the criteria for irritable bowel syndrome, although abdominal conditions such as osteoarthritis, rheumatoid arthritis and pain and/or bloating may be present but are not predominant chronic allergies [16]. Given the growing prevalence of symptoms. Symptom onset should occur at least 6 months diabetes-associated chronic constipation, it is important to fo- before diagnosis, and symptoms should be present during cus attention on early identification and appropriate manage- the last 3 months [21]. ment of these complications for improving both diabetic care Functional constipation is divided into two subtypes: slow- and quality of life of the affected patient. transit constipation or colonic inertia is characterized by a There is no universally accepted definition of constipation. prolonged length of time for stool to pass through the entire In a real-world clinical setting, constipation tends to be a sub- colon [22]; obstructive defecation (also called pelvic floor jective diagnosis. Frequency of bowel movement is an impor- dyssynergia, dyssynergic defecation, anismus, or outlet ob- tant factor in the assessment of constipation, yet there is no struction) is characterized by difficulty in evacuation or a consensus on how often the ‘normal’ bowel opens. There is sense of incomplete evacuation after defecation. wide variation between individuals in ‘normal’ frequency of bowel movements, ranging from three times per day to three times per week, but many patients have expectations of a daily Pathophysiology bowel movement. In addition to frequency of stools, consis- tency of the stool is also important. The Bristol Stool Form The exact pathogenesis of chronic constipation in diabetes Scale is a useful visual aid that was designed to assist in the is not well understood. The autonomic nervous system is evaluation of patients with self-reported constipation who do intimately involved in the control of GI motility and sensi- not have infrequent bowel movements, to establish that hard tivity, and a disturbance of this system may be involved in or lumpy stools are indeed present [17]. the pathophysiology of constipation [15]. Autonomic dys- Based on definition, the prevalence of constipation varies function with a lack of synchronicity between the gut mus- between different populations across the world. The Rome culature and the sphincters is thought to be the major con- classification is widely recognized as a standardized tributing factor [23]. Battle et al. [24]intheirstudyofco- symptom-based classification of functional GI disorders, in- lonic myoelectric and motor activity, demonstrated that di- cluding functional constipation (Table 1)[18]. Other defini- abetic patients with chronic constipation had absent gastro- tions of constipation are consistent with the Rome criteria but colonic response to feeding, resulting in mild to moderate are less quantitative and more subjective [19]. The Rome constipation. High blood sugar levels in both types 1 and 2 criteria are however used principally for research purposes diabetes can lead to loss of interstitial cells of cajal (ICC) and are not widely applied in clinical practice [20]. The re- and diabetic neuropathy. Damage to the nerves controlling cently developed Rome IV classification defines functional the digestive tract motility can lead to chronic constipation constipation as a functional bowel disorder in which symp- and sometimes alternating bouts of diarrhea [25–28]. For toms of difficult, infrequent or incomplete defecation predom- many patients, this condition is chronic, with symptoms inate. Patients with functional constipation should not meet persisting 3 months or more [29]. Indian J Gastroenterol

Clinical evaluation practical approach to managing chronic constipation is sum- marized in Fig. 1. A complete history and physical examination is needed to elicit the cause of constipation. It is imperative to rule out Evidence-based management malignancy or other organic causes prior to making the diag- nosis of chronic constipation. Evaluation includes recording Non-pharmacological treatment exhaustive medical and social history including the patient’s psychological status, blood sugar levels, obstetric history (for It is imperative to understand the patient’s views and defini- women) and a complete list of medications that can be asso- tions of chronic constipation, which may often differ from ciated with constipation. It is important to determine the du- medical criteria. Treatment aims to improve symptoms and ration of symptoms to distinguish chronic from transient con- restore bowel function by accelerating colonic transit and fa- stipation, the amount of fiber the patient has as part of diet and cilitating defecation [37]. laxatives or other self-prescribed over-the-counter constipa- Many patients’ symptoms can be relieved with life- tion treatments the patient has indulged in, if any. A complete style and dietary modification, both of which should be physical examination with emphasis on the abdomen and per- implemented before opting for unnecessary tests or pre- ineum is imperative. scription medications. The patient should be encouraged The aim of clinical assessment should be to establish a to follow a healthy lifestyle, which includes a high-fiber symptom profile, in order to plan individualized bowel care. diet, increased water intake and physical activity [38]. A Evidence-based guidelines suggest that a structured approach formal evaluation of dietary fiber and fluid intake is required when assessing a patient with chronic constipation. should be carried out, before recommending further in- Routine extensive diagnostic and physiological testing is not crease in dietary fiber [39]. recommended for chronic constipation [30, 31]. However, in patients not responding to initial treatment, physiological tests Food and dietary changes can be used to assess anorectal disorders [32–35]. The objective of this manuscript is to provide an overview Dietary fiber can be defined as a plant-derived material of the clinical assessment and evidence-based treatment op- that is resistant to digestion by human alimentary en- tions for managing diabetes-associated chronic constipation. zymes [40, 41]. There are two main types of fiber, insoluble and soluble. Insoluble fiber is not acted on by colonic bacteria and does not create colon gas. It is an important fiber because it retains water within Methods the colon, promoting a large, bulky stool and improved regularity. Soluble fiber is fermented by colonic bacte- A literature search of published medical reports in English ria. Taken together and in adequate quantities, soluble language was performed using the OVID portal, from and insoluble fibers help improve constipation and min- PUBMED and the Cochrane Database of Systematic eral absorption. Reviews, from inception to October 2015. Abstracts were ini- The American Diabetes Association (ADA) guide- tially obtained using the following keywords: chronic consti- lines recommend lifestyle changes involving dietary pation’, type 1 diabetes’, type 2 diabetes’, treatment’ and and physical activity as first-line therapy for most indi- trials’. Manual searches of references and review articles sup- viduals with diabetes [42]. These are also first-line ther- plemented the computerized search, and only full-length arti- apy for patients who suffer from chronic constipation. cles were considered. The literature search was done by VGM Dietary fiber has a role to play in increasing stool Prasad along with an independent external agency. They then weight and improving bowel movement [43]. However, selected studies that satisfied the following inclusion criteria: before recommending changes or increase in dietary fi- (1) involving human subjects over the age of 18 years and (2) ber, a formal evaluation of dietary fiber and fluid intake describing at least one form of treatment for chronic constipa- needs to be conducted as excessive fiber intake can tion and chronic constipation in diabetes mellitus. Selected aggravate bloating and flatulence and lead to abdominal studies were evaluated by each reviewer for their quality and cramps. The generally recommended daily dietary fiber evidence according to the Strength of Recommendations intake in adults is 20–30g[39]. Vegetarianism is asso- Taxonomy (SORT), with levels of evidence from I to III and ciated with high dietary fiber intake. Therefore, thor- recommendations from A to C (Tables 2 and 3)[36]. ough evaluation of type of dietary fiber and recom- A total of 145 abstracts were identified; duplicate publica- mended dose should be conducted [44]. tions were removed and 95 relevant full-text articles were Although there is some evidence from controlled trials retrieved for potential inclusion. Based on the findings, a confirming the efficacy of high-fiber diets, this treatment fails Indian J Gastroenterol

Table 2 Laxatives used in management of chronic constipation and their level of recommendations

Category Drugs Mechanism Benefits Side effects Contraindications Level of Comments of action recommendation

Bulk-forming laxatives Wheat bran, Luminal Useful treatment Flatulence and Difficulty in Psyllium At least 3 psyllium water for small hard abdominal swallowing, [108–111]:A well-designed seed husk, binding stools. Benefit distension, GI intestinal RCTs showing methylcellu- increases irritable bowel obstruction or obstruction, benefits over lose stool bulk syndrome impaction colonic atony, placebo and patients, and and fecal Bran [112, 113]: Two controlled reduces colostomy and impaction B trials showed consistency ileostomy benefits in patients reducing use of laxatives Methylcellulose Only one [114]:B controlled trial of medium quality Osmotic laxatives Undigestible Lactulose [62, Luminal Gentle and Bloating, Galactosemia, A Two systematic disaccharides 115] water effective flatulence, intestinal reviews of binding by laxative action, diarrhea (with obstruction RCTs with creating prebiotic effect; large doses) benefits over osmotic does not increase BToo sweet placebos gradient blood sugar taste^ can be masked by diluting in water Synthetic Polyethylene Luminal Does not increase Abdominal Intestinal A At least 3 RCTs macromolecule glycol (PEG) water colonic gas distension perforation or showing [62, 116, binding and pain, obstruction, benefits over 117] nausea, paralytic ileus, placebo excessive severe diarrhea (can inflammatory be controlled conditions of with dose the GI tract adjustment) Stimulant laxatives Diphenylmethane Bisacodyl, Act locally to Patients Abdominal Intestinal Senna At least 3 derivatives sodium stimulate unresponsive or cramp, obstruction [118–120]:A controlled trials picosulfate colonic intolerant to fiber hypokalemia showing Anthraquinones Senna, aloe, motility, benefits over cascara decrease placebo water absorption from large intestine

A Strength of Recommendation Taxonomy (SORT) scale was used to grade the available evidence based on the quality, quantity, and consistency of available evidence. The SORT grading system emphasizes the use of patient-oriented outcomes that matter to patients, such as morbidity, symptom improvement, cost reduction, changes in quality of life, and mortality. A grade A recommendation is based on consistent (studies with similar or coherent conclusions) and good quality patient-oriented evidence (systematic review/meta-analysis of randomized controlled trials (RCTs) or individual high quality RCTs); Grade B recommendation is based on inconsistent and limited quality patient-oriented evidence (systematic review/meta-analysis of lower quality clinical trials or of studies with inconsistent findings, lower quality clinical trial, cohort or case-control study); and grade C recommendation is based on consensus guidelines, extrapolations from usual practice, expert opinions, disease-oriented evidence, or case series for diagnosis, treatment, prevention or screening to normalize bowel movements in up to 40% of patients, es- patients without a pathological finding became symptom- pecially in those with slow transit or impaired defecation free while 80% of patients with slow transit did not respond. [45–47]. Voderholzer et al. [48] conducted an observational Health practitioners regularly recommend increased study among 149 patients with chronic constipation when fluid intake to alleviate chronic constipation, although treated with dietary fiber (plantago ovate seeds); 85% of evidence suggesting benefit is limited. Indian J Gastroenterol

Table 3 Evidence-based recommendations of non- Treatment Level of Comments pharmacological treatments for recommendation chronic constipation Non-pharmacological Increasing dietary C No RCTs, data from multiple observational studies, results fiber [121–127] conflicting. More likely to be beneficial in people with fibers deficiency Increasing exercise B Two small RCTs with opposite results and two other cohorts [123, 128–130] showing benefits. More likely to be beneficial in people with lack of exercise Increasing fluids C One observational study and one controlled trial, the latter showing [131, 132] benefits of increased fluids only in the presence of sufficient fiber intake

A Strength of Recommendation Taxanomy (SORT) scale was used to grade the available evidence based on the quality, quantity, and consistency of available evidence. The SORT grading system emphasizes the use of patient- oriented outcomes that matter to patients, such as morbidity, symptom improvement, cost reduction, changes in quality of life, and mortality. A grade A recommendation is based on consistent (studies with similar or coherent conclusions) and good quality patient-oriented evidence (systematic review/meta-analysis of RCTS or individual high quality RCTs); Grade B recommendation is based on inconsistent and limited quality patient-oriented evidence (systematic review/meta-analysis of lower quality clinical trials or of studies with inconsistent findings; lower quality clinical trial, cohort or case-control study); and grade C recommendation is based on consensus guidelines, extrapolations from usual practice, expert opinions, disease-oriented evidence, or case series for diagnosis, treatment, prevention or screening

Exercise and lifestyle changes therapy. The Asian Neurogastroenterology and Motility Association and Rome IV recommend that therapy Regular physical exercise helps not only in the digestion should begin with a bulk-forming agent, followed by process but is also recommended in the ADA guidelines treatment with an osmotic laxative and stimulant laxa- as a key feature in managing diabetes, which in turn can tive in patients with inadequate response to bulk- improve GI complications by reducing diabetic neuropa- forming agents [39]. thy [49]. The ADA recommends moderate-intensity exer- Laxatives aid defecation by decreasing stool consis- cise for ≥150 min per week over ≥3 times per week with tency (softening) and/or artificially or indirectly stimu- no more than two consecutive days’ gap without exercise, lating colon motility via one or more mechanism for diabetes patients. The guidelines also recommend re- (Table 2)[20]. These formulations can be taken by ducing sedentary time (break up >90 min spent sitting). A mouth (liquids, tablets, capsules), or can be given via number of studies across different populations have the rectum (e.g. suppositories, enemas) [20]. Well-de- shown that lifestyle changes can reduce the incidence of signed, placebo-controlled, blinded, clinical trials of type2diabetesby28to59%,withtheeffectsseenmany older laxatives are sparse; similarly, there is a lack of years after the intervention [50–56]. head-to-head comparisons. As chronic constipation can be caused by a host of While developing treatment strategies, it is important lifestyle factors, such as change in routine, lack of reg- to recognize that patients with diabetes have composi- ular exercise, or ignoring the urge to defecate, lifestyle tional changes in the intestinal microbiota compared to modification incorporating appropriate amount of exer- non-diabetic patients. Gut microbiota are essential for cise is generally recommended as an initial management the digestion and production of organic acids to main- tool for treating mild to moderate symptoms of chronic tain an appropriate pH environment in the gut [57]. In constipation in diabetes mellitus patients [42]. diabetes patients, there is a loss of gut microbial diver- sity with an increase in opportunistic pathogens. In a Medical management study of 36 men, the relative abundance of Firmicutes (specifically Bacteroides vulgatus, Faecalibacterium If adequate relief is not obtained with dietary and life- prauznitzii) and the Bifidobacterium and Roseburia ge- style changes, a range of pharmacological agents can be nuses were observed to be significantly lower, while the considered. The most recognized and acceptable treat- proportion of Bacteroidetes and Proteobacteria was ment is the use of laxatives (Tables 2 and 3). There found to be somewhat higher in diabetic persons com- are no studies assessing a stepwise approach to laxative pared to their non-diabetic counterparts [58]. Indian J Gastroenterol

Fig. 1 Flow-chart for History and diabetes examination management of chronic (A1C >6.5% / FPG >126 mg/dL / 2-hour No constipation in diabetes patients plasma glucose >200 mg/dL during [20, 39] OGTT)

Yes Consider other diagnoses

Fulfilling Rome IV criteria for chronic constipation?

Yes Tests for pelvic floor dysfunction (PFD)

Normal Investigations for colonic colonic transit time transit PFD confirmed No PFD

Slow colonic transit Biofeedback

Inadequate Adequate intake of response dietary fiber, fluids or Partial division exercise of puborectalis

Start with bulk- Inadequate Consider osmotic agents like forming agents like response lactulose, polyethylene glycol psyllium or bran

Inadequate Consider stimulants like Inadequate response bisacodyl and senna response

Consider chloride channel activators, 5-HT4 antagonist, and guanylate cyclase-c receptor agonist

Probiotics and prebiotics can eradicate gut dysbiosis and Tramonte et al. (1997) listed six trials on treatment with fiber ameliorate inflammatory, metabolic and molecular imbal- laxatives, which resulted in increase of 1.4 bowel movement ances, thus preventing or treating diabetes and development per week [62]. A double-blind trial reported that fiber laxa- of neurodegenerative disease. Probiotic therapies increase in- tives gave significant symptom improvement, improved stool sulin sensitivity, inflammation, oxidative stress and GI dis- consistency and resulted in fewer complaints of abdominal tress. Prebiotics were shown to increase the level of species pain [63–65]. in the Bifidobacterium genus, an effect that positively corre- Psyllium husk is reported from well-designed, randomized, lates with improved glucose tolerance and glucose-induced placebo-controlled studies to improve symptoms and provide insulin secretion and reduced inflammatory markers [59, 60]. natural constipation relief by improving colonic transit time and stool consistency [66–68]. This is an edible soluble fiber Bulk-forming laxatives and a prebiotic. Psyllium husk swells when combined with water or another liquid, and produces more bulk, which stim- Bulk-forming laxatives, also known as fiber laxatives, add ulates the intestines to contract. It is also known to have pos- soluble fiber to the stool. This helps in retaining fluid in the itive effects on heart health, blood pressure and cholesterol stool, thus making stool soft and easier to pass. Commonly levels. It is safe, well-tolerated and improves glycemic control prescribed bulk-forming laxatives include ispaghula/psyllium in people with diabetes. In adults with chronic idiopathic con- husk, bran and methylcellulose [61]. A systematic review by stipation, psyllium increased the mean number of stools per Indian J Gastroenterol week by 0.9, compared to no change in the placebo group stimulating the growth or activity of one or a limited number (p < 0.05), in one 8-week trial [68]. Another trial found that of colonic bacteria (bifidogenic effect). This is supported by adults with chronic constipation who received 2 weeks of data from a prospective, randomized, controlled trial compar- psyllium were more likely to report normalization of bowel ing the effect of lactulose and PEG-4000 on colonic flora in 65 function than those who received placebo (87% vs. 30%, patients with chronic idiopathic constipation; fecal p<0.001) [64]. A third, 2-week study found that 87% of pa- bifidobacterial counts were higher in the lactulose group than tients allocated to psyllium reported improvement in symp- in the PEG group (p = 0.04). The study showed that lactulose toms compared to 47% of those who received placebo [63]. induced significant changes in the composition of fecal flora, One study found that psyllium not only improved blood sugar whereas PEG inhibited most of the metabolic activities of the in type 2 diabetic patients but also reduced the risk of coronary flora [74]. Bifidobacteria result in acidification of the colonic heart disease, suggesting that it can be considered as an effi- content, which is important for the energy metabolism and cacious option for diabetes patients with chronic constipation normal development of colonic epithelial cells and acts as a [69]. protective factor against colonic disease. In another random- ized controlled study, comprising 12 healthy volunteers per Osmotic laxatives group, the effect of lactulose, lactitol and placebo on colonic microflora and enzymatic activity was evaluated. Lactulose Osmotic laxatives work by creating an osmotic gradient that provided a better effect on colonic microflora and thus better increases the retention of water in the stool, making them soft prebiotic effect than lactitol. Lactulose was a better carbon and enhancing their passage. Osmotic laxatives include both source for the probiotic intestinal bacteria Bifidobacterium inorganic salts (magnesium compounds) and organic sugars and Lactobacillus than lactitol, resulting in a reduction in det- or alcohols such as lactulose, lactitol and polyethylene glycol rimental species [75]. (PEG). Their dose can be titrated according to the stool output, The clinical efficacy and safety of lactulose in treating and they are used for both chronic and occasional constipation chronic constipation have been established in randomized [70]. Lactulose and PEG have been shown to be effective and controlled studies. In a double-blind trial comparing lactulose safe treatments for chronic constipation and are commonly (60 mL/day) with placebo, lactulose produced significant in- used in both pediatric and adult populations. The alternative crease in stools per week (4.5 vs. 1.6 stools/week; p<0.05) as osmotic laxatives of magnesium hydroxide or magnesium well as stools of a softer consistency. Similarly, in another salts are satisfactory for occasional use or where rapid evacu- randomized, double-blind, placebo-controlled trial, lactulose ation is required but tend not to be used in the long-term [71]. (30 mL of 50% solution) was superior to placebo in improv- Osmotic agents are useful when first-line bulk-forming agents ing mean bowel movement frequency per week and reducing do not provide satisfactory outcomes. Abdominal bloating, severity of symptoms such as cramping, bloating and flatu- nausea and flatulence are side effects with some osmotic lax- lence [76, 77]. Lactulose has demonstrated superiority to atives [70]. ispaghula in terms of mean bowel movement frequency per Lactulose is a synthetic disaccharide that does not get week, and a trend of causing less abdominal pain was ob- absorbed in the small intestine nor is it broken down by human served [78]. Connolly et al. [79] reported that, after 1-week enzymes. It stays as a bolus and causes retention of water treatment with lactulose (15 mL twice daily), consistently through osmosis, leading to soften stool. It has a secondary more patients continued to produce normal stools than when laxative effect in the colon, where it is completely fermented they had received stimulant laxatives. Thus, lactulose can be by gut flora, producing metabolites that have osmotic abilities considered as an effective osmotic laxative in treating consti- and peristalsis-stimulating effect [72]. Fermentation also leads pation, with a possible positive effect on glycemic control in to production of lactic acid and volatile fatty acids especially diabetes patients. It has a superior prebiotic effect as com- acetic acids, which may interfere with glucose metabolism by pared to PEG and lactitol in the context of the growing rec- decreasing glucose hepatic production [73]. A small study ognition of gut dysbiosis in the pathogenesis of diabetes and evaluated the effect of purified lactulose (27–33 g/day) on constipation, along with the added benefit of carry-over ef- glucose tolerance in seven non-insulin dependent diabetic pa- fect, thus making it a suitable laxative for managing consti- tients during two randomized 10-day periods. At the end of pation in diabetics. the two periods, blood glucose levels during oral glucose tol- Another group of osmotic laxatives that is commonly used erance test were significantly lower when patients received is formulations containing polyethylene glycol.Highdosesof lactulose [72]. PEG-based formulations were originally used primarily for In healthy humans, the ingestion of lactulose has been colon cleansing prior to colonoscopy. They have also been shown to increase bifidobacterial degradation of primary to shown to be useful for fecal disimpaction in both children secondary bile acids. Lactulose can therefore be considered and the elderly [67, 80, 81]. These formulations are now used as a prebiotic as it positively affects host health by selectively to treat chronic constipation. Daily doses of 17 g have been Indian J Gastroenterol given for up to 6 months in adults [82, 83]. These are also safe stimulate the muscles in the digestive tract through their direct for use in children, pregnant women and the elderly. The most stimulant/irritant properties. They are usually used on a short- common side effect is diarrhea with liquid stools, which ap- term basis and start working between 6 and 12 h [95]. The pears to be a function of the dose, occurring in up to 17% with most commonly prescribed stimulant laxatives are senna, single dose and up to 36% with double dose; thus patients bisacodyl and sodium picosulphate. They are hydrolyzed in have to be taught to titrate the dose according to their response the gut by enterocyte enzymes or colonic flora, stimulate peri- [71]. Some formulations contain sodium and potassium; it is stalsis and sensory nerve endings, and possibly interfere with not known whether the small quantities present give rise to electrolyte flux to inhibit water absorption [66]. hypernatremia and hyperkalemia in the elderly and those with impaired renal functions [84]. Newer agents PEG provides well-tolerated and effective relief in consti- pated patients [85, 86]. In a 6-month placebo-controlled study, Prucalopride is a highly selective 5-HT4 agonist stimulating 304 patients with chronic constipation received either 17 g per prokinetic activity of the colon with minimal activity on 5- day PEG or placebo. Fifty-two percent of PEG-treated pa- HT3 and hERG receptors. It is reported to accelerate transit tients compared with 11% of placebo-treated patients and stool output in volunteers and patients [96, 97 ]. Three (p < 0.001) were successfully relieved for more than 50% of large studies in the USA and Europe [19, 98, 99], having their treatment weeks. No treatment-related safety differences identical inclusion criteria (laxative-refractory patients, with were observed, with the exception of abdominal distension, 80% having less than one spontaneous complete bowel move- diarrhea, loose stools, flatulence and nausea (39.7% of PEG- ment per week), reported that prucalopride was associated treated patients vs. 25% of placebo-treated patients; p=0.015), with increase in bowel frequency to more than 3 per week in which are considered usual effects of laxative use [87]. A 24% of patients compared with 11% in the placebo group. retrospective study of institutionalized patients with chronic Prucalopride is approved in Europe for the treatment of chron- constipation reported good long-term results for up to ic constipation [20]. 12 months [82], and for up to 5 months in randomized pro- Lubiprostone, a derivative of prostaglandin E1, is a spective studies in adult [88] and pediatric patients [89]. chloride-channel activator that stimulates intestinal fluid se- Most comparative data suggest that lactulose and PEG cretion. It acts on the enterocytes from the luminal side and is have similar efficacy in treating patients with chronic consti- not systemically absorbed, accelerating colonic transit and pation [85, 90]. A randomized, triple-crossover study of 57 softening stool consistency [100]. Three double-blind, ran- patients comparing PEG with lactulose showed that the agents domized, placebo-controlled trials have shown the efficacy have equal effect and were better than having nothing or pla- of lubiprostone in increasing spontaneous bowel movements cebo, in improving stool frequency and ease of defecation and improving self-reported symptoms of chronic constipa- [91]. A multicenter, randomized, controlled study conducted tion [101–103]. The long-term use of lubiprostone is reported among 65 patients reported the same results [74]. There are no to be safe [12]. Lubiprostone has been approved by the US data on the efficacy and safety of PEG in diabetes patients. FDA for treatment of chronic idiopathic constipation, consti- Milk of magnesia (magnesium hydroxide) is an osmotic pation caused by irritable bowel syndrome and opioid- laxative where the poorly absorbable magnesium ions cause induced constipation in adults with chronic, non-cancer pain water to be retained in the intestinal lumen; stimulation of [104]. cholecystokin in release and activation of constitutive nitric oxide synthase might contribute to its laxative actions [92, 93]. Evidence for its efficacy from randomized controlled trials Linaclotide is limited. One crossover study in 64 chronic constipated pa- tients aged 65 years or older revealed that magnesium hydrox- Linaclotide is a guanylate cyclase-C agonist that stimulates ide at mean dose of 25 mL daily for 8 weeks produced signif- intestinal fluid secretion and transit. It has been approved by icantly more normal stool consistency, more frequent bowel the US FDA for treatment of irritable bowel syndrome with movements and reduced requirement for bisacodyl treatment constipation and chronic idiopathic constipation, though it is compared with bulk laxative [94]. Reporting of adverse events currently not licensed in the EU. Results from two phase III is limited. In view of the risk of hypermagnesemia, it should not studies conducted among 1272 patients with chronic consti- be used in patients with renal impairment. pation reported linaclotide to improve bowel function in 20% of the patients. Abdominal symptoms, global measures of Stimulant laxatives constipation and quality of life were also seen to be signifi- cantly improved with no evidence of rebound constipation If the stool is soft but there is still difficulty in passing it, [105, 106]. Common adverse events were GI-related with stimulant laxatives can be prescribed. These laxatives diarrhea being the most common [107]. Indian J Gastroenterol

Conclusion constipation and associated complex medication regimens, reduce complications and improve adherence and related Chronic constipation is one of the most common GI symp- costs. Patient preferences such as cost, convenience and toler- toms in patients with diabetes, and occurs more frequently ance should be considered while selecting treatment regimens. than in healthy individuals [7, 8]. For some, this condition Lastly, patients who report frequent use of laxatives need to can be chronic, where symptoms can be severe and can sig- be educated about the potential complications that can result nificantly affect a patient’s quality of life. As clinical manage- from their long-term use. When prescribing laxatives to treat ment of diabetes improves and enables better glycemic control chronic constipation, especially in the diabetic patient, the to be achieved, prevention and clinical improvement of asso- primary healthcare provider should explain the rationale for ciated GI complications may be realized. This improvement in the prescription to the patient. As a means of increasing com- glycemic control could be particularly relevant to diabetes- pliance to prescribed medications, physicians should address associated changes in the ICC, which are considered to be a and alleviate probable concerns of diabetic patients by major underlying cause of many GI complications. The prev- highlighting the benefits of taking the prescribed agent, for alence of chronic constipation is higher in older adults, wom- example, describing the prebiotic effect and safety of lactulose en than men and among patients with diabetes who are taking in patients of diabetes with constipation. The patient should medications that can promote chronic constipation (e.g. also be instructed to contact the provider if short-term use of calcium-channel blockers) [9, 14]. Although it is not well the prescribed laxative fails to restore the patient’s regular understood, chronic constipation in this patient population bowel routine. This will discourage the patient from most likely results from slow transit caused by loss of ICC attempting self-treatment with one or more of the many laxa- function and smooth muscle myopathy. Moreover, autonomic tives that are available over the counter. neuropathy and neuroendocrine imbalances may also play a role [15]. Anorectal dysfunction, either because of anorectal Acknowledgements The assistance for conducting literature search sensory or motor abnormalities, should be considered, be- and writing was provided by Shalaka Marfatia of pharmEDGE and her team. cause these patients can benefit from biofeedback training. As there is no specific treatment for diabetes-associated Compliance with ethical standards chronic constipation, these patients are generally treated in thesamewayasthosewithchronicconstipation.Astep- Conflicts of interest VGMP, and PA declare that they have no conflicts wise approach is recommended while handling these pa- of interest. tients, given the multiple risk factors, coexisting morbid conditions and medication-induced causes. Management of medication-induced causes, lifestyle modification and non-pharmacologic therapies should be the first step, in References order to avoid unnecessary drug therapy. There is limited evidence to guide the order in which ther- 1. 5th Edition of the Diabetes Atlas released on World Diabetes Day. Brussels, Belgium: International Diabetes Federation, 2011. Available apeutic agents should be used, but detailed patient history via DIALOG http://www.ncbi.nlm.nih.gov/pubmed/26371734. along with an understanding of the patient’sglycemiccontrol, Accessed 6 April 2013. an understanding of slow or normal transit and absence of 2. Hu FB. Globalization of diabetes—the role of diet, lifestyle, and – defecatory dysfunction, can assist in developing patient- genes. Diabetes Care. 2011;34:1249 57. 3. Estimates by ‘Public health foundation of India’. Available via. specific treatment pathways. These usually comprise initiating DIALOG http://ccebdm.org/news.php. Accessed 16 May 2016. therapy with a bulk-forming agent, except in those who are 4. Forgacs I, Patel V. Diabetes and the gastrointestinal tract. bedridden, are cognitively impaired, or have other contraindi- Medicine. 2011;39:288–92. cations. For patients with a contraindication or lack of re- 5. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonom- ic neuropathy. Diabetes Care. 2003;26:1553–79. sponse to a bulking agent, an osmotic agent, such as lactulose 6. Phillips LK, Rayner CK, Jones KL, Horowitz M. An update on or PEG 3500 is indicated, followed by stimulants (bisacodyl, autonomic neuropathy affecting the gastrointestinal tract. Curr picosulfate, or senna), and finally the newer agents (chloride- Diab Rep. 2006;6:417–23. channel activators or 5-HT4 agonist) for severe or resistant 7. Ueno N, Inui A, Satoh Y. The effect of mosapride citrate on con- stipation in patients with diabetes. Diabetes Res Clin Pract. cases. 2010;87:27–32. Educational interventions and self-management programs 8. Cheng C, Chan AO, Hui WM, Lam SK. Coping strategies, illness directed at medication management and counseling have the perception, anxiety and depression of patients with idiopathic con- potential to improve clinical, humanistic, adherence and cost stipation: a population-based study. Aliment Pharmacol Ther. – outcomes. The underlying objective of these interventions 2003;18:319 26. 9. Maleki D, Locke GR 3rd, Camilleri M, et al. Gastrointestinal tract should be to assist patients better manage their diabetes along symptoms among persons with diabetes mellitus in the communi- with existing comorbid conditions such as chronic ty. Arch Intern Med. 2000;160:2808–16. Indian J Gastroenterol

10. Enck P, Rathmann W, Spiekermann M, et al. Prevalence of gas- 34. Bharucha AE, Wald AM. Anorectal disorders. Am J trointestinal symptoms in diabetic patients and non-diabetic sub- Gastroenterol. 2010;105:786–94. jects. Z Gastroenterol. 1994;32:637–41. 35. Muller-Lissner S. The pathophysiology, diagnosis and treatment 11. Schvarcz E, Palmer M, Ingberg CM, Aman J, Berne C. Increased of constipation. Dtsch Arztebl Int. 2009;106:424–31. prevalence of upper gastrointestinal symptoms in long-term type 1 36. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation diabetes mellitus. Diabet Med. 1996;13:478–81. taxonomy (SORT): a patient-centered approach to grading evi- 12. Janatuinen E, Pikkarainen P, Laakso M, Pyorala K. dence in the medical literature. J Am Board Fam Pract. 2004;17: Gastrointestinal symptoms in middle-aged diabetic patients. 59–67. Scand J Gastroenterol. 1993;28:427–32. 37. Bleser S, Brunton S, Carmichael B, Olden K, Rasch R, Steege J. 13. Ray G. Evaluation of the symptoms of constipation in Indian Management of chronic constipation: recommendations from a patients. J Clin Diagn Res. 2016;10:OC01–3. consensus panel. J Fam Pract. 2005;54:691–8. 14. Oh JH, Choi MG, Kang MI, et al. The prevalence of gastrointes- 38. Jamshed N, Lee ZE, Olden KW. Diagnostic approach to chronic tinal symptoms in patients with non-insulin dependent diabetes constipation in adults. Am Fam Physician. 2011;84:299–306. mellitus. Korean J Intern Med. 2009;24:309–17. 39. Gwee KA, Ghoshal UC, Gonlachanvit S, et al. Primary care man- 15. Maxton DG, Whorwell PJ. Functional bowel symptoms in diabe- agement of chronic constipation in Asia: the ANMA chronic con- tes—the role of autonomic neuropathy. Postgrad Med J. 1991;67: stipation tool. J Neurogastroenterol Motil. 2013;19:149–60. 991–3. 40. Kay RM. Dietary fiber. J Lipid Res 1982;23:221–42. 16. Belsey J, Greenfield S, Candy D, Geraint M. Systematic review: 41. Stephen AM, Cummings JH. Mechanism of action of dietary fiber – impact of constipation on quality of life in adults and children. in the human colon. Nature. 1980;284:283 4. Aliment Pharmacol Ther. 2010;31:938–49. 42. American Diabetes Association. Standards of medical care in di- — – 17. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intes- abetes 2016. Diabetes Care. 2016;39:S1 S106. tinal transit time. Scand J Gastoenterol. 1997;32:920–4. 43. Chen HL, Haack VS, Janecky CW, Vollendorf NW, Marlett JA. 18. Drossman DA. The functional gastrointestinal disorders and the Mechanisms by which wheat bran and oat bran increase stool – Rome III process. Gastroenterology. 2006;130:1377–90. weight in humans. Am J Clin Nutr. 1998;68:711 9. 19. Tack J, Muller-Lissner S. Treatment of chronic constipation: cur- 44. Tandon R, Babu S, Chhabra M, et al. Constipation, New Delhi/ – rent pharmacologic approaches and future directions. Clin Gurgaon, Reed Elsevier India Pvt. Ltd, 2013;1 60. Gastroenterol Hepatol. 2009;7:502–8. 45. Badiali D, Corazziari E, Habib FI, et al. Effect of wheat bran in treatment of chronic nonorganic constipation. A double-blind con- 20. Tack J, Muller-Lissner S, Stanghellini V, et al. Diagnosis and trolled trial. Dig Dis Sci. 1995;40:349–56. treatment of chronic constipation—a European perspective. 46. Graham DY, Moser SE, Estes MK. The effect of bran on bowel Neurogastroenterol Motil. 2011;23:697–710. function in constipation. Am J Gastroenterol. 1982;77:599–603. 21. MearinF,LacyBE,ChangL,etal.Boweldisorders. 47. Francis CY, Whorwell PJ. Bran and irritable bowel syndrome: Gastroenterology. doi:10.1053/j.gastro.2016.02.031. time for reappraisal. Lancet. 1994;344:39–40. 22. Vrees DM, Weiss EG. The evaluation of constipation. Clin Colon 48. Voderholzer WA, Schatke W, Muhldorfer BE, Klauser AG, Rectal Surg. 2005;18:65–75. Birkner B, Muller-Lissner SA. Clinical response to dietary fiber 23. Bekele G, Kabadi UM. Gastrointestinal manifestations of diabetes treatment of chronic constipation. Am J Gastroenterol. 1997;92: mellitus. Int J Diab Dev Countries. 1996;16:54–8. 95–8. 24. Battle WM, Snape WJ, Alavi A, Cohen S, Braunstein S. Colonic 49. Colberg SR, Sigal RJ, Fernhall B, et al. Exercise and type 2 dia- dysfunction in diabetes mellitus. Gastroenterology. 1980;79: betes. Diabetes Care. 2010;33:e147–67. – 1217 21. 50. Testa MA, Simonson DC. Health economic benefits and quality of 25. Fedorak RN, Field M, Chang EB. Treatment of diabetic diarrhea life during improved glycemic control in patients with type 2 – with clonidine. Ann Intern Med. 1985;102:197 9. diabetes mellitus: a randomized, controlled, double-blind trial. 26. Takahashi T, Matsuda K, Kono T, Pappas TN. Inhibitory effects of JAMA. 1998;280:1490–6. hyperglycemia on neural activity of the vagus in rats. Intensive 51. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in – Care Med. 2003;29:309 11. preventing NIDDM in people with impaired glucose tolerance. 27. Horvath VJ, Vittal H, Lorincz A, et al. Reduced stem cell factor The Da Qing IGT and diabetes study. Diabetes Care. 1997;20: links smooth myopathy and loss of interstitial cells of cajal in 537–44. – murine diabetic gastroparesis. Gastroenterology. 2006;130:759 52. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle 70. interventions to prevent diabetes in the China Da Qing diabetes 28. Sanders KM. Interstitial cells of cajal at the clinical and scientific prevention study: a 20-year follow-up study. Lancet. 2008;371: interface. J Physiol. 2006;576 Pt 3:683–7. 1783–9. 29. Pare P, Ferrazzi S, Thompson WG, Irvine EJ, Rance L. An epide- 53. Knowler WC, Fowler SE, Hamman RF, et al. For diabetes pre- miological survey of constipation in Canada: definitions, rates, vention program research group. 10-year follow-up of diabetes demographics, and predictors of health care seeking. Am J incidence and weight loss in the diabetes prevention program out- Gastroenterol. 2001;96:3130–7. comes study. Lancet. 2009;374:1677–86. 30. American College of Gastroenterology Chronic Constipation Task 54. Lindstrom J, Ilanne-Parikka P, Peltonen M, et al. Sustained reduc- Force. An evidence-based approach to the management of chronic tion in the incidence of type 2 diabetes by lifestyle intervention: constipation in North America. Am J Gastroenterol. 2005;100 follow-up of the Finnish diabetes prevention study. Lancet. Suppl 1:S1–4. 2006;368:1673–9. 31. Spiller RC, Thompson WG. Bowel disorders. Am J Gastroenterol. 55. Tuomilehto J, Lindstrom J, Eriksson JG, et al. For Finnish diabetes 2010;105:775–85. prevention study group. Prevention of type 2 diabetes mellitus by 32. Rao SS, Welcher KD, Leistikow JS. Obstructive defecation: a changes in lifestyle among subjects with impaired glucose toler- failure of rectoanal coordination. Am J Gastroenterol. 1998;93: ance. N Engl J Med. 2001;344:1343–50. 1042–50. 56. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, 33. Rao SS. Dyssynergic defecation. Gastroenterol Clin N Am. Vijay V. For Indian Diabetes Prevention Programme (IDPP). The 2001;30:97–114. Indian Diabetes Prevention Programme shows that lifestyle Indian J Gastroenterol

modification and metformin prevent type 2 diabetes in Asian 77. Wesselius-De Casparis A, Braadbaart S, Bergh-Bohlken GE, Indian subjects with impaired glucose tolerance (IDPP-1). Mimica M. Treatment of chronic constipation with lactulose syr- Diabetologia. 2006;49:289–97. up: results of a double-blind study. Gut. 1968;9:84–6. 57. Tremaroli V, Bäckhed F. Functional interactions between the gut 78. Rouse M, Chapman N, Mahapatra M, Grillage M, Atkinson SN, microbiota and host metabolism. Nature. 2012;489:242–9. Prescott P. An open, randomised, parallel group study of lactulose 58. Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota versus ispaghula in the treatment of chronic constipation in adults. in human adults with type 2 diabetes differs from non-diabetic Br J Clin Pract. 1991;45:28–30. adults. PLoS One. 2010; 5: e9085. 79. Connolly P, Hughes IW, Ryan G. Comparison of BDuphalac^ 59. Cani PD, Neyrinck AM, Fava F, et al. Selective increases of Band irritant^ laxatives during and after treatment of chronic bifidobacteria in gut micrflora improve high-fat-diet-induced dia- constipation: a preliminary study. Curr Med Res Opin. betes in mice through a mechanism associated with endotoxaemia. 1974;2:620–5. Diabetologia. 2007;50:2374–83. 80. Culbert P, Gillett H, Ferguson A. Highly effective new oral ther- 60. Tuohy KM, Rouzaud GC, Bruck WM, Gibson GR. Modulation of apy for faecal impaction. Br J Gen Pract. 1998;48:1599–600. the human gut microflora towards improved health using prebi- 81. Chen CC, Su MY, Tung SY, Chang FY, Wong JM, Geraint M. otics—assessment of efficacy. Curr Pharm Des. 2005;11:75–90. Evaluation of polyethylene glycol plus electrolytes in the treat- 61. Embarrassing bodies. Constipation. Treatment. NHS choices. ment of severe constipation and faecal impaction in adults. Curr Available via DIALOG.http://www.channel4embarrassingillnesses. Med Res Opin. 2005;21:1595–602. com/men-in-white-coats/constipation/treatment. Accessed 17 82. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A random- May 2016. ized, multicenter, placebo-controlled trial of polyethylene glycol ’ 62. Tramonte SM, Brand MB, Mulrow CD, Amato MG, O Keefe laxative for chronic treatment of chronic constipation. Am J ME, Ramirez G. The treatment of chronic constipation in adults. Gastroenterol. 2007;102:1436–41. – A systematic review. J Gen Intern Med. 1997;12:15 24. 83. Paille FCN, Alleaume B, Vicari F. An open six-month study of the 63. Odes HS, Madar Z. A double-blind trial of a celandin, aloevera safety of Transipeg for treating constipation in community medi- and psyllium laxative preparation in adult patients with constipa- cine. J Clin Res. 1992;2:65–76. – tion. Digestion. 1991;49:65 71. 84. Chaussade S, Minić M. Comparison of efficacy and safety of two 64. Coggrave M, Norton C, Cody JD. Management of faecal inconti- doses of two different polyethylene glycol-based laxatives in the nence and constipation in adults with central neurological dis- treatment of constipation. Aliment Pharmacol Ther. 2003;17:165– eases. Cochrane Database Syst Rev. 2014; CD002115. 72. 65. Suares NC, Ford AC. Systematic review: the effects of fibre in the 85. Dupont C, Leluyer B, Maamri N, et al. Double-blind randomized management of chronic idiopathic constipation. Aliment evaluation of clinical and biological tolerance of polyethylene gly- Pharmacol Ther. 2011;33:895–901. col 4000 versus lactulose in constipated children. J Pediatr 66. McRorie JW, Daggy BP, Morel JG, Diersing PS, Miner PB, Gastroenterol Nutr. 2005;41:625–33. Robinson M. Psyllium is superior to docusate sodium for treat- 86. Di Palma JA, Cleveland MV,McGowan J, Herrera JL. A random- ment of chronic constipation. Aliment Pharmacol Ther. 1998;12: ized, multicenter comparison of polyethylene glycol laxative and 491–7. tegaserod in treatment of patients with chronic constipation. Am J 67. Cheskin LJ, Kamal N, Crowell MD, Schuster MM, Whitehead Gastroenterol. 2007;102:1964–71. WE. Mechanisms of constipation in older persons and effects of fiber compared with placebo. J Am Geriatr Soc. 1995;43:666–9. 87. Migeon-Duballet I, Chabin M, Gautier A, et al. Long-term effica- 68. Ashraf W, Park F, Lof J, Quigley EM. Effects of psyllium therapy cy and cost-effectiveness of polyethylene glycol 3350 plus elec- trolytes in chronic constipation: a retrospective study in a disabled on stool characteristics, colon transit and anorectal function in – chronic idiopathic constipation. Aliment Pharmacol Ther. population. Curr Med Res Opin. 2006;22:1227 35. 1995;9:639–47. 88. Corazziari E, Badiali D, Bazzocchi G, et al. Long term efficacy, 69. Sierra M, Garcia JJ, Fernandez N, Diez MJ, Calle AP. Therapeutic safety and tolerability of low daily doses of isosmotic polyethyl- effects of psyllium in type 2 diabetic patients. Eur J Clin Nutr. ene glycol electrolyte balanced solution (PMF-100) in the treat- – 2002;56:830–42. ment of functional chronic constipation. Gut. 2000;46:522 6. 70. Emmanuel A. Current management of strategies and therapeutic 89. Loening-Baucke V, Pashankar D. A randomized, prospective, targets in chronic constipation. Therap Adv Gastroenterol. 2011;4: comparison study of polyethylene glycol 3350 without electro- 37–48. lytes and milk of magnesia for children with constipation and fecal – 71. Lee-Robichaud H, Thomas K, Morgan J, Nelson RL. Lactulose versus incontinence. Pediatrics. 2006;118:528 35. polyethylene glycol for chronic constipation. Cochrane Database Syst 90. Petticrew M, Rodgers M, Booth A. Effectiveness of laxatives in Rev. 2010; CD007570. adults. Qual Health Care. 2001;10:268–73. 72. Genovese S, Riccardi G, Rivellese AA. Lactulose improves blood 91. Freedman MD, Schwartz HJ, Roby R, Fleisher S. Tolerance and glucose response to an oral glucose test in non-insulin dependent efficacy of polyethylene glycol 3350/electrolyte solution versus diabetic patients. Diabetes Nutr Metab. 1992;5:295–7. lactulose in relieving opiate induced constipation: a double- 73. Cummings JH, Englyst HN. Fermentation in the human large blinded placebo-controlled trial. J Clin Pharmacol. 1997;37:904– intestine and the available substrates. Am J Clin Nutr. 1987;45: 7. 1243–55. 92. Izzo AA, Gaginella TS, Mascolo N, Capasso F. Nitric oxide as a 74. Bouhnik Y, Neut C, Raskine L, et al. Prospective, randomized mediator of the laxative action of magnesium sulphate. Br J parallel-group trial to evaluate the effects of lactulose and polyeth- Pharmacol. 1994;113:228–32. ylene glycol-4000 on colonic flora in chronic idiopathic constipa- 93. Izzo AA, Gaginella TS, Capasso F. The osmotic and intrinsic tion. Aliment Pharmacol Ther. 2004;19:889–99. mechanisms of the pharmacological laxative action of oral high 75. Ballongue J, Schumann C, Quignon P. Effects of lactulose and doses of magnesium sulphate. Importance of the release of diges- lactitol on colonic microflora and enzymatic activity. Scand J tive polypeptides and nitric oxide. Magnes Res. 1996;9:133–8. Gastroenterol Suppl. 1997;222:41–4. 94. Kinnunen O, Salokannel J. Constipation in elderly long-stay pa- 76. Sanders JF. Lactulose syrup assessed in a double-blind study of tients: its treatment by magnesium hydroxide and bulk-laxative. elderly constipated patients. J Am Geriatr Soc. 1978;26:236–9. Ann Clin Res. 1987;19:321–3. Indian J Gastroenterol

95. Constipation treatment. NHS choices. Available via DIALOG. 112. Sturtzel B, Elmadfa I. Intervention with dietary fiber to treat con- http://www.nhs.uk/Conditions/Constipation/Pages/Treatment. stipation and reduce laxative use in residents of nursing homes. aspx. Accessed 17 May 2016. Ann Nutr Metab. 2008;52:54–6. 96. Emmanuel A, Cools M, Vandeplassche L, et al. Prucalopride im- 113. Sturtzel B, Mikulits C, Gisinger C, Elmadfa I. Use of fiber instead proves bowel function and colonic transit time in patients with of laxative treatment in a geriatric hospital to improve the chronic constipation: an integrated analysis. Am J Gastroenterol. wellbeing of seniors. J Nutr Health Aging. 2009;13:136–9. 2014;109:887–94. 114. Hamilton JW, Wagner J, Burdick BB, Bass P. Clinical evaluation 97. Emmanuel AV, Roy AJ, Nicholls TJ, Kamm M. Prucalopride, a of methylcellulose as a bulk laxative. Dig Dis Sci. 1988;33:993–8. systemic enterokinetic, for the treatment of constipation. Aliment 115. Petticrew M, Watt I, Sheldon T. Systematic review of the effec- Pharmacol Ther. 2002;16:1347–56. tiveness of laxatives in the elderly. Health Technol Assess. 1997;1: 98. Quigley EM, Vandeplassche L, Kerstens R, Ausma J. Clinical 1–52. trial: the efficacy, impact on quality of life, and safety and tolera- 116. DiPalma JA, DeRidder PH, Orlando RC, Kolts BE, Cleveland bility of prucalopride in severe chronic constipation: a 12-week, MB. A randomized, placebo-controlled, multicenter study of the randomized, double-blind, placebo-controlled study. Aliment safety and efficacy of a new polyethylene glycol laxative. Am J Pharmacol Ther. 2009;29:315–28. Gastroenterol. 2000;95:446–50. 99. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo- 117. Cleveland MV, Flavin DP, Ruben RA, Epstein RM, Clark GE. controlled trial of prucalopride for severe chronic constipation. N New polyethylene glycol laxative for treatment of constipation Engl J Med. 2008;358:2344–54. in adults: a randomized, double-blind, placebo-controlled study. – 100. Sweetser S, Busciglio IA, Camilleri M, et al. Effect of a chloride South Med J. 2001;94:478 81. channel activator, lubiprostone, on colonic sensory and motor 118. Passmore AP, Davies KW, Flanagan PG, Stroker C, Scott MG. A functions in healthy subjects. Am J Physiol Gastrointest Liver comparison of Agiolax and lactulose in elderly patients with – Physiol. 2009;296:G295–301. chronic constipation. Pharmacology. 1993;47:249 52. 101. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, 119. Passmore AP, Wilson-Davies K, Stoker C, Scott ME. Chronic double-blind, randomized, placebo-controlled trial of constipation in long stay elderly patients: a comparison of – lubiprostone, a locally-acting type-2 chloride channel activator, lactulose and a senna-fiber combination. BMJ. 1993;307:769 71. in patients with chronic constipation. Am J Gastroenterol. 120. Marlett JA, Li BU, Patrow CJ, Bass P. Comparative laxation of 2008;103:170–7. psyllium with and without senna in an ambulatory constipated population. Am J Gastroenterol. 1987;82:333–7. 102. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride 121. Muller-Lissner S, Kamm MA, Musoglu A, Earnest DL, Dunger- channel activator, in adult patients with chronic constipation: a Baldauf C, Shetzline MA. Safety, tolerability, and efficacy of double-blind, placebo-controlled, doseranging study to evaluate tegaserod over 13 months in patients with chronic constipation. efficacy and safety. Aliment Pharmacol Ther. 2007;25:1351–61. Am J Gastroenterol. 2006;101:2558–69. 103. Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and safety 122. Towers AL, Burgio KL, Locher JL, Merkel IS, Safaeian M, Wald of lubiprostone in patients with chronic constipation. Dig Dis Sci. A. Constipation in the elderly: influence of dietary, psychological, 2010;55:1090–7. and physiological factors. J Am Geriatr Soc. 1994;42:701–6. 104. Sucampo receives marketing authorization for Amitiza in 123. Dukas L, Willett WC, Giovannucci EL. Association between physical Switzerland for treatment of chronic idiopathic constipation, activity, fiber intake, and other lifestyle variables and constipation in a 2009. Sucampo Pharma Europe Ltd. Available via DIALOG. study of women. Am J Gastroenterol. 2003;98:1790–6. http://www.sucampo.com. Accessed 7 June 2010. 124. Murakami K, Sasaki S, Okubo H, et al. Association between die- 105. Lembo AJ, Kurtz CB, Macdougall JE, et al. Efficacy of linaclotide tary fiber, water and magnesium intake and functional constipation for patients with chronic constipation. Gastroenterology. among young Japanese women. Eur J Clin Nutr. 2007;61:616–22. – 2010;138:886 95. 125. Okubo H, Sasaki S, Murakami K, et al. Dietary patterns associated 106. Carson RT, Tourkodimitris S, Macdougall JE, et al. Effect of with functional constipation among Japanese women aged 18 to linaclotide on quality of life in adults with chronic constipation: 20 years: a cross-sectional study. J Nutr Sci Vitaminol (Tokyo). results from two randomized, double-blind, placebo-controlled 2007;53:232–8. – phase 3 trials. Presented at DDW, May 1 5 2010. Abstract [847d]. 126. Lindeman RD, Romero LJ, Liang HC, Baumgartner RN, Koehler 107. Johnston JM, Schneier H, Lavins BJ, et al. Results from the ran- KM, Garry PJ. Do elderly persons need to be encouraged to drink domized withdrawal period of a phase 3 clinical trial of linaclotide more fluids? J Gerontol A Biol Sci Med Sci. 2000;55:M361–5. – in chronic constipation. Presented at DDW, May 1 5 2010. 127. Leung FW. Etiologic factors of chronic constipation: review of the Abstract [T1817]. scientific evidence. Dig Dis Sci. 2007;52:313–6. 108. McRorie JW, Daggy BP, Morel JG, Diersing PS, Miner PB, 128. Brown WJ, Mishra G, Lee C, Bauman A. Leisure time physical Robinson M. Psyllium is superior to docusate sodium for treat- activity in Australian women: relationship with well being and ment of chronic constipation. Aliment Pharmacol Ther. 1998;12: symptoms. Res Q Exerc Sport. 2000;71:206–16. 491–7. 129. De Schryver AM, Keulemans YC, Peters HP, et al. Effects of 109. Cheskin LJ, Kamal N, Crowell MD, Schuster MM, regular physical activity on defecation pattern in middle-aged pa- Whitehead WE. Mechanisms of constipation in older persons tients complaining of chronic constipation. Scand J Gastroenterol. and effects of fiber comparedwithplacebo.JAmGeriatr 2005;40:422–9. Soc. 1995;43:666–9. 130. Meshkinpour H, Selod S, Movahedi H, Nami N, James N, Wilson 110. Ashraf W, Park F, Lof J, Quigley EM. Effects of psyllium therapy A. Effects of regular exercise in management of chronic idiopathic on stool characteristics, colon transit and anorectal function in constipation. Dig Dis Sci. 1998;43:2379–83. chronic idiopathic constipation. Aliment Pharmacol Ther. 131. Robson KM, Kiely DK, Lembo T. Development of constipation in 1995;9:639–47. nursing home residents. Dis Colon Rectum. 2000;43:940–3. 111. Tomas-Ridocci M, Anon R, Minguez M, Zaragoza A, Ballester J, 132. Anti M, Pignataro G, Armuzzi A, et al. Water supplementation en- Benages A. The efficacy of Plantago ovata as a regulator of intes- hances the effect of high-fiber diet on stool frequency and laxative tinal transit: a doubleblind study compared to placebo. Rev Esp consumption in adult patients with functional constipation. Enferm Dig. 1992;82:17–22. Hepatogastroenterology. 1998;45:727–32.