healthmedicinet

Epidemiology

Similarly to most FGID, chronic constipation is more commonly diagnosed in female
patients (M/F ratio: 1: 2–3) (1, 2). Constipation is a prevalent disorders in Western
countries that may affect up to 30 % of the general population subject to the caveats
that definitions of constipation vary across studies (2). The financial burden of
chronic constipation is considerable, due to direct costs of the healthcare system
such as consultations, investigations, and drug therapy 9].

About 85 % of constipated patients that require medical care are already using laxatives
and, every year, in the United States approximately 82 million dollars are spent for
over-the-counter laxatives 10], 11].

Variability across studies on the prevalence of constipation is due to several factors,
including the age of the population under investigation, the definition of constipation
used and “those who propose it” (i.e., reported by patient or by a health care professional),
as well as the context in which the studies are carried out (i.e., community people
or hospitalized patient). The prevalence of constipation increases with age: in over
65 year-old population studies, 26 % of women compared to 16 % of men considered themselves
to be constipated, while in a 84 year-old subgroup of patients, the proportion of
sufferers increased to 34 % in women and 26 % in men, thus showing that age apparently
leads to a substantial levelling between sexes 12], 13]. Moreover, when the prevalence of self-reported constipation was investigated in
a door-to-door survey of 209 community-dwelling elderly 30 % of men and 29 % of women
described themselves as constipated at least once a month 14]. The primary symptom used to define constipation was having to strain in order to
defecate. The number of chronic illnesses and the number of medications were significantly
related to constipation 14]. In addition, frailty in older persons is very common and is associated with immobility,
poor food intake, and dehydration 15]: an old study reported that constipation is present in 45 % of frail elderly persons
16]. In a community-based study from Olmsted County (Minnesota, USA), which included
100 patients aged 65 years-old or older, the overall prevalence of constipation reported
by patients was 40 %: 24.4 % affected by functional constipation and 20.5 % by outlet
dysfunction 17]. In a recent study, data from the Australian Longitudinal Study of Ageing were used
to compare differences in constipation and laxative use in 239 community elderly between
1992–93 and 2003–04. Over the years, the prevalence of self-reported constipation
increased from 14 to 21 % as well as laxative use from 6 to 15 %. Persistent chronic
constipation was reported by 9 % of the cohort. Female prevalence was evident at both
time points. Unexpectedly, the association between laxative use and self-reported
constipation was poor (less than a third of cases) suggesting sub-optimal management
of constipation in the elderly 18].

When defining constipation on the basis of the number of weekly bowel movements, its
prevalence decreases to values of 10 % or lower using a cut-off of more than 2 evacuations
or less per week. Interestingly, among people who report constipation, only up to
10 % have less than two bowel movements per week while almost half of them have a
daily bowel movement 14], 19], 20].

Constipation is more frequent among elderly patients forced to periods of long-term
care in hospital or nursing homes 21], 22]. A Finnish study showed a prevalence of constipation or evacuation disturbances in
57 % of women and 64 % of men among the general population whereas the prevalence
increased to 79 and 81 %, respectively, among guests of a nursing home 23]. Moreover, up to 74 % of patients staying in long-term care facilities uses laxatives
on a daily basis 23]. A recent prospective study on elderly inpatients aimed to explore predictors associated
with constipation during acute hospitalization comparing stroke patients (?=?55) with orthopaedic patients (?=?55) 23]. The incidence of “de novo” constipation was high for both stroke (33 %) and orthopaedic
patients (27 %; p?=?0.66) with bedpan use and longer length of stay both increasing new-onset constipation
24]. The high rate of constipation in the elderly population not only results in worsening
of quality of life and incremental economic costs, but can also increase the risk
of several complications including overflow faecal incontinence thus prolonging hospitalization
20]–22].

Quality of life

It is generally assumed that constipation affects unfavourably patients’ quality of
life (QOL) 2], 3]. Rather unexpectedly, few solid data have been reported particularly in the elderly
population. A recent study by Rao and co-workers analysed the effects of constipation
on QOL and psychological status in 158 subjects with 76 having a functional defecation
disorder and 38 slow colon transit constipation, while 44 were controls 25]. Subjects had to answer an 8-domain-questionnaire on health status, including general
health, vitality, social functioning, emotional role (limitation of daily activities
causing emotional problems) and mental health. A higher score was associated with
a normal healthy status. Compared with patients with slow transit constipation and
control subjects, patients with dyssynergic defecation had greater psychological distress
and impaired health-related quality of life (HR-QOL) 25]. The latter group also showed a higher prevalence of paranoid ideation, hostility
and obsessive-compulsive disorder compared to controls. Moreover, anxiety disorders,
depression as well as somatization and psychosis had a significantly higher prevalence
in both groups of patients with constipation symptoms compared to controls 25].

Similarly, in 126 community-dwelling older adults, respondents with chronic constipation
had lower Short-Form 36 (SF-36) scores for physical functioning, mental health, general
health perception, and bodily pain when compared to respondents without constipation
26]. Data were replicated using the Psychological General Well-Being (PGWB) index in
84 elderly subjects with constipation showing lower PGWB total scores and lower domain
scores for anxiety, depression, well-being, self-control and general health subscales,
indicating worse HR-QOL 3]. In addition, improvements on HR-QOL were noted with effective treatment of constipation.
Increasing weekly bowel movements was associated with patients’ report of fewer urinary
symptoms, better sexual function and improved mood 5]. More recently, in a study by Talley and co-workers, a questionnaire was proposed
to 100 people over the age of 65 years in order to evaluate the impact of chronic
constipation on their quality of life 27]. A markedly higher prevalence of physical pain and a decrease in perception of health
in constipated patients compared to healthy controls was shown. The study also confirmed
that constipation negatively affected both social and working life of patients 27].

Constipation is often associated with other symptoms that influence negatively the
daily life. Indeed, an epidemiological survey of constipation performed in Canada
showed that 32 % of constipated patients also need to make efforts during defecation,
20 % eliminate hard stools and 13 % has the feeling of incomplete evacuation or difficult
stool passage 28].

Pathogenesis of constipation

From a pathogenetic point of view, chronic constipation may itself be the disease,
such as in primary forms, or be part of a complex clinical picture, as in secondary
forms. This distinction is crucial for a proper management of constipation.

Primary forms are further distinguished according to their pathophysiological characteristics:

1) Slow transit constipation is characterized by prolonged transit time of stool through the colon and an often
reduced rectal sensitivity. In physiological conditions colon motor activity is irregular,
since it increases after meals and after wake up while it decreases during sleep 29]. It is characterized mainly by not propagated waves, that allow the mixing of intraluminal
content in order to promote water and electrolytes absorption, and also by propulsive
waves, including high (HAPCs) and low amplitude propagated contractions (LAPCs) 29]–31]. HAPCs promote rapid movements of intraluminal content and their presence is often
associated with evacuation 29].

Patients suffering from chronic constipation showed a significantly HAPCs reduction
(5 per day) compared to healthy controls 29]–31]. In addition, gastro-colic reflex, which exerts an important control on colonic peristalsis,
is deficient in patients with chronic constipation 32]. Thus, altered colonic motility plays a major role in the slowdown of gastrointestinal
transit in patients with slow-transit constipation.

Slow transit constipation may be associated with several endocrine and metabolic disorders,
such as hypothyroidism, hypercalcemia, porphyria or diabetes mellitus, or may occur
without any other significant systemic, gastrointestinal or neurological diseases
2].

Recent studies on slow transit constipation aimed to define alterations involved in
cellular mechanisms of intestinal coordination and motor function, such as smooth
muscle innervation (intrinsic or extrinsic) and interstitial cells of Cajal (ICC,
the pace-maker of gastro-entero-colonic motility) 33]. In particular, histological studies of biopsy specimens obtained from patients who
underwent colectomy for severe constipation have shown alterations in both enteric
neurons (apoptotic type which justify a greater tendency to neurodegeneration) and
enteric glial cells (cells that support enteric neurons), leading to neuronal survival
impairment; indeed, glial cells produce neurotrophic factors, the lack of which could
act as a trigger signal of neurodegeneration 33]–35]. Enteric neuronal function abnormalities are associated with a reduced amplitude
of nerve inhibitor impulses on colon circular muscular layer and, hence, with a lack
of coordination between colonic segments 32].

Furthermore, surgical specimens obtained from patients undergoing colectomy for severe
constipation have shown a marked depletion of ICC 36]; how and why these pacemaker cells alterations can influence neuro-mediated mechanisms
remains unclear in the pathophysiology of slow transit constipation.

Colonic structural abnormalities can include neuropathies/myopathies/mesenchymopathies, if ICC are affected, or can be often combined (neuro-ICC-myopathies); furthermore,
the resulting dysfunction may diffusely involve alimentary canal 36]. In this case constipation is part of a generalized gastrointestinal motility disorder
such as that of chronic intestinal pseudo-obstruction 33], 36].

Two relevant aspects of slow transit constipation pathophysiology have been noticed
specifically in elderly: an increased deposit of collagen in the ascending colon,
which may cause both motor and compliance alterations 34], and the presence of a greater number of binding sites for plasmatic endorphins 37]. Both these mechanisms, although apparently not connected to each other, may contribute
to slowing down the faecal transit, leading to constipation.

2) Outlet obstruction: (constipation by difficult or unsatisfactory expulsion of faeces from rectum) may result from a lack of coordination between abdominal muscles contraction and
pelvic floor muscle relaxation on straining, and/or from an obstructed perineal transit
due to anorectal structural abnormalities or uro-gynecological diseases 2].

The anal sphincter pressure reduction, both at rest and on squeezing, may be caused
by loss of muscular mass and contractility along with a damage of the pudendal nerve
17]. In particular, in the elderly it is also associated with a lower elasticity of the
rectal wall, with a fibro-adipose degeneration and with an increased thickness of
the internal anal sphincter 38], 39]. Therefore, during events such as anal stenosis or fissures, proctitis, rectocele,
haemorrhoids and uro-gynecological disorders pelvic floor dysfunction may develop
causing both faecal incontinence and constipation on the aged anorectum 39].

3) Constipation in IBS: in this case the typical symptom is abdominal pain that tends to resolve or markedly
fade with evacuation. Although IBS is more common in younger individuals, elderly
subjects are not spared by this FGID and the diagnosis might be overlooked 40]. A recent survey of 230 consecutive elderly attending an elderly care clinic, showed
that symptoms suggestive of IBS were reported by 22 % of the sample often associated
with disabling non-colonic symptomatology 40]. However, a physician diagnosis was only made in one patient without taking the chance
of reducing the overall burden of suffering in those potentially affected 40].

Different types of primary constipation may be present alone or coexist in the same
patient 41].

On the other hand, secondary forms of constipation can be caused by several systemic
diseases as well as by some drugs of common use, including opiates, anticholinergics,
calcium channel blockers and NSAIDs 2]. The most common causes of secondary constipation are summarized in (Table 1).

Table 1. Common causes of secondary constipation?

Constipation may be induced by all conditions that alter the integrity of both structural
and functional components of neuro-muscular bowel system such as amyloidosis, Hirschsprung’s
disease and diabetes mellitus neuropathy, neurodegenerative diseases (Alzheimer’s
disease, PD and tauopathies in general) and paraneoplastic syndromes 2], 12]. Thus, since the prevalence all these conditions increases with age, also does constipation
12], 22]. Moreover, dyssynergic defecation with outlet dysfunction is relevant aetiology for
constipation in PD and correlates with the severity of the neurology disease 42].

In addition, chronic constipation may occur in patients suffering from psychological/psychiatric
disorders, endocrine abnormalities (especially hypothyroidism), and hydroelectrolytic
abnormalities, such as hypokalemia and hypercalcemia, all common conditions in the
elderly 22].

Finally, elderly patients often live a sedentary lifestyle, reduce water intake resulting
in dehydration, and eat less fibre in their diet affecting gastrointestinal transit
and promoting constipation 14], 22]. We have recently reported on the incidence of new onset constipation in six out
of ten healthy young males with symptoms suggestive for outlet dysfunction after 1 month
of experimental bed rest 43].

Diagnosis

In clinical practice, dealing with a constipated patient requires accurate collection
of anamnestic data, with particular attention to family history, medications (especially
those that are known to slow down the gastrointestinal transit) and comorbidities,
together with a physical examination that includes digital rectal examination 2].

In an effort to improve diagnostic categorization, an International group of experts
has proposed a number of symptom-based criteria for FGID, including chronic constipation,
known as the Rome criteria. In Table 2 are listed the main criteria as reported in the latest edition (Rome III) 41]. These, together with the exclusion of alarm symptoms (such as rapid weight loss,
hematochezia, family history of colorectal cancer or inflammatory bowel disease, positive
faecal occult blood test, iron deficiency anaemia and a recent onset constipation)
may lead to the diagnosis of functional constipation, often avoiding unnecessary and
costly examinations. The presence of any alarm symptom requires further investigations,
including colonoscopy.

Table 2. Rome III diagnostic criteria for chronic constipation

While the diagnostic predictivity of Rome III criteria in irritable bowel syndrome-related
constipation has been evaluated in several studies, data on chronic constipation are
still lacking 44]. In addition, although often applied in clinical trials the Rome III criteria are
not commonly used in the clinical practice 44]. O the other hand, the Bristol stool scale could be a useful tool in daily practice
45]. This is a seven level scale based on the texture degree and morphology of faeces,
which correlates with gastrointestinal transit times. The first two levels are representative
of slow intestinal transit, while stool consistency levels of 6 and 7 correlate to
an accelerated transit and diarrhea 45].

A well performed digital rectal examination may reveal the presence of morphology
alterations of the pelvic floor (proctitis, rectal prolapse, rectal cancer, etc.),
additionally allowing for functional evaluation of the anorectum (anal sphincter tone,
evacuatory dysfunction) 2], 7].

Furthermore, rectal examination is highly relevant on diagnosing faecal impaction,
a major cause of bowel obstruction in the elderly 7]. In some cases, faecal impaction can induce pseudo-diarrhoea due to the passage of
fluid and mucus around the faecal conglomerate (overflow) 7]. If clinically misinterpreted, pseudo-diarrhoea can lead to the administration of
anti-diarrheal drugs that further aggravate intestinal obstruction 7]. Rectal examination can be integrated with the use of an anoscope or a proctoscope,
which allows a direct view of anal canal and rectum 2]. A simple Foley catheter balloon expulsion test has been proved reliable and useful
test to diagnose an evacuation disorder of both functional and altered morphology
origin 46]. In addition, to obtain a complete evaluation a standard abdominal radiograph and
a barium enema could eventually be considered to look for megabowel and/or massive
stool retention 47].

In the absence of alarm signs, a correct management of constipated patients is based
on the use of an empiric therapy, followed by the observation of clinical effects,
which can lead the clinician to a specific diagnosis 47]. In non-responders to conservative treatment, some functional tests are useful to
clarify pathophysiological changes in patients with constipation after consideration
of performing endoscopy.

A gastrointestinal transit time evaluation, which consists in ingesting radio-opaque
markers, followed by an abdominal radiological evaluation to check the distribution
of markers, allows us to differentiate slow transit constipation (markers distributed along colic frame) from outlet obstruction (markers located almost exclusively in rectal ampulla) 31]. So far colonic manometry had a minimal clinical value and has been used only for
research purposes 47]. The improvement of this test with the spatio-temporal map evolution, through high-resolution
manometry, is expected to open new clinical perspectives to the manometric assessment
of the colon 31].

Gastrointestinal and/or ano-rectal manometric tests may be clinically useful to reveal
an underlying neuropathy or myopathy of gut, as well as to determine if motor patterns
(inter-digestives and post-prandial) anomalies can be identified in the small intestine
33]. Some years ago, a study by our group clearly showed that approximately two thirds
of patients with constipation had small intestine motor abnormalities 48]. Thus, proposing a colectomy to patients with severe slow transit constipation, without
having evaluated the motility of both ano-rectum and small bowel by manometry, should
be avoided. Indeed, the more the motor disorder is extended throughout the alimentary
tract, the less is the long-term therapeutic success of colectomy in constipated patients
49]. In addition to standard techniques, colonic transit can also be measured using the
wireless motility capsule (WMC) which simultaneously provides valuable transit time
information about the stomach and small bowel as well. This becomes particularly relevant
when a multi regional motility disorder is suspected and tolerance to invasive procedures
is limited. A recent WMC study on 161 FGID patients has provided evidence of multiregional
intestinal dismotility in approximately half of the subjects that was poorly gained
by the clinical picture 50].

In outlet obstruction, anorectal manometry detects changes in the anal sphincters contraction and relaxation,
related to the presence of faeces. These tests are important not only for diagnostic
purposes but also to set therapies based on rehabilitation techniques such as bio-feedback
51].

Finally, dynamic videoproctography or MR defecography can be used to further investigate
cases of constipation due to obstructed defecation 47]. Diagnostic strategies do not appear to depend upon age, but this needs to be evaluated
on a case-to-case basis.

Treatment

Non-pharmacological treatment, which consists in diet and lifestyle modifications
is traditionally considered the first step of a comprehensive treatment program to
effectively manage constipation. 47]. A number of patients would believe that they need to have a bowel movement every
day; counselling on simple lifestyle changes may improve their perception of bowel
regularity and a diary log reporting on stool pattern and consistency may be helpful
as well 11]. In addition, patients should be educated on recognizing and responding to any urge
to defecate. A regular daily routine, starting with a light physical activity, is
particularly recommended. The optimal times to have a bowel movement are soon after
waking and after meals, when normal colon accentuates its motor activity 29]. Therefore, patients should be advised to attempt defecation first thing in the morning
and in the post-prandial intervals to profit most of the gastro-colic reflex 29].

A gradually increasing intake of fluids and fibres up to 30 g/day is suggested 11], 12]. This goal can be achieved by recommending patient to integrate the diet with more
fruits, vegetables and nuts in addition to adding varying amounts of bran. However,
in elderly patients, increments in fluid intake should be monitored especially in
those with cardiac and renal disease 12]. In a classical study, this approach has been reported to fasten colon transit time
in the constipated elderly without mirroring significant improvement on symptoms 52]. On the contrary, a recent small sized study reported on the efficacy of diet and
lifestyle modification on symptoms and QOL in 23 constipated elderly showing a significant
improvement on both parameters 53]. Moreover, the position paper of the American College of Gastroenterology on constipation
had concluded that fibre are effective treatment in adults, but adverse events, bloating,
distension, flatulence, and cramping may limit their use, especially if increases
in fibre intake are not introduced gradually 54]. In addition, fibres appear to be scarcely useful not only in patients with proven
slow transit constipation, but also in those who suffer from pelvic floor dysfunction
31]. Although very rarely, bowel sub-obstruction secondary to high fibres dietary intake
have been reported in elderly patients 55]. In an effort to overcome bran side effects a number of soluble fibres have been
developed among them: naturally occurring (psyllium seeds), semi-synthetic (methyl
cellulose) and synthetic (calcium polycarbophil) 56]. These compounds might also be regarded as bulking forming laxatives for the mechanism
of increasing stool bulk by holding liquid in the gut 56]. Psyllium and calcium polycarbophil have both been shown more effective than placebo
in randomized controlled trials 56]. However, low palatability and occurrence of side effects, such as flatulence and
abdominal bloating likely due to fermentation by intestinal microbiota have been associated
with high drop-out rates in the elderly 57]. Finally, a recent randomized controlled trial (RCT) showed that dried plums were
more effective than psyllium on improving bowel frequency and stool consistency in
adults with mild to moderate constipation 58].

Other currently available non-pharmacological treatment options for constipation are
probiotics. Nowadays, probiotics are familiar to the public as the components of bioyoghurts
and dietary supplements, are widely available, and commonly prescribed. The faecal
flora changes markedly with age mostly by a fall in numbers of bifidobacteria 55]. However, it is still unclear whether this is a cause or the effect of constipation.
It has been repeatedly reported that probiotics in the elderly may both shorten bowel
transit and soften stools most likely by the increased short chain fatty acid concentration
59]. A logical choice would be to consider probiotics as a mainstay of treatment for
their lack of side effects and absence of inference with medications. Preliminary
data supported this consideration, but large, randomized, controlled trials have failed
to show a significant benefit on the complex clinical picture of constipation in the
elderly 55], 59].

Biofeedback therapy to teach adequate defecatory effort is effective treatment in
adults with dyssynergic defecation 51]. The treatment protocol employed in most RCTs performed in the adult population includes
four steps: 1)Patient education on appropriate defecation effort, 2) Straining training
to improve abdominal pushing effort, 3) Training to relax pelvic floor muscles while
straining by visual feedback of anal canal pressure or averaged anal EMG activity,
4) Practice simulated defecation by using inflated rectal balloon 60]. Some Centers include optional sensory training which is intended to lower the threshold
for the sensation of urgency to defecate 60]. In the older ones, data are limited to a single RCT reporting on clinical and anorectal
physiology benefit associated with EMG-biofeedback treatment in 15 elderly patients
with dyssynergia when compared to an analogue control group 61]. In community dwelling constipated elderly biofeedback might be considered a therapeutic
option for dyssynergic defecation, but larger RCT are eagerly awaited 62].

Although widely practiced, stool softeners have limited evidence in the management
of constipation in the elderly 62]. Suppositories and enemas may be used in institutionalized patients to help rectal
evacuation in an effort to prevent faecal impaction 22]. Side effects such as electrolyte imbalances and rectal mucosal damage have been
reported with the use of phosphate and soapsuds enema, respectively. When indicated,
tap water enema is the safest way to go 22].

Pharmacological therapy

Usually, when simple changes to lifestyle and diet do not improve constipation, the
use of laxatives is recommended 62]. However, the use of laxatives must be individualized with special attention to cardiac
and renal co-morbid conditions, drug interactions, and side effects particularly in
the frail elderly 22], 62]. This heterogeneous group of drugs includes many products which differ in pharmacological
characteristics and mechanism of action, but all of them having the common purpose
of stimulating defecation or softening the consistency of faeces in order to facilitate
their expulsion (Table 3). Many types of laxatives are nowadays available, however we will focus mainly on
those with major indications for the treatment of chronic constipation in the elderly.

Table 3. Laxative compounds commonly used to treat chronic constipation?

Stimulant laxatives are a diverse class of agents derived primarily from anthraquinones
and diphenylmethanes 31]. These drugs have a stimulating and irritating action on the intestinal mucosa that
increases its secretory activity, thereby increasing water content in the intestinal
lumen. In addition, these laxatives have probably a direct action on the enteric innervation
(the enteric nervous system), increasing intestinal motor activity 55], 57]. To this class of laxatives belong senna, cascara, rhubarb, aloe, bisacodyl and sodium
picosulfate 31]. Notwithstanding their limited cost, stimulant laxative chronic use has historically
been discouraged based on anecdotal fears of potential complications 62]. In classical studies, silver staining studies suggested their chronic use may result
in enteric neuropathies, including replacement of ganglia by Schwann cells and losses
of neurons in the smooth muscle of the colon and myenteric plexus 31], 47]. More advanced techniques have failed to confirm these findings 31], 47]. Melanosis coli (dark colour of colonic mucosa) is a typical endoscopy finding in
patients with prolonged use of stimulant laxatives, but it does not have a pathological
significance 47].

In recent RCTs both bisacodyl and sodium picosulfate proved effective on increasing
the number of complete spontaneous bowel movements/week compared to placebo in constipated
adults, but data in the elderly are lacking 62]. However, a senna fibre combination in 77 constipated elderly residents in long term
hospital or nursing home care improved stool frequency, stool consistency, and ease
of evacuation when compared to lactulose 63].

Osmotic laxatives are hyperosmolar agents that cause secretion of water into the intestinal
lumen by osmotic activity thus improving bowel transit and stool consistency. Lactulose,
lactitol and macrogol are the most commonly and safest compounds used in the elderly
55], 57], 64].

Lactulose and lactitol are both synthetic, non-digestible disaccharides that are fermented
by colonic bacteria to increase stool water content and soften the stool 57]. This process may enhance proliferation of lactobacilli (prebiotic action) and shorten
bowel transit by promoting stool acidification 57].

In a multicenter trial of 164 patients including a group of elderly, lactulose was
found to be more effective on improving bowel frequency by day seven compared with
laxatives containing senna, anthraquinone derivatives, or bisacodyl 64]. In a similar study comparing osmotic compounds sorbitol was as effective as lactulose
on improving constipation, but was cheaper and better tolerated 65]. Lactitol efficacy has been extensively evaluated in the constipated adults, but
the efficacy in the elderly is limited 66]. A recent meta-analysis concluded that the efficacy on improving symptoms of constipation
of lactitol and lactulose are similar as well as tolerance to the drugs 66]. Finally, a double blind vs placebo study conducted by Ouwehand et al. studied the
effects of a symbiotic combination of Lactitol and Lactobacillus acidophilus NCFM on bowel function and immune parameters in a small group of healthy elderly 67]. The symbiotic preparation was more effective than placebo on increasing bowel movements
and improving gut mucosal immune function, thus suggesting future therapeutic applications.

Among osmotic agents, polyethylene glycol (PEG) or macrogol 3350–4000 is the one where
sound evidence of effectiveness on improving constipation in RCTs is best provided
54]. PEG is made from organic, iso-osmotic, non-absorbable polymers, that do not act
by modifying osmotic exchanges but by retaining water introduced with diet within
the intestinal lumen, hence increasing the faecal mass and reducing stool consistency
68]. Two pivotal RCTs, one in the US and the other in Europe, have shown that PEG is
more effective than placebo on achieving long term treatment success in constipated
adults 69], 70]. In the US based one, treatment success was defined as relief of modified Rome criteria
for constipation for 50 % or more of weeks of treatment 69]. In this study the treatment effectiveness was similar when a subgroup analysis involving
75 elderly patients was performed 69]. In a large sized RCT, PEG 17 g daily was more effective than placebo at 4 weeks
on improving drug induced constipation, a common problem in the elderly 71]. In a multicenter, placebo controlled study, PEG was shown to correct bowel movements
also in IBS adult patients with constipation, but with no significant effects on digestive
symptoms 72]. Bloating and flatulence represent the most frequent side effects of osmotic laxatives
with some PEG studies failing to report on the total number of side effects 54]. A recent meta-analysis, showed that PEG, compared to placebo or to other laxatives
(usually lactulose), significantly increased the number of bowel movements per week
in constipated adults 73].

However, two recent reviews concluded that despite increasing efforts on including
the elderly in RCTs, most studies on the use of laxatives in constipated older adults
provide limited evidence for small sample size and methodology biases 57], 62]. In addition, severe laxative side effects as dehydration, electrolyte imbalances,
allergic reaction, and hepatotoxicity have all been reported in the elderly suggesting
a tailored approach in this potentially frail population 22].

Despite the wide range of laxatives, it is estimated that about half of constipated
patients do not achieve satisfactory results with the drugs so far described 74]. Thus, new products based on more physiological mechanisms of action have been developed
in the attempt to treat a larger share of constipated subjects 54], 62]. Among the new therapeutic options for constipation, emerging drugs in clinical practice
include pro-secretory products (lubiprostone and linaclotide) and serotonergic agents
(Table 4) 54], 74].

Table 4. New treatment options for laxative-resistant chronic constipation?

Among drugs with intestinal secretagogue action, lubiprostone acts by activating type
2 chloride channel (CCl2), located in the apical membrane of enterocytes 75]. This effect determines chloride secretion in the intestinal lumen followed by passive
diffusion of sodium and water 75]. It therefore causes an increase in faecal content of water, which increases the
distension of intestinal walls with activation of the peristalsis, without having
a direct effect on smooth muscle of digestive tract 76]. Lubiprostone at a dosage of 24 ?g twice daily has been consistently shown in RCTs
more effective than placebo on increasing number of spontaneous bowel movements (SBM)
per week as well as improving stool consistency, straining, and constipation severity
in the adult population 76]–80]. The percentage of elderly patients included in the RCTs varied, but in one of these
studies 10 % of the participants were elderly 78]. Moreover, data from three open-label clinical trials were combined to obtain a pool
of elderly patients with chronic idiopathic constipation and published as abstracts
suggesting similar benefit 80]. However, extrapolation of the results of clinical trials performed in the overall
adult population to elderly patients must be done with caution and additional RCTs
are warranted before confirming the efficacy of the treatment in elderly patients.
While it does not cause electrolyte disturbances, lubiprostone evokes nausea (30 %
of patients), and headache, probably due to its prostaglandin-like structure 77], 79]. Nevertheless, this drug appears to be tolerated more by older people since side
effects appear to be less frequent than in younger people 80].

Linaclotide is a receptor agonist of guanylate cyclase C, located on the apical side
of intestinal epithelial cells 81]. This drug causes an increase in intra and extra-cellular cyclic guanosine monophosphate,
which is followed by an increase in secretion of chloride, bicarbonate and water into
intestinal lumen, resulting in an activation of the peristalsis and acceleration of
the intestinal transit 81]. The administration of linaclotide (150–300 micrograms a day) causes an increase
in the number of complete SBM per week and reduces stool consistency and straining
during defecation 81]–84].

In a study by Rao and colleagues, among 1602 patients with severe abdominal symptoms
(44 % of subjects had bloating, 44 % fullness, 32 % discomfort, 23 % pain and 22 %
cramping, with considerable overlap among symptoms), 805 were treated with linaclotide
while 797 received placebo 84]. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean
changes from baseline severity scores ranged from ?2.7 to ?3.4 for linaclotide vs
?1.4 to ?1.9 for placebo (P??.0001) 84]. Linaclotide improved global measures (P??.0001) and IBS-QOL scores (P??.01) compared to placebo 84]. In one of the pivotal study, 10 % of the whole sample where elderly subjects, who
showed similar results in safety and improvement of weekly spontaneous bowel movements,
stool consistency, straining, abdominal discomfort, and quality of life to the entire
study population 83]. However, solid data on the efficacy and safety of Linaclotide in the constipated
elderly are still lacking. The most common side effect is represented by a dose-dependent
diarrhoea, but less than 5 % of patients are reported to discontinue treatment due
to side effects 81]–84].

After the withdrawal of cisapride from distribution in 2000 and the significant restrictions
in the use of tegaserod (not marketed in Europe), new serotonergic drugs, including
prucalopride, velusetrag and norcisapride, have emerged as effective new treatment
options for chronic constipation 85]. To understand the mechanism of action of these drugs is necessary to analyse the
basis of the physiological mechanisms of gastrointestinal motility 85]. Mechanical and chemical stimulation on the intestinal walls evokes peristalsis,
a motor pattern fundamental for life of any living being with a gastrointestinal tract
85]. In fact, bolus (or endoluminal enteric content) evokes distortion/stimulation of
enterochromaffin cells (cells containing a biogenic amine, serotonin or 5-hydroxytryptamine,
5-HT) that, distributed along the surface of digestive tract mucosa, react by secreting
5-HT. This mediator activates neural circuits that trigger peristalsis by binding
to specific receptors at the level of enteric neurons (myenteric and submucosal plexus)
74], 85].

Among the seven types of serotonin receptors, 5-HT4 possesses a strong excitatory
activity on neurons of the myenteric plexus causing release of acetylcholine and producing
an increase in peristaltic movements 74], 85]. In this perspective, prucalopride is a high affinity agonist of 5-HT4 receptors,
has high bioavailability and is not metabolized by cytochrome P3A4 which is associated
with fewer interactions with other active ingredients, compared to other 5-HT4 receptor
agonists 85]. The safety and efficacy of prucalopride in constipation has been evaluated in three
large sized trials 86]–88]. All studies were 12 weeks in duration with similar design: multicenter, randomized,
double-blind, placebo-controlled, and parallel group 86]–88]. To be included patients had to report infrequent defecation, hard stools and/or
frequent straining resistant to laxatives. In all studies, the primary efficacy endpoint
was the proportion of patients having three or more complete SBM per week, averaged
over the 12-week period, using an intention-to-treat analysis. Secondary endpoints
included average increase of one or more complete SBM per week, patient subjective
satisfaction, QOL questionnaires, changes in bowel symptoms, stool consistency and
straining at stool. All RCTs were concordant on reporting Prucalopride as effective
treatment for chronic constipation in the adult population non responding to laxatives
86]–88]. Most study participants were females, the preferred schedule was 2 mg/daily, since
no differences in clinical efficacy were noticed between 2 and 4 mg schedules, the
latter dose being associated with more frequent side effects including headache, nausea
(usually mild and short-lived) and diarrhoea 86]. A post-hoc analysis showed that prucalopride not only favourably affects bowel movements, but
also improves anorectal and abdominal symptoms including pain, bloating and distension
87]. The efficacy of prucalopride has also been tested short term in the constipated
older ones 88]. Three hundred chronically constipated patients aged 65 years and over were randomized
to receive prucalopride at the dosage of 1 mg, 2 mg, 4 mg or placebo once daily for
four weeks. Approximately one third of study participants were males. Inclusion criteria,
primary and secondary outcome parameters were the same as the pivotal studies run
in the adult population 86]. Additional testing on cardiovascular function was performed. Prucalopride, in the
dose range tested (1–4 mg once daily) was effective treatment for constipated elderly
improving both symptoms and quality of life 88]. The lowest schedule was as effective as the 4 mg/day and the Authors speculated
a potential drug clearing slower than in the adult population. The drug was safe and
well tolerated with headache as the most commonly reported side effects (6.6 % on
1 mg schedule). In addition, the safety and effectiveness of Prucalopride have also
been confirmed by a small sized RCT on 84 elderly nursing home residents with chronic
constipation resistant to laxatives 89]. In both studies, prucalopride did not cause QT prolongation (reported in patients
treated with cisapride) or other vascular disorders (i.e., ischemic colitis as rarely
reported in tegaserod trials) 88], 89].

The new horizons in the treatment of chronic constipation include a variety of new
compounds, such as other serotonergic drugs (velusetrag and norcisapride, both 5-HT4
receptor agonists) as well as molecules inhibiting the bile acid transporter (elobixibat)
and a new guanylate cyclase-C agonist (plecanatide) 85], 90]–94]. Velusetrag in a recent randomized-controlled trial study of 4 weeks was found to
be effective and well tolerated in patients with chronic constipation 90], while in a pharmacodynamics study norcisapride has been shown to accelerate colonic
transit in healthy volunteers 91]. Elobixibat, an enantiomer of 1,5-benzothiazepine, acts locally in the lumen of the
gastrointestinal tract, binding and inhibiting the ileal bile acid transporter, thereby
increasing bile acid content in the colon 85]. A randomized phase II placebo-controlled study with 3 different doses of elobixibat,
demonstrated that the number of complete SBM raised progressively with the increase
of the drug dosage compared to placebo 92]. Abdominal pain and diarrhoea were reported as main adverse events in this study
92]. Finally, similarly to linaclotide, plecanatide is a guanylate cyclase C agonist,
which leads to secretion of fluids into the intestinal lumen, facilitating bowel movements
85]. A phase I study assesses the safety, tolerability, and pharmacokinetics of a single
dose (ranging from 0.1 to 48 mg) of oral plecanatide in 79 healthy controls. Plecanatide
was demonstrated to be safe and well tolerated, and no measurable systemic absorption
of oral plecanatide was observed at any of the oral doses studied 93]. Moreover, a multicenter randomized trial compared 12 weeks of treatment with plecanatide
(0.3, 1 or 3 mg daily) with placebo in 946 patients with chronic constipation. Plecanatide
3 mg was more effective than placebo on improving number of CSBM/week, stool consistency,
straining and QOL score 94].