Dig Dis 2006;24:228242

DOI: 10.1159/000092876

Gastrointestinal Motility Disorders:

An Update
Brian E. Lacy Kirsten Weiser
Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., USA

Abstract
Gastrointestinal motility disorders encompass a wide array of signs and symptoms that can occur anywhere
throughout the luminal gastrointestinal tract. Motility
disorders are often chronic in nature and dramatically
affect patients quality of life. These prevalent disorders
cause a tremendous impact both to the individual patient
and to society as a whole. Significant progress has been
made over the last 5 years in understanding the etiology
and pathophysiology of gastrointestinal motility disorders. This clinical update will focus on seven of the most
common gastrointestinal motility disorders (achalasia,
non-achalasia esophageal motility disorders, dyspepsia,
gastroparesis, chronic intestinal pseudo-obstruction, irritable bowel syndrome, and chronic constipation) with
an emphasis on current treatment options and new therapeutic modalities.
Copyright 2006 S. Karger AG, Basel

Introduction

Gastrointestinal (GI) motility disorders are highly

prevalent, produce an extensive array of symptoms, and
occur anywhere throughout the lumen of the GI tract.

2006 S. Karger AG, Basel

02572753/06/02440228$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com

Accessible online at:

www.karger.com/ddi

Patients with motility disorders have a reduced quality

of life [14]. As well, these disorders impose a signicant
economic burden to both the individual patient and to
society as a whole [57]. In this section of the journal, we
will provide a summary of advances in the eld of GI
motility disorders over the last 5 years, with an emphasis
on advances in treatment.

Methods

Ovid MEDLINE and PubMed databases were used to

search the published literature. In the interest of providing an update, rather than providing a comprehensive
review, our search was limited to the last 6 years. For
Ovid MEDLINE (2000 to September 2005, English language only) 14 primary search terms (achalasia, esophagus, esophageal motility disorders, esophageal dysmotility, stomach, dyspepsia, gastroparesis, small intestine,
chronic intestinal pseudoobstruction, colon, irritable
bowel syndrome, constipation, motility disorders, diarrhea) were individually combined with a larger number
of secondary search terms, including but not limited to
(in alphabetical order): ABT229, alosetron, alternative
medicine, alvimopan, antibiotics, biofeedback, botulinum toxin, buspirone, cilansetron, cisapride, complementary medicine, domperidone, erythromycin, gastric
pacing, gastric stimulation, GM-611, itopride, levosulpiride, lubiprostone, medications, metoclopramide, mosapride, motilin, neostigmine, neurokinin, octreotide,
pelvic oor, prucalopride, renzapride, sildenal, suma-

Brian E. Lacy, PhD, MD

Division of Gastroenterology and Hepatology, Area 4C
Dartmouth-Hitchcock Medical Center
1 Medical Center Drive, Lebanon, NH 03756 (USA)
Tel. +1 603 650 9454, Fax +1 603 650 5225, E-Mail brian.lacy@hitchcock.org

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Key Words
Motility disorders
Achalasia
Dyspepsia

Gastroparesis
Constipation
Irritable bowel
syndrome
Chronic intestinal pseudo-obstruction

Achalasia

Achalasia is the classic motility disorder of the esophagus. The annual incidence of achalasia is estimated at
1/100,000 persons [8]. Clinically, achalasia is characterized by dysphagia, chest pain, and bland regurgitation.
Manometrically, achalasia is dened by incomplete relaxation of the lower esophageal sphincter (LES) in combination with aperistalsis of the body of the esophagus.
Pathophysiologically, achalasia develops as a result of denervation of the intrinsic nervous system of the esophagus, with loss of nitric-oxide containing neurons [9].
Current treatment options for achalasia include pneumatic dilation, surgery, or botulinum toxin injection
(BTX). Although all three treatments can improve symptoms, none of these treatments restore esophageal peristalsis or normalize LES function. In the last 5 years, new
data has emerged regarding methods to assess esophageal
emptying, the efcacy and long-term outcome of standard
treatments, and the use of new treatments.
The timed barium swallow (or timed barium esophagram) provides objective evidence of esophageal emptying [10]. Patients drink as much barium sulfate as they
can over a 30- to 45-second period. Upright radiographs
are taken 1, 2, and 5 min after the last swallow of barium.
The distance from the gastroesophageal junction to the
top of the barium column is then measured, along with
the width of the esophagus at the widest point. This study
is repeated after treatment and compared to baseline.
This test provides an objective measure of therapeutic
response, in contrast to a subjective response based on
symptom scores.
A recent study evaluated the long-term results of pneumatic dilation in 249 patients with achalasia [11]. 125
patients completed the questionnaire (58%), with an average follow-up of 12 years. A median of 4 dilations was
required, and the long-term success rate was estimated at
only 4050%. These interesting results are in contrast to
earlier studies (see below), and may indicate the need for
earlier surgical referral. For example, Katz et al. [12] reported that after a mean follow-up of 6.5 years, 85% of
their patients noted an improvement in symptoms after

Update on Gastrointestinal Motility

Disorders

pneumatic dilation. A recent analysis of 232 achalasia

patients treated at the Cleveland Clinic found that 86%
of 111 patients had symptomatic improvement after
pneumatic dilation [13]. Heller myotomy led to symptomatic improvement in 89% of 72 patients, while BTX
injection of the LES improved symptoms in only 57% of
patients, with benets lasting 6 months on average.
Sildenal, a phosphodiesterase-5 inhibitor, is a potent
smooth muscle relaxant. In normal volunteers, sildenal
reduces LES resting pressure and the amplitude of contractions in the distal esophagus [14, 15]. Similar ndings
were reported in two studies of patients with achalasia
using 50 mg of sildenal [15, 16].

Non-Achalasia Esophageal Motility Disorders

The primary esophageal motility disorders include diffuse esophageal spasm (DES), nutcracker esophagus (NE),
isolated hypertensive LES, idiopathic hypotensive LES,
and ineffective esophageal motility (IEM) [17]. As a group,
these disorders are associated with a number of non-specic symptoms, which include chest pain, dysphagia, and
heartburn symptoms. Pathophysiologically, symptoms
may develop due to abnormalities in either excitatory or
inhibitory innervation to either the LES or the esophageal
body. As an example, unopposed excitatory innervation
to the body of the esophagus is associated with high-amplitude contractions that characterize NE and DES [18].
Although the exact incidence and prevalence of these disorders is not known, several studies have estimated that
11.433% of patients referred for esophageal manometry
have one of these disorders [19, 20].
The treatment of non-achalasia motility disorders includes medical therapy, endoscopic therapy, and surgery.
Previous studies have shown that neither metoclopramide
nor domperidone effectively stimulate esophageal body
motility, although both agents increase LES resting pressure in healthy volunteers [21, 22]. Although several studies initially reported that cisapride increased both LES
pressure and the amplitude of contractions in the distal
esophagus [2325], a number of other studies failed to
conrm any direct prokinetic effects of cisapride on the
esophagus [20, 26]. No studies evaluating the effects of
metoclopramide, domperidone, or cisapride on esophageal motor function have been published in the last 5
years.
Erythromycin acts as a motilin agonist and has welldocumented gastrokinetic effects (see below). The effects
of intravenous erythromycin (200 mg) on esophageal mo-

Dig Dis 2006;24:228242

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triptan, surgery, tachykinins, technology, tegaserod, therapies, treatment, tricyclic antidepressants. A similar
search process was followed for PubMed (2000 to September 2005). All identied articles were then manually
searched for other relevant studies. Abstracts were generally not included, except in limited circumstances.

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Dig Dis 2006;24:228242

Mosapride, a benzisoxazole derivative, is a selective

5-HT4 agonist; its main metabolite is a 5-HT3 antagonist
[38]. A prospective, randomized, blinded, cross-over
study of 41 patients with GERD compared mosapride to
cisapride [39]. Mosapride (30 mg p.o. t.i.d.) improved
several parameters of acid reux (duration of longest episode of reux, reux fraction time), and slightly increased
the amplitude of contractions in the lower esophageal
body. LES function was not reported in this study. Mosapride increased the rate of esophageal bolus transit,
measured by multichannel intraluminal impedance manometry, in a study of 20 healthy volunteers using a double-blinded, placebo-controlled, cross-over design [40].
No changes were noted, however, in LES pressure or amplitude, duration, and velocity of esophageal body contractions.
Two separate studies found that sildenal (50 mg) reduces elevated LES tone and the amplitude of contractions in the distal esophageal body in patients with isolated hypertensive LES [41, 42]. A recent study of patients
with hypercontractile motility disorders demonstrated
that sildenal reduced the amplitude of contractions by
more than 70% in both healthy volunteers and patients,
although improvement in symptoms occurred in only
36% of subjects, and 50% of these patients had signicant
side effects [43].
Itopride, a benzamide derivative shown to stimulate
gastric motility [44], has primarily been evaluated in dyspepsia and gastroparesis (see below). The utility of itopride was assessed in a study of 26 patients with mild acid
reux disease [45]. Patients with mild esophagitis (Savary-Miller Grade I or II) were randomized to either 50
or 100 mg of itopride t.i.d. for 4 weeks. Compared to placebo, patients treated with either dose of itopride noted
a signicant improvement in reux symptoms compared
to baseline. Patients treated with 300 mg of itopride daily also had a statistically signicant improvement in pH
measurements compared to baseline. Esophageal motility was not assessed in this study, and thus the mechanism
of reduced acid exposure remains unclear.
In an interesting use of theophylline, Rao et al. [46]
demonstrated in an open-label trial that this adenosine
antagonist increased the sensory threshold for distention
induced chest pain. No changes in motor function were
noted, and a placebo-controlled, blinded study has yet to
be performed.
The benecial effects of BTX in patients with achalasia led to its use in other motility disorders of the esophagus. BTX of the LES relieved symptoms, and normalized manometric abnormalities, in a patient with hyper-

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tility were assessed in 18 healthy volunteers in a doubleblinded, randomized study [27]. Compared to placebo,
erythromycin signicantly increased the amplitude of
contractions in the distal esophagus, increased the duration of esophageal peristalsis, and increased the resting
pressure of the LES. These effects were felt to be due to
stimulation of cholinergic pathways, since they could be
blocked by pretreatment with atropine. Similar ndings
were demonstrated in a study of 15 patients with gastroesophageal reux disease (GERD) [28]. In a study of 45
patients with non-insulin-dependent diabetes mellitus,
oral erythromycin (250 mg p.o., q.a.c.) shortened mean
transit time in the esophagus and accelerated gastric emptying [29]. In a similar manner, intravenous clarithromycin was shown to increase LES tone, and both the amplitude and duration of esophageal contractions, in a doubleblind, placebo-controlled study of 15 normal volunteers
[30]. In a randomized, double-blind, placebo-controlled
trial, ABT-229, a motilin agonist, did not affect LES tone,
esophageal motility, or the incidence of transient LES relaxations (TLESRs) in 24 GERD patients [31].
Baclofen, a selective
-aminobutyric acid agonist, reduced the number of TLESRs in patients with GERD
[32]. A double-blind, placebo-controlled, cross-over study
of 37 patients with GERD conrmed that baclofen reduces the incidence of reux episodes by inhibiting
TLESRs [31]. Baclofen did not affect LES pressure or
esophageal clearance.
Previous studies in healthy volunteers revealed that
6 mg of subcutaneous sumatriptan, a 5-HT1 agonist, increased LES tone and the amplitude of contractions in
the distal esophagus [33]. Sumatriptan also affects the
frequency of post-prandial TLESRs [34]. A double-blind,
randomized, cross-over trial of 10 patients with IEM
found that 6 mg of subcutaneous sumatriptan increased
the number of swallows and the number of primary
esophageal motor waves. In contrast to healthy volunteers, however, sumatriptan did not inuence LES tone
or the amplitude of contractions [35].
Tegaserod, a specic 5-HT4 receptor partial agonist,
initiates gut peristalsis, stimulates chloride secretion in
the small intestine, and alters visceral sensation [36]. A
prospective, double-blinded trial of 19 patients compared
four different doses of tegaserod to placebo over separate
2-week trial periods [37]. Low-dose tegaserod (1 mg/day)
reduced post-prandial esophageal acid exposure and decreased the number of post-prandial reux episodes. No
signicant changes were identied in LES resting pressure or in the amplitude of distal esophageal contractions.

tensive LES [47]. Nine patients with DES were treated

with multiple intraesophageal injections of BTX (100 U
total) [48]. Eight of 9 patients had a signicant reduction
in total symptom score (chest pain, dysphagia, regurgitation) at 4 weeks, and these effects persisted for 6 months.
Twenty-nine patients with spastic disorders of the esophagus (DES, hypertensive LES, IEM, NE) were enrolled in
an open-label trial to evaluate the efcacy of BTX injection of the LES for the treatment of chest pain [49]. Twenty-one patients (72%) responded with at least a 50% reduction in their chest pain score. The type of underlying
motility disorder did not predict response to therapy, although women generally responded better than men.
The role of surgery for patients with esophageal motility disorders remains controversial. In a retrospective
review of a prospectively collected database, Patti et al.
[19] reported on the results of myotomy in 397 patients
with esophageal motility disorders. Of 19 patients with
DES, 8086% noted an improvement in dysphagia, while
6580% noted an improvement in complaints of chest
pain. Of 12 patients with NE, 6083% reported an improvement in dysphagia, while 4050% reported a good
or excellent response for their symptoms of chest pain.
A smaller study of 16 patients with spastic disorders of
the esophagus found that resting pressure and relaxation
of the LES improved after long myotomy, although peristalsis did not [50]. In general, patients with a diverticulum and localized manometric abnormalities did better
than patients with a diffuse pattern of disordered motility.
Antireux surgery is now one of the most commonly
performed elective surgeries. During pre-operative evaluation most patients undergo esophageal manometry,
and many are identied as having a motility disorder of
the esophagus. Of 239 patients referred for antireux surgery, 57 (24%) were identied as having a non-specic
motility disorder of the esophagus [51]. In this study, all
named esophageal motility disorders (achalasia, DES,
NE, hypertensive LES) were excluded from further analysis. The majority of patients underwent laparoscopic
Nissen fundoplication; median follow-up was 30 months.
Overall, patients with non-specic motility disorders
were found to do as well post-operatively as patients with
normal pre-operative esophageal manometry. In a similar light, Heider et al. [52] reported that 48 of 262 patients referred for antireux surgery had IEM. Nineteen
of these patients agreed to perform follow-up manometry
after surgery, and only 1 had a worsening of esophageal
motility. These data, combined with previously published studies, support the concept that complete fundo-

plication is unlikely to produce signicant dysphagia or

chest pain in patients with minor or mild disorders of
esophageal motility.
Gastric banding is now frequently performed for morbid obesity. A recent study found that gastric banding
reduced the amplitude of contractions in the distal esophagus, although LES tone was not affected [53]. This
raises the question of whether morbidly obese patients
identied pre-operatively with IEM and acid reux should
be referred for an alternative procedure, such as a Rouxen-Y gastric bypass.
Finally, electrical acupoint stimulation was recently
evaluated to determine its effect on TLESRs in a study
of 14 healthy volunteers [54]. Electric acupoint stimulation inhibited the frequency of TLESRs compared to
sham stimulation, although it did not change LES pressure, esophageal motility, or the duration of TLESRs.

Update on Gastrointestinal Motility

Disorders

Dig Dis 2006;24:228242

Dyspepsia is dened as discomfort or pain centered in

the upper abdomen, often associated with negative symptoms of fullness, bloating or early satiety [55, 56]. Symptoms tend to wax and wane, and relapse is common. Dyspepsia is categorized into two large groups: organic and
functional dyspepsia. Once investigated, the majority of
patients are diagnosed with functional dyspepsia [57].
Functional dyspepsia (FD) is dened as at least a 3-month
history of dyspeptic symptoms for which no denite
structural or biochemical explanation can be found [58].
Patients with classic symptoms of heartburn are excluded
from the formal denition of dyspepsia.
The optimal initial evaluation and management of
dyspepsia continues to be debated [5961]. Options include: prompt endoscopy; empiric therapy with an antisecretory or a prokinetic agent, or a test-and-treat strategy for Helicobacter pylori [62]. Up-front endoscopy reduces patient anxiety, with an improvement in patient
sense of well-being within the rst week of endoscopy
[63]. In patients with uninvestigated dyspepsia, endoscopy led to improved patient satisfaction regardless of the
ndings [64]. The cost-effectiveness of prompt endoscopy, especially in the younger patient, has been questioned
[65].
Empiric treatment with an antisecretory agent is commonly employed since many dyspeptic patients have increased acid sensitivity [66]. Concerns with empiric therapy focus on the likelihood of missing an organic lesion.
However, recent studies suggest improved patient satis-

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Dyspepsia

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Levosulpiride, another dopamine antagonist, decreases the perception of gastric distention [88]. In FD
patients, levosulpiride was found to be as effective as cisapride [89] at providing symptom relief.
The chronic abdominal pain of FD can be difcult to
treat. Tricyclic antidepressants have been used with modest success [90, 91]. Fluoxetine did not lead to any improvement in FD patients, as evaluated by electrogastrography [92]. Alosetron, a 5-HT3 receptor antagonist
has also shown potential benet in decreasing upper abdominal pain [93].
Fundic relaxation may be impaired in patients with
FD, leading to symptoms of post-prandial pain, discomfort, and nausea. 5-HT1 agonists such as sumatriptan and
buspirone should theoretically increase gastric accommodation and improve symptoms in a subset of FD patients.
Large controlled trials have not yet been performed, however. Clonidine, an -adrenergic receptor agonist, may
also decrease pain perception with gastric distention
[94].
A number of non-conventional therapies have been
used in the treatment of dyspepsia, including ginger, peppermint oil, caraway oil, red pepper (capsaicin) and
Iberogast (combination of 9 different herbs). One small
randomized study showed some benet of capsaicin compared to placebo [95]. A meta-analysis found Iberogast to
be more effective at relieving symptoms than placebo
[96]. Artichoke leaf extract may also improve some symptoms of dyspepsia [97, 98].
Psychotherapy, behavioral therapy and hypnotherapy
all may have a role in the treatment of dyspepsia, although
their efcacy has not been clearly established [99103].
It appears that symptom pattern and psychological characteristics are independent predictors of treatment response, with patients having high scores for reux-like
symptoms and high scores for somatization demonstrating greater response to acid suppressants [104].

Gastroparesis

Gastroparesis is dened as the impaired transit of intraluminal contents from the stomach to the duodenum
in the absence of mechanical obstruction. Diabetes accounts for 25% of cases, while idiopathic gastroparesis
accounts for nearly 50% [105].
The goals of treatment include relief of symptoms, improved nutrition, and the prevention of complications,
such as bezoar formation. Therapeutic intervention is often multidimensional, including diet, lifestyle changes,

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faction and outcome with prompt endoscopy and testand-treat strategy, as discussed below.
The role of H. pylori in FD continues to evolve. Several trials have demonstrated that test-and-treat strategies
have outcomes similar to prompt endoscopy, and are
more effective than a short course of PPI alone [6769].
At present, no clear association exists between H. pylori
and symptoms of FD, and the benet of H. pylori therapy
on symptoms continues to be debated [7073]. A recent
meta-analysis of 17 randomized controlled trials found
that there was an 8% relative risk reduction in the eradication group and the number needed to treat to cure 1
case of dyspepsia was 18 [74]. Thus, eradication of H.
pylori appears to have a small, but statistically signicant
effect in FD.
Lifestyle modications are often prescribed for the
treatment of dyspepsia, although no studies have been
published on this subject in the last 5 years. As such,
antisecretory agents such as H2RAs and PPIs are a
mainstay of therapy for FD. The efcacy of these treatments remains unclear, however, due to awed study
designs with failure to exclude patients with peptic ulcer
disease and predominant GERD. A meta-analysis on
the use of H2RAs found that these agents had little or
no benet when compared to placebo [75], although
famotidine has demonstrated some promise in the treatment of FD [7678]. A randomized, placebo-controlled
trial comparing omeprazole, ranitidine, cisapride and
placebo demonstrated superior symptom relief with
omeprazole [79].
Prokinetic therapy is often employed in the treatment
of FD, since nearly 40% of patients demonstrate a mild
to moderate delay in gastric emptying [80]. Although
metoclopramide is commonly used, its efcacy has been
questioned in a recent meta-analysis [81]. On the other
hand, another meta-analysis of 8 studies found domperidone to be more effective than placebo at improving global symptoms, with an odds ratio of 7.0 [82].
Tegaserod, a partial selective 5-HT4 agonist, has been
shown to accelerate gastric emptying [83]. Preliminary
studies demonstrate improved upper GI symptoms in female patients with FD [84]. Mosapride, another 5-HT4
receptor agonist, has also improved some symptoms of
FD in an early clinical trial [85].
Itopride hydrochloride is a benzamide derivative and
acts as a dopamine antagonist. In an open-label, noncomparative study, itopride (50 mg t.i.d) was well tolerated and relieved symptoms of dyspepsia [86]. Another
study found itopride to be comparable to domperidone
in providing symptom relief [87].

published in the last 5 years on the efcacy of cisapride

in gastroparesis.
Preliminary studies have shown that mosapride has
prokinetic effects on many areas of the GI tract [124,
125]. In one study, mosapride improved gastric motility
in diabetic gastropathy and also improved glycemic control with a corresponding decrease in HgA1C [126,
127].
Other new prokinetic agents under investigation include the dopamine receptor antagonist levosulpiride and
the cholecystokinin receptor antagonist loxiglumide [128,
129]. In animal studies, itopride increases gastric motility through its antidopaminergic and antiacetylcholinesterase actions [130].
In patients with refractory gastroparesis, psychotropic
medications such as tricyclic antidepressants may provide relief of nausea, vomiting and associated abdominal
pain [131, 132]. Alternative therapies include ginger
[133], acupuncture with stimulation of the PC6 point on
the wrist [134, 135], or the ST36 (Zusanli) point below
the patella [136].
Endoscopic and surgical interventions are now available for gastroparetic patients with refractory symptoms.
Endoscopically, BTX injection into the pylorus inhibits
the release of acetylcholine from synaptic vesicles at the
synaptic junction, thereby inducing a state of transient
muscle paralysis. Efcacy of BTX has been demonstrated
in diabetic gastroparesis as well as idiopathic gastroparesis. Long-term outcomes have not been determined to
date [137, 138].
Surgical options include gastric resection and gastric
electrical stimulation. In general, gastric resection appears to be of limited benet and should only be used as
a last resort for patients with profound symptoms and
gastric stasis [139, 140]. Gastric electrical stimulation
(GES) uses an implantable neurostimulator that delivers
a high-frequency, low-energy signal with short pulses. An
initial study showed a decrease in nausea and vomiting
in 20 of 26 patients at 3 and 6 months after implantation
[141]. A second study of the implantable neurostimulator
involved a double-blind sham stimulation-controlled trial for 2 months followed by activation of all devices for
1 year [142]. The study consisted of 33 patients with either diabetic or idiopathic gastroparesis. Of 33 patients,
21 preferred having the stimulator in the on mode. In
phase 2 of the trial, all devices were turned on. Follow-up
at the end of 1 year showed a relative decrease in vomiting frequency from 25 to 6 times per week with associated improvements in quality of life, primarily in the diabetic gastroparesis subgroup. A subset of 12 patients in

Update on Gastrointestinal Motility

Disorders

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and medications. If a patient is unable to maintain adequate nutritional status, total parenteral nutrition or a
jejunostomy feeding tube may be required [106].
Small, frequent meals are an essential component of
therapy. Meals should be low in ber, to prevent bezoar
formation, and low in fat, as fat delays gastric emptying.
Liquids should be emphasized over solid foods. A recent
study found that walking after eating increases the normal
3-cpm activity in the stomach and thus may improve gastric emptying in some patients [107].
A large number of antiemetic agents are now available
to treat nausea in gastroparetic patients [108]. The most
commonly used agents include phenothiazines and 5HT3 receptor antagonists. Antihistamines exhibit central
antiemetic effects and, though well established for use of
motion sickness, the efcacy in gastroparesis is not well
described [109]. Other agents that have been used include benzodiazepines and cannabinoids. Given the refractory nature of nausea, patients frequently require
multiple agents, usually one each from different chemical classes.
Prokinetic agents used in the treatment of gastroparesis include metoclopramide, erythromycin, domperidone
and tegaserod. Metoclopramide has both prokinetic and
antiemetic properties [110]. No studies evaluating the
utility of metoclopramide in gastroparetic patients have
been published in the last 5 years. Erythromycin is a potent gastrokinetic [111115], although its efcacy in relieving symptoms has not been clearly demonstrated
[116]. GM-611, a motilin agonist, is under development.
Preliminary animal studies have shown that this agent
accelerates gastric emptying; its effects in the human GI
tract have not been characterized.
Domperidone, another dopamine antagonist, improves symptoms and quality of life in patients with diabetic gastroparesis, although this medication is not readily obtainable in the USA [117119].
Tegaserod, a selective 5-HT4, increases gastric emptying in diabetic mice, increases gastric emptying in patients with dyspepsia and delayed gastric emptying, and
increases orocecal transit time in women with constipation [36, 120, 121]. Tegaserod has also been shown to accelerate gastric emptying, small intestinal transit and colonic transit in healthy male subjects [122]. In a small case
series, tegaserod was successfully used as a prokinetic
agent in critically ill patients with impaired gastric motility [123]. Tegaserod is not yet approved by the FDA for
use in gastroparetic patients.
Cisapride, a mixed 5-HT4 agonist/5-HT3 antagonist,
is available only under limited use. No studies have been

Chronic Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction (CIP) is characterized by signs and symptoms (present for at least 6
months) which suggest mechanical obstruction of the intestinal tract. While the clinical symptoms of CIP are usually indistinguishable from mechanical obstruction, the
etiology, pathology and treatment are quite different.
First identied in 1958, it is estimated that approximately 100 infants are born each year in the USA with congenital pseudo-obstruction. CIP may be categorized as
primary (neuropathic, myopathic, or mesenchymopathic), secondary (collagen vascular disease, endocrine, neoplastic, neurologic), or idiopathic in nature [146, 147].
The most common symptoms of CIP are abdominal pain,
vomiting, bloating, constipation, and diarrhea. Additional symptoms may include dysphagia, reux, early satiety,
and genitourinary symptoms, such as difculty voiding.
Treatment options for CIP are limited, and focus on correcting nutritional deciencies, minimizing symptoms,
and preventing weight loss and malnutrition. Previous
treatments have included cisapride, domperidone, metoclopramide, and octreotide although none have been
uniformly successful [146].
A recent study evaluated the effects of oral erythromycin (500 mg t.i.d. or q.i.d.) in 15 consecutive patients with
CIP who had failed standard medical therapy [148]. Six
patients (40%) responded with a decrease in nausea, vomiting, and abdominal pain. Men appeared to respond better than women, and responders were less likely than nonresponders to be taking long-term narcotics.
Neostigmine, an acetylcholinesterase inhibitor, is
used to treat acute colonic pseudo-obstruction [149]. A
recent case report describes the daily use of neostigmine
(2 mg i.v. q 6 h) for several months in a hospitalized patient with chronic colonic pseudo-obstruction [150]. To

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Dig Dis 2006;24:228242

date, neostigmine has not been studied in a controlled

manner in patients with CIP. No formal trials have been
conducted to date using tegaserod, mosapride, renzapride, or levosulpiride; although all of these prokinetic
agents theoretically could improve symptoms in patients
with CIP.
Surgery is generally avoided in patients with CIP, for
fear of precipitating an acute episode. However, intestinal transplantation may be a viable treatment for patients with severe CIP who cannot be maintained on parenteral nutrition. Six patients with CIP underwent intestinal transplantation (isolated small bowel in 5, and
stomach, duodenum, pancreas, and small bowel in 1)
after medical management had failed [151]. Mean follow-up was 25 months. All 5 patients who underwent
isolated small bowel transplant survived, and 3 were able
to stop parenteral nutrition; the 1 patient who underwent
a more extensive graft died from hemolytic-uremic syndrome. Multivisceral transplantation has been described
in pediatric patients (median age 4 years) with severe
CIP [152]. Ten patients survived after 2 years; all were
off parenteral nutrition and were tolerating enteral feedings.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is characterized by abdominal pain with disturbed defecation [153]. IBS is
highly prevalent and is associated with a signicant reduction in quality of life [154]. A large number of clinical
studies have been published over the last 5 years in the
eld of IBS. For patients with IBS and constipation, ber
supplementation may improve symptoms of constipation, although abdominal pain is unlikely to improve
[155157]. Tegaserod, a 5-HT4 agonist, improves global
symptoms of IBS and constipation in women with constipation-predominant IBS [158, 159]. Renzapride, a
mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist, accelerates colonic transit in constipation-predominant IBS patients [160]. Based on animal studies, mosapride, another 5-HT4 receptor agonist, may have a role
in the treatment of constipation-predominant IBS [124,
125].
For diarrhea-predominant IBS, loperamide can reduce loose stools, urgency and fecal soiling [161, 162].
Alosetron, a 5-HT3 receptor antagonist, was shown to improve diarrhea and urgency in women [163, 164]. Alosetron was removed from the market by the FDA due to
concerns over an association with ischemic colitis. Re-

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the Gastric Electromechanical Stimulation (GEMS)

Study Group was extensively evaluated with regards to
nutritional parameters before and after stimulator implantation. GES improved symptoms in addition to body
weight, body mass index and serum albumin at 3 and 6
months [143]. A small study of diabetic patients with
drug-refractory gastroparesis showed symptom improvement after GES implantation and also improved glycemic control at 6 and 12 months [144]. Despite signicant
cost of the device and its implantation, in the long term,
GES may be more cost effective than intensive medical
therapy [145].

Update on Gastrointestinal Motility

Disorders

and tachykinins. Asimadoline, a -opioid agonist, showed

decreased overall perception of pain with colonic distention in a study of female patients with IBS [176].
Alternative therapies are commonly used by patients
with IBS. Dried turmeric extracts improved IBS symptoms when compared to placebo in a partially blinded
randomized pilot study [177]. Two small pilot studies in
diarrhea-predominant IBS patients suggest that transcutaneous electrical acustimulation at ST36 and P6, but not
sham stimulation, increased the threshold of rectal sensation of gas, desire to defecate and pain [178, 179]. Finally, hypnosis has been reported to improve global IBS
symptoms in a recent study and review [180, 181].

Chronic Constipation

Chronic constipation is not a single disorder, but instead represents a number of different pathophysiologic
processes, including colonic inertia, normal transit constipation, and pelvic oor dyssynergia [182, 183]. Many
patients suffer from two of these processes at the same
time (i.e., both colonic inertia and pelvic oor dysfunction). The data presented below is thus for a heterogeneous group of patients, rather than for a pure population
of patients with only one pathophysiologic abnormality.
The prevalence of chronic constipation is estimated at
1219%, while the incidence is estimated at 4 per 100
person-years of follow-up [184, 185]. Although studies are
limited, chronic constipation can both reduce patients
quality of life and impose a substantial economic burden
[186].
Lactulose, a non-absorbable synthetic disaccharide,
has been used to treat constipation for over 20 years. Only
one study using lactulose in patients with chronic constipation has been published since 2000. This study employed a parallel-group, multicenter, randomized design
and compared lactulose (33 patients) to polyethylene glycol (PEG) (32 patients). No signicant difference was
found between the groups with regard to stool frequency,
stool consistency, or straining [187]. A recent systematic
review found that lactulose was less effective than PEG
or bulk laxatives at relieving symptoms of constipation
[188].
PEG is a large, non-absorbable, chemically inert polymer which acts as an osmotic agent to retain water in the
stool. Cleveland et al. [189] conducted a randomized,
double-blind, cross-over study in 23 patients and compared PEG (17 g/day) to placebo over a 2-week trial period. PEG was found to improve stool frequency and

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cently, patients with IBS have been shown to have a twoto-fourfold increased risk of ischemic colitis, so the actual medication risk of alosetron is unclear [164, 165].
Preliminary data on cilansetron, another 5-HT3 receptor
antagonist, shows that this medication may improve
symptoms of IBS and diarrhea in both men and women.
A review by the FDA in the spring of 2005 did not lead
to a letter of approval, however, and further clinical trials
were requested.
Smooth muscle antispasmodics alleviate symptoms of
abdominal pain and bloating in some patients with IBS.
In one meta-analysis, 5 drugs showed efcacy over placebo (cimetropium bromide, pinaverium bromide, octylonium bromide, trimebutine, and mebeverine) [166].
Although commonly used in the clinical setting, this
meta-analysis did not show that dicyclomine and hyoscyamine were effective. Tricyclic antidepressants (TCAs)
and serotonin reuptake inhibitors (SSRIs) have been
shown to alter visceral sensitivity, reduce central pain
perception, and treat concurrent psychiatric co-morbidities. It is thought that TCAs work centrally rather than
peripherally to reduce pain [167]. A recent Cochrane database review found that, in IBS patients, the relative response to TCAs was 1.34 and the number needed to treat
was 6. Low-dose TCAs may be helpful if pain is constant
in nature, rather than intermittent. SSRIs may improve
visceral hypersensitivity, particularly in constipationpredominant IBS, although the efcacy of this class of
medications continues to be debated [168, 169]. Finally,
SSRIs have been shown to improve patients sense of
well-being, even in non-depressed patients [170].
In addition to medical therapy, a number of different
psychological interventions have been evaluated. In a
randomized trial in the primary care setting, cognitive
behavior therapy, in addition to antispasmodic treatment, showed additional benets when compared to
medication therapy alone at 6 months, although the effects had waned by 12 months [171]. Overall, the efcacy
of psychological intervention remains unclear [172,
173].
Probiotics are a potential new therapy for the treatment of IBS [174]. It is believed that probiotics act to
normalize the ratio of anti-inammatory to pro-inammatory cytokines in the gut, thereby alleviating symptoms. A recent trial showed improvement in cytokine balance with associated improved QOL assessments in patients taking Bidobacterium (B. infantis 35624) in a
malted milk drink [175].
Newer agents under current investigation, all of which
require further study, include CCK1 receptor antagonists

236

Dig Dis 2006;24:228242

were randomized to placebo, 3 mg, or 9 mg of NT-3 given subcutaneously either weekly or three times weekly
[198]. Colon transit time and stool frequency were the
primary endpoints measured. Weekly dosing of NT-3
was not effective, although 9 mg of NT-3 given three
times weekly led to a signicant improvement in stool
frequency, stool consistency, and straining. In addition,
colonic transit was accelerated. The clinical utility of this
agent will likely be limited by the fact that patients will
require an injection, and also by the fact that 3350% of
the patients who received NT-3 had injection site reactions.
Lubiprostone is a bicyclic fatty acid that acts to open
specic chloride channels (ClC-2) within the GI tract,
thereby enhancing uid secretion. It is not presently
known whether this agent acts with greater afnity or
specicity in one portion of the GI tract compared to another. Although clinical data is limited and still mostly in
abstract form, it appears that this oral medication does
not appear to alter electrolyte levels in either normal volunteers or patients. A multicenter, randomized, doubleblinded study showed that 24 g b.i.d. of lubiprostone
was more effective than placebo with regards to improving stool frequency, stool consistency, and straining [199].
Several studies involving lubiprostone and patients with
chronic constipation were recently presented at the annual meeting of the American College of Gastroenterology in October 2005. Lubiprostone (24 g b.i.d.) was
compared to placebo in a multicenter, parallel-group, 4week, double-blind study of 237 patients with idiopathic
constipation [200]. More patients treated with lubiprostone noted a spontaneous bowel movement within the
rst 24 h, compared to placebo (p ! 0.001). Stool frequency over the 4-week trial period was signicantly improved for the lubiprostone group compared to placebo
(p ! 0.05). One concern from these studies, however, is
that lubiprostone has been associated with a signicant
incidence of nausea up to 31.7% of all subjects in one
study. Publication of the data in full manuscript form is
eagerly awaited.
Mosapride, a 5-HT4 agonist with 5-HT3 antagonist
properties, has been evaluated in an open-label study of
14 Parkinsonian patients with constipation [201]. Both
subjective (straining, difculty with evacuation), and objective (frequency) measurements of constipation and colon motility (colonic transit time and rectoanal videomanometry) were recorded at baseline and after 3 months
of treatment with 15 mg/day. Mosapride improved symptoms of constipation (frequency and straining) and also
improved colonic transit time, particularly in the left co-

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stool consistency; no discontinuations were reported. DiPalma et al. [190] randomized 151 patients to either PEG
(17 g/day) or placebo in a double-blinded, multicenter
study which lasted 10 days. No signicant adverse events
were reported in the 135 patients who completed the
study. PEG was found to be statistically superior to placebo in regards to stool frequency and stool passage. Similar results on the efcacy of PEG have been reported
elsewhere [191].
Two large randomized, placebo-controlled trials have
been performed to evaluate the efcacy and safety of tegaserod in the treatment of chronic constipation. Kamm et
al. [192] compared tegaserod (2 or 6 mg) to placebo in
1,264 women and men over a 12-week trial period. The
primary efcacy variable was the responder rate for complete spontaneous bowel movements during the rst 4
weeks of treatment. Both the 6- and 2-mg dose, given
b.i.d., were more effective than placebo (p ! 0.0001 and
p ! 0.01, respectively). In another randomized, doubleblind, placebo-controlled of 1,348 men and women with
chronic constipation, Johanson et al. [193] found that
both 2 mg and 6 mg b.i.d. were more effective than placebo at increasing the number of complete spontaneous
bowel movements.
Prucalopride, a 5-HT4 agonist, has been shown to accelerate GI transit and improve symptoms of constipation in several different studies. In a double-blind, parallel-group design of 40 patients with functional constipation but without evidence of a rectal evacuation disorder,
4 mg of prucalopride accelerated gastric, small bowel, and
colonic transit [194]. Emmanuel et al. [195], in a doubleblind, placebo-controlled trial of 74 patients, found that
1 mg of prucalopride daily accelerated orocecal transit,
increased stool frequency, and improved symptoms of
constipation. A 4-week, double-blind, placebo-controlled
trial found that 4 mg of prucalopride daily improved
whole gut transit, reduced straining, and reduced time to
rst stool in 53 patients with chronic constipation [196].
Finally, prucalopride (either 1 or 2 mg) was shown to improve symptoms of constipation and reduced mean colonic transit time in a double-blind, placebo-controlled,
cross-over study of 28 patients with chronic constipation
[197]. Concerns over possible cardiac arrhythmias with
prucalopride use have halted further studies for now.
Neurotrophin-3 (NT-3) is a neurotrophic growth factor that enhances the growth and development of neurons, especially those of the enteric nervous system. A
double-blind, randomized, placebo-controlled, multicenter study was performed using NT-3 in 107 patients
with functional constipation (Rome II criteria). Patients

lon. Mosapride also resulted in larger amplitude of rectal

contractions.
Alvimopan is a novel orally active -opioid receptor
antagonist [202]. Early studies have focused on the role
of alvimopan on reversing narcotic-induced constipation
and improving post-operative ileus. A recent abstract reported that alvimopan improves whole bowel transit time
in adults with chronic constipation [203].
Biofeedback has been evaluated in a number of studies
of patients with chronic constipation due to pelvic oor
dysfunction. However, no placebo or sham controlled trials have been performed in adults. A recent study of 52
patients conrms the clinical view that biofeedback is effective at treating symptoms of constipation due to pelvic
oor dyssynergia, although it is not effective at treating
constipation due to slow transit constipation [204]. For
further details, the reader is referred to a recent comprehensive review that nicely summarizes studies performed
to date for biofeedback and functional anorectal disorders [205].

Conclusions

Motility disorders of the GI tract are highly prevalent

in the clinical setting and are now readily diagnosed in
the motility laboratory. In the last 5 years, several advances have taken place, notably the development of multichannel impedance, increasing use of electrogastrography, and greater clinical use of gastric stimulation. A
number of new therapies are now available to treat symptoms of GI dysmotility. Many of these target the serotonin system, which has been recognized as playing a critical role in normal gut pathophysiology. However, due to
ever increasing concerns over safety, future studies of
medications will need to be performed for longer periods
of time, involve more patients, include an extended investigation time. Finally, although at least 35% of adults
routinely use some form of alternative or complementary
medication, there are few well-designed trials evaluating
the efcacy and safety of these agents. These will be required if these agents are to become accepted by the clinician.

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