Clinical Medicine Insights: Therapeutics

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Gastric Acid-Related Diseases: Focus on Esomeprazole

B. Al-Judaibi1, N. Chande1, G.K. Dresser2, N. Sultan2 and J.C. Gregor1

Division of Gastroenterology, 2Internal Medicine, The University of Western Ontario, London, ON, Canada.
1

Email: baljuda@uwo.ca

Abstract: Esomeprazole (S-omeprazole) is a single optical enantiomer proton-pump inhibitor (PPI) approved for the management
of gastro-oesophageal reflux disease, the prevention and treatment of Non-Steroidal Anti-Inflammatory Drugs (NSAID) associated
gastric ulcer disease, treatment of duodenal ulcer disease associated with Helicobacter pylori infection, and the treatment of Zollinger-
Ellison syndrome. Esomeprazole has been shown to be safe and effective during pregnancy and was introduced to the market in 2001.
PPI therapy may interact with clopidogrel by cytocrome 2C19. Clopidogrel is a prodrug which is partially activated by cytochrome
2C19 and esomeprazole is a competitive inhibitor of 2C19. Esomeprazole is more effective than other PPIs in controlling esophageal
and gastric pH, but efficacy in symptom relief is less clear.

Keywords: peptic ulcer disease, reflux esophagitis, esomeprazole, gastroesophageal reflux disease, dyspepsia, pregnancy, pharma­
cokinetics, 2C19 and Zollinger Ellison syndrome

Clinical Medicine Insights: Therapeutics 2010:2 439–452

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Clinical Medicine Insights: Therapeutics 2010:2 439

Judaibi et al
Introduction
Proton pump inhibitors inhibit the gastric H+/K+-
ATPase enzyme (the proton pump) and are the
most potent suppressors of gastric acid secretion,
diminishing daily production of gastric secretion and
increasing intragastric pH.1,2 Five proton pump inhib-
itors are available clinically: omeprazole, esomepra-
zole, lansoprazole, rabeprazole, and pantoprazole,3–6
with a new PPI, tenatoprazole, having a 5- to
7-fold longer elimination half-life than other PPIs.7
Esomeprazole, the S-isomer of omeprazole (a racemic
mixture of S- and R- optical isomers), is the first
proton pump inhibitor to be developed as a single
optical isomer, has a better pharmacokinetic profile,
and provides greater acid suppression than omepra-
zole.8 Esomperazole is a white to slightly coloured
crystalline powder, containing 3 water molecular
of hydration. The solubility in water is 0.3  mg/ml.
The pKa of benzimidazole (omeprazole base) is 8.8.
The molecular mass of esomeprazole is 767.2 g/mol
(trihydrate) and 713.1  g/mol (anhydrous bases).
The molecular formula is C34H36N6O6S2MG●3H2O
and the chemical name is Di –(s)-5-methoxy-2-
[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-
sulfinyl]-1H-benzimidazole magnesium trihydrate.9
This article reviews the pharmacological profile,
tolerability, safety, and efficacy of esomeprazole,
It also provides an update on the use of the drug
in common clinical practice as well its use in rare
conditions such as Zollinger-Ellison syndrome.
Mechanism of Action, Metabolism,
and Pharmacokinetic Profile
Mechanism of action
Like other PPIs, esomeprazole suppresses gastric acid
secretion from gastric parietal cells. Esomeprazole
is a weak base that is concentrated in the acidic
environment of parietal cells and converted to the
active inhibitor, achiral sulphonamide. This inhibitor
binds irreversibly to specific cysteines, resulting in
an inhibition of H+/K+-ATPase enzyme activity.10
Inhibition of gastric acid secretion is dose dependent,
being observed in the range of 20–40 mg/day.11
Metabolism and pharmacokinetic profile
Esomeprazole is rapidly absorbed orally, with a peak
concentration in the plasma (Cmax) occurring at 0.5 h
440 Clinical Medicine Insights: Therapeutics 2010:2
post-administration with an oral solution containing
20 mg, and after up to 3.5 h with a 40 mg capsule.12
The bioavailability of the drug is 64% and is highly
dependent on concomitant food intake, which delays
and decreases absorption but does not appear to have
an effect on intragastric acidity.13
PPIs are metabolized via hepatic cytochrome
P450 enzymes, primarily CYP2C19.14 Both optical
isomers of omeprazole are converted to hydroxyl
and 5-0-desmethyl metabolites by the CYP2C19
isoenzyme, and to the sulphone by CYP3A4.15
Approximately 80% of the drug is eliminated by the
kidney and the rest through feces.14 Esomeprazole is
metabolized more by CYP3A4 than CYP2C19,15 has
a lower total intrinsic clearance than omeprazole and
the R-isomer, and shows less first-pass metabolism
than omeprazole. Esomeprazole therefore shows
a higher area under the plasma concentration-time
curve (AUC) and may achieve better acid suppression
than omeprazole in clinical practice.14,15
CYP2C19 affects PPI metabolism.16 CYP2C19
activity is influenced by gene polymorphisms, with
two inactivating mutations occurring most commonly
in Asian populations.17 Five percent of Caucasians
are homozygous for this mutation, exhibiting a poor
metabolizer phenotype. Bioequivalence data for
esomeprazole indicates that area under the curve
(AUC) values differ by less than two-fold between
poor metabolizers and the rest of the popula-
tion, and a dose reduction is not necessary in these
individuals.18
Esomeprazole shows similar pharmacokinetics in
the elderly19 or in patients with renal impairment20
or mild to moderate hepatic impairment. However,
esomeprazole levels increase in patients with severe
hepatic impairment.21 Esomeprazole is available as
a tablet, capsule, and oral suspension, with similar
absorption for all three,22,23 as well as for intravenous
usage.24
Esomeprazole has a low potential for interac-
tion with other drugs,14 but may interact with induc-
ers or inhibitors of CYP2C19 and CYP3A4, such as
voriconazole and clarithromycin, which can double
esomeprazole systemic exposure. Esomeprazole may
also interfere with gastric absorption that is influenced
by gastric pH (e.g. ketoconazole, iron salts, and
digoxin), and international normalized ratio (INR)
may need to be monitored if given with warfarin.25–27
 Esomeprazole for gastric acid-related diseases

Esomeprazole may increase the plasma concentration
of diazepam phenytoin, warfarin, cisapride, digoxin
and may reduce plasma levels of antiretroviral agents
(atazanavir, nelfinavir, ininavir, lopinavir and tiprana-
vir). However, none of those drug interactions were
clinically relevant.28,29
Clopidogrel is prodrug which is converted to active
metabolites by CYP2C19. PPIs may interfere with
clopidogrel function via CYP2C19,30,31 which could
lead to cardiovascular events.32,33 A 40% relative
increase in the risk of recurrent myocardial infraction
was observed in a case-control study34 but other
studies did not reveal any drug-drug interactions.35,36
Omeprazole is the PPI most likely to have a significant
interaction with clopidogrel but more studies are
needed to determine that the clinical implications of
that interaction.37
The effect of esomeprazole on serum gastrin was
evaluated in approximately 2700 patients in clinical
trials for up to 8 weeks and in over 1300 patients for
up to 12  months. The mean gastrin level plateaued
within 3  months and returned to baseline within
4 weeks after discontinuation of therapy.38
Clinical Studies
Several studies have compared the effects of esome-
prazole and other PPIs in gastro-esophageal reflux
disease (GERD) management as well peptic ulcer
disease. Below the efficacy of esomeprazole has
been updated in common gastrointestinal disorders
and NSAID-induced gastric ulcer disease, as well as
­non-ulcer dyspepsia, non-variceal upper gastrointes-
tinal bleeding, and Zollinger-Ellison syndrome.
Gerd
GERD is characterized by the reflux of gastric contents
into the esophagus, leading to reflux symptoms
sufficient to affect patients’ well being and/or cause
complications.39 Esomeprazole efficacy and activity on
intra-esophageal pH profiles have been compared
to other PPIs.40,41 One study compared 40  mg of
esomeprazole to 30 mg of lansoprazole in 30 patients
with complicated GERD.42 Esomeprazole was superior
to lansoprazole in both total (75% vs. 28%, P = 0.026)
and supine position (93% vs. 50%, P = 0.012) nocturnal
esophageal acid exposure.42 A number of random-
ized, double blind, multicenter trials have compared
the effects of esomeprazole with other PPIs in erosive
GERD using intent-to-treat analysis of healing rates
and GERD symptoms (Table 1).43–50 All patients had
endoscopy to confirm erosive GERD at baseline and
most of them had a follow-up endoscopy 4 and 8 weeks
later. The Los Angeles (LA) classification system was
used to grade the severity of reflux esophagitis.51 The
main exclusion criteria were other gastrointestinal
diseases, or severe or unstable cardiovascular, pulmo-
nary, or endocrine diseases.
Two studies compared esomeprazole to lanso­
prazole.47,48 Esomeprazole (40  mg, n  =  2624) sho­
wed a higher healing rate and was more effective

Table 1. The efficacy of esomeprazole vs. other PPIs in the management of erosive gastroesophageal reflux disease.

Reference Study design Treatment regimen No. patients End point Results
Gillessen et al Double-blinded, Esomeprazole vs. 114 vs. 113 Healing of GERD 90% vs. 95%
randomized pantoprazole
Kahrilas et al Double-blinded, Esomeperazole vs. 654 vs. 650 Healing of GERD 94.1% vs. 86.9%
randomized omeprazole
Richter et al Double-blinded, Esomeprazole vs. 1216 vs. 1209 Healing of GERD 93.7% vs. 84.2%
randomized omeprazole
Schmitt et al Double-blinded, Esomeprazole vs. 576 vs. 572 Healing of GERD 92.2% vs. 89.8%
randomized omeprazole
Castell et al Double-blinded, Esomeprazole vs. 2624 vs. 2617 Healing of GERD 92.6% vs. 88.8%
randomized lansoprazole
Fennerty et al Double-blinded, Esomeprazole vs. 498 vs. 501 Healing of GERD 82.4% vs. 77.5%
randomized lansoprazole
Labenz et al Double-blinded, Esomerpazole vs. 1562 vs. 1589 Healing of GERD 96% vs. 92%
randomized pantoprazole
Bardhan et al Double-blinded, Esomeprazole vs. 293 vs. 289 Healing of GERD 94% vs. 98%
randomized pantoprazole

Clinical Medicine Insights: Therapeutics 2010:2 441

Judaibi et al

then lansoprazole (30  mg, n  =  2617) in resolving
heartburn.47 A smaller study (total n =  999) showed
similar outcomes.48 Two studies indicated that esome-
prazole had a higher healing rate and better symptom
control than omeprazole in mild reflux esophagitis,44,45
but a third one did not,46 although esomeprazole was
superior to lansoprazole at 4 weeks (60.8% vs. 47.9%,
P = 0.02) and 8 weeks (88.4% vs. 77.5%, P = 0.007) in
patients with moderate to severe esophagitis. Esome-
prazole may have a better effect in more severe disease
than other PPIs.47,49 In one trial, 3170 patients were
randomly assigned to either esomeprazole or panto-
prazole. Esomeprazole had higher healing rates than
pantoprazole at 4 weeks (81% vs. 75%, P , 0.001)
and 8 weeks (96% vs. 92%, P , 0.001) and provided
better resolution of GERD symptoms,49 but there was
no difference in another study.43,46
Heliobacter pylori infection did not affect the
healing rates in multiple studies after 8 weeks of
treatment,38,45–47,52 but other studies showed that
H. pylori-positive patients may have higher healing
rates.49,50 Several meta-analyses showed that esome-
prazole had higher healing rates than other PPIs,53–58
particularly for severe esophagitis, producing num-
bers needed to treat for LA grades A, B, C, and D of
50, 33, 14, and 8, respectively.57
Maintenance therapy of healed
erosive GERD
Patients with severe erosive esophagitis have a higher
relapse rate than patients with moderate or mild
disease, but the overall relapse rate is 80% within
12 months of stopping therapy.59,60 Another study found
that 20% of GERD patients could discontinue their
PPIs without developing symptoms.61 Esomeprazole
40  mg is superior to 20  mg and 20  mg superior to
placebo in maintenance therapy for patients with
healed erosive GERD.62,63 In one study, 375 patients
with endoscopically healing esophagitis were ran-
domized to receive esomeprazole (40  mg, 20  mg
or 10  mg od) or placebo.63 After 6  months, more
patients remained healed with esomeprazole 40  mg
(87.9%), 20  mg (78.7%), and 10  mg (52.4%) com-
pared to placebo (29.1%) (P , 0.001). Esomeprazole
(20  mg) was more effective in maintaining therapy
than lansoprazole (15  mg) 6  months after endos-
copy-confirmed healing.64 A similar second study
found 83% of the esomeprazole group was in remis-
sion compared to 74% of the lansoprazole group
at 6  months (P  ,  0.0001), and more patients were
symptom-free.65 Esomeprazole was superior to pan-
toprazole in one study, but not another, in maintaining
healed erosive esophagitis and relief of gastroesopha-
geal symptoms (Table 2).66,67 Heartburn relapse rates
after esophagitis were lower with esomeprazole than
pantoprazole (ratio 2.08; P , 0.0001).68
Barrett’s esophagus
Barrett’s esophagus results from long standing
GERD and is an important risk factor for esophageal
adenocarcinoma.69,70 In a study involving 41 patients
with Barrett’s esophagus that received open-label
consecutive treatment with esomeprazole and lanso-
prazole with no washout period, 24-h intragastric pH

Table 2. The efficacy of esomeprazole vs. other PPIs in the maintenance therapy of healed erosive gastroesophageal reflux
disease.

Reference Study design Treatment regimen No. patients End point Results
Johnson et al Double-blinded, Esomeprazole vs. 82 vs. 77 Healing rate 93.6% vs. 57.1%
randomized omeprazole at 6 months
Vakil et al Double-blinded, Esomeperazole vs. 92 vs. 94 Healing rate 87.9% vs. 29.1%
randomized placebo at 6 months
Devault et al Double-blinded, Esomeprazole vs. 512 vs. 514 Healing rate 84.8% vs. 75.9%
randomized lansoprazole at 6 months
Lauritsen et al Double-blinded, Esomeprazole vs. 619 vs. 617 Healing rate 83% vs. 74%
randomized lansoprazole at 6 months
Goh et al Double-blinded, Esomeprazole vs. 672 vs. 642 Healing rate 84% vs. 85%
randomized pantoprazole at 6 months
Labenz et al Double-blinded, Esomeprazole vs. 1377 vs. 1389 Healing rate 87% vs. 79.4%
randomized pantoprazole at 6 months

442 Clinical Medicine Insights: Therapeutics 2010:2


was measured on the last day of each treatment.71
Esomeprazole was more effective in controlling the
intragastric pH, measured as the time with intragas-
tric pH .  4.0, in patients with Barrett’s esophagus
(P = 0.016).
Laryngopharyngeal reflux disease
On a recent double blind, prospective, randomized trial,
62 patients with laryngopharyngeal reflux disease
(LRP) were randomized to either esomeprazole
20 mg PO BID or placebo for 3 months . The total
reductions of the reflux finding score and reflux of
symptom index were higher in the esomepraozle group
compared to placebo after three months (P , 0.01).72
However, in the treatment group a high placebo effect
can be observed. In another study, the efficacy of
esomeprazole 40  mg once daily together with life-
style modification was determined in 49 patients by
24 hours pH monitoring before and after treatment.73
In conclusion, esomepraozle 40 mg once daily with
life style modification may improved LRP disease.
On the other hand, one study showed no therapeu-
tic benefit of esomeprazole (40  mg) once daily for
16 weeks compared to placebo in patients with lar-
yngopharyngeal reflex disease.74 The diagnosis of
LRP is still controversial and the treatment with PPI
therapy is based on weak evidence.75
Eosinophilic esophagitis
Although topical or oral steroids have been assessed
in eosinophilic esophagitis,76 only one study compared
the efficacy of esomeprazole to fluticasone. This small
study (n = 41) did not show improvement in dysphagia
or eosinophilic infiltrate with esomeprazole therapy.77
Non-erosive reflux disease
PPIs are the first line therapy in patients with
functional dyspepsia or non-erosive reflux esophagitis.
Rabeprazole had similar efficacy to esomeprazole
in suppressing GERD-related symptoms in Asian
patients with non-erosive esophagitis.78 Esomepra-
zole and omeprazole gave similar symptom-free
(heartburn) outcomes (60% of patients) in endoscopy
negative reflux disease at 4 weeks.79 Esomeprazole and
pantoprazole showed similar symptom relief in daily
assessments using a questionnaire.80 Esomeprazole
was more effective then placebo in the resolution of
heart burn and time to symptom-free status.81
Clinical Medicine Insights: Therapeutics 2010:2 443
Esomeprazole for gastric acid-related diseases
On-demand therapy
Most patients with GERD will have symptom relapse
within a year.59,60 Esomeprazole (20 mg) was superior
to placebo for on-demand therapy in patients with
endoscopy—negative GERD.82,83 In those studies,
patients received 4 weeks of esomeprazole or ome-
prazole and then were randomized to placebo or
esomeprazole groups after they had achieved complete
resolution of heartburn and had a normal endoscopy.
Esomeprazole was more effective in controlling heart-
burn and less patients discontinued therapy compared
to placebo due to inefficacy.82,83 Esomeprazole (20 mg)
on-demand therapy was economically more effec-
tive then lansoprazole 15 mg daily after 6 months in
endoscopy-negative GERD.84 Patients received a short
course of esomeprazole for 4 weeks and then were
randomized to continue therapy with lansoprazole or
on-demand therapy with esomeprazole. Esomeprazole
showed better symptom control and more patients
were willing to continue on-demand therapy than use
lansoprazole on daily basis (93% vs. 88%, P , 0.02).
On demand therapy required treatment only 38% of
the time, producing direct cost savings of 36%. Daily
esomeprazole (40 mg) showed better efficacy than an
on-demand regimen: 81% of patients on daily therapy
were still in remission compared to 58% who took on-
demand therapy 6 months after endoscopy-confirmed
healing (P , 0.0001).85
Uninvestigated dyspepsia and
health-related quality of life
The efficacy of esomeprazole in uninvestigated dys­
pepsia was assessed in two studies86,87 by evaluating if
one week of esomeprazole could produce a response
at 8 weeks in patients with functional or uninvesti-
gated dyspepsia. Patients were randomized to either
40 mg od, bid, or placebo for one week followed by
esomeprazole 40 mg po od or placebo for 7 weeks.
Patients rated the severity of their symptoms (epigas-
tric pain and/or burning) on a daily basis. The primary
efficacy endpoint in both studies was the percentage
of patients who responded after 8 weeks of treatment,
as a function of the sum of symptom scores during
the first week of acid suppression. Esomeprazole
was more effective then placebo in symptom control
at 4 and 8 weeks, but the response to esomeprazole
treatment at one week did not predict the clinical
response at 8 weeks.
Judaibi et al
Patients with GERD experience impaired
health-related quality of life and are less productive
compared to the general population,88–91 especially
patients with night symptoms.89 Esomeprazole can
improve quality of life and work productivity.91–94
GERD patients (n = 1902) were treated for 4 weeks
with esomeprazole (40 mg od) followed by 6-month
treatment with 20  mg of esomeprazole od, on
demand therapy, or ranitidine 150  mg bid.92 Both
esomeprazole treatments were more effective than
ranitidine in improving the quality of life and patient
satisfaction (80.2% vs. 77.8% vs. 47%; P , 0.001).
Short-term therapy with esomeprazole for 4 weeks
was more effective then placebo in improving sleep
quality and saved more work hours per week than at
baseline (11.6 h vs. 6.2 h; P , 0.001).94
H. pylori eradication and prevention
Esomeprazole is effective in intragastric acid
control and eradication of H. pylori,95,96 and
is more effective than other PPIs in control-
ling intragastric pH in healthy volunteers.1,95 The
IV formulation of esomeprazole provides faster
and more effective intragastric acid control than
40  mg of IV pantoprazole.97 In one of the studies,
24 H. pylori-negative subjects were randomized in a
two-period crossover study: tenatporazole or esome-
prazole 40 mg daily were given before breakfast for
2 consecutive days with a 2-week wash out period.
Tenatoprazole showed better efficacy than esomepra-
zole on intragastric acid control during the first 48 h in
healthy volunteers (median pH: 4.3 vs. 3.9, P , 0.08;
percent of time above pH 4: 57% vs. 49%, P , 0.03;
proportion of subjects with at least half of the time
above pH 4: 71% vs. 46%). Tenatoprazole has better
night-time acid control than esomeprazole (first night
median pH: 4.2 vs. 2.9 , P , 0.0001; second night: 4.5
vs. 3.2, P , 0.0001) but acid control was similar dur-
ing the day.98 In a similar study comparing tenatopra-
zole to esomeprazole 40 mg once daily for 7 days in
controlling the intragastric pH in healthy volunteers,
tenatoprazole was more effective than esomeprazole in
acid inhibition (24 h median pH: 4.6 vs. 4.2, P , 0.05;
night time: 4.7 vs. 3.6, P , 0.01).99 In an open label,
crossover study of 130 patients with symptoms of
GERD received esomeprazole 40 mg or omeprazole
40  mg once daily for 5  days. The 24-hr intragastric
pH was monitored in day 1 and 5 of each treatment.
444 Clinical Medicine Insights: Therapeutics 2010:2
Esomeprazole was more effective than omeprazole in
acid control ( mean percent of pH on day one: 48.6%
vs. 40.6%, day 5: 68.4% vs. 62%, P , 0.001).100
First-line treatment for H. pylori infection is
triple therapy with a PPI, amoxicillin/metronidazole,
and clarithromycin. Esomeprazole-based triple
therapy induces H. pylori eradication and healing of
duodenal and gastric ulcers.96,101 H. pylori patients
(n  =  446) with active duodenal ulcer disease were
randomly assigned to esomeprazole 20  mg BID
or omeprazole 20  mg BID in combination with
amoxicillin 1  gram and clarithromycin 500  mg for
one week, followed by continuation of omeprazole
or placebo for the esomeprazole group. Ulcer healing
was assessed by EGD after completing the therapy and
H. pylori status was assessed by the C-urease breath
test and histology 4–6 weeks later. Ulcer healing rates
were similar: 91% for esomeprazole versus 92% in
the omeprazole group, and H. pylori eradication rates
of 86% in the esomeprazole group compared with
88% in the omeprazole group (Table 3).101 Similarly,
a one-week regimen of ­esomeprazole-based H. pylori
therapy was as effective as omeprazole-based tri-
ple therapy followed by an additional 3 weeks
of monotherapy for duodenal ulcer healing and
eradication of H. pylori.102 Esomeprazole-based triple
therapy led to H. pylori eradication, ulcer healing,
and prevented relapse.96 High and low-dose esome-
prazole triple therapy in Taiwanese patients showed
similar H. pylori eradication rates (92% high dose
vs. 90% low dose, P  .  0.05).103 Esomeprazole and
rabeprazole showed similar efficacy in H. pylori erad-
ication (89.4% esomeprazole vs. 90.5% rabeprazole,
P = 0.72).104 A meta-analysis of PPIs in eradication of
H. pylori included 11 trials and 2159 subjects, show-
ing eradication rates with esomeprazole and antibi-
otic of 86% and 81%, an odds ratio of 1.38 (95%
CI = 1.09–1.75).105 A similar result was obtained from
another meta-analysis.106
Non variceal bleed
Patients (n = 70) with active bleeding ulcers or ulcers
with non-bleeding visible vessels were treated with
epinephrine injection followed by thermocoagulation
and treated with esomeprazole 40  mg po BID for
3  days or placebo.107,108 Bleeding reoccurred within
30  days in 2 patients (5.7%) in the esomeprazole
group compared to 3 (8.6%) in the placebo group

Table 3. The efficacy of esomeprazole vs. other PPIs in the management of H. Pylori.
Reference Study design Treatment regimen
Tulassay et al Double-blinded, Esomeprazole vs.
randomized omeprazole
Subei et al Double-blinded, Esomeperazole vs.
randomized omeprazole
Wu et al Double-blinded, Esomeprazole vs.
randomized rabeprazole
Hsu et al Double blinded, Esomeprazole
randomized (20 mg vs. 40 mg)
(P  =  0.999), and blood transfusion requirements
and the duration of hospitalization were similar.108
Intravenous esomeprazole after endoscopic therapy in
patients with high risk peptic ulcer disease was more
effective than placebo in reducing the risk of recur-
rent bleeding at 7 and 30 days (P = 0.012), although
endoscopic therapy was not completely standardized
and some patients received monotherapy with an
epinephrine injection, thermal coagulation, or hemo-
clips, and others received combination therapy.107
NSAID-associated gastrointestinal
symptoms and gastric ulcer
healing or prevention
NSAIDs are often associated with upper
gastrointestinal symptoms, including heartburn and
acid regurgitation, and esomeprazole controls these
symptoms.109–111 Two studies (NASA1, n = 794; and
SPACE1, n = 848) recruited patients taking NSAIDs
that were free of peptic ulcer, erosive esophagitis, and
H. pylori. Patients received 4 weeks of esomeprazole
(20 or 40 mg) or placebo once daily. Patients reported
their GI symptoms (pain, discomfort, or burning in
the upper abdomen) 7 days before therapy and in the
last 7 days using a score sheet for severity. Symptom
improvement was 2.3 on esomeprazole (20 mg) and
2.03 on 40 mg versus 1.84 in placebo in the NASA1,
and 2.17 on 20 mg, 2.12 on 40 mg, and 1.56 in placebo
(P , 0.001).109 In another study, heartburn resolved in
61% and 62% of the patients taking esomeprazole 20
and 40 mg with NSAID compared with 36% on pla-
cebo (P , 0.001). Acid regurgitation resolved in 65%
and 67% in the esomeprazole 40 and 20 mg groups
compared to 48% in the placebo group (P , 0.001).111
Esomeprazole was more effective then placebo in
preventing symptoms for 6 months in patients taking
Clinical Medicine Insights: Therapeutics 2010:2 445
Esomeprazole for gastric acid-related diseases
No. patients End point Results
222 vs. 224 H. Pylori 86% vs. 88%
eradication rate
186 vs. 188 H. Pylori 74% vs. 76%
eradication rate
209 vs. 211 H. Pylori 89.4% vs. 90.5%
eradication rate
120 vs. 120 H. Pylori 90% vs. 92%
eradication rate
NSAIDs or selective cyclo-oxygenase-2 (COX-2)
inhibitors. Symptom relapse was higher in the
placebo group (39.1%) than the 20 mg esomeprazole
group (29.3%) (P = 0.006) and 40 mg group (26.1%)
at 6 months of treatment (P , 0.001).110
In one study, patients with gastric ulcer confirmed
by EGD and receiving non-specific or COX-2-
selective NSAIDs were randomly assigned to
esomeprazole 20  mg or 40  mg or ranitidine for
8 weeks. Gastric ulcer healing was confirmed at
4 weeks by EGD and the healing rate at 8 weeks
was 91.5% with esomeprazole 40  mg vs. 88.4%
with 20 mg vs. 74.2% with ranitidine (P , 0.05).112
A second study compared endoscopic healing rates
at 4 and 8 weeks after treatment with esomepra-
zole 20 or 40  mg once daily or ranitidine 150  mg
twice daily in patients (n  =  444) with gastric ulcer
confirmed by EGD and receiving cyclooxygenase-
2-selective or non-selective NSAID therapies. The
gastric ulcer healing rate at 8 weeks was 85.7% in
the 40 mg esomeprazole group vs. 84.8% for 20 mg
esomeprazole vs. 76.3% in the ranitidine group,
with esomeprazole superior to ranitidine at 4 weeks
(P , 0.01).113
Esomeprazole also reduces the risk of gastric ulcer
formation in patients using nonselective NSAIDs
and COX-2 inhibitors (Table 4).114,115 Gastroduodenal
ulcer free patients (n  =  991) on daily aspirin were
randomly assigned to esomeprazole 20 mg or placebo
for 26 weeks; 27 patients (5.4%) in the placebo group
developed gastric or duodenal ulcers compared
to 8 patients (1.6%) in the esomeprazole group
(P , 0.0007).114 In two similar studies (VENUS and
PLUTO), patients over 60 years old and with an ulcer
history using non-selective NSAIDs or COX-2 inhib-
itors received esomeprazole 20 or 40 mg or placebo
Judaibi et al

Table 4. The efficacy of esomeprazole in the management NSAID-associated gastrointestinal symptoms and gastric ulcer
healing or prevention.

Study Study design Treatment regimen No. patients End point Results
NASA1 Double-blinded, Esomeprazole vs. 198 vs. 202 Resolution of 71.7% vs. 58%
randomized placebo symptoms
SPACE1 Double-blinded, Esomeperazole vs. 173 vs. 186 Resolution of 67.5% vs. 50.6%
randomized placebo symptoms
Goldstein et al Double-blinded, Esomeprazole vs. 129 vs. 132 Gastric ulcer 91.5% vs. 74.2%
randomized ranitadine healing rate
Yeomans et al Double blinded, Esomeprazole vs. 493 vs. 498 Occurrence of 1.8% vs. 5.4%
randomized placebo GU (prevention)*
VENUS Double blinded, Esomeprazole vs. 271 vs. 267 Occurrence of 4.7% vs. 20.4%
randomized placebo GU (prevention)*
PLUTO Double blinded, Esomeprazole vs. 196 vs. 185 Occurrence of 4.4% vs. 12.3%
randomized placebo GU (prevention)*
*Prevention of gastric ulcer.

daily for 6  months. For VENUS, 20.4% of patients
developed an ulcer at 6  months on placebo, 5.3%
on esomeprazole 20  mg (P  ,  0.001), and 4.7% on
esomeprazole 40  mg (P  ,  0.0001). The PLUTO
study found 12.3% on placebo, 5.2% on esomepra-
zole 20 mg (P = 0.018), and 4.4% with esomeprazole
40 mg (P = 0.007).115 The combination of ASA and
esomeprazole was superior to clopidogrel alone in
prevention of recurrent ulcer bleeds in 2 studies per-
formed in Hong Kong.116,117
Zollinger Ellison syndrome
Zollinger Ellison Syndrome is characterized by
ulceration of the proximal jejunum, hypersecretion
of gastric acid, and non-beta islet cell tumors of the
pancreas.118 An open-label, multicenter study using
40 mg or 80 mg esomeprazole twice a day measured
acid output at baseline, day 10, and at months 3, 6,
and 12.119 EGD was performed at baseline and at 6 and
12 months. Esomeprazole was titrated up to 240 mg/
day to achieve better control of the acid output, and no
patients had endoscopic evidence of mucosal disease
at 6 or 12  months. One patient developed a serious
adverse event (hypomagnesaemia).
Safety
The safety of esomeprazole has been evaluated in
several trials.57 Long term use of PPIs may lead to
hypomagnesemia120,121 via an unclear mechanism
probably involving an idiosyncratic reaction or
inhibition of the magnesium transporter in the
intestine.120 Esomeprazole may also lead to vitamin
B12 deficiency, but the data are conflicting,25,121,122
and it is less likely that esomeprazole leads to atro-
phic gastritis.38 Esomeprazole may influence the
absorption of calcium carbonate,123 and its effect on
iron absorption is not clear.124,125
The safety of esomerpazole has been evaluated
in the primary care setting of 11595 patients in Eng-
land using prescription event monitoring.126 Several
adverse events were reported in the observational
cohort study (diarrhea 3/1000 , nausea and vomiting
2/1000, abdominal pain 3/1000, dyspepsia 4/1000,
headache and migraine 2/1000, respiratory tract
infection 3/1000 , malaise and joint pain 1/1000).126
The safety of esomeprazole has been evaluated in the
short (8 weeks) and long term (up to one year), with
similar rates of adverse events reported (diarrhea 6%,
headache 7%, flatulence 3%, constipation 2%, dry
mouth 1%, respiratory infection 4%, sinusitis 2%,
pharyngitis 1%, dizziness 1%).9,45,62,64,67,96 In addition
to these adverse events, other symptoms have been
reported in longer follow up (urinary tract infection
3.7% , allergy 2.1%, bronchitis 3.6%, arthralgia 3%,
hypertension 3%, insomnia 2.1%, dyslipidemia 2%,
anxiety 2%, flu-like disorder 1%, myalgia 1% and
fever 1.5% ).9,45,62,64,67,96
The use of PPIs by pregnant women is not associ-
ated with increased risk of congenital malformation
or birth defects,127–129 and esomeprazole is a class B
drug. A meta-analysis of PPI use in the first trimes-
ter using the Mantel-Haenszel method to calculate
relative risk and 95% confidence intervals revealed
a relative risk of 1.18 (95% CI, 0.72–1.94) for major

446 Clinical Medicine Insights: Therapeutics 2010:2


malformations after PPI exposure. Omeprazole had
an overall malformation rate of 2.8%.127
Gastric acid plays an important role in facilitating
the absorption of calcium.130 Long term or high dose
PPI therapy increases the risk of hip fracture,131,132
but this risk is lower in patients without major risk
factors for osteoporosis.133 In a prospective study
of 1211 postmenopausal women, omeprazole
was associated with an increased risk of vertebral
fractures (RR = 3.50, 95% CI 1.14–8.44).134 Further
studies are needed to assess the relationship between
esomeprazole and osteoporosis.
Decreased gastric acidity increases gastric bacteria
levels, and PPIs may increase the risk of developing
Clostridium difficile diarrhea (C. difficile).135,136 Pati­
ents (n = 1187) that received PPIs and antibiotics for
9 months showed more C. difficile diarrhea (CDAD;
adjusted OR 2.1, 95% CI 1.2–3.5 ),137 but other stud-
ies did not show that effect.138,139 In a prospective
study designed to evaluate the incidence of nosoco-
mial CDAD and a case-control study to determine
the risk factors for the disease. A total of 1703 epi-
sodes of CDAD were observed among 1719 patients
at 12 hospitals, with an incidence rate of 22.5/1000
admissions. Exposure to PPIs was not significantly
associated with development of CDAD.139
Several studies assessed the association between
PPI therapy and risk of developing community
acquired pneumonia.140–142 The risk to benefit ratio
favors using acid suppressive therapy for conditions
in which efficacy has been demonstrated.143 In a ret-
rospective analysis of thirty one studies, there was no
casual association between esomeprazole and increase
the risk of community acquired pneumonia.142
Long term PPIs therapy may stimulate the
enterochromaffin-like (ECL) cell proliferation and
increase the ECL mass even after discontinuation of
therapy .This will lead to increase in the gastric acid
production until there is a normalization of the ECL
mass (2–3 months after stopping therapy).144,145 With-
drawal of PPI therapy in patients with reflux esophagi-
tis may lead to worsening of there symptoms due to
rebound acid hypersecration.146,147 In a randomized,
double blind, placebo controlled trial of 120 healthy
volunteers, withdrawal of PPI therapy after 8 weeks
of treatment was associated with acid related symp-
toms comparable to placebo.148 However, there was
no strong evidence for a clinically relevant increased
Clinical Medicine Insights: Therapeutics 2010:2 447
Esomeprazole for gastric acid-related diseases
of acid production after withdrawal of PPI therapy in
a systemic review of 8  studies due to heterogeneity
in design, methods and outcome.149 Further studies
are required to assess the causality of symptoms due
acid hypersecretion and withdrawal of esomeprazole
therapy .
Conclusions
PPI therapy is more effective than other acid
suppressive therapies. Esomeprazole is more effec-
tive for control of esophageal and gastric acid
than other PPIs. However, it is not more effective
clinically except in patients with severe esophagitis.
Esomeprazole (S-omeprazole) is a single opti-
cal enantiomer proton-pump inhibitor (PPI) and
the rational of developing this drug was its higher
metabolic stability, which will lead to a higher
bioavailability and increase in the area under the
plasma concentration-time curve (AUC), which
will provide more effective control of gastric acid
secretions compared to other PPIs therapy. Esome-
prazole is converted to the active metabolite (achiral
sulphanomide) by the presence of the acidic envi-
ronment through parietal cells and it will inhibit
H+/K+-ATPase activity. The efficacy of esomepra-
zole in clinical practice compared to omprazole is
unclear. However, in one study, esomerpazole was
a slightly weaker inhibitor of CYP2C19 compared
to omeprazole, which would favor the use of esom-
prazole although the potential for drug interaction
in practice is similar between these two agents. This
could be explain by the higher standard dose used
for esomeprazole (40  mg) compared to omepra-
zole (20 mg) resulting in a higher plasma exposure
level.150
Esomeprazole can treat gastric acid disorders and
help maintain remission, but the cost-effectiveness
is unclear. Esomeprazole 40  mg daily is more
effective for healing gastric ulcers in patients with
NSAID therapy compared to ranitidine 150 mg twice
daily at 8 weeks (91.5% vs. 74.2%, P  ,  0.05).112
A meta-analysis of 11 studies, compared the effi-
cacy of PPI therapy to ranitidine in treating patients
with bleeding peptic ulcers.151 Persistent or recur-
rent ­bleeding was lower in the PPI therapy group
compared to the ranitidine group (6.7% vs. 13.4%,
P = 0.09) and the need for surgical intervention was
lower as well in the PPIs group (5.2 vs. 6.9, P = 0.09).
Judaibi et al
Esomeprazole may interact with clopidogrel, but the
data are conflicting.
Esomeprazole is generally well tolerated. PPI
therapy is effective and safe during pregnancy,
but the long-term effects on the gastric mucosa are
unclear and may include achlorhydria and carcinoid
tumor. PPI therapy can be chosen based on several
factors, including doctor preference, patient toler-
ance, symptomatic response, and cost.
Disclosures
This manuscript has been read and approved by
all authors. This paper is unique and is not under
consideration by any other publication and has not
been published elsewhere. The authors and peer
reviewers of this paper report no conflicts of interest.
The authors confirm that they have permission to
reproduce any copyrighted material.
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