Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002), pp.

954 –958 (© 2002)

Effect of Esomeprazole 40 mg vs
Omeprazole 40 mg on 24-Hour Intragastric
pH in Patients with Symptoms of
Gastroesophageal Reflux Disease
KERSTIN RÖHSS, PhD,* GÖRAN HASSELGREN, MD, PhD,* and HANS HEDENSTRÖM, MD†

Maintenance of intragastric pH ⬎ 4 is vital for effective management of gastroesophageal

reflux disease (GERD). Esomeprazole 40 mg, the first proton pump inhibitor developed as
an optical isomer, demonstrates improved acid inhibition over omeprazole 20 mg. Our aim
was to compare esomeprazole 40 mg with omeprazole 40 mg, once-daily, on intragastric
acidity in patients with symptoms of GERD. In this open-label, crossover study, 130 patients
with symptoms of GERD received esomeprazole 40 mg or omeprazole 40 mg once-daily for
five days. The 24-hr intragastric pH was monitored on days 1 and 5 of each treatment period.
The mean percentage of the 24-hr period with intragastric pH ⬎ 4 was significantly greater
(P ⬍ 0.001) with esomeprazole 40 mg than with omeprazole 40 mg on days 1 (48.6% vs
40.6%) and 5 (68.4% vs 62.0%). Interpatient variability was significantly less with esomepra-
zole than omeprazole. Esomeprazole was well tolerated. In conclusion, esomeprazole 40 mg
provides more effective acid control than twice the standard dose of omeprazole.

KEY WORDS: esomeprazole; omeprazole; gastroesophageal reflux disease; intragastric pH; pharmacodynamics.

Gastric acid is central to the development of mucosal appropriate threshold for discriminating between
injury and symptoms in gastroesophageal reflux dis- normal and pathological reflux (3, 4). Conversely,
ease (GERD), with 24-hr esophageal pH monitoring healing of mucosal injury correlates with the duration
suggesting a direct relationship between the degree of suppression of intragastric acidity at pH ⬎ 4 (1).
and duration of esophageal acid exposure and the Accordingly, maintenance of intragastric pH ⬎ 4 for
extent of mucosal injury (1, 2). The proportion of the the greater part of each 24-hr period provides the key
24-hr period with intraesophageal pH ⬍ 4 increases to effective management of GERD.
progressively from endoscopy-negative GERD Proton pump inhibitors (PPIs) are well-established
through the worsening grades of esophagitis (2). Fur- agents for the treatment of GERD, and according to
thermore, pH 4 is generally accepted as the most recently published US and European guidelines, offer
the most effective means of ensuring rapid symptom
Manuscript received July 11, 2001; revised manuscript received relief and esophageal healing (5, 6).
October 29, 2001; accepted November 12, 2001. It is apparent, however, that although rates of
From *AstraZeneca R&D Mölndal, Mölndal, Sweden; and †De- symptom resolution are generally high with PPIs,
partment of Medical Sciences, Clinical Physiology, University Hos-
pital, Uppsala, Sweden. some PPIs fail to achieve complete resolution of
This study was sponsored by AstraZeneca R&D Mölndal, Möln- heartburn and other GERD symptoms (7, 8). Indeed,
dal, Sweden.
Address for reprint requests: Kerstin Röhss, AstraZeneca R&D in a large US survey comparing H2 -receptor antag-
Mölndal, S-43183 Mölndal, Sweden. onists with omeprazole and lansoprazole (9), less

954 Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002)
0163-2116/02/0500-0954/0 © 2002 Plenum Publishing Corporation
GASTRIC pH: ESOMEPRAZOLE VS OMEPRAZOLE

than one half of patients reported being totally satis- an assessment of H. pylori status using the [13C] urea breath
fied with their heartburn medication. Thus, despite test.
the high efficacy of PPIs, an opportunity clearly exists Eligible patients were randomized to receive esomepra-
zole 40 mg or omeprazole 40 mg capsules once daily in the
to improve clinical outcomes in patients with GERD. morning. Doses were administered 30 min before breakfast.
Esomeprazole, the S isomer of omeprazole, is the No antisecretory or prokinetic drugs were allowed for
first PPI to be developed as a single optical isomer for two weeks before and during each study period. Antacids
the treatment of acid-related disorders. Esomepra- were allowed as required for the control of reflux symptoms
zole has higher systemic bioavailability than racemic during the period up to midnight on the day preceding the
omeprazole, and when administered at a dose of 40 clinic visit, but were not permitted on study days 1 or 5.
Other concomitant medication considered necessary for the
mg provides more effective and sustained inhibition patients’ welfare was administered at the investigator’s dis-
of 24-hr intragastric acidity than omeprazole 20 mg cretion. Medication bottles were checked on day 5 of each
(10), lansoprazole 30 mg (11), pantoprazole 40 mg treatment period to assess treatment compliance.
(12), or rabeprazole 20 mg (13). Moreover, the Alcohol was prohibited for two days before and during
greater acid control provided by esomeprazole 40 mg each treatment period and during the interval prior to the
follow-up visit. Food and beverages, except water, were not
has been shown to translate into improved symptom permitted for 12 hr before the dose and 30 min after the
resolution and mucosal healing when compared with dose on days 1 and 5 in each treatment period. Water was
omeprazole 20 mg in patients with erosive esophagi- not permitted from midnight the previous evening until 30
tis. (14, 15) min after the dose except for drug dosing. All meals were
Given the greater efficacy of esomeprazole 40 mg standarized during study days 1 and 5 to ensure consistent
intragastric pH measurements were determined.
over omeprazole 20 mg, it is also of interest to con- Measurement of Intragastric pH. After an overnight fast
sider the effects of equal milligram doses of these two patients came to the clinic on days 1 and 5 of each dosing
PPIs on intragastric pH. As such, this study compares period. Study medication was administered under the su-
the effect of esomeprazole 40 mg and twice the stan- pervision of study personnel, and 24-hr intragastric pH was
dard dose of omeprazole (ie, 40 mg) on 24-hr intra- recorded using a microelectrode (Ingold bipolar glass)
linked to a Digitrapper pH 400 recorder (Medtronic Syn-
gastric acidity after both single- and repeated-dose etics AB). The electrode was positioned 10 cm below the
administration in patients with symptoms of GERD. lower esophageal sphincter. The percentages of time with
intragastric pH ⬎ 3 and pH ⬎ 4 along with 24-hr median
MATERIALS AND METHODS intragastric pH were calculated for each patient during each
recording period using the Polygram 98 PH programe
Patients. Male and female patients ⬎20 years of age with (Medtronic Synetics AB).
symptoms of GERD, experiencing significant symptoms Safety and Tolerability. All spontaneously reported ad-
(heartburn and/or acid regurgitation) on at least two days verse events, as well as those elicited by open questioning or
per week during the last two months, were eligible for study observed by the investigator, were recorded. Blood and
inclusion. Patients were required to be Helicobacter pylori- urine sampling for screening of routine laboratory safety
negative, as determined by a [13C]urea breath test. The variables was performed at the prestudy visit, at the end of
main exclusion criteria were symptoms indicative of com- each treatment period, and at the follow-up visit. Patients
plications of GERD (eg, melena, hematemesis), primary with clinically significant changes in laboratory variables
esophageal motility disorder, or previous gastric surgery were either excluded or withdrawn from the study and/or
and any pharmacotherapy for GERD within the previous followed-up until normalization or for as long as the inves-
two weeks. Patients with a history of drug addiction and/or tigator considered necessary.
alcohol abuse, moderate to heavy smoking (⬎10 cigarettes/ Statistical Analysis. The study was designed to enroll a
day) or other nicotine use, and those with significant con- maximum of 130 patients and to have 115 evaluable pa-
comitant disease were also excluded from enrollment. Preg- tients, thereby providing an estimated power of 99% for a
nant or nursing women, and those of childbearing potential two-sided paired ttest at the 5% significance level.
who were deemed unlikely to be using adequate contracep- The percentage of time with intragastric pH ⬎ 4 and
tive measures during the course of the study were excluded. pH ⬎ 3 as well as 24-hr median pH during the 24-hr period
The study was performed according to the ethical principles following drug administration was analyzed using a mixed-
of the Declaration of Helsinki, and the protocol was ap- model ANOVA with fixed effects for period, sequence, and
proved by the Ethics Committee of the University of Upp- treatment and a random effect for patient within sequence.
sala, Sweden, prior to study commencement. Informed writ- The mean value for each treatment and the mean treatment
ten consent was obtained from all participating patients. difference (esomeprazole ⫺ omeprazole) were estimated
Study Design. This was a single-center, randomized, with 95% confidence intervals (CIs). The percentage of
open-label, crossover study comprising two five-day treat- time with intragastric pH ⬎ 4 on day 5 was the primary
ment periods separated by a washout interval of at least 13 outcome variable. The interpatient variability in percent-
days. An initial screening visit included determination of ages of time with intragastric pH ⬎ 4 on day 1 and on day
patients’ complete medical history, physical examination, 5 was evaluated by testing for equal variance where the
and measurement of laboratory safety variables as well as estimated variances are correlated, according to the method

Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002) 955
 RÖHSS ET AL

TABLE 1. BASELINE DEMOGRAPHICS AND CLINICAL tients were analyzed for intragastric pH on day 1 and
CHARACTERISTICS OF RANDOMIZED PATIENTS (N ⫽ 130)
114 on day 5.
Gender, male:female (%) 60:70 (46:54%) Intragastric pH. The mean percentage of time with
Age [years, mean (range)] 31.7 (20–79)
Body weight, [kg, mean (range)] 74.4 (51–100)
intragastric pH ⬎ 4 was significantly greater with
Smokers, [N (%)] 32 (25%) esomeprazole 40 mg than with omeprazole 40 mg on
Duration of GERD symptoms [N (%)] day 1 (48.6% vs 40.6%, P ⬍ 0.001) and day 5 (68.4%
⬍1 year 12 (9%)
1–5 years 66 (51%)
vs 62.0%, P ⬍ 0.001) (Table 2). The estimated mean
⬎5 years 52 (40%) value for the difference between treatment groups
was 8.1% and 6.4% on days 1 and 5, respectively,
which corresponds to an additional 1.9 hr and 1.5 hr
described by Snedecor and Cochran(16). Data for days 1 over the 24-hr period with intragastric pH ⬎ 4 fol-
and 5 were analyzed separately. Adverse events are pre- lowing esomeprazole treatment on day 1 and day 5,
sented descriptively.
respectively. Similarly, the percentage of time with
intragastric pH ⬎ 3 was significantly higher with es-
RESULTS
omeprazole 40 mg than with omeprazole 40 mg on
Patients. Baseline demographic and clinical char- day 1 (63.3% vs 55.6%, P ⬍ 0.001) and day 5 (79.9%
acteristics of the 130 patients randomized to treat- vs 74.9%, P ⬍ 0.001) (Table 2). Consequently, mean
ment are summarized in Table 1. All patients were 24-hr median intragastric pH was significantly higher
Caucasian except for one who was black. Approxi- with esomeprazole 40 mg than with omeprazole 40
mately 25% of patients were smokers. The specific mg on both days 1 (3.86 vs 3.41, P ⬍ 0.001) and 5
reflux symptoms (epigastric pain, heartburn, regurgi- (4.78 vs 4.50, P ⬍ 0.001) (Table 2).
tation, and water brash) were of mild to moderate Interpatient variability (as indicated by coefficient
intensity in most patients. of variation) in the percentage of time with intragas-
Of the 130 randomized patients, a total of 120 tric pH ⬎ 4 was significantly less with esomeprazole
completed the study; 10 patients discontinued due to 40 mg (14.8%) than with omeprazole 40 mg (17.4%)
either adverse events (N ⫽ 5) or other reasons (N ⫽ on day 5 (P ⫽ 0.02 for test of equal variance).
5) and were excluded from the intragastric pH anal- In terms of individual patient responses, after five
ysis. In addition, due to technical failure, pH record- days of treatment an intragastric pH ⬎ 4 was main-
ing data was missing for a further nine patients on day tained for at least 12 hr in 88% of patients receiving
1 (N ⫽ 5) and/or day 5 (N ⫽ 5), all of whom were esomeprazole 40 mg and 75% of patients receiving
excluded from the intragastric pH analysis for corre- omeprazole 40 g (P ⬍ 0.01). In addition, an intragastric
sponding study days. A further patient who received pH ⬎ 4 was maintained for at least 16 hr in 55% and
the wrong study drug on day 5 of the first study period 44% of patients receiving esomeprazole 40 mg and
was also excluded from the pH analysis for day 5. All omeprazole 40 mg, respectively (P ⬍ 0.05) (Figure 1).
other patients completing the study took the study Safety and Tolerability. Esomeprazole 40 mg daily
drugs according to the protocol. Therefore, 115 pa- was well tolerated, displaying a similar pattern and

TABLE 2. PHARMACODYNAMIC DATA FOLLOWING ADMINISTRATION OF ESOMEPRAZOLE OR OMEPRAZOLE ONCE DAILY IN PATIENTS WITH
SYMPTOMS OF GASTROESOPHAGEAL REFLUX DISEASE

Treatment group

Day 1 (N ⫽ 115) Day 5 (N ⫽ 114)

Esomeprazole Omeprazole Esomeprazole Esomeprazole Omeprazole Esomeprazole

40 mg 40 mg ⫺ omeprazole 40 mg 40 mg ⫺ omeprazole

Mean percent time with 48.6 40.6 8.1* 68.4 62.0 6.4*
intragastric pH ⬎ 4 (95% CI) (45.1, 52.2) (37.0, 44.1) (5.5, 10.7) (65.4, 71.4) (59.0, 65.0) (4.0, 8.8)

Mean percent time with 63.3 55.6 7.7* 79.9 74.9 5.0*
intragastric pH ⬎ 3 (95% CI) (59.7, 66.8) (52.0, 59.1) (5.1, 10.4) (77.5, 82.3) (72.5, 77.3) (3.1, 6.9)

Mean 24-hr median intragastric 3.86 3.41 0.45* 4.78 4.50 0.28*
pH (95% CI) (3.67, 4.05) (3.22, 3.60) (0.31, 0.60) (4.64, 4.92) (4.36, 4.64) (0.17, 0.39)
*P ⬍ 0.001.

956 Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002)
GASTRIC pH: ESOMEPRAZOLE VS OMEPRAZOLE

Fig 1. Percentage of patients maintaining intragastric pH ⬎ 4 for at least 12 and 16 hr of

the 24-hr period, following treatment with esomeprazole 40 mg and omeprazole 40 mg
once daily for five days.

incidence of adverse events to omeprazole 40 mg repeated once-daily dose administration in patients

daily. The most commonly reported adverse events in with symptoms of GERD. These findings reinforce
either group were headache (⬃20%), nausea (⬃8%), previous evidence regarding the greater acid-
and abdominal pain (⬃6%). suppressant effect of esomeprazole 40 mg compared
Abnormal laboratory values were reported in two with omeprazole 20 mg in patients with symptoms of
patients at the last study visit; an increase in alkaline GERD (10). Importantly, doubling the omeprazole
phosphatase after receiving omeprazole 40 mg during dose from the recommended standard dose of 20 mg
the second treatment period (N ⫽ 1) and an increase to 40 mg does not deliver the same long-lasting de-
in alanine aminotransferase after receiving esomepra- gree of acid control that is provided by esomeprazole
zole 40 mg during the second treatment period (N ⫽ 40 mg. Indeed, intragastric pH remained above 4 for
1). A decrease in platelet count also was observed at approximately 2 hr longer with esomeprazole 40 mg
the last study visit in a third patient following treat- than omeprazole 40 mg when assessed on day 1, and
ment with esomeprazole 40 mg during the second 1.5 hr longer when assessed on day 5. Furthermore,
treatment period. However, no particular trend was when compared with omeprazole 40 mg, esomepra-
observed for changes in laboratory safety variables zole 40 mg was associated with significantly less in-
after esomeprazole or omeprazole treatment and no terindividual variation in the percentage of time with
safety concerns were raised. intragastric pH ⬎ 4. Interestingly, marked intersub-
ject variability in the degree of acid control obtained
DISCUSSION with omeprazole 40 mg daily has been reported in a
In GERD, the degree of mucosal injury (1) and previous study in healthy volunteers (8).
frequency of reflux symptoms (17) are a function of The improved intragastric pH control noted with
esophageal acid exposure. Indeed, the response to esomeprazole 40 mg in the present study (as reflected
antisecretory agents can be predicted by the duration in an intragastric pH ⬎ 4 for 68% of the 24-hr period)
of suppression of intragastric acidity (as indicated by is in close agreement with previous findings with this
a pH ⬎ 4) over the 24-hr period (1). Therefore, PPI (intragastric pH ⬎ 4 for 70% of the 24-hr period)
maintaining intragastric pH ⬎ 4 is important in (10). Importantly, these pharmacodynamic findings
achieving esophageal healing and symptom relief in also reinforce those of previous 24-hr intragastric pH
GERD. studies, indicating greater acid control with esome-
In the present study, intragastric pH ⬎ 4 was main- prazole 40 mg over standard doses of lansoprazole
tained for significantly longer with esomeprazole 40 (11), pantoprazole (12), and rabeprazole (13).
mg than with omeprazole 40 mg after both single and Since a correlation has been suggested between

Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002) 957
 RÖHSS ET AL

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Mowinckel P: Heartburn treatment in primary care: Random-
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958 Digestive Diseases and Sciences, Vol. 47, No. 5 (May 2002)