Alimentary Pharmacology & Therapeutics

Clinical trial: the effects of adding ranitidine at night to twice

daily omeprazole therapy on nocturnal acid breakthrough and
acid reflux in patients with systemic sclerosis – a randomized
controlled, cross-over trial
P. JANIAK*, M. THUMSHIRN*, D. MENNE , M. FOX*, S. HALIMà, M. FRIED*, P. BRÜHLMANNà,
O. DISTLERà & W. SCHWIZER*

*Clinic of Gastroenterology and SUMMARY

Hepatology, University Hospital of
Zürich, Switzerland;  Menne Biomed, Background
Tübingen, Germany; àDepartment of
Gastro-oesophageal reflux disease (GERD) is an important problem in
Rheumatology, University Hospital of
Zürich, Switzerland systemic sclerosis due to impaired salivation and oesophageal function.

Correspondence to: Aim

Dr M. Fox, Clinic of Gastroenterology
and Hepatology, University Hospital
of Zürich, Raemistr. 100, CH-8091
Zürich, Switzerland.
E-mail: mark.fox@usz.ch
Publication data
Submitted 12 June 2007
First decision 25 June 2007
Resubmitted 30 July 2007
Accepted 15 August 2007
To determine the efficacy of adding ranitidine at bedtime to control
nocturnal acid breakthrough (NAB) and GERD in patients with systemic
sclerosis already prescribed high-dose omeprazole.
Methods
Patients with systemic sclerosis and GERD symptoms (n = 14) were trea-
ted with omeprazole 20 mg b.d. and either placebo or ranitidine
300 mg at bedtime for 6 weeks in a randomized, cross-over, placebo
controlled study. At the end of each period a 24 h pH-study with intra-
gastric and oesophageal pH measurement was performed.

Results
Pathological acid reflux occurred in eight patients with omeprazole ⁄ pla-
cebo and in seven with omeprazole ⁄ ranitidine (P = ns) with technically
adequate oesophageal pH-studies (n = 13). NAB was present in eight
patients with omeprazole ⁄ placebo and six with omeprazole ⁄ ranitidine
(P = ns) in whom technically adequate gastric pH-studies were obtained
(n = 10). The addition of ranitidine had no consistent effect on patient
symptoms or quality of life.

Conclusion
Many patients with systemic sclerosis experienced NAB and pathologi-
cal oesophageal acid exposure despite high-dose acid suppression with
omeprazole b.d. Adding ranitidine at bedtime did not improve NAB,
GERD or quality of life in this population.

Aliment Pharmacol Ther 26, 1259–1265

ª 2007 The Authors 1259

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doi:10.1111/j.1365-2036.2007.03469.x
1260 P . J A N I A K et al.
INTRODUCTION
Gastro-oesophageal reflux disease (GERD) is a major
problem in patients with systemic sclerosis, leading to
significant morbidity and reduced patient-rated quality
of life. Decreased lower oesophageal sphincter pres-
sure, impaired peristalsis, diminished saliva produc-
tion, and delayed gastric emptying may also be
present and play a role in the pathogenesis of GERD.1
High-dose acid suppression is important in this group
of patients to avoid severe oesophagitis and complica-
tions such as oesophageal strictures and Barrett’s
oesophagus; however, there is limited information
on the optimal therapy of acid reflux in systemic
sclerosis.
The circadian rhythm of gastric acid secretion
exhibits low secretion in the morning, greater output
in the evening and peak secretion around midnight.2
Studies have shown a drop in nocturnal gastric pH in
patients and healthy volunteers taking a proton pump
inhibitor twice daily (PPI b.d.).3, 4 This drop in gastric
pH, termed nocturnal acid breakthrough (NAB), is
defined as a gastric pH < 4 for at least one continuous
hour during the night. The percentage of healthy vol-
unteers with NAB ranged from 35% to 75% and in
patients with GERD from 67% to 100%.4–7.This is clin-
ically important because the prevalence of abnormal
oesophageal acid exposure during NAB is much higher
in patients with GERD (33%) and Barrett’s oesophagus
(50%) compared with that in healthy volunteers (8%).5
Patients with systemic sclerosis have a high prevalence
of GERD and its complications. Prolonged oesophageal
acid exposure at night secondary to NAB is prevalent
in these patients because of weak lower oesophageal
sphincter function and poor oesophageal motility.
Thus, patients with systemic sclerosis are a relevant
group to study the clinical impact and the appropriate
treatment directed at the control of NAB.
Studies indicate that, for patients requiring more
than a standard daily dose of a PPI, adding a second
dose before dinner leads to a 24 h acid control supe-
rior to doubling the morning dose.8, 9 Twice daily
omeprazole together with ranitidine at bedtime proved
to be the optimal regimen to reduce NAB in normal
volunteers.10, 11 The aim of this randomized, double
blind, placebo controlled study was to evaluate the
role of adding ranitidine to twice daily omeprazole in
controlling gastric and oesophageal pH for patients
with systemic sclerosis complaining of typical reflux
symptoms.
MATERIALS AND METHODS
Patients and study design
Patients meeting the American Rheumatism Associa-
tion criteria for systemic sclerosis and a history sug-
gesting of GERD were entered into the study. Patients
were recruited from the systemic sclerosis patient self-
help group of the German speaking part of Switzer-
land. Inclusion criteria were the presence of typical
reflux symptoms (heartburn or acid regurgitation).
There was no requirement for ‘classic’ changes in sys-
temic sclerosis on oesophageal motility. Exclusion cri-
teria were pregnancy or lactation, alcohol or drug
abuse, severe concomitant organic or psychiatric dis-
ease and previous oesophageal or gastric surgery. Acid
suppression therapy with H2-receptor antagonists was
discontinued for at least 2 weeks prior to the study.
The study fulfilled the principles of the ‘Declaration of
Helsinki’ and was approved by the local Ethics com-
mittee of the University Hospital of Zurich. Written
informed consent was obtained.
Patients were studied in a randomized, double-blind,
cross-over, placebo controlled study lasting 12 weeks.
Each patient was treated with omeprazole (AstraZeneca,
Zug, Switzerland) 20 mg b.d. and bedtime placebo for
6 weeks (Arm 1) and omeprazole 20 mg b.d. and bed-
time ranitidine 300 mg for 6 weeks (Arm 2) (omepra-
zole taken before breakfast and dinner). At baseline
upper gastrointestinal endoscopy was performed and
standardized, validated questionnaires to assess gastro-
intestinal related quality of life12 reflux symptoms13
and the burden of disease related to systemic sclero-
sis,14 were completed. In each 6-week treatment per-
iod, 3 weeks after start of dosing, quality of life and
reflux symptoms were assessed by a telephone inter-
view. At the end of each 6 weeks treatment period an
upper endoscopy and a 24 h pH-study were performed
and patients were asked again to complete the ques-
tionnaires regarding quality of life and reflux symp-
toms.
Methods
Physiological measurements of gastro-oesophageal
function
High resolution manometry (Advanced Manometry
Systems, Melbourne, Australia) using a 22 channel
water perfused catheter with a sleeve sensor
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(Dentsleeve, Wayville, South Australia) was performed
to document lower oesophageal sphincter function and
oesophageal motility, as described previously.15
Manometry results were analysed using Trace! Soft-
ware (Advanced Manometry Systems) and classified
according to standard criteria.16
The 24 h pH-study was performed using two cathe-
ters. The oesophageal pH-study was performed with a
catheter containing four 5 cm spaced solid state pres-
sure transducers and a pH glass-electrode mounted at
the tip of the catheter (Unisensor, Attikon, Switzer-
land). After an over night fast a pull-through manom-
etry with the solid state pressure catheter was
performed first to define the position of the lower
oesophageal sphincter. The catheter was positioned
with the oesophageal pH-electrode to be 5 cm above
the lower oesophageal sphincter. Intragastric pH was
monitored by a second glass electrode (Ingold, Urdorf,
Switzerland) and was placed 10 cm below the lower
end of the lower oesophageal sphincter. Patients were
instructed to continue their normal daily activities, to
indicate changes in their body position, start and end
of meals and time of drug intake on a digital data log-
ger. Each individual was free to choose from a selec-
tion of three standardized meals for breakfast, lunch
and dinner on all occasions when a 24 h pH-measure-
ment was monitored. The standardized meals were the
same during both 24 h pH-studies.
To analyse the nocturnal gastric and oesophageal pH,
the pH-data were synchronized to the individual time of
drug intake and truncated from 2 h before to 10 h after
the intake of ranitidine or placebo. The 2 h pH-data
prior to the drug-intake give the baseline values. For
the gastric and oesophageal pH-data the median intra-
gastric pH values in intervals of 2 h were computed.
NAB was defined as a drop of intragastric pH below 4
for at least 1 h or more during the nocturnal period.
Gastro-oesophageal reflux was defined as a drop of
oesophageal pH < 4. The oesophageal pH data were
analysed for the same 10 h nocturnal period as the in-
tragastric pH-data and the fraction of time below pH 4
was computed in 2 h intervals. Pathological acid reflux
on treatment (i.e., failure of acid suppression) was
defined as >1.6% time with pH < 4 during the test per-
iod.5
Upper endoscopy
In all patients upper endoscopy was performed at
baseline, after 6 and 12 weeks with standard flexible
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endoscope by two experienced clinicians. Reflux
oesophagitis was graded according to the modified
Savary-Miller-Monnier classification.
Statistical analysis
Power calculations indicate that, assuming a 30% day
to day intra-individual variation in oesophageal pH
and symptom measurement,17, 18 a study population of
14 patients provides a 90% chance of detecting a clin-
ically meaningful (30%) improvement in measured
variables for alpha <0.05. A study size of 10 patients
would provide an 80% chance of detecting the same
improvement.
Data from the clinical records were manually entered
into a relational database system, the 24-h pH monitor-
ing was analysed with a modified version of the
program Scan (Medical Instruments Corporation, Sol-
othurn, Switzerland); extracted indices were directly
imported into a database by a custom computer pro-
gram. Statistical analysis for the pH data was performed
with the program Statistica 5.5 (Statsoft, Tulsa, OK,
USA). Oesophageal and intra-gastric pH data were
analysed by repeated measurement ANOVA.
Symptom scores were analysed with a mixed model
using the program R.19 To compensate for study
effects, a linear regression model with the five visits
as time axis, common slope and separate intercepts
were fitted to the total symptom score. Three levels
of treatment (baseline, omeprazole + placebo and
omeprazole + ranitidine) were included as factors.
Contrasts and their significances of both were
computed.
RESULTS
Patient characteristics
Fourteen systemic sclerosis patients with gastrointesti-
nal involvement (12 women and 2 men, age range
51–79) participated in this study whose baseline
characteristics are shown in Table 1. Gastric and
oesophageal pH measurements were not available for
one patient following the second treatment arm
because of failed placement of the pH probe. Thus
13 ⁄ 14 patients completed the study, in addition three
gastric 24 h pH recordings during treatment
with omeprazole ⁄ ranitidine were unsuccessful for rea-
sons of technical failure (excluded from gastric pH
analysis).
1262 P . J A N I A K et al.

recording between the electrodes occurred in approxi-

Table 1. Baseline characteristics of the study population
Mean age (range) 61.7 (51–79)
Sex 2 men ⁄ 12 women
Helicobacter pylori status 1 positive ⁄ 14 negative
Systemic sclerosis subgroup (n)
Unclassified 1 oesophageal acid exposure was similar during the noc-
Diffuse 8 turnal period for both treatment regimens (Figure 2).
Limited 5
Years since disease onset 15.6 years (6–36)
Years since gut involvement 7.6 years (1–25)
High resolution manometry
Classic findings of aperistalsis with weak lower
oesophageal sphincter pressure (<12 mmHg) were pres-
ent in 5 ⁄ 13 systemic sclerosis patients (Figure 3a), all
but one of whom had persistent pathological oesopha-
geal acid exposure despite high-dose omeprazole treat-
ment. Hypotensive, ineffective motility (<30 mmHg in
distal oesophagus) was present in six patients, two of
whom had an incompetent reflux barrier (Figure 3b).
Normal oesophageal function was found in 2 ⁄ 13
patients (Figure 3c). Pathological acid exposure on
omeprazole b.d. was present also in 5 ⁄ 8 patients with
some preservation of oesophageal function (P = ns;
compared to aperistaltic group). In this small group,
there was no correlation between oesophageal dysmo-
tility and reflux severity. There was also no association
between severe skin and oesophageal disease.
mately one quarter of the cases. Moreover the duration
of NAB did not correlate closely with the duration of
pathologic nocturnal oesophageal acid exposure (a
fraction of the overall duration of NAB), and intra-
Oesophageal pH-measurement
The percentage of total time for oesophageal pH < 4
during the 24-h period was similar in the omepra-
zole ⁄ placebo group (2.4%; 0–30) and the omepra-
zole ⁄ ranitidine group (2.1%; 0.2–21.6) and there were
no significant differences between pH measurements
obtained during the 10-h nocturnal study period and
the full 24-h period in the placebo (0.8%; 0–24.5 vs.
2.4%; 0–30) or ranitidine (1.5%; 0–40.6 vs. 2.1%; 0.2–
21.6) study arms. Pathological reflux on treatment
(pH < 4 for more than 1.6% of total time; normal limit
under PPI treatment) occurred in 8 ⁄ 13 patients (62%)
in the omeprazole ⁄ placebo group and in 7 ⁄ 13 patients
(54%) in the omeprazole ⁄ ranitidine group (P = ns). The
DeMeester score was pathological in 4 ⁄ 14 patients
(29%) with omeprazole ⁄ placebo (median 7.6) and in
5 ⁄ 13 patients (38%) with omeprazole ⁄ ranitidine (med-
ian 8.2; P = ns) (Table 3).
Table 2. Median 24 h intragastric pH
Median 24 h intragastric pH

Gastric pH-measurement Min Q25 Median Q75 Max

The 24-h intragastric pH profile (Table 2) and median Omeprazole ⁄ placebo 3.2 3.6 4.9 5.0 6.2
intragastric pH in the 10-h nocturnal period were sim- Omeprazole ⁄ ranitidine 1.8 3.2 4.4 5.7 7.0
ilar during both treatment regimens (Figure 1), and All 1.8 3.6 4.7 5.4 7.0
there were no significant differences in mean gastric
pH during the 10-h nocturnal study period and the full
24-h period in the placebo (pH 4.5; 3.1–6.6 vs. pH 4.9; Table 3. Results of 24 h oesophageal 24 h pH measure-
3.2–6.1) or ranitidine (pH 4.3; 1.7–7.0 vs. pH 4.4; 1.8– ments for omeprazole ⁄ placebo and omeprazole ⁄ ranitidine
7.0) study arms. Similar pH tracings were obtained Omeprazole ⁄ Omeprazole ⁄
from 2 h before to 4 h after drug intake, suggesting pH-study placebo ranitidine
reliable measurements and good synchronization with
drug intake. The pH recordings showed a high intra- % of time 2.35 (0–30) 2.1 (0.2–21.6)
and inter-individual variability. NAB was similar with oesophageal pH < 4
both treatments and occurred in 8 ⁄ 10 patients treated DeMeester score 7.6 (0.2–63.8) 8.2 (1.0–94.5)
Oesophageal acid 8 ⁄ 13 7 ⁄ 13
with omeprazole ⁄ placebo and in 6 ⁄ 10 patients treated
exposure >1.6% ⁄ 24 h
with omeprazole ⁄ ranitidine (P = ns). Oesophageal acid 4 ⁄ 13 6 ⁄ 13
Acid reflux occurred most often during periods of exposure >1.6% ⁄ 10 h
NAB; however, discrepancies during simultaneous pH

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7.5
Endoscopies
7.0
Eight patients had normal baseline endoscopies; one
6.5 patient had a grade 4, 3 and 2 oesophagitis respectively
and two grade 1 oesophagitis. In six patients the sever-
6.0
ity of oesophagitis improved over the treatment period
5.5 [normal endoscopy (n = 5), decreased grade 3 to grade 1
pH Stomach

(n = 1)], one patient developed oesophagitis grade 1.

5.0
There were no differences between the groups.
4.5

4.0 Disease severity, symptom and quality of life

3.5
scores

3.0
The median systemic sclerosis skin score reported by
patients enrolled in the study was 26.5 (5–35). The
2.5 Placebo
Ranitidine
mean baseline value of the gastrointestinal-related
2.0 quality of life score was 93.6, s.d. 12.8. There was a
–2–0 0–2 2–4 4–6 6–8 8–10 non-significant increase of 0.5 score units per visit as
Hours after placebo/ranitidine intake
a non-treatment related study effect. At the end of the
omeprazole ⁄ placebo treatment phase a non-significant
Figure 1. Median intragastric pH during the nocturnal increase of 3.8 units compared to baseline was found
period after ingestion of placebo or ranitidine in addition
(P = 0.24). In the omeprazole ⁄ ranitidine period the
to high-dose acid suppression (proton pump inhibitor
b.d.). score increased by 7.3 units (95% CI 1.4–13.1,
P < 0.02) compared to baseline; however, there was no
difference in scores (or improvement in scores)
between the treatment groups (P = 0.26). In addition,
0.5 no correlation was present between the quality of life
assessment and intra-oesophageal acid exposure.
Placebo
0.4 Ranitidine
DISCUSSION
Fraction of time below (pH < 4 )

This study confirms that NAB and prolonged, noctur-

0.3
nal oesophageal acid exposure are common in patients
with systemic sclerosis despite high-dose acid suppres-
0.2
sion with omeprazole 20 mg b.d. Adding ranitidine at
bedtime did not significantly increase intragastric pH,
reduce gastro-oesophageal acid reflux or improve
0.1 symptoms in this population. Gastrointestinal-related
quality of life improved slightly on combined raniti-
dine and omeprazole acid suppression; however, there
0.0 was no difference in symptom scores between the two
arms of the study. Moreover there was no association
between the presence of NAB and pathological
–0.1
–2–0 0–2 2–4 4–6 6–8 8–10 oesophageal acid exposure with quality of life or
Hours after placebo/raniditine intake reflux symptoms.
There are several possible explanations for the nega-
Figure 2. Fraction of time with oesophageal pH < 4 tive findings of this study. The number of patients with
after ingestion of placebo or ranitidine in addition systemic sclerosis recruited was relatively small, altho-
to high-dose acid suppression (proton pump inhibitor
ugh comparable to most treatment trials in this rare
b.d.).
condition (compliance was excellent in this informed

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1264 P . J A N I A K et al.

Figure 3. High resolution manometry from representative patients recruited in the study. Spatiotemporal plots display oesoph-
ageal pressure activity. Time is on the x-axis, distance from the nares on the y axis and pressure is represented by colour leg-
end (right of figures).15 (a) Classic ‘scleroderma oesophagus’ with aperistalsis and weak lower oesophageal sphincter (LOS)
pressure (5 ⁄ 13). Also note raised intra-bolus pressure indicating poor oesophageal clearance of swallowed fluid. (b) Hypoten-
sive, ineffective motility with failure to maintain pressure >30 mmHg in distal oesophagus (6 ⁄ 13). (c) Normal oesophageal and
LOS motility (2 ⁄ 13).

and motivated population). In addition, as reported
previously,2, 7, 20, 21 the variability of gastric acid secre-
tion and suppression with PPIs and H2-receptor-anatag-
onists (H2RAs) was high, which impacts on the power of
the study to show significant effects. This is likely
because of inhomogeneous mixing of acid with the
meal, anatomical variations of intragastric pH (antrum
< fundus), entrapment of pH electrodes within mucosal
folds and the loss of fluid contact by the probe when
positioned in an air pocket.2, 22 Notwithstanding these
technical limitations, the most likely explanation for
this negative finding is that H2RA such as ranitidine lose
the ability to inhibit acid secretion on prolonged admin-
istration.20, 21 Fackler et al. demonstrated a significant
increase in gastric pH in healthy volunteers and patients
with GERD after 1 day of additional H2RA-therapy.21
However, in a study comparing several regimens of acid
suppression in patients with GERD over 14 days (omep-
razole b.d., omeprazole every 8 h, omeprazole before
breakfast and at bedtime and omeprazole b.d. with rani-
tidine at bedtime), no single treatment regimen resulted
in a more significant suppression of NAB than the oth-
ers.20 Consistent with the latter finding, this study found
no significant effect of adding ranitidine to omeprazole
b.d. treatment 3 and 6 weeks after the start of treatment.
To date the mechanisms behind the development of tol-
erance of H2RAs remain unclear, but may include the
up-regulation of H2-receptors in response to acid sup-
pression.23 In contrast, the efficacy of acid suppression
with omeprazole remains unchanged after continuous
intake.2
Similar to previous reports, we observed a drop in
gastric pH in the late evening. This circadian pattern has
been demonstrated in healthy volunteers with placebo
and persists after administration of omeprazole;2 how-
ever, the hypothesis that NAB is an important mecha-
nism in reflux disease affecting patients with systemic
sclerosis could not be confirmed. Many of the patients
continued to have severe acid reflux despite omeprazole
20 mg b.d. Although acid reflux occurred most often
during periods in which gastric contents were acid, the
duration of NAB did not correlate with the duration of
pathologic nocturnal oesophageal acid exposure (a frac-
tion of the overall duration of NAB) or symptoms. This
suggests that although NAB may be prerequisite for
nocturnal acid reflux, factors other than the presence of
NAB (e.g. structure and function of the gastro-oesopha-
geal junction, oesophageal clearance) appear to deter-
mine the severity of nocturnal oesophageal acid
exposure in systemic sclerosis. Consistent with this
statement, most of the systemic sclerosis patients stud-
ied had moderate to severe oesophageal dysfunction
and an incompetent reflux barrier (Figure 3). The indi-
rect mechanistic association between the presence of
gastric acid and the occurrence of reflux probably
explains the lack of association between NAB and
oesophageal acid exposure in small studies in GERD,20
whereas a larger study by Xue et al. documented a
weak, but significant, link.24 This study was not pow-
ered to establish this link in systemic sclerosis. Subopti-
mal acid suppression could also mask the contribution
of NAB; however, Hendel et al. reported that patients

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with systemic sclerosis taking doses up to 80 mg omep-
razole daily still showed acid reflux on oesophageal pH-
measurements.25 Other mechanisms, such as digestive
dysmotility and impaired intestinal absorption in this
group of patients, may lead to altered and lower bio-
availability of acid suppressant medications. Similar
reasons may explain the relative failure to control
symptoms in this population. Non-acid, ‘volume’ reflux
through an incompetent gastro-oesophageal junction
and poor clearance of refluxate because of ineffective
oesophageal motility persist despite treatment with PPI.
These issues cannot be assessed by pH monitoring
(requires the addition of impedance techniques).
In conclusion, the addition of ranitidine at night to
high-dose acid suppression with omeprazole 20 mg
b.d. did not reduce NAB or acid reflux in patients with
systemic sclerosis. Thus, adding a regular H2RA at
bedtime is not a useful therapeutic strategy in this
population, although use of these medications may be
beneficial for short-term acid and symptom control in
an on-demand basis.21
ACKNOWLEDGEMENTS
Declaration of personal interests: None. Declaration of
funding interests: None.

omeprazole 40 mg daily. Aliment Phar- 18 Scarpulla G, Camilleri S, Galante P,

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ª 2007 The Authors, Aliment Pharmacol Ther 26, 1259–1265

Journal compilation ª 2007 Blackwell Publishing Ltd