Alimentary Pharmacology & Therapeutics
Nonsteroidal anti-inflammatory drug use as a risk factor for
gastro-oesophageal reflux disease: an observational study
P. RUSZNIEWSKI*, C. SOUFFLET  & P. BARTHÉLÉMY
*Department of Gastroenterology,
Beaujon Hospital, Clichy, France;
 Laboratoire AstraZénéca, Rueil-
Malmaison, France
Correspondence to:
Prof. P. Ruszniewski, Department of
Gastroenterology, Beaujon Hospital,
100 Bd Général Leclerc, 92110 Clichy,
France.
E-mail: philippe.ruszniewski@
bjn.aphp.fr
Publication data
Submitted 9 May 2008
First decision 31 May 2008
Resubmitted 22 July 2008
Accepted 28 July 2008
Epub Accepted Article 30 July 2008
1134
 
SUMMARY
Background
Although the associations between nonsteroidal anti-inflammatory
drugs (NSAIDs) and peptic ulcer disease or dyspepsia are well estab-
lished, fewer data exist concerning the relationship between NSAIDs
and gastro-oesophageal reflux disease (GERD).
Aim
To examine the relationship between NSAIDs and GERD.
Methods
A self-administered questionnaire covering NSAID use and GERD symp-
toms (heartburn and acid regurgitation) was sent to a representative
national sample of 10 000 French adults (‡18 years) between 14
October and 21 November 2005. Risk factors associated with GERD were
identified by logistic regression analysis in respondents who were not
taking aspirin or proton pump inhibitors.
Findings
A total of 7259 completed questionnaires were returned of which 6823
were evaluable. Overall, 2262 respondents (33%) reported using NSAIDs
during the previous 3 months. The lifetime and 3-month prevalence
rates of GERD symptoms were 37% and 21% respectively. GERD symp-
toms were significantly more common among NSAID users than among
non-users (27% vs. 19%, P £ 0.001) and a similar trend was seen for
aspirin use. Proton pump inhibitors were received by 31% of respon-
dents who reported experiencing GERD symptoms within the previous
3 months compared with 6% of those without symptoms (P < 0.01);
however, only 20% of NSAID-treated respondents were receiving proton
pump inhibitors. NSAID use, age and female gender were independent
predictors of GERD symptoms.
Conclusion
NSAID or aspirin use is a significant risk factor for GERD symptoms.
Aliment Pharmacol Ther 28, 1134–1139
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2008.03821.x

INTRODUCTION
Upper gastrointestinal symptoms such as dyspepsia
occur in approximately 15–25% of patients treated
with nonsteroidal anti-inflammatory drugs (NSAIDs)
including the selective cyclooxygenase (COX)-2 inhibi-
tors.1, 2 Such symptoms have been shown to be a risk
factor for NSAID-related ulcer complications,3–5 but
there is no correlation between symptom severity and
the risk of such complications.6–8
Nonsteroidal anti-inflammatory drugs have
also been implicated in the pathogenesis of gastro-
oesophageal reflux disease (GERD).9 However, while
the associations between NSAID use and peptic ulcer
disease or dyspepsia are well documented, there are
fewer data on the relationship between NSAIDs and
GERD. In a prospective case–control study, the preva-
lence of erosive oesophagitis in NSAID-treated patients
with osteoarthritis was 21%,10 while a prospective
endoscopy study found that the use of nonselective
NSAIDs was a significant predictor of GERD.11 We
performed an observational study to investigate the
relationship between NSAID use and GERD symptoms.
METHODS
The study was a cross-sectional questionnaire survey
conducted in France by TNS Healthcare, Montrouge,
France. Between 14 October and 21 November 2005, a
four-page self-administered questionnaire was sent by
post to a representative sample of 10 000 adults (age
18 years and above). The sample was selected to be
representative of the general French population in
terms of gender, age, occupation and regional distribu-
tion (including urban and rural areas). Participants
were asked about their use of NSAIDs and aspirin dur-
ing the previous 3 months and about the presence of
GERD symptoms (heartburn, acid regurgitation or
both) during this time.
Three months prior to the study, the questionnaire
was tested on 1000 subjects during a pilot phase with
a response rate of 73.3%. The questionnaire was then
modified to account for difficulties in the wording ⁄
understanding of the questions.
Statistical analysis
Analysis of the demographic characteristics of non-
responders (see below) showed certain biases including
under-representation of males, young people and
ª 2008 The Authors, Aliment Pharmacol Ther 28, 1134–1139
Journal compilation ª 2008 Blackwell Publishing Ltd
N S A I D U S E A S A R I S K F A C T O R F O R G E R D 1135
residents of the Paris region. A computational weight-
ing was therefore applied to the sample to fit a refer-
ence population.12 The efficiency of the imputation
was excellent (96.2%), with maximum and minimum
weightings of 0.53 and 1.72 respectively.
Quantitative variables were described by the mean
and standard deviation. Categorical variables were
described by the numbers and relative proportions in
the relevant categories. Where appropriate, differences
between groups were compared by the Student’s t-test
(if the size of the groups to be compared was >30) for
quantitative data or by the Z-test for categorical data.
To avoid potential bias resulting from the use of anti-
secretory drugs, a further analysis was performed,
which excluded patients who were currently receiving
proton pump inhibitors.
Logistic regression analysis was performed using
the LOGISTIC procedure in SAS version 9.1.3 (SAS
Institute Inc., Cary, NC, USA) to identify factors asso-
ciated with GERD symptoms in patients who were
not receiving daily treatment with aspirin or proton
pump inhibitors. Odds ratios and the corresponding
95% confidence intervals (CIs) were calculated for the
presence or absence of GERD symptoms in partici-
pants who had experienced such symptoms within
the previous 3 months compared with those without
GERD symptoms in the previous 3 months.
Role of the funding source
The authors designed the study and contributed to the
analysis and interpretation of data. The TNS Health-
care Sofres institute carried out the statistical analysis.
The study was funded by AstraZeneca France.
RESULTS
A total of 7259 (72.6%) recipients returned the ques-
tionnaire and 6823 of the completed questionnaires
were considered evaluable for NSAID use and GERD
symptoms. Demographic characteristics of the partici-
pants with evaluable questionnaires are summarized in
Table 1. There were no significant differences between
the characteristics of these participants and those of
the overall study sample.
Overall, 2262 respondents (33%) reported using at
least one NSAID during the previous 3 months. Of
these, 84% had received noncontinuous treatment and
6% had received continuous treatment; data were
missing in 10% of respondents. In total, 50% of
1136 P . R U Z N I E W S K I et al.

this period and further 166 (4%) reported daily use of

Table 1. Demographic characteristics of participants with
evaluable questionnaires (n = 6823) aspirin. Demographic characteristics of these groups
are summarized in Table 2. A total of 781 respondents
Males ⁄ females 3251 ⁄ 3572 (11%) reported using proton pump inhibitors during
(48% ⁄ 52%)
the previous 3 months.
Age (years) (mean  s.d.) 48  18
18–34 1956 (29%)
35–44 1442 (21%) Prevalence of GERD symptoms
45–64 1911 (28%)
‡65 1514 (22%) Overall, 2501 respondents (37%) reported experiencing
Employed ⁄ unemployed 4046 ⁄ 2777 GERD symptoms at some time in their life and 1463
(59% ⁄ 41%)
(21%) had experienced such symptoms during the pre-
Location of residence
Rural 1532 (23%) vious 3 months. Among the latter respondents, 22%
Urban (2000–20 000 inhabitants) 1042 (15%) rated their symptoms as severe or very severe. GERD
Urban (20 000–100 000 inhabitants) 757 (11%) symptoms were significantly more common among
Urban (>100 000 inhabitants) 2208 (32%) NSAID users than among non-users (27% vs. 19%
Paris conurbation 1285 (19%)
respectively; P £ 0.001). The odds ratio for GERD
symptoms in NSAID users compared with non-users
was 1.61 (95% CI: 1.42, 1.80). A similar pattern was
NSAID users had received NSAIDs for 6 days or less seen in respondents who were not receiving proton
during the previous 3 months and 21% had been trea- pump inhibitors: the prevalence of GERD symptoms
ted for 1–2 weeks. The most widely used agents were was 23% in NSAID users and 15% in non-users
ketoprofen (24%), diclofenac (19%), solubilized ibupro- (P £ 0.01) giving an odds ratio of 1.65 (95% CI: 1.43,
fen (19%) and ibuprofen (17%); 4% of respondents 1.91). The duration of NSAID use was longer in
were using COX-2 inhibitors. Among the respondents respondents with GERD symptoms within the previous
who did not report any use of NSAIDs during the pre- 3 months than in those without such symptoms: 48%
vious 3 months and who returned completed question- of respondents with GERD symptoms had used NSAIDs
naires for ASA use and GERD symptoms (n = 4512), for 6 days or more compared with 37% of those
1504 (33%) reported using aspirin at some time during without symptoms (P < 0.01).

Table 2. Demographic characteristics of the aspirin groups

Daily use of aspirin Using aspirin at some No use of aspirin

during the last time during the last during the last
3 months (n = 166) 3 months (n = 1504) 3 months (n = 2842)

Male ⁄ female 96 ⁄ 69 (58% ⁄ 42%)  774 ⁄ 730 (51% ⁄ 49%) 1399 ⁄ 1443 (49% ⁄ 51%)
Age (years) (mean  s.d.) 65  15**,   44  16 50  18
18–34 9 (5%)**,   524 (35%) 742 (26%)
35–44 10 (6%)**,   373 (25%) 539 (19%)
45–64 52 (31%) 402 (27%) 834 (29%)
‡ 65 95 (58%)**,   206 (13%) 728 (26%)
Employed ⁄ unemployed 42 ⁄ 124 (25% ⁄ 75%)**,   1043 ⁄ 461 (69% ⁄ 31%) 1590 ⁄ 1252 (56% ⁄ 44%)
Location of residence
Rural 27 (16%)*,  348 (23%) 660 (23%)
Urban (2000–20 000 inhabitants) 26 (16%) 200 (13%) 445 (16%)
Urban (20 000–100 000 inhabitants) 22 (13%) 156 (10%) 332 (12%)
Urban (>100 000 inhabitants) 51 (31%) 473 (32%) 918 (32%)
Paris conurbation 39 (24%)  326 (22%) 487 (17%)

* P < 0.05 and ** P < 0.01 vs. group; using aspirin at some time during the last 3 months.
  P < 0.05 and    P < 0.01 vs. group; no use of aspirin during the last 3 months.

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Journal compilation ª 2008 Blackwell Publishing Ltd

Proton pump inhibitors were received by 31% of
respondents who reported experiencing GERD symp-
toms within the previous 3 months compared with 6%
of those without symptoms (P < 0.01); however, only
20% of NSAID-treated respondents were receiving pro-
ton pump inhibitors. Respondents aged 50 years and
above with GERD symptoms were more likely to be
receiving proton pump inhibitors than younger
respondents (43% vs. 19% respectively).
Among respondents receiving daily aspirin treat-
ment, the prevalence of GERD symptoms was 25%
compared with 18% in respondents who were not
receiving daily aspirin (P £ 0.05); the corresponding
odds ratio was 1.5 (95% CI: 1.05, 2.15).
Acid regurgitation was the most common GERD
symptom being reported by 27% of respondents with
any lifetime experience of GERD symptoms and 14%
of those experiencing symptoms within the previous
3 months. Heartburn was reported by 19% and 11% of
respondents respectively. Among the respondents who
reported experiencing symptoms within the previous
3 months, 22–48% (depending on the symptom or
symptoms reported) experienced symptoms on fewer
than 1–3 days ⁄ month: 9–13% reported experiencing
symptoms once per week, and 6–12% reported daily
symptoms.
Gastrointestinal oesophageal reflux disease symp-
toms within the previous 3 months were significantly
(P < 0.01) more common in respondents aged 65 years
or above (27%) than in those aged 45–64 years (22%)
or 18–44 years (19%). The prevalence was also signifi-
cantly higher in women than in men (23% vs. 20%
respectively; P < 0.01). Logistic regression analysis in
respondents who were not receiving aspirin or proton
pump inhibitors showed that NSAID use, age and
female gender were independent predictors of GERD
symptoms (Table 3).
Table 3. Odds ratios and 95% confidence intervals for
independent predictors of GERD symptoms, identified by
linear regression analysis
Odds ratio (95%
confidence interval)
NSAID use within 1.64 (1.36, 1.98)
previous 3 months
Age ‡65 years 1.34 (1.04, 1.73)
Female gender 1.22 (1.02, 1.46)
ª 2008 The Authors, Aliment Pharmacol Ther 28, 1134–1139
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N S A I D U S E A S A R I S K F A C T O R F O R G E R D 1137
DISCUSSION
The associations between NSAID use and peptic ulcer
disease13–15 and dyspepsia2, 16, 17 are well-established.
In contrast, data concerning the relationship between
NSAID use and GERD are more limited. In a study of
163 000 Medicaid patients in the US, the relative risk
of GERD in NSAID users compared with non-users
was 2.11,18 while a large community-based study in
the UK showed that GERD symptoms were more com-
mon in NSAID users than in non-users.19 Similarly,
the risk of oesophageal disorders in patients with
rheumatoid arthritis has been reported to be twice as
high in NSAID users as in non-users.20 Evidence for
an association between NSAID use and GERD comes
from a prospective endoscopy study that found that
NSAID use was an independent risk factor for GERD
(odds ratio 2.0; CI: 1.3, 3.0; P < 0.001).11 Similarly, in
a case–control study using data from the UK General
Practice Research Database, the odds ratio for GERD
associated with current NSAID use was 1.5 (95% CI:
1.3, 1.7).21
Information on the mechanism through which
NSAIDs may cause GERD is even more limited,
although data from one study suggest that they may act
to increase the duration of acid reflux.22 This was a pro-
spective double-blind, randomized, placebo-controlled
cross-over study in 17 patients with symptomatic
GERD, which used 24-h oesophageal pH-monitoring at
baseline and during treatment with ibuprofen or pla-
cebo. The results showed that ibuprofen significantly
increased the percentage of time during the 24-h period
that the oesophageal pH was below 4 compared with
both baseline and placebo treatment (P < 0.05 in both
cases). Among these patients, who were already suffer-
ing from GERD symptoms, this increased duration of
acid reflux was not associated with a significant
increase in heartburn frequency or intensity.22 Never-
theless, there is an established relationship between the
percentage of time the oesophageal pH is below 4 and
the frequency of heartburn and acid regurgitation.23
Therefore, in a patient who previously did not suffer
from GERD, any increased oesophageal acid exposure
associated with NSAID therapy could result in GERD
symptoms.
This study in a large French population confirms
that NSAID use is a significant predictor of GERD
symptoms that increases the risk of such symptoms by
approximately 60%: indeed, in this study, it was the
strongest risk factor to be identified. Similar findings
1138 P . R U Z N I E W S K I et al.

were obtained when patients receiving treatment with
proton pump inhibitors were excluded from the analy-
sis. Daily use of aspirin was also associated with a sig-
nificantly increased risk of GERD symptoms. A
majority of NSAID users in this study were receiving
nonselective agents: only 4% were receiving selective
COX-2 inhibitors. Although it has traditionally been
assumed that selective COX-2 inhibitors should offer a
more favourable gastrointestinal toxicity profile than
nonselective agents, recent data indicate that there is
little clinically significant difference between the
incidence of dyspepsia with the two classes of drugs.24
It therefore seems unlikely that the high prevalence
of GERD symptoms among NSAID users in this study
was biased by the predominant use of nonselective
agents.
The overall lifetime prevalence of GERD symptoms
in this study (37%) was significantly (P £ 0.01) higher
than that reported in a similar survey in France in
2003,25 in which 31% of participants reported experi-
encing GERD symptoms at least once. This increase
was because of a significantly higher proportion of
patients who reported experiencing symptoms less
than once a month (24% vs. 18%, P £ 0.01).
In conclusion, this observational study has shown
that NSAID or aspirin use is a significant risk factor
for GERD symptoms. NSAID-related upper gastrointes-
tinal symptoms can markedly impair patients’ quality
of life26, 27 and may necessitate dose reduction or dis-
continuation of treatment.28, 29
ACKNOWLEDGEMENTS
Declaration of personal interests: Professor Ruszniewski
acts as a consultant to AstraZeneca, France.
Declaration of funding interests: The authors would
like to thank AstraZeneca France, which funded the
study, and Ann McIlhinney for her assistance in
writing this manuscript, which was also funded by
AstraZeneca France.
SUPPORTING INFORMATION
Additional supporting information may be found in
the online version of this article.
Questionnaire. You and your health over the last
3 months.
Please note: Wiley-Blackwell are not responsible for
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