Med Clin (Barc).

2016;146(6):267–272

www.elsevier.es/medicinaclinica

Review

Appropriate prescription, adherence and safety of non-steroidal

anti-inflammatory drugs夽
Carlos Sostres a,b,c,∗ , Ángel Lanas a,b,c
a
Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
b
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
c
Universidad de Zaragoza, Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most numerous category of drugs sharing the
Received 16 June 2015 same mechanism of action and therapeutic activities (anti-inflammatory, analgesic and anti-pyretic).
Accepted 30 September 2015 Despite having similar efficacy for pain relieve, the different available NSAIDs show variability in its
Available online 16 June 2016
safety profile. The risk of gastrointestinal and cardiovascular complications varies depending on the dose
of NSAID and also the presence of different risk factors. It is necessary, therefore, an individualised case
Keywords: assessment before establishing the indication of the best NSAID for each patient, taking account of the
Non-steroidal anti-inflammatory drugs
best gastroprotection strategy. Improved prescription and enhanced treatment adherence are central
Safety profile
Side effects
objectives to reduce NSAID-related complications. A recent consensus of the Spanish Association of Gas-
Adherence troenterology and the Spanish societies of Cardiology and Rheumatology intends to promote the rational
use of NSAIDs according to new recent studies. This review provides additional aspects to facilitate the
optimal decision-making process in the routine use of these drugs in clinical practice.
© 2015 Elsevier España, S.L.U. All rights reserved.

Prescripción apropiada, adherencia y seguridad de los antiinflamatorios no

esteroideos

r e s u m e n

Palabras clave: Los antiinflamatorios no esteroideos (AINE) configuran la familia más numerosa de fármacos que com-
Antiinflamatorios no esteroideos parten los mismos mecanismos de acción y actividades terapéuticas (antiinflamatoria, analgésica y
Seguridad antipirética). A pesar de tener una eficacia similar para controlar el dolor, los diferentes AINE disponibles
Efectos secundarios
presentan variabilidad en su perfil de seguridad. El riesgo de complicaciones gastrointestinales y cardio-
Adherencia
vasculares varía en función del AINE y de la dosis que utilicemos, además de la presencia de factores de
riesgo. Es necesaria una evaluación individualizada de cada caso antes de sentar tanto la indicación del
AINE «ideal» como la estrategia de prevención gastrointestinal si fuera necesaria. Una correcta prescrip-
ción y una adecuada adherencia al tratamiento gastroprotector son los objetivos que hay que plantearse
para conseguir reducir las complicaciones secundarias al tratamiento con AINE. Recientemente se han
publicado unas recomendaciones de prescripción adecuada fruto de la colaboración de la Asociación
Española de Gastroenterología y las sociedades españolas de Reumatología y Cardiología que tiene por
objeto impulsar un uso racional de los AINE en función de los últimos estudios publicados. Esta revisión
completa aspectos adicionales necesarios para facilitar la toma de decisiones óptima en el uso habitual
de estos fármacos en la práctica clínica diaria.
© 2015 Elsevier España, S.L.U. Todos los derechos reservados.

Introduction

夽 Please cite this article as: Sostres C, Lanas Á. Prescripción apropiada,
adherencia y seguridad de los antiinflamatorios no esteroideos. Med Clin (Barc).
2016;146:267–272.
∗ Corresponding author.
E-mail address: carlossostres@gmail.com (C. Sostres).
Pain is one of the main factors contributing to the global bur-
den of disease, measured by years lived with disability. Patients
in pain, especially musculoskeletal pain, represent a significant
percentage of the population and demand treatment; the most

2387-0206/© 2015 Elsevier España, S.L.U. All rights reserved.

268 C. Sostres, Á. Lanas / Med Clin (Barc). 2016;146(6):267–272
commonly used medication for this scenario are nonsteroidal anti-
inflammatory drugs (NSAIDs), of the analgesic variety.1 Traditional
NSAIDs are associated with a significantly increased risk of gas-
trointestinal (GI) events, which varies depending on the NSAID
and dose, and the existence of risk factors.2 Within NSAIDs, COX-
2 inhibitors, also known as coxibs, have a better GI safety profile,
but as a result of their marketing it became known that these, and
subsequently other non-selective NSAIDs, increased cardiovascu-
lar (CV) risk, which led to different regulatory agencies stating that
NSAIDs in general may pose a significant risk to health.3
Thus, despite the undoubted beneficial effects of NSAIDs to
control pain and inflammation in musculoskeletal diseases, the
presence of adverse GI events and CV risk mean that the ‘ideal’
choice of NSAID is a sometimes complicated decision in routine
clinical practice. Recently a consensus document was published by
3 Spanish scientific societies on the appropriate prescription based
on the secondary effects of different NSAIDs.4 This article also dis-
cussed other issues that decisively affect the end safety of patients
being prescribed NSAIDs, while also referring to the appropriate-
ness of the prescription and adherence to treatment by patients.
Nonsteroidal anti-inflammatory drugs and gastrointestinal
damage
The main indication of NSAIDs is the reduction of pain. Clinical
practice guidelines recommend their prescription after assessing
other non-pharmacological or paracetamol options.5 The response
to NSAIDs varies from patient to patient, but no NSAID (including
coxibs) has proven to be more effective than another.6 Today it is
widely accepted that NSAIDs (traditional and coxibs) can damage
the entire GI tract, although there are clear differences between tra-
ditional NSAIDs and coxibs in this regard. The spectrum of lesions
is variable, ranging from ulcers or erosions to severe complications
such as bleeding and perforation. Many of these lesions are asymp-
tomatic. However, more than 40% of NSAID takers have reported
symptoms in the upper GI tract during treatment, the most fre-
quent being gastroesophageal reflux and dyspeptic symptoms.7
Approximately 1–4% of patients will have symptomatic GI ulcers
or complications from treatment with NSAIDs. Observational stud-
ies have shown that the average relative risk (RR) of developing a
peptic ulcer complication is 4–5 times higher in patients treated
with NSAIDs compared to those who are not.8 There is less evi-
dence available of damage to the lower GI tract caused by NSAIDs
than for the upper GI tract. It has recently been shown that hospital
admissions for lower GI complications are increasing, while upper
GI tract complications are decreasing.9
The risk of GI complications is not the same for all patients,
but depends–aside from the dose and type of NSAID–on a series
of risk factors that must be taken into account when deciding on
treatment. Age, >60 years-old, is an independent risk factor for the
occurrence of GI complications. Risk increases progressively with
age. The presence of a history of gastroduodenal peptic ulcer has
proven to be the most important risk factor for developing GI com-
plications in patients taking NSAIDs.2 The combination of 2 or more
NSAIDs increases the risk of bleeding associated for each NSAID
individually. This increased risk is also observed with the involve-
ment of a classic NSAID or coxib with acetylsalicylic acid (ASA)
at low doses, a combination very often used in clinical practice.
Based on these risk factors, patients requiring NSAIDs have been
categorised into 3 groups4 :
1. High risk: a complicated personal history of peptic ulcers; use of
anticoagulants or combination of >2 accepted risk factors.
2. Medium risk: patients without a history of complicated ulcer and
no anticoagulation with some other isolated risk factor.
3. Low risk: patients without risk factors. No consumption of ASA.
Nonsteroidal anti-inflammatory drugs and cardiovascular
damage
The patient who requires NSAIDs also requires a CV risk assess-
ment. CV risk is currently measured by following the Systematic
Coronary Risk Evaluation10 model, based on studies with European
populations. It is well established that the administration of NSAIDs
increases the risk of developing acute coronary syndrome or other
CV risk episodes of an atherothrombotic nature. This has been cer-
tified by data published since coxibs entered the market, current
clinical practice guidelines, consensus documents and regulatory
agencies.4,11,12
The most recent large meta-analysis study indicates that cox-
ibs and NSAIDs have an increased cardiovascular risk compared to
placebo, with no significant differences between them in general.
From all the traditional NSAIDs, the one that posed a greater risk
of CV risk was diclofenac, presenting a similar risk to that of cox-
ibs. Naproxen at doses of 500 mg/12 h was not associated with an
increased CV risk, unlike ibuprofen and diclofenac.13 More recently
the Spanish Medicines Agency (AEMPS) has warned that available
data indicate the need to emphasise that ibuprofen at high doses
(2400 mg/day) and dexibuprofen (1200 mg/day) (medications that
are widely used in Spain and available without prescription)
present a CV risk similar to coxibs at standard doses, such that,
except at doses at or below 1200 mg/day or 600 mg/day, respec-
tively, and used for only short periods of time, these molecules
should be taken with the same precautions than coxibs.14
Prescribing recommendations based on gastrointestinal
and cardiovascular risk
The main objective of managing patients treated with NSAIDs is
preventing the development of complications. For this, a GI and CV
risk profile must be made for each case before prescribing the ‘ideal’
NSAID, in addition to a gastroprotection strategy if necessary. This
full profile would be what guides the type, dose and schedule for
NSAIDs administered in each case (Fig. 1).
We know that the GI safety profile of coxibs is superior to
that of traditional NSAIDs.15 A recent meta-analysis study showed
that compared with traditional NSAIDs, celecoxib is associated
with a significantly lower risk of all clinically significant GI events
throughout the entire GI tract.16 Naproxen has the lowest CV risk,
while other medications like diclofenac and etoricoxib pose the
greatest risk at present. This was confirmed by a recent meta-
analysis study13 which showed that CV risks from diclofenac and
ibuprofen at high doses are comparable to coxibs, while doses of
500 mg/12 h of naproxen are associated with lower CV risks. In any
case, if coxibs (especially celecoxib at doses of 200 mg/day) has the
safest GI profile, naproxen has the safest CV risk profile. Celecoxib
and diclofenac do not interfere with antiplatelet activity of ASA at
low-dosis17 or clopidogrel. This would make celecoxib at low-doses
the most suitable NSAID for patients receiving ASA; however, the
EMA (European Medicines Agency) maintains contraindication of
its use in patients taking ASA for secondary prevention. There are
conflicting data regarding the interference of the antiplatelet effect
of ASA in the presence of naproxen; in any case, this interaction
appears to be lower than that observed with ibuprofen.
Current recommendations are reflected in a consensus docu-
ment prepared by three Spanish scientific societies.4 Based on these
recommendations, any NSAID is acceptable in patients with low
CV and GI risk. Patients at high GI risk should avoid treatment
with NSAIDs; if it is necessary, Helicobacter pylori should be erad-
icated in patients with history of ulcers and infected ulcers and
prescribed celecoxib + proton-pump inhibitor (PPI) if CV risk is low.
In patients with high CV risk the best treatment option is naproxen
 C. Sostres, Á. Lanas / Med Clin (Barc). 2016;146(6):267–272 269

Avoid NSAIDs
If it is not possible:
High risk of CV
Clecoxib 200 mg+IBPo
(taking ASA)
Naproxen 2 h after
ASA+PPI

Avoid NSAIDs
If it is not possible:
High risk of GI High risk of CV
Clecoxib 200 mg+PPI or
Naproxen+PPI

Low risk of CV Clelecoxib 200 mg+IPB

Patients who
need to take
NSAIDs

Clelecoxib 200 mg or
High risk of CV
Naproxen 2 h after
(taking ASA)
ASA

Low risk of GI Naproxen or Clelecoxib

High risk of CV
200 mg

Low risk of CV Any non-selective NSAID

Fig. 1. Therapeutic algorithm for patients requiring simplified nonsteroidal anti-inflammatory drugs in the long term depending on gastrointestinal risk and cardiovascular
risk factors. ASA: acetylsalicylic acid; NSAIDs: nonsteroidal anti-inflammatory drugs; PPI: proton-pump inhibitor; CV risk: cardiovascular risk; GI risk: gastrointestinal risk.
Naproxen at doses of 500 mg every 12 h. Helicobacter pylori infection should be investigated and treated in patients with a history of peptic ulcers. Source: Modified from
Lanas et al.4

with or without PPI, depending on the GI risk. Naproxen with PPI particular context. Taking naproxen 2 h after ASA could reduce the
is a reasonable option, but its possible interference with low-dose impact of such interference, but its effect on chronic to long-term
ASA–until we have more conclusive data–means that its use should treatments is unknown.18 Fig. 2 summarises the main characteris-
be restricted to less time if NSAIDs must necessarily be used in this tics of the clinical impact of the most prescribed NSAIDs in Spain.

Gastrointestinal damage (high and low) Cardiovascular damage Interference with ASA or ACO

Naproxen Diclofenac
Ibuprofen
Ibuprofen Etoricoxib
Naproxen
Diclofenac Celecoxib
Diclofenac

Etoricoxib Ibuprofen
Etoricoxib

Celecoxib Naproxen
Celecoxib

Fig. 2. Summary of the most important secondary effects of the nonsteroidal anti-inflammatory drugs that are most commonly used in clinical practice. ASA: acetylsalicylic
acid; OAC: oral anticoagulants. Source: Modified from Lanas et al.4
270 C. Sostres, Á. Lanas / Med Clin (Barc). 2016;146(6):267–272
100
90
80
70
n=1283
60
50.2
50
40
30 29.2
20
10
0
CV – CV +
Low risk of GI
Fig. 3. Rates of unsuitable prescription of nonsteroidal anti-inflammatory drugs and proton-pump inhibitors according to gastrointestinal and cardiovascular risk levels. CV:
cardiovascular risk; GI: gastrointestinal. Source: Modified from Lanas et al.4
Prescription of nonsteroidal anti-inflammatory drugs,
gastroprotection and adherence to treatment. Do we do it
properly?
Proper prescription
An important question is whether the recommendations of clin-
ical practice guidelines are followed in routine practice. The data
indicate that in most countries prescriptions do not comply with
guidelines recommendations or those of regulatory agencies.
A Dutch retrospective study showed that the vast majority
(>80%) of patients with GI risk did not follow their treatment prop-
erly (coxib or traditional NSAID + PPI). Another recent study in the
US found that less than half patients conducted a correct pre-
scription and that only 37% of high-risk GI patients were taking
appropriate preventive measures. Another Spanish observational
study19 showed that 86.6% of patients with osteoarthritis had at
least one GI risk factor (22.3% were patients with high GI risk). CV
risk was high in 44%, and average in 28.5% of patients. 15.5% of
these patients had a high GI and CV risk. These data imply that
most patients on chronic NSAID therapy should also receive pre-
ventive measures. These data were confirmed in another study20
that included 17,105 patients with osteoarthritis (Fig. 3). Globally,
more than 90% of patients were at risk of GI and/or CV, and for 51%
of them the treatment prescribed to them was not in accordance
with the indications of clinical practice guidelines.
A European multicentre21 study with patients at risk of GI
taking NSAIDs showed that the rate of gastroprotection was vari-
able and unacceptably low. A German database covering 9 million
people showed a significant deficit of PPI co-prescription for
elderly patients who were starting treatment with traditional
NSAIDs. However, not all data are negative. A Spanish retrospective
observational study found that 90% of patients did take gastropro-
tection, the most frequent being chronic takers with associated
risk factors. Another study that includes data from 3 European
countries, showed an increase in the correct prescription of up
to 20% between the 90s and the first decade of the 21st century.
Despite this, about 35–40% of the population taking NSAIDs is
doing so without a proper prescription and are exposed to side
effects.
n=10 311
74.4
60
n=5511
32
24
CV – CV + CV – CV +
Medium risk of GI High risk of GI
Adherence to treatment
A Dutch study showed that only 15% of patients with at least
one GI risk factor taking NSAIDs followed the gastroprotective
treatment prescribed to them, and that the risk of GI complica-
tions increased by 16% for every 10% decrease in adherence to that
gastroprotective treatment. Patients who were not undergoing gas-
troprotective treatment had between 2.5 and 4 times more risk
of developing high GI complications than those who were. More
recently, the study of a cohort of 618,684 NSAID takers in 3 differ-
ent European countries (Holland, Italy and the UK) found that the
risk of GI bleeding and/or GI ulcer was significantly higher (RR 2.39
[95% CI 1.09–3.28]) in patients not taking proper gastroprotection
compared to those who did take it.22 Another study showed similar
results in patients treated with coxibs (an increase of 9% for every
10% decrease of adherence to treatment).
A Spanish prospective study23 assessed adherence to treatment
of NSAID + PPI, as well as the causes and consequences of non-
adherence to the treatment. It was observed that the optimum
adherence reported by patients to NSAIDs and PPIs was 79.7% (95%
CI 76.9–82.2) and 84.1% (95% CI 81.7–86.3), respectively (Fig. 4).
Patients who did not properly adhere to PPI showed a greater
number of GI adverse events compared to those who complied
with treatment (22.1 compared to 1.9%, p < 0.0001). The most com-
mon causes for non-adherence was the absence of rheumatic pain
for NSAIDs and forgetting to take medication for PPIs. Another
Swedish study included 3649 patients who had upper gastroin-
testinal bleeding secondary to taking NSAIDs. Patients with low
adherence to gastroprotective treatment(<20% of the days) had a
greater risk of high GI complications (OR 1.88 [95% CI 1.22–2.88])
compared with patients with good adherence (>80% of the
days).
Proposals to improve suitable prescription and patient
adherence to treatment
1. Suitable prescription. Evidence available in this field is scarce.
A Canadian study found that factors associated with a worse pre-
scription included the doctors’ age and the number of years since
they graduated. A double-blind randomised study for taking
 C. Sostres, Á. Lanas / Med Clin (Barc). 2016;146(6):267–272
NSAIDs
(n=1040)
Do not initiate
Tt 7.4% Begin Tt
92.6%
Not taking it as
prescribed 223
(25.7%)
Taking it as
prescribed 674
(74.3%)
12.2±19 days
Reasons:
No pain: 42.8%
Secondary effects: 22.8%
Forgetting to take it 18.5%
Taking another medication:
13.5%
Fig. 4. Distribution and causes of non-adherence to prescribed treatment by patients with osteoarthritis and risk factors who are receiving nonsteroidal anti-inflammatory
drugs and proton-pump inhibitors. NSAIDs: nonsteroidal anti-inflammatory drugs; PPI: proton-pump inhibitor; Tt: treatment. Source: Modified from Lanas et al.23
diclofenac or etoricoxib24 that included 23,504 chronic NSAIDs
takers. 69% had a high-risk of GI and they were prescribed treat-
ment with PPI (free). Halfway through the study, a letter was sent
to their doctors indicating the need to continue the prescription
with PPI. The inclusion of a direct communication that urged
a written response significantly increased correct prescription
(43–61%), although without reaching adequate prescription lev-
els (<50%). In a Spanish study25 in which 456 specialists and
3728 patients participated, data on the correct prescription of
PPIs were collected before and after attending an update sym-
posium on evidence of secondary GI damage from taking NSAIDs
as well as on indications of gastroprotection. The study con-
cluded that the update seminar programme did not change the
results of suitable prescription. Finally, a Dutch study26 found an
increase in prescriptions of PPIs in patients treated with NSAIDs
between 2001 and 2007 (from 40 to 70%). In turn, it observed
a clear decrease in the number of hospitalisations secondary to
high GI bleeding due to peptic ulcer in the last decade,9 being
at least partly due to a better prescription of gastroprotection in
the population.
2. Increase adherence. If proper prescription is important, so is
increasing adherence to treatment, as this is inversely related to
the occurrence of GI complications.27 The most common cause of
non-adherence is forgetting to take the medication; other causes
described include the absence of prescription of PPIs by doc-
tors after 2 years or more of treatment, the female sex and the
absence of side effects. To try to prevent/reduce non-adherence,
one single tablet/capsule has been designed that contains both
NSAID and PPI. The fixed dose combination of naproxen and
esomeprazole combines the effectiveness of naproxen with a
favourable CV safety profile dose of 500 mg/12 h, a lower inci-
dence of ulcers associated with NSAIDs and better tolerability in
the upper digestive tract because of the esomeprazole. Its effec-
tiveness in osteoarthritis is equivalent to that of coxibs, it has
shown that it maintains its GI and CV safety profile even in the
long-term, and has a favourable pharmacoeconomic profile in
the Spanish population.28 There are no direct data of improve-
ment in adherence with the use of this combination. However,
indirect published data comparing a combination of ibuprofen
and famotidine with ibuprofen in mono-dose showed that a
significantly greater number of patients adhered to treatment
when their medication was combined.29 In turn, data from other
271
PPI
(n=1040)
Do not initiate
Tt 14.1% Begin Tt
85.9%
Not taking it as
prescribed 48
(6.6%) Taking it as
prescribed 680
(93.4%)
8.5±26 days
Reasons:
Forgetting to take it 47.3%
No pain: 39.4%
Secondary effects: 7.9%
Taking another medication: 2.6%
specialties30 evidenced a clear improved adherence with the use
of “polypills’.
Conclusions
The need for treatment with NSAIDs and an increase in
rheumatic diseases in an ageing population such as the Spanish
one remains high. The need for a suitable prescription to prevent
side effects in patients treated with NSAIDs is evident, not only
because it has been endorsed by several scientific societies and
regulatory agencies, and requires individual assessment of GI and
CV risk. Thus, the most common options (but not the only ones)
recommended today for the treatment of rheumatic diseases are
prescribing celecoxib with or without PPI, depending on the GI risk,
and naproxen for patients with high CV risk, with or without PPI,
depending on the GI risk. Two problems in the proper treatment
of patients requiring NSAIDs have been identified: one is suitable
prescription by the doctor, and the other is patient adherence to
prescribed treatment.
Although proper prescription of NSAIDs and gastroprotective
treatment has improved in recent years, the current rate in this area
is far from acceptable. The presence of secondary GI and CV effects
and existing co-morbidities in the population in need of NSAIDs
make the decision-making process increasingly complicated. This
is why strategies to improve doctors’ education and training are
required as well as making tools that facilitate the decision-making
process (simplified algorithms, risk calculators, clinical practice
guidelines) available in clinical practice. Increasing patient adher-
ence to treatment is also necessary. The appearance on the market
of pills that combine medications is a step in the right direction. In
summary, therapeutic innovation in its many facets and innovation
in the availability of appropriate tools to facilitate clinical decision-
making are essential elements on which to build a safer future for
pain treatment.
Conflict of interest
Dr. Ángel Lanas has participated in studies funded by
AstraZeneca and has conducted investigator-driven research that
has been partially or fully funded by AstraZeneca, without the
company taking part in development of the study. Finally, he has
272 C. Sostres, Á. Lanas / Med Clin (Barc). 2016;146(6):267–272
received small payments for participating as a speaker at meetings
supported by AstraZeneca, Bayer and Pfizer.
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