MeReC Monthly No.

Update on the prescribing of NSAIDs

Summary
• Diclofenac (especially 150mg/day) is associated with a similar thrombotic risk to COX-2
selective inhibitors (coxibs). Naproxen (1000mg/day) and low-dose ibuprofen (e.g.
<1200mg/day) are associated with a lower thrombotic risk; they are a more appropriate
choice for patients who require a non-steroidal anti-inflammatory drug (NSAID) and where
cardiovascular (CV) risk is of concern.
• Although prescribing of diclofenac appears to have declined slightly over the last year, in
January 2008 diclofenac still accounted for 44% of the total number of NSAID items
prescribed.
• NICE guidance for osteoarthritis recommends first-line use of paracetamol or topical
NSAIDs, ahead of oral NSAIDs, for pain relief. Where NSAIDs are necessary, the lowest
effective dose should be used for the shortest possible time. Either a traditional NSAID or
a coxib (other than etoricoxib 60mg) can be used, taking into account individual patient risk
factors, including age. NICE recommends co-prescription of a proton-pump inhibitor (PPI)
with an NSAID regardless of which is chosen.
• There is no robust evidence that prescribing a coxib plus a PPI offers any significant
advantage over prescribing a traditional NSAID plus a PPI in preventing GI complications.

Background items over the same period (a 2% relative

In October 2006, in a review of the
cardiovascular (CV) safety of selective and
non-selective non-steroidal anti-inflammatory
drugs (NSAIDs), the Commission on Human
Medicines identified that diclofenac (especially
150mg/day) was associated with a small
increased thrombotic risk similar to that of
etoricoxib and possibly other COX-2 selective
inhibitors (coxibs).1 High-dose ibuprofen (e.g.
2400mg/day) also appeared to be associated
with a small increased thrombotic risk, whereas
low-dose ibuprofen (e.g. <1200mg/day) and
naproxen (1000mg/day) were not.1,2 Taking into
account the high prescribing volume of
diclofenac and the increased thrombotic risk,
the prescribing of diclofenac could be
associated with up to 2000 extra or premature
CV events in England each year, compared
with no treatment.2
In November 2007, in MeReC Extra 30,2 we
recommended reviewing the prescribing of
NSAIDs and, where they were still necessary,
reconsidering which to prescribe based on an
assessment of the patient’s CV and
gastrointestinal (GI) risk. For patients where
CV risk is of concern, low-dose ibuprofen or
naproxen with a proton pump inhibitor (PPI) is
a more appropriate choice than diclofenac.2
Prescribing trends for traditional NSAIDs
Examination of trends in prescribing data
from January 2007 to January 2008,
indicates that total NSAID prescribing
decreased from 1.47 to 1.44 million items (a
decrease of 2%).3 Diclofenac prescribing
decreased from 45% to 44% of total NSAID
This MeReC Publication is produced by the NHS for the NHS
reduction); however, some individual PCTs
demonstrated relative reductions of more
than 20%. Naproxen prescribing increased
from about 7% to 9% of the total number of
NSAID items prescribed (a relative increase Naproxen
of 25%). Ibuprofen prescribing levels re- (1000mg/day)
mained essentially unchanged at 26% of and low-dose
total NSAID items prescribed. 3 Although ibuprofen (e.g.
there are some encouraging trends towards
1200mg/day or
more appropriate prescribing of NSAIDs,
there is continued need for medication less) are a more
reviews to reconsider their use, and the appropriate
prescribing of diclofenac in particular. choice for patients
who require an
NICE guidance on NSAIDs for osteoarthritis? NSAID and where
In February 2008, the National Institute for (CV) risk is of
Health and Clinical Excellence (NICE) issued concern.
its clinical guideline on the management of
osteoarthritis.4 This was reviewed in a recent
NPCi blog.5 In addition to core treatments (e.g.
exercise, advice and access to information,
weight loss if overweight/obese), NICE
recommends considering paracetamol and/or
topical NSAIDs ahead of oral NSAIDs
(traditional or coxibs) or opioids. Where oral
NSAIDs are necessary, the lowest effective
dose for the shortest possible time should be
used. In view of potential GI, cardio-renal or
liver toxicity, health professionals should take
account of individual patient risk factors,
including age.4 When prescribing these drugs,
consideration should be given to appropriate
assessment and/or ongoing monitoring of
these risk factors.4 This publication was
correct at the time of
NICE also recognises that all NSAIDs may preparation:
antagonise the cardioprotective effects of May 2008
 MeReC Monthly
Extra No.No.
29 2

aspirin,6 and recommends that where a incidences of serious GI complications

patient with osteoarthritis needs to take low-
dose aspirin, other analgesics should be
considered before substituting or adding an
NSAID if pain relief was ineffective or
insufficient.4
In developing the guideline, NICE evaluated
the cost-effectiveness of paracetamol,
There is no robust traditional NSAIDs and coxibs at doses
evidence that relevant to clinical practice, and also assessed
prescribing a the impact of the addition of PPIs. NICE
coxib plus a PPI recognised that the choice of NSAID is
offers any influenced by their separate side-effect profiles,
significant which tended to favour coxibs, whereas cost
advantage over tended to favour traditional NSAIDs.6 However,
because of the uncertainties over the relative
prescribing a
incidences of adverse effects, especially when
traditional NSAID co-prescribed with a PPI, clear conclusions
plus a PPI in about relative cost-effectiveness could not be
preventing GI made. Only etoricoxib 60mg was specifically
complications. ruled out as a first-line choice on this basis.6
Health economic modelling found that it was
always more cost-effective to prescribe a PPI
with an NSAID than not to do so, because of
their effect in reducing serious GI problems.6
Regardless of which NSAID is prescribed,
NICE recommends co-prescription of a PPI,
choosing the one with the lowest acquisition
cost.4
Do coxibs offer advantages over other
NSAIDs when co-prescribed with a PPI?
There is evidence from a systematic review
that, as a class, coxibs are associated with
a lower GI risk than traditional NSAIDs
when prescribed without a PPI.7 Analysis of
data from the MEDAL study suggested that
use of etoricoxib reduced the risk of upper
GI clinical events and dyspepsia compared
with diclofenac.8 However, the reductions in
risk of these clinical events were seen only
in the more common, but less serious,
uncomplicated events. 8
Two large, observational studies in elderly
people provide additional information on the
following the prescribing of coxibs or
traditional NSAIDs, with or without a PPI.9,10 In
both studies, the 95% confidence intervals
(CIs) of the hazard ratios (HRs) for the
comparisons between traditional NSAIDs plus
PPI and coxib plus PPI overlapped.
Therefore, these studies do not provide
evidence for a significant difference in the risk
of GI complications between these two
approaches.
The first study examined the effect of co-
prescribing a PPI with celecoxib or traditional
NSAIDS in more than 2 million elderly people
in Canada. The adjusted HRs for
hospitalisation for GI complications versus
celecoxib alone were 0.69 (95%CI 0.52 to
0.93) for celecoxib plus PPI, 0.98 (95%CI 0.67
to 1.45) for traditional NSAIDs plus PPI, and
2.18 (95%CI 1.82 to 2.61) for traditional
NSAIDs alone.9
The second study examined the medical
records of nearly half a million elderly (98%
male) patients (mean age 74) in the USA.
After adjusting for confounding influences,
compared with periods of non-exposure, the
HRs of serious of upper GI events were 1.8
(95%CI 1.5 to 2.0) during exposure to coxibs
and 1.8 (95%CI 1.6 to 2.0) during exposure to
other NSAIDs. During periods in which a PPI
was co-prescribed, the HRs were not
statistically significantly different for coxibs
(HR 1.1, 95%CI 0.6 to 5.2) or other NSAIDs
(HR 1.1, 95%CI 0.7 to 4.6) compared with
periods of non-exposure.10
It remains uncertain whether or not GI benefits
for coxibs are maintained over traditional
NSAIDs when both are prescribed with a PPI.
Randomised controlled clinical trials are
required to specifically answer this point.
You can find more information on the risks and
benefits of NSAIDs on the musculoskeletal
pain floor of NPCi.

References
1. Duff G. Chairman, Commission of Human Medicines. Safety of selective and non-selective. NSAIDs. Letter. October 2006. Accessed from www.mhra.gov.uk/home/idcplg?IdcService
=GET_FILE&dDocName=CON2025036&RevisionSelectionMethod=Latest on 23/04/08
2. National Prescribing Centre. Cardiovascular and gastrointestinal safety of NSAIDs. MeReC Extra 30. November 2007. Accessed from www.npc.co.uk/MeReC_Extra/2008/no30_2007.html
on 23/04/08
3. Personal communication. NHS Business Service Authority Prescription Pricing Division. April 2008
4. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and management of osteoarthritis in adults. NICE clinical guideline 59. February 2008. Accessed from
www.nice.org.uk/guidance/index.jsp?action=byID&o=11926 on 23/04/08
5. National Prescribing Centre. NICE publishes clinical guidance on management of osteoarthritis. NPCi blog 85. March 2008. Accessed from www.npci.org.uk/blog/?p=85 on 23/04/08
6. The National Collaborating Centre for Chronic Conditions. Osteoarthritis: national clinical guideline for care and management in adults. NICE Full Clinical Guideline 59. Accessed from
www.nice.org.uk/guidance/index.jsp?action=download&o=39720 on 23/04/08
7. Rostom A, Muir K, Dube C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol 2007;5:818–28
8. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib
and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007;369:465-73
9. Rahme E, Barkun AN, Toubouti Y, et al. Do proton-pump inhibitors confer additional gastrointestinal protection in patients given celecoxib? Arthritis Rheum 2007; 57:748–55
10. Abraham NS, Hartman C, Castillo D, et al. Effectiveness of national provider prescription of PPI gastroprotection among elderly NSAID users. Am J Gastroenterol 2008;103:323–32

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