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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 reduction); however, some individual PCTs
cardiovascular (CV) safety of selective and demonstrated relative reductions of more
non-selective non-steroidal anti-inflammatory than 20%. Naproxen prescribing increased
drugs (NSAIDs), the Commission on Human from about 7% to 9% of the total number of
Medicines identified that diclofenac (especially NSAID items prescribed (a relative increase Naproxen
150mg/day) was associated with a small of 25%). Ibuprofen prescribing levels re- (1000mg/day)
increased thrombotic risk similar to that of mained essentially unchanged at 26% of and low-dose
etoricoxib and possibly other COX-2 selective total NSAID items prescribed. 3 Although ibuprofen (e.g.
inhibitors (coxibs).1 High-dose ibuprofen (e.g. there are some encouraging trends towards
1200mg/day or
2400mg/day) also appeared to be associated more appropriate prescribing of NSAIDs,
with a small increased thrombotic risk, whereas there is continued need for medication less) are a more
low-dose ibuprofen (e.g. <1200mg/day) and reviews to reconsider their use, and the appropriate
naproxen (1000mg/day) were not.1,2 Taking into prescribing of diclofenac in particular. choice for patients
account the high prescribing volume of who require an
diclofenac and the increased thrombotic risk, NICE guidance on NSAIDs for osteoarthritis? NSAID and where
the prescribing of diclofenac could be In February 2008, the National Institute for (CV) risk is of
associated with up to 2000 extra or premature Health and Clinical Excellence (NICE) issued concern.
CV events in England each year, compared its clinical guideline on the management of
with no treatment.2 osteoarthritis.4 This was reviewed in a recent
NPCi blog.5 In addition to core treatments (e.g.
In November 2007, in MeReC Extra 30,2 we exercise, advice and access to information,
recommended reviewing the prescribing of weight loss if overweight/obese), NICE
NSAIDs and, where they were still necessary, recommends considering paracetamol and/or
reconsidering which to prescribe based on an topical NSAIDs ahead of oral NSAIDs
assessment of the patient’s CV and (traditional or coxibs) or opioids. Where oral
gastrointestinal (GI) risk. For patients where NSAIDs are necessary, the lowest effective
CV risk is of concern, low-dose ibuprofen or dose for the shortest possible time should be
naproxen with a proton pump inhibitor (PPI) is used. In view of potential GI, cardio-renal or
a more appropriate choice than diclofenac.2 liver toxicity, health professionals should take
account of individual patient risk factors,
Prescribing trends for traditional NSAIDs including age.4 When prescribing these drugs,
Examination of trends in prescribing data consideration should be given to appropriate
from January 2007 to January 2008, assessment and/or ongoing monitoring of
indicates that total NSAID prescribing these risk factors.4 This publication was
decreased from 1.47 to 1.44 million items (a correct at the time of
decrease of 2%).3 Diclofenac prescribing NICE also recognises that all NSAIDs may preparation:
decreased from 45% to 44% of total NSAID antagonise the cardioprotective effects of May 2008
This MeReC Publication is produced by the NHS for the NHS
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- following the prescribing of coxibs or
dose aspirin, other analgesics should be traditional NSAIDs, with or without a PPI.9,10 In
considered before substituting or adding an both studies, the 95% confidence intervals
NSAID if pain relief was ineffective or (CIs) of the hazard ratios (HRs) for the
insufficient.4 comparisons between traditional NSAIDs plus
PPI and coxib plus PPI overlapped.
In developing the guideline, NICE evaluated Therefore, these studies do not provide
the cost-effectiveness of paracetamol, evidence for a significant difference in the risk
There is no robust traditional NSAIDs and coxibs at doses of GI complications between these two
evidence that relevant to clinical practice, and also assessed approaches.
prescribing a the impact of the addition of PPIs. NICE
coxib plus a PPI recognised that the choice of NSAID is The first study examined the effect of co-
offers any influenced by their separate side-effect profiles, prescribing a PPI with celecoxib or traditional
significant which tended to favour coxibs, whereas cost NSAIDS in more than 2 million elderly people
advantage over tended to favour traditional NSAIDs.6 However, in Canada. The adjusted HRs for
because of the uncertainties over the relative hospitalisation for GI complications versus
prescribing a
incidences of adverse effects, especially when celecoxib alone were 0.69 (95%CI 0.52 to
traditional NSAID co-prescribed with a PPI, clear conclusions 0.93) for celecoxib plus PPI, 0.98 (95%CI 0.67
plus a PPI in about relative cost-effectiveness could not be to 1.45) for traditional NSAIDs plus PPI, and
preventing GI made. Only etoricoxib 60mg was specifically 2.18 (95%CI 1.82 to 2.61) for traditional
complications. ruled out as a first-line choice on this basis.6 NSAIDs alone.9
Health economic modelling found that it was
always more cost-effective to prescribe a PPI The second study examined the medical
with an NSAID than not to do so, because of records of nearly half a million elderly (98%
their effect in reducing serious GI problems.6 male) patients (mean age 74) in the USA.
Regardless of which NSAID is prescribed, After adjusting for confounding influences,
NICE recommends co-prescription of a PPI, compared with periods of non-exposure, the
choosing the one with the lowest acquisition HRs of serious of upper GI events were 1.8
cost.4 (95%CI 1.5 to 2.0) during exposure to coxibs
and 1.8 (95%CI 1.6 to 2.0) during exposure to
Do coxibs offer advantages over other other NSAIDs. During periods in which a PPI
NSAIDs when co-prescribed with a PPI? was co-prescribed, the HRs were not
There is evidence from a systematic review statistically significantly different for coxibs
that, as a class, coxibs are associated with (HR 1.1, 95%CI 0.6 to 5.2) or other NSAIDs
a lower GI risk than traditional NSAIDs (HR 1.1, 95%CI 0.7 to 4.6) compared with
when prescribed without a PPI.7 Analysis of periods of non-exposure.10
data from the MEDAL study suggested that
use of etoricoxib reduced the risk of upper It remains uncertain whether or not GI benefits
GI clinical events and dyspepsia compared for coxibs are maintained over traditional
with diclofenac.8 However, the reductions in NSAIDs when both are prescribed with a PPI.
risk of these clinical events were seen only Randomised controlled clinical trials are
in the more common, but less serious, required to specifically answer this point.
uncomplicated events. 8
You can find more information on the risks and
Two large, observational studies in elderly benefits of NSAIDs on the musculoskeletal
people provide additional information on the 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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