Yorkshire Palliative Medicine Guidelines Group
GUIDELINES ON THE USE OF NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs) AND SELECTIVE CYCLO-OXYGENASE-2 (COX-2)
INHIBITORS IN PALLIATIVE CARE
April 2010
Authors: Dr Julia Barnes, Dr Rachel Sorley and Dr Milind Arolker on behalf of
the Yorkshire Palliative Medicine Clinical Guidelines Group.
Overall Objective: Using a ‘Frequently Asked Questions’ format we present
evidence and recommendations relating to the use, and with particular
emphasis on reducing some risks, of using NSAIDs and selective COX-2
inhibitors.
Search strategy: Evidence was examined and summarised from systematic
reviews, meta-analyses and national guidelines and Medline/Embase
databases were searched if the above provided insufficient information. A
hierarchy of information sources was agreed within the group:
1. Cochrane/ Database of Abstracts of Reviews of Effectiveness
(DARE)
2. SIGN/NICE
3. Clinical Knowledge Summaries (CKS)
4. Bandolier
5. Palliative Care Formulary, third edition
6. Medline/Embase via Search 2.0: search drug & adverse effect
(with thesaurus mapping)
Searches were limited to papers published in English. See appendix 1 for the
Cochrane/Medline/Embase search strategy.
Level of evidence: Evidence has been graded according to criteria described
by Keeley (2003) – see appendix 2.
Review date: August 2013
Competing interests: None declared
Disclaimer: These guidelines are the property of the Yorkshire Palliative
Medicine Guidelines Group. It is intended that they be used by qualified,
specialist palliative medicine professionals as an information resource. They
should be used in the clinical context of each individual patient’s needs and
reference to appropriate prescribing literature should also be made. The
Yorkshire Palliative Medicine Guidelines Group takes no responsibility for any
consequences of any actions taken as a result of using these guidelines.
Contact details: Dr Lynne Russon, Consultant in Palliative Medicine, Leeds
Teaching Hospitals NHS Trust/Sue Ryder Care Wheatfields Hospice, Grove
Road, Headingley, Leeds LS6 2AE
E-mail: Lynne.Russon@suerydercare.org
2
CONTENTS
Introduction
4
Summary of conclusions/recommendations
7
NSAIDs/selective COX-2 inhibitors and:
Gastro-intestinal bleeding
References
11
15
Concomitant use of corticosteroids
References
21
23
Concomitant use of aspirin
References
27
28
Concomitant use of anti-coagulants
References
31
33
Bronchospasm/asthma
References
38
40
Heart failure
References
42
44
Thrombotic events
References
47
50
Renal impairment
References
56
58
Cancer-induced bone pain
References
63
66
Subcutaneous ketorolac
References
69
71
Appendices:
1.
2.
3.
4.
Search strategies
Grading of evidence
Glossary of italicised terms
Acknowledgements and authors
3
74
75
76
78
INTRODUCTION
NSAIDs/selective COX-2 inhibitors are commonly used classes of drugs with
around one-third of people over the age of 65 in developed countries thought
to be using an NSAID on a daily basis.1 Patients in the palliative care
population often have multiple co-morbidities and polypharmacy which
compound their risks of experiencing adverse drug effects. These sideeffects can adversely affect their quality of life and symptom control.
NSAIDs are anti-inflammatory, anti-pyretic and analgesic drugs and work by
inhibiting cyclo-oxygenase. This enzyme converts arachidonic acid to
thromboxanes and prostaglandins (See figure 12). There are 2 types of COX
enzymes: COX-1 is ‘constitutive’ and present in most tissues of the body at
constant levels. It catalyses the initial step in the formation of thromboxane A2
and prostaglandins involved in the regulatory and cytoprotective functions in
platelets, renal cells and gastrointestinal mucosa. COX-2 is ‘inducible’ by
inflammation and produces prostaglandins that mediate pain and
inflammation. Prostaglandin synthesis in tissues and the CNS is reduced by
NSAIDs which results in analgesia.
NSAIDs vary in how selective they are for COX-1 and COX-2 pathways. This
selectivity can vary according to dose. The degree of selectivity for COX-1
relative to COX-2 can be used to classify NSAIDs 2:

Non-selective e.g. ibuprofen, naproxen, aspirin

Preferential COX-1 inhibitors e.g. indomethacin, ketorolac

Preferential COX-2 inhibitors e.g. diclofenac, etodolac, meloxicam
The above 3 classes are regarded as ‘NSAIDs’ for the purposes of this
guideline.

Selective COX-2 inhibitors(coxibs)
4
Figure 1: Non-Steroidal Anti-Inflammatory Drugs 2
What adverse effects of NSAIDs/selective COX-2 inhibitors should we be
concerned about?
Adverse effects include:



Upper gastrointestinal complications:

Dyspepsia

Ulcer

Perforation

Obstruction

Bleeding
Cardiovascular and renal complications:

Myocardial infarction

Stroke

Cardiac failure

Hypertension

Renal impairment
Platelet inhibition:


Prolonged bleeding
Hepatotoxicity
5
These guidelines focus on the evidence relating to the use and/or side
effects of NSAIDs/selective COX-2 inhibitors with respect to
gastrointestinal bleeding, co-administration with corticosteroids, aspirin,
anti-coagulants, bronchospasm/asthma, heart and renal failure and
thrombotic events. We also include reviews of the evidence relating to
cancer-induced bone pain and subcutaneous ketorolac.
References
1. Mamdani M et al. Observational study of upper gastrointestinal
haemorrhage in elderly patients given selective cyclo-oxygenase-2
inhibitors or conventional non-steroidal anti-inflammatory drugs. British
Medical Journal 2002; 325: pp. 624-629
2. Neal MJ (ed). Medical Pharmacology at a Glance, fifth edition. Oxford:
Blackwell Publishing, 2005
3. Twycross R and Wilcock W (eds). Palliative Care Formulary third
edition. Nottingham: Palliativedrugs.com Ltd, 2007.
6
SUMMARY
NSAIDs/selective COX-2 inhibitors and Gastro-Intestinal (GI) bleeding
1. Ibuprofen is probably the ‘safest’ NSAID. 4,5,6,7
2. Selective COX-2 inhibitors increase the risk of developing upper GI
bleeding complications less than NSAIDs. The absolute risk reduction is
0.4%. 8
3. Individuals at a particularly high risk of upper GI bleeding or perforation
have most to gain (in terms of risk reduction) from receiving a selective
COX-2 inhibitor compared to a traditional NSAID.
4. No particular selective COX-2 inhibitor has any superiority over another 8
when it comes to reducing the risk of GI bleeding.
5. Celecoxib poses less of a GI risk than ibuprofen 2400 mg/day 8 but the
evidence for this superiority is less robust with ibuprofen doses up to 2400
mg/day. 5
6. Ketorolac has the highest risk of causing GI bleeding and so unless this is
not a relevant issue e.g. in the case of an imminently dying patient, it
should only be used when other NSAIDs are ineffective (see
subcutaneous ketorolac section page 69).
7. Gastroprotection with a proton pump inhibitor (PPI) should be considered
unless the patient is under 45 with no other risk factors and is likely to be
using an NSAID for short-term use e.g. less than 1 month.
8. Any NSAID or selective COX-2 inhibitor should be used at the lowest
effective dose and for the shortest duration. 11
9. Avoid modified release (M/R) preparations if possible.
NSAIDs/selective COX-2 inhibitors and corticosteroids
1. If at all possible avoid co-prescribing steroids and NSAIDs especially if
other risk factors are present, as risks appear to be cumulative. 6,9,10
2. If we take the baseline incidence of upper GI complications (UGIC)
necessitating hospitalisation in the general population as one per thousand
persons per year 10, according to this study:
o In those receiving steroid alone, relative risk is increased to ≈2
events
o In those receiving NSAIDs alone, relative risk is increased to ≈4
events
o In those receiving both steroids and NSAIDs, relative risk is
increased to ≈8 events
o The cumulative risk of UGIC events in patients receiving steroids,
NSAIDs, aspirin and full dose paracetamol is ≈18 events per
thousand persons per year
3. If needing to co-prescribe, ensure steroid dose is as low as possible for
the shortest length of time.
4. Steroid use may mask clinical signs and symptoms of serious
gastrointestinal complications such as gastro-intestinal perforation.
Tachycardia may be the predominant clinical sign and pain/peritonism may
be absent. 7
7
5. No specific evidence exists for which NSAID or type of gastroprotection to
use when co-prescribing with steroids so the prescriber should prescribe
an appropriate NSAID tailored to that individual’s circumstances together
with a PPI.
NSAIDs/selective COX-2 inhibitors and aspirin
1. If a patient requires both aspirin and a NSAID, ibuprofen and celecoxib
are the agents found to place the patient under the lowest level of
additional GI bleeding risk. 4,5
2. Clinical Knowledge Summaries recommend adding in a proton pump
inhibitor rather than switching to clopidogrel for patients who are on aspirin
and NSAIDs. 6,7.
NSAIDs/COX-2 inhibitors and warfarin/Low Molecular Weight Heparin
(LMWH)
1. NSAIDs and selective COX-2 inhibitors have the potential to interact with
warfarin resulting in an increased bleeding time as measured by the INR.
1,13,14
2. There is less robust evidence of the increased risk of interaction with
warfarin in the case of the older NSAIDs, in particular nabumetone. 1
3. There is no evidence to suggest that patients anti-coagulated on LMWH
are less at risk of alteration in the bleeding time compared to patients on
warfarin if they are commenced on NSAIDs.
4. For patients on anticoagulant therapy NSAIDs/COX-2 inhibitors should be
introduced with caution and the INR (for patients on warfarin) monitored
after the initiation of the drug or alteration of the dose.
NSAIDs/selective COX-2 inhibitors and bronchospasm/asthma
1. Anyone with a history of an asthmatic reaction to aspirin or another NSAID
or if they have high risk features (severe asthma, nasal polyps, urticaria or
chronic rhinitis) should avoid all products containing aspirin or NSAIDs. 1
2. If an NSAID is absolutely necessary, use of a selective COX-2 inhibitor
should be preferentially considered which should be given under medical
supervision. 4
3. NSAID-naïve asthmatic patients can take an NSAID but they need to be
aware of potential risks and advised if a respiratory reaction occurs they
must stop treatment and seek medical help. As aspirin-induced asthma
can develop in asthmatics > 40 years old, it has been suggested that this
group avoid NSAIDs, be warned of the risks and that if NSAIDs are
absolutely necessary that the first dose be taken under medical
supervision. 1
8
NSAIDS/selective COX-2 inhibitors and heart failure
1. They should not be used in patients with severe heart failure and should
be used with caution in those with a history of cardiovascular disease or
risk factors for cardiovascular disease as they are at higher risk of
developing heart failure. 3
2. They should be used with caution in the elderly [>65] even in the absence
of other risk factors, as there is a greater risk of developing heart failure.
3. There is little evidence to show that any one drug has lower risk factors for
cardiac failure than any other, but celecoxib seems to pose a similar
degree of risk as traditional NSAIDs. 2,4,5,6
4. NSAIDs with a longer half-life (such as naproxen) and controlled release
preparations may have an increased risk of causing heart failure. 3 These
should be avoided in high-risk patients.
NSAIDs/selective COX-2 inhibitors and thrombotic events
1. As NSAIDs and selective COX-2 inhibitors excluding naproxen are
associated with an increased risk of cardiovascular thrombotic events
1,2,3,4,5 their use for palliative care patients depends on a balance of risks
and benefits.
2. Naproxen appears to carry the lowest risk of increasing cardiovascular
events 1,5 and may be the most suitable for patients at higher risk of
cardiovascular disease.
3. A second option would be ibuprofen up to 1200mg daily.
4. Avoid diclofenac.
5. Use celecoxib at doses of 200 mg/day or less.
NSAIDs/selective COX-2 inhibitors and renal impairment
1. Avoid NSAIDs or COX-2 inhibitors if possible in patients with renal
impairment.
2. Celecoxib is overall the safest agent to use. 1,5,6,7
3. Ibuprofen seems to be the safest traditional NSAID. 1,5,6,7
4. Changes in renal function are higher with cumulative dose 1,2, but changes
in renal function can be seen up to and beyond 6 months of initiating
therapy. 3,4
5. Particular care is needed when prescribing for patients with low circulating
volumes [congestive cardiac failure/diuretic therapy]. 3,4
9
The use of NSAIDs/selective COX-2 inhibitors for Cancer-Induced Bone
Pain (CIBP)
1. There is some evidence that using an NSAID for bone pain secondary to
metastatic cancer can have an analgesic effect and reduce the opioid
requirement. 3
2. There is conflicting evidence as to whether NSAIDs/selective COX-2
inhibitors have a clinically meaningful adverse effect on bone healing. 9
Subcutaneous ketorolac
1. S/c ketorolac may improve pain even when oral NSAIDs haven’t.
2. Despite ketorolac being used for up to 6 months without any adverse
effects 7, elderly people, patients with GI cancer and patients receiving
other drugs which increase the risk of bleeding/renal failure are particularly
at risk. 1,2,6,7 If appropriate, renal function should be monitored and
ketorolac used at the lowest effective dose and for the shortest duration
possible.
3. Gastroprotection (a PPI) should be co-administered if appropriate.
10
NSAIDs/selective COX-2 inhibitors and Gastro-Intestinal (GI) bleeding
Q.1 How do these drugs cause GI bleeding?
They damage the GI mucosa by topical and systemic actions:
 Absorption across the gastric mucosa causes direct injury to the
epithelium.
 Systemic effects occur through the inhibition of COX-1. In the
gastroduodenal mucosa COX-1 produces prostaglandins which protect
the mucosal lining from injury by the luminal acid pepsin.1
Factors contributing to GI risks
Many studies looking at GI side-effects specifically exclude people with
conditions such as coagulopathies, cancer, chronic liver disease or a history
of alcoholism. Where the patient has additional risk factors for GI bleeding
their risk may therefore be higher than that found in the study population. Comorbid conditions such as cardiovascular disease, diabetes and renal
impairment also increase the risk of GI bleeding.
Many other drugs also increase the risk of GI bleeding including aspirin, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors
(SSRIs).
Treatment should be individualised as the benefit/burden of commencing a
NSAID will vary according to each patient’s circumstances.
-
Age
Non-users of NSAIDs are thought to have an estimated rate of 1
occurrence of serious gastrointestinal ulcer complication (perforation or
bleeding) per 1,000 persons/year. 2 This increases with age with one
study finding a rate of 2.2 upper GI haemorrhages per 1000
persons/year in people aged 66 or over. 3
11
Compared to non-users of NSAIDs, the relative risk of upper GI bleeding,
perforation or other serious upper GI tract events resulting in hospitalisation is
increased across all age groups and rises with age 4:
Graph from Bandolier
-
Past history

A past history of a bleeding/perforated peptic ulcer significantly increases
the risk of the above events in the order of 15-fold. 4

A past history of an ulcer also increases the risk, but by a lesser extent. 4
-
Dose
The risk of developing an upper GI bleeding event increases with increased
daily dose of the NSAID (see below).
Q.2 Short-acting and long-acting agents – is there any difference in risk?
Yes. Slow-release formulations and those drugs with longer half-lives are
associated with a higher risk of bleeding due to a more sustained inhibition of
cyclo-oxygenase. 5 Drugs with longer half-lives include naproxen, sulindac
and meloxicam. 5
Q.3 What about duration of use and its effect on risk?
There are differences in opinion between epidemiological studies and some
authors think this is probably due to methodological problems such as
uncontrolled confounding. Because of ‘self-selection’ (only patients who can
tolerate NSAIDs will remain on treatment) or measures taken to reduce
gastrotoxicity, patients on long-term NSAIDs probably have lower risks than
those recently starting treatment.
One study has tried to clarify this – but found the same phenomenon. 6
12
Q.4 Are any NSAIDs less risky than others?
Yes and broadly speaking similar hierarchies have been demonstrated
although levels of risk vary 4,5,6,7 (see reference section).
Q.5 Are selective COX-2 inhibitors any safer?
Taking a selective COX-2 inhibitor increases the risk of developing upper GI
bleeding complications by a lower amount than traditional NSAIDs 8 and this
is also dose-dependent.
Broadly speaking: compared with non-use, NSAIDs increase risk 3-4 times,
selective COX-2 inhibitors 2-3 and the risk reduction increase may be even
greater in high-risk patients. 5
Q.6 Which NSAID is the most gastrotoxic?
Ketorolac.
4,9
Q.7 Gastroprotection – what and who for?


People younger than 45 and at low risk of GI adverse events (e.g no
history of GI bleeding or Helicobacter Pylori infection and not on
aspirin, warfarin or corticosteroids may not need a gastroprotective
drug.10
A proton pump inhibitor (PPI) is the preferred choice of gastroprotective
drug. 10
PPIs reduce ulcer recurrence and prevent ulcer development in previously
ulcer-free at-risk patients on chronic NSAIDs. 1
Conclusions and recommendations
1. Ibuprofen seems to be the ‘safest’ traditional NSAID. 4,5,6,7
2. The dose of the intended NSAID may affect the risk profile and if we
take the Richy study 6 as the strongest evidence, meloxicam may be
slightly less toxic than diclofenac/naproxen, although overall the
differences are small between all the commonly used NSAIDs.
3. Selective COX-2 inhibitors increase the risk of developing upper GI
bleeding complications by a lower amount than NSAIDs . The absolute
risk reduction is 0.4%. 8
4. Individuals at a particularly high risk of upper GI bleeding or perforation
have most to gain (in terms of risk reduction) from receiving a selective
COX-2 inhibitor compared to a traditional NSAID.
5. No particular selective COX-2 inhibitor has any superiority over another
when it comes to reducing the risk of GI bleeding. 8
13
6. Celecoxib poses less of a GI risk than ibuprofen 2400 mg/day 8 but the
evidence for this superiority is less robust with respect to ibuprofen
doses up to 2400 mg/day. 5
7. Ketorolac has the highest risk of causing GI bleeding and so unless
this is not a relevant issue e.g. in the case of an imminently dying
patient, it should only be used when other NSAIDs are ineffective (see
subcutaneous ketorolac section page 69).
8. Gastroprotection with a PPI should be considered unless the patient is
under 45 with no other risk factors and is likely to be using an NSAID
for short-term use 10 e.g less than 1 month.
9. Any NSAID/selective COX-2 inhibitor should be used at the lowest
dose and for the shortest duration. 11
10. Avoid M/R preparations if possible. 5
14
References
Cross-sectional and retrospective analyses are more likely to over-estimate
risks compared with RCTs and longitudinal cohort studies because RCTs can
more accurately control for confounding factors and bias. Smaller studies (e.g.
with < 1000 participants) can produce relative risks that demonstrate
variability when these studies are compared to each other.
Q.1 How do NSAIDs cause GI bleeding?
1. Schlansky B & Hwang J. Prevention of nonsteroidal anti-inflammatory
drug-induced gastropathy. Journal of Gastroenterology 2009; 44 (S19)
pp. 44-52
Review
2. Hernandez-Diaz S & Garcia Rodriguez L. Incidence of serious upper
gastrointestinal bleeding/perforation in the general population: Review of
epidemiologic studies. Journal of Clinical Epidemiology 2002; 55: pp. 157163
Review
3. Mamdani M et al. Observational study of upper gastrointestinal
haemorrhage in elderly patients given selective cyclo-oxygenase-2
inhibitors or conventional non-steroidal anti-inflammatory drugs. British
Medical Journal 2002; 325: pp. 624-629
Level of evidence: 2++
 Population based retrospective cohort study with subjects aged ≥ 66
years
 Controls numbered 100,000
 Study duration was 1 year
 Unable to control for smoking and alcohol consumption
4. Hernandez-Diaz S & Garcia Rodriguez L. Association between
Nonsteroidal Anti-inflammatory Drugs and Upper Gastrointestinal Tract
Bleeding/Perforation. Archives of Internal Medicine 2000; 160: pp. 20932099
Level of evidence: 2++

Pooled meta-analysis of 18 case-control/cohort studies on non-aspirin
NSAID use and severe upper GI bleeding events
15








Analysed to compare NSAID use with non-use and to generate RR
Didn’t include patients on COX-2 inhibitors.
All but 2 studies attempted to control for potential confounders such as
age
It found variable risks associated with individual NSAIDS (different
studies used different doses to define low/medium/high doses) – see
graph below
Ibuprofen being least harmful at doses below 2400 mg/day (RR 2.1,
95% CI 1.6-2.7)
Low-medium dose diclofenac ( ≤ 100 mg or ≤ 75 mg) had a slightly
lower RR (3.1, 95% CI 2.0-4.7) than low-medium dose naproxen (≤
1000mg or ≤ 750 mg) which had a RR of 3.5 (95% CI 2.8-4.3)
High dose diclofenac had a lower RR than both high dose ibuprofen
and naproxen:
o High dose diclofenac: RR 3.6 (95% CI 2.3-5.6)
o High dose naproxen: RR 5.1 (95% CI 3.8-6.9)
o High dose ibuprofen: RR 5.5 (95% CI 3.0-10.00)
Low-medium doses of the NSAIDs were associated with relative risks
of 2-4.
Graph from
Bandolier
Q.2 Short-acting and long-acting agents – is there any difference in risk?
5. Garcia Rodriguez L and Tolosa L. Risk of Upper Gastrointestinal
Complications Among Users of Traditional NSAIDs and COXIBs in the
General Population. Gastroenterology 2007; 132: pp. 498-506
Level of evidence: 2++






Retrospective population based cohort study with a nested casecontrol analysis
Cohort derived from UK patients on a GP database
Aged 40-85 – excluded cancer, coagulopathies, liver and alcohol
disorders
1561 cases and 10,000 controls
Estimates of RR adjusted for peptic ulcer disease, smoking, alcohol,
steroids, aspirin, warfarin
Calculated RR of upper GI bleeding/perforation of traditional NSAIDs
and COXIBs compared to non-use
16


The RR for each drug was not specified but was represented
graphically. This has made accurate interpretation of the results difficult
95% CI for the RRs weren’t specified but were diagrammatically
illustrated in the paper. Etoricoxib had extremely wide confidence
intervals at both dose ranges.
Low/medium doses:
o Ibuprofen had the lowest RR (approx 2)
o Meloxicam and indomethacin next lowest (wider CI for
indomethacin)
o Then celecoxib and diclofenac - comparable RRs
o Then naproxen (around 4)
o Etoricoxib had the highest RR of approx 10
High doses:






Ibuprofen lowest RR
Then Celecoxib
Then Diclofenac
Then Naproxen
Then Indomethacin
Then Etoricoxib
Q.3 What about duration of use and its effect on risk?
6. Richy F et al. Time dependent risk of gastrointestinal complications
induced by non-steroidal anti-inflammatory drug use: a WHO consensus
statement using a meta-analytic approach. Annals of Rheumatic
Diseases 2004; 63: pp. 759-766
Level of evidence: 1+






RCTs and controlled cohort studies were identified between 1985 and
2003
Oral preparations and had to be given for at least 5 days
Didn’t include patients on selective COX-2 inhibitors
Eventually 32 RCTs and 13 major cohort studies were identified with
duration of treatment ranging from 5-1825 days
In the RCTs patients had to be matched at inclusion for age, sex and
history of GI events and most of the cohort studies matched for age
and sex
Median daily doses were: ibuprofen 1200 mg, naproxen 875 mg,
diclofenac 150 mg, etodolac 800 mg, indomethacin 75 mg, meloxicam
15 mg, piroxicam 20 mg
17

Meta-regression analysis shows that the maximum level of risk
appears at 50 days of treatment for non-indomethacin NSAIDs, then
begins to decrease

Seven NSAIDs were investigated more than others in RCTs (see
above for median doses) and this meta-analysis showed that
compared to placebo or non-exposed group:
o
o
o
o
o
o
Ibuprofen had the lowest RR =1.19 (95% CI 0.93-1.54)
Meloxicam RR=1.24 (95% CI 0.98-1.56)
Piroxicam RR=1.66 (95% CI 1.14-2.44)
Diclofenac RR=1.73 (95% CI 1.21-2.46)
Naproxen RR=1.83 (95% CI 1.25-2.68)
Indomethacin RR=2.25 (95% CI 1.10-5.07)
Q.4 Are any NSAIDS less risky than others?
See also references 2 and 4.
7. Lewis S et al. Dose-response relationships between individual nonaspirin
nonsteroidal anti-inflammatory drugs and serious upper gastrointestinal
bleeding: a meta-analysis based on individual patient data. British Journal
of Clinical Pharmacology 2002; 54: pp. 320-326
Level of evidence: 2++








Pooled results from 3 case-control studies
All studies included patients experiencing acute upper GI
haemorrhage
All patients matched for age and sex
All studies excluded patients with gastric carcinoma.
Didn’t include patients on selective COX-2 inhibitors
Doses of NSAIDs were coded as low, medium or high based on
dose ranges recommended in the BNF.
It also found dose-response relationships (expressed as odds
ratios), summarised as:
Low doses:
o
o
o
o
o

ibuprofen (<1200 mg) OR 1.1 (95% CI 0.6-2.0)
diclofenac (<75 mg) OR 2.2 (95% CI 0.8-5.8)
indomethacin (≤50 mg) OR 3.2 (95% CI 1.1-9.5)
naproxen (< 500 mg) OR 4.8 (95% CI 1.3-18.1)
piroxicam (≤ 10 mg) OR 9.0 (95% CI 2.1-39.2)
Medium doses:
o ibuprofen (1200-1799 mg) OR 1.8 (95% CI 0.8-3.7)
18
o
o
o
o

diclofenac (75-149 mg) OR 3.2 (95% CI 1.9-5.5)
naproxen (500-999 mg) OR 5.4 (95% CI 2.9-9.9)
indomethacin (51-149 mg) OR 6.8 (95% CI 3.6-12.9)
piroxicam (11-20 mg) OR 12 (95% CI 6.5-22.1)
High doses:
o
o
o
o
o
ibuprofen (≥ 1800 mg) OR 4.6 (95% CI 0.9-22.3)
diclofenac (≥ 150 mg) OR 12.2 (95% CI 5.6-26.7)
naproxen (≥ 1000 mg) OR 15.6 (95% CI 8.1-30.2)
indomethacin (≥ 150 mg) OR 20.4 (95% CI 4.2-99.7)
piroxicam (≥ 21 mg) OR 79 (95% CI 9.9-631.8)
Q.5 Are COX-2 inhibitors any safer?
See also reference 3.
8. Rostom A et al. Gastrointestinal Safety of Cyclo-Oxygenase-2 Inhibitors:
A Cochrane Collaboration Systematic Review. Clinical Gastroenterology
and Hepatology 2007; 5: pp. 818-828
Level of evidence: 1++





Systematic review of RCTs assessing the upper GI harms of
greater than 4 weeks use of COX-2s (celecoxib, etoricoxib,
valdecoxib, lumiracoxib) compared with non-selective NSAIDs and
placebo in arthritis sufferers
For ulcer perforation, obstruction or bleeding, an absolute risk
reduction of ≈ 0.4% resulted from using COX-2s compared with
non-selective NSAIDs
Selective COX-2s were statistically superior to naproxen and
ibuprofen for the above endpoints. All included studies used
ibuprofen 2400 mg/day
Celecoxib showed a non-significant trend towards less frequently
occurring perforation, obstruction or bleeding episodes compared to
diclofenac
Authors concluded that COX-2 inhibitors provide better GI safety
and found similar results across all types of selective COX-2s
Q.6 Which NSAID is the most gastrotoxic?
See also reference 2.
9. Garcia Rodriguez L et al. Risk of Hospitalisation for Upper
Gastrointestinal Tract Bleeding Associated with Ketorolac, Other
Nonsteroidal Anti-inflammatory Drugs, Calcium Antagonists and Other
Antihypertensive drugs. Archives of Internal Medicine 1998; 158: pp. 3339
19
Level of evidence: 2++


Prospective case-control cohort study of 1505 patients; patients
followed up until they were hospitalised for an upper GI
bleed/perforation
Ketorolac was either oral or IM; IM was associated with a higher
risk than oral
Q.7 Gastroprotection – what and who for?
See also reference 1.
10. Clinical Knowledge Summaries. NSAIDs – prescribing issues. [Online].
Available from: http://cks.library.nhs.uk [Accessed 31 August 2009].
Included in recommendations
11. Medicines and Healthcare Products Regulatory Agency. Drug Safety
Update. 2007; Volume 1 Issue 3 [Online]. Available from:
http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate
[Accessed 31 August 2009}.
20
NSAIDs and steroids
Steroids and gastrointestinal complications


Corticosteroids are specific COX-2 inhibitors 1 and may contribute to
the delayed healing of gastric erosions caused by NSAIDs 2
Evidence suggests that there is a low incidence of major
gastrointestinal complications associated with corticosteroid
monotherapy and there is conflicting evidence with regard to any dosedependent increased risk of ulceration in steroid-treated patients 2,3,4,5,6
Q.1 What are the risk factors for gastrointestinal complications with
steroids?
Drawing definite conclusions regarding risk factors associated with
corticosteroids and peptic ulcers from limited studies is very difficult. The
paucity of work in some areas provides too little data for meaningful
interpretation and comparison of studies is difficult due to lack of uniform
diagnostic criteria and varying exclusion criteria. 2

Total dose of steroid:
o Increasing dose of steroid may be associated with an increased risk
of perforations/peptic ulcers and different studies quote different
steroid doses at which there is an association 3,4,5,6,7 (Note that 5mg
prednisolone ≡ 0.75mg dexamethasone).

Previous history of peptic ulcer:
o Increases the risk of peptic ulceration 3

Advanced malignancy:
o

May increase the risk of developing a peptic ulcer 8
Concurrent prescribing of NSAIDs:
o Evidence suggests that the incidence of peptic
ulcers/haemorrhages is higher in people who are taking both
NSAIDs and steroids 6,9,10

Length of time on steroids and NSAID:
o Possibly an increased risk if on both for longer than 90 days
but few papers address this directly.
21
9
Conclusions and recommendations
1. If at all possible avoid co-prescribing steroids and NSAIDs especially if
other risk factors are present, as risks appear to be cumulative. 6,9,10
2. If we take the baseline incidence of upper GI complications (UGIC)
necessitating hospitalisation in the general population as one per
thousand persons per year 10, according to this study:
 In those receiving steroid alone, relative risk is increased to ≈2
events
 In those receiving NSAIDs alone, relative risk is increased to ≈4
events
 In those receiving both steroids and NSAIDs, relative risk is
increased to ≈8 events
 The cumulative risk of UGIC events in patients receiving
steroids, NSAIDs, aspirin and full dose paracetamol is ≈18
events per thousand persons per year
3. If needing to co-prescribe, ensure steroid dose is as low as possible for
the shortest length of time.
4. Steroid use may mask clinical signs and symptoms of serious
gastrointestinal complications such as gastro-intestinal perforation.
Tachycardia may be the predominant clinical sign and pain/peritonism
may be absent. 7
5. No specific evidence exists for which NSAID or type of gastroprotection
to use when co-prescribing with steroids.
6. See also the guidance in the Gastrointestinal Bleeding section (page
11).
22
References
Steroids and gastrointestinal complications
1. Dickman A & Ellershaw J. NSAIDS: gastroprotection or selective COX2 inhibitor. Palliative Medicine 2004; 18: pp. 275-286.
2. Ellershaw JE & Kelly MJ. Corticosteroids and peptic ulceration.
Palliative Medicine 1994; 8: pp. 313-319.
Review articles
3. Conn HO & Blitzer BL. Medical progress: non association of
adrenocorticosteroid therapy and peptic ulcer. New England Journal of
Medicine 1976; 294: pp. 473-479.
Level of evidence: 1
Analysis of 26 prospective RCTs (3558 cases) and 16 prospective
controlled non double-blinded investigations (1773 cases).

Study design has been criticised by other researchers

Frequency of peptic ulcer was slightly higher in steroid group but not
statistically significant. Neither haemorrhage nor perforation from ulcer
occurred significantly more often in the steroid group compared to the
placebo group. .
Patients with a previous history of peptic ulcer had a significantly higher
risk of peptic ulcer perforation if on steroids 0.1% vs 4.8%, (p<0.001).
While greater than 20 mg prednisolone/day was not associated with a
significantly higher risk of developing a peptic ulcer, a total dose of
more than 1000 mg prednisolone was


4. Messer J et al. Association of adrenocorticosteroid therapy and pepticulcer disease. New England Journal of Medicine 1983; 309: pp. 21-24.
Level of evidence: 1
Meta-analysis of pooled data from 71 controlled trials (not all were
double-blind)

Studies were excluded if patients received antacids

Study design has been criticised by other researchers

The overall incidence of diagnosed ulcers was 1.8 % in the steroidtreated patients and 0.8% in the controls (p<0.001), RR 2.3 (CI 1.4-3.7)
23

There was a higher rate of haemorrhage from ulcers in the steroid
group, although this did not reach statistical significance

The incidence of ulcers was significantly increased even if patients
received steroids for less than 1 month and in those receiving a total
dose of less than 1000 mg prednisolone
5. Conn HO & Poynard T. Corticosteroids and peptic ulcer: meta-analysis
of adverse events during steroid therapy. Journal of Internal Medicine
1994; 236: pp. 619-632.
Level of evidence: 1+


Meta-analysis of 93 double-blind RCTs
Patients received a mean dose of 35 mg (or equivalent) of
prednisolone for a mean duration of 64 days

Of 3267 patients in the control (non-exposed) group, 0.3% developed
ulcers and in the study group 13 out of 3335 (0.4%) did. This was not
statistically significant.
There were no statistically significant differences in the rates of
perforation/haemorrhage
Although the incidence of peptic ulcer increased with increasing
duration of therapy, the differences did not become statistically
significant



‘Symptoms of peptic ulcer’ (undefined by authors) did occur more
frequently in the steroid group which was statistically significant.
6. Rodríguez L & Hernández-Díaz S. The risk of upper gastrointestinal
complications associated with nonsteroidal anti-inflammatory drugs,
glucocorticoids, acetaminophen, and combinations of these agents.
Arthritis Research 2001; 3: pp. 98–101.
Review article examining a nested case control study involving 958,000
patients age 40-79 years




Study population excluded those with cancer
Study didn’t look at COX-2 inhibitors
852 patients meeting criteria matched to 6768 controls
Estimates of RR adjusted for age, smoking and concomitant
medications including omeprazole and anticoagulants

The risk of upper GI complications (bleeding or perforation) (UGIC)
was 2.1 (95% CI 1.4–3.0) times higher for current users of steroids
than for non-users (expressed as RR)
Addition of corticosteroid increased the RR of peptic ulcer or ulcer
complication from 3.6 (95% CI 2.9 - 4.3) in those receiving NSAID
monotherapy to 8.5 (95% CI 3.9 - 18.9) in those on NSAID and steroid

24

So if we take the baseline incidence of UGIC events necessitating
hospitalisation in the general population as one per thousand persons
per year10 , according to this study:
o In those receiving steroid alone, relative risk is increased to ≈2
events
o In those receiving NSAIDs alone, relative risk is increased to ≈4
events
o In those receiving both steroids and NSAIDs, relative risk is
increased to ≈8 events
o The cumulative risk of UGIC events in patients receiving
steroids, NSAIDs, aspirin and full dose paracetamol is ≈18
events per thousand persons per year
Q.1 What are the risk factors for gastrointestinal complications with
steroids?
See also references 2,3,4,5,6.
7. Dayton MT, Kleckner SC, Brown DK et al. Peptic ulcer perforation
associated with steroid review. Archives of Surgery 1987; 122: pp. 376380.
Level of evidence: 3

10-year retrospective chart review of hospital patients who had had
steroid treatment within 1 week of peptic ulcer perforation
 17% of peptic ulcer perforations during this period were associated with
steroid use (25 patients), mean age 45 years
 Only 36% of patients with steroid-associated perforations were
receiving antacid prophylaxis
 Mean dose of corticosteroid at time of perforation was 14mg
dexamethasone (or equivalent)
8. Schell HW. Adrenal corticosteroid therapy in far advanced cancer.
Geriatrics 1972; 27: pp. 131-141
Level of evidence: 3



Post-mortem case series showing that a higher proportion of peptic
ulcers were present in patients dying of cancer who received steroids
(for at least 2 weeks) compared to those who did not (10% in steroid
group compared to 3% in no-steroid group).
This study did not mention NSAID prescribing.
5% of group who had received steroids had a complicated peptic ulcer
contributing to death compared to 1% in the group not receiving
steroids.
9. Piper J, Ray W, Daugherty J, Griffin M. Corticosteroid Use and Peptic
Ulcer Disease: Role of Nonsteroidal Anti-inflammatory Drugs. Annals of
Internal Medicine 1991; 114: pp. 735-740.
25
Level of evidence: 2++



Retrospective case-control study of 1415 patients over the age of 65
who were hospitalised with a confirmed gastric or duodenal ulcer or an
episode of gastrointestinal haemorrhage.
Analysis compared the risk of developing peptic ulcer disease in
patients taking both NSAIDS and steroids with those on neither drug
and calculated an estimated RR of 14.6 (CI 6.7 - 32.0)
Increasing duration of NSAID use (more than 90 days) was associated
with a higher RR of peptic ulcer disease, compared to non-use
10. Hernandez-Diaz S & Garcia Rodriguez L. Incidence of serious upper
gastrointestinal bleeding/perforation in the general population: Review
of epidemiologic studies. Journal of Clinical Epidemiology 2002; 55: pp.
157-163
26
NSAIDs/selective COX-2 inhibitors and aspirin
This section looks at which NSAID is best to prescribe for a patient on aspirin
with respect to the risk of causing gastrointestinal (GI) bleeding.
Q.1 How is aspirin different to NSAIDs?
Aspirin is a salicylate and suppresses the production of prostaglandins and
thromboxane A2 due to its irreversible inactivation of the COX-1 enzyme 1
(see Figure 1 page 5). This is different from other NSAIDs, such as diclofenac
and ibuprofen, which are reversible inhibitors.
Low-dose, long-term aspirin use irreversibly blocks the formation of
thromboxane A2 in platelets, producing an inhibitory effect on platelet
aggregation. This makes aspirin useful for reducing the incidence of heart
attacks but also makes patients more prone to bleeding. 1,2,3 Enteric coated
formulations/ modified release formulations of aspirin do not modify the effect
on GI bleeding. 3
Q.2 Which NSAID should I prescribe for a patient taking aspirin?
Evidence suggests that ibuprofen is the NSAID with the lowest associated risk
of GI bleeding; celecoxib is slightly higher. 4,5 Risk varies with different
NSAIDs 4 (see table 1, page 29).
Q.3 Should I switch aspirin to clopidogrel when adding in NSAIDs?
There is no evidence to guide practice when adding in NSAIDs to patients
taking aspirin. There is evidence showing that the risk of GI bleeding is
significantly lower when aspirin is used with a proton pump inhibitor (PPI)
rather than switching to clopidogrel. 6,7
Recommendations
1. If a patient requires both aspirin and a NSAID, ibuprofen and celecoxib
are the agents found to place the patient under the lowest level of
additional GI bleeding risk. 4,5
2. Clinical Knowledge Summaries recommend adding in a PPI rather than
switching to clopidogrel for patients who are on aspirin and NSAIDs. 6,7
27
References
Q.1 How is Aspirin different to NSAIDs?
1. Neal MJ (ed). Medical Pharmacology at a Glance, fifth edition. Oxford,
Blackwell Publishing, 2005
2. Loeb S, Klusek H & Blake G (eds). Nursing students guide to drugs, first
edition. Springhouse, Pennsylvania, Springhouse Corporation, 1993.
3. Derry S & Loke Y. Risk of gastrointestinal haemorrhage with long term
use of aspirin: meta-analysis. British Medical Journal 2000; 321: pp. 11831187
Level of evidence: 1++
Meta Analysis




24 RCTs with ≈ 66,000 patients
Included a sub-analysis of ≈ 50,000 patients taking doses of aspirin
ranging from 50-162.5 mg/day for a mean duration of 28 months
GI haemorrhage occurred in 2.3% of patients taking aspirin compared
with 1.45% taking placebo (pooled OR 1.59, 95% CI 1.4-1.8, p<0.0001)
NNH/year = 248 for doses 50-1500 mg/day
Q.2 Which NSAID should I prescribe for a patient taking aspirin?
4. Rahme E, Nedjar H, Bizzi A & Morin S. Hospitalization for gastrointestinal
adverse events attributable to the use of low-dose aspirin among patients
50 years or older also using non-steroidal anti-inflammatory drugs: a
retrospective cohort study. Alimentary Pharmacology and Therapeutics
2007; 26 (10): pp. 1387-1398
Level of evidence: 2++
Retrospective cohort study






Over 1.5 million people on combinations of NSAIDs and aspirin
Median daily dose of ibuprofen was 1600 mg, naproxen 750 mg and
celecoxib 200 mg
Only 29% were taking aspirin ≤ 81 mg/day
There were much lower numbers of prescriptions for piroxicam and
ibuprofen issued during the study period which may have biased the
results
Adjusted data to take account of patients already on a proton pump
inhibitor
Factors associated with a higher rate of bleeding included previous
ulcers, heart and renal failure
28
Table 1: Association between COX-2 inhibitors, Non selective-NSAIDs
and acetaminophen and hospitalization for upper GI
events

Hazard ratios and 95% CI for upper GI bleeding when compared to
people on paracetamol (acetaminophen) - the overlapping confidence
intervals for naproxen, piroxicam and ibuprofen suggest that coincident use of aspirin does not change the bleeding risk with these
agents. However, bleeding risks with diclofenac and celecoxib are
approximately doubled when aspirin is used concomitantly.
Drug
No aspirin
With aspirin
Naproxen
2.5 (2.1-3.0)
2.2 (1.6-3.0)
Piroxicam
1.8 (0.8-2.8)
2.0 (0.8-5.4)
Diclofenac
1.5 (1.2-1.7)
2.8 (2.2-3.5)
Ibuprofen
0.9 (0.6-1.4)
1.4 (0.8-2.7)
Celecoxib
0.7 (0.6-0.8)
1.8 (1.5-2.1)
5. Rahme E, Bardou M, Dasgupta K et al. Hospitalization for gastrointestinal
bleeding associated with non-steroidal anti-inflammatory drugs among
elderly patients using low-dose aspirin: a retrospective cohort study.
Rheumatology 2007; 46: pp. 265-272
Level of evidence: 2Retrospective cohort study of ≈ 332,000 patients ≥ 66 years




Compared patients on celecoxib and aspirin with those on nonselective
NSAIDs and aspirin
Naproxen accounted for 24% of all non-selective NSAIDs
Median aspirin dose was 325 mg/day with 23% using 80 mg/day
Celecoxib and aspirin was associated with a lower rate of admission for
gastrointestinal bleeding compared to nonselective NSAIDs and aspirin
(hazard ratio 1 compared to 1.6)
29
Q.3 Should I switch aspirin to clopidogrel when adding in NSAIDs?
6. Chan FKL, Ching JYL, Hung LCT et al. Clopidogrel versus aspirin and
esomeprazole to prevent recurrent ulcer bleeding. New England Journal
of Medicine 2005; 352(3): pp. 238-244
Level of evidence: 1+
Double-blind prospective RCT






320 high-risk patients, average age 72 years, with proven past history
of aspirin-induced ulcer bleeding
Fully healed ulcers at time of inclusion
Randomised to receive either clopidogrel 75 mg plus esomeprazole
placebo or aspirin 80 mg/day plus esomeprazole 20 mg bd
Followed for 12 months
Clopidogrel group: 8.6% had recurrent bleeds
Aspirin plus esomeprazole group: 0.7% had recurrent bleeds (p=0.001)
7. Lai KC, Hui WM, Wong BC et al. Esomeprazole with Aspirin Versus
Clopidogrel for Prevention of Recurrent Gastrointestinal Ulcer
Complications. Clinical Gastroenterology and Hepatology 2006; 4(7): pp.
860-865
Level of evidence: 1+
Double-blind prospective RCT






170 high-risk patients, average age 75 years with proven past history
of aspirin-induced ulcer bleeding
Fully healed ulcers at time of inclusion
Randomised to receive either clopidogrel 75 mg/day or aspirin 100 mg
and esomeprazole 20 mg od
Followed for a median time of 52 weeks
Clopidogrel group: 13.6% incidence of recurrent bleeds
Aspirin plus esomeprazole group: 0% (p=0.0019)
30
NSAIDs/selective COX-2 inhibitors and Warfarin/Low Molecular Weight
Heparin (LMWH)
NSAIDs and platelet function
NSAIDs work by reversibly inhibiting cyclo-oxygenase which catalyses the
formation of prostaglandins and thromboxanes from arachidonic acid (AA) –
see table 1 page 5. Thromboxane A2 is the major product of the AA
metabolism in platelets and stimulates vasoconstriction and platelet
aggregation. A reduction in thromboxane A2 can cause impaired platelet
aggregation.
Although NSAIDs inhibit platelet function, bleeding time has been shown to be
prolonged by only about 33% in both volunteer and clinical studies and is not
associated with haemorrhagic complications. This is because many other
agonists including thrombin and collagen can promote platelet activation in
the presence of a cyclo-oxygenase inhibitor. Such a modest increase in
bleeding time prolongation is unlikely to be of major clinical significance in
normal subjects.
Nabumetone is thought to have less of an inhibitory effect on platelet
aggregation than other NSAIDs. 1
Q.1 Anticoagulants and NSAIDs – does the risk of bleeding increase?
Theoretically, several NSAIDs have the potential to displace warfarin from its
binding sites on proteins and increase the plasma level of its more
pharmacologically active free fraction. 1 Most of the trial evidence does not
demonstrate an interaction between NSAIDs and warfarin but these studies
used healthy volunteers. 2,3,4,5 Most evidence suggests that nabumetone
does not affect the INR of patients on warfarin 1 although a case report to the
contrary has been found. 6
Three studies have examined the possible interaction of LMWH and NSAIDs:
-
Two were in post operative patients 7,8 and concluded that there was no
clinically significant increased risk of bleeding postoperatively but caution
was advised because of theoretical risk.
-
One study used healthy volunteers 9 and here ketorolac significantly
increased the bleeding time which was then further increased by the
addition of dalteparin. Dalteparin alone had no effect on the bleeding
time.
Case reports of prolonged bleeding times in patients taking both NSAIDs
(indomethicin, ketoprofen, piroxicam and sulindac) and anticoagulants have
been published. 1
31
Q.2 Is it safer to prescribe a NSAID to a patient being anticoagulated on
LMWH than warfarin?
There is no evidence to support this. There are no trials comparing the safety
of NSAID use in patients on warfarin vs LMWH therapy.
Q.3 Is there any difference between traditional NSAIDs and COX-2
inhibitors in their effect on the bleeding time of anticoagulated patients?
There is conflicting evidence with regards to the potential of COX-2 inhibitors
to interact with warfarin resulting in an increased INR.

Trials in healthy volunteers show either no effect or a ‘clinically
insignificant effect’ when warfarin is combined with celecoxib 10,11 and
etoricoxib 12

One small study in which patients on warfarin were commenced on
celecoxib 200 mg/day showed an increase in the INR of > 15 % 13

A case has been reported of an increased INR following the
commencement of celecoxib 14

The recommendations from this trial and also from the other trials
where a ‘clinically insignificant effect’ direct effect on the INR was noted
was that because of potential interactions, bleeding risk and the
variability of the non-study healthy volunteer patient, the INR should be
monitored when COX-2 inhibitors are initiated or changed.
Conclusions
1. Traditional NSAIDs and selective COX-2 inhibitors have the potential to
interact with warfarin resulting in an increased bleeding time as
measured by the INR. 1,13,14
2. There is less robust evidence of the increased risk of interaction with
warfarin in the case of the older NSAIDs, in particular nabumetone. 1
3. There is no evidence to suggest that patients anti-coagulated on
LMWH are less at risk of alteration in the bleeding time compared to
patients on warfarin if they are commenced on NSAIDs.
Recommendation
1. For patients on anticoagulant therapy NSAIDs/selective COX-2
inhibitors should be introduced with caution and INR (for patients on
warfarin) monitored after the initiation of the drug or alteration of the
dose.
32
References
Q.1 Anticoagulants and NSAIDs – does the risk of bleeding increase?
1. Hilleman DE, Mohiuddin SM, Lucas BD. Nonsteroidal Anti-inflammatory
Drug Use in Patients Receiving Warfarin; Emphasis on Nabumetone.
American Journal of Medicine 1993; 95: (S 2A)
Review article and case series
Level of evidence: 3
a) Evaluated the addition of nabumetone 1000 mg or 2000 mg/day taken
‘as needed’
b) 58 patients, already stabilised on chronic warfarin
c) None had previously taken nabumetone
d) No significant differences in INR found after 6 weeks of nabumetone
2. Vesell ES, Passananti TG, Johnson AO. Failure of Indomethacin and
Warfarin to Interact in Normal Volunteers. Journal of Clinical
Pharmacology 1975; 15: pp. 486-495
Level of evidence: 1+
2 double-blind, randomised placebo-controlled trials:
a)


16 healthy people age 19-28 received warfarin that prolonged their PT
to 1.5-2.5 control
Administration of indomethacin or placebo failed to alter the PT
b)



19 healthy people age 22-27 given loading dose warfarin and PT
monitored
20 days later started on either indomethacin or placebo and 11 days
later another warfarin dose given and PT monitored
No significant differences between indomethacin and placebo with
respect to their effects on warfarin induced hypoprothrombinaemia and
plasma warfarin half-life
3. Eichler HG, Jung M, Kyrle PA, Rotter M, Korn A. Absence of interaction
between tenoxicam and warfarin. European Journal of Clinical
Pharmacology 1992; 42: pp. 227-229
Level of evidence: 1Open randomized, cross-over design
a) Single dose study
33




8 volunteers given single dose warfarin on 2 separate occasions
4 weeks apart
One dose given without tenoxicam, the other following 14 days
of it
Tenoxicam continued for 1 week after warfarin
No significant difference in PT between treatment cycles
b) Steady state study
 8 people given tenoxicam for 2 weeks and clotting tests done
 3 week wash-out period
 Given warfarin, dose stabilised then given tenoxicam for another
2 weeks
 Tenoxicam then stopped and warfarin continued for another 4
weeks
 No changes in clotting results
4. Mieszczak C & Winther K. Lack of interaction of ketoprofen with warfarin.
European Journal of Clinical Pharmacology 1993; 44: pp. 205-206
Level of evidence: 1Double-blind, randomised placebo-controlled trial



13 healthy male volunteers, mean age 34, acting as their own controls
Ketoprofen given for 7 days after stabilisation on warfarin
Ketoprofen did not affect the PT and no clinical evidence of bleeding
5. Fitzgerald D. Nabumetone, a novel anti-inflammatory. Royal Society of
Medicine 1985; (Vol 69): pp. 47-52
Level of evidence: 2Double blind, placebo-controlled multi-dose trial



12 volunteers stabilized on warfarin.
Placebo or nabumetone for 2 weeks
No significant differences in INR, thrombin time or bleeding time
6. Dennis VC, Thomas BK, Hanlon JE. Potentiation of Oral Anticoagulation
and Hemarthrosis Associated with Nabumetone. Pharmacotherapy 2000;
20(2): pp. 234-239
Level of evidence: 3
Case report

Haemarthrosis in a patient on stable dose warfarin who commenced
nabumatone one week earlier and whose INR had increased from 2.1
to 3.7
34
7. Kristensen SS et al. Combined treatment with Indomethacin and Low
Dose Heparin After Total Hip Replacement. Journal of Bone and Joint
Surgery 1990; 72-B: pp.447-449
Level of evidence: 1Double blind, randomised placebo-controlled trial




235 patients undergoing total hip replacement on prophylactic LMWH
from day of surgery
Randomised to indomethacin or placebo from day 1 post-op for 6
weeks
More post-op bleeding occurred in the indomethacin group but it wasn’t
statistically significant
The period of heparin treatment was considerably lower in the
indomethacin group because of earlier mobilisation
8. Weale AE, Durant N, Warwick DJ, Prothero D. Is there a clinical
interaction between low molecular weight heparin and non-steroidal
analgesics after total hip replacement? Annals of the Royal College of
Surgeons of England 1995; 77: pp. 35-37
Level of evidence: 1Prospective randomised controlled trial




60 patients undergoing total hip replacement - all on enoxaparin postop
Any previous NSAID was stopped 4 weeks prior to admission
26 patients given I/M ketorolac pre-op and for 4 days post-op; others
randomised to opioid and paracetamol
No clinically detectable GI haemorrhage in either group and no
differences in wound oozing
9. Greer IA et al. Effect of ketorolac and low-molecular weight heparin
individually and in combination on haemostasis. Blood Coagulation and
Fibrinolysis 1999; 10: pp. 367-373
Level of evidence: 1
Double blind, randomized, placebo-controlled crossover study




24 healthy male volunteers age 18-48 who avoided aspirin and other
NSAIDs for 2 weeks before and during the study
Ketorolac with dalteparin studied
Minimal interval between treatments 1 week
There was no interaction between ketorolac and dalteparin with
regards to platelet aggregation, anti-factor Xa activity or activated
partial thromboplastin time
35



Ketorolac administration significantly prolonged skin bleeding time and
addition of dalteparin enhanced the bleeding time further
Authors state that skin bleeding time is not a predictor of surgical
bleeding
Therefore no evidence to suggest a clinically significant increased risk
of bleeding postoperatively with combination of LMWH and NSAIDs but
caution advised because of theoretical risk.
Q3. Is there any difference between traditional NSAIDs and COX-2
inhibitors in their effect on the bleeding time of anticoagulated patients?
10. Karim A et al. Celecoxib Does Not Significantly Alter the Pharmacokinetic
or Hypoprothrombinemic Effect of Warfarin in Healthy Subjects. Journal of
Clinical Pharmacology 2000; 40: pp. 655-663
Level of evidence: 1Open label, multiple dose, randomized, placebo-controlled, parallel-group
study






24 healthy volunteers age 19-50 given warfarin for 8 days
Then randomised to celecoxib 200mg bd or placebo for 7 days while
continuing warfarin
Prothrombin times (PT) were monitored and did not differ significantly
between the 2 groups
Celecoxib did not significantly alter the steady-state pharmacokinetics
of warfarin
There were no adverse bleeding events
Authors comment that all participants were ‘normal’ metabolisers of the
hepatic enzyme P450 CYP2C9. Genetic variations of this enzyme
could result in ‘poor’ metabolisers and hence potential alterations in PT
11. Dentali F et al. Does Celecoxib Potentiate the Anti coagulant Effect of
Warfarin? A Randomised, Double-Blind, Controlled Trial. Annals of
Pharmacotherapy 2006; 40: pp. 1241-1247
Level of evidence: 1Randomised, double-blind, controlled, crossover trial





15 patients on long-term warfarin, mean age 70
Phase 1: celecoxib 200mg/day or codeine phosphate 3-4 times/day for
5 weeks
Phase 2: Swap over, no drug free interval
Weekly INR for 10 weeks
Celecoxib did not significantly affect the INR although one patient in the
celecoxib group was withdrawn from the study when the INR increased
from a baseline of 3.6 to 4.9.
36
12. Schwartz JI et al. The Effect of Etoricoxib on the Pharmacodynamics
and Pharmacokinetics of Warfarin. Journal of Clinical Pharmacology
2007; 47: pp. 620-627
Level of evidence: 1Double-blind, placebo-controlled, randomized, crossover trial





18 healthy volunteers age 19-44 were given warfarin during a 28-day
run-in period
Then randomised to take either etoricoxib 120mg/day or placebo for 21
days while continuing warfarin
Crossed over for another 21 days
14 subjects eventually analysed
Etoricoxib increased the mean INR by 13% which the authors classed
as of ‘uncertain clinical significance’
13. Schaefer MG, Plowman BK, Morreale AP, Egan M. Interaction of
rofecoxib and celecoxib with warfarin. American Journal of HealthcareSystem Pharmacy 2003; 60: pp. 1319-1323
Level of evidence: 1Prospective, open-label, randomised cross over study




16 patients on stable warfarin therapy and all on a COX-2 comparator
agent eg traditional NSAID prior to enrolment
Randomly received celecoxib 200mg/day or rofecoxib 25mg/day for 3
weeks
After one week washout period they were switched to treatment with
the opposite COX-2 inhibitor (they could take their pre-study analgesic
during this period).
8 in both groups had a >15% increase in their INR. Only 4 had a rise
with both COX-2 inhibitors therefore it appears unpredictable whether
patients will have elevated INRs with different COX-2 inhibitors.
14. Brown A et al. An interaction between warfarin and COX-2 inhibitors:
Two case studies. The Pharmaceutical Journal 2003; 271: p. 782
Level of evidence: 3
Case report
 Woman age 65 with previously stable INR averaging 2.5 found the INR
increased to 5.8 after taking celecoxib 200 mg od for 3 weeks
37
NSAIDs/selective COX-2 inhibitors and bronchospasm/asthma
Mechanism
Some patients, with or without an atopic asthma history, experience aspirin or
NSAID induced asthma. Studies suggest a prevalence in the general adult
population of about 20%. 1
People with aspirin-induced asthma possibly depend more on the
bronchodilating activity of Prostaglandin E2. Aspirin and other NSAIDs inhibit
the production of PGE2 (see Figure 1 page 5) so more arachidonic acid is
available for leukotriene production. Leukotrienes C4 and D4 are potent
bronchoconstrictors and mucous secretagogues. 1
Q.1 Can asthmatics who are NSAID-naïve have an NSAID?
Yes, but see recommendations.
Q.2 Can asthmatics who have wheezed with aspirin have an NSAID?
They should avoid NSAIDs. 1
Q.3 Are any of the traditional NSAIDS less prone to induce wheeze?
No evidence found so answer unknown.
Q.4 Are selective COX-2 inhibitors safer?
Evidence suggests that celecoxib 2,3 is safer although a case report illustrates
that the risk is not completely removed. 4
Q.5 Are topical NSAIDs safe to use in asthmatics sensitive to oral
NSAIDs?
Probably yes but unwanted side effects such as asthma have been reported
rarely with topical NSAIDs. Studies of long term unwanted effects of topical
NSAIDs are lacking.
Recommendations
1. Anyone with a history of an asthmatic reaction to aspirin or another
NSAID or if they have high risk features (severe asthma, nasal polyps,
urticaria or chronic rhinitis) should avoid all products containing aspirin
or NSAIDs. 1
2. If an NSAID is absolutely necessary, use of a selective COX-2 inhibitor
should be preferentially considered which should be given under
medical supervision. 4
38
3. NSAID-naïve asthmatic patients can take an NSAID but they need to
be aware of potential risks and advised if a respiratory reaction occurs
they must stop treatment and seek medical help. As aspirin-induced
asthma can develop in asthmatics > 40 years old, it has been
suggested that this group avoid NSAIDs, be warned of the risks and
that if NSAIDs are absolutely necessary that the first dose be taken
under medical supervision. 1
39
References
Mechanism and Q.2 Can asthmatics who have wheezed with aspirin
have an NSAID?
1. Twycross R and Wilcock W (eds). Palliative Care Formulary third
edition. Nottingham: Palliativedrugs.com Ltd, 2007.
Q.4 Are COX-2 inhibitors safer?
2. Dicpinigaitis P. Effect of the cyclooxygenase-2 inhibitor celecoxib on
bronchial responsiveness and cough reflex sensitivity in asthmatics.
Pulmonary Pharmacology and Therapeutics 2001; 14: pp. 93-97
Level of evidence: 1Randomised double blind cross over study



8 patients
One week of therapy with celecoxib did not appear to significantly
affect basal airway tone or the airway receptors controlling
bronchoconstriction and cough.
Results of this trial cannot be extrapolated to patients with severe
asthma, or those suffering an asthmatic exacerbation. Authors stated
that: ‘In such conditions of enhanced inflammatory response, the role
of selective cox-2 inhibition remains to be elucidated’
3. Gyllfors P et al. Biochemical and clinical evidence that aspirinintolerant asthmatic patients tolerate the cyclooxygenase 2-selective
analgesic drug celecoxib. Journal of Allergy and Clinical Immunology
2003; 111 (5): pp. 1116-1121
Level of evidence: 1+
Double-blind, randomised cross-over trial





33 patients with proven aspirin sensitivity
Increasing dose challenge with placebo or celecoxib on 2 occasions 7
days apart
Then all subjected to 2 doses of celecoxib 200mg 2 hours apart
Lung function, clinical symptoms and urinary excretion of LTE4
measured
No changes in the above including at the highest recommended daily
dose of celecoxib
40
4. Baldassarre S et al. Asthma attacks induced by low doses of
celecoxib, aspirin and acetaminophen. Journal of Allergy and Clinical
Immunology 2006; 117 (1): pp. 215-217
Level of evidence: 3
Case report of a single-blind, placebo controlled challenge


45-year old woman with proven aspirin-induced asthma developed
severe bronchospasm after 15mg celecoxib
Authors conclude that even though such reactions to COX-2 inhibitors
are rare, first doses should be given under medical supervision.
41
NSAIDS/selective COX-2 inhibitors and heart failure
How can NSAIDs/selective COX-2 inhibitors increase the risk developing
heart failure?
Experimental studies have shown that giving NSAIDs to susceptible people
can increase systemic vascular resistance and reduce renal blood flow,
glomerular filtration rate (GFR) and sodium excretion. The combination of
these mechanisms increases the risk of developing heart failure. This is
thought to occur because of the effects of NSAIDs on prostaglandins:

Prostaglandins have both vasoconstriction and vasodilatation
actions. Patients with impaired ventricular function produce more
vasodilatory prostaglandins to reduce peripheral resistance.

Prostaglandin production is inhibited by NSAIDs so this
compensatory mechanism is switched off when NSAIDs are given
to a patient with impaired ventricular function. This results in raised
peripheral resistance and reduced renal perfusion.
Q.1 What is the risk of developing heart failure?
The general population seems to be at slightly higher risk of developing heart
failure if taking NSAIDs. 1,2
Q.2 Who is at risk?


The greatest risk appears to be for those with a history of heart failure
or risk factors for cardiovascular disease. 3
Consistent with the proposed mechanism of effect, there is also a
higher risk of heart failure in patients on diuretics, ACE-inhibitors and
beta-blockers at start of use of an NSAID. 1,2,3
Q.3 Are traditional NSAIDs safer than selective COX-2 inhibitors?
The risk of taking selective COX-2 inhibitors and NSAIDs appears to be
similar. 2,4,5,6
Q.4 Does the risk of taking NSAIDs vary with different preparations?
There is some evidence that the risks are slightly increased for NSAIDs with a
long plasma half-life and slow-release formulations. 3 In this study drugs were
placed in the following half-life categories: ≤ 4 hours (diclofenac, ibuprofen,
ketoprofen, mefanamic acid), 4-12 hours (indomethacin, sulindac, ketoprofen
S/R) and ≥ 12 hours (naproxen, piroxicam, tenoxicam).
42
Recommendations
1. NSAIDS and selective COX-2 inhibitors should not be used in patients
with severe heart failure.
2. NSAIDS and selective COX-2 inhibitors should be used with caution in
those with a history of cardiovascular disease or risk factors for
cardiovascular disease as they are at higher risk of developing heart
failure. 3
3. NSAIDS and selective COX-2 inhibitors should be used with caution in
the elderly [>65] even in the absence of other risk factors, as there is a
greater risk of developing heart failure.
4. There is little evidence to show that any one drug has lower risk factors
for cardiac failure than any other, but celecoxib seems to pose a similar
degree of risk as traditional NSAIDs. 2,4,5,6
5. NSAIDs with a longer half-life (such as naproxen) and controlled
release preparations have been associated with an increased risk of
causing heart failure. 3 These should be avoided in high-risk patients.
43
References
Q.1 What is the risk of developing heart failure?
1. Huerta et al. Non-steroidal anti-inflammatory drugs and risk of
first hospital admission for heart failure in the general population
Heart 2006; 92: pp.1610-1615.
Level of evidence 2+
Case-controlled study based on the UK General Practice Research Database







Cases were 1396 people with a first hospital admission for non-fatal
heart failure; controls were a random sample of 5000 people.
The study did not include people prescribed COX-2 inhibitors.
The incidence rate of first admission for heart failure was 2.7 per
1000 person-years.
Results:
o 14% of cases and 10% of controls were current users of NSAID.
o Risk of hospitalisation (adjusted for confounding factors) for
NSAID users versus non-NSAID users:
 All NSAIDs: RR 1.3 (95% CI 1.1 to 1.6).
 Diclofenac: RR 1.1 (95% CI 0.8 to 1.5).
 Ibuprofen: RR 1.4 (95% CI 1.0 to 2.0).
 Indometacin: RR 3.4 (95% CI 1.5 to 7.7).
No clear effects of dose and duration were found.
Risks were slightly increased for NSAIDs with a long plasma half-life
and for NSAIDs in slow-release formulations.
Higher risk of heart failure in patients on diuretics, ACE-I and betablockers at start of use of NSAID.
2. Scott PA et al. Non-steroidal anti-inflammatory drugs and cardiac
failure: meta-analyses of observational studies and randomised
controlled trials. European Journal of Heart Failure 2008; 10: pp.11021107
Level of evidence 1+
Meta-analysis of observational studies and RCTs



Five case-control studies showed a non-significant association
between NSAIDs and cardiac failure.
Two cohort studies showed a significant risk of cardiac failure with
NSAIDs.
Six placebo controlled trials in non-rheumatoid disease showed more
cardiac failure with NSAIDs.
44




Six RCTs comparing coxibs with NSAIDs in arthritis showed no
difference in cardiac failure risk.
There are no trials comparing coxibs and NSAIDs in non-rheumatic
disease.
They were unable to break down results for individual NSAIDs because
of heterogeneity of studies and low numbers of cases for individual
drugs.
Conclusion: All NSAIDs cause heart failure in susceptible individuals.
The risk of COX-2 inhibitors and NSAIDs is similar. Patients with a
history of heart failure are at greatest risk.
Q.2 Who is at risk?
3. Page et al. Consumption of NSAIDs and the development of
congestive heart failure in elderly patients. Archives of Internal
Medicine 2000; 160: pp.777-784.
Level of evidence 2+
Case-control study of the relationship between recent NSAID use and
hospitalisation with congestive cardiac failure (CCF).




Cases were 365 patients admitted with primary diagnosis of CCF
Controls were 658 patients admitted to the same hospital without CCF
NSAID use gave OR of 2.1 (95% CI 1.2-3.3) for admission with CCF
Risk slightly greater with long acting and slow release preparations.
Q.3 Are traditional NSAIDs safer than COX-2 inhibitors?
See also reference 2.
4. Mamdani et al. Cyclo-oxygenase-2 inhibitors versus non-selective nonsteroidal anti-inflammatory drugs and congestive heart failure
outcomes in elderly patients: a population based cohort study. The
Lancet 2004; 363: pp.1751-1756
Level of evidence 2++
Canadian population-based cohort study in people older than 66 years



Information obtained from drug database to identify new users of
rofecoxib (14 583), celecoxib (18 908), NSAID (11 606) and age and
sex matched controls (100 000).
Primary end point: admission with congestive cardiac failure.
Results given as RR: celecoxib 1.0, NSAID 1.4.
5. Whelton et al. Cardiorenal effects of celecoxib as compared with the
NSAID diclofenac and ibuprofen. Kidney International 2006; 70:
pp.1495-1502
45
Level of evidence 1+




Osteo and rheumatoid arthritis patients.
Observational study of patients on Celecoxib Long-term Arthritis Safety
Study (CLASS) database (randomised, double blind parallel group
study.) Celecoxib 400mg bd (n=3986) vs. diclofenac 75mg bd (n=1996)
vs. ibuprofen 800mg tds (n=1985).
6.1% of ibuprofen patients developed oedema compared to 4.1% of
diclofenac and celecoxib patients (p<0.05).
No significant difference in congestive cardiac failure between groups.
6. Farkouh et al. Cardiovascular outcomes in high-risk patients with OA
treated with ibuprofen, naproxen or lumiracoxib. Annals of
Rheumatological Disease 2007; 66: pp.764-770
Level of evidence 1+

Data used from TARGET trial,
o 18 325 patients with osteoarthritis (OA), 2 parallel sub studies
comparing lumiracoxib with either ibuprofen or naproxen.
o Patients stratified into high and low cardiac risk.
o High-risk group divided into aspirin users and non-aspirin users.
o Primary end point all cardiovascular mortality, heart attack and
stroke at 1yr.
o Secondary end point congestive cardiac failure (CCF).
 Overall CCF developed in 1.28% of ibuprofen patients compared
to 0.14% of lumiracoxib patients (p=0.031).

No differences were found in CCF rates in the naproxen sub study.
Q.4 Does the risk of taking NSAIDs vary with different preparations?
See reference 3.
46
NSAIDs/selective COX-2 inhibitors and thrombotic events
Q.1 Do NSAIDs/COX-2 inhibitors increase the risk of thrombotic cardiac
events?
The exact mechanism by which NSAIDs are prothrombotic is unknown.
Theoretically selective COX-2 inhibitors could be prothrombotic:

They allow COX-1 mediated enzyme activity to continue, which
includes stimulation of platelet aggregation and vasoconstriction.
This effect is exacerbated, since inhibiting COX-2 mediated enzyme
activity causes blocking of vasodilation and removal of inhibition of
platelet aggregation

COX-2 inhibitors may impair ischaemic preconditioning.This is the
phenomenon whereby an initial period of sub-critical myocardial
ischaemia appears to offer both initial and more sustained
protection against subsequent ischaemia.

An increased risk of cardiac events could also be indirect via
NSAIDs’ effect on the cardiorenal mechanism. This can result in
salt and water retention together with loss of vasodilator
prostaglandins, which cause a raised blood pressure and an
increased risk of congestive cardiac failure.
Q.2 What are the risks?
The data shows increased risk for cardiac thrombotic events for NSAIDs and
selective COX-2 inhibitors excluding naproxen. 1,2,3,4,5 There does not appear
to be an increased risk of cerebrovascular thrombotic events. The thrombotic
risk as summarised on Clinical Knowledge Summaries is shown below:

COX-2 inhibitors:
o Coxibs (including celecoxib at doses in excess of 200mg/day
and etoricoxib) increase the risk for atherothrombosis by about
3 events per 1000 people per year (compared with placebo).

Standard NSAIDs:
o Naproxen 1000 mg daily has a lower thrombotic risk than COX-2
inhibitors. Overall, epidemiological data do not suggest an
increased risk of myocardial infarction.
o Ibuprofen may have a small thrombotic risk at high doses (e.g.
2400 mg daily), but at lower doses (e.g.1200 mg daily or less),
epidemiological data do not suggest an increased risk of
myocardial infarction.
47
o
o

Diclofenac, meloxicam, and indomethacin were associated with
a increased risk of cardiovascular thrombotic events (compared
with non-use).
Other NSAIDs have less evidence on thrombotic risks, but they
may all be associated with a small risk of thrombotic events.
COX-2 inhibitors and standard NSAIDs:
o People with risk factors for cardiovascular (cv) events are at
higher risk of thrombotic adverse events than those without such
risks. Their relative risk of thrombotic events with antiinflammatory drugs, compared with non-users, is the same as
that of people without cv risks, but because the baseline risk of
events in people with cv risk factors exceeds that of people with
no cv risk factors, the excess risk to such individuals posed by
anti-inflammatory drugs is considerable.
Adverse effects may manifest early, and the risk may persist throughout and
beyond treatment.
Table 1. (From CKS) Risk of serious cardiovascular events associated with
nonsteroidal anti-inflammatory drugs (NSAIDs) compared with placebo.
NSAID
Relative risk
(NSAID versus
placebo)
95% confidence
interval
Number of
studies
Diclofenac†
Rofecoxib†
Indometacin†
Meloxicam†
Piroxicam†
Ibuprofen†
Celecoxib†
Celecoxib — pooled
data‡
400 mg QD‡
200 mg BID‡
400 mg BID‡
Naproxen†
1.40
1.36
1.36
1.24
1.16
1.09
1.06
1.6
1.19 to 1.65*
1.18 to 1.58*
1.15 to 1.61*
1.06 to 1.45*
0.86 to 1.56
0.99 to 1.20
0.92 to 1.22
1.1 to 2.3*
1.1
1.8
3.1
0.99
0.6 to 2.0
1.1 to 3.1*
1.5 to 6.1*
0.89 to 1.09
10
12
7
4
5
17
12
6 (7950
participants)
—
—
—
16
* Increased relative risk statistically significant.
Data from: [McGettigan and Henry, 2006†; Solomon et al, 2008‡]
48
Q.3 What is the risk of cerebrovascular accidents?
There is some evidence that NSAIDs or COX-2 inhibitors increase the risk of
cerebrovascular accidents - Andersohn et al Stroke 2006, Lee et al AJM
2007, Roumie et al Stroke 2007 – to mention a few. It is beyond the scope of
this review to answer this question with certainty.
Q. 4 Who is at risk?
The risk applies to the general population but those with risk factors for
cardiovascular disease may be of higher risk. 7
Q.5 Are traditional NSAIDs safer than COX-2 inhibitors? 2,4,7
No






Diclofenac, rofecoxib,meloxicam, and indomethacin were associated
with an increased risk of cardiovascular thrombotic events (compared
with non-use)
The risk of cardiovascular thrombotic events with diclofenac was
similar to that associated with rofecoxib
The risk with indomethacin was similar to that with diclofenac and
rofecoxib
Naproxen was not associated with an increased risk of thrombotic
events .
Ibuprofen was not associated with increased risk.
Celecoxib at doses of 200mg/day was not associated with increased
risk.
Q.6 Does the risk increase with higher doses?

One study looking at celecoxib suggests that it does. 7
Recommendations
1. As NSAIDs and COX-2 inhibitors excluding naproxen are associated
with an increased risk of cardiovascular thrombotic events 1,2,3,4,5 their
use for palliative care patients depends on a balance of risks and
benefits.
2. Naproxen appears to carry the lowest risk of increasing cardiovascular
events 1,5 and may be the most suitable for patients at higher risk of
cardiovascular disease.
3. A second option would be ibuprofen up to 1200mg daily.
4. Avoid diclofenac
5. Use celecoxib at doses of 200mg/day or less.
49
References
Q.2 What are the risks of NSAIDs/selective COX-2 inhibitors causing
thrombotic events?
1. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of
selective and nonselective inhibitors of cyclo-oxygenase-2. Journal Of
The American Medical Association 2006; 296 (13): pp. 1633-1644
Level of evidence: 2 ++


Trials between 1985 and 2006
17 case controlled studies and 6 cohort studies

There was no significant increase in the RR of a cardiovascular event
with celecoxib or meloxicam.
There was an increased RR for diclofenac
There was no significant increase in cardiovascular risks with
naproxen, ibuprofen or piroxicam,


2. Kearney P M et al. Do selective cyclo-oxygenase-2 inhibitors and
traditional non-steroidal anti-inflammatory drugs increase the risk of
atherothrombosis: meta-analysis of randomised trials. British Medical
Journal 2006; 332 (7553): pp. 1302-1308.
Level of evidence: 1

Included studies that compared a selective COX-2 inhibitor with a
placebo or traditional NSAID for at least 4 weeks

COX-2 inhibitors were associated with a moderately increased
incidence of serious vascular events (RR 1.42, 95% CI 1.13-1.78)
There was no statistically significant difference in the rate of a serious
vascular event between those receiving COX-2 inhibitors and any
NSAID (RR 1.16, 95% CI 0.97-1.38)
When compared with naproxen,COX-2 inhibitors were associated with
an increased incidence of serious vascular events (RR 1.57, 95% CI
1.21-2.03)


3. Caldwell B et al. Risk of cardiovascular events and celecoxib: a
systematic review and meta-analysis. Journal of the Royal Society of
Medicine 2006; 99 (3): pp. 132-140.
Level of evidence: 1

6 RCTs with a total of 12,780 patients
50


None of the studies were either adequately powered or specifically
designed to assess the risk of cardiovascular thromboembolic events
with celecoxib treatment
Celecoxib was administered for at least 6 weeks

Studies comparing celecoxib with any other treatment showed the risk
of myocardial infarct was significantly higher in the celecoxib groups
(OR 1.88, 95% CI 1.15-3.08)

No difference in deaths from cardiovascular events between those
taking celecoxib and those taking placebo.
4. Chen LC & Ashcroft DM. Risk of myocardial infarction associated with
selective COX-2 inhibitors: meta-analysis of randomised trials.
Pharmacoepidemiology Drug Safety 2007; 7: pp. 762-772.
Level of evidence: 1

Included 55 RCTs

COX-2 inhibitors were associated with a significantly increased risk
of heart attack compared with placebo / NSAIDs (OR 1.46, 95% CI
1.02-2.09) or NSAIDs (OR 1.45, 95% CI 1.09-1.93)
5. Singh G, Wu O, Langhorne P, Madhok R. Risk of acute myocardial
infarction with non-selective non-steroidal anti-inflammatory drugs: a
meta-analysis. Arthritis Research Therapeutics 2006; 8 (5): R153
Level of evidence: 2 ++






Studies of non-selective NSAIDs where acute myocardial infarct (MI)
was objectively confirmed
Included 14 observational studies
Non-selective NSAIDs were associated with a statistically significant
increase in the occurrence of MI when compared with non-use (RR
1.19, 95%CI 1.08-1.31)
Diclofenac was associated with a statistically significant increase in the
occurrence of MI when compared with non-use (RR 1.38, 95% CI 1.221.57)
Ibuprofen was associated with a statistically significant increase in the
occurrence of MI when compared with non-use (RR 1.11, 95% CI 1.061.17)
Naproxen was not associated with a statistically significant increase in
the occurrence of MI when compared with non-use
51
Q.3 What is the risk of cerebrovascular accidents?
See also reference 2.
3. Caldwell B et al. Risk of cardiovascular events and celecoxib: a
systematic review and meta-analysis. Journal of the Royal Society of
Medicine 2006; 99 (3): pp. 132-140.
Level of evidence: 1



Four studies (n=4,422) compared celecoxib with placebo and assessed
cerebrovascular events
Six studies (n=12,780) compared celecoxib with any other treatment
and assessed cerebrovascular events
There was no difference in the occurrence of cerebrovascular events
between the groups
6. Chen L C & Ashcroft D M. Do selective COX-2 inhibitors increase the
risk of cerebrovascular events: a meta-analysis of randomised
controlled trials. Journal Of Clinical Pharmacology Therapy 2006;
31(6): pp. 565-576
Level of evidence: 1
 Included 40 RCTs comparing any individual COX-2 inhibitor used for
at least 4 weeks, against placebo or other active treatment
 Reported the proportion of patients experiencing cerebrovascular
events

Concluded that there is no evidence of a significantly increased risk of
cerebrovascular events associated with selective cyclooxygenase-2
inhibitors compared with placebo or active treatment such as nonsteroidal anti-inflammatory drugs.
Q.4 Who Is at risk?
7. Scott D & Solomon. Cardiovascular risk of celecoxib in 6 randomised
placebo controlled trials. Circulation 2008; 117: pp. 2104-2113
Level of evidence: 1

This study assessed the cardiovascular risk associated with celecoxib
in 3 dose regimens and the relationship between baseline
cardiovascular risk and the effect of celecoxib on cardiovascular events
Graph showing risk of cardiovascular events:
52

Higher dose is associated with increased risk in groups with higher
cardiovascular risk

Patients at highest baseline risk have an increased relative risk for
celecoxib-related adverse cardiovascular events
Q.5 Are traditional NSAIDs safer than COX-2 inhibitors?
Naproxen appears to be the safest NSAID (see Table 1):
53
Table 1 (from CKS). Risk of serious cardiovascular events associated with
nonsteroidal anti-inflammatory drugs (NSAIDs) compared with placebo.
NSAID
Relative risk
(NSAID versus
placebo)
95% confidence
interval
Number of
studies
Diclofenac†
Rofecoxib†
Indometacin†
Meloxicam†
Piroxicam†
Ibuprofen†
Celecoxib†
Celecoxib — pooled
data‡
400 mg QD‡
200 mg BID‡
400 mg BID‡
Naproxen†
1.40
1.36
1.36
1.24
1.16
1.09
1.06
1.6
1.19 to 1.65*
1.18 to 1.58*
1.15 to 1.61*
1.06 to 1.45*
0.86 to 1.56
0.99 to 1.20
0.92 to 1.22
1.1 to 2.3*
1.1
1.8
3.1
0.99
0.6 to 2.0
1.1 to 3.1*
1.5 to 6.1*
0.89 to 1.09
10
12
7
4
5
17
12
6 (7950
participants)
—
—
—
16
* Increased relative risk statistically significant.
Data from: [McGettigan and Henry, 2006†; Solomon et al, 2008‡]
See references 2, 4, 5 and 7.
8. Jones S C. Relative thromboembolic risks associated with COX-2
inhibitors. Annals of Pharmacotherapy 2005; 39 (7-8): pp. 1249-1259.
Level of evidence: 1

RCTs, retrospective and prospective cohort studies and case-control
studies were eligible for inclusion

High-dose celecoxib (400 mg twice daily) was associated with a
significant increase in cardiovascular events compared with placebo
(RR 3.4, 95% CI 1.4-7.8)
There was no significant difference between low-dose celecoxib (200
mg twice daily) and placebo.
Based on existing data, celecoxib was the safest COX-2 inhibitor when
given in the lowest possible dose for the shortest time in the ideal
target population.


54
Q.6 Does the risk increase with higher doses?
See reference 7:

Increased celecoxib dose is associated with increased risk of
cardiovascular events:
55
NSAIDs/selective COX-2 inhibitors and renal impairment
Q.1 How do NSAIDs/selective COX-2 inhibitors cause renal impairment?
There are 3 main sites and mechanisms of injury to the renal system:

The first and most common mechanism is by blocking the
prostaglandins’ vasodilatory action on the afferent arterioles of the
glomeruli. This causes reduced glomerular perfusion, which results in
reduced glomerular filtration rate.
 The second mechanism is an allergic type reaction resulting in
interstitial nephritis and this can occur days to weeks after starting
NSAIDs/COX-2 inhibitors.
 The third mechanism is immune-mediated resulting in membranous
glomerulonephritis which can cause nephrotic syndrome.
Q.2 What is the risk of renal toxicity?
Traditional NSAIDs and COX-2 inhibitors can induce renal impairment and
many studies suggest that cumulative dose contributes to the risk 1,2.
Q.3 Who is at risk? 3,4



The risk applies to the general population but those with risk factors for
cardiovascular disease may be at higher risk, especially those taking
diuretics.
There is also some evidence that elderly and cachectic patients are at
greater risk.
Changes in renal function can be seen up to and beyond 6 months
from initiating therapy.
Q.4 Are traditional NSAIDs safer than COX-2 inhibitors? 1,5,6,7



The greatest risk comes from using NSAIDs such as indomethacin.
The safest NSAID is ibuprofen, closely followed by diclofenac.
Amongst the COX-2 inhibitors, celecoxib is associated with a lower risk
of renal dysfunction and hypertension – even compared to diclofenac
and ibuprofen.
Recommendations
There is limited evidence to support these findings in relation to those with
moderate renal impairment – most studies involve those with normal renal
function or very mild renal impairment. Caution must therefore be used in
extrapolation.
1. Avoid NSAIDs or COX-2 inhibitors if possible in patients with renal
impairment.
56
2. Celecoxib is overall the safest agent to use. 1,5,6,7
3. Ibuprofen seems to be the safest traditional NSAID. 1,5,6,7
4. Changes in renal function are higher with cumulative dose 1,2, but
changes in renal function can be seen up to and beyond 6 months of
initiating therapy. 3.4
5. Particular care is needed when prescribing for patients with low
circulating volumes [congestive cardiac failure/diuretic therapy]. 3,4
57
References
Q.2 What is the risk of renal toxicity?
1. Swan S et al. Effect of Cyclooxygenase-2 Inhibition on Renal Function in
Elderly Persons Receiving a Low-Salt Diet. Annals of Internal Medicine
2000; 133: pp. 1-9.
Level of evidence: 1+





RCT comparing rofecoxib with indomethacin in healthy subjects aged
60-80.
Used low-salt diet to increase the dependence on prostaglandins for
maintaining renal function.
2 separate studies.
o Single dose study – 15/16 Patients with Creatinine Clearance
(Cr Cl) >40ml/min. Randomly assigned to single dose of
rofecoxib 250mg, indomethacin 75mg, or placebo. Glomerular
Filtration Rate (GFR) was calculated before and after
administration. GFR was significantly reduced in both treatment
arms compared to placebo, but no significant differences were
found between the treatment arms.
o Multiple dose study – 60/71 Patients with Cr Cl 30-80ml/min.
Randomly assigned to rofecoxib 12.5mg od, rofecoxib 25mg od,
indomethacin 50mg tds, or placebo for 5 days. Calculated
baseline GFR and day 6. Lowest GFR result at 3 consecutive
intervals was recorded. No significant differences found between
the treatment arms.
In patients with low effective circulating volume (congestive cardiac
failure, diuretic use, cirrhosis) NSAID-induced alterations can result in
clinically significant renal insufficiency.
Decreases in GFR are similar regardless of whether COX-2 inhibitors
or non-selective inhibitors are used.
2. Evidence as quoted on Clinical Knowledge Summaries:
Level of evidence: 1
Their evidence for renal and renovascular risks associated with COX-2
inhibitors and standard NSAIDs comes from three systematic reviews:
a) Morrison A et al. Systematic review of trials of the effect of continued
use of oral non-selective NSAIDs on blood pressure and hypertension.
Current Medical Research & Opinion 2007; 23 (10): pp. 2395-2404.
There was a small increase in the risk of hypertension with ibuprofen.
58
b) Zhang J, Ding E & Song Y.et al. Adverse effects of cyclooxygenase 2
inhibitors on renal and arrhythmia events: meta-analysis of randomized
trials. Journal of the American Medical Association 2006; 296 (13): pp.
1619-32.
A systematic review of 114 RCTs assessed the risks of renal adverse
events (renal dysfunction, hypertension, and peripheral oedema)
associated with COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib,
parecoxib, etoricoxib, and lumiracoxib)




There was no evidence of a class effect for COX-2 inhibitors on renal
adverse events
Celecoxib:
o Peripheral oedema: RR 1.09 (95% CI 0.91 - 1.31).
o Hypertension: RR 0.83 (95% CI 0.71 - 0.97).
o Renal dysfunction: RR 0.61 (95% CI 0.40 - 0.94).
Etoricoxib:
o Peripheral oedema: RR 0.95 (95% CI 0.68 - 1.32).
o Hypertension: RR 1.07 (95% CI 0.72 - 1.58). A total of 35 people
needed to be treated for one person to develop hypertension
within about 12 weeks (NNH 35, 95% CI 27 to 47).
o Renal dysfunction: RR 0.59 (95% CI 0.10 to 3.32).
Other COX-2 inhibitors were not significantly associated with risk
c) Aw T et al. Meta-analysis of cyclooxygenase-2 inhibitors and their
effects on blood pressure. Archives of Internal Medicine 2005; 165 (5):
pp. 490-496.
Incidence of hypertension: the risk for COX-2 inhibitors was increased
compared with placebo and with standard NSAIDs.
These studies found increased risks of hypertension and elevated blood
pressure (particularly systolic blood pressure):

The results are not entirely consistent among the studies.

The risks for hypertension vary among drugs (indicating that this risk
may not be a class effect); they may be greatest for ibuprofen and
naproxen and least for celecoxib and diclofenac.

The risks of renal and cardiorenal adverse effects from COX-2
inhibitors and standard NSAIDs may be greater in people with existing
renal or cardiorenal compromise (e.g. cardiac failure).

The systematic reviews and case-controlled study did not report
absolute risk increases or numbers needed to treat.
59
Q.3 Who is at risk?
3. Jerkic M et al. The mechanism of increased renal susceptibility to toxic
substances in the elderly. International Urology and Nephrology 2001; 32:
pp. 539-547
Review article




Reduced body fat increases the concentration of water soluble agents
in non-fat compartments
Reduced albumin levels increase the plasma levels of bound drugs
Ageing reduces the activity of renin-angiotensin aldosterone system
The elderly are more susceptible to the inhibitory effects of vasodilatory
prostaglandins
4. Toto R et al. Effects of acute and chronic dosing of NSAIDs in patients
with renal insufficiency. Kidney International 1986; 30: pp. 760-768
Level of evidence: 2






Study of 8 normal subjects and 12 patients with chronic renal
insufficiency of various etiology (Creatinine Clearance 19-83ml/min).
Looked at effects of acute (0-4 days) and chronic (5 days) dosing of
indomethacin 50mg tds compared to ketoprofen 50mg qds.
Acute dosing of both agents resulted in significant decreases of
Glomerular Filtration Rate in those with renal impairment.
With chronic dosing, each dose of NSAID caused transient, reversible
decreases in renal haemodynamics that may ‘dampen with time’.
Caution must be exercised in extrapolation of these findings to other
settings.
Modified release preparations ‘might cause sufficiently prolonged
effects to prevent recovery between doses and cause an overall
adverse effect’.
The authors noted that their findings were in ‘apparent conflict’ with
those of Ciabattoni et al and suggested a difference in renal pathology
as a cause for this (Effects of sulindac and ibuprofen in patients with
chronic glomerular disease. Evidence for dependence of renal function
on prostacyclin. New England Journal of Medicine 1984; 310: pp. 279283).

This was a small study, unmatched and not blinded. There was
no evidence of randomisation to treatment arms.
Q.4 Are traditional NSAIDs safer than COX-2 inhibitors?
See reference 1.
60
5. Strand V. Are Cox-2 inhibitors preferable to non-selective non-steroidal
anti-inflammatory drugs in patients with risk of cardiovascular events
taking low-dose aspirin? The Lancet 2007; 370 (9605): pp. 2138-2151
Review


Large clinical review looking into cardiovascular and gastrointestinal
effects of NSAIDs/COX-2 inhibitors, in particular for patients taking
aspirin.
Several studies suggest that celecoxib is associated with fewer
adverse renal effects than other non-selective NSAIDs, and could be
protective against aspirin-induced changes in renal function
6. Whelton, Lefkowith, West and Verburg. Cardiorenal effects of celecoxib as
compared with nonsteroidal anti-inflammatory drugs diclofenac and
ibuprofen. Kidney International 2006; 70: pp. 1495-1502.
Level of evidence: 1






Paper reporting on large database accumulated on cardiorenal safety
during the CLASS trial (Celecoxib Longterm Arthritis Safety Study).
This compared the upper GI safety of celecoxib 400mg bd with normal
full therapeutic doses of diclofenac (75mg bd) and ibuprofen (800mg
tds) in rheumatology outpatients.
o 8059 patients enrolled, with 7968 given medication on an
intention to treat basis (3987 given celecoxib, 3981 given
ibuprofen or diclofenac).
o Followed up for 9 months.
o Mean age of population was 60 yrs.
o All had normal baseline BP and renal function.
Significant reductions in renal function were seen with diclofenac
compared to celecoxib.
Non-significant reductions were seen with ibuprofen compared to
celecoxib.
A substantial proportion of patients exhibited changes 6 months or
longer after initiating treatment.
In patients with mild renal impairment (normal creatinine, Urea>20), the
incidence of clinically important changes in renal function was 2 fold
lower in celecoxib compared with diclofenac or ibuprofen.
o This cohort were more likely to withdraw from the study owing to
renal adverse events.
o Withdrawal rate was lower in the celecoxib arm (1.5%),
diclofenac (3.7%), ibuprofen (4.2%).
7. Winkelmayer, Waiker, Mogun and Solomon. Nonselective and
Cyclooxygenase-2-selective NSAIDs and Acute Kidney Injury. American
Journal of Medicine 2008; 121: p. 12
Level of evidence: 3
61








Subjects were selected as those enrolled to Medicare and a
pharmaceutical assistance programme between 1999-2004
Patients were excluded with any history of renal problems.
Co-morbidities were determined from other medications prescribed for
those individuals
Gathered information for those patients prescribed a new NSAID/COX2 inhibitor that they had not received in the previous 6 months.
Followed up for 45 days and assessors searched for any incidence of
acute kidney injury, either as an outpatient or requiring inpatient stay.
962 patients had an event
Celecoxib was taken as the reference group, as it was the most
frequently prescribed anti-inflammatory agent.
They concluded that compared to celecoxib, ibuprofen and
indomethacin had a greater risk of acute kidney injury.
62
The use of NSAIDs/selective COX-2 inhibitors for Cancer-Induced Bone
Pain (CIBP)
Background to CIBP







Up to 85% patients with bone metastases will suffer pain, often
associated with anxiety and depression, reduced performance status
and a poor quality of life 1
It is considered a complex pain syndrome with a triad of
characteristics1:
o Background element – typically opioid responsive, dull quality
o Spontaneous breakthrough element
o Incident pain – harder to treat with opioids
Radiotherapy is considered the gold-standard treatment 1
Bone metastases are painful because tumours invading and growing
within the medullary space of the bone can activate primary afferent
nerve fibres which transmit noxious stimuli to the dorsal horn of the
spinal cord 2
Cancer cells can secrete prostaglandins which activate the primary
afferents 2
Invading tumours can also encourage the production of an
inflammatory infiltrate and alter the balance between osteoblasts and
osteoclasts 2
Suggested paradigm for management: see schematic 11
63
New Bone Pain
Analgesics & request imaging where
appropriate
Pathologic fracture or high risk criteria on x-ray
(e.g. osteopaenia, osteoporotic fracture)
Surgery (if
appropriate)
yes
no
Exclude non-malignant bone pain (e.g. Pagets,
OA, osteoporotic collapse, etc) or confirm the
primary malignancy
Diffuse Pain
Hormone sensitive cancer  hormone therapy
Chemo-sensitive cancer  Chemo therapy
+/bisphosphonates
isotopes (strontium)
radiotherapy
Schematic from reference 1
64
Localisable Pain
Radiotherapy
Q.1 What is already known about NSAIDs/selective COX-2 inhibitors and
CIBP?
There is a lack of robust, clinical evidence. There are no recorded outcomes
for incident pain and no studies have addressed the use of COX-2 inhibitors.





A Cochrane Systematic Review 3 of cancer pain has incorporated
randomised control trials looking at NSAID vs placebo, opioid vs
NSAID+opioid 4,5 , NSAID vs opioid 6,7 , NSAID vs NSAID 8 and NSAID
vs NSAID+opioid
The heterogeneity of study designs, type of pain and baseline pain
severity limited the scope for meta-analysis
Data related to CIBP has been extracted from this review, where the
authors provide some evidence that this type of pain was investigated.
These studies give us mixed results (see table 1 page 65)
There is insufficient information for a systematic review on the efficacy
of NSAIDs for CIBP
Q.2 Do NSAIDs/selective COX-2 inhibitors inhibit bone healing?
There is a lack of high quality evidence. There is none from randomised
controlled trials, nor evidence from large good quality observational studies. 9


Theoretically, because osteoblasts produce prostaglandins, NSAIDs
could inhibit bone healing.
Some studies looking at rates of healing from non-pathological
fractures have suggested an association between NSAIDs and poor
healing. However, evidence has been conflicting and it must be
remembered that the study may not have controlled for confounding
variables such as smoking, which is known to significantly inhibit bone
healing. 9
Conclusions


There is some evidence that using an NSAID for bone pain secondary
to metastatic cancer can have an analgesic effect and reduce the
opioid requirement. 3
There is conflicting evidence as to whether NSAIDs/COX-2 inhibitors
have a clinically meaningful adverse effect on bone healing. 9
65
References
Background
1. Delaney B, Fleetwood-Walker SM, Colvin LA, Fallon M. Translational
Medicine: Cancer pain mechanisms and management. British Journal
of Anaesthesia 2008; doi: 10.1093/bja/aen100
Review
2. Urch C. The pathophysiology of cancer-induced bone pain: current
understanding. Palliative Medicine 2004; 18: pp. 267-274
Review
Q.1 What is already known about NSAIDs/selective COX-2 inhibitors and CancerInduced Bone Pain?
3. McNicol ED, Strassels S, Goudas L, Lau J, Carr DB. NSAIDS or
paracetamol, alone or combined with opioids, for cancer pain.
Cochrane Database of Systematic Reviews 2005; Issue 2. Art. No.:
CD005180. DOI: 10.1002/14651858.CD005180.
Level of evidence: 1++
Qualitative systematic review due to heterogeneity of sample, patient
populations and outcomes

See table 1 for references 4-8
4. Weingart WA, Sorkness C, Earhart R. Analgesia with oral narcotics
and added ibuprofen in cancer patients. Clinical Pharmacy 1985; 4(1):
pp. 53-58.
5. Lomen PL et al. Flurbiprofen for the Treatment of Bone Pain in Patients
with Metastatic Breast Cancer. American Journal of Medicine 1986;
80(3A): pp. 83-87.
6. Tonachella R, Gallo Curcio C, Grossi E. Diclofenac sodium in cancer
pain: A double-blind within-patients comparison with pentazocine.
Current Therapeutic Research 1985; 37(6): pp. 1130-1133.
7. Stambaugh JE Jr, Drew J. The combination of ibuprofen and
oxycodone/acetominophen in the management of chronic cancer pain.
Clinical Pharmacology & Therapeutics 1988; 44(6): pp. 665-669
66
8. Levick S et al. Naproxen sodium in treatment of bone pain due to
metastatic cancer. Pain 1988; 35(3): pp. 253-258
Q.2 Do NSAIDs/selective COX-2 inhibitors inhibit bone healing?
9. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/NSAIbo
ne.html [Accessed February 1 2009]
Table 1: Summary of evidence from Cochrane review (page 68)
67
Author and
grade of
evidence
Type of
comparison
n
Age
Weingart
WA et al
1985 4
Level of
evidence:
1+
Lomen PL
et al. 1986 5
Level of
evidence:
1Tonachella
R et al.
1985 6
Level of
evidence:
1Stambaugh
JE Jr, Drew
J. 1988 7
Level of
evidence:
1Levick S et
al. 1988 8
Level of
evidence:
1+
Opioid vs
NSAID+opioid
Opioid vs
NSAID+opioid
NSAID vs
Opioid
10
17
16
NSAID/Opioid
combination
compared with
NSAID/Opioid
combination
30
Low dose
NSAID vs.
supramaximal
dose NSAID
100
39-67
35-79
mean
60
Cancer type
2 breast, 2
colo-rectal, 3
gynae, 1 lung,
1 bladder, 1
melanoma
All had
metastatic
disease, 6 with
bony
involvement
stable
metastatic
breast cancer
not stated
18-80
not stated
19-81
Mean
62
not stated
Type of pain
stated?
not clear
Bone pain
bone pain in
20% of group
receiving opioid
then NSAID, &
in 50% in group
receiving
NSAID then
opioid
Bone pain due
to metastatic
cancer
Bone pain due
to metastatic
cancer
Chronicity
of pain
Comparators
Study
duration
Outcomes
4 months 20 years
(mean 55.3
months)
Ibuprofen 400mg qds
or placebo on top of
existing constant
opioid
9 days,
crossover
at day 4
and day 7
Pain relief by
VAS
NSAID superior to placebo.
8/10 improved pain score by
mean 39% (3-76%)
Not stated;
cannot
extrapolate
from
disease
duration
Flurbiprofen orally,
dose not stated, or
placebo in addition to
usual therapeutic
regimen. Opioid doses
allowed to vary.
3 weeks
then
crossover
Pain score on 04 scale
Overall NSAID superior to
placebo. Results not
statistically significant.
8 days
not stated
Diclofenac im 75mg
bd or Pentazocine im
30mg bd. Cross over
after 3 day period + 1
day placebo washout
Daily pain score
on 0-12 scale
“chronic”
not stated
Ibuprofen 60mg qds
(15) or placebo (15)
in addition to stable
as-needed doses of
oxycodone
(5mg)/paracetamol
(325mg)
Naproxen 1650 mg/
day vs. Naproxen
825 mg/ day
7 days
3 days
Pain relief by
global rating of
patient and
investigator
(scales poorly
described)
2hrly patient and
investigator Pain
intensity scores
(VAS)
Results/Conclusions
Each drug significantly
reduced pain intensity
(p<0.01), Diclofenac provided
a greater reduction when
given compared to
pentazocine (p<0.047)
Ibuprofen reduced the need
for oxycodone/paracetamol. 5
days required for maximal
dose reduction effect.
Baseline pain: 2 moderate,
and 13 severe in the
ibuprofen group. 6 moderate,
and 9 severe in placebo
group
Pain intensity decreased by
one-third in both high dose
(n=51) and low dose (n=49)
groups. Responders gave
better pain scores if on higher
dose (but not statistically
significant)
Subcutaneous ketorolac
Q.1 What is it?
Ketorolac is a cyclic proprionate compound structurally related to
indomethacin. The analgesic effect is much greater than its anti-inflammatory
effect. It comes in tablets/liquid form and is licensed for use IV/IM for the
short-term management of moderate to severe acute post-operative pain.
Evidence surrounding its safety and efficacy is largely based on short-term
studies looking at acute pain.
It is renally excreted with a dose-dependent effect on the risk of GI bleeding
(see page 12).
Manufacturer’s recommendations:



Start with an initial dose of 10 mg and use a total daily dose of 90 mg
for ‘non-elderly’ and 60 mg for elderly, renally impaired and patients
weighing less than 50 kg with a maximum duration of treatment of 2
days.
Reduce dose for patients weighing less than 50kg
Contra-indications include people already on aspirin, severe heart
failure and serum creatinine greater than 160 mmol
Q.2 What are the side effects/risks in the general population?
A study looking at post-operative use showed a dose-response relationship
between daily dose and GI bleeding with a higher risk of GI bleeding if
therapy lasted more than 5 days. 1
Another study of patients who had received parenteral ketorolac showed a
possibly higher risk of acute renal failure after more than 5 days of therapy. 2
Ketorolac and the palliative care patient
Subcutaneous ketorolac can be used for its analgesic effect when oral
NSAIDs are unable to be administered. As repeated injections can be painful,
it is recommended that it is used in a syringe driver. 3
Q.3 What are the reasons for using it?
The use of ketorolac in palliative care is for the management of bone pain,
visceral pain, neuropathic pain or pain of mixed aetiology. Here are examples
of clinical situations in the literature where it has been used:
1. When opioid related side effects may limit titration of the opioid and
hence adequate analgesia
2. Where there is poor analgesia despite opioid and oral NSAID
3. Where there is good analgesia but severe opioid related sideeffects
It can have a significant opioid-sparing effect.
Q.4 What side-effects have been noted in palliative care patients?
Evidence takes the form of case series/reports. 4,5,6,7,8,9 GI bleeding has
occurred, especially in patients with GI malignancies or taking steroids (see
table 1 page 73).
Q.5 What about the toxicities of other subcutaneous (s/c) NSAIDs ?
There is no comparative evidence in the literature with regards to s/c ketorolac
vs diclofenac vs naproxen.
For subcutaneous naproxen, a case study did not report any specific
reactions. 10
For subcutaneous diclofenac, a retrospective case series noted 1 site
reaction.11
Conclusions
1. S/c ketorolac may improve pain even when oral NSAIDs haven’t.
2. There are more examples of the use of s/c ketorolac in the palliative
care literature compared to s/c naproxen or diclofenac with regards to
efficacy and side-effects, although this evidence is low-grade.
Recommendations
1. Despite ketorolac being used for up to 6 months without any adverse
effects 7, elderly people, patients with GI cancer and patients receiving
other drugs which increase the risk of bleeding/renal failure are
particularly at risk. 1,2,6,7 If appropriate, renal function should be
monitored and ketorolac used at the lowest effective dose and for the
shortest duration possible.
2. Gastroprotection (a PPI) should be co-administered if appropriate.
70
References
1. Strom, B et al. Parenteral ketorolac and risk of gastrointestinal and
operative site bleeding. A postmarketing surveillance study. Journal of
the American Medical Association 1996; 275 (5): pp. 376-382
Level of evidence: 2+

surveillance study showed a dose-response relationship between daily
dose and GI bleeding with a higher risk of GI bleeding if therapy lasted
more than 5 days
2. Feldman, H et al. Parenteral Ketorolac: The Risk for Acute Renal
Failure. Annals of Internal Medicine 1997; 126 (3): pp. 193-199
Level of evidence: 2+

Cohort study of 9850 patients who had received parenteral ketorolac

Showed a possibly higher risk of acute renal failure after more than 5
days of therapy and an increased risk if there was concomitant cancer,
renal impairment, hypertension, cirrhosis or use of aminoglycoside
antibiotics.
3. Twycross R and Wilcock W (eds). Palliative Care Formulary third
edition. Nottingham: Palliativedrugs.com Ltd, 2007.
For further details of references 4-9 see table1 below.
4. Blackwell N et al. Subcutaneous ketorolac – a new development in
pain control. Palliative Medicine 1993; 7: pp. 63-65
5. Duncan A, Hardy J & Davis C. Subcutaneous ketorolac. Palliative
Medicine 1995; 9: pp. 77-78
6. Myers K & Trotman I. Use of ketorolac by continuous subcutaneous
infusion for the control of cancer-related pain. Postgrad Medical
Journal 1994; 70: pp. 359-362
7. Hughes A, Wilcock A & Corcoran R. Ketorolac: Continuous
Subcutaneous Infusion for Cancer Pain. Journal of Pain and Symptom
Management 1997; 13 (6): pp. 315-316
71
8. De Conno F et al. Tolerability of Ketorolac Administered via Continuous
Subcutaneous Infusion for Cancer Pain: A Preliminary Report. Journal
of Pain and Symptom Management 1994; 9 (2): pp. 119-121
9. Ripamonti C et al. Continuous Subcutaneous Infusion of Ketorolac in
Cancer Neuropathic Pain unresponsive to Opioid and Adjuvant Drugs:
A Case Report Tumori 1996; 82: pp. 413-415
10. Toscani F et al. Sodium Naproxen: continuous subcutaneous infusion
in neoplastic pain control. Palliative Medicine 1989; 3: pp. 207-211
Level of evidence: 3





Case series of 14 patients age 46-68 with cancer pain and switched
from oral naproxen to CSCI at same doses
Pain types included bone, visceral, neuropathic and nociceptive
All patients given ranitidine
Average duration of treatment was 21 days (7-112)
No ‘generalised reactions’ noted
11. Hall E. Subcutaneous diclofenac: an attractive alternative? Palliative
Medicine 1993; 7: pp. 339-340
Level of evidence: 3




Retrospective study of 27 patients
15 patients had 150mg, 4 patients 225 mg and 8 patients 300 mg
Duration of administration ranged from 7 hours – 14 days, median 48
hours
1 patient developed a severe site reaction
Table 1: Summary of Palliative Care literature discussing subcutaneous
ketorolac (page 73)
72
Author and
evidence grading
No. of patients
Age
Dose range (mg)
Duration of
treatment (days)
Gastroprotection
Toxicity/nature
Blackwell4 1993
Grade 3
7
30-90
8-31
Misoprostol
None
50-150
3-22
No comment
No comment
36
Majority 60
3-115
Misoprostol
4 patients developed GI bleeding:
Age 19-79
Range 60-120
Median 15
Age 52-81
Duncan5
1995
Grade 3
Myers & Trotman6
1994
Grade 3
10
Age 29-36
1 patient bled when high dose dexamethasone was added
2 patients had upper GI cancer
1 patient had ? radiation proctitis
1 patient had a colonic perforation
Hughes7 1997
Grade 3
25 with 30
episodes of use
60-90
3-185
Majority misoprostol,
others omeprazole
Malaena in patient age 81 after 22 days of 75mg
PR bleeding in patient age 67 after 27 days of 90 mg
Mean 20
Age 43-83
Bleeding resolved on stopping drug
De Conno8 1994
Grade 3
10
90-120
Fixed at 7 days
No comment
No comment except with regards to site
120
75
Misoprostol
None
40-73
Mean 56
Ripamonti9 1996
Grade 3
1
Age 48
APPENDIX 1
Cochrane Library search strategy (December 2008)
ID
Search
#1
Meloxicam
#2
Nabumetone
#3
Indometacin
#4
Indomethacin
#5
Dexibuprofen
#6
Fenbufen
#7
Dexketoprofen
#8
Tiaprofenic acid
#9
Azapropazone
#10 Aceclofenac acid
#11 Tenoxicam
#12 MeSH descriptor Anti-Inflammatory Agents, Non-Steroidal explode all
trees
#13 Ketorolac
#14 Ketorolac trometamol
#15 Aspirin
#16 Mefenamic acid
#17 Flurbiprofen
#18 Ibuprofen
#19 Naproxen
#20 Salicylate*
#21 Diclofenac
#22 Etodolac
#23 MeSH descriptor Cyclooxygenase 2 Inhibitors, this term only
#24 Celecoxib
#25 Etoricoxib
#26 Rofecoxib
#27 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10
OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26)
#28 (#23 OR #24 OR #25 OR #26)
#29 (#27 OR #28)
A list of the same NSAIDs and COX-2 selective drugs was used in similar
searches of the literature in Medline and Embase.
APPENDIX 2
Levels of Evidence______________________
________________
1++
High-quality meta-analyses, systematic reviews of randomised
controlled trials (RCTs), or RCTs with very low risk of bias
1+
Well-conducted meta-analyses, systematic reviews of RCTs, or
RCTs with a low risk of bias
1Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk
of bias
2++
High-quality systematic reviews of case-control or cohort studies or
high-quality case-control or cohort studies with a very low risk of
confounding, bias, or chance and a high probability that the
relationship is causal
2+
Well-conducted case-control or cohort studies with a low risk of
confounding, bias, or chance and a moderate probability that the
relationship is causal
2Case-control or cohort studies with a high risk of confounding, bias,
or chance and a significant risk that the relationship is not causal
3
Non-analytic studies, e.g., case reports, case series
4
Expert opinion
Keeley PW. Clinical Guidelines. Palliative Medicine 2003; 17: pp. 368-374
75
APPENDIX 3
Glossary of terms
Absolute risk reduction (ARR)1
The proportion by which an intervention reduces the risk of an event.
Bleeding time
A test of the time taken for blood to clot – assessed by making a cut on the
arm/earlobe and is usually 3-8 minutes.
Case-control study1
A retrospective study which looks at the relationship between a risk factor and
one or more outcomes. Patients are selected who already have the condition
or outcome (cases) and are matched to patients who do not (controls). The
effect of the risk factor is then compared between the 2 groups.
Cohort study1
A prospective, observational study that follows a cohort over a period of time
and investigates the effect of a treatment or risk factor.
Confidence Interval (CI)1
Statisticians can calculate a range (interval) in which we can be fairly sure
(confident) that the true population value lies. A 95% CI is commonly given
which implies that we can be 95% confident that the true population value lies
within that range. Note that the size of the CI is related to the sample size in
the study – larger studies usually have a narrower CI because the bigger the
study population, the closer we are to getting the true population’s value.
Hazard Ratio (HR)1
This is the ratio of the hazard (i.e chance of a harmful event happening) in
one group of observations divided by the hazard of the event in another
group. A HR of 2 implies twice the risk. The HR should be stated with its CI.
International Normalised Ratio (INR)
A standardised measure of Prothrombin Time (PT) based on the World Health
Organisation’s reference thromboplastin, where INR = 1 is normal
Meta-analysis 2
This is a way of collating results from a number of similar studies to give one
overall estimate of effect e.g relative risk. It can be considered a particular
type of systematic review that concentrates on the numerical results.
76
Number Needed to Harm (NNH)1
We can calculate the amount by which a treatment increases the risk of an
adverse event. The reciprocal of the difference in risk i.e 1 divided by the
additional amount of risk gives us the NNH. This is the number of patients that
need to be treated for 1 to be harmed by the treatment. The larger the NNH
the better.
Odds Ratio (OR)1
The odds of an event are obtained by dividing the number of people with an
event by the number who did not have the event. The odds ratio therefore is
worked out by dividing the odds of an outcome in one group by the odds of
the same outcome in a different group.
Prothrombin Time (PT) 3
The time taken for blood clotting to occur in a sample of blood to which
calcium and thromboplastin have been added. A prolonged PT indicates a
deficiency of coagulation factors. See also INR.
Relative Risk (RR)
In randomised controlled trials, this is the chance of an outcome while on a
specific treatment compared with the chance while on an alternative/no
treatment. It is worked out by dividing the rate of the event in one group of
study patients by the rate in another comparative group and is usually given
as a fraction or proportion.
Risk
This describes the likelihood of an event happening compared with the total
number of possible events e.g if 5 people out of 100 die the risk of death is
5%.
Systematic Reviews 2
These form an integral part of evidence-based medicine. They are a
formalised and stringent process of combining information from relevant
studies. The Cochrane Library contains a database of such reviews.
References
1. Harris M & Taylor G (eds). Medical Statistics Made Easy first edition.
London: Martin Dunitz, 2004
2. Petrie A & Sabin C (eds). Medical Statistics at a Glance second edition.
Oxford: Blackwell Publishing Ltd, 2005
3. Martin E (ed). Concise Colour Medical Dictionary. Oxford: Oxford
University Press, 1996
77
APPENDIX 4
Acknowledgements
The clinical guidelines group would like to thank Dr Patricia McGettigan,
Senior Lecturer in Medical Education and Medicine at Hull York Medical
School for her advice during the development of this document.
The group is also grateful to those who provided advice and comments during
the local peer-review process.
List of authors
Consultants in Palliative Medicine
Dr Katherine Lambert
Dr Lynne Russon
Advanced Pharmacist in Palliative Care and Pain
Sue Ayers
Specialist Registrars in Palliative Medicine
Dr Milind Arolker
Dr Julia Barnes
Dr Lucy Close
Dr Amy Gadoud
Dr Adam Hurlow
Dr Lucy Nicholson
Dr Clare Rayment
Dr Carina Saxby
Dr Jenny Smith
Dr Rachel Sorley
78
79