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NSAID Regional Audit Group

Presentation

Audit Group: Dr Richard Latten, Ruth Clark,

Dr Sarah Fradsham, Dr Seamus Coyle,

Claire Johnston

Thank you from the audit group for all who

participated in the data collection for this audit.

Our External/ Expert reviewers unfortunately cannot

make it today but have and will be involved in the

refinements of the S&G

Andrew Dickman, Dr Victor Pace.

Agenda

• Current Standards and Guidelines (CJ)

• Literature Review (SC)

• Audit method and results (RC)

• Proposed updated Standards and Guidelines

(RL)

• Questions and discussion

NSAIDs

Current Standards and Guidelines

Claire Johnston

Community SPC CNS

General principles

• Non-steroidal anti-inflammatory drugs (NSAIDs) consist

of a heterogenous group of compounds that can be

subdivided by virtue of their pharmacology;

-Non-selective NSAIDs inhibit both COX-1 and COX-2

receptors e.g. ibuprofen, naproxen.

-COX-2 selective NSAIDs display some selectivity for

COX-2 receptors but this diminishes as the dose

increases e.g. etodolac, meloxicam.

-COX-2 inhibitors specifically inhibit COX-2 receptors at

therapeutic doses whilst being COX-1 sparing e.g.

celecoxib, etoricoxib.

General principles

• All NSAIDs have significant cardiovascular and

gastrointestinal toxicity.

• Consider whether alternative treatment would be

appropriate (e.g. topical NSAIDs, paracetamol, tramadol).

• Prescribe the lowest possible dose of NSAID for the

shortest possible time necessary.

Current guidelines –

Cardiovascular Risk

• COX-2 inhibitors are contraindicated for use in patients with established ischaemic heart disease and/or cerebrovascular disease, and also in patients with peripheral arterial disease.[Level1]

• Despite conflicting evidence, non-selective NSAIDs and COX -2 selective are currently licensed for use in these groups of patients, although they should be used with caution. [Level 4]

Current guidelines- Renal

Dysfunction

• Renal function should be assessed prior to the introduction of an NSAID and within 7 days of starting treatment or increasing the dose.[Level 4]

• Care is required when prescribing NSAIDs for patients with heart failure, ascites or impaired renal function, particularly those who are dehydrated or have a low effective circulating volume. [Level 4]

Current guidelines- Renal

Dysfunction

• Long term administration of NSAIDs has been linked to papillary

necrosis and other renal injuries. Patients with impaired renal

function, heart failure, liver dysfunction, the elderly and those

taking diuretics and/or angiotensin-converting enzyme inhibitors

are at greatest risk from this reaction. Discontinuation of NSAIDs

therapy is usually followed by recovery to the pre-treatment

state.[Level 4]

• Use of NSAIDS in patients with advanced renal disease is not

recommended due to a lack of safety data from controlled

clinical studies. If NSAIDs are prescribed it is essential that renal

function is monitored closely.[Level 4]

Current guidelines-

Gastrointestinal Toxicity

• Patients at high risk of gastrointestinal side effects from NSAIDs include the following;[Level 4]

- Elderly (age>65 years),

-Previous upper gastroduodenal perforation,ulcers and bleeds.

-Concurrent use of aspirin, warfarin,corticosteroids or selective serotonin reuptake inhibitors (SSRIs)

-Patients receiving maximum doses of NSAIDs.

• Undesirable gastric side effects from celecoxib are significantly less than from non-selective NSAIDs although it is not clear whether this lower risk continues with long term use.[Level 4]

• In patients taking clopidogrel, it is advisable to use an H2 antagonist at a higher dose than usual e.g. ranitidine 300mgs bd. [Level 4]

Current Guidelines PPIs

• A PPI should be co-prescribed with a NSAID, regardless of

which actual drug is chosen. [Level 4]

• This is cost effective in the treatment of Osteoarthritis, but the

benefit of a PPI with a COX-2 inhibitor in other situations is

unclear. [Level 4]

• The relationship between H. pylori infection and NSAIDs in

duodenal pathology is complex. Eradication of H pYlori infection

may prevent peptic ulcer disease in patients who are naiive

users of NSAIDs. Patients receiving long term PPI treatment for

prevention of NSAID ulcers should be tested for H Pylori.

Eradiction of H Pylori will reduce the risk of accelerated loss of

specialised glands and atrophic gastritis. [Level 4]

Current Guidelines- PPI

• Appropriate PPIs and oral doses include:

- Esomeprazole 20mg od

- Lansoprazole 30mg od

- Omeprazole 20mg od

- Pantoprazole 40mg od

• Misoprostol is a synthetic prostaglandin analogue with gastric

anti-secretory and protective properties which can be used to

protect against NSAID-induced gastrointestinal damage. It is

more effective than PPIs but can be poorly tolerated. Side

effects include colic and diarrhoea. A suggested starting dose is

200mcg od, increasing by 200mcg every 1-2 days to a normal

dose of 200mcg qds.

Current Guidelines- Choice of

NSAID

• Before deciding which NSAID to use, the prescriber must first

asses patient risk factors for cardiovascular and gastrointestinal

toxicity (figure 29.1) [Level 4]

• Table 29.1 lists NSAIDs currently recommended for use.

• Table 29.2 lists additional NSAIDs that may be considered

second line options. [Level 4]

Current Guidelines-

Monitoring Effectiveness

• NSAIDs should be presribed for at least seven days before

reviewing their clinical effectiveness. The analgesic effect of the

drug becmes apparent within the first few days of treatment. The

anti-inflammatory response may take at least 2 weeks to

become evident. [Level 4]

• It may be appropriate to use an alternative NSAID before

concluding that NSAIDs are ineffective. [Level 4]

• Due to the increased risk of renal and gastroduodenal toxicity,

ketorolac should only be used for refractory pain. A PPI should

always be co-prescribed with ketorolac unless the patient is in

the dying phase. [Level 4]

Current Standards.

1. Cox-2 inhibitors are contra-indicated for use in patients with

existing ischaemic heart, peripheral vascular disease or

cerebrovascular disease [GradeB]

2. In patients with existing cardiovascular disease, alternate

analgesia should be considered before introducing a non-

selective NSAID or a COX-2 selective NSAID. If NSAID’s are to

be used the lowest dose possible should be prescribed and the

patient should be reviewed within 7 days. [Grade D]

3. It may be appropriate to use an alternative NSAID before

concluding that NSAIDs are ineffective. [Grade D]

Current Standards

4. Patients with risk factors for gastrointestinal toxicity should be

prescribed proton pump inhibitors or misoprostol for gastric

protection [Grade B]

5. A PPI should be prescribed for all patients receiving

subcutaneous NSAID’s, unless they are in the dying

phase.[Grade D]

6. Renal function should be assessed prior to the introduction of a

NSAID and within 7 days of starting treatment or increasing the

dose. [Grade D]

Table 29.1- NSAIDS currently

recommended for use

Class

of

NSAID

Name of

drug

Oral dose CSCI over

24 hours

Additional notes

Non-

selective

Naproxen 500mg bd n/a Suitable 1st line choice, together

with PPI for patients with CV risk

Non-

selective

Ibuprofen 400mg-

800mg tds

n/a Low dose brufen(<1200mgs)

suitable1st line choice, together

with PPI, for patients with CV risk.

If low dose aspirin is co-

prescribed, ibuprofen should be

given at least 8 hours before or

30 minutes after. Alternatively,

Change aspirin to clopidogrel.

COX-2

inhibitor

Celecoxib 100-200mg

bd

n/a Suitable 1st line choice in patients

at high risk of GI toxicity and low

CV risk. PPI should be co-

prescribed in high GI risk

patients.

Table 29.2. Additional NSAIDs avaliable for

use [Level 4]

Class of

NSAID

Name of

drug

Oral

dose

CSCI

over 24

hours

Additional notes

Non-

selective

Diclofenac

sodium

50mg tds

75mg m/r

bd

Painful.

Dose

150mg

daily

150mg daily via rectal route. Diclofenac is

associated with similar thrombotic risk to

COX-2 inhibitors

Non-

selective

Nabumetone 500mg

od-1g bd

n/a/ Lowest GI risk of all non-selective NSAIDS.

Some units may user first line.

Non-

selective

Ketorolac n/a/ 30mg-

90mg

Can give 10mg stat subcutaneous dose.

Carries greater risk of renal and

gastrointestinal toxicity compared to other

NSAIDs. Due to the propensity for toxicity,

the continued need for a CSCI of ketorolac

should be reviewed on a weekly basis.

Non

selective

Piroxicam

melt

20mg od

S/L

Increased risk of GI toxicity and

serious skin reactions. Not to be

used for first line treatment.

Table 29.2 Cont

Class of

NSAID

Name of

drug

Oral dose CSCI over

24 hours

Additional notes

COX-2

selective

Etodolac 600mg m/r od n/a n/a

COX-2

inhibitor

Etoricoxib 60mg-120mg

od

n/a NICE do not recommend

etoricoxib for first line

use in osteoarthritis. For

this reason, consider as

2nd line choice.

Consider whether alternative treatment would be appropriate

Assessment of cardiovascular (CV) history

No CV History CV History

Assessment of gastrointestinal (GI)

risk factors

Assessment of gastrointestinal (GI)

risk factors

Low GI Risk >1 GI Risk Low GI Risk >1 GI Risk

List A List B List C List D

Figure 29.1 – Flow diagram of NSAID

choice

Table 29.3. Choice of NSAID according to

CV history and GI risk factors

Step List A

No CV history

No GI risk

List B

No CV history

GI risk

List C

CV history

No GI risk

List D

CV history

GI risk

1 Alternative analgesia

e.g. topical NSAID,

paracetamol, tramadol

Alternative analgesia

e.g. topical NSAID,

paracetamol, tramadol.


e.g. topical NSAID

paracetamol,

tramadol.


e,.g. topical NSAID,

paracetamol, tramadol.

2 Low dose ibuprofen

(<1200mg/day) +PPI or

Nabumetpone plus PPI

COX-2 Inhibitor

e.g. celecoxib + PPI

Low dose ibuprofen

(<1200mg/day) +PPI

or naproxen +PPI

Low dose ibuprofen

(<1200mg/day) +PPI or

naproxen + PPI

3 Non-selective NSAID

e.g. diclofenac + PPI or

naproxen + PPI

COX-2 inhibitor e.g.

etoricoxib + PPI

Non selective NSAID

e.g. nabumetone +

PPI

Non selective NSAID e.g.

nabumetone + PPI

4 COX-2 selective

NSAID e.g. etodolac +

PPI

Low dose ibuprofen

(1200mgs/day) + PPI or

nabumetone plus PPI

5 COX-2 inhibitor e.g.

celecoxib

COX-2 selective NSAID

e.g. etodolac + PPI

NSAID Audit

-Literature Review

Dr Seamus Coyle

Academic Clinical Fellow

Overview

• Literature search

• Rational of NSAIDs

– including indications

• NSAIDs in non-cancer conditions

• Topical NSAIDs

• Risks/Side effects of NSAIDs

• Palliative Overview

Literature Search

• Literature Survey of NSAIDs over the last 5

years

– 105 NSAID review articles

• all articles for ‘NSAIDs and Palliative care’

• The Cochrane library

• NICE guidelines

Rational of NSAIDs

• NSAIDs more effective than placebo for cancer pain

– Cancer pain = as a result of the cancer itself, a side effect of therapy or procedures or unrelated to the cancer

• Clear evidence to support safety or efficacy of one NSAID over another is lacking

• Slight but statistically significantly advantage (9 out of 14 papers) combining Paracetamol with a NSAID compared with either single entity

NSAIDs or Paracetamol, alone or combined with opioids for cancer pain Cochrane Review 2011 McNicol ED Strassels S, Goudas L, Lau J, Carr DB

• 13 out of 14 studies found no difference or low clinical difference when combining an NSAID plus an opioid versus either drug alone. 4 papers increased efficacy with increased dose - the majority of studies were of less than 7 days duration

• No studies addressed use of COX2 inhibitors to manage cancer pain

• Meta-analysis of 4 trials demonstrated significantly lower proportion of patients reported adverse events while being administered NSAIDs vs opioids (OR=0.38 [95% CI, 0.15 to 0.97]


• Short duration of studies undermines generalisation of their findings on efficacy and safety of NSAIDs for cancer pain

• the use of NSAIDs for cancer pain is widely recommended, the long term safety profile of NSAIDs in patients with cancer has not been established in a randomised study.

• WHO recommends addition of a 'weak' opioid for mild to moderate pain. ..findings do not substantiate this recommendation. It may be advisable to increase to a maximum acceptable dose of their NSAIDs (or adjuvant drug) before the addition of, or replacement with, an opioid.


Advice to Healthcare professionals

• Patients should use the lowest effective dose and the shortest duration of NSAID treatment necessary to control symptoms, and the need for long-term treatment should be reviewed periodically

• NSAIDs increase the risk of Cardiovascular events but that the balance of benefits to risks remained favourable

MHRA Public Assessment Report Jan 2010

NSAIDs in non-cancer conditions

Pharmacological management of osteoarthritis*

• When paracetamol/topical NSAIDs ineffective for pain

relief,

– substitution with an oral NSAID/COX-2 inhibitor

should be considered.

• Where paracetamol/topical NSAIDs provide insufficient

pain relief

– addition of an oral NSAID/COX-2 inhibitor to

paracetamol should be considered.

• Oral NSAIDs/COX-2 inhibitors should be used at the lowest

effective dose for the shortest possible period of time.

*Pharmacological management of osteoarthritis NICE Guidelines 2008

Pharmacological management of

osteoarthritis*

• First choice should be either a standard NSAID or a

COX-2 inhibitor (other than etoricoxib 60 mg)

– co-prescribed with a PPI



osteoarthritis*

• All oral NSAIDs/COX-2 inhibitors have analgesic

effects of a similar magnitude but vary in their potential

gastrointestinal, liver and cardio-renal toxicity;

– take into account individual patient risk factors,

including age.

– appropriate assessment and/or ongoing monitoring of

these risk factors.



osteoarthritis*

• When patient needs to take low-dose aspirin and pain

relief is ineffective or insufficient

• consider other analgesics before substituting or adding

an NSAID / COX-2 inhibitor (with a PPI)


Oral analgesics

• Paracetamol and/or topical non-steroidal anti-

inflammatory drugs (NSAIDs) should be considered ahead

of oral NSAIDs / COX-2 inhibitors or opioids.

• If paracetamol or topical NSAIDs are insufficient for pain

relief then the addition of

– opioid analgesics should be considered.

• Risks and benefits should be considered

• particularly in the elderly

Pharmacological management of osteoarthritis NICE Guidelines 2008

NSAIDs and highly selective COX-2 inhibitors

• Increased role for COX-2 inhibitors, with an increased

awareness of all potential adverse events

(gastrointestinal, liver and cardio-renal) and a

recommendation to co-prescribe a PPI.*

• based on up-to-date evidence on efficacy, adverse

events, current costs and an expanded health-

economic analysis of cost effectiveness.*


NSAIDs may be tolerated in patients with mild

chronic liver disease but should be avoided in

all patients with cirrhosis because of increased

risk of hepatorenal syndrome

Pain Management in the Cirrhotic patient Chandok Watt 2010 Mayo Clin Proc.

2010 May;85(5):451-8.

Topical NSAIDs

• Topical NSAIDs can provide good levels of pain relief in acute

conditions such as sprains, strains and overuse injuries*

– Probably similar to that provided by oral NSAIDs.

– Little difference in analgesic efficacy between diclofenac, ibuprofen,

ketoprofen and piroxicam but indomethacin is less effective, and

benzydamine is no better than placebo.

– No increased incidence of local reactions compared to placebo

– Do not cause systemic problems

* Topical NSAIDs for acute pain in adults (review) The Cochrane Collaboration 2012

• Topical NSAIDs can provide good levels of pain relief*

– without the systemic adverse events associated with oral NSAIDs

– when used to treat acute musculoskeletal conditions.

• No serious adverse events reported in studies reviewed*

* Topical NSAIDs for acute pain in adults (review) The Cochrane Collaboration 2012

Risks/Side effects of NSAIDs

• All NSAID users may be at an increased CV risk, irrespective of their baseline risk for cardiovascular illness or the duration of NSAID use


• Since 2006 2 important studies have been published which examine the risk of thrombotic cardiovascular events, such as MI in association with NSAIDs. (non-selective NSAIDs and COX-2 inhibitors) – UK THIN (The Health Improvement Network)

– Danish group


• Both studies found a very small increase in the risk of CVS events..that may apply to all users of NSAIDs, not only those with baseline CVS risk factors ..after a relatively short-term NSAID use (that may increase with increasing duration of use). association with the following specific NSAIDs;

• celecoxib (any dose); high dose diclofenac (>150mg/day); high dose ibuprofen (>1200mg/day)

• No detectable effect on CV risk was demonstrated for another specific NSAID, naproxen, at any dose.


• Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

• Cardiovascular outcomes with etoricoxib and diclofenac in patients

with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

• Cannon et al The Lancet 2006 Vol 368 p1771 – 1781

Rationale for discontinuing Cox-2 inhibitors*

• VIGOR Study – significantly higher incidence of

cardiovascular thrombotic events with rofecoxib cf

naproxen (Bombardier et al NEJM 2000) 5 fold increase

risk of MI

• APPROVE study confirmed above – evaluated

adenomatous polyps in patients treated with rofecoxib ct

placebo. 2 fold increase MI risk (Bresalier et al NEJM 2005)

• Meta-analysis of Rofecoxib (Juni Lancet 2004)

• Rofecoxib and valdecoxib withdrawn * Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr

2008 Mar-Apr;19(2):102-7.

Rationale for discontinuing Cox 2 inhibitors*

• No increase in cardiovascular events or all cause mortality

was observed for celecoxib vs diclofenac, ibuprofen and

naproxen (Varas-Lorenzo et al 2007)

• Pooled analysis no increase CVS events with celecoxib but at

higher doses higher risk of MI (Juni et al Br Med J 2002)

• risk of death and recurrent CHF combined was higher in

patients prescribed NSAIDs or rofecoxib than in those

prescribed celecoxib

* Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr 2008

Mar-Apr;19(2):102-7.

• Cox-2 inhibitors appear to be prescribed preferentially to patients

who were at an increased risk of cardiovascular events compared

with patients prescribed non-specific NSAIDs*

• When the overall risk of CVS complications is relatively low and

an anti-inflammatory agent is required, current evidence suggests

that celecoxib is an agent of choice because of its lower

cardiovascular toxicity potential compared to NSAIDs and other

Cox-2 inhibitors *

• Most patients, particularly the young, can benefit from NSAIDs

without the risk of serious adverse GI or CVS events... previous

history of serious GI complications and the elderly .. do require

alternatives*

* Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr

2008 Mar-Apr;19(2):102-7.

• South African Rheumatoid Arthritis Association Guidelines

Nov 2005 - Cox-2 inhibitors for elderly patients (>60) with

previous gastropathy and those on warfarin and / or

corticosteroids, providing they do not have

contraindications.

• Caution prescribing Cox-2 inhibitors for patients with risk

factors for heart disease

• Celecoxib does not increase small intestinal permeability

and does not cause lower intestinal bleeding

* Review of the CVS safety of CoxiBs compared to NSAIDs Moodley Cardiovasc J Afr

2008 Mar-Apr;19(2):102-7.

A Palliative Overview

• There were no studies with NSAIDs and

Palliative Care / EOL care

• Long term safety profile of NSAIDs in patients

with cancer has not been established in a

randomised study.

• No studies addressed use of COX2 inhibitors

to manage cancer pain

NSAIDs

Results of Prospective Survey

Ruth Clark

Pharmacist

Audit Methodology

• Prospective audit on patients newly commenced or

admitted on NSAIDs or COX-2 Inhibitors

• Standardised paper audit tool that could be

completed electronically or by hand (not survey

monkey)

• Included all the regional ICNs and completed by any

member of the MDT

• Data collected between 29th October 2012 – 7th

December 2012, i.e. total of 6 weeks

ICN

0

5

10

15

20

Aintre

e

Halton

Isle o

f Man

Liverp

ool

St H

elens a

nd...

West

ern C

heshire

WLS

&F

Wirr

al

Warri

ngton

Unknow

n

Total of 58 responses

Setting

0 5 10 15 20 25

SPC In

patientHospita

lHom

eOutp

atient

Gender

24

31

3

Male

Female

Unkown

Age

58

0123456789

10111213141516

<40yrs 40-54yrs 55-64yrs 65-74yrs >75yrs Unknown

Diagnosis

28

2

28

Cancer

Non-cancer

Unknown

Non Cancer: systemic sclerosis and end stage COPD

Indication

7

10

10

62

34

Bone Pain

Visceral pain

NeuropathicPainInflammatoryPainUnknown

Other

Indications

One 49

Two 7

Three 2

Choice of NSAID/COX-2 Inhibitor

0

2

4

6

8

10

12

14

16

Ibuprofen Naproxen Nabumetone

Diclofenac Etoricoxib Etodolac Celecoxib Piroxicam Ketorolac

sc

400mg tds

200mg tds

120mg od

90mg od

60mg od

Arthrotec

Rectal

200mg bd

100mg bd

Oral

First NSAID/COX-2 Inhibitor? Tried (changed to):

Naproxen → celecoxib

Ibuprofen → celecoxib

Celecoxib → nabumetone

Meloxicam → arthrotec 75

Celecoxib & Ibuprofen →nabumetone)

Celecoxib→ etoricoxib

Ibuprofen → Ketorolac → naproxen

Ibuprofen, naproxen → diclofenac

Ibuprofen→ (diclofenac mr)

10

9

39

Yes

No

Unknown

How long has the patient been on this

NSAID/COX-2 Inhibitor?

0

2

4

6

8

10

12

14

16

18

20

22

24

Newly

Started

<1 week 1 wk -

1month

1month -

6months

6months - 1

yr

>1 year Unknown

Who initially prescribed this NSAID/Cox-

2 Inhibitor?

11

9

16

10

40

53

GP

Palliative Care Team

(Community)Hospital Specialist Palliative

Care TeamPalliative Care Team

(Hospice)Hospital Team (non Palliative

Care)Pain Specialist

Unknown

Other

Co-Morbidities

Co-morbidity No of Patients

Ischaemic Heart Disease 5

Peripheral vascular disease 1

Cerebrovascular disease 0

Peptic ulcer disease 0

Renal Impairment 7 (eGFR range 13-78ml/min)

Standard 1: Cox-2 inhibitors are contraindicated for

use in patients with existing ischaemic heart disease,

peripheral vascular disease or cerebrovascular

disease

• Patients with ischaemic heart disease were prescribed

– Etoricoxib, ibuprofen x 2, diclofenac and arthrotec

– Patient on arthrotec had previously been on meloxicam

– Patient on etoricoxib had previously been on celecoxib

• Patient with peripheral vascular disease was prescribed Ibuprofen

Standard 2: In patients with existing cardiovascular

disease, alternative analgesia should be considered

before introducing a non-selective NSAID or a COX-2

selective NSAID (e.g. paracetamol, tramadol, topical

NSAID).

• Of the five patients:

– 3 were prescribed paracetamol

– 5 were prescribed an opiate (one tramadol)

– 1 was prescribed amitriptyline

Concurrent Analgesics

Drug Number of patients

Paracetamol 43

Codeine 7

Tramadol 1

Morphine 26

Oxycodone 24

Pregabalin 16

Gabapentin 4

Topical NSAIDs 0

Ketamine 1

Fentanyl patch 4

Amitriptyline 3

Lidocaine Patch 2

Alfentanil 1

Clonazepam 1

Number of analgesics prescriber per patient

No of analgesics Number of patients

None 1

One 11

Two 25

Three 17

Four 4

Concurrent Analgesics

Concurrent Medication (which will

increase risk of bleeding) 3

4

20

13

21 1

SSRI

Mirtazapine

Steroid

LMWH

Aspirin

Clopidogrel

Warfarin

No of

medica

tions

No of

pts

None 24

One 24

Two 10

Other cautions/precautions

47

5

5

No Yes Unknown

Risk Factors: •COPD

•Dyspepsia

•Alcohol Excess

•Active Chemo

•Low Hb

Patients not prescribed gastroprotection

4

54On PPI Not on PPI

4 patients not on

a PPI:

•3 low GI risk

•1 pt declined

Standard 4: Patients with risk factors for GI

toxicity should be prescribed PPI or

misoprostal for gastric protection

Gastro-protection used

2 2 26 4

0 7 8 3

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Lansoprazole

Omeprazole

No dose

15mg L / 20mg O

30mg L / 40mg O

60mg L / 80mg O

One patient on omeprazole and misoprostal (part of arthrotec)

Was renal function checked prior to

treatment?

Yes, 30

No, 10

Admitted

on trt, 4

Unknown,

14

eGFR range:

34->90ml/min

Standard 6: Renal function should be assessed

prior to the introduction of a NSAID and within

7 days of starting treatment or increasing the dose

When was renal function checked after

commencement?

0

2

4

6

8

10

12

14

16

18

20

22

1-3 days 4-7 days 8-14 days >14 days Not

Checked

Admitted on

trt

Unknown

Standard 6: Renal function should be assessed

prior to the introduction of a NSAID and within

7 days of starting treatment or increasing the dose

When was treatment reviewed after

commencement?

0

2

4

6

8

10

12

14

16

18

20

1-3 days 4-7 days 8-14 days >14 days Not

Checked

Admitted on

trt

Unknown

Was treatment continued?

7

37

3

3

11

2

4

Yes - full relief of pain Yes- partial relief of pain No - no relief from pain No - renal function declined

No - alternative to be tried No - gastric side effects No - other Unknown

Summary - Standards

1. COX-2 inhibitors are contraindicated for use in patients with existing ischaemic heart disease, peripheral vascular disease or cerebrovascular disease

• One patient was prescribed a COX-2 with IHD

2. In patients with existing cardiovascular disease, alternative analgesia should be considered before introducing a non-selective or a COX-2 selective NSAID. If NSAIDs are to be used, the lowest dose possible should be prescribed and the patient should be reviewed within 7 days

• All five patients prescribed co-analgesics

3. It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective.

• At least 10 patients had tried a previous NSAID and one patient was going to try another following the audit

Summary - Standards

4. Patients with risk factors for gastrointestinal toxicity should be prescribed proton pumps or misoprostol for gastric protection

• All patients with risk factors were prescribed a PPI

5. A PPI should be prescribed for all patients receiving subcutaneous NSAIDs, unless they are in the dying phase.

• Patient on sc ketorolac was prescribed lansoprazole

6. Renal function should be assessed prior to the introduction of a NSAID and within 7 days of starting treatment or increasing the dose.

• 51% (30) had their renal function checked before treatment, 41% (24) had their renal function checked within 7 days

NSAIDs

Proposed updated Standards and

Guidelines

Dr Richard Latten

Consultant in Palliative Medicine

General Principles

• Cyclo-oxygenase (COX) 1 and 2 are involved in the

inflammatory pathways. COX 1 is primarily involved in

homeostatic functions including platelet function,

gastroprotection and the maintenance of renal function.

COX 2 is primarily involved in inflammation but also has

some homeostatic functions . See figure 29.1

• Figure 29.1 Will give a summary of the COX 1

and COX 2 pathways

Figure 29.1 – Cyclo-oxygenase pathways

82

Arachidonic Acid

COX- 1 COX- 2

HOMEOSTATIC FUNCTIONS

e.g gastroprotection, renal function, platelet aggregation

INFLAMMATION

General principles

• Non-steroidal anti-inflammatory drugs (NSAIDs) consist

of a heterogenous group of compounds that can be

subdivided by virtue of their pharmacology;

-Non-selective NSAIDs inhibit both COX-1 and COX-2

receptors e.g. ibuprofen, naproxen.

-COX-2 selective NSAIDs display some selectivity for

COX-2 receptors but this diminishes as the dose

increases e.g. etodolac, meloxicam.

-COX-2 inhibitors specifically inhibit COX-2 receptors at

therapeutic doses whilst being COX-1 sparing e.g.

celecoxib, etoricoxib.

General principles

• All NSAIDs have cardiovascular and gastrointestinal

toxicity.

• Indications for NSAIDs include:

– Bone Pain

– Musculoskeletal Pain

– Inflammatory conditions (including OA and RA)

– Paraneoplastic Pyrexia and Sweating

– Fever

General principles

• The WHO analgesic ladder recommends NSAIDs be

considered as an adjunct in each step if appropriate.

• It is recommended that in the first instance consideration

is made as to whether an alternative treatment would be

appropriate (e.g. topical NSAIDs, paracetamol, tramadol,

?Pregabalin).

• It is recommended that the lowest possible dose of NSAID

be precribed for the shortest possible time necessary.

Guidelines – Cardiovascular Risk

• COX-2 inhibitors are contraindicated for use in patients with established ischaemic heart disease and/or cerebrovascular disease, and also in patients with peripheral arterial disease.[Level1]

• Despite conflicting evidence, non-selective NSAIDs and COX -2 selective are currently licensed for use in these groups of patients, although they should be used with caution. [Level 4]

• Diclofenac is associated with similar thrombotic risks as COX 2 inhibitors. [Level 1]

• All NSAIDs are contraindicated in patients with severe heart failure. [Level 1]

Guidelines – Cardiovascular Risk

• Etoricoxib may be associated with more frequent and

severe effects on blood pressure than some other COX-2

inhibitors and NSAIDs, particularly at high doses.

Etoricoxib treatment should therefore not be initiated in

patients whose hypertension is not under control and

careful monitoring of blood pressure is advised for

patients taking etoricoxib. [Level 1]

• NSAIDs differ in their effect on platelet function and bleeding

time. Some non-selective NSAIDs whilst not having an

antiplatelet effect do interfere with the action of Aspirin. [Level 1]

Guidelines- Renal

Dysfunction

• Renal function should be assessed prior to the introduction of an NSAID and within 7 days of starting treatment or increasing the dose.[Level 4]

• Care is required when prescribing NSAIDs for patients with heart failure, ascites or impaired renal function, particularly those who are dehydrated or have a low effective circulating volume. [Level 4]

Guidelines- Renal

Dysfunction

• Long term administration of NSAIDs has been linked to papillary

necrosis and other renal injuries. Those patients at greater risk

of this reaction include: [Level 4]

– impaired renal function,

– heart failure,

– liver dysfunction,

– the elderly

– Concurrent use of angiotensin-converting enzyme

(ACE) inhibitors, diuretics or Angiotensin 2 receptor

blockers .

• Discontinuation of NSAIDs therapy is usually followed by

recovery to the pre-treatment state.[Level 4]

Guidelines- Renal

Dysfunction

• Use of NSAIDS in patients with advanced renal disease is

not recommended due to a lack of safety data from

controlled clinical studies. If NSAIDs are prescribed it is

essential that renal function is monitored closely.[Level 4]

Guidelines- Gastrointestinal

Toxicity

• Patients at high risk of gastrointestinal side effects from

NSAIDs include the following;[Level 4]

- Elderly (age>65 years),

-Previous upper gastroduodenal perforation,ulcers

and bleeds.

-Concurrent use of aspirin, warfarin,corticosteroids or

selective serotonin reuptake inhibitors (SSRIs)

-Patients receiving maximum doses of NSAIDs.


Toxicity

• Of the non selective NSAIDs, low dose ibruprofen is

associated with the lowest GI risk.[Level 1]

• Undesirable gastric side effects from celecoxib are

significantly less than from non-selective NSAIDs

although it is not clear whether this lower risk continues

with long term use.[Level 4]


Toxicity

• In patients taking clopidogrel, it is advisable to use an H2

antagonist at a higher dose than usual e.g. ranitidine

300mgs bd or Lansoprazole 30mg od for gastric

protection. Omeprazole and Esomeprazole should be

avoided due to the potential for interactions. [Level 4]

Guidelines PPIs

• A PPI should be co-prescribed with a NSAID including COX-2

inhibitor, regardless of which actual drug is chosen. [Level 4]

• The relationship between H. pylori infection and NSAIDs in

duodenal pathology is complex. Eradication of H pYlori infection

may prevent peptic ulcer disease in patients who are naiive

users of NSAIDs. Patients receiving long term PPI treatment for

prevention of NSAID ulcers should be tested for H Pylori.

Eradiction of H Pylori will reduce the risk of accelerated loss of

specialised glands and atrophic gastritis. [Level 4]

Guidelines- PPI

• Appropriate PPIs and oral doses include:[Level 4]

- Lansoprazole 30mg od

- Omeprazole 20mg od

- Pantoprazole 40mg od

- Esomeprazole 20mg od

• Misoprostol is a synthetic prostaglandin analogue with gastric anti-secretory and protective properties which can be used to protect against NSAID-induced gastrointestinal damage. It is more effective than PPIs but can be poorly tolerated. Side effects include colic and diarrhoea. A suggested starting dose is 200mcg od, increasing by 200mcg every 1-2 days to a normal dose of 200mcg qds. Some combined preparations are avaliable e.g Napratec (Naproxen and Misoprostol). [Level 1]

Guidelines- Choice of NSAID

• Before deciding which NSAID to use, the prescriber must

first asses patient risk factors for cardiovascular and

gastrointestinal toxicity (figure 29.1) Figure 29.2 then

recommends first line and second line options for NSAIDs

depending on these risk factors. [Level 4]

• Table 29.1 lists NSAIDs currently avaliable for use along

with cautions and recommended doses.[Level 4]

Guidelines- Monitoring

Effectiveness

• NSAIDs should be presribed for at least seven days before

reviewing their clinical effectiveness. The analgesic effect of the

drug becmes apparent within the first few days of treatment. The

anti-inflammatory response may take at least 2 weeks to

become evident. [Level 4]

• It may be appropriate to use an alternative NSAID before

concluding that NSAIDs are ineffective. [Level 4]

• Due to the increased risk of renal and gastroduodenal toxicity,

ketorolac should only be used for refractory pain. A PPI should

always be co-prescribed with ketorolac unless the patient is in

the dying phase. [Level 4]

Standards.

1. Cox-2 inhibitors are contra-indicated for use in patients with

existing ischaemic heart, peripheral vascular disease or

cerebrovascular disease. All NSAIDS are contraindicated for

use in patients with severe heart failure.[GradeB]

2. In patients with existing cardiovascular disease, alternate

analgesia should be considered before introducing a non-

selective NSAID or a COX-2 selective NSAID. If NSAID’s are to

be used the lowest dose possible should be prescribed and the

patient should be reviewed within 7 days. [Grade D]

3. It may be appropriate to use an alternative NSAID before

concluding that NSAIDs are ineffective. [Grade D]

Standards

4. All patients prescribed NSAIDS should be prescribed proton

pump inhibitors or misoprostol for gastric protection [Grade B]

5. A PPI should be prescribed for all patients receiving

subcutaneous NSAID’s, unless they are in the dying

phase.[Grade D]

6. Renal function should be assessed prior to the introduction of a

NSAID and within 7 days of starting treatment or increasing the

dose. [Grade D]

Consider whether alternative treatment would be appropriate e.g topical

NSAID, paracetamol

Assessment of cardiovascular (CV) history

No CV History CV History

Assessment of gastrointestinal (GI) risk

factors

Assessment of gastrointestinal (GI) risk

factors

Low GI Risk >1 GI Risk Low GI Risk 1 > GI Risk

Figure 29.2 – Flow diagram of NSAID choice

101

Involve patient / relative in discussions regarding benefit vs risk of proposed NSAID

Step List A

No CV history

Low GI risk

List B

No CV history

GI risk

List C

CV history

Low GI risk

1 Low dose

ibuprofen

(<1200mg/day)

+PPI or

Nabumetone plus

PPI

COX-2 Inhibitor

e.g. celecoxib + PPI

Low dose ibuprofen (<1200mg/day) +PPI or

naproxen +PPI

2 Non-selective

NSAID e.g.

naproxen + PPI

COX-2 inhibitor e.g.

etoricoxib + PPI

Non selective NSAID e.g. nabumetone + PPI

Table 29.1- NSAIDS currently avaliable

for use

Class of

NSAID

Name of

drug

Route Dose Additional notes

COX-2

inhibitor

Celecoxib Oral 100-200mg bd Suitable 1st line choice in

patients at high risk of GI

toxicity and low CV risk. PPI

should be co-prescribed in

high GI risk patients.

COX-2

selective

Etodolac Oral 600mg m/r od n/a

COX-2

inhibitor

Etoricoxib Oral 30-90mg od NICE do not recommend

etoricoxib for first line

use in osteoarthritis. For

this reason, consider as

2nd line choice. May be

associated with

hypertension.

Table 29.1- NSAIDS currently avaliable for

use

Class of

NSAID

Name of

drug

Oral dose Dose Additional notes

Non-

selective

Diclofenac

sodium

Oral 50mg bd

75mg m/r bd

NOT RECOMMENDED FOR USE

DUE TO CARDIOVASCULAR AND

GI RISKS

Non-

selective

Ibuprofen Oral 400mg tds Low dose ibruprofen (<1200mg)

suitable1st line choice, together with

PPI, for patients with CV risk. If low

dose aspirin is co-prescribed,

ibuprofen should be given at least 8

hours before or 30 minutes after.

Alternatively, Change aspirin to

clopidogrel.

Non-

selective

Ketorolac S/C 30mg-90mg

via syringe

pump over

24hrs

Can give 10mg stat subcutaneous

dose. Carries greater risk of renal and

gastrointestinal toxicity compared to

other NSAIDs. Due to the propensity

for toxicity, the continued need for a

CSCI of ketorolac should be reviewed

on a weekly basis.

Table 29.1 NSAIDs currently avaliable for

use [Level 4]

Class of

NSAID

Name of

drug

Route Dose Additional notes

Non-

selective

Nabumetone Oral 500mg od-

1g bd

Lowest GI risk of all non-selective

NSAIDS. Some units may user first line.

Non-

selective

Naproxen Oral 500mg bd Suitable 1st line choice, together with PPI

for patients with CV risk

Non

selective

Piroxicam

melt

Sublingual 20mg od Increased risk of GI toxicity and

serious skin reactions. Not to be

used for first line treatment.

nsaid regional audit group presentationnsaid and within 7 days of starting treatment or increasing...

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