nsaids much of a muchness?guildfordadvancedcourses.co.uk/wp-content/uploads/... · 80% had some...

Much

of a

muchness

Dr Victor Pace

St Christopher ’s Hospice

NSAIDs

Do NSAIDs

still

matter

• Use in some hospices much

diminished

• Much greater awareness of risks

• Some have called for a ban on OTC

NSAIDs and a restriction on

indications for use

Do NSAIDs

still

matter

• Risk of myocardial infarction

• Risk of GI bleeding, perforation

or stricture – stomach and

small intestine

• Risk of renal failure

“The report of my death was an

exaggeration” Mark Twain

Do NSAIDs

still

matter

By not listed -marktwainhouse.blogs

pot.com, Public Domain,

https://commons.wikimedia.org/w/index.php

?curid=11351273

New roles in prevention of cancer, Parkinson’s, ? dementia

New safer forms of NSAID HS-NSAIDs, NO-NSAIDs, LOX-COX inhibitors, PC-NSAIDs….

Backlash against opioid prescribing in chronic pain (43 deaths a day from prescription opioids in US in 2014)

American Society of Addiction Medicine

https://commons.wikimedia.org/w/index.php?curid=11351273

• Block prostaglandin (PG) release

• Inflammation causes massive PG release.

• But some PGs are constitutively produced and have important physiological roles e.g. mucus production in stomach

nnndonn

NSAIDs

work?

How

Arachidonic acid

PGG2

PGH2

PGD2

PGI2PGE2

TXA2

TXB2

COX-1, COX-2

COX-1, COX-2

Aspirin

NSAIDs

Aspirin

NSAIDs

Cell membrane

phospholipids

Cell damage:

phospholipase A2

COX-1 thought to mediate housekeeping functions e.g. gastric mucus production

COX-2 thought to be produced mostly in inflammation.

Blocking COX-2 but not COX-1 would allow normal functions but block inflammation and pain.

COX-1 and COX-2

What

DIFFERENCES

shall wen

explorenn

• Chemical differences Are they relevant?

• Differences in effectiveness

• Differences in safety

– Cardiovascular

– Gastrointestinal

• Differences in individual metabolism: pharmacogenomics

• Celebrating diversity, making choices

– Renal

– Other

Are

CHEMICALdifferences

relevant?

Almost all derivatives of acids

Salicylic acid

Aspirin

Diflunisal

Acetic acid

Indometacin

Ketorolac

Tolmetin

Fenamic acid

Mefenamic acid

Diclofenac

Propionic acid

Fenoprofen

Ketoprofen

Naproxen

AlkanonesNabumetone

Enolic acid

Piroxicam

Phenylbutazone

Diaryl heterocyclics

(COX-2 inhibitors)

Celecoxib

Etoricoxib

Salsalate

Magnesium salicylate

Etodolac

Sulindac

Meclofenamate

Ibuprofen

Flurbiprofen

Oxaprozin

Meloxicam

Valdecoxib

Do chemical families have

any clinical significance?

Hypersensitivity to one NSAID may be associated to others from same family.

Hypersensitivity reaction to

NSAID cream

e.g. patients intolerant of ibuprofen are more likely to be intolerant of naproxen.

Do chemical families have

any clinical significance?

Some other group differences e.g.

• Larger % of oxicams faecally excreted that for other NSAIDs.

More likely to be associated with small bowel damage.

Longer half life.

Chemistry can also confer

individual properties

• Indometacin when metabolised by demethylation, resembles 5-HT, accounting for more CNS effects

0-Desmethyl indometacin 5-hydroxytryptamine (serotonin)

Does

EFFECTIVENESSdiffer

Important: an anti-inflammatory is not just anti-inflammatory

The analgesic effects of an NSAID are separate from its anti-inflammatory activity McCormack & Brune Drugs 1991

COX is not the only mechanism of action: all NSAIDs act (variously) in other ways too.

It clearly can’t be just down to COX

No difference between NSAIDs in

• chronic low backpain Enthoven Cochrane Database Syst Rev 2016

• axial spondyloarthritis Kroon Cochrane Database Syst Rev 2015

• cancer pain McNicol Cochrane Database Syst Rev 2004 (withdrawn

– out of date)

• Diclofenac, ketoprofen, ibuprofen gel and diclofenac plaster most effective in acute musculoskeletal pain

Derry Cochrane Database Syst Rev 2015

Most studies found poor data quality in primary studies

NSAIDs > placebo

No conclusive proof that any NSAID superior.

NSAID + opioid ~ NSAID or opioid alone McNicol 2004

NSAIDs in cancer pain

Systematic review results

16/42 studies compared different NSAIDs

4/16 revealed differences between NSAIDs

2/4 used clinical doses

1 / 2 lasted > 2 days

NSAIDs in cancer pain

Can one draw anymeaningful conclusionsfrom this material?

McNicol 2005

Is there a

difference

in

CARDIO

SAFETYvascular

Thrombosis and

NSAIDs Non-selective NSAIDs, as well as COX-2 inhibitors, increase thrombosis risk

probably not stroke

mainlymyocardial

infarction

Inflammation, injury or pro-thrombotic state induces platelet adhesion

sets off

produces arterial thrombus

causes myocardial infarct or brain

infarct

Thrombosis

Main findings: vs placebo

CNT Collaboration Lancet 2013

Drug Major vascular events

Vascular death

COX-2 inhibitors / diclofenac

↑ 30% ↑ > 30%

Ibuprofen x2 No

Naproxen No No

How big is the risk?

• Coxib or diclofenac 3 major vascular events /1000 participants / year, one of which is fatal

• Risk for ibuprofen less well quantified but probably not much less, especially at high doses.

• No evidence for increased risk of stroke with any NSAID

How big is the risk of MI?

• Risk of hospitalisation from heart failure doubled by all NSAIDs studied - COX-2 or traditional NSAIDs

• COX-2 inhibitor increases risk of death from any cause, but diclofenac, ibuprofen or naproxen do not



Why NSAIDs / COX-2 inhibitors

increase thrombosis risk (1)

COX stimulates Arachidonic acid

PGG2

PGH2

PGD2

PGI2PGE2

TXA2

TXB2

COX-1, COX-2

COX-1, COX-2

Aspirin

NSAIDs

Aspirin

NSAIDs

Cell membrane

phospholipids

Cell damage:

phospholipase A2

PGF2




PGG2

PGH2

PGD2

PGI2PGE2

TXA2

TXB2

COX-1, COX-2

COX-1, COX-2

Aspirin

NSAIDs

Aspirin

NSAIDs

Cell membrane

phospholipids

Cell damage:

phospholipase A2

PGF2

Platelet thromboxane (TXA2)vasoconstrictor, increases platelet adhesion.




PGG2

PGH2

PGD2

PGI2PGE2

TXA2

TXB2

COX-1, COX-2

COX-1, COX-2

Aspirin

NSAIDs

Aspirin

NSAIDs

Cell membrane

phospholipids

Cell damage:

phospholipase A2

PGF2


Endothelial prostacyclin (PGI2)vasodilator, reduces platelet

adhesion. Mainly COX-2




PGG2

PGH2

PGD2

PGI2PGE2

TXA2

TXB2

COX-1, COX-2

COX-1, COX-2

Aspirin

NSAIDs

Aspirin

NSAIDs

Cell membrane

phospholipids

Cell damage:

phospholipase A2

PGF2


Endothelial prostacyclin (PGI2)vasodilator, reduces platelet

adhesion. Mainly COX-2

Incr

ease

s ri

sk! R

edu

ces risk!



• Increase blood pressure = risk factor for thrombosis. How long term is this increase?

• Increase risk of renal insufficiency and reduce vasodilator nitric oxide, at least in mice

Yu, Sci Transl Med 2012

Why is naproxen (probably)

cardioprotective?

Inflammation or injury causes >1000x increase in TXA2

Requires platelet COX-1 suppression ≥ 97% to neutralise this -

achieved by aspirin (irreversibly) but not by most NSAIDs.

Naproxen is the only ns-NSAID which, if taken at 500mg bd,

suppresses platelet COX-1 activity by > 95%, reducing TXA2 levels

effectively like aspirin can. Long t1/2 means TXA2 cannot recover.

But it is also the ns-NSAID most strongly associated with

hypertension …

Celecoxib?

• All COX-2 inhibitors seemed to increase risk of vascular events by roughly similar proportion. ? dose-dependent.

• Celecoxib 200mg daily vascular risk is statistically uncertain - most studies used higher doses not often used clinically.


Is there a

difference

in

GASTROINTESTINALSAFETY


All NSAIDs increase risk of major upper GI

events, but COX-2 and diclofenac least

Risk of upper GI complication increased

x2-4, least by COX-2 inhibitors. GI less

often fatal / disabling than cardiovascular

Only 2% of upper GI events were fatal


NSAID Relative risk for UGI complications

aceclofenac 1.43 (95% CI 0.65, 3.15)

celecoxib 1.45; 95% CI 1.17, 1.81

ibuprofen 1.84; 95% CI 1.54, 2.20

rofecoxib 2.32; 95% CI 1.89, 2.86

sulindac 2.89; 95% CI 1.90, 4.42

diclofenac 3.34; 95% CI 2.79, 3.99

meloxicam 3.47; 95% CI 2.19, 5.50

nimesulide 3.83; 95% CI 3.20, 4.60

ketoprofen 3.92; 95% CI 2.70, 5.69

tenoxicam 4.10; 95% CI 2.16, 7.79

naproxen 4.10; 95% CI 3.22, 5.23

indometacin 4.14; 95% CI 2.91, 5.90

diflunisal 4.37; 95% CI 1.07, 17.81

piroxicam 7.43; 95% CI 5.19, 10.63

ketorolac 11.50; 95% CI 5.56, 23.78

azapropazone 18.45 (95% CI 10.99, 30.97) Castellsague Drug Safety 2012

Does giving NSAIDs by a non-oral route

reduce the risk of ulceration?

Yes?

No?

It depends?

YES if …

• sulindac• aspirin• ibuprofen

NO if …

• indomethacin• diclofenac• ketoprofen

All the drugs that are just as dangerous parenterally

are secreted in bile. The others are not.

Is there a

difference

in

RENAL SAFETY

Effect on the kidney

• Prostaglandins maintain kidney circulation in shock and other states of low circulating volume.

• NSAIDs block prostaglandin production, increasing risk of acute renal failure in this setting.

Kidney infarcts in haemorrhagic shock

Risk to the kidneys

Chronic renal failure

x 8.8 if > 5000 NSAIDs consumed Perneger 1994

Acute renal failure

Risk x 1.6 - x 3 if on NSAIDs Griffin et al 2000; Huerta 2005

Combination with diuretics and ACE inhibitors is particularly dangerous

Townsend Evid Based Med 2013

http://eyepathologist.com/images/KL3962.jpg

• Blood loss• Dehydration• Heart failure• Nephrotic

syndrome

• Cirrhosis• Diuretics• Severe diarrhoea or

vomiting• Severe ascites

IN THESE CONDTIONS NSAIDs BLOCK THE

MECHANISM PRESERVING NEPHRON CIRCULATION

AND CAN PRECIPITATE RENAL FAILURE!

Who is at risk of

acute renal failure?

Is there a

difference

in

BLEEDING risk

Effect on platelets

• Non-selective NSAIDs reduce platelet adherence, inhibiting efficient clot formation.

• Must not be used in patients with low platelet counts or with defective platelets

• Platelets only contain COX-1 ─ not affected by COX-2 inhibitors

Can I use any NSAID in someone with a

low platelet count?

• Diclofenac , nabumetone

• COX-2 inhibitors eg celecoxib are safest: platelets do not contain COX-2

The strange case of ketorolac?

• Can be given orally, sublingually, intranasally, topically (ophthalmic*), parenterally* (* = available in UK.)

• Effective in acute pain e.g. postop Brown Pharmacotherapy 1990, He Curr

Med Res Opin 2012

• Some suggest opioid sparing effect in this situation. Chen Clin J Pain 2009, Hong J Urol 2010

• “Short term management of moderate to severe postop pain only ”. Licensed for 2 days use in UK. (BNF)

• ½ dose in >65s

Ketorolac in cancer pain: randomised

double blind studies

• Single doses i.m. > placebo, 10mg as good as higher doses in 15 patients Staquet J Clin Pharmacol 1989

• > placebo but < paracetamol + codeine when given p.o.to 75 patients x 7 days Carlson Pharmacotherapy 1990

• 51 patients 10mg ≡ 10mg morphine, both i.m. 6-hrly Jameel Int J Oncol 1995

• 180 patients. 10mg i.m.≡ 30mg ≡ diclofenac 75mg i.m. Minotti Pharmacotherapy 1998

• 36 patients sc infusion of 60 to 120mg for up to 115 days (mean 21 days, median 15) . 80% had some pain relief.

• All had misoprostol 200mcg tds po. Myers Postgrad Med J 1994

• “Four patients experienced gastrointestinal bleeding and one colonic perforation to which treatment with ketorolac may have been a contributory factor. “

• 2 had upper GI primaries, 1 had radiation proctitis, one bled after high dose dexamethasone added.

The downside: risk

• Highest risk of hospitalisation for acute MI among non-specific NSAIDs and celecoxib for both oral and parenteral ketorolac Shau BMC Cardiovascular Disorders 2012

• Highest risk (RR 11.50; 95% CI 5.56, 23.78) of upper GI complications after azapropazone (next highest piroxicamwith RR of 7.43) Castellsague Drug Safety 2012

• Highest risk of upper GI bleeding (RR 14.54 vs piroxicam8.00) of ns-NSAIDs and COX-2 inhibitors

Gonzalez Arthritis Rheumatism 2010

Ketorolac

Make your mind up

• Effective in cancer pain (fairly small trials, old –methodology)

• Highest risk both CVS and GIT

• Risks to individual patient not high

• No head to head shows greater effectiveness than other parenteral NSAID

Timefor some

Balancing risks and effectiveness

Drug GI risk CV risk Effectiveness

Naproxen Low moderate Negligible ++

Low dose ibuprofen Low Low? +

High dose ibuprofen Moderate Moderate ++

Celecoxib Very low ? Low at 200mg daily , high at higher doses

++

Indometacin High High ++

Piroxicam Very high Very low ++

Diclofenac Low moderate High ++

Nabumetone Very low ? ++

Time course

The highest risk for ulcers is when you start using NSAIDs

while the highest risk for myocardial infarction is with prolonged use.


Sensible choices

• Best for high GI risk celecoxib, ? nabumetone

• Best for high CV risk naproxen

• Best if bleeding risk or asthma celecoxib

• AVOID piroxicam, indometacin, ? ketorolac.

• Overall risk low in absence of risk factors - but no excuse for not using safest alternatives.

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