NSAIDs Much of a muchness Dr Victor Pace St Christopher s Hospice ’ 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 By not listed - marktwainhouse.blogs Do NSAIDs pot.com, Public Domain, https://commons.wiki still media.org/w/index.php ?curid=11351273 matter “The report of my death was an exaggeration” Mark Twain 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 nnn How donn • Block prostaglandin (PG) NSAIDs release ? • Inflammation causes massive work PG release. Cell membrane • But some PGs are constitutively phospholipids Cell damage: produced and have important phospholipase A2 physiological roles e.g. mucus Arachidonic acid production in stomach Aspirin COX-1, COX-2 NSAIDs PGG2 Aspirin COX-1, COX-2 NSAIDs PGH2 PGI 2 TXA2 PGE2 PGD2 TXB2 COX-1 and COX-2 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. What • Chemical differences DIFFERENCES Are they relevant? shall wen • Differences in effectiveness explorenn • Differences in safety – Cardiovascular – Renal – Gastrointestinal – Other • Differences in individual metabolism: pharmacogenomics • Celebrating diversity, making choices Are CHEMICAL differences relevant? Almost all derivatives of acids Salicylic acid Propionic acid Aspirin Salsalate Fenoprofen Ibuprofen Diflunisal Magnesium Ketoprofen Flurbiprofen salicylate Naproxen Oxaprozin Acetic acid Alkanones Indometacin Etodolac Nabumetone Ketorolac Sulindac Enolic acid Tolmetin Piroxicam Meloxicam Fenamic acid Phenylbutazone Mefenamic acid Meclofenamate Diaryl heterocyclics Diclofenac (COX-2 inhibitors) Celecoxib Valdecoxib Etoricoxib Do chemical families have any clinical significance? Hypersensitivity to one NSAID may be associated to others from same family. e.g. patients intolerant of ibuprofen are more likely to be intolerant of naproxen. Hypersensitivity reaction to NSAID cream 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 EFFECTIVENESS differ 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 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 in cancer pain Systematic review results NSAIDs > placebo No conclusive proof that any NSAID superior. NSAID + opioid ~ NSAID or opioid alone McNicol 2004 NSAIDs in cancer pain 16/42 studies compared different NSAIDs Can one draw 4/16 revealed differences any between NSAIDs meaningful conclusions 2/4 used clinical doses from this material? 1 / 2 lasted > 2 days McNicol 2005 Is there a difference in CARDIO vascular SAFETY Thrombosis and NSAIDs Non - selective NSAIDs, as well as COX-2 inhibitors, increase thrombosis risk mainly myocardial infarction probably not stroke Inflammation, injury or pro- thrombotic state induces Thrombosis platelet adhesion sets off produces arterial thrombus causes myocardial infarct or brain infarct Main findings: vs placebo Drug Major vascular Vascular death events COX-2 inhibitors ↑ 30% ↑ > 30% / diclofenac Ibuprofen x2 No Naproxen No No CNT Collaboration Lancet 2013 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? How big is the risk of MI? How big is the risk of MI? Main findings: vs placebo • 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 CNT Collaboration Lancet 2013 Why NSAIDs / COX-2 inhibitors increase thrombosis risk (1) Cell membrane phospholipids Cell damage: phospholipase A2 COX stimulates Arachidonic acid Aspirin COX-1, COX-2 NSAIDs PGG2 Aspirin COX-1, COX-2 NSAIDs PGH2 PGI 2 TXA2 PGE2 PGD2 TXB2 PGF2 Why NSAIDs / COX-2 inhibitors increase thrombosis risk (1) Platelet thromboxane (TXA2) vasoconstrictor, increases platelet adhesion. Cell membrane phospholipids Cell damage: phospholipase A2 COX stimulates Arachidonic acid Aspirin COX-1, COX-2 NSAIDs PGG2 Aspirin COX-1, COX-2 NSAIDs PGH2 PGI 2 TXA2 PGE2 PGD2 TXB2 PGF2 Why NSAIDs / COX-2 inhibitors increase thrombosis risk (1) Endothelial prostacyclin (PG ) Platelet thromboxane (TX ) I2 A2 vasodilator, reduces platelet vasoconstrictor, adhesion. Mainly COX-2 increases platelet adhesion. Cell membrane phospholipids Cell damage: phospholipase A2 COX stimulates Arachidonic acid Aspirin COX-1, COX-2 NSAIDs PGG2 Aspirin COX-1, COX-2 NSAIDs PGH2 PGI 2 TXA2 PGE2 PGD2 TXB2 PGF2 Why NSAIDs / COX-2 inhibitors increase thrombosis risk (1) Endothelial prostacyclin (PG ) risk! Reduces Platelet thromboxane (TX ) I2 A2 vasodilator, reduces platelet vasoconstrictor, adhesion. Mainly COX-2 increases platelet adhesion. Increases risk! Increases Cell membrane phospholipids Cell damage: phospholipase A2 COX stimulates Arachidonic acid Aspirin COX-1, COX-2 NSAIDs PGG2 Aspirin COX-1, COX-2 NSAIDs PGH2 PGI 2 TXA2 PGE2 PGD2 TXB2 PGF2 Why NSAIDs / COX-2 inhibitors increase thrombosis risk (2) • 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. CNT Collaboration Lancet 2013 Is there a difference in GASTROINTESTINAL SAFETY Main findings: vs placebo 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 CNT Collaboration Lancet 2013 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? NO if … • indomethacin • diclofenac YES • ketoprofen if … • sulindac • aspirin • ibuprofen 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 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 Risk to the kidneys http://eyepathologist.com/images/KL3962.jpg Who