see also eicosanoids including prostaglandins, pain, analgesia and analgesics, salicylate poisoning, aspirin (acetylsalicylic acid), colchicine

• NSAIDs are a group of drugs which have anti-inflammatory and analgesic effects via their inhibitory action upon cyclooxygenase (COX) which is involved in the synthesis of prostaglandins.

• NSAID use can be potentially fatal in high doses, prolonged used or in those at risk of their adverse effects, particularly, peptic ulceration/perforation and acute renal failure.
• they should be avoided where possible in:
  • the elderly
  • PH peptic ulceration, alcohol abuse
  • congestive cardiac failure
  • hypertension
  • stroke/AMI risk
  • those who are hypovolaemic or dehydrated, particularly if they are also on ACE inhibitors
  • in addition, patients with asthma, nasal polyps or with past history of allergic reaction are at higher risk of having an life threatening acute allergic reaction
  • pregnancy
  • post-partum period in those who had pre-eclampsia or premature delivery
  • lactation
  • young children
  • renal impairment (CRN > 180umol/L)
  • coagulopathy
  • post-op for surgery with high risk of bleeding
  • PH Stevens-Johnson synd. or bullous / blistering rashes
  • suspected or confirmed intracranial bleeding
  • concurrent use of other NSAIDs
• paracetamol (acetaminophen) is a much safer option in those with non-inflammatory pain (eg. mechanical pain due to osteoarthritis) as NSAIDs add little more benefit but expose the patient to much higher risks unnecessarily.

• allergy and hypersensitivity reactions - bronchospasm is a particular concern
• gastritis, peptic ulceration +/- perforation - rarely, this may occur even in previously well young adults within only a few days of Rx!
• acute renal failure - particularly if dehydrated or on ACE inhibitors
• nausea, diarrhoea, constipation
• salt and water retention and worsening congestive cardiac failure
• hypertension
• regular use may cause hearing loss
• photosensitivity and rashes
• may also cause a number of other effects including raised LFTs, priapism, oesophagitis, etc - see full PI
• COX-2 selective agents in particular, appear to increase the risk of thrombotic events such as stroke, and AMI
• diclofenac may increase risk of Clostridium difficile by 35% ¹⁾
• aspirin also increases risk of bleeding such as epistaxis

• There appears to be variability in this enzyme depending on the tissue, resulting in variable effects of NSAID's, but it may be possible to develop tissue-selective inhibitors;
• Mechanism:
  • aspirin 40mg permanently acetylates the enzyme so that one dose is sufficient to block this enzyme for the life of a platelet (8-11days) as plat. cannot regenerate the enzyme;
    • NB. salicylate cannot acetylate the enzyme!
  • other agents competitively inhib. the enzyme:
    • NSAIDs & COX-2 inhibitors have analgesic & anti-inflammatory action via inhibition of COX-2 enzyme, this isoenzyme is massively up-regulated in inflammatory states such as RhA, so inhibiting it reduces inflammation.
    • paracetamol can only block the enzyme in environments free of peroxides & thus usually only in hypothalamus & is thus a poor antiinflammatory agent;
• → decr. PGD2 → decr. all PG's & TX's
• → decr. TXA2 → decr. 2nd phase of plat.aggreg.
• COX-1 in platelets produces TXA2 which promotes platelet aggregation & vasoconstriction
• COX-2 in endothelial cells produces prostacyclin (PGI2) which inhibits platelet aggregation & causes vasodilatation, thus COX-2 inhibitors could be predicted to increase risk of thrombosis and thus ischaemic stroke and AMI, as well as the usual NSAID adverse effects on increasing BP, exacerbating CCF, & impairing renal function.
• COX-1 is the primary source of protective gastric mucosal PGs, hence the focus on COX-2 inhibitors to reduce the gastric toxicity associated with NSAIDs with the risk of serious upper GIT ulceration & bleeding reduced by 50-60% when using COX-2 inhibitors instead of NSAIDs.
• in addition to analgesic, antipyretic & anti-inflammatory uses, COX-2 inhibitors may be of use in:
  • prophylaxis of colon cancer BUT risk of stroke & AMI outweighed the benefits

• acetylsalicylic acid (aspirin)
  • additional anti-platelet activity
• diclofenac (Voltaren)
  • may increase risk of Clostridium difficile by 35% ²⁾
• indomethacin (Indocid)
  • usual adult dose 25-50mg tds o or 100mg rectal suppository bd
• ibuprofen (Brufen, Nurofen)
  • usual adult dose 400mg tds
  • at daily doses up to 1200mg is said to have less adverse GIT effects than the other non-selective NSAIDs
• ketorolac
• mefenamic acid (Ponstan)
  • used mainly in Rx of dysmenorrhoea but tends to cause diarrhoea
• naproxen (Naprosyn/Naprogesic)
• piroxicam (Feldene)

• meloxicam:
  • an enolcarboxamide related to piroxicam
  • 3-77x more selective for COX-2 than COX-1
  • slowly absorbed with tmax of 5-6hrs
  • half life 20hrs ⇒ once daily dosing
  • gastric injury as for placebo at 7.5mg/d but increases with higher doses
• nimesulide:
  • introduced in 1985
  • extensively metabolised with half life of 1.6-5 hrs
  • analgesic, anti-inflammatory & anti-pyretic but similar gastric toxicity as other NSAIDs!
  • in 2/1/1999 Lancet, report of fatal fulminant hepatic failure in a woman taking this drug with temporal relationships suggesting causality

• all increase risk of thrombotic events such as ischaemic stroke & AMI, thus should be used with care in at risk patients, preferably at lowest dose possible for short periods and with low dose aspirin or other anti-thrombotic Rx.
• celecoxib:
  • 1,5 diaryl pyrazole-based compound
  • 375x more selective for COX-2 than COX-1 based on human recombinant enzyme assays
  • does not effect serum thromboxane or platelet function at usual doses up to 600mg bd
  • extensively metabolised with half life 11.2hrs
  • efficacy: 100-200mg bd equivalent to naproxen 500mg bd for osteoarthritis or RhA over 12wks
  • approved by US on 31/12/1998
  • dose:
    • RhA: 100mg bd (max. 800mg/d)
    • osteoarthritis: 200mg mane (max. 400mg/d)
    • analgesia: 100-400mg stat equal to aspirin for dental procedures
• rofecoxib:
  • withdrawn from Australia in 2004 due to concerns of adverse effects such as stroke, AMI.
  • a methylsulphonylphenyl derivative
  • >800x more selective for COX-2 than COX-1
    • ⇒ even at 10-20x usual doses does not effect bleeding time nor cause gastric injury any more than placebo
  • long acting ⇒ once daily
• parecoxib (Dynastat):
  • prodrug of valdecoxib
  • analgesia begins within 15 minutes of an intravenous or intramuscular injection and reaches a peak in two hours
  • extensively metabolised and most of the metabolites are excreted in the urine
  • may inhibit CYP2C19 and CYP2D6
  • 40 mg dose of parecoxib iv/im was significantly better than 20 mg
  • only approved for use as a single perioperative injection so most of the safety data refer to single doses.³⁾
• etoricoxib (Arcoxia):
  • introduced in Australia in 2009
  • long acting ⇒ once daily
  • usual dose 60-120mg once daily (tablets are 30mg, 60mg, 120mg)
  • 120mg dose gives similar analgesia as:
    • 400mg ibuprofen or 550mg naproxen in Mx of dysmenorrhoea or dental pain.
    • 50mg tds indomethacin for acute gout
  • max. daily dose 120mg/d for maximum of 8 days.
  • C/I in severe renal or hepatic impairment
  • care with drugs which interact with NSAIDs.

• Medicinal effects of barks of some plants incl. willow known to several cultures for centuries;
• Rev.Edmund Stone (UK) used willow bark in fever of malaria;
• Salicin the bitter glycoside active ingredient of willow bark isolated in 1829 by Leroux who also demonstrated its antipyretic effect.
• Sodium salicylate derived from salicin 1st used in RhF & fevers 1875;
• Acetylsalicylic acid introduced by Dresser in 1899 as aspirin (acetylsalicylic acid).
• Acetanilide the parent member of para-aminophenol gp introduced into medicine in 1886 as antifebrin after its antipyretic activities accidentally discovered;
• paracetamol (acetaminophen) 1st introduced 1887 & used in combination with other analgesics until realised in 1949 that it was the active metabolite of both acetanilide & phenacetin & thus gained popularity;
• Aspirin clearly shown to be gastrotoxic in 1938.
• Phenylbutazone the most important of the pyrazolone gp, introduced in 1949 but serum sickness/marrow suppression/hepatitis/nephritis;;
• Other pyrazolones: antipyrine (phenazone), amidopyrine used 19thCent.
• The fenamates' (mefenamic acid,etc) biological activities discovered in 1950's but did not gain widespread acceptance mainly due to diarrhoea.
• No clear Rx advantage over other NSAID's but used in 1° dysmenorrhoea;
• Indomethacin was the 1st of allied NSAID's to be widely used - introduced 1963 then sulindac & since then many more have been synthesised;
• Tolmetin introduced in 1976 (US) as better tolerated than aspirin;
• Propionic acid derivatives (ibuprofen, naproxen) are usually better tolerated than aspirin or indomethacin;
• Piroxicam (Feldene) an oxicam derivative
• Diclofenac (Voltaren) the 1st of the phenylacetic acid derivative as NSAID;
• COX-2 gene discovered in 1990-91.
• Ketorolac trometamol (Toradol) introduced 1992 (Aust) as periph. acting PG synthetase inhibitor developed specially for its analgesic properties as a 30mg IM replacement for pethidine 50-100mg or morphine 6-12mg IM;
• In 1996-98, some existing NSAIDs shown to be COX-2 preferential (meloxicam, nimesulide)
• New drugs designed to be COX-2 “selective”:
  • celecoxib (approved in US 31/12/1998)
  • rofecoxib (likely to be approved in US in 1999)
• 2003, reports of hypertensive crises & deaths when NSAIDs given in post partum period to women with PH pre-eclampsia or premature delivery. Advised to carefully watch BP in such pts if must use NSAIDs
• 2004: Vioxx (rofecoxib) withdrawn as long term Rx shown to increase risk of thrombotic events such as AMI and stroke. TGA places new restrictions on COX-2 inhibitors in Australia including avoidance in patients with high risk of cardiovascular events such as PH AMI, and the maximal long term dose of Celebrex (celecoxib) reduced to 200mg/d for other patients.
• 2005: Pfizer believes that the restrictions to Celebrex should apply to all NSAIDs not just COX-2 inhibitors.
• 2012: diclofenac reported to increase risk of Clostridium difficile by 35% ⁴⁾