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1. Non-steroidal Anti-
inflammatory Drugs
Dr Alex Dodoo Ph.D. MPSGH, MRPharmS
Centre for Tropical Clinical Tropical Pharmacology &
Therapeutics, UGMS
Accra, GHANA
alexooo@yahoo.com OR anododoo@ug.edu.gh
2. Outline
NSAIDs
Indications
Mechanism(s) of Action
Non-specific Cox or Cox-2
Side-effects
Selection
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
3. NSAIDs
Non-steroidal anti-inflammatory drugs
Compare with opoid analgesics (usually
required for moderate to severe pain;
narcotic; usually addictive) e.g. morphine;
codeine
Compare with paracetamol which has very
little or no anti-inflammatory activity
Most are organic ACIDS
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
6. Indications
Pain and inflammation in rheumatic diseases
Musculoskeletal disorders
Post-operative analgesia
Acute Gout
Migraine
Dysmenorrhoea
Fever and pain in children (including post-immunization pyrexia)
Pyrexia
Dental pain
Less well-defined conditions of back pain and soft-tissue disorders
Patients NOT responsive to one NSAID may well respond to
another – need to tailor treatment to the individual patient. Full
analgesic effect may take up to three weeks
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
7. Mechanism(s) of Action
Inhibition of prostaglandin synthesis
Inhibition of Cox-1
Inhibition of Cox-2
Cox-2 is induced 10-80 fold in inflammation
Inhibition of Cox-2 is the main mechanism for the anti-
pyretic, analgesic and anti-inflammatory actions
Inhibition of Cox-1 leads to side effects
Most NSAIDS are non-selective but there are
“selective” Cox-2 inhibitors
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
8. Non-selective Cox or Cox-2?
Non-selective
Ibuprofen, Diclofenac, Indometacin, naproxen,
Piroxicam, ketoprofen, azapropazone
Cox-2
Newer
Provides protection against gastrointestinal side
effects of NSAIDS
Celecoxib, Rofecoxib, Etoricoxib, Lumiracoxib,
Rofecoxib
Parecoxib, Valdecoxib
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
9. Nonselective Cox or Cox-2?
Action of NSAIDs due to inhibition of Cox-2
Side effects usually due to inhibition of Cox-1
Extensive experience with Non-selective Cox
Inhibitors
Cox-2 expensive
Evidence for cost-effectiveness of Cox-2
(see www.npc.co.uk)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
10. CSM Advice on NSAIDS (BNF 53)
All NSAIDs are associated with serious
gastrointestinal toxicity
Relative risk higher in the elderly
Among 7 non-selective NSAIDs, Ibuprofen has the
lowest side effect profile with Azapropazone having
the highest side effect profile
Piroxicam, ketoprofen, indometacin, naproxen and
diclofenac intermediate
Selective Cox-2 inhibitors have lower risk of serious
upper GI side effects than non-selective NSAIDS
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
11. CSM Advice on NSAIDS (BNF 53)
Ibuprofen generally preferred; start at lowest
recommended dose
Not to use more than ONE NSAID at a time
All NSAIDs (including Cox-2 inhibitors) contraindicated in
patients with ACTIVE peptic ulceration
Non-selective NSAIDs contraindicated in patients with
peptic ulceration
Combination of a NSAID with low dose aspirin may
increase GI side effects
Any degree of worsening of asthma may be related to the
ingestion of NSAID!!!
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
12. NSAIDS and Cardiovascular events:
CSM Advise on selective Cox-2 inhibitors
In the light of emerging concerns abut CV safety, Cox-2 inhibitors
should be used in preference to non-selective NSAIDS ONLY
when specifically indicated (i.e. for patients who are at
particularly high risk of developing gastro duodenal ulcer,
perforation or bleeding and after an assessment of CV risk.
CHM advised (October 2006) that the lowest effective dose of
NSAID or Cox-2 inhibitor should be prescribed for the shortest
period of time to control symptoms and that the need for long-
term treatment should be reviewed periodically
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
13. Examples
Ibuprofen
Lowest incidence of side effects
Lowest (?) potency
Maximum daily dose 2.4g
Useful alternative to aspirin in children under 12 (16 years!) –
Reye’s syndrome
Sustained-Release preparations e.g. Brufen Retard
Various oral preparations
Combination products with paracetamol (e.g. Parafen), codeine
(Nurofen Plus; Codafen Continus)
Topical preparations e.g. Ibugel, Ibuleve, Proflex
Useful in dysmenorrhoea, dentistry
Not strong enough in acute gout
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
14. Examples
Diclofenac
Moderate potency
Useful in acute gout
Moderate side effects (compared to ibuprofen)
Maximum daily dose (by ANY route) is 150mg!!!
Tablets, Suppositories, Gels, Injections
Sustained Release Products
Combination of strengths? E.g. Voltarol Retard 100mg +
Voltarol ec 50mg; Naklofen-Duo 75 mg (dual release 25mg
immediate release and 50mg m/r)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
15. Examples
Aspirin
Avoid in under 12 (under 16s) because of Reye’s syndrome
Useful in juvenile arthritis
Irreversible inhibitor of platelet aggregation
Low dose aspirin for prevention of cardiovascular events and
DVT?
Combination of low dose aspirin and NSAID not recommended
Dose 300-900mg every 4 to 6 hours
Present in several OTC products – watch out for accidental over
dosage (e.g. Alka Seltzer, Anadin etc)
Combination products – with paracetamol, caffeine, codeine etc
No topical preparation
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
16. Side-Effects
Most notorious side effect
adverse gastrointestinal events including gastric or intestinal
ulceration
2 mechanisms responsible for GI side effects
Local erosion of orally administered agents
(THEREFORE they are to be taken with or after meals)
Inhibition of biosynthesis of cytoprotective prostaglandins PGI2
and PGE2
Hence NSAIDs still do cause GI side effects despite the ROUTE of
administration
Administration of cytoprotectants e.g. misoprostol [AVOID IN PRE-
MENOPAUSAL WOMEN] for GI protection
May be given with proton pump inhibitors e.g. omeprazole,
esomeprazole, rabeprazole, lansoprazole for GI protection
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
17. Side Effects
Others include:
Nephrotoxicity - possible interactions with ACE
Inhibitors
Renal failure may be provoked by NSAIDs especially in
patients with pre-existing renal impairment
Hypersensitivity reactions including rashes,
urticaria, brochoconstriction
Anaphylaxis (rare)
Hepatotoxicity
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
18. Caution/Contraindication
Avoid ALL NSAIDs in patients with active
peptic ulceration
Caution in those with peptic ulceration
(risk/benefit)
Asthma – any worsening of asthma should be
investigated
Pregnancy; Breastfeeding ; allergic
conditions
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
19. Selection
Which NSAID
Combination of optimum strength with least side effects
Which Route
Oral; rectal;
Parenteral reserved for inpatient use
Topical for musculoskeletal pain etc
Wash hands thoroughly after use
Which Patient
Caution in elderly; those requiring chronic care; those with
allergies
Fixed Dose Combination products?
Combination with other analgesics?
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
20. Selection
Chronic or acute pain?
Gastroprotection?
Cox-2 inhibitors
Benefits only few patients hence should be given
ONLY when benefits are clear
Avoid concomitant use of aspirin as benefit of Cox-2
inhibition is lost
Side effects? (low GI side effects but other side effects
notably serious cardiotoxicity exist!): Rofecoxib and
Valdecoxib withdrawn due to association with excess
cardiac-related mortality following long-term use
Use in patients with cancer
Use post-operatively
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
21. Other Drugs for Inflammation
Gout
NSAIDs for acute gout
Aspirin usually contraindicated as it inhibits
excretion of uric acid, even at low doses
Allopurinol
Colchicine
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
22. Other drugs for pain and
inflammation
Disease Modifying Anti-rheumatic Drugs
(DMARDs)
antimalarials (chloroquine; hydroxychloroquine)
Penicillamine
Sulfasalazine
Immunosuppresants e.g. azathioprine,
cyclophosphamide, methotrexate
Gold compounds
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
23. Other drugs for pain and
inflammation
Tricyclic antidepressants, e.g. amitriptyline
especially for neuropathic pain
Benzodiazepines
Baclofen (a skeletal muscle relaxant)
Anticonvulsants, typically Carbamazepine in
trigeminal neuralgia; phenytoin and gabapentin have
also been tried. Pregabalin is licensed for trigeminal
neuralgia
Transcutaneous electrical nerve stimulation (TENS)
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008
24. Rubefacients and topical antirheumatics
Rubefacients act by counter-irritation.
Topical NSAIDs provide slight relief of pain in
muscoloskeletal conditions
Examples include:
Ibuprofen
Piroxicam
Ketoprofen
Felbinac
Diclofenac
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008