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

4. NSAIDs Types
Salicylates (Salicylic Aspirin
acid derivatives) Diflusinal
Sodium Salicylate
Acetic Acid derivatives Indometacin
Sulindac
Etodolac
Diclofenac
Non-Steroidal Anti-Inflammatory Drugs
18th July 2008

5. NSAIDs Types
Propionic Acid Ibuprofen
Derivatives Naproxen
Ketoprofen
Flurbiprofen
Enolic Acids Piroxicam
Phenylbutazone
Non-acidic compounds Nabumetone
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
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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