Nonsteroidal Antiinflammatory Drugs

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Non-steroidal Anti-inflammatory Drugs

• Dr Alex Dodoo Ph.D. MPSGH, MRPharmS
• Centre for Tropical Clinical Tropical
  Pharmacology Therapeutics, UGMS
• Accra, GHANA
• alexooo_at_yahoo.com OR anododoo_at_ug.edu.gh

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Outline

• NSAIDs
• Indications
• Mechanism(s) of Action
• Non-specific Cox or Cox-2
• Side-effects
• Selection

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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

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NSAIDs Types
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NSAIDs Types
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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

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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

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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,
  Parecoxib, Valdecoxib

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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)

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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

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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!!!

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NSAIDS and Cardiovascular eventsCSM 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

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Examples

• Ibuprofen
• Lowest incidence of side effects
• Lowest (?) potency
• Maximum daily dose 2.4g
• Useful alternative to aspirin in children under
  12 (16 years!) Reyes 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

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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)

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Examples

• Aspirin
• Avoid in under 12 (under 16s) because of Reyes
  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

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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

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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

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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

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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?

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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

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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

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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

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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)

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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