Mechanism of Action of Painkillers


Mechanism of Action of Painkillers

Mechanism of Action of Painkillers: Ibuprofen and Anti-Inflammatories, Paracetamol and OTC Opioids

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  • Any condition with the term 'itis' is kind of inflammation, e.g. gingivitis, blepharitis, arthritis, precarditis
  • The term 'inflammatory reaction' refers to the events which occur in the tissues in response to an invading pathogen or the presence of a noxious substance.
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What happens when tissues are damaged?

  • Release of chemical mediators
  • Such as prostaglandins, bradykinin, histamine
  • Activation of C-fibres
  • Inflammation - a protective mechanism
    • Moving plasma and leukocytes from blood into injured tissues
    • Results in swelling, heat and pain
    • No beneficial function
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  • Chemical messengers made from fatty acids that play a role in influencing pain signals, and regulation of inflammation
  • Transmission or pain information to the brain
  • Modulation of the hypothalamic thermostat
  • Inflammation
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Cyclooxygenase (COX)

  • Enzyme responsible for formation of Prostaglandins
  • 2 known forms:
    • COX 1 - always present in most cells
    • COX 2 - induced in inflammatory cells

Arachidonic Acid + COX --> Prostaglandins or Thrombaxanes 

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Inflammatory Pathway

Arachidonic acid + COX-1 enzyme (physiological) --> TXA2 (control of platelet aggregation) or PGI 2 (protection of gastric mucosa) or PGE2 (control of renal bloodflow) 


Arachidonic acid + COX-2 enzyme (induced) --> Prostaglandins (inflammation)

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Vascular Events of Acute Inflammation

Arachidonic Acid + COX --> histamine or PGI2 or PGE2

Dilation of the small arterioles

Increased blood flow

Stasis of the blood

Increase in permeability of postcapillary venules

Exudation of fluid - plasma and leukocytes into damaged area

Activation of the complement system, fibrolytic system, coagulation system and kinin system

Note: PGE2 and PGI2 are not directly created from arachidonic acid

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Anti-Inflammatory Effects

  • NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) reduce maily those components of the inflammatory and immune response in which products of COX-2 action play a significant part, such as:
  • Decreased vasodilation
  • Decreased oedema (indirectly: the vasodilation facilitates the action of mediators such as histamine which increase permeability of postcapillary venules)
  • Decreased pain
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  • NSAIDs include a variety of different agents of different chemical class. Most have three major types of effect:
  • Anti-inflammatory effects
  • Analgesic effects - decrease production of the prostaglandins that sensitise nociceptors to inflammatory mediators such as bradykinin
  • Antipyretic effect - NSAIDs reset the thermostat by inhibition of E-type prostaglandin production in the hypothalamus
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  • The primary action of NSAIDs is the inhibition of COX enzymes
  • Most NSAIDs inhibit both isoenzymes but vary in the degre of inhibition of each

Aspirin                      More COX-1 specific




Rofecoxib                   More COX-2 specific

Aspirin and ibuprofen have the same properties but are used in different conditions because of their COX selectivity and available forms

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Common Unwanted Effects

  • Gastrointestinal disturbance: dyspepsia, nausea and vomiting due to effects on gastric mucosa
  • Skin reactions, e.g. rash
  • Reversible renal insufficiency
  • Can trigger asthma attacks

NSAIDs should be avoided in the elderly because this group of patients already suffer from mild renal dysfunction

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  • Non-selective and irreversibly inhibits both COX-1 and COX-2
  • Inhibits prostaglandins to combant inflammation and pain (300mg - 900mg every 4-6 hours)
  • Blocks the formation of thromboxane in platelets, producing an inhibitory effect on platelet aggregation
  • Anti-inflammatory effect through prostaglandin reduction
  • Anticoagulant property makes aspirin useful for reducing the incidence of heart attacks (75mg)
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  • Non-selective, reversible COX inhibitor (200/400mg - 400mg 3x per day)
  • Milder antiplatelet effect
  • The analgesic, antipyretic and anti-inflammatory activity or NSAIDs is achieved mainly through inhibition of COX-2
  • Inhibition of COX-1 would be responsible for unwanted effects on platelet aggregation and the gatrointestinal tract
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When should they be used? - OTC

  • Aspirin - never to under 16s 
    • headaches, fever, toothace, flu, general aches and pain
  • Ibuprofen - adults and children
  • Diclofenac, Naproxen - adults (OTC/POM) and children (POM only)
    • menstrual cramps, joint pain, sprains, rheumatoid arthritis, gout
    • never use for chicken pox - increased risk of secondary bacterial infection
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  • Very effective, tolerable analgesic
  • Excellent anti-pyretic
  • Mild anti-inflammatory
  • Underused
  • Safe the majority
  • First step on WHO analgesic ladder
  • Should be used regularly in chronic pain alongside additional analgesia if needed
  • Can cause fatal heaptotoxicity, but it is safe when dosage is kept within therapeutic guidelines
  • Be aware of the contents and effects of combination products
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Paracetamol Action

  • Anti-inflammatory at low levels of arachidonic acid, not at high levels (alleviates toothache, not rheumatoid arthritis), good gastrointestinal tolerability, poor anti-platelet action
  • Anti-pyretic effect - fever occurs when there is a disturbance in hypothalamus temperature regulation, causing sweating and dilation of superficial blood vessels. Paracetamol works as a thermo regulator in the hypothalamus
  • Analgesic - reduced levels of 5-HT (serotonin) transmission, may act through opioid and cannabinoid pathways also
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When is paracetamol toxic?

  • Adult dose - 2 x 500mg four times per day, maximum dose 4g per day OTC
  • Toxic dose highly variable: 150mg/kg (50kg adult - 7.5g) = 16 tablets twice daily limit - severe adverse effects
  • Hepatotoxicity (liver damage) can occur at 12g in an acute dose - potentially fatal
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Adjuncts to NSAIDs and paracetamol

  • Caffeine (adenosine agonist) - weak stimulant and vasodilator (hedex extra, solpadine plus) - increase speed
  • Buclizine (antihistamine) - anti-emetic (migraleve)
  • Doxylamine, diphenhydramine (antihistamine) - muscle relaxant and sedative
  • Opioid drugs
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Pain Pathway: Mild to Moderate Pain

  • Paracetamol 15 to 20 mg/kg orally or rectally (maximum 1g)


  • Ibuprofen 10 mg/kg orally (maximum 400mg)
  • Contraindicated if severe asthma, surgery in the last 2 weeks, gastrointestinal bleeding/ulcer
  • If still in significant pain, use further analgesia as per 'Moderate' or 'Severe' pain
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Pain Pathway: Moderate Pain

  • Intranasal (IN) Fentanyl 1.5 mcg/kg (maximum 100mcg)


  • Paracetamol and/or ibuprofen
    • +/- tramadol
    • +/- morphine (orally)
    • +/- codeine
  • If still in significant pain, use further analgesia as per 'Severe' pain
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The Pain Pathway: Severe Pain

  • Morphine IV 0.1 mg/kg (0.05 mg/kg if <1 year/prior opiate)
  • Be aware of late apnoea if under 6 months of age
  • Consider N2O or IN fentanul and Ametop prior to IV insertion depending on severity or the requirement for other therapy
  • If still in significant pain give further 0.05 mg/kg morphine blouses
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  • OTC
    • Weak opioids
    • Codeine, dihydrocodeine - in combination with NSAIDs/paracetamol
  • POM
    • Morphine and many others
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Mechanism of Action

  • No antipyretic or anti-inflammatory action
  • Analgesic - mainly through mu opioid receptors
  • Side effects of euphoria, sedation, decreased respiration, decreased gastrointestinal function (constipation)
  • Inhibition of pain transmission at spinal cord and brain
  • Possible direct action on peripheral tissues
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