Pain, Inflammation, and Fever

Unit Learning Outcomes: Pain, Inflammation, and Fever

• Describe the effects of prostaglandins on the body
• List and differentiate between the various isoforms of cyclooxygenase
• List the different groups of drugs used in pain, fever, and inflammation with drug examples in each group
• Differentiate between the indications and mechanisms of action for the different groups of drugs
• Explain why aspirin is used to reduce platelet aggregation
• Briefly describe the treatment of migraine
• Briefly describe the treatment of gout (acute and chronic)

Pain, Inflammation, and the Inflammatory Cascade

• NSAIDs and corticosteroids are used in the cascade
• Non-painkillers for specific pain syndromes, e.g., gout, migraine, and neuropathy may be used
• Opioids and paracetamol modulate central perception

The Inflammatory Cascade (Arachidonic Acid Pathway)

• Infection, antibodies, or physical injury can initiate the cascade
• Membrane phospholipids are converted into arachidonic acid by phospholipase C and phospholipase A2
• NSAIDs inhibit the cyclooxygenase (COX) enzymes
• Corticosteroids inhibit phospholipase A2
• Arachidonic acid is converted to prostaglandin H2 by cyclooxygenase (COX 1, 2 & 3)
• Prostaglandin H2 turns into leukotrienes by 5-lipoxygenase
• Leukotrienes are inhibited by LOX-inhibitors
• Leukotriene antagonists reduce the effects of leukotrienes
• Prostaglandin D2 is involved in bronchoconstriction and vasoconstriction and acts opposite PGE2
• Prostaglandin E2 regulates pain, inflammation and various physiological processes
• Prostaglandin F2α causes uterine contraction
• Dinoprostone causes uterine contraction, vasoconstriction and maintains ductus arteriosus
• Prostacyclin (PGI2) causes vasodilation and inhibits platelet activation and regulates CVS homeostasis
• Thromboxane (TXA2) is an eicosanoid that causes vasoconstriction and platelet activation

Non-Selective NSAIDs

• Non-selective NSAIDs block both COX-1 and COX-2 enzymes
• These drugs have gastric side effects that can cause gastric and duodenal ulcers
• Examples of non-selective NSAIDs available orally include:
  • Salicylic acid derivatives
  • Piroxicam (relative selectivity for COX-2)
• Available as rectal preparations (suppositories):
• Indomethacin
• Naproxen
• Mefenamic acid
• Diclofenac (relative selectivity for COX-2)
• Available as injections for IM or IV:
• Ketorolac
• Ibuprofen
• Diclofenac
• Lornoxicam

Selective NSAIDs

• Blocks COX-2 selectively; much less gastric SEs
• Preferred in patients with risk factors for peptic ulcers
• Higher risk of cardiovascular thrombotic events if used chronically
• Available in South Africa:
  • Celecoxib (oral)
  • Etoricoxib (oral)
  • Parecoxib (IV)
  • Meloxicam (preferential; IM and oral)

Salicylic Acid Derivatives - Aspirin

• Aspirin is only available orally and binds COX irreversibly
• Aspirin is 90% plasma-protein bound, leading to important drug interactions
• Aspirin excretion is hastened by alkalinizing the urine
• Cross-sensitivity for adverse effects with aspirin use below 20% when using COX-2 inhibitors
• Indications include cardioprotection (MI, stroke, angina) at 75-300mg OD
• Antipyretic and analgesic effects are achieved at 300-650mg q6h
• Inflammation treatment requires 1000mg q6h
• Side effects of aspirin include excessive bleeding, GIT pain, and gastric and duodenal ulcers
• Aspirin is contraindicated in young children (Reye's syndrome) and can exacerbate pulmonary inflammation
• Prolonged use of aspirin may increase uric acid levels, triggering gout
• Overdose of aspirin stimulates the CNS directly leading to hyperpnoea
• Overdose symptoms include nausea/vomiting, diarrhea, restlessness, tinnitus, vertigo, hyperpyrexia, hypovolemia, pulmonary edema, dysrhythmias, acute renal failure, seizures, and coma
• No specific antidote exists for aspirin overdose; treatment involves activated charcoal
• Urinary alkalinisation may be beneficial
• Hemodialysis is used in severe poisoning cases

Indications for the use of NSAIDs

• Rectal and parenteral administration is often used after a C-section, vaginal delivery, or pelvic/other surgery to reduce gastric effects and first-pass metabolism
• Administered IM or IV in hospital for post-surgical pain or other inflammatory pain
• Oral administration is common for muscle injuries, traumatic injuries, joint pain, inflammatory conditions, gout, fever, arthritis, and dysmenorrhoea
• Indomethacin is used in premature infants to promote closure of the ductus arteriosus

The Glucocorticosteroids

• Side effects (mostly due to chronic administration) and include:
  • Immune suppression
  • HPA-axis suppression
  • Osteoporosis
  • Cataracts
  • Increased IOP
  • Ophthalmic infections
  • Hyperglycaemia
  • Hypertension
  • Weight gain
  • Abnormal fat distribution
  • GIT disturbances
  • Growth retardation (paediatric patients)
  • Atrophy of the epidermis and dermal collagen (topical)
• Indications:
  • Pain and inflammation
  • Rheumatic and other inflammatory disorders
  • Gout
  • Joint and tendon pain (intra-articular administration)
  • Allergic, immune and autoimmune disorders

DMARDs

• Disease-Modifying AntiRheumatic Drugs (DMARDs) are used for chronic inflammatory conditions like tendinitis, osteoarthritis and autoimmune disorders.
• DMARDS modify the progression of disease and treat inflammation
• Synthetic drugs
  • Sulphasalazine is anti-inflammatory
  • Methotrexate acts as an antifolate in cancer chemotherapy
• Biological agents:
  • Monoclonal antibodies include infliximab, adalimumab, rituximab, etc.
  • Receptor fusion proteins include etanercept and abatacept

Paracetamol

• Paracetamol is widely available, inhibits COX3 in the central nervous system, and has no peripheral inflammatory effects
• Indications are pain and fever, and is the drug of choice for children, infants, and pregnant women
• Side effects are few at therapeutic doses, with hypothermia
• Symptoms include pallor, malaise and sweating.

• 150 mg/kg is considered toxic

• Treatment of overdose:
  • Acetylcystein (Parvolex)
  • Administer 150 mg/kg in 200 mL 5% dextrose over 1 hour
  • Followed by 50 mg/kg in 500 mL 5% dextrose over 4 hours
  • Followed by 100 mg/kg in 1L 5% dextrose over 16 hours
  • Total dose is 300 mg/kg over 24 hours
  • Followed by 150 mg/kg in 1L 5% dextrose over 24 hours

Opioids

• Opioids are used for analgesia, including anaesthesia
• Include opiates drugs derived from opium, including morphine
• They act as agonists on mu, kappa and delta opioid receptors
• Indications include suppression of diarrhoea and cough, and replacement therapy for opioid use disorder
• Side effects include sedation, nausea, respiratory depression, constipation, euphoria, tolerance and physical dependence
• Overdose symptoms include pinpoint pupils, respiratory depression, and a decreased level of consciousness
• Naloxone is a life-saving medication that can reverse an overdose from opioids
• Naloxone is a lipophilic compound that is a non-selective and competitive opioid receptor antagonist

Specific Pain Disorders: Gout

• A familial metabolic disease caused by increased plasma uric acid levels
• Uric acid is an end product of purine metabolism (protein breakdown)
• Uric acid crystals form in joints, causing pain and inflammation
• Gout can be of an acute or chronic nature and usually appears in small joints, e.g. MP joint
• Foods that trigger gout include red meat, alcohol and fructose
• Treatment includes:
  • Lifestyle adjustment
  • ↓Pain & inflammation: NSAIDs; colchicine; glucocorticoids
  • ↑Renal clearance of uric acid: uricosuric drugs (probenecid)
  • ↓Conversion of purines to uric acid: xanthine oxidase inhibitors (allopurinol)

Specific Pain Disorders: Migraine

• Migraine is a severe and debilitating headache, often unilateral, feeling like it is behind the eye
• May include vision disturbances, photophobia, nausea, and vomiting
• Often preceded by prodrome and aura
• Treatment includes
  • NSAIDs and paracetamol; opioids (analgesics)
  • Triptans (5HT1B&D agonists): rizatriptan; sumatriptan; zolmitriptan; naratriptan; eletriptan
  • Ergot alkaloids (5HT1&2 agonists): ergotamine
  • Preventative: beta-blockers; anti-epileptics; calcium channel blockers; antidepressants