Aches and pains

1. Aches and pains Non-opiate analgesics, drugs for arthritis and opiates.

2. This talk • Pain • Arthritis • osteoarthrosis • rheumatoid arthritis • gout • Analgesics – paracetamol and NSAIDs • Drugs for arthritis • Opiates

3. Pain • Somatic • inflammation of epithelial surfaces, trauma, sepsis • felt at site of pathology • Visceral • e.g. myocardial ischaemia, colic • poor localisation, often ‘referred’ • Neurogenic • e.g. neuralgia • no response to analgesics

4. The Ladybird book of arthritis: osteoarthrosis • A disease of cartilage • More common in women than men • Aetiology: • Mechanical insults • Age: osteo. usually a problem in late middle age onwards • Abnormalities of cartilage: genetics

5. Osteoarthrosis continued • Usually large weight-bearing joints: hips, knees. • Primary familial osteo: distal interphalangeal joints (Heberden’s nodes). • Pain, limited movement, inflammation, crepitus • Joint space narrowing, osteophytes

7. Heberden’s nodes

8. Rheumatoid disease • Rd-D affects many tissues other than joints. • A chronic inflammatory condition of unknown cause • Autoantibodies are often present

9. Rheumatoid disease • Can affect any age group • Insidious onset of inflammation of small joints: hands, feet, neck • In the hands: proximal IPJ and MCPJ • Inflammation, deformity, Rh-D nodules (commonly at the elbow)

10. Proximal interphalangeal joints Metacarpo-phalangeal joints

11. Olecrannon bursitis (fluid-filled) Rheumatoid nodule (solid and rubbery)

12. Gout • Abnormal uric acid metabolism. • Most common in middle-aged males. • Commonest in the first MTPJ of the foot. • But can involve any joint (other than the axial skeleton). • Uric acid may also be deposited in tissues, and may form urinary stones

13. Gout • Acute gout • sudden onset of severe arthritis • a disease of paroxysms • Chronic tophaceous gout

14. First metatarso- phalangeal joint

18. Drugs: overview • Paracetamol • Aspirin • Other NSAIDs • Rh-D ‘disease-modifying’ drugs’ • Drugs specifically for gout

19. Paracetamol • Mechanism of analgesic activity not fully understood: ?  prostaglandin synthesis in the CNS • Mechanism of antipyretic activity:  PG-E2 in the hypothalamus

20. Paracetamol • Safe effective analgesic used OTC • analgesia • lowering elevated temperature • it has no anti-inflammatory effect

21. Dangerous in overdose

22. Dangerous in overdose saturated

23. Dangerous in overdose The main problem is hepatotoxicity Takes around 24-36 h to become apparent saturated There is an antidote But you need to use it in the first 24 h The degree of damage correlates with paracetamol conc.

24. NSAIDs

25. Phospholipase A2 Arachidonic acid COX-I COX-II Leukotrienes PGs with gastric protective effects PGs with inflammatory effects Membrane phospholipid

26. steroids X Membrane phospholipid Phospholipase A2 Arachidonic acid COX-I COX-II Leukotrienes PGs with gastric protective effects PGs with inflammatory effects

27. steroids X Membrane phospholipid Phospholipase A2 Older NSAIDs Arachidonic acid X X COX-I COX-II Leukotrienes PGs with gastric protective effects PGs with inflammatory effects

28. steroids X Membrane phospholipid Phospholipase A2 Arachidonic acid COX-II inh X COX-I COX-II Leukotrienes PGs with gastric protective effects PGs with inflammatory effects

29. Aspirin • Acetylsalicylic acid • Analgesic/antipyretic at low dose • Anti-inflammatory at high dose • (Anti-platelet activity at low dose) • Upper GI irritation and bleeding

30. Aspirin • Partly eliminated unchanged in the urine • Revisit the Henderson-Hasselbach equation and it’s relevance to aspirin OD.

31. Older NSAIDs • (Ibuprofen: OTC as an analgesic) • Naproxen • Diclofenac • Useful in osteo, rheumatoid and gout • Diminish inflammation • No effect on disease progression in Rh-D

32. COX-II inhibitors • Rofecoxib • Anti-inflammatory, useful for Rh-D • Much more expensive than older NSAIDs • Reserve for selected patients with PUD or GORD. • Rofecoxib withdrawn because of SAEs - ? A class effect?

33. NSAID adverse effects • GI • Salt and water retention • Renal impairment • Asthma may be precipitated

34. ‘Disease modifying drugs’ for Rh-D • Gold (sodium aurothiomalate) • Penicillamine • Used to slow disease progression • Do not have immediate impact • Limited by adverse effects: serious and frequent

35. ‘Disease modifying drugs’ for Rh-D • Gold • rashes • nephritis • blood dyscrasias • Penicillamine • rashes • nephropathy (proteinuria) • loss of taste • blood dyscrasias and haemolysis

36. Xanthine oxidase Acute and chronic gout • NSAID • Steroid • Allopurinol purines URIC ACID

37. Xanthine oxidase Acute gout • NSAID • Steroid • Allopurinol purines X URIC ACID

38. Opiates • Endorphins are endogenous compounds released in the CNS in response to pain. Three receptor sub-types. •  - analgesia and euphoria •  - analgesia •  - dysphoria and hallucination • Opiate analgesics bind to endorphin receptors.

39. Effects of the opiates • CNS: analgesia, euphoria, sedation (inc. resp depression), cough suppression, nausea. • GI tract: slow transit, constipation, sphincter of Oddi contraction. • CVS: vasodilatation leading to drop in BP and heart work.

40. Clinical PK of the opiates • All are well absorbed from IM and SC injection. • All subject to first-pass metabolism. • All are terminated by liver metabolism.

41. Examples • Codeine: relatively low potency • Pethidine: higher potency, short half-life. Less effect on sphincter of Oddi. • Morphine and diamorphine: most potent, longer half-life than pethidine.

42. Uses • Severe somatic and visceral pain. • No benefit in patients with neurogenic pain. • Pulmonary oedema. • Cough suppression. • Diarrhoea.

43. Adverse effects and contraindications • ADRs: • Nausea • Constipation • Addiction • Respiratory depression: type-2 resp failure. • Biliary colic. • Contraindications: • Severe respiratory problems • Hepatic impairment • Head injury (resp depression and CO2 retention

44. Reversal • Naloxone. • Rapid elimination: • Faster than the opiates. • You may be suffering a false sense of security: the patient needs observation. • Dose may need to be repeated. • Infusion may be required.