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The Mechanisms of Action of NSAIDs in Analgesia

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Summary

Traditionally, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained on the basis of their inhibition of the enzymes that synthesise prostaglandins. However, it is clear that NSAIDs exert their analgesic effect not only through peripheral inhibition of prostaglandin synthesis but also through a variety of other peripheral and central mechanisms.

It is now known that there are 2 structurally distinct forms of the cyclo-oxygenase enzyme (COX-1 and COX-2). COX-1 is a constitutive member of normal cells and COX-2 is induced in inflammatory cells. Inhibition of COX-2 activity represents the most likely mechanism of action for NSAID-mediated analgesia, while the ratio of inhibition of COX-1 to COX-2 by NSAIDs should determine the likelihood of adverse effects. In addition, some NSAIDs inhibit the lipoxygenase pathway, which may itself result in the production of algogenic metabolites. Interference with G-protein-mediated signal transduction by NSAIDs may form the basis of an analgesic mechanism unrelated to inhibition of prostaglandin synthesis.

There is increasing evidence that NSAIDs have a central mechanism of action that augments the peripheral mechanism. This effect may be the result of interference with the formation of prostaglandins within the CNS. Alternatively, the central action may be mediated by endogenous opioid peptides or blockade of the release of serotonin (5-hydroxytryptamine; 5-HT). A mechanism involving inhibition of excitatory amino acids or N-methyl-D-aspartate receptor activation has also been proposed.

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References

  1. Rang HP, Bevan S, Dray A. Chemical activation of nociceptive peripheral neurones. Br Med Bull 1991; 47: 534–48

    PubMed  CAS  Google Scholar 

  2. Dray A. Inflammatory mediators of pain. Br J Anaesth 1995; 75: 125–31

    PubMed  CAS  Google Scholar 

  3. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63: 139–46

    Article  PubMed  CAS  Google Scholar 

  4. Woolf CJ. Generation of acute pain: central mechanisms. Br Med Bull 1991; 47: 523–33

    PubMed  CAS  Google Scholar 

  5. Dahl J, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth 1991; 66: 703–12

    Article  PubMed  CAS  Google Scholar 

  6. Dahl J, Kehlet H. The value of preemptive analgesia in the treatment of postoperative pain. Br J Anaesth 1993; 70: 434–9

    Article  PubMed  CAS  Google Scholar 

  7. Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Acta Anaesthesiol Scand 1995; 39 Suppl. 103: 1–44

    Google Scholar 

  8. Ferreira SH. Inflammatory pain, prostaglandin hyperalgesia and the development of peripheral analgesics. Trends Pharmacol Sci 1981; 2: 183–6

    Article  CAS  Google Scholar 

  9. Raja S, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology 1988; 68: 571–90

    Article  PubMed  CAS  Google Scholar 

  10. Jordan CC. Anatomical and physiological aspects of pain perception. In: Kaufman L, editor. Anaesthesia review 2. Edinburgh: Churchill Livingstone, 1984: 87–107

    Google Scholar 

  11. Besson JM, Chaouch A. Peripheral and spinal mechanisms of nociception. Physiol Rev 1987; 67: 67–186

    PubMed  CAS  Google Scholar 

  12. Davies SN, Lodge D. Evidence for involvement of N-methyl-D-aspartate receptors in ‘wind up’ of class 2 neurones in the dorsal horn of the rat. Brain Res 1987; 424: 402–6

    Article  PubMed  CAS  Google Scholar 

  13. Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin induced tissue injury. J Neurosci 1992; 12: 3665–70

    PubMed  CAS  Google Scholar 

  14. Vane JR, Botting RM. The mode of action of anti-inflammatory drugs. Postgrad Med J 1990; 66 Suppl. 4: S2–17

    PubMed  CAS  Google Scholar 

  15. Dray A, Bevan S. Inflammation and hyperalgesia: highlighting the team effort. Trends Pharmacol Sci 1993; 14: 287–90

    Article  PubMed  CAS  Google Scholar 

  16. Watanabe M, Yamade M, Mue S, et al. Enhancement by cyclooxygenase inhibitors of platelet-activating factor production in thapsigargin-stimulated macrophages. Br J Pharmacol 1995; 116: 2141–7

    Article  PubMed  CAS  Google Scholar 

  17. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from spleen. Nature 1971; 231: 237–9

    Article  CAS  Google Scholar 

  18. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) 1971; 231: 232–5

    CAS  Google Scholar 

  19. Ferreira SH. Peripheral analgesia: mechanism of the analgesic action of aspirin like drugs and opiate-antagonists. Br J Clin Pharmacol 1980; 10: 237S–45S

    Article  PubMed  Google Scholar 

  20. Ferreira SH. Prostaglandins, aspirin-like drugs and analgesia. Nature (New Biol) 1972; 240: 200–3

    Article  CAS  Google Scholar 

  21. Higgs GA. Arachidonic acid metabolism, pain and hyperalgesia: the mode of action of non-steroid analgesics. Br J Clin Pharmacol 1980; 10: 233S–5S

    Article  PubMed  Google Scholar 

  22. Higgs GA, Higgs EA, Salmon JA. Prostacyclin in inflammation. In: Vane JR, Bergstrom S, editors. Prostacyclin. New York: Raven Press, 1979: 187–92

    Google Scholar 

  23. Higgs GA, Salmon JA, Henderson B, et al. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Natl Acad Sci USA 1987; 84: 1417–20

    Article  PubMed  CAS  Google Scholar 

  24. Lands WEM. Actions of anti-inflammatory drugs. Trends Pharmacol Sci 1981; 2: 78–80

    Article  CAS  Google Scholar 

  25. Rome LH, Lands WEM. Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Natl Acad Sci USA 1975; 72: 4863–5

    Article  PubMed  CAS  Google Scholar 

  26. Tsai AL, Kulmacz RJ, Palmer G. Spectroscopic evidence for reaction of prostaglandin H synthase-1 tyrosyl radical with arachidonic acid. J Biol Chem 1995; 270: 10503–8

    Article  PubMed  CAS  Google Scholar 

  27. Hemler M, Lands WEM. Evidence for a peroxide-initiated free radical mechanism of prostaglandin biosynthesis. J Biol Chem 1980; 255: 6253–61

    PubMed  CAS  Google Scholar 

  28. Lands WEM, Cook HW, Rome LH. Prostaglandin biosynthesis: consequences of oxygenase mechanisms on in vitro assays of drug effectiveness. Adv Prostaglandin Thromboxane Leukot Res 1976; 1: 7–17

    CAS  Google Scholar 

  29. Vane JR, Flower RJ, Botting RM. The mechanism of action of aspirin. In: Vane JR, Botting RM, editors. Aspirin and other salicylates. London: Chapman & Hall Medical, 1992: 35–59

    Google Scholar 

  30. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. 1. Acetylation of a particiulate fraction protein. J Clin Invest 1975; 56: 624–32

    Article  PubMed  CAS  Google Scholar 

  31. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandm synthase by aspirin. Proc Natl Acad Sci USA 1975; 72: 3073–6

    Article  PubMed  CAS  Google Scholar 

  32. Kulmacz RJ, Lands WEM. Stoichometry and kinetics of the interaction of prostaglandin H synthase with anti-inflammatory agents. J Biol Chem 1985; 260: 12572–8

    PubMed  CAS  Google Scholar 

  33. Picot D, Loll PJ, Garavito RM. The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994; 367: 243–9

    Article  PubMed  CAS  Google Scholar 

  34. Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 1995; 2: 637–43

    Article  PubMed  CAS  Google Scholar 

  35. Kulmacz RJ. Topography of prostaglandin H synthase: anti-inflammatory agents and the protease-sensitive arginine 253 region. J Biol Chem 1989; 264: 14136–44

    PubMed  CAS  Google Scholar 

  36. Mitchell A, Akarasereenont P, Thiermann C, et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1993; 90: 11693–7

    Article  PubMed  CAS  Google Scholar 

  37. Vane JR, Mitchell JA, Appleton I, et al. Inducible isoforms of cyclooxygenase and nitric oxide synthase in inflammation. Proc Natl Acad Sci USA 1994; 91: 2046–50

    Article  PubMed  CAS  Google Scholar 

  38. Xie W, Robertson DL, Simmons DL. Mitogen-inducible prostaglandin G/H synthase: a new target for nonsteroidal anti-inflammatory drugs. Drug Dev Res 1992; 25: 249

    Article  CAS  Google Scholar 

  39. Jones DA, Carlton DP, McIntyre TM, et al. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 1993; 268: 9049–54

    PubMed  CAS  Google Scholar 

  40. Coleman RA, Smith WL, Narimiya S. Classification of prostanoid receptors: properties, distribution and structure of the receptors and their subtypes. Pharmacol Rev 1994; 46: 205–29

    PubMed  CAS  Google Scholar 

  41. Seibert K, Zhinag Y, Leahy K, et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 1994; 91: 12013–7

    Article  PubMed  CAS  Google Scholar 

  42. Hla T, Nielson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1992; 89: 7388–9

    Article  Google Scholar 

  43. Rang HP, Urban L. New molecules in analgesia. Br J Anaesth 1995; 75: 145–56

    PubMed  CAS  Google Scholar 

  44. Panara MR, Greco A, Santini G, et al. Effects of the novel anti-inflammatory compounds, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398) and 5-methanesulphonamido-6- (2,4-difluorothiophenyl)-1- in-danon (L-745,337), on the cyclo-oxygenase activity of human blood prostaglandin endoperoxide synthases. Br J Pharmacol 1995; 116: 2429–34

    Article  PubMed  CAS  Google Scholar 

  45. McCormack K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994; 59: 9–43

    Article  PubMed  CAS  Google Scholar 

  46. Vane JR. Towards a better aspirin. Nature 1994; 367: 215–6

    Article  PubMed  CAS  Google Scholar 

  47. Anon. Will new drugs make old NSAIDs redundant? Pharm J 1995; 255: 537

  48. Hayllar J, Bjarnason I. NSAIDs, Cox-2 inhibitors, and the gut. Lancet 1995; 346: 521–2

    Article  PubMed  CAS  Google Scholar 

  49. Boyce S, Chan C, Gordon R, et al. A selective inhibitor of cyclooxygenase-2 elicits antinociception but not gastric secretion in rats. Neuropharm 1994; 33: 1609–11

    Article  CAS  Google Scholar 

  50. Vane J. NSAIDs, Cox-2 inhibitors, and the gut [letter]. Lancet 1995; 346: 1105–6

    Article  PubMed  CAS  Google Scholar 

  51. Ku EC, Lee W, Kothari HV, et al. Effect of diclofenac sodium on the arachidonic acid cascade. Am J Med 1986; 80 Suppl. 4B: 18–23

    Article  PubMed  CAS  Google Scholar 

  52. O’Neil LAJ, Lewis GP. Inhibitory effects of diclofenac and indomethacin on interleukin-1-induced changes in PGE2 release. Biochem Pharmacol 1989; 38: 3707–11

    Article  Google Scholar 

  53. Abramson S, Korchak HM, Ludewig R, et al. Modes of action of aspirin-like drugs. Proc Natl Acad Sci USA 1985; 82: 7227–31

    Article  PubMed  CAS  Google Scholar 

  54. Minta JO, Williams MD. Some nonsteroidal antiinflammatory drugs inhibit the generation of Superoxide anions by activated polymorphs by blocking ligand-receptor interactions. J Rheumatol 1985; 12: 751–7

    PubMed  CAS  Google Scholar 

  55. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs —differences and similarities. NEngl J Med 1991; 324: 1716–25

    Article  CAS  Google Scholar 

  56. Lim LK, Hunt NH, Eichner RD, et al. Cyclic AMP and the regulation of prostaglandin production by macrophages. Biochem Biophys Res Commun 1983; 114: 248–54

    Article  PubMed  CAS  Google Scholar 

  57. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32: 1–9

    Article  PubMed  CAS  Google Scholar 

  58. Brune K, Beck WS, Geisslinger G, et al. Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition. Experientia 1991; 47: 257–61

    Article  PubMed  CAS  Google Scholar 

  59. McCormack K, Brune K. Dissociation between the antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs: a survey of their analgesic efficacy. Drugs 1991; 41: 533–47

    Article  PubMed  CAS  Google Scholar 

  60. McCormack K. The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects. Drugs 1994; 47 Suppl. 5: 28–45

    Article  PubMed  CAS  Google Scholar 

  61. Hunskaar S. Similar effects of acetylsalicylic acid and morphine on immediate responses to acute noxious stimulation. Pharmacol Toxicol 1987; 60: 167–70

    Article  PubMed  CAS  Google Scholar 

  62. Carlsson K-H, Mangel W, Jurna I. Depression by morphine and the non-opioid analgesic agents, metamizol (dipyrone), lysine acetylsalicylate, and paracetamol, of activity in rat thalamus neurones by electrical stimulation of nociceptive afferents. Pain 1988; 32: 313–26

    Article  PubMed  CAS  Google Scholar 

  63. Jurna I, Brune K. Central effect of the non-steroid anti-inflammatory agents, indomethacin, ibuprofen, and diclofenac, determined in C fibre-evoked activity in single neurones of the rat thalamus. Pain 1990; 41: 71–80

    Article  PubMed  CAS  Google Scholar 

  64. Wang BC, Li D, Hiller J. The antinociceptive effect of S-(+)-ibuprofen in rabbits: epidural versus intravenous administration. Anesth Analg 1995; 80: 92–6

    PubMed  CAS  Google Scholar 

  65. Moore UJ, Marsh VR, Ashton CH, et al. Effects of peripherally and centrally acting analgesics on somatosensory evoked potentials. Br J Clin Pharmacol 1995; 40: 111–7

    Article  PubMed  CAS  Google Scholar 

  66. Devoghel J-C. Small intrathecal doses of lysine-acetylsalicylate relieve intractable pain in man. J Int Med Res 1983; 11: 90–1

    PubMed  CAS  Google Scholar 

  67. Hougaard K, Nilsson B, Wieloch T. Fatty acid cyclo-oxygenase inhibitors and the regulation of cerebral blood flow. Acta Physiol Scand 1983; 117: 585–7

    Article  PubMed  CAS  Google Scholar 

  68. Wennmalm R, Carlsson A, Edlund A, et al. Central and peripheral haemodynamic effects of non-steroidal anti-inflammatory drugs in man. Arch Toxicol Suppl. 1984; 7: 350–9

    Article  PubMed  CAS  Google Scholar 

  69. Abdel-Halim MS, Sjoqvist B, Anggard E. Inhibition of prostaglandin synthesis in rat brain. Acta Pharmacol Toxicol 1978; 43: 266–72

    Article  CAS  Google Scholar 

  70. Attal N, Kayser V, Eschalier A, et al. Behavioural and electro-physiological evidence for an analgesic effect of a nonsteroidal anti-inflammatory agent, diclofenac. Pain 1988; 35: 341–8

    Article  PubMed  CAS  Google Scholar 

  71. Martini A, Bondiolotti GP, Sacerdote P, et al. Diclofenac increases beta-endorphin plasma concentrations. J Int Med Res 1984; 12: 92–5

    PubMed  CAS  Google Scholar 

  72. Saccerdote P, Monza G, Mantegazza P, et al. Diclofenac and pirprofen modify pituitary and hypothalamic beta-endorphin concentrations. Pharmacol Res Commun 1985; 17: 679–84

    Article  Google Scholar 

  73. Vescovi P, Passeri M, Gerra G, et al. Naloxone inhibits the early phase of diclofenac analgesia in man. Pain Clinic 1987; 19: 151–5

    Google Scholar 

  74. Groppetti A, Braga PC, Biella G, et al. Effect of aspirin on serotonin and met-enkaphalin in brain: correlation with the antinociceptive activity of the drug. Neuropharmacol 1988; 27: 499–505

    Article  CAS  Google Scholar 

  75. Domer F. Characterization of the analgesic activity of ketorolac in mice. Eur J Pharmacol 1990; 177: 127–35

    Article  PubMed  CAS  Google Scholar 

  76. Gerra G, Vescovi PP, Pezzarossa A, et al. Successful treatment of opiate withdrawal using lysine acetylsalicylate. Current Ther Res 1983; 33: 733–9

    Google Scholar 

  77. Gerra G, Ceresini G, Rastelli G, et al. Effect of diclofenac on the opiate withdrawal syndrome. Giornale Clin Med 1985; 66: 459–60

    CAS  Google Scholar 

  78. Smullin DH, Skilling SR, Larson AA. Interactions between substance P, calcitonin gene-related peptide, taurine and excitatory amino acids in the spinal cord. Pain 1990; 42: 93–101

    Article  PubMed  CAS  Google Scholar 

  79. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992; 257: 1276–9

    Article  PubMed  CAS  Google Scholar 

  80. Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Ther 1992; 263: 136–46

    CAS  Google Scholar 

  81. Malmberg AB, Yaksh TL. Antinociception produced by the spinal delivery of the S and R enantiomers of flurbiprofen in the formalin test. Eur J Pharmacol 1994; 256: 205–9

    Article  PubMed  CAS  Google Scholar 

  82. Hunskaar S, Fasmer OB, Hole K. Acetylsalicylic acid, paracetamol and morphine inhibit behavioural response to intra-thecally administered substance P or capsaicin. Life Sci 1985; 37: 1835–41

    Article  PubMed  CAS  Google Scholar 

  83. Day RO, Williams KM, Graham GG, et al. Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 1988; 43: 480–7

    Article  PubMed  CAS  Google Scholar 

  84. McCormack K, Urquhart E. Correlation between nonsteroidal anti-inflammatory drug efficacy in a clinical pain model and the dissociation of their anti-inflammatory and analgesic properties in animal models. Clin Drug Invest 1995; 9: 88–97

    Article  CAS  Google Scholar 

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  1. Department of Anaesthetics, St George’s Hospital, Blackshaw Road, London, SW17 OQT, England

    Jeremy N. Cashman

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Cashman, J.N. The Mechanisms of Action of NSAIDs in Analgesia. Drugs 52 (Suppl 5), 13–23 (1996). https://doi.org/10.2165/00003495-199600525-00004

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