Skip to main content
SpringerLink
Log in

The antialgesic drugs: Human therapeutic correlates of their potency in laboratory animal models of hyperalgesia

  • Immunosuppression and Inflammation
  • Review
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

This survey discusses the correlation between the oral potency of antialgesic drugs in several pharmacology laboratories and their human oral dose in clinical practice. We also present a brief overview of a few biological assays that have been successfully used to direct the synthesis of newer antialgesic drugs. The laboratory assay that our analysis showed to be most predictive of the clinical analgesic dose is based upon the response of rats to flexion of an arthritic joint. Laboratory ED50 values from the ACh-induced abdominal constriction assay in mice are nearly as predictive while the predictive power of the yeast-induced hyperalgesia assay in rats is somewhat less. Probably because of the small number of experiments, the correlation between the efficacy of these agents in a canine model of synovitis and their clinical doses only reached borderline statistical significance (p=0.0651). Regression equations are presented that permit calculations of single clinical analgesic doses from efficacy data in individual tests. Calculation of stepwise multiple regression showed that the clinical dose could be best predicted when efficacy data obtained in the joint flexion assay in rats and the ACh-induced constriction assay in mice are both taken into account. We have concluded that the effective doses are highly predictive of clinical efficacy because these animal assays have been designed to reflect the action of drugs upon prostanoid-induced hyperalgesia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. S. H. Ferreira and J. R. Vane,New aspects of the mode of action of non-steroidal antiinflammatory drugs. Ann. Rev. Pharmacol.14, 57–73 (1974).

    Google Scholar 

  2. S. H. Ferreira, M. Nakamura and N. S. Castro,The hyperalgesic effects of prostacyclin and prostaglandin E 2. Prostaglandins16, 31–37 (1978).

    PubMed  Google Scholar 

  3. S. H. Ferreira and M. I. Nakamura,Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins18, 179–190 (1979).

    PubMed  Google Scholar 

  4. N. A. Cummings and G. L. Nordby,Measurement of synovial fluid pH in normal and arthritic knees. Arthritis Rheum.9, 47–51 (1966).

    PubMed  Google Scholar 

  5. H. O. Handwerker, InAdvances in Pain Research and Therapy. Vol. 1. Proceedings of the First World Congress on Pain (J. J. Bonica and D. Albe-Fessards, eds.) Raven press, New York, 1976, p. 41.

    Google Scholar 

  6. H. O. Handwerker, InAdvances in Pain Research and Therapy. Vol. 1. Proceedings of the First World Congress on Pain (J. J. Bonica and D. Albe-Fessards, eds.) Raven press, New York, 1976, p. 17.

    Google Scholar 

  7. S. H. FerreiraProstaglandins, aspirin-like drugs and analgesia. Nature, New Biol.240, 200–203 (1972).

    Google Scholar 

  8. C. A. Keele and D. Armstrong,Substances producing pain and itch. Edward Arnold, London 1964.

    Google Scholar 

  9. B. Dubinsky and J. J. Schupsky,Mechanism of action of suprofen, a new peripheral analgesic, as demostrated by its effects on several nociceptive mediators. Prostaglandins28, 241–253 (1984).

    PubMed  Google Scholar 

  10. R. J. Capetola, M. E. Rosenthale, B. Dubinsky and J. L. McGuire,Peripheral Antialgesics: A review. J. Clin. Pharm.23, 545–556 (1983).

    Google Scholar 

  11. J. R. Vane,Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs Nature, New Biol.231, 232–235 (1971).

    Google Scholar 

  12. R. J. Flower,Drugs which inhibit prostaglandin biosynthesis. Pharmacol. Rev.20, 33–67 (1974).

    Google Scholar 

  13. W. T. Beaver,Analgesic development: A brief history and perspective. J. Clin. Pharmacol.20, 213–215 (1980).

    Google Scholar 

  14. G. W. Snedecor and W. G. Cochran,Statistical Methods. Sixth edition, Iowa State Univ. Press, Ames, Iowa, 1967.

    Google Scholar 

  15. E. A. Siegmund, R. A. Cadmus and G. Lu,A method for evaluating both non-narcotic and narcotic analgesics. Proc. Soc. Exp. Biol. Med.95, 729–731 (1957).

    PubMed  Google Scholar 

  16. R. Koster, M. Anderson and E. J. de Beer,Acetic acid for analgesic screening. Fed. Proc.18, 412 (1959).

    Google Scholar 

  17. R. J. Capetola, D. A. Shriver and M. E. Rosenthale,Suprofen, a new peripheral analgesic. J. Pharmacol. Exp. Ther.214, 16–23 (1980).

    PubMed  Google Scholar 

  18. H. O. J. Collier, L. C. Dinneen, C. A. Johnson and C. Schneider,Thie abdominal constriction response and its suppression by analgesic drugs in the mouse. Br. J. Pharmac. Chemother.32, 295–310 (1968).

    Google Scholar 

  19. H. O. J. Collier, A. R. Hammond, S. Horwood-Barrett and C. Schneider,Rapid induction by acetylcholine, bradykinin and potassium of a nociceptive response in mice and its selective antagonism by aspirin. Nature204, 1316–1318 (1964).

    Google Scholar 

  20. N. H. Andersen and P. W. Ramwell,Biological aspects of prostaglandins, Arch. Intern. Med.133, 30–50 (1974).

    PubMed  Google Scholar 

  21. S. F. Pong, S. M. Demuth, C. M. Kinney and P. Deegan,Prediction of human analgesic dosages of nonsteroidal antiinflammatory drugs from analgesic ED 50 values, in mice. Arch. int. Pharmacodyn.273, 212–220 (1985).

    PubMed  Google Scholar 

  22. L. O. Randall and J. J. Selitto,A method for measurement of analgesic activity on inflamed tissue. Arch. int. Pharmacodyn. Ther111, 409–419 (1957).

    PubMed  Google Scholar 

  23. C. A. Winter and L. Flataker,Nociceptive thresholds as affected by parenteral administration of irritants and of various antinociceptive drugs. J. Pharmacol. Exp. Ther.148, 373–379 (1965).

    PubMed  Google Scholar 

  24. D. Romer,Pharmacological evaluation of mild analgesics. Br. J. Clin. Pharmac.10, 247S-251S (1980).

    Google Scholar 

  25. K. Hirose and H. Jyoyama,Measurement of arthritic pain and effects of analgesics in the adjuvant-treated rat. Japan. J. Pharmacol.21, 717–720 (1971).

    Google Scholar 

  26. S. Kuzuna and K. Kawai,Evaluation of analgesic agents in rats with adjuvant arthritis. Chem. Pharm. Bull.23, 1184–1191 (1975).

    PubMed  Google Scholar 

  27. A. W. Pircio, C. T. Fedele, and M. E. Bierwagen,A new method for the evaluation of analgesic activity using adjuvant-induced arthritis in the rat. Eur. J. Pharmacol.31, 207–215 (1975).

    PubMed  Google Scholar 

  28. C. A. Winter, P. L. Kling, D. J. Tocco and K. Tanabe,Analgesic activity of diflunisal [MK-647; 5-(2,4-difluorophenyl) salicylic acid] in rats with hyperalgesia induced by Freund's adjuvant. J. Pharmacol. Exp. Ther.211, 678–685 (1979).

    PubMed  Google Scholar 

  29. J. S. Faires and D. J. McCarty, Jr.,Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals. Lancet2, 682–685 (1962).

    Google Scholar 

  30. D. J. McCarty Jr. and J. S. Faires,A comparison of the duration of local anti-inflammatory effect of several adrenocorticosteroid esters—a bioassay technique. Curr. Ther. Res.5, 284–290 (1963).

    PubMed  Google Scholar 

  31. E. Fujihara, T. Mori, M. Nakazawa and H. Ozawa,A simple method for evaluating analgesic efficacy of nonsteroidal anti-inflammatory drugs. Chem. Pharm. Bull.19, 1506–1508 (1971).

    PubMed  Google Scholar 

  32. M. E. Rosenthale, J. Kassarich and F. Schneider, Jr.,Effect of anti-inflammatory agents on acute experimental synovitis in dogs. Proc. Soc. Exp. Biol. Med.122, 693–696 (1966).

    PubMed  Google Scholar 

  33. C. G. van Arman, R. P. Carlson, E. A. Risley, R. H. Thomas and G. W. Nuss,Inhibitory effects of indomethacin, aspirin and certain other drugs on inflammations induced in rat and dog by carrageenan, sodium urate and ellagic acid. J. Pharmacol. Exp. Ther.175, 459–468 (1970).

    PubMed  Google Scholar 

  34. M. E. Rosenthale, A. Dervinis, J. Kassarich and S. Singer,Prostaglandins and antiinflammatory drugs in the dog knee joint. J. Pharm. Pharmacol.24, 149–150 (1972).

    PubMed  Google Scholar 

  35. Y. H. Chang and E. J. Gralla,Suppression of urate crystal-induced canine joint inflammation by heterologous antipolymorphonuclear leukocyte serum. Arthritis Rheum.11, 145–150 (1976).

    Google Scholar 

  36. Y. H. Chang,Studies on phagocytosis. II. The effect of nonsteroidal anti-inflammatory drugs on phagocytosis and on urate crystal-induced canine joint inflammation. J. Pharmacol. Exp. Ther.183 235–244 (1972).

    PubMed  Google Scholar 

  37. T. G. Kantor, Peripherally-acting analgesics. InAnalgesics: Neurochemical, Behavioral and Clinical Perspectives (Ed. M. Kuhar and G. Pasternak) Raven Press, New York 1984.

    Google Scholar 

  38. H. M. Silberman,Multidose comparison of suprofen, aspirin and placebo in the treatment of musculoskeletal pain. Pharmacology27 (Suppl. 1), 65–73 (1983).

    Google Scholar 

  39. D. E. Bowers, S. Honig, J. L. Miller and M. C. Gardner,A long-term double-blind evaluation of suprofen and aspirin in osteoarthritis. Pain (Suppl. 2), S 237 (1984).

    Google Scholar 

  40. R. A. Seymour and M.D. Rawlins,Efficacy and pharmacokinetics of aspirin in post-operative dental pain. Br. J. Clin. Pharmacol.13, 807–810 (1982).

    PubMed  Google Scholar 

  41. R. A. Seymour,Use of analgesics in postoperative dental pain: A review. J. Royal Soc. Med.77, 949–954 (1984).

    Google Scholar 

  42. P. J. Desjardins, S. Cooper, B. Wagenberg, R. Eskow, D. Reynolds, O. Gallegos and G. Krager,Analgesic efficacy of suprofen in two dental pain models. Clin. Pharmacol. Ther.29, 240 (1981).

    Google Scholar 

  43. A. Sunshine, I. Marrero, N. Z. Olson, E. M. Laska and N. McCormick,Oral analgesic efficacy of suprofen compared to aspirin plus codeine and placebo in patients with postoperative dental pain. Pharmacology27 (Suppl. 1), 31–40 (1983).

    PubMed  Google Scholar 

  44. D. R. Mehlisch, N. Friedmann and A. W. Van Horn,A double-blind evaluation of suprofen, aspirin and an oxycodone combination analgesic in post-operative pain. Pain (Suppl. 2), S 237 (1984).

    Google Scholar 

  45. S. A. Cooper, B. Wagenberg, R. Eskow, and J. Zissu,Double-blind evaluation of suprofen and aspirin in the treatment of periodontal pain. Pharmacology27 (Suppl. 1), 23–30 (1983).

    Google Scholar 

  46. L. Winter, Jr., E. Bass, B. Recant and J. F. Cahalay,Analgesic activity of ibuprofen (Motrin) in postoperative oral surgical pain. Oral Surg.45, 159–166 (1978).

    PubMed  Google Scholar 

  47. S. S. Bloomfield, T. P. Barden and J. Mitchel,Aspirin and codeine in two postpartum pain models. Clin. Pharmacol. Ther.20, 499–503 (1976).

    PubMed  Google Scholar 

  48. F. D. Berry,Clinical evaluation of the analgesic effects of two dose levels of suprofen (100 mg and 200 mg), aspirin 650 mg and placebo in the treatment of pain-episiotomy. Unpublished report, Ortho Pharmaceutical Corporation, 1984.

  49. W. Heffron, S. Gordon, J. May, D. Mehlisch, L. Gravlee, M. Costin, P. Budoff, Y. Dawood, H. Levin, J. Jehle and N. Friedmann,A double-blind evaluation of two dosage regimens of suprofen and ibuprofen in primary dysmenorrhea. Pain (Suppl. 2), S 238 (1984).

    Google Scholar 

  50. C. Van Winzum and B. Rodda,Diflunisal: Efficacy in postoperative pain. Br. J. Clin Pharmacol4, 395–435 (1977).

    Google Scholar 

  51. T. P. Pruss, J. F. Gardocki, R. J. Taylor and L. D. Muschek,Evaluation of the analgesic properties of zomepirac. J. Clin. Pharmacol.20, 216–222 (1980).

    PubMed  Google Scholar 

  52. W. H. Forrest, Jr.,Orally administered zomepirac and parenterally administered morphine. J. Am. Med. Assoc.244, 2298–2302 (1980).

    Google Scholar 

  53. S. L. Wallenstein, A. Rogers and R. F. Daiko,Relative analgesic potency of oral zomepirac and intramuscular morphine in cancer patients with postoperative pain. J. Clin. Pharmacol.20, 250–258 (1980).

    PubMed  Google Scholar 

  54. S. S. Adams, K. F. McCullough and J. S. Nicholson,The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch. int. Pharmacodyn. Therap.178, 115–129 (1969).

    Google Scholar 

  55. J. J. Loux, S. Smith and H. Salem,Comparative analgesic testing of various compounds in mice using writhing techniques. Arzneim.-Forsch.28, 1644–1647 (1978).

    Google Scholar 

  56. S. S. Adams, K. F. McCullough and J. S. Nicholson,Some biological properties of flurbiprofen, an anti-inflammatory, analgesic and antipyretic agent. Arzneim.-Forsch.25, 1786–1791 (1975).

    Google Scholar 

  57. G. M. Milne and T. M. Twomey,The analgetic properties of piroxican in animals and correlation with experimentally determined plasma levels. Agents and Actions10, 31–37 (1980).

    PubMed  Google Scholar 

  58. C. A. Stone, C. G. Van Arman, V. J. Lotti, D. H. Minsker, E. A. Risley, W. J. Bagdon, D. L. Bokelman, R. D. Jensen, B. Mendlowski, C. L. Tate, H. M. Peck, R. E. Zwickley and S. E. McKinney,Pharmacology and toxicology of diflunisal. Br. J. Clin. Pharmacol.4, 19S-29S (1977).

    PubMed  Google Scholar 

  59. A. P. Roszkowski, W. H. Rooks II, A. J. Tomolonis and L. M. Miller,Anti-inflammatory and analgesic properties of d-2-(6′-methoxy-2′-naphthyl)-propionic acid (Naproxen). J. Pharmacol. Exp. Ther.179, 114–123 (1971).

    PubMed  Google Scholar 

  60. A. S. Watnick, R. I. Taber and I. I. A. Tabachnik,Anti-inflammatory and analgesic properties of clonixin [2-(2′ methyl-3′ chloroanilino) nicotinic acid]. Arch. int. Pharmacodyn. Ther.190, 78–90 (1971).

    PubMed  Google Scholar 

  61. R. E. Chipkin, M. B. Latranyi, L. C. Iorio and A. Barnett,Determination of analgesic drug efficaties by modification of the Randall and Selitto rat yeast paw test. J. Pharmacol. Methods10, 223–229 (1983).

    PubMed  Google Scholar 

  62. R. J. Capetola,Personal communication. 1985.

  63. C. J. E. Niemegeers and P. A. J. Janssen,Suprofen, a potent antagonist of sodium urate crystal-induced arthritis in dogs. Arzneim.-Forsch.25, 1512–1515 (1975).

    Google Scholar 

  64. M. E. Rosenthale,Personal communication. 1985.

  65. Facts and Comparisons: Drug Information, Updated Monthly. J. B. Lippincott Co., St. Louis 1985.

  66. A. Sunshine, E. Laska and M. Meisner,Analgesic studies of indomethacin as analyzed by computer techniques. Clin. Pharmacol. Ther.5, 599–707 (1964).

    Google Scholar 

  67. Physicians Desk Reference. 39th Edition, Medical Economics Co., Inc., Oradell 1984.

  68. C. J. Smyth and J. S. Percy,Comparison of indomethacin and phenylbutazone in acute gout. Ann. Rheum. Dis.32, 351–353 (1973).

    PubMed  Google Scholar 

  69. S. S. Bloomfield, T. P. Barden and J. Mitchell,Comparative efficacy of ibuprofen and aspirin in episiotomy pain. Clin. Pharmacol. Ther.15, 565–570 (1974).

    PubMed  Google Scholar 

  70. S. A. Cooper, S. E. Needle and G. O. Kruger,Comparative analgesic potency of aspirin and ibuprofen. J. Oral Surg.35, 898–903 (1977).

    PubMed  Google Scholar 

  71. T. G. Kantor,Ibuprofen. Ann Int. Med.91, 877–882 (1979).

    PubMed  Google Scholar 

  72. R. R. Miller,Evaluation of the analgesic efficacy of ibuprofen. Pharmacotherapy1, 21–27 (1981).

    PubMed  Google Scholar 

  73. M. O. Pulkkinen and A. I. Csapo,The effect of ibuprofen on the intrauterine pressure and menstrual pain of dysmenorrhea patients. Prostaglandins15, 1055–1062 (1978).

    PubMed  Google Scholar 

  74. P. W. Budoff,Use of mefenamic acid in the treatment of primary dysmenorrhea. J. Am. Med. Assoc.241, 2713–2716 (1979).

    Google Scholar 

  75. G. Tausch,Placebo controlled study of piroxicam in the treatment of rheumatoid arthritis. Am. J. Med.72, (Suppl.), 18–22 (1982).

    Google Scholar 

  76. J. A. Forbes, J. P. Calderazzo and M. W. Fowser,A 12 hour evaluation of the analgesic efficacy of diflunisal, aspirin and placebo in postoperative dental pain. J. Clin. Pharmacol.22, 89–96 (1982).

    PubMed  Google Scholar 

  77. J. M. Lopez,Treatment of acute tendonitis and bursitis with fentiazac—a double-blind comparison with placebo. Clin. Ther.5, 79–84 (1982).

    PubMed  Google Scholar 

  78. W. J. Reynolds, S. F. Shaar, A. Buik and W. J. Lancee,Oxaprozin: A once-daily treatment regimen in rheumatoid arthritis. J. Rheumatol.6, 345–350 (1979).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Laboratories, Ortho Pharmaceutical Corporation, 08869, Raritan, New Jersey

    B. Dubinsky, S. Gebre-Mariam, R. J. Capetola & M. E. Rosenthale

Authors
  1. B. Dubinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Gebre-Mariam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. J. Capetola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. E. Rosenthale
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dubinsky, B., Gebre-Mariam, S., Capetola, R.J. et al. The antialgesic drugs: Human therapeutic correlates of their potency in laboratory animal models of hyperalgesia. Agents and Actions 20, 50–60 (1987). https://doi.org/10.1007/BF01965625

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01965625

Keywords

Search

Navigation