Skip to main content
Log in

Anti-hyperalgesic and anti-inflammatory effects of Ketorolac Tromethamine gel using pulsed ultrasound in inflamed rats

  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The aim of this study was to determine if a Ketorolac Tromethamine (KT) gel solution could be administered in vivo via phonophoretic transdermal delivery using pulsed ultrasound by examining its anti-hyperalgesic and anti-inflammatory effects in a rat carrageenen inflammation model. 1% carrageenan was injected into the plantar surface of the right hindpaw of a rat, and anti-hyperalgesic and anti-inflammatory effects of KT via phonophoretic transdermal delivery were examined. The changes in the mechanical and thermal hyperalgesia, nociceptive flexor reflex (NFR), as well as the swelling changes were determined. According to the anti-hyperagesia and anti-inflammation tests, which were used to determine the change in the pain thresh-old, NFR and swelling showed that the group given the phonophoretic transdermal delivery of KT exhibited significantly more noticeable anti-hyperalgesic and anti-inflammatory effects than those treated with the simple application of a KT gel. The transdermal application of KT gel using phonophoresis had significant anti-hyperalgesic and anti-inflammatory effects. These findings suggest that the transdermal administration of a KT gel using phonophoresis using pulsed ultrasound might be useful for treating acute inflammation and pain.

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

Access this article

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

  • Abramson, S. B. and Weissmann, G., The mechanisms of action of nonsteroidal anti-inflammatory drugs. Arthritis Rheum., 32, 1–9 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Anderson, C. R., Morris, R. L., Boeh, S.D., Panus, P. C., and Sembrowich, W. L., Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention. Phys. Ther., 83, 161–170 (2003).

    PubMed  Google Scholar 

  • Asano, J., Suisha, F., Takada, M., Kawasaki, N., and Miyazaki, S., Effect of pulsed output ultrasound on the transdermal absorption of indomethacin from an ointment in rats. Biol. Pharm. Bull., 20, 288–291 (1997).

    PubMed  CAS  Google Scholar 

  • Bare, A., McAnaw, M., and Pritchard, A., Phonophoretic delivery of 10% hydrocortisone through the epidermis of humans as determined by serum cortisol concentrations. Phys. Ther., 76, 738–749 (1996).

    PubMed  CAS  Google Scholar 

  • Behrens, B. J. and Michlovitz, S. L., Physical agents theory and practice for the physical therapist assistant, Yeongmun. Publishing. Company. Seoul. 95–102 (1996).

  • Bertolucci, L. E., Introduction of anti-inflammatory drugs by iontophoresis: Double blind study. J. Orthop. Sports. Phys. Ther., 4, 103–108 (1982).

    Google Scholar 

  • Bommannan, D., Okuyama, H., Staufer, P., and Guy, R. H., Sonophoresis, I: the use of high frequency ultrasound to enhance transdermal drug delivery. Pharm. Res., 9, 559–564 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Cagnie, B., Vinck, E., Rimbaut, S., and Vanderstraeten, G., Phonophoresis versus topical application of ketoprofen: comparison between tissue and plasma levels. Phys. Ther., 83, 707–712 (2003).

    PubMed  Google Scholar 

  • Cesare, P. and McNaughton, P., Peripheral pain mechanisms. Curr. Opin. Neurobiol., 7, 493–499 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Chapman, V. and Dickenson, A. H., The spinal and peripheral roles of bradylcinin and prostaglandins in nociceptive processing in the rat. Eur. J. Pharmacol., 219, 427–433 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Chen, X., Tanner, K., and Levine, J. D., Mechanical sensitization of cutaneous C-fiber nociceptors by prostaglandin E2 in the rat. Neurosci. Lett., 267, 105–108 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Ciccone, C. D., Leggin, B. G., and Callamaro, J., Effects of ultrasound and trolamine salicylate phonophoresis on delayedonset muscle soreness. Phys. Ther., 71, 666–678 (1991).

    PubMed  CAS  Google Scholar 

  • Devor, M., Fovin-Lippman, R., and Raper, P., Corticosteroids suppress ectopic neural discharge originating in experimental neuromas. Pain., 22, 127–137 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Dirig, D. M., Isakson, P. C., and Yaksh, T. L., Effect of COX-1 and COX-2 inhibition on induction and maintenance of carrageenan-evoked thermal hyperalgesia in rats. J. Pharmacol Exp Ther., 285, 1031–1038 (1998).

    PubMed  CAS  Google Scholar 

  • Feltenstein, M. W., Schqhly, W., Warnick, J. E., Fischer, N. H., and Sufka, K. J., Anti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot. Pharmacol. Biochem. Behav., 79, 299–302 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Fereira, S. H., Moncada, S., and Vane, J. R., Prostaglandin and the mechanism of analgesia produced by aspirin-like drugs. Br. J. Pharmacol., 49, 86–97 (1973).

    Google Scholar 

  • Francischi, J. N., Chaves, C. T., Moura, A. C. L., Lima, A. S., Rocha, O. A., Ferreira-Alves, D. L., and Bakhle, Y. S., Selective inhibitors of cyclo-oxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation. Br. J. Pharmacol., 137, 837–844 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Foldvari, M., Non-invasive administration of drugs through the skin: challenges in delivery system design. Pharm. Sci. Technol., 3, 417–425 (2000).

    Article  CAS  Google Scholar 

  • Herrero, J. F., Parrado, A., and Cervero, F., Central and peripheral actions of the NSAID Ketoprofen on spinal cord nociceptive reflexes. Neurophamcology, 36, 1425–1431 (1997).

    Article  CAS  Google Scholar 

  • Hsieh, Y. L., Effects of ultrasound and diclofenac phonophoresis on inflammatory pain relief: suppression of inducible nitric oxide synthase in arthritic rats. Phys. Ther., 86, 39–49 (2006).

    PubMed  Google Scholar 

  • Jadoul, A., Bouwstra, J., and Preat, V., Effects of iontophoresis and electroporation on the stratum corneum Review of the biophysical studies. Advanced Drug Delivery Reviews. Adv. Drug. Deliv. Rev., 35, 89–105 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Jane, E. C., Pandit, S., Santoro, J. C., Freund, C., Luell, S., Harris, G., Forrest, M. J., and Sitlani, A., Skeletal muscle: a dual system to measure glucocorticoid-dependent transactivation and transrepression of gene regulation. J. Steroid Biochem. & Mol. Biol., 88, 191–201 (2004).

    Article  CAS  Google Scholar 

  • Jett, M. F., Rameshe, C. S., Brown, C. D., Chiu, S., Emmett, C., Voronin, T., Sun, T., Yang, C., Hunter, J. C., Eglen, R. M., and Johnson, R. M., Characterization of the Analgesic-Inflammatory Activities of Ketorolac and Its Enantiomers in the Rat. J. Pharmacol. Exp. Ther., 288, 1288–1297 (1999).

    PubMed  CAS  Google Scholar 

  • Kearns, G. L., Heacook, J., Daly, S. J., Singh, H., and Alander, S. W., Percutaneous lidocaine administration via a new iontophoresis system in children-tolerability and absence of systemic bioavailability. Pediatrics, 112, 578–582 (2003).

    Article  PubMed  Google Scholar 

  • Kleinkort, J. A. and Wood, A. F., Phonophoresis with 1% versus 10% hydrocortisone. Phys. Mer. 55, 1320–1324 (1975).

    CAS  Google Scholar 

  • Kozanoglu, E., Basaran, S., Guzel, R., and Guler-Uysal, F., Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis. Swiss. Med. Wkly. 14; 133(23–24), 333–338 (2003).

    Google Scholar 

  • Lee, E. K., Shin, Y. H., and Lee, C. H., Anti-inflammatory activity of ketoprofen soft hydrogel. J. Kor. Pharm. Sci., 29, 137–143 (1999).

    CAS  Google Scholar 

  • McCormack, K., Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain, 59, 943 (1994).

    Article  Google Scholar 

  • Matsuzaki, S., Hayashi, I., Nara, Y., Kamata, K., Yamanaka, M., Okamoto, H., Hoka, S., and Majima, M., Role of kinin and prostaglandin in cutaneous thermal nociception. Int. Immunopharmacol., 2, 2005–2012 (1969).

    Article  Google Scholar 

  • McElnay, J. C., Kennedy, T. A., and Harland, R., The influence of ultrasound on the percutaneous absorption of fluocinolone acetonide. Int. J. Pharm., 40, 105–110 (1987).

    Article  CAS  Google Scholar 

  • Median, V. M., Walmsley, A. D., and Irwin, W. J., Phonophoresis — is it a reality? Int. J. Pharm., 118, 129–149 (1995).

    Article  Google Scholar 

  • Merino, V., Kalia, Y. N., and Guy, R. H., Transdermal therapy and diagnosis by iontophoresis. Trends Biotehnol., 15, 288–290 (1997).

    Article  CAS  Google Scholar 

  • Nowicki, K. D., Hummer, C. D. 3rd., Heidt, R. S. Jr., and Colosimo, A. J., Effects of iontophoretic versus injection administration of dexamethasone. Med. Sci. Sports Exerc., 34, 1294–1301 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Nyborg, W. L., Mechanisms, In: Nyborg, W. L., Ziskin, M. C., eds. Biological Effects of Ultrasound. NY Churchill Livingstone Inc., 23–33 (1985).

  • Penzes, T. P., Blazs, G., Aigner, Z., Falkay, G., and Eros, I., Topical absorption of piroxicam from organogels — in vitro and in vivo correlations. Int. J. Pharm., 298, 47–54 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Riviere, J. E. and Heit, M. C., Electrically-assisted transdermal drug delivery. Pharm. Res., 14, 687–697 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Samad, T. A., Moore, K. A., Sapirstein, A., Billet, S., Allchorne, A., Poole, S., Bonventre, J. V., and Woolf, C. J., Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature, 410, 471–475 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Schrier, D. J., Moniot, S., Gluckman, M. I., and Gibertson, R. B., The topical anti-inflammatory effects of a topical preparation of meclofenamic acid on carrageenan-induced footpad swelling in mice. J. Pharm. Pharmcol., 39, 57 (1987).

    CAS  Google Scholar 

  • Seybold, V. S., Jia, Y. P., and Abrahams, L. G., Cyclo-oxygenase-2 contributes to central sensitization in rats with peripheral inflammation. Pain, 105, 47–55 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Shin, S. M. and Choi, J. K., Effect of indomethacin phonophoresis on the relief of temporomandibular joint pain. Cranio, 15, 345–348 (1997).

    PubMed  CAS  Google Scholar 

  • Snels, I. A., Beckerman, H., Twisk, J. W., Dekker, J. H., PeterDe, Koning, Koppe, P. A., Lankhorst, G. J., and Bouter, L. M., Effect of triamcinolone acetonide injections on hemiplegic shoulder pain; A randomized clinical trial. Stroke, 31, 2396–2401 (2000).

    PubMed  CAS  Google Scholar 

  • Tyle, P. and Agrawala, P., Drug delivery by phonophoresis. Pharm. Res., 6, 355–359 (1989).

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Vlak, T., Comparative study of the efficacy of ultrasound and sonophoresis in the treatment of painful shouder syndrome. Reumatizam., 46, 5–11 (1999).

    PubMed  CAS  Google Scholar 

  • Varghese, E. and Khar, R. K., Enhanced skin permeation of diclofenac by iontophoresis: in vitro and in vivo studies. J. Control. Release, 38, 21–27 (1996).

    Article  CAS  Google Scholar 

  • Yang, J. H., Kim, D. K., Kim, T. Y., Kim, G. Y., and Shin, S. C., Anti-inflammatory effects by transdermal application of triamcinolone acetonide gel using phonophoresis in rats. Int. J. Pharm., 302, 39–46 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, R., Lao, L., Wang, X., Ren, K., and Berman, B. B., Electroacupuncture combined with indomethacin enhances antihyperalgesia in inflammatory rats. Pharmacol. Biochem. Behav., 78, 793–797 (2004).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sang-Chul Shin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, JH., Kim, TY., Lee, JH. et al. Anti-hyperalgesic and anti-inflammatory effects of Ketorolac Tromethamine gel using pulsed ultrasound in inflamed rats. Arch. Pharm. Res. 31, 511–517 (2008). https://doi.org/10.1007/s12272-001-1186-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-001-1186-5

Key words

Navigation