Topical NSAIDs forms: efficiency and safety
A.E. Karateev, A.M. Lila
V.A. Nasonova Scientific Research Institute of Rheumatology, Moscow
Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective musculoskeletal pain treatment, but the systemic use of these drugs — oral and rectal administration, injections — can cause gastrointestinal, cardiovascular and renal complications. Of great interest are topical NSAIDs forms (TF) — gels and ointments for cutaneous administration, in use of which the risk of systemic side effects is low. TF administration is included in local and international recommendations for the treatment of the most common chronic joint disease — osteoarthritis (OA). The efficacy of TF in OA and soft tissue injuries has been proven. The probability of achieving a significant improvement (≥50%) when using TF is 25–50% higher in relation to placebo. Data from controlled trials and the corresponding meta-analysis demonstrate a low incidence of serious adverse events when using TF, which is alm ost equal to that when using the placebo. One of the most popular drugs from the NSAIDs group used as an active substance for TF is ibuprofen. To increase this drug effectiveness, a gel was created containing a combination of ibuprofen and levomenthol. The combined preparation shows good analgesic and anti-inflammatory potential, which in some parameters exceeds the TF effect containing only ibuprofen.
Keywords: musculoskeletal pain, treatment, NSAIDs, topical forms, efficacy, safety, ibuprofen, levomenthol.
For citation: Karateev A.E., Lila A.M. Topical NSAIDs forms: efficiency and safety. RMJ. Medical Review. 2019;11(II):75–80.
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21. Meng Z., Huang R. Topical Treatment of Degenerative Knee Osteoarthritis. Am J Med Sci. 2018;355(1):6–12. DOI: 10.1016/j.amjms.2017.06.006.
22. Zeng C., Wei J., Persson M. et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52(10):642–650. DOI: 10.1136/bjsports-2017-098043.
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27. Waikakul S., Danputipong P., Soparat K. Topical analgesics, indomethacin plaster and diclofenac emulgel for low back pain: a parallel study. J Med Assoc Thai. 1996;79(8):486–490.
28. Honvo G., Leclercq V., Geerinck A. et al. Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. 2019;36(Suppl 1):45–64. DOI: 10.1007/s40266-019-00661-0.
29. Patel A., Bell M., O’Connor C. et al. Delivery of ibuprofen to the skin. Int J Pharm. 2013;457(1):9–13. DOI: 10.1016/j.ijpharm.2013.09.019.
30. Камчатнов П.Р., Евзельман М.А., Чугунов А.В. Препараты для локального трансдермального применения при лечении пациентов с дорсалгией. Медицинский совет. 2017;17:44–48. [Kamchatnov P.R., Evzelman M.A., Chugunov A.V. Preparations for local transdermal use in the treatment of patients with dorsalgia. Medical advice. 2017;17:44–48 (in Russ.)].
31. Kamatou G.P., Vermaak I., Viljoen A.M., Lawrence B.M. Menthol: a simple monoterpene with remarkable biological properties. Phytochemistry. 2013;96:15–25. DOI: 10.1016/j.phytochem.2013.08.005.
32. Wade A.G., Crawford G.M., Young D. et al. Comparison of diclofenac gel, ibuprofen gel, and ibuprofen gel with levomenthol for the topical treatment of pain associated with musculoskeletal injuries. J Int Med Res. 2019 Jul 29:300060519859146. DOI: 10.1177/0300060519859146. [Epub ahead of print]
33. Воробьева О.В., Лысенко А.С. Комбинированный гель, содержащий ибупрофен и левоментол, в терапии острой боли в шее/плечевом поясе, вызванной болезненным мышечным спазмом. Лечащий врач. 2018;10:39. [Vorobyova O.V., Lysenko A.S. Combination gel containing ibuprofen and levomenthol in the treatment of acute neck/shoulder pain caused by painful muscle spasm. Therapist. 2018;10:39 (in Russ.)].
34. Денисов Л.Н., Прозоровская З.А., Иванова О.Н., Сороцкая В.Н. Повышает ли комбинация нестероидных противовоспалительных препаратов и ментола эффективность локальной терапии? Научно-практическая ревматология. 2006;1:34–36. [Denisov L.N., Prozorovskaya Z.A., Ivanova O.N., Sorotskaya V.N. Does the combination of non-steroidal anti-inflammatory drugs and menthol increase the effectiveness of local therapy? Scientific and practical rheumatology. 2006;1:34–36 (in Russ.)].
35. Шостак Н.А., Шеметов Д.А., Клименко А.А. и др. Боль в спине — оптимизация локальной терапии с использованием геля двойного действия Дип Рилиф. Научно-практическая ревматология. 2006;3:47–50. [Shostak N.A., Shemetov D.A., Klimenko A.A. et al. Pain in the back — optimization of local therapy using the double-acting Deep Reelif gel. Scientific and practical rheumatology. 2006;3:47–50 (in Russ.)].
2. Day R.O., Graham G.G. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ. 2013;346:f3195. DOI: 10.1136/bmj.f3195.
3. Ali A., Arif A.W., Bhan C. et al. Managing Chronic Pain in the Elderly: An Overview of the Recent Therapeutic Advancements. Cureus. 2018;10(9):e3293. DOI: 10.7759/cureus.3293.
4. Каратеев А.Е., Насонов Е.Л., Ивашкин В.Т. и др. Рациональное использование нестероидных противовоспалительных препаратов. Клинические рекомендации. Научно-практическая ревматология. 2018;56:1–29. https://doi.org/10.14412/1995–4484–2018–1-29. [Karateev A.E., Nasonov E.L., Ivashkin V.T. et al. Rational use of non-steroidal anti-inflammatory drugs. Clinical recommendations. Scientific and practical rheumatology. 2018;56:1–29. https://doi.org/10.14412/1995–4484–2018–1-29 (in Russ.)].
5. Bannuru R.R., Osani M.C., Vaysbrot E.E. et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Jul 3. pii: S1063–4584(19)31116–1. DOI: 10.1016/j.joca.2019.06.011. [Epub ahead of print]
6. Rannou F., Pelletier J.P., Martel-Pelletier J. Efficacy and safety of topical NSAIDs in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45(4 Suppl):S18–21. DOI: 10.1016/j.semarthrit.2015.11.007.
7. Irvine J., Afrose A., Islam N. Formulation and delivery strategies of ibuprofen: challenges and opportunities. Drug Dev Ind Pharm. 2018;44(2):173–183. DOI: 10.1080/03639045.2017.1391838.
8. Barkin R.L. Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome. Am J Ther. 2015;22(5):388–407. DOI: 10.1097/MJT.0b013e3182459abd.
9. Singh M.R., Pradhan K., Singh D. Lipid matrix systems with emphasis on lipid microspheres: potent carriers for transcutaneous delivery of bioactives. Curr Drug Deliv. 2012;9(3):243–254.
10. Yu J., Zhang Y., Kahkoska A.R., Gu Z. Bioresponsive transcutaneous patches. Curr Opin Biotechnol. 2017;48:28–32. DOI: 10.1016/j.copbio.2017.03.001.
11. Hui X., Hewitt P.G., Poblete N. et al. In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers. Pharm Res. 1998;15:1589–1595.
12. Kienzler J.L., Gold M., Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010;50(1):50–61. DOI: 10.1177/0091270009336234.
13. Brunner M., Davies D., Martin W. et al. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. Br J Clin Pharmacol. 2011;71(6):852–859. DOI: 10.1111/j.1365-2125.2011.03914.x.
14. Erdogan F., Ergün H., Gökay N.S. et al. The diffusion of nimesulide gel into synovial fluid: a comparison between administration routes. Int J Clin Pharmacol Ther. 2006;44(6):270–275.
15. Manoukian M.A., Migdal C.W., Tembhekar A.R. et al. Topical Administration of Ibuprofen for Injured Athletes: Considerations, Formulations, and Comparison to Oral Delivery. Sports Med Open. 2017 Oct 5;3(1):36. DOI: 10.1186/s40798-017-0103-2.
16. Miyatake S., Ichiyama H., Kondo E., Yasuda K. Randomized clinical comparisons of diclofenac concentration in the soft tissues and blood plasma between topical and oral applications. Br J Clin Pharmacol. 2009;67(1):125–129. DOI: 10.1111/j.1365-2125.2008.03333.x.
17. Dominkus M., Nicolakis M., Kotz R. et al. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration. Arzneimittelforschung. 1996;46(12):1138–1143.
18. Brunner M., Dehghanyar P., Seigfried B. et al. Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation. Br J Clin Pharmacol. 2005;60(5):573–577.
19. Hong E., Kraft M.C. Evaluating anterior knee pain. Med Clin North Am. 2014;98(4):697–717. DOI: 10.1016/j.mcna.2014.03.001.
20. Toktas H., Dundar U., Adar S. et al. Ultrasonographic assessment of pes anserinus tendon and pes anserinus tendinitis bursitis syndrome in patients with knee osteoarthritis. Mod Rheumatol. 2015;25(1):128–133. DOI: 10.3109/14397595.2014.931909.
21. Meng Z., Huang R. Topical Treatment of Degenerative Knee Osteoarthritis. Am J Med Sci. 2018;355(1):6–12. DOI: 10.1016/j.amjms.2017.06.006.
22. Zeng C., Wei J., Persson M. et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52(10):642–650. DOI: 10.1136/bjsports-2017-098043.
23. Derry S., Wiffen P.J., Kalso E.A. et al. Topical analgesics for acute and chronic pain in adults — an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017 2;5:CD008609. DOI: 10.1002/14651858.CD008609.pub2.
24. Vuurberg G., Kerkhoffs G.M. Topical NSAIDs significantly reduces pain in adults with acute musculoskeletal injuries. Evid Based Med. 2016;21(5):187–188. DOI: 10.1136/ebmed-2016-110406.
25. Derry S., Moore R.A., Gaskell H. et al. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst Rev. 2015;(6):CD007402. DOI: 10.1002/14651858.CD007402.pub3.
26. Serinken M., Eken C., Tunay K., Golcuk Y. Ketoprofen gel improves low back pain in addition to IV dexketoprofen: a randomized placebo-controlled trial. Am J Emerg Med. 2016;34(8):1458–1461. DOI: 10.1016/j.ajem.2016.04.028.
27. Waikakul S., Danputipong P., Soparat K. Topical analgesics, indomethacin plaster and diclofenac emulgel for low back pain: a parallel study. J Med Assoc Thai. 1996;79(8):486–490.
28. Honvo G., Leclercq V., Geerinck A. et al. Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. 2019;36(Suppl 1):45–64. DOI: 10.1007/s40266-019-00661-0.
29. Patel A., Bell M., O’Connor C. et al. Delivery of ibuprofen to the skin. Int J Pharm. 2013;457(1):9–13. DOI: 10.1016/j.ijpharm.2013.09.019.
30. Камчатнов П.Р., Евзельман М.А., Чугунов А.В. Препараты для локального трансдермального применения при лечении пациентов с дорсалгией. Медицинский совет. 2017;17:44–48. [Kamchatnov P.R., Evzelman M.A., Chugunov A.V. Preparations for local transdermal use in the treatment of patients with dorsalgia. Medical advice. 2017;17:44–48 (in Russ.)].
31. Kamatou G.P., Vermaak I., Viljoen A.M., Lawrence B.M. Menthol: a simple monoterpene with remarkable biological properties. Phytochemistry. 2013;96:15–25. DOI: 10.1016/j.phytochem.2013.08.005.
32. Wade A.G., Crawford G.M., Young D. et al. Comparison of diclofenac gel, ibuprofen gel, and ibuprofen gel with levomenthol for the topical treatment of pain associated with musculoskeletal injuries. J Int Med Res. 2019 Jul 29:300060519859146. DOI: 10.1177/0300060519859146. [Epub ahead of print]
33. Воробьева О.В., Лысенко А.С. Комбинированный гель, содержащий ибупрофен и левоментол, в терапии острой боли в шее/плечевом поясе, вызванной болезненным мышечным спазмом. Лечащий врач. 2018;10:39. [Vorobyova O.V., Lysenko A.S. Combination gel containing ibuprofen and levomenthol in the treatment of acute neck/shoulder pain caused by painful muscle spasm. Therapist. 2018;10:39 (in Russ.)].
34. Денисов Л.Н., Прозоровская З.А., Иванова О.Н., Сороцкая В.Н. Повышает ли комбинация нестероидных противовоспалительных препаратов и ментола эффективность локальной терапии? Научно-практическая ревматология. 2006;1:34–36. [Denisov L.N., Prozorovskaya Z.A., Ivanova O.N., Sorotskaya V.N. Does the combination of non-steroidal anti-inflammatory drugs and menthol increase the effectiveness of local therapy? Scientific and practical rheumatology. 2006;1:34–36 (in Russ.)].
35. Шостак Н.А., Шеметов Д.А., Клименко А.А. и др. Боль в спине — оптимизация локальной терапии с использованием геля двойного действия Дип Рилиф. Научно-практическая ревматология. 2006;3:47–50. [Shostak N.A., Shemetov D.A., Klimenko A.A. et al. Pain in the back — optimization of local therapy using the double-acting Deep Reelif gel. Scientific and practical rheumatology. 2006;3:47–50 (in Russ.)].
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