Complex therapy of musculoskeletal pain: the role of centrally acting muscle relaxants

Chronic pain is the main manifestation of musculoskeletal diseases (MSDs), leading to deterioration of quality of life and loss of ability to work. The importance of this problem is determined by the widespread prevalence of MSDs, osteoarthritis (OA), acute and chronic non-specific back pain (NBP), periarticular soft tissues lesions. Introduction of effective methods of treatment of musculoskeletal pain (MSP) into medical practice is one of the fundamental tasks of modern medicine.

The pathogenesis of MSP includes mechanisms such as injury, inflammation, peripheral sensitization, biomechanical disorders, dysfunction of the nociceptive system and psychoemotional disorders. Painful muscle tension plays an important role in the development of MSP, especially in NBP. Given the complex pathogenesis of MSP, its treatment is based on the combined use of drugs with different mechanisms of action and nonpharmacological methods. Non-steroidal anti-inflammatory drugs (NSAIDs) have a central place in this context. However, they can cause serious adverse reactions (ARs), so when choosing NSAIDs, it is necessary to consider comorbid pathology and risk factors. One of the most acceptable NSAIDs with a pronounced analgesic effect and low incidence of ARs is aceclofenac, which is available in various dosage forms (tablets, sachets, topical cream for external use). This medication is characterized by proven efficacy and good tolerability.

Centrally acting muscle relaxants (CM) play an important role in the treatment of MSP. They eliminate muscle spasm, enhance the effect of analgesics and reduce the need for NSAIDs. The effect of CM has been demonstrated in spasticity and NBP. However, the use of many drugs of this group can be associated with serious ARs, which limits their use.

Tolperisone has the best combination of efficacy and favorable safety profile among CM. Its positive effect in the complex treatment of NBP has been confirmed in several well-organized, placebo-controlled trials. There are also studies demonstrating the efficacy of tolperisone in OA. An important advantage of this drug is virtually no sedative effect, and no negative impact on hemodynamics and on the ability to perform concentration-intensive work. Emergence of a new form of tolperisone – extended-release tablets (Mydocalm® Long 450 mg) – increases patient compliance with CM therapy and facilitates the physician's work.

1. Nasonov EL, Yakhno NN, Karateev AE, et al. General principles of treatment for musculoskeletal pain: Interdisciplinary consensus. Nauchno-Prakticheskaya Revmatologiya. 2016;54(3):247-265. (In Russ.)

2. Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021 May 29; 397(10289):2082-2097. doi: 10.1016/S0140-6736(21)00393-7.

3. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019 Aug;123(2): e273-e283. doi: 10.1016/j.bja.2019.03.023. Epub 2019 May 10.

4. Sunzini F, Schrepf A, Clauw DJ, Basu N. The Biology of Pain: Through the Rheumatology Lens. Arthritis Rheumatol. 2023 May; 75(5):650-660. doi: 10.1002/art.42429. Epub 2023 Mar 20.

5. Asahi MG, Briganti D, Cam E, Seffinger MA. The Role of Musculoskeletal Disorders in Chronic Disease: A Narrative Review. J Am Osteopath Assoc. 2020 Oct 1;120(10): 665-670. doi: 10.7556/jaoa.2020.134

6. Scheuing WJ, Reginato AM, Deeb M, Acer Kasman S. The burden of osteoarthritis: Is it a rising problem? Best Pract Res Clin Rheumatol. 2023 Aug 24:101836. doi: 10.1016/j.berh.2023.101836.

7. Chen S, Chen M, Wu X, et al. Global, regional and national burden of low back pain 1990-2019: A systematic analysis of the Global Burden of Disease study 2019. J Orthop Translat. 2021 Sep 10;32:49-58. doi: 10.1016/j.jot.2021.07.005.

8. Crookes T, Wall C, Byrnes J, et al. Chronic shoulder pain. Aust J Gen Pract. 2023 Nov; 52(11):753-758. doi: 10.31128/AJGP-04-23-6790.

9. Leyland KM, Gates LS, Sanchez Santos MT, et al. Knee osteoarthritis and timeto all-cause mortality in six communitybased cohorts: an international meta-analysis of individual participant-level data. Aging Clin Exp Res. 2021 Mar;33(3):529-545. doi: 10.1007/s40520-020-01762-2. Epub 2021 Feb 15.

10. Subramanian M, Venkatesan P. The predictors for altered central pain modulation in individuals with nonspecific chronic low back pain: A systematic review. Pain Pract. 2022 Feb;22(2):276-284. doi: 10.1111/papr.13081. Epub 2021 Oct 6.

11. Guven Kose S, Kose HC, Celikel F, et al. Chronic Pain: An Update of Clinical Practices and Advances in Chronic Pain Management. Eurasian J Med. 2022 Dec;54(Suppl1):57-61. doi: 10.5152/eurasianjmed.2022.22307.

12. Qaseem A, Wilt TJ, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017 Apr 4;166(7):514-530. doi: 10.7326/M16-2367. Epub 2017 Feb 14.

13. Friedman BW, Conway J, Campbell C, et al. Pain One Week After an Emergency Department Visit for Acute Low Back Pain Is Associated With Poor Three-month Outcomes. Acad Emerg Med. 2018 Oct;25(10): 1138-1145. doi: 10.1111/acem.13453. Epub 2018 Jun 6.

14. Henschke N, Wouda L, Maher CG, et al. Determinants of patient satisfaction 1 year after presenting to primary care with acute low back pain. Clin J Pain. 2013 Jun;29(6):512-7. doi: 10.1097/AJP.0b013e318274b3e6.

15. Carey TS, Garrett JM, Jackman AM. Beyond the good prognosis. Examination of an inception cohort of patients with chronic low back pain. Spine (Phila Pa 1976). 2000 Jan;25(1):115-20. doi: 10.1097/00007632-200001010-00019.

16. Paladini A, Rawal N, Coca Martinez M, et al. Advances in the Management of Acute Postsurgical Pain: A Review. Cureus. 2023 Aug 4;15(8):e42974. doi: 10.7759/cureus.42974.

17. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017 Sep 25;10:2287-2298. doi: 10.2147/JPR.S144066.

18. Akin-Akinyosoye K, Sarmanova A, Fernandes GS, et al. Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort. Osteoarthritis Cartilage. 2020 Feb;28(2):173-181. doi: 10.1016/j.joca.2019.11.004. Epub 2019 Dec 10.

19. Lila AM, Mazurov VI, Martynov AI, et al. Resolution of the consensus of the Russian Federation experts on the diagnosis and treatment of osteoarthritis, 2022. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2022;16(6):106-116. (In Russ.)

20. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020 Feb;72(2):220-233. doi: 10.1002/art.41142. Epub 2020 Jan 6.

21. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578-1589. doi: 10.1016/j.joca.2019.06.011. Epub 2019 Jul 3.

22. Bruyere O, Honvo G, Veronese N, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019 Dec; 49(3):337-350. doi: 10.1016/j.semarthrit.2019.04.008. Epub 2019 Apr 30.

23. Parfenov VA, Yakhno NN, Davydov OS, et al. Chronic nonspecific (musculoskeletal) low back pain. Guidelines of the Russian Society for the Study of Pain (RSSP). Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2019;11(2S):7-16. (In Russ.)

24. Yang Z, Mathieson S, Kobayashi S, et al. Prevalence of Nonsteroidal Antiinflammatory Drugs Prescribed for Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies. Arthritis Care Res (Hoboken). 2023 Nov;75(11):2345-2358. doi: 10.1002/acr.25157. Epub 2023 Jun 19.

25. Barr A, Eilat-Tsanani S. Prescribing Analgesics for Low Back Pain: Is There a Gender Difference? J Womens Health (Larchmt). 2022 Jan;31(1):79-83. doi: 10.1089/jwh.2021.0039. Epub 2021 Oct 6.

26. Togo K, Ebata N, Yonemoto N, Abraham L. Safety risk associated with use of nonsteroidal anti-inflammatory drugs in Japanese elderly compared with younger patients with osteoarthritis and/or chronic low back pain: A retrospective database study. Pain Pract. 2022 Feb;22(2):200-209. doi: 10.1111/papr.13079. Epub 2021 Oct 4.

27. Nicol V, Verdaguer C, Daste C, et al. Chronic Low Back Pain: A Narrative Review of Recent International Guidelines for Diagnosis and Conservative Treatment. J Clin Med. 2023 Feb 20;12(4):1685. doi: 10.3390/jcm12041685.

28. Geczy QE, Thirumaran AJ, Carroll PR, et al. What is the most effective and safest Non-steroidal anti-inflammatory drug for treating osteoarthritis in patients with comorbidities? Expert Opin Drug Metab Toxicol. 2023 Jul-Dec;19(10):681-695. doi: 10.1080/17425255.2023.2267424. Epub 2023 Oct 27.

29. Rockwell MS, Oyese EG, Singh E, et al. Scoping review of interventions to de-implement potentially harmful non-steroidal antiinflammatory drugs (NSAIDs) in healthcare settings. BMJ Open. 2024 Apr 17;14(4): e078808. doi: 10.1136/bmjopen-2023-078808.

30. da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal antiinflammatory drugs and opioid treatment for knee and hip osteoarthritis: network metaanalysis. BMJ. 2021 Oct 12;375:n2321. doi: 10.1136/bmj.n2321.

31. Cashin AG, Wand BM, O'Connell NE, et al. Pharmacological treatments for low back pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2023 Apr 4;4(4):CD013815. doi: 10.1002/14651858.CD013815.pub2.

32. Boudreault J, Desmeules F, Roy JS, et al. The efficacy of oral non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy: a systematic review and meta-analysis. J Rehabil Med. 2014 Apr;46(4):294-306. doi: 10.2340/16501977-1800.

33. Smith SR, Deshpande BR, Collins JE, et al. Comparative pain reduction of oral nonsteroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthritis Cartilage. 2016 Jun; 24(6):962-72. doi: 10.1016/j.joca.2016.01.135.

34. Zeng C, Wei J, Persson MS, 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 May; 52(10):642-650. doi: 10.1136/bjsports-2017-098043. Epub 2018 Feb 7.

35. Atkinson TJ, Fudin J. Nonsteroidal Antiinflammatory Drugs for Acute and Chronic Pain. Phys Med Rehabil Clin N Am. 2020 May; 31(2):219-231. doi: 10.1016/j.pmr.2020.01.002. Epub 2020 Mar 10.

36. Gupta A, Bah M. NSAIDs in the Treatment of Postoperative Pain. Curr Pain Headache Rep. 2016 Nov;20(11):62. doi: 10.1007/s11916-016-0591-7.

37. Shatsky М. Evidence for the use of intramuscular injections in outpatient practice. Fam Physician. 2009 Feb 15;79(4):297-300

38. Sproviero E, Albamonte E, Costantino C, et al. Efficacy and safety of a fixed combination of intramuscular diclofenac 75 mg + thiocolchicoside 4 mg in the treatment of acute low back pain: a phase III, randomized, double blind, controlled trial. Eur J Phys Rehabil Med. 2018 Oct;54(5):654-662. doi: 10.23736/S1973-9087.17.04923-1. Epub 2017 Dec 21.

39. Zippel H, Wagenitz A. A multicentre, randomised, double-blind study comparing the efficacy and tolerability of intramuscular dexketoprofen versus diclofenac in the symptomatic treatment of acute low back pain. Clin Drug Investig. 2007;27(8):533-43. doi: 10.2165/00044011-200727080-00002.

40. Babej-Dölle R, Freytag S, Eckmeyer J, et al. Parenteral dipyrone versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer-blind multicenter study. Int J Clin Pharmacol Ther. 1994 Apr;32(4):204-9.

41. Alekseev VV, Podchufarova EV. The use of meloxicam (movalis) in the treatment of lumboishialgic syndrome. Bol'. 2004;(4):49-53 (In Russ.)

42. Karateev AE, Lila AM, Pogozheva EYu, et al. Factors affecting the effectiveness of nonsteroidal anti-inflammatory drugs in acute lower back pain. The results of the multicenter observational study KARAMBOL (Clinical Analysis of the Results of Meloxicam Analgesia and its Safety in Acute Lumbalgia). Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2019;13(2):31-37. (In Russ.)

43. Scally B, Emberson JR, Spata E, et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):231-241. doi: 10.1016/S2468-1253(18)30037-2. Epub 2018 Feb 21.

44. Zhang S, Qing Q, Bai Y, et al. Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. Dig Dis Sci. 2013 Jul;58(7):1991-2000. doi: 10.1007/s10620-013-2606-0. Epub 2013 Feb 28.

45. Dooley M, Spencer CM, Dunn CJ. Aceclofenac: a reappraisal of its use in the management of pain and rheumatic disease. Drugs. 2001;61(9):1351-78. doi: 10.2165/00003495-200161090-00012.

46. Patel PB, Patel TK. Efficacy and safety of aceclofenac in osteoarthritis: A meta-analysis of randomized controlled trials. Eur J Rheumatol. 2017 Mar;4(1):11-18. doi: 10.5152/eurjrheum.2017.160080. Epub 2017 Mar 1.

47. Castellsague J, Riera-Guardia N, Calingaert B, et al; Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and metaanalysis of observational studies (the SOS project). Drug Saf. 2012 Dec 1;35(12): 1127-46. doi: 10.2165/11633470-000000000-00000.

48. Masclee GMC, Straatman H, Arfe A, et al. Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project. PLoS One. 2018 Nov 1;13(11):e0204746. doi: 10.1371/journal.pone.0204746. eCollection 2018.

49. Karateev AE, Tsurkan AV. Aceclofenac: the experience of Russian research. Sovremennaiya revmatologiya = Modern rheumatology. 2017;11(4):89-94. (In Russ.)

50. Karateev AE, Pogozheva EYu, Filatova EA, et al. Factors affecting the results of analgesic therapy. Results of the Russian multicentre study of NOTE (NSAID: Open-label Trial of Efficacy). Terapevticheskii arkhiv. 2018; 90(6):65-73. (In Russ.)

51. Karateev AE, Pogozheva EYu, Amirdzhanova VN, et al. Regular use of non-steroidal anti-inflammatory drugs can effectively control pain and global health in patients with moderate activity of rheumatoid arthritis. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2021;15(2):57-63. (In Russ.)

52. Karateev AE, Polishchuk EYu, Filatova ES, et al. Long-term use of nonsteroidal anti-inflammatory drugs for pain control in patients with osteoarthritis: results of the 12-month observational study AELITA (Analgesia: Effective Treatment Using The Therapeutic Algorithm). Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2021; 15(6):84–90. (In Russ.)

53. Sharapova EP, Kashevarova NG, Anikin SG, et al. The use of new aceclofenac dosage forms in patients with osteoarthrosis in reallife clinical practice. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2014;8(1): 73–76 (In Russ.)

54. Iskra DA, Kamchatnov PR, Doshchuk NA, et al. Topical therapy of acute nociceptive pain: results of an open randomized clinical trial of the domestic drug Alental cream. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2022;122(3):72-77. (In Russ.)

55. https://www.vidal.ru/drugs/airtal__32953

56. Li W, Gong Y, Liu J, et al. Peripheral and Central Pathological Mechanisms of Chronic Low Back Pain: A Narrative Review. J Pain Res. 2021 May 27;14:1483-1494. doi: 10.2147/JPR.S306280.

57. See S, Ginzburg R. Choosing a skeletal muscle relaxant. Am Fam Physician. 2008 Aug 1;78(3):365-70.

58. Abdel Shaheed C, Maher CG, Williams KA, McLachlan AJ. Efficacy and tolerability of muscle relaxants for low back pain: Systematic review and meta-analysis. Eur J Pain. 2017 Feb;21(2):228-237. doi: 10.1002/ejp.907. Epub 2016 Jun 22.

59. Killam-Worrall L, Brand R, Castro JR, et al. Baclofen and Tizanidine Adverse Effects Observed Among Community-Dwelling Adults Above the Age of 50 Years: A Systematic Review. Ann Pharmacother. 2024 May; 58(5):523-532. doi: 10.1177/10600280231193080. Epub 2023 Aug 17.

60. Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone. Clin Ther. 2004 Sep;26(9):1355-67. doi: 10.1016/j.clinthera.2004.09.008.

61. Browning R, Jackson JL, O'Malley PG. Cyclobenzaprine and back pain: a metaanalysis. Arch Intern Med. 2001 Jul 9; 161(13):1613-20. doi: 10.1001/archinte.161.13.1613.

62. Harden RN, Argoff C. A review of three commonly prescribed skeletal muscle relaxants. J Back Musculoskelet Rehabil. 2000 Jan 1;15(2):63-6. doi: 10.3233/bmr-2000-152-303.

63. Alekseev VV. Midocalm and myogenic pain syndromes. Russkii meditsinskii zhurnal. 2012; (10):500. (In Russ.)

64. Pratzel HG, Alken RG, Ramm S. Efficacy and tolerance of repeated oral doses of tolperisone hydrochloride in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial. Pain. 1996 Oct;67(2-3):417-25. doi: 10.1016/0304-3959(96)03187-9.

65. Li M, Huang Y, Chen R, et al. Efficacy and safety of tolperisone versus baclofen among Chinese patients with spasticity associated with spinal cord injury: a non-randomized retrospective study. Braz J Med Biol Res. 2021 Sep 3;54(11):e11293. doi: 10.1590/1414-431X2021e11293.

66. Stamenova P, Koytchev R, Kuhn K, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke. Eur J Neurol. 2005 Jun;12(6):453-61. doi: 10.1111/j.1468-1331.2005.01006.x.

67. Agarwal S, Patel T, Shah N, Patel BM. Comparative study of therapeutic response to baclofen vs tolperisone in spasticity. Biomed Pharmacother. 2017 Mar;87:628-635. doi: 10.1016/j.biopha.2017.01.005. Epub 2017 Jan 10.

68. Rao R, Panghate A, Chandanwale A, et al. Clinical comparative study: efficacy and tolerability of tolperisone and thiocolchicoside in acute low back pain and spinal muscle spasticity. Asian Spine J. 2012 Jun;6(2):115-22. doi: 10.4184/asj.2012.6.2.115. Epub 2012 May 31.

69. Prabhoo R, Keny S, Prabhoo T, et al. A phase IV observational multi-centre, openlabel study on efficacy and safety of tolperisone 150 mg in patients with painful muscle spasm associated with degenerative or inflammatory diseases of the musculoskeletal system. J Assoc Physicians India. 2011 Jan;59:33-7.

70. Hodinka L, Meilinger M, Szabo J, Zalavari I. Treatment of acute lumbar pain with Midocalm. The results of an international multicenter randomized double-blind placebocontrolled clinical trial. Russkii meditsinskii zhurnal. 2003;(5):246. (In Russ.)

71. Vaughan SA, Torres K, Kaye R. RESUME-1: a Phase III study of tolperisone in the treatment of painful, acute muscle spasms of the back. Pain Manag. 2022 Jan; 12(1):25-33. doi: 10.2217/pmt-2021-0041. Epub 2021 Jul 1.

72. Kukushkin ML, Brylev LV, Laskov VB, et al. Results of a randomized double blind parallel study on the efficacy and safety of tolpersione in patients with acute nonspecific low back pain. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2017;117(11):69-78. (In Russ.)

73. Alekseeva LI, Bratygina EA, Kashevarova NG, et al. The use of muscle relaxants in the complex therapy of osteoarthritis. Consilium Medicum. 2008;10(2):30-32. (In Russ.)

74. Dulin J, Kovacs L, Ramm S, et al. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry. 1998 Jul; 31(4):137-42. doi: 10.1055/s-2007-979315.

75. Caron J, Kaye R, Wessel T, et al. An assessment of the centrally acting muscle relaxant tolperisone on driving ability and cognitive effects compared to placebo and cyclobenzaprine. J Clin Pharm Ther. 2020 Aug;45(4):774-782. doi: 10.1111/jcpt.13165. Epub 2020 May 10.

76. Parfenov VA, Bogdanov EI, Laskov VB, et al. Multicenter, randomized, double-blind study of the efficacy and safety of prolonged release tolperisone hydrochloride 450 mg (Mydocalm® Long, once daily) and tolperisone hydrochloride 150 mg (three times daily) for acute non-specific lower back pain. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2021; 13(6):14-22. (In Russ.)