Фиксированная комбинация диклофенака и орфенадрина в лечении острых болевых синдромов

Острая боль, особенно скелетно-мышечная и послеоперационная, является широко распространенной патологией, сопряженной с ухудшением качества жизни пациентов, временной нетрудоспособностью, склонностью к рецидивированию, а в ряде случаев и к хроническому течению, поэтому ее своевременное и адекватное лечение важно, в том числе с точки зрения профилактики серьезных медицинских, социальных и экономических последствий.
При скелетно-мышечной боли в качестве средств первого выбора в современных рекомендациях рассматриваются нестероидные противовоспалительные препараты (НПВП). Базовым компонентом лечения дорсалгий также являются миорелаксанты центрального действия и их комбинации с НПВП. Однако доказательная база имеется лишь для отдельных миорелаксантов, в частности для  орфенадрина. Включение НПВП в состав мультимодальной послеоперационной аналгезии значительно уменьшает потребность в опиоидах, снижает риск развития нежелательных реакций последних и повышает удовлетворенность пациентов качеством обезболивания. Целесообразно использование в составе мультимодальной аналгезии и центральных миорелаксантов, обладающих аналгезирующими свойствами, например тизанидина и орфенадрина.
В статье обсуждаются фармакологические свойства фиксированной комбинации диклофенака и орфенадрина (Неодолпассе®), ее преимущества перед монотерапией отдельными ингредиентами и результаты клинических исследований данной комбинации при болевых спинальных синдромах и в послеоперационном периоде.

острая боль, скелетно-мышечная боль, послеоперационная боль, нестероидные противовоспалительные препараты, центральные миорелаксанты, диклофенак, орфенадрин, фиксированная комбинация

1. Allegri M, Clark MR, De Andres J, Jensen TS. Acute and chronic pain: where we are and where we have to go. Minerva Anestesiol. 2012 Feb;78(2):222-35. Epub 2011 Nov 18.

2. Pergolizzi JV Jr, Raffa RB, Taylor R Jr. Treating acute pain in light of the chronification of pain. Pain Manag Nurs. 2014 Mar;15(1): 380-90. doi: 10.1016/j.pmn.2012.07.004. Epub 2012 Aug 25.

3. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc. 2015 Feb;90(2):284-99. doi: 10.1016/j.mayocp.2014.09.008.

4. Binder A. The diagnosis and treatment of nonspecific neck pain and whiplash. Eura Medicophys. 2007 Mar;43(1):79-89.

5. Hoy D, March L, Brooks P, et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014 Jun;73(6):968-74. doi: 10.1136/annrheumdis-2013-204428. Epub 2014 Mar 24.

6. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Aug 22; 386(9995):743-800. doi: 10.1016/S0140-6736(15)60692-4. Epub 2015 Jun 7.

7. Airaksinen O, Brox JI, Cedraschi C, et al. Chapter 4. European guidelines for the management of chronic nonspecific low back pain. Eur Spine J. 2006;15 Suppl 2:S192-300. doi: 10.1007/s00586-006-1072-1.

8. Heuch I, Foss IS. Acute low back usually resolves quickly but persistent low back pain often persists. J Physiother. 2013 Jun;59(2):127. doi: 10.1016/S1836-9553(13)70166-8.

9. Pengel LH, Herbert RD, Maher CG, Refshauge KM. Acute low back pain: systematic review of its prognosis. BMJ. 2003 Aug 9; 327(7410):323. doi: 10.1136/bmj.327.7410.323

10. Stasiowska MK, Ng SC, Gubbay AN, Cregg R. Postoperative pain management. Br J Hosp Med (Lond). 2015 Oct;76(10):570-5. doi: 10.12968/hmed.2015.76.10.570.

11. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-73. doi: 10.1097/ALN.0b013e31823c1030.

12. Nimmo SM, Foo ITH, Paterson HM. The Enhanced recovery after surgery: Pain management. J Surg Oncol. 2017 Oct;116(5): 583-591. doi: 10.1002/jso.24814.

13. Fletcher D, Stamer UM, Pogatzki-Zahn E, et al. Chronic postsurgical pain in Europe: an observational study. Eur J Anaesthesiol. 2015 Oct;32(10):725-34. doi: 10.1097/EJA.0000000000000319.

14. Pak DJ, Yong RJ, Kaye AD, Urman RD. Chronification of Pain: Mechanisms, Current Understanding, and Clinical Implications. Curr Pain Headache Rep. 2018 Feb 5;22(2):9. doi: 10.1007/s11916-018-0666-8.

15. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016 Jun 7;(6):CD012230. doi: 10.1002/14651858.CD012230.

16. Chou R, Deyo R, Friedly J, et al. Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017;166(7):480-492. doi: 10.7326/M16-2458.

17. Graham GG, Davies MJ, Day RO, et al. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013; 21(3):201-32. doi: 10.1007/s10787-013-0172-x.

18. Schreijenberg M, Koes BW, Lin CC. Guideline recommendations on the pharmacological management of non-specific low back pain in primary care – is there a need to change? Expert Rev Clin Pharmacol. 2019 Feb;12(2): 145-157. doi: 10.1080/17512433.2019.1565992.

19. Верткин АЛ, Каратеев АЕ, Кукушкин МЛ и др. Ведение пациентов с болью в спине для терапевтов и врачей общей практики (Клинические рекомендации). Терапия. 2018;(2):24-32.

20. Wong JJ, Cote P, Ameis A, et al. Are nonsteroidal anti-inflammatory drugs effective for the management of neck pain and associated disorders, whiplash-associated disorders, or non-specific low back pain? A systematic review of systematic reviews by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J. 2016;25(1):34-61. doi: 10.1007/s00586-015-3891-4.

21. Machado GC, Maher CG, Ferreira PH, et al. Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and metaanalysis. Ann Rheum Dis. 2017;76(7):1269-1278. doi: 10.1136/annrheumdis-2016-210597.

22. Abdet Shaheed C, Maher CG, Williams KA, et al. Efficacy, Tolerability, and Dose-Dependent Effects of Opioid Analgesics for Low Back Pain: A Systematic Review and Meta-analysis. JAMA Intern Med. 2016;176(7): 958-68. doi: 10.1001/jamainternmed.2016.1251.

23. Vadivetu N, Kai AM, Kodumudi V, et al. The Opioid Crisis: a Comprehensive Overview. Curr Pain Headache Rep. 2018 Feb 23;22(3):16. doi: 10.1007/s11916-018-0670-z.

24. Manchikanti L, Kaye AM, Knezevic NN, et al. Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain Physician. 2017 Feb;20(2S):S3-S92.

25. 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.

26. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. Pain Symptom Manage. 2004 Aug;28(2):140-75. doi: 10.1016/j.jpainsymman.2004.05.002.

27. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. 2003;(2):CD004252. doi: 10.1002/14651858.CD004252.

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

29. Kjaer P, Kongsted A, Hartvigsen J, et al. National clinical guidelines for non-surgical treatment of patients with recent onset neck pain or cervical radiculopathy. Eur Spine J. 2017;26(9):2242-2257. doi: 10.1007/s00586-017-5121-8.

30. Stochkendahl MJ, Kjaer P, Hartvigsen J, et al. National Clinical Guidelines for non-surgical treatment of patients with recent onset low back pain or lumbar radiculopathy. Eur Spine J. 2018;27(1):60-75. doi: 10.1007/s00586-017-5099-2.

31. Simpson JC, Bao X, Agarwala A. Pain Management in Enhanced Recovery after Surgery (ERAS) Protocols. Clin Colon Rectal Surg. 2019;32(2):121-128. doi: 10.1055/s-0038-1676477.

32. Soffin EM, Wu CL. Regional and Multimodal Analgesia to Reduce Opioid Use After Total Joint Arthroplasty: A Narrative Review. HSS J. 2019;15(1):57-65. doi: 10.1007/s11420-018-9652-2.

33. 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.

34. Michelet D, Andreu-Gallien J, Bensalah T, et al. A meta-analysis of the use of nonsteroidal antiinflammatory drugs for pediatric postoperative pain. Anesth Analg. 2012;114(2):393-406. doi: 10.1213/ANE.0b013e31823d0b45.

35. Yoo JS, Ahn J, Buvanendran A, Singh K. Multimodal analgesia in pain management after spine surgery. J Spine Surg. 2019;5(Suppl 2): S154-S159. doi: 10.21037/jss.2019.05.04.

36. Albrecht E, Kirkham KR, Liu SS, Brull R. Perioperative intravenous administration of magnesium sulphate and postoperative pain: a metaanalysis. Anaesthesia. 2013 Jan;68(1): 79-90. doi: 10.1111/j.1365-2044.2012.07335.x. Epub 2012 Nov 1.

37. Yazicioglu D, Caparlar C, Akkaya T, et al. Tizanidine for the management of acute postoperative pain after inguinal hernia repair: A placebo-controlled double-blind trial. Eur J Anaesthesiol. 2016;33(3):215-22. doi: 10.1097/EJA.0000000000000371.

38. Fry EN. Orphenadrine and postoperative pain. Br J Anaesth. 1978 Feb;50(2):205. doi: 10.1093/bja/50.2.205-a.

39. Hunskaar S, Donnell D. Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions. J Int Med Res. 1991 Mar-Apr; 19(2):71-87. doi:10.1177/030006059101900201.

40. Gombotz H, Lochner R, Sigl R, et al. Opiate sparing effect of fixed combination of diclophenac and orphenadrine after unilateral total hip arthroplasty: A double-blind, randomized, placebo-controlled, multi-centre clinical trial. Wien Med Wochenschr. 2010;160(19-20): 526-34. doi: 10.1007/s10354-010-0829-7.

41. Varrassi G, Hanna M, Macheras G, et al. Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol. Curr Med Res Opin. 2017;33(6):1165-1173. doi: 10.1080/03007995.2017.1310092.

42. Raffa RB, Clark-Vetri R, Tallarida RJ, Wertheimer AI. Combination strategies for pain management. Expert Opin Pharmacother. 2003; 4(10):1697-708. doi: 10.1517/14656566.4.10.1697.

43. O'Brien J, Pergolizzi J, van de Laar M, et al. Fixed-dose combinations at the front line of multimodal pain management: perspective of the nurse-prescriber. Nursing: Research and Reviews. 2013 Feb;2013(3):9-22. doi: 10.2147/NRR.S36876.

44. Todd PA, Sorkin EM. Diclofenac sodium: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1988 Mar;35(3):244-85. doi: 10.2165/00003495-198835030-00004.

45. Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010;26(7):1715-31. doi: 10.1185/03007995.2010.486301.

46. Bushuven S, Heise D, Bolbrinker J. Diclofenac up2date – Part 1: Pharmacology and comparison with other drugs. Anasthesiol Intensivmed Notfallmed Schmerzther. 2014;49(10):588-98. doi: 10.1055/s-0034-1395170.

47. Howard ML, Isaacs AN, Nisly SA. Continuous Infusion Nonsteroidal AntiInflammatory Drugs for Perioperative Pain Management. J Pharm Pract. 2018;31(1):66-81. doi: 10.1177/0897190016665539.

48. George NE, Gurk-Turner C, Etcheson JI, et al. The Addition of Diclofenac to a Multimodal Pain Control Regimen Decreases Postoperative Pain and Opioid Consumption. Surg Technol Int. 2017 Dec 22;31:346-351.

49. McNicol ED, Ferguson MC, Schumann R. Single-dose intravenous diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018 Aug 28;8:CD012498. doi: 10.1002/14651858.CD012498.pub2.

50. Abd-Elsalam S, El-Kalla F, Ali LA, et al. Pilot study of orphenadrine as a novel treatment for muscle cramps in patients with liver cirrhosis. United European Gastroenterol J. 2018;6(3): 422-427. doi: 10.1177/2050640617731261.

51. Fernandez-Sanchez MT, Diaz-Trelles R, Groppetti A, et al. Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity. Amino Acids. 2002; 23(1-3):31-6. doi: 10.1007/s00726-001-0106-6.

52. Chen YW, Tzeng JI, Chen YC, et al. Intrathecal orphenadrine elicits spinal block in the rat. Eur J Pharmacol. 2014 Nov 5;742: 125-30. doi: 10.1016/j.ejphar.2014.08.035. Epub 2014 Sep 6.

53. Kornhuber J, Parsons CG, Hartmann S, et al. Orphenadrine is an uncompetitive n-methyl-d-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. doi: 10.1007/bf01281158.

54. Schaffler K, Reitmeir P, Gschanes A, Eggenreich U. Comparison of the analgesic effects of a fixed-dose combination of orphenadrine and diclofenac (Neodolpasse) with its single active ingredients diclofenac and orphenadrine: a placebo-controlled study using laser-induced somatosensory-evoked potentials from capsaicin-induced hyperalgesic human skin. Drugs in R&D. 2005;6(4):189-99. doi: 10.2165/00126839-200506040-00001.

55. Desaphy JF, Dipalma A, De Bellis M, et al. Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine. Pain. 2009 Apr;142(3):225-35. doi: 10.1016/j.pain.2009.01.010. Epub 2009 Feb 12.

56. Uitz E, Aglas F, Wurm A, Rainer F. Diclofenac/orphenadrine infusion therapy in patients with active arthrosis. Wien Med Wochenschr. 1998;148(7):179-82.

57. Aglas F, Fruhwald FM, Chlud K. Results of efficacy study with diclofenac/orphenadrine infusions in patients with musculoskeletal diseases and functional disorders. Acta Med Austriaca. 1998;25(3):86-90.

58. Friedman BW, Cisewski D, Irizarry E, et al. A Randomized, Double-Blind, PlaceboControlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain. Ann Emerg Med. 2018 Mar; 71(3):348-356.e5. doi: 10.1016/j.annemergmed.2017.09.031. Epub 2017 Oct 28.

59. Grecu I, Muresan A, Nicolau M, Grintescu I. Diclofenac/orphenadrine versus paracetamol for analgesia after total hip arthroplasty. Eur J Anaesthesiol. 2006;23(37):236-7. doi: 10.1097/00003643-200606001-00851.

60. Borsodi M, Nagy E, Darvas K. Diclofenac/orphenadrine as a combined analgetic in post-operative relief of pain. Orv Hetil. 2008;149(39):1847-52. doi: 10.1556/OH.2008.28419.

61. Malek J, Nedelova I, Lopourova M, et al. Diclofenac 75 mg. and 30 mg. orfenadine (Neodolpasse) versus placebo and piroxicam in postoperative analgesia after arthroscopy. Acta Chir Orthop Traumatol Cech. 2004;71(2):80-3.