Naproxen plus paracetamol combination for pain control in musculoskeletal diseases: a new classic
https://doi.org/10.14412/1996-7012-2026-2-122-130
Abstract
Chronic pain is the most burdensome manifestation of rheumatic diseases (RD), a syndrome with a complex multifactorial pathogenesis and a serious threat to the patient’s health and life. It develops when acute pain is insufficiently controlled, against the background of persistent inflammation, degenerative processes, dysfunction of the nociceptive system, and psycho-emotional disturbances. The leading strategy of analgesic therapy in RD is a multimodal approach using drugs and treatment methods targeting the main elements of pain pathogenesis. For pain relief in diseases of the joints and spine, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are generally used. One way to increase the effectiveness of analgesic therapy is a rational combination of analgesics. In particular, combined use of NSAIDs and paracetamol increases treatment efficacy by 30–40%. Given that most patients with RD are older individuals with comorbid cardiovascular diseases, the use of naproxen in combination products is of great interest. This NSAID has high analgesic potential and, at the same time, the best cardiovascular safety profile. Therefore, a new drug comprising a combination of naproxen 275 mg and paracetamol 500 mg, which has recently entered Russian medical practice, can be considered one of the most successful tools for controlling musculoskeletal pain in RD.
Keywords
pain management,
musculoskeletal diseases,
osteoarthritis,
nonspecific low back pain,
nonsteroidal anti-inflammatory drugs,
naproxen plus paracetamol combination
Supporting agencies: This article has been supported by KRKA.
About the Author
A. E. Karateev
V.A. Nasonova Research Institute of Rheumatology
Russian Federation
Russian Federation
Andrey Evgenyevich Karateev
34A, Kashirskoe Shosse, Moscow 115522
References
1. Nasonov EL, Yakhno NN, Karateev AE, et al. General principles of treatmet for musculoskeletal pain: interdisciplinary consensus. Nauchno-prakticheskaya revmatologiya. 2016;54(3):247-265. (In Russ.).
2. Rometsch C, Martin A, Junne F, Cosci F. Chronic pain in European adult populations: a systematic review of prevalence and associated clinical features. Pain. 2025 Apr 1; 166(4):719-731. doi: 10.1097/j.pain.0000000000003406.
3. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 2019 Jan;160(1):19-27. doi: 10.1097/j.pain.0000000000001384.
4. Kloppenburg M, Namane M, Cicuttini F. Osteoarthritis. Lancet. 2025 Jan 4;405(10472): 71-85. doi: 10.1016/S0140-6736(24)02322-5.
5. Rajkumar RP. The influence of cultural and religious factors on cross-national variations in the prevalence of chronic back and neck pain: an analysis of data from the global burden of disease 2019 study. Front Pain Res (Lausanne). 2023 May 25;4:1189432. doi: 10.3389/fpain.2023.1189432.
6. Uke P, Maharaj A, Adebajo A. A review on the epidemiology of rheumatoid arthritis: An update and trends from current literature. Best Pract Res Clin Rheumatol. 2025 Mar;39(1): 102036. doi: 10.1016/j.berh.2025.102036.
7. Reveille JD, Eder L, Ziade N, et al. Global epidemiology of spondyloarthritis. Nat Rev Rheumatol. 2025 Oct;21(10):580-598. doi: 10.1038/s41584-025-01286-x.
8. Asghari KM, Zahmatyar M, Seyedi F, et al. Gout: global epidemiology, risk factors, comorbidities and complications: a narrative review. BMC Musculoskelet Disord. 2024 Dec 19;25(1):1047. doi: 10.1186/s12891-024-08180-9.
9. Koyama K, Ohba T, Koizumi R, Haro H. Prevalence and Predictors of Residual Symptoms in Rheumatoid Arthritis Patients in SDAI Remission: A Cross-Sectional Study Using the Illustrated Okomarigoto Sheet. Clin Rheumatol. 2025 Sep;44(9):3497-3504. doi: 10.1007/s10067-025-07592-9.
10. Perniola S, Bruno D, Di Mario C, et al. Residual pain and fatigue are affected by disease perception in rheumatoid arthritis in sustained clinical and ultrasound remission. Clin Rheumatol. 2025 Mar;44(3):1019-1029. doi: 10.1007/s10067-025-07331-0.
11. Soares Fonseca L, Pereira Silva J, Bastos Souza M, et al. Effectiveness of pharmacological and non-pharmacological therapy on pain intensity and disability in older people with chronic nonspecific low back pain: a systematic review with meta-analysis. Eur Spine J. 2023 Sep;32(9):3245-3271. doi: 10.1007/s00586-023-07857-4.
12. Reynolds CA, Minic Z. Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity. Int J Mol Sci. 2023 Mar 11;24(6):5378. doi: 10.3390/ijms24065378.
13. Barrett JE, Kohut AR. A historical perspective and recent advances on the evolution of the relationship between acute and chronic pain and cardiovascular disease. Biochem Pharmacol. 2024 Oct;228:116357. doi: 10.1016/j.bcp.2024.116357.
14. Taylor HE, Salf JC, Roper-Marchand CR, et al. Are adults with chronic pain more likely to develop hypertension than adults without chronic pain? A systematic review and metaanalysis. Br J Anaesth. 2025 Sep;135(3): 685-696. doi: 10.1016/j.bja.2025.06.006.
15. Aaron RV, Ravyts SG, Carnahan ND, et al. Prevalence of Depression and Anxiety Among Adults With Chronic Pain: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Mar 3;8(3):e250268. doi: 10.1001/jamanetworkopen.2025.0268.
16. Fayaz A, Ayis S, Panesar SS, et al. Assessing the relationship between chronic pain and cardiovascular disease: A systematic review and meta-analysis. Scand J Pain. 2016 Oct; 13:76-90. doi: 10.1016/j.sjpain.2016.06.005.
17. Robinson RL, Schnitzer TJ, Barlow S, et al. Satisfaction with Medications Prescribed for Osteoarthritis: A Cross-Sectional Survey of Patients and Their Physicians in the United States. Pain Ther. 2022 Mar;11(1):191-208. doi: 10.1007/s40122-021-00350-0.
18. Flores-Cortes M, Stanton TR, Cuenca-Martinez F. The Role of Patient Expectations in Treatment Outcome and Satisfaction in Osteoarthritis: A Scoping and Mapping Review. J Clin Med. 2025 Nov 28;14(23): 8440. doi: 10.3390/jcm14238440.
19. Geurts JW, Willems PC, Lockwood C, et al. Patient expectations for management of chronic non-cancer pain: A systematic review. Health Expect. 2017 Dec;20(6):1201-1217. doi: 10.1111/hex.12527.
20. Hallberg S, Rolfson O, Karppinen J, et al. Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study. Scand J Pain. 2022 Jul 20;23(1):126-138. doi: 10.1515/sjpain-2021-0212.
21. Tassou A, Richebe P, Rivat C. Mechanisms of chronic postsurgical pain. Reg Anesth Pain Med. 2025 Feb 5;50(2):77-85. doi: 10.1136/rapm-2024-105964.
22. Anyfanti P, Evangelidis P, Tragiannidis K, et al. Targeting Inflammatory Pathways in Chronic Low Back Pain: Opportunities for Novel Therapeutics. Pharmaceuticals (Basel). 2025 Oct 24;18(11):1612. doi: 10.3390/ph18111612.
23. Nasir A, Afridi M, Afridi OK, et al. The persistent pain enigma: Molecular drivers behind acute-to-chronic transition. Neurosci Biobehav Rev. 2025 Jun;173:106162. doi: 10.1016/j.neubiorev.2025.106162.
24. Rutter-Locher Z, Arumalla N, Norton S, et al. A systematic review and meta-analysis of questionnaires to screen for pain sensitisation and neuropathic like pain in inflammatory arthritis. Semin Arthritis Rheum. 2023 Aug; 61:152207. doi: 10.1016/j.semarthrit.2023.152207.
25. Zolio L, Lim KY, McKenzie JE, et al. Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip osteoarthritis. Osteoarthritis Cartilage. 2021; 29(8):1096-1116. doi: 10.1016/j.joca.2021.03.021.
26. Schuttert I, Timmerman H, Petersen KK, et al. The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review. J Clin Med. 2021;10(24): 5931. doi: 10.3390/jcm10245931.
27. Cnockaert E, Musch K, Elbers S, et al. Longitudinal Outcome Evaluations of Interdisciplinary Multimodal Pain Treatment Programs for Patients With Chronic Primary Musculoskeletal Pain: A Living Systematic Review. Eur J Pain. 2026 Jan;30(1):e70174. doi: 10.1002/ejp.70174.
28. Grant CH, Walker H, Barnett KN, et al. Multimorbidity and analgesic-related harms: a systematic review. Br J Anaesth. 2025 Jun; 134(6):1717-1745. doi: 10.1016/j.bja.2025.02.012. Epub 2025 Mar 20.
29. Swain S, Sarmanova A, Coupland C, et al. Comorbidities in Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies. Arthritis Care Res (Hoboken). 2020 Jul;72(7):991-1000. doi: 10.1002/acr.24008.
30. Karateev AE, Popkova TV, Novikova DS, et al. Assessment of the risk of gastrointestinal and cardiovascular complications associated with nonsteroidal anti-inflammatory drugs in the CIS population: preliminary data from the CORONA-2 epidemiological study. Nauchnoprakticheskaya revmatologiya. 2014;52(6): 600-606. (In Russ.).
31. Finneman Z, Swartz C, Drymalski M. Navigating Low Back Pain: A Multidisciplinary Approach to Diagnosis, Management, and Education. Mo Med. 2025 May-Jun; 122(3):193-198.
32. Przybyla GW, Szychowski KA, Gminski J. Paracetamol – an old drug with new mechanisms of action. Clin Exp Pharmacol Physiol. 2021 Jan;48(1):3-19. doi: 10.1111/1440-1681.13392.
33. Al-Kuraishy HM, Al-Gareeb AI, Albuhadily AK, et al. Paracetamol: the potential therapeutic pathways defining its clinical use. Inflammopharmacology. 2025 Jun;33(6): 2907-2918. doi: 10.1007/s10787-025-01779-x.
34. Leopoldino AO, Machado GC, Ferreira PH, et al. Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019 Feb 25;2(2):CD013273. doi: 10.1002/14651858.CD013273.
35. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016 Jun 7;2016(6): CD012230. doi: 10.1002/14651858.CD012230.
36. Cornelius B, Freeman B, Mordecai A. Pharmacology of Pain Management. Nurs Clin North Am. 2025 Dec;60(4):591-618. doi: 10.1016/j.cnur.2025.01.005.
37. https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=57c90ee4-f701-475f-9a9e-6200b71cfc75
38. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol. 2007 Mar;34(3):543-55.
39. Zhang X, Li X, Xiong Y, et al. Efficacy and Safety of Tramadol for Knee or Hip Osteoarthritis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Arthritis Care Res (Hoboken). 2023 Jan;75(1):158-165. doi: 10.1002/acr.24750.
40. Tölle T, Fitzcharles MA, Häuser W. Is opioid therapy for chronic non-cancer pain associated with a greater risk of all-cause mortality compared to non-opioid analgesics? A systematic review of propensity score matched observational studies. Eur J Pain. 2021 Jul;25(6):1195-1208. doi: 10.1002/ejp.1742.
41. Karateev AE, Lila AM, Mazurov VI, et al. Expert consensus 2024: rational use of nonsteroidal anti-inflammatory drugs. Modern Rheumatology Journal. 2025;19(Suppl. 1): 1-40. (In Russ.). doi: 10.14412/1996-7012-2025-1S-1-40.
42. 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.
43. Moore RA, Moore OA, Derry S, et al. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Ann Rheum Dis. 2010 Feb;69(2):374-9. doi: 10.1136/ard.2009.107805.
44. Hopkins S, Yang V, Liew DF. Choosing a nonsteroidal anti-inflammatory drug for pain. Aust Prescr. 2025 Aug;48(4):139-144. doi: 10.18773/austprescr.2025.032.
45. Manca A, Cugusi L, van Tulder M, et al. Oral non-benzodiazepine muscle-relaxants for people with acute and chronic primary low back pain: a systematic review with metaanalysis. Eur Spine J. 2025 Jun;34(6):2347- 2366. doi: 10.1007/s00586-025-08786-0.
46. Birkinshaw H, Friedrich CM, Cole P, et al. Antidepressants for pain management in adults with chronic pain: a network metaanalysis. Cochrane Database Syst Rev. 2023 May 10;5(5):CD014682. doi: 10.1002/14651858.CD014682.pub2.
47. Ayub S, Bachu AK, Jain L, et al. Nonopioid psychiatric medications for chronic pain: systematic review and meta-analysis. Front Pain Res (Lausanne). 2024 Oct 10; 5:1398442. doi: 10.3389/fpain.2024.1398442.
48. Weisman SM, Ciavarra G, Cooper G. What a pain in the … back: a review of current treatment options with a focus on naproxen sodium. J Pharm Pharm Sci. 2024 Feb 7; 27:12384. doi: 10.3389/jpps.2024.12384.
49. Derry C, Derry S, Moore RA, McQuay HJ. Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009 Jan 21; 2009(1):CD004234. doi: 10.1002/14651858.CD004234.pub3.
50. Janssens HJ, Janssen M, van de Lisdonk EH, et al. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008 May 31;371(9627):1854-60. doi: 10.1016/S0140-6736(08)60799-0.
51. JiaoYi P, YongQi S, KeChun G, et al. Assessing the efficacy and safety of different nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis: A systematic review and network meta-analysis based on RCT trials. PLoS One. 2025 May 7;20(5): e0320379. doi: 10.1371/journal.pone.0320379.
52. 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.
53. Parfenov VA. Therapeutic outcomes in patients with acute non-specific (musculoskeletal) pain according to the FORTE observational study. Neurology, Neuropsychiatry, Psychosomatics. 2024;16(3):88-95. (In Russ.). doi: 10.14412/2074-2711-2024-3-88-95.
54. Levin OS, Skoromets AA, Tabeeva GR, et al. Efficacy of Naproxen in Treatment of Nonspecific Lumbalgia: The results of an Open Multi-Center Study. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2019;119(5): 27-31. (In Russ.).
55. Minhas D, Nidhaan A, Husni ME. Recommendations for the Use of Nonsteroidal Anti-inflammatory Drugs and Cardiovascular Disease Risk: Decades Later, Any New Lessons Learned? Rheum Dis Clin North Am. 2023 Feb;49(1):179-191. doi: 10.1016/j.rdc.2022.08.006.
56. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011 Sep;8(9):e1001098. doi: 10.1371/journal.pmed.1001098.
57. Coxib and traditional NSAID Trialists' (CNT) Collaboration; Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013 Aug 31;382(9894):769-79. doi: 10.1016/S0140-6736(13)60900-9.
58. Garegnani L, Oltra G, Burgos MA, et al. Proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug-induced ulcers and dyspepsia. Cochrane Database Syst Rev. 2025 May 8;5(5):CD014585. doi: 10.1002/14651858.CD014585.pub2.
59. Tena-Garitaonaindia M, Rubio JM, Martinez-Plata E, et al. Pharmacological bases of combining nonsteroidal antiinflammatory drugs and paracetamol. Biomed Pharmacother. 2025 Jun;187:118069. doi: 10.1016/j.biopha.2025.118069.
60. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg. 2010 Apr 1;110(4):1170-9. doi: 10.1213/ANE.0b013e3181cf9281.
61. Cao Z, Han K, Lu H, et al. Paracetamol Combination Therapy for Back Pain and Osteoarthritis: A Systematic Review and MetaAnalyses. Drugs. 2024 Aug;84(8):953-967. doi: 10.1007/s40265-024-02065-w.
62. Golden HE, Moskowitz RW, Minic M. Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee. Am J Ther. 2004 MarApr;11(2):85-94. doi: 10.1097/00045391-200403000-00002.
63. Schiff M, Minic M. Comparison of the analgesic efficacy and safety of nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoarthritis of the knee. J Rheumatol. 2004 Jul;31(7):1373-83.
64. Seideman P. Additive effect of combined naproxen and paracetamol in rheumatoid arthritis. Br J Rheumatol. 1993 Dec;32(12): 1077-82. doi: 10.1093/rheumatology/32.12.1077.
65. Seideman P, Samuelson P, Neander G. Naproxen and paracetamol compared with naproxen only in coxarthrosis. Increased effect of the combination in 18 patients. Acta Orthop Scand. 1993 Jun;64(3):285-8. doi: 10.3109/17453679308993626..
66. https://www.drugs.com/medical-answers/proxalin-plus-3566994/
67. https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=9f6a6036-5c26-4255-bd03-6da27f9cba36
Review
For citations:
Karateev AE. Naproxen plus paracetamol combination for pain control in musculoskeletal diseases: a new classic. Sovremennaya Revmatologiya=Modern Rheumatology Journal. 2026;20(2):122-130. (In Russ.) https://doi.org/10.14412/1996-7012-2026-2-122-130
Views:
840
JATS XML
Email this article 
