A combination without illusions: paracetamol and diclofenac under «the microscope» of evidence

The combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) is often perceived as an automatic ‘enhancement’ of analgesia, but evidence-based medicine data demonstrate the selectivity of the effect. Diclofenac is one of the most effective oral NSAIDs for osteoarthritis and provides sufficient analgesia as monotherapy in many clinical situations. The addition of paracetamol may be justified mainly in acute postoperative pain, whereas in acute traumatic musculoskeletal pain, there is often no increase in efficacy. Combined/alternating regimens increase the risk of dosing errors and additional toxicity; the simultaneous use of two NSAIDs should be avoided. A practical approach is to select one NSAID, use the minimum effective dose and the shortest course; combination with paracetamol should only be considered when clearly indicated.

References

1. Paul S.P., Kini P.K., Tibrewal S.R. et al. (2022) NICE guideline review: fever in under 5s: assessment and initial management (NG143). Arch. Dis. Child. Educ. Pract. Ed., 107(3): 212–216. doi: 10.1136/archdischild-2021-321718.
2. Qaseem A., McLean R.M., O’Gurek D. et al. (2020) Nonpharmacologic and Pharmacologic Management of Acute Pain From Non-Low Back, Musculoskeletal Injuries in Adults: A Clinical Guideline From the American College of Physicians and American Academy of Family Physicians. Ann. Intern. Med., 173(9): 739–748.
3. Maeßen T., Korir N., Van de Velde M. et al. (2023) Pain management after cardiac surgery via median sternotomy: A systematic review with procedure-specific postoperative pain management (PROSPECT) recommendations. Eur. J. Anaesthesiol., 40(10): 758–768. doi: 10.1097/EJA.0000000000001881.
4. Carrasco-Labra A., Polk D.E., Urquhart O. et al. (2023) Evidence-based clinical practice guideline for the pharmacologic management of acute dental pain in children: A report from the American Dental Association Science and Research Institute, the University of Pittsburgh School of Dental Medicine, and the Center for Integrative Global Oral Health at the University of Pennsylvania. J. Am. Dent. Assoc., 154(9): 814–825.e2. doi: 10.1016/j.adaj.2023.06.014.
5. Fallon M., Giusti R., Aielli F. et al. (2018). Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann. Oncol., 29(Suppl. 4): iv166–iv191.
6. Kolasinski S.L., Neogi T., Hochberg M.C. et al. (2020) 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol., 72(2): 220–233.
7. Oliveira C.B., Maher C.G., Pinto R.Z. et al. (2018) Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview. Eur. Spine J., 27(11): 2791–2803. doi: 10.1007/s00586-018-5673-2.
8. Ozleyen A., Yilmaz Y.B., Donmez S. et al. (2023) Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention. J. Cancer Res. Clin. Oncol., 149(5): 2095–2113.
9. Freo U., Ruocco C., Valerio A. et al. (2021) Paracetamol: A Review of Guideline Recommendations. J. Clin. Med., 10(15): 3420. doi: 10.3390/jcm10153420.
10. Tena-Garitaonaindia M., Rubio J.M., Martínez-Plata E. et al. (2025) Pharmacological bases of combining nonsteroidal antiinflammatory drugs and paracetamol. Biomed. Pharmacother., 187: 118069. doi: 10.1016/j.biopha.2025.118069.
11. da Costa B.R., Pereira T.V., Saadat P. et al. (2021) Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ, 375: n2321. doi: 10.1136/bmj.n2321.
12. da Costa B.R., Reichenbach S., Keller N. et al. (2017) Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet, 390(10090): e21–e33.
13. Atzeni F., Masala I.F., Sarzi-Puttini P. (2018) A Review of Chronic Musculoskeletal Pain: Central and Peripheral Effects of Diclofenac. Pain Ther., 7(2): 163–177.
14. Clinard F., Sgro C., Bardou M. et al. (2004) Association between concomitant use of several systemic NSAIDs and an excess risk of adverse drug reaction. A case/non-case study from the French Pharmacovigilance system database. Eur. J. Clin. Pharmacol., 60(4): 279–83. doi: 10.1007/s00228-004-0761-0.
15. Panchal N.K., Prince Sabina E. (2023) Non-steroidal anti-inflammatory drugs (NSAIDs): A current insight into its molecular mechanism eliciting organ toxicities. Food Chem. Toxicol., 172: 113598. doi: 10.1016/j.fct.2022.113598.
16. Cooper C., Chapurlat R., Al-Daghri N. et al. (2019) Safety of Oral Non-Selective Non-Steroidal Anti-Inflammatory Drugs in Osteoarthritis: What Does the Literature Say? Drugs Aging, 36(Suppl. 1): 15–24. doi: 10.1007/s40266-019-00660-1.
17. MacIntyre I.M., Turtle E.J., Farrah T.E. et al. (2022) Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial. Circulation, 145(6): 416–423. doi: 10.1161/CIRCULATIONAHA.121.056015.
18. NICE Clinical Knowledge Summaries (CKS) (2024) NSAIDs — prescribing issues. cks.nice.org.uk/topics/nsaids-prescribing-issues/management/nsaids-prescribing-issues.
19. NHS GGC (2023) Non-steroidal anti-inflammatory drugs (NSAIDs) Guideline. http://www.rightdecisions.scot.nhs.uk/media/2649/32-oral-non-steroidal-anti-inflammatory-nsaid.pdf.
20. Lanas A., Benito P., Alonso J. et al. (2014) Safe prescription recommendations for non steroidal anti-inflammatory drugs: consensus document ellaborated by nominated experts of three scientific associations (SER-SEC-AEG). Reumatol. Clin., 10(2): 68–84. doi: 10.1016/j.reuma.2013.10.004.
21. Ibuprofen for adults (Nurofen) (2025) Ibuprofen for adults. http://www.nhs.uk/medicines/ibuprofen-for-adults.