pain, inflammation, caffeine, non-narcotic analgesics, nonsteroidal anti-inflammatory drugs, pharmaceutical composition.


The review article summarizes the date of literature and our own research on the creation of more effective and safe domestic combined drugs with a pronounced anti-inflammatory and analgesic effects. Untimely treatment of inflammatory processes often leads to long-term disability and even disability, so today there is an active search for new effective and safe domestic combination drugs with pronounced anti-inflammatory and analgesic effects. The constant search for innovative drugs causes a significant number of diseases, pathological conditions for which treatment with existing drugs is not effective or causes addiction and a large number of side effects. Because of, inflammatory processes can be accompanied by severe pain, spasms, increased convulsive activity of the brain, other disorders of the body, so non-narcotic analgesics and nonsteroidal anti-inflammatory drugs are combined with other drugs that can cause complementary effects or potentiate each other's effects. Caffeine is a useful adjuvant of nonsteroidal anti-inflammatory drugs of various chemical structures in terms of anti-inflammatory and analgesic effects. The review article presents a literature review of the current state of treatment of inflammation and pain, conducting research to expand the therapeutic capabilities of known pharmaceuticals, the creation of pharmaceutical compositions of nonsteroidal anti-inflammatory drugs with caffeine.


Kyrychok, L. T., Trutaiev, I. V., & Fedorin, H. F. (2001). Kombinovani fitopreparaty – nove perspektyvne dzherelo farmakoterapii [Combined phytopreparations are new promising sources of pharmacotherapy]. Farmakolo-hiia 2001 – krok u maibutnie: materialy II Natsionalnoho zizdu farmakolohiv Ukrainy, Dnipropetrovsk [Pharmacology 2001 ‒ a step into the future: materials of the 1st National Congress of Pharmacologists of Ukraine, Dnipropetrovsk].

Lourens, D. R., & Bennyt, P. N. (1991). Vospalenye y nesteroydnye protyvovospalytelnye sredstva [Inflammatory and nonsteroidal anti-inflammatory drugs]. Klynycheskaia farmakolohyia [Clinical Pharmacology]. M., Medytsyna.

Ivanova, V.V., Govorova, L.V., Erbasskaya, A.V., & Alekseeva, L.A. (2012). Features of the response to in-flammatory process in children with high and low intensity of free radical oxidations in lymphocytes during the acute period of the disease in various ethnic groups. Journal Infectology, 4(3), 46‒52.

Brenneis, C., Coste, O., Altenrath, K., et al. (2011). Anti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation. J Biol Chem. 286(3), 2331-2342.

Crofford, L. J., Lipsky, P. E., Brooks, P., Abramson, S. B., Simon, L. S., & van de Putte, L. B. (2000). Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis and rheumatism, 43(1), 4–13.<4::AID-ANR2>3.0.CO;2-V

Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., … & Baigent, C. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (London, England), 382(9894), 769–779.

Das, S., Haldar, P. K., Pramanik, G., Panda, S. P., & Bera, S. (2011). Evaluation of analgesic and anti-inflammatory activity of diospyros cordifolia extract. African journal of traditional, complementary, and alternative medicines : AJTCAM, 8(1), 11–14.

Morrison, A., Ramey, D. R., van Adelsberg, J., & Watson, D. J. (2007). Systematic review of trials of the ef-fect of continued use of oral non-selective NSAIDs on blood pressure and hypertension. Current medical research and opinion, 23(10), 2395–2404.

Páramo, J. A., Beloqui, O., & Orbe, J. (2006). Ciclooxigenasa 2: 'una nueva diana terapéutica en la aterosclero-sis? [Cyclooxygenase-2: a new therapeutic target in atherosclerosis?]. Medicina clinica, 126(20), 782–786. [In Spanish].

Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis, thrombosis, and vascular biology, 31(5), 986–1000.

Vu, D., Murty, M., & McMorran, M. (2002). Selective COX-2 inhibitors: suspected cardiovascu-lar/cerebrovascular adverse reaction. Canad. Adverse Reaction Newsletter, 12, 1‒4.

Nasonov, E. L., Yakhno, N. N., Karateev, A. E., et al. (2016). General principles of the treatment of musculo-skeletal pain: interdisciplinary consensus. Scientific and practical rheumatology, 54(3), 247‒265.

Laufer, S., Gay, S., & Brune, K. (2003). Inflammation and Rheumatic Diseases: The molecular basis of novel therapies. New York: Georg Thieme Verlag.

Visha, M. G. (2013). Selective Cox-2 inhibitor. Int. J. Pharm. Sci Interv., 3(2), 28‒33.

Schjerning Olsen, A. M., Gislason, G. H., McGettigan, P., Fosbøl, E., Sørensen, R., Hansen, M. L., … & Lamberts, M. (2015). Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA, 313(8), 805–814.

Bresalier, R. S., Sandler, R. S., Quan, H., Bolognese, J. A., Oxenius, B., Horgan, K., … & Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. The New England journal of medicine, 352(11), 1092–1102. 10.1056/NEJMoa050493

Fanelli, A., Ghisi, D., Aprile, P. L., & Lapi, F. (2017). Cardiovascular and cerebrovascular risk with nonsteroi-dal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Therapeutic advances in drug safety, 8(6), 173–182.

Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., … & Baigent, C. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (London, England), 382(9894), 769–779.

FitzGerald, G. A., & Patrono, C. (2001). The coxibs, selective inhibitors of cyclooxygenase-2. The New Eng-land journal of medicine, 345(6), 433–442.

Brune, K., & Patrignani, P. (2015). New insights into the use of currently available non-steroidal anti-inflammatory drugs. Journal of pain research, 8, 105–118.

Walter, M. F., Jacob, R. F., Day, C. A., Dahlborg, R., Weng, Y., & Mason, R. P. (2004). Sulfone COX-2 in-hibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs. Atherosclerosis, 177(2), 235–243.

Solomon, S. D., McMurray, J. J., Pfeffer, M. A., Wittes, J., Fowler, R., Finn, P., … & Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. The New England journal of medicine, 352(11), 1071–1080.

Simon, L. S. (2000). Are the biologic and clinical effects of the COX-2-specific inhibitors an advance compared with the effects of traditional NSAIDs? Current opinion in rheumatology, 12(3), 163–170. 00002281-200005000-00001

Smith, W. L., & Langenbach, R. (2001). Why there are two cyclooxygenase isozymes. The Journal of clinical investigation, 107(12), 1491–1495.

Wallace, J. L. (1999). Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of nonsteroidal anti-inflammatory drugs (NSAIDs). The American journal of medicine, 107(6A), 11S–17S.

Wallace, J. L., Bak, A., McKnight, W., Asfaha, S., Sharkey, K. A., & MacNaughton, W. K. (1998). Cycloox-ygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. Gastroen-terology, 115(1), 101–109.

Dey, I., Lejeune, M., & Chadee, K. (2006). Prostaglandin E2 receptor distribution and function in the gastroin-testinal tract. British journal of pharmacology, 149(6), 611–623.

Van Hecken, A., Schwartz, J. I., Depré, M., De Lepeleire, I., Dallob, A., Tanaka, W., … & De Schepper, P. J. (2000). Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. Journal of clinical pharmacology, 40(10), 1109–1120.

Lanas, A., García-Rodríguez, L. A., Arroyo, M. T., Gomollón, F., Feu, F., González-Pérez, A., … & Aso-ciación Española de Gastroenterología (2006). Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut, 55(12), 1731–1738.

Barracchini, A., Franceschini, N., Amicosante, G., et al. (1998). Biochemistry: Can Non-steroidal Anti-inflammatory Drugs Act as Metalloproteinase Modulators? An In-vitro Study of Inhibition of Collagenase Activity. J. Pharm. Pharmacol., 50(12), 1417‒1423.

Holgate, S. T., Peters-Golden, M., Panettieri, R. A., & Henderson, W. R., Jr (2003). Roles of cysteinyl leuko-trienes in airway inflammation, smooth muscle function, and remodeling. The Journal of allergy and clinical immu-nology, 111(1 Suppl), S18–S36.

Burnett, B. P., & Levy, R. M. (2012). 5-Lipoxygenase metabolic contributions to NSAID-induced organ toxici-ty. Advances in therapy, 29(2), 79–98.

Williams, C. M., Maher, C. G., Latimer, J., McLachlan, A. J., Hancock, M. J., Day, R. O., & Lin, C. W. (2014). Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial. Lancet (London, England), 384(9954), 1586–1596.

Moore, R. A., Tramèr, M. R., Carroll, D., Wiffen, P. J., & McQuay, H. J. (1998). Quantitative systematic re-view of topically applied non-steroidal anti-inflammatory drugs. BMJ (Clinical research ed.), 316(7128), 333–338.

Mason, L., Moore, R. A., Edwards, J. E., Derry, S., & McQuay, H. J. (2004). Topical NSAIDs for acute pain: a meta-analysis. BMC family practice, 5, 10.

Komatsu, T., & Sakurada, T. (2012). Comparison of the efficacy and skin permeability of topical NSAID prepa-rations used in Europe. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 47(5), 890–895.

Ballerini, R., Casini, A., Chinol, M., Mannucci, C., Giaccai, L., & Salvi, M. (1986). Study on the absorption of ketoprofen topically administered in man: comparison between tissue and plasma levels. International journal of clinical pharmacology research, 6(1), 69–72.

Wilbrink, B., Van der Veen, M. J., Huber, J., Van Roy, J. L., & Huber-Bruning, O. (1991). In vitro influence of ketoprofen on the proteoglycan metabolism of human normal and osteoarthritis cartilage. Agents and actions, 32(3‒4), 154–159.

Weinberg, B. A., & Bealer, B. K. (2004). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge, 235.

Derry, C. J., Derry, S., & Moore, R. A. (2012). Caffeine as an analgesic adjuvant for acute pain in adults. The Cochrane database of systematic reviews, (3), CD009281.

Syrova, H. O. (2010). Patent Ukrainy na korysnu model No.51082 "Sposib potentsiiuvannia protybolovoi dii kaliievoi soli 2,4-dykhlorbenzoinoi kysloty" [Patent of Ukraine for utility model No.51082 "Method of potentiation of the analgesic effect of the potassium salt of 2,h-dichlorobenzoic acid"], MPK: A61K 31/00 on June 25, 2010. Bull No.12.

Syrova, H. O., Hrabovetska, Ye. R., Shapoval, L. R., Nakonechna, S. A., Vakulenko, N. V., & Boiko, S. P. Patent Ukrainy na korysnu model No.59396. "Zastosuvannia kompozytsii nesteroidnykh protyzapalnykh zasobiv z kofeinom yak preparativ z antyeksudatyvnoiu aktyvnistiu" [Patent of Ukraine for utility model No.59396 "The use of composites of nonsteroidal anti-inflammatory drugs with caffeine as drugs with antiexudative activity"], MPK: A61KZ1/00-31/80 on May 10, 2011. Bull No.1.

Syrova, H. O., Bachynskyi, R. O., Vakulenko, N. V., & Boiko, Ye. P. (2011). Eksperymentalne vyvchennia vplyvu kofeinu na protybolovu diiu vidomykh nesteroidnykh protyzapalnykh zasobiv riznoi khimichnoi budovy [Ex-perimental study of the effect of caffeine on the anti-inflammatory effect of known non-steroidal anti-inflammatory drugs of different chemical structure]. Zaporozhskyi medytsynskyi zhurnal [Zaporizhzhya Medical Journal], 13(5), 60‒62.

Syrova, H. O. (2012). Eksperymentalne vyvchennia spetsyfichnoi dii kaliievoi soli 2,4-dykhlorbenzoinoi kysloty i yii kompozytsii z kofeinom [Experimental study of the specific action of the potassium salt of 2,h-dichlorobenzoic acid and other compositions with caffeine]. Ukrainskyi biofarmatsevtychnyi zhurnal [Ukrainian bio-pharmaceutical journal], 5/6, 59‒62.

Syrovaya, A. O., Bachinskiy, R. O., & Grabovetskaya, E. R. (2014). Creation of new drug compositions and pharmacological substantiation of their suitability for pain syndromes and inflammations in experimental rats. Inter Colleqas, 1, 13‒24.

Syrova, H. O. (2014). Eksperymentalne vyvchennia protybolovoi dii karbamazepinu, paratsetamolu i kofeinu ta yikh kompozytsii [Experimental study of the analgesic effect of carbamazepine, paracetamol and caffeine and their com-positions]. Ukrainskyi biofarmatsevtychnyi zhurnal [Ukrainian biopharmaceutical journal], 6, 8‒12.

Lukiyanova, L. V. (2016). Experiments on new pharmacological compositions under formalin edema. Der Pharma Chemica, 8(19), 182‒186.

Syrova, G. O., Lukianova, L. V., & Chalenko, N. M. (2018). The experimental research on the antiinflammato-ry action of the new piroxicamcaffeine pharmaceutical composition. Science Review, 4, (3(10)), 72‒76.

Syrova, G. O., Tishakova, T. S., Levashova, O. L., Savelieva, O. V. (2018). Biochemical Confirmation of An-ti-Inflammatory Activity of Oxicam Based Pharmaceutical Compositions. Jotcsa, 5(3), 1407‒1412.

Syrova, A., Lukyanova, L., Kozub, S., Zavada, О., Levashova, О., & Shaposhnik, V. (2020). Investigation of the Peripheral Analgesic Activity of Oxicams and Their Combinations with Caffeine. Turkish Journal оf Pharmaceuti-cal Sciences, 17(4), 408‒411.

Lukiyanova, L.V. (2016). Experiments on the influence of organic compounds with nitrogen and their composi-tions on the emotional-behavioral reactions of laboratory animals under formalin edema. Der Pharma Chemica, 8(19), 581‒585.

Syrova, G., Lukianova, L., Sinelnik, V., Krasnikova, Yu., Logina, S. (2019). Experimental investigation of the effect of pharmaceutical composition on the central nervous system. Inter Collegas, 6(3), 162‒167.

Karateev, A. E. (2017). What is safer for the gastrointestinal-tract: Coxibs or meloxicam? Modern Rheumatology Journal, 11(1), 72–78.

Malmstrom, K., Fricke, J. R., Kotey, P., Kress, B., & Morrison, B. (2002). A comparison of rofecoxib versus celecoxib in treating pain after dental surgery: a single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study using the dental impaction pain model. Clinical therapeutics, 24(10), 1549–1560.

Sommer, I. E., de Witte, L., Begemann, M., & Kahn, R. S. (2012). Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. The Journal of clinical psychiatry, 73(4), 414–419.

Arber, N., Eagle, C. J., Spicak, J., Rácz, I., Dite, P., Hajer, J., … & PreSAP Trial Investigators (2006). Celecoxib for the prevention of colorectal adenomatous polyps. The New England journal of medicine, 355(9), 885–895.

Bertagnolli, M. M., Eagle, C. J., Zauber, A. G., Redston, M., Solomon, S. D., Kim, K., … & APC Study Investigators (2006). Celecoxib for the prevention of sporadic colorectal adenomas. The New England journal of medi-cine, 355(9), 873–884.

Rahme, E., Barkun, A. N., Toubouti, Y., & Bardou, M. (2003). The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology, 125(2), 404–412.

Basler, J. W., & Piazza, G. A. (2004). Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective in-hibitors for prostate cancer chemoprevention. The Journal of urology, 171(2 Pt 2), S59–S63.

Silverstein, F. E., Faich, G., Goldstein, J. L., Simon, L. S., Pincus, T., Whelton, A., … & Geis, G. S. (2000). Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheuma-toid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA, 284(10), 1247–1255.

McGettigan, P., & Henry, D. (2013). Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS medicine, 10(2), e1001388.

Chalenko, N., Demchenko, A., & Syrova, G. (2019). Synthesis of potential antiexudative preparations for 2-((4-amino-5-(furan-2-il)-1,2,4-triazole-(4H)-3-yl)-sulfanyl)-N-acetamide series. Scientific Journal «ScienceRise: Pharmaceu-tical Science», 3(19), 22‒29.

Syrovaya, A. O., Chalenko, N. N., & Demchenko, A. M. (2016). The Synthesis of Potential Anti-Inflammatory Substances among 4-Amino-5-(Pyridin-4-yl)-1,2,4-Triazole(4H)-3-yl-Thioacetamides and their Chemical Modification. Der Pharma Chemica, 8(21), 17‒21.

Adamu, I., & Chalenko, N. (2017). Synthesis, prediction and experimental confirmation of pharmakological ac-tivity of 2-((4-amino-5-(furan-2-yl)-4H-1,2,4-triazole-3-yl)sulfanyl)-n-acetamide derivatives. X-th International Scientific Interdisciplinary Conference (ISIC) for medical students and young scientists, Ukraine, Kharkiv, 3.

Öztürk, S., Akkurt, M., Cansiz A., et al. (2004). 4-(4-Chlorophenyl)-3-(furan-2-yl)-1H-1,2,4-triazole-5(4H)-thione. Acta Cryst, 60, 425‒427.

Ali, A., Nasim, V., Abbas, T. S., Abbas, K. S. (2007). Synthesis, anticonvulsant and muscle relaxant activities of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole. Acta chim (Sloven.), 2(54), 317‒324.

Cai, H., Huang, X., Xu, S., Shen, H., Zhang, P., Huang, Y., … & Xu, J. (2016). Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy. European journal of medicinal chemistry, 108, 89–103.

Sondhi, S.M., Dinodia, M., & Singh, J. (2007). Heterocyclic Compounds as Anti-Inflammatory Agents. Cur-rent Bioactive Compounds, 2(3), 91‒108.

Jiang, B., Zeng, Y., Li, M. J., Xu, J. Y., Zhang, Y. N., Wang, Q. J., … & Wu, X. M. (2010). Design, syn-thesis, and biological evaluation of 1,5-diaryl-1,2,4-triazole derivatives as selective cyclooxygenase-2 inhibitors. Archiv der Pharmazie, 343(9), 500–508.

Cao, L., Zhang, L., & Cui, P. (2004). Synthesis of 3-(3-alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl)aminocarbonylchromones. Chem. Heterocyclic Compounds, 40(5), 635–640.

Singh, R., Sylvain, C., & Holland, S. (2013). Pat. US 8389557 B2, A61K31/41 "Triazole derivatives useful as Axl inhibitors".

Plech, T., Wujec, M., & Majewska, M. (2013). Microbiologically active Mannich bases derived from 1,2,4-triazoles. The effect of C-5 substituent on antibacterial activity. Med. Chem. Res., 22, 2531‒2537.

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