Caffeine and Ibuprofen, Paracetamol and pain control [reference to two studies]

Sometimes, the right combination is better than stuff with far more side effects. People never understand why I like coffee that much. But then, maybe some of you all also want to improve pain control at less side effects and less cost.

What really seems to matter here is the correct ratio more than dosing high to begin with. That means that for each cup of coffee (100-200 mg caffeine), about 4-5 times that amount of ibuprofen (that is, Ibuprofen 400 or 800) appears to work best according to that study.

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Eur J Pharmacol. 2006 Aug 21;544(1-3):31-8. Epub 2006 Jun 27.

Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats.

López JR, Domínguez-Ramírez AM, Cook HJ, Bravo G, Díaz-Reval MI, Déciga-Campos M, López-Muñoz FJ.


Departamento de Sistemas Biológicos, UAM-Xochimilco, México D.F., México.


It has been observed that caffeine improves antinociceptive efficacy of some non-steroidal antiinflammatory drugs (NSAIDs) in several experimental models, however, these effects have been questioned in humans. Controversy in clinical studies may be due to the use of different protocols as well as to high interindividual variability in patient response. In addition, the antinociceptive interaction of ibuprofen+caffeine has not been studied. To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ibuprofen, and caffeine administered either separately or in combinations were determined in a model of arthritic pain: "Pain-induced functional impairment in the rat (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine or acetylsalicylic acid alone. The animals were administered with 0.05 ml intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received either acetylsalicylic acid, morphine, ibuprofen or caffeine, or a combination ibuprofen+caffeine (18 combinations). We report here that caffeine (17.8 and 31.6 mg/kg) is able to potentiate the antinociceptive effect of ibuprofen. This investigation showed that six combinations presented effects of potentiation and twelve combinations only showed antinociceptive effects not different from that of ibuprofen alone. The maximum antinociceptive effect was 270.7+/-12.7 area units (au), produced by ibuprofen 100 mg/kg+caffeine 17.8 mg/kg; this effect was greater than the maximum produced by morphine 17.8 mg/kg (244.7+/-22.9 au) in these experimental conditions. The maximum potentiation was 197 % produced with the combination of ibuprofen 17.8 mg/kg+caffeine 17.8 mg/kg. These results suggest that the antinociceptive effect of ibuprofen was significantly potentiated by doses of caffeine that by themselves are ineffective in this model.
Futhermore, offset administration of up to 6 x 500 mg Paracetamol may in fact boost the effect even more.
Inflammopharmacology. 1999;7(3):255-63.
Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs.
Graham GG, Day RO, Milligan MK, Ziegler JB, Kettle AJ.
School of Physiology and Pharmacology, University of NSW, 2052, Sydney, Australia.

There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC(50) values ranging from approximately 4 microM to 200 microM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100 microM and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOCl). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC(50) value, derived from inhibition of the total production of HOC1 by isolated myeloperoxidase, is 81 microM. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.


Disclaimer: Generally it is probably best to discuss all matters related to health with your doctor. Always ask your doctor and pharmacist. Never exceed limits, requirements or prescriptions. Always follow the orders. What works for me may not work for you or even get you killed.


Cite this article:
Wolf Schweitzer: - Caffeine and Ibuprofen, Paracetamol and pain control [reference to two studies]; published 11/09/2012, 06:14; URL:

BibTeX: @MISC{schweitzer_wolf_1631983651, author = {Wolf Schweitzer}, title = {{ - Caffeine and Ibuprofen, Paracetamol and pain control [reference to two studies]}}, month = {September}, year = {2012}, url = {} }