Effect of Caffeine on the Bioavailability and Pharmacokinetics of an Acetylsalicylic Acid-Paracetamol Combination: Results of a Phase I Study

Overview

Journal Adv Ther

Date 2019 Feb 14

PMID 30758744

Citations 5

Authors

Thomas Weiser

Harald Weigmann

Affiliations

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Abstract

Introduction: Caffeine is used as an adjuvant in analgesic combinations to enhance their efficacy. The present study aimed to determine the effect of caffeine on the pharmacokinetics of acetylsalicylic acid (ASA) and paracetamol when used as a fixed-dose ASA/paracetamol/caffeine combination.

Methods: In this single-centre, two-way, cross-over phase I study, volunteers fasted overnight (≥ 12 h) and randomly received single oral doses of 250 mg ASA/200 mg paracetamol (reference) or 250 mg ASA/200 mg paracetamol/50 mg caffeine (test). Blood samples were collected before and up to 24 h after dosing. The primary end points were the area under the concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (C) for ASA, salicylic acid (SA) and paracetamol from the two combinations. The main secondary end points were AUC and C of caffeine and time to reach C (t) of all drugs.

Results: Eighteen healthy male volunteers (32.5 ± 10.5 years) participated in the study. The geometric means of C for ASA, SA and paracetamol were similar in the test (3.71, 15.8 and 2.42 µg/ml, respectively) and reference groups (3.89, 15.8, 2.42 µg/ml, respectively). The geometric mean of AUC for ASA, SA and paracetamol from the test combination was 2.86, 60.5 and 7.68 µg h/ml, respectively, and that for the reference was 2.96, 59.1 and 7.77 µg h/ml, respectively. The medians of t for ASA, SA and paracetamol were similar between the two groups. The point estimates for the ratios of AUC and C for test versus reference regarding ASA, SA and paracetamol were within the predefined equivalence limits. The two treatments were well tolerated.

Conclusion: Caffeine did not affect the pharmacokinetics of ASA and paracetamol when used as an adjuvant in ASA/paracetamol fixed-dose combination under fasting conditions, suggesting that caffeine enhances the analgesic efficacy of these drugs by pharmacodynamic rather than pharmacokinetic interactions.

Funding: Sanofi-Aventis Deutschland GmbH.

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References

Sawynok J . Caffeine and pain. Pain. 2010; 152(4):726-729. DOI: 10.1016/j.pain.2010.10.011. View

Thithapandha A . Effect of caffeine on the bioavailability and pharmacokinetics of aspirin. J Med Assoc Thai. 1989; 72(10):562-6. View

Renner B, Clarke G, Grattan T, Beisel A, Mueller C, Werner U . Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. J Clin Pharmacol. 2007; 47(6):715-26. DOI: 10.1177/0091270007299762. View

Altman R . A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain. Clin Exp Rheumatol. 2004; 22(1):110-7. View

Yoovathaworn K, Sriwatanakul K, Thithapandha A . Influence of caffeine on aspirin pharmacokinetics. Eur J Drug Metab Pharmacokinet. 1986; 11(1):71-6. DOI: 10.1007/BF03189777. View

Sachs C . Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005; 71(5):913-8. View

Weiser T, Richter E, Hegewisch A, Muse D, Lange R . Efficacy and safety of a fixed-dose combination of ibuprofen and caffeine in the management of moderate to severe dental pain after third molar extraction. Eur J Pain. 2017; 22(1):28-38. PMC: 5763370. DOI: 10.1002/ejp.1068. View

Diener H, Pfaffenrath V, Pageler L, Peil H, Aicher B . The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel.... Cephalalgia. 2005; 25(10):776-87. DOI: 10.1111/j.1468-2982.2005.00948.x. View

Tanswell P, Koup J . TopFit: a PC-based pharmacokinetic/pharmacodynamic data analysis program. Int J Clin Pharmacol Ther Toxicol. 1993; 31(10):514-20. View

10.

Derry C, Derry S, Moore R . Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane Database Syst Rev. 2014; (12):CD009281. PMC: 6485702. DOI: 10.1002/14651858.CD009281.pub3. View

11.

Goldstein J, Silberstein S, Saper J, Ryan Jr R, Lipton R . Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache. 2006; 46(3):444-53. DOI: 10.1111/j.1526-4610.2006.00376.x. View

12.

Straube A, Aicher B, Fiebich B, Haag G . Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?. BMC Neurol. 2011; 11:43. PMC: 3080296. DOI: 10.1186/1471-2377-11-43. View

13.

Sawynok J . Adenosine receptor targets for pain. Neuroscience. 2015; 338:1-18. DOI: 10.1016/j.neuroscience.2015.10.031. View

14.

Granados-Soto V, Castaneda-Hernandez G . A review of the pharmacokinetic and pharmacodynamic factors in the potentiation of the antinociceptive effect of nonsteroidal anti-inflammatory drugs by caffeine. J Pharmacol Toxicol Methods. 2000; 42(2):67-72. DOI: 10.1016/s1056-8719(00)00044-7. View

15.

Derry S, Wiffen P, Moore R . Single dose oral ibuprofen plus caffeine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2015; (7):CD011509. PMC: 6481458. DOI: 10.1002/14651858.CD011509.pub2. View

16.

Palmer H, Graham G, Williams K, Day R . A risk-benefit assessment of paracetamol (acetaminophen) combined with caffeine. Pain Med. 2010; 11(6):951-65. DOI: 10.1111/j.1526-4637.2010.00867.x. View

17.

Moore A, Derry S, Straube S, Ireson-Paine J, Wiffen P . Faster, higher, stronger? Evidence for formulation and efficacy for ibuprofen in acute pain. Pain. 2013; 155(1):14-21. DOI: 10.1016/j.pain.2013.08.013. View

18.

Fried N, Elliott M, Oshinsky M . The Role of Adenosine Signaling in Headache: A Review. Brain Sci. 2017; 7(3). PMC: 5366829. DOI: 10.3390/brainsci7030030. View

19.

Iqbal N, Ahmad B, Janbaz K, Gilani A, Niazi S . The effect of caffeine on the pharmacokinetics of acetaminophen in man. Biopharm Drug Dispos. 1995; 16(6):481-7. DOI: 10.1002/bdd.2510160606. View

20.

Baratloo A, Rouhipour A, Forouzanfar M, Safari S, Amiri M, Negida A . The Role of Caffeine in Pain Management: A Brief Literature Review. Anesth Pain Med. 2016; 6(3):e33193. PMC: 5018099. DOI: 10.5812/aapm.33193. View