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. 2008 Sep 25;9(6):367–373. doi: 10.1007/s10194-008-0071-5

Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium

Luigi Alberto Pini 1, Enrico Del Bene 10, Giorgio Zanchin 2, Paola Sarchielli 3, Girolamo Di Trapani 4, Maria Pia Prudenzano 5, Giovanni LaPegna 6, Lidia Savi 7, Giorgio Di Loreto 8, Paolo Dionisio 8, Franco Granella 9,✉
PMCID: PMC3452084  PMID: 18815727

Abstract

The main aim of this study was to confirm in an Italian population affected by tension-type headache (TTH) the good profile of safety and tolerability of the combination paracetamol 1,000 mg–caffeine 130 mg (PCF) observed in previous studies, by a comparison with naproxen sodium 550 mg (NAP) and placebo (PLA). A secondary objective was to assess the efficacy of PCF in the acute treatment of TTH. This was a multicentre, randomised, double-blind, double-dummy, crossover, placebo-controlled trial. Tolerability was assessed by recording adverse events by the patient in the 4-h post-dose treatment. To assess the efficacy, the sum of pain intensity differences (SPID) and the total pain relief (TOTPAR) were calculated. Comparing PCF and NAP and PCF and PLA for tolerability, the difference was nonsignificant but the result regarding noninferiority was inconclusive, whilst NAP was noninferior to PLA. As regards SPID and TOTPAR, both PCF and NAP were better than placebo (P < 0.05), but not significantly different from each other. In conclusion, PCF was well-tolerated and effective in the treatment of acute TTH.

Keywords: Tension-type headache, Acute treatment, Paracetamol, Caffeine, Paracetamol–caffeine combination, Naproxen sodium

Full Text

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Acknowledgments

This work was supported by a grant from Angelini Farmaceutici, ACRAF SpA (Rome, Italy).

Conflict of interest

The study was sponsored by Angelini Farmaceutici, ACRAF SpA. Two of the authors (G. Di Loreto, P. Dioniso) are Angelini employees.

References

  • 1.Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27:193–210. doi: 10.1111/j.1468-2982.2007.01288.x. [DOI] [PubMed] [Google Scholar]
  • 2.Lyngberg AC, Rasmussen BK, Jørgensen T, et al. Has the prevalence of migraine and tension-type headache changed over a 12-year period? A Danish population survey. Eur J Epidemiol. 2005;20:243–249. doi: 10.1007/s10654-004-6519-2. [DOI] [PubMed] [Google Scholar]
  • 3.Rasmussen BK, Jensen R, Olesen J. Impact of headache on sickness absence and utilisation of medical services: a Danish population study. J Epidemiol Community Health. 1992;46:443–446. doi: 10.1136/jech.46.4.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Lyngberg AC, Rasmussen BK, Jensen R, et al. Secular changes in health care utilization and work absence for migraine and tension-type headache. A population based study. J Epidemiol Com Health. 2005;20:1007–1014. doi: 10.1007/s10654-005-3778-5. [DOI] [PubMed] [Google Scholar]
  • 5.Schwartz BS, Stewart WF, Simon D, et al. Epidemiology of tension-type headache. JAMA. 1998;279:381–383. doi: 10.1001/jama.279.5.381. [DOI] [PubMed] [Google Scholar]
  • 6.Lenaerts ME. Burden of tension-type headache. Curr Pain Headache Rep. 2006;10:459–466. doi: 10.1007/s11916-006-0078-z. [DOI] [PubMed] [Google Scholar]
  • 7.Verhagen AP, Damen L, Berger MY. Is any one analgesic superior for episodic tension-type headache? J Fam Pract. 2006;55:1064–1072. [PubMed] [Google Scholar]
  • 8.Tfelt-Hansen P. Acute pharmacotherapy of migraine, tension-type headache, and cluster headache. J Headache Pain. 2007;8:127–134. doi: 10.1007/s10194-007-0373-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Ward N, Whitney C, Avery D, et al. The analgesic effects of caffeine in headache. Pain. 1991;44:151–155. doi: 10.1016/0304-3959(91)90129-L. [DOI] [PubMed] [Google Scholar]
  • 10.Migliardi JR, Armellino JJ, Friedman M, et al. Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther. 1994;56:576–586. doi: 10.1038/clpt.1994.179. [DOI] [PubMed] [Google Scholar]
  • 11.Miller DS, Talbot CA, Simpson W, et al. A comparison of naproxen sodium, acetaminophen and placebo in the treatment of muscle contraction headache. Headache. 1987;27:392–396. doi: 10.1111/j.1526-4610.1987.hed2707392.x. [DOI] [PubMed] [Google Scholar]
  • 12.Lange R, Lentz R. Comparison ketoproten, ibuprofen and naproxen sodium in the treatment of tension-type headache. Drugs Exp Clin Res. 1995;21:89–96. [PubMed] [Google Scholar]
  • 13.Prior MJ, Cooper KM, May LG, et al. Efficacy and safety of acetaminophen and naproxen in the treatment of tension-type headache. A randomized, double-blind, placebo-controlled trial. Cephalalgia. 2002;22:740–748. doi: 10.1046/j.1468-2982.2002.00419.x. [DOI] [PubMed] [Google Scholar]
  • 14.Headache Classification Subcommittee of the International Headache Society The International Classification of Headache Disorders, 2nd edn. Cephalalgia. 2004;24(Suppl 1):1–160. doi: 10.1111/j.1468-2982.2003.00824.x. [DOI] [PubMed] [Google Scholar]
  • 15.International Headache Society Committee on Clinical Trials Guidelines for trials of drug treatments in tension-type headache (1st edn) Cephalalgia. 1995;15:165–179. doi: 10.1046/j.1468-2982.1995.015003165.x. [DOI] [PubMed] [Google Scholar]
  • 16.Piaggio G, Elbourne DR, Altman DG, et al. Reporting of noninferiority and equivalence randomized trials. An extension of the CONSORT statement. JAMA. 2006;295:1152–1160. doi: 10.1001/jama.295.10.1152. [DOI] [PubMed] [Google Scholar]
  • 17.Piletta P, Porchet HC, Dayer P. Central analgesic effect of acetaminophen but not of aspirin. Clin Pharmacol Ther. 1991;49:350–354. doi: 10.1038/clpt.1991.40. [DOI] [PubMed] [Google Scholar]
  • 18.Pini LA, Vitale G, Ottani A, et al. Naloxone-reversible antinociception by paracetamol in the rat. J Pharmacol Exp Ther. 1997;280:934–940. [PubMed] [Google Scholar]
  • 19.Sandrini M, Romualdi P, Capobianco A, et al. The effect of paracetamol on nociception and dynorphin A levels in the rat brain. Neuropeptides. 2001;35:110–116. doi: 10.1054/npep.2001.0852. [DOI] [PubMed] [Google Scholar]
  • 20.Botting RM. Mechanism of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis. 2000;31(suppl 5):S202–S210. doi: 10.1086/317520. [DOI] [PubMed] [Google Scholar]
  • 21.Daly JW, Bruns RF, Snyder SH. Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. Life Sci. 1981;28:2083–2097. doi: 10.1016/0024-3205(81)90614-7. [DOI] [PubMed] [Google Scholar]
  • 22.Galloway MP, Roth RH. Neuropharmacology of 3-isobutylmethylxanthine: effects on central noradrenergic systems in vivo. J Pharmacol Exp Ther. 1983;227:1–8. [PubMed] [Google Scholar]
  • 23.Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev. 1993;45:43–85. [PubMed] [Google Scholar]
  • 24.Onrot J, Shaheen O, Biaggioni I, et al. Reduction of liver plasma flow by caffeine and theophylline. Clin Pharmacol Ther. 1986;40:506–510. doi: 10.1038/clpt.1986.215. [DOI] [PubMed] [Google Scholar]
  • 25.Iqbal N, Ahmad B, Janbaz KH, et al. The effect of caffeine on the pharmacokinetics of acetaminophen in man. Biopharm Drug Dispos. 1995;16:481–487. doi: 10.1002/bdd.2510160606. [DOI] [PubMed] [Google Scholar]
  • 26.Laska EM, Sunshine A, Mueller F, et al. Caffeine as an analgesic adjuvant. JAMA. 1984;251:1711–1718. doi: 10.1001/jama.251.13.1711. [DOI] [PubMed] [Google Scholar]
  • 27.Schoenen J, Wang W. Tension-type headache. In: Goadsby PJ, Silberstein SD, editors. Headache. Boston: Butterworth-Heinemann; 1997. pp. 177–200. [Google Scholar]

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