Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

Andreas Straube, Bernhard Aicher, Bernd L Fiebich, Gunther Haag, Andreas Straube, Bernhard Aicher, Bernd L Fiebich, Gunther Haag

Abstract

Background: Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.

Discussion: In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.

Summary: Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.

References

    1. Kennedy JD. Neuropathic pain: molecular complexity underlies continuing unmet medical need. J Med Chem. 2007;50:2547–2556. doi: 10.1021/jm061023c.
    1. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–898. doi: 10.1038/nature05413.
    1. Piguet V, Allaz AF. Complexite de la douleur: du savoir a la provocation [The complexity of pain and its origins - in French] Rev Medicale Suisse. 2005;1(25):1651–1652.
    1. Brooks J, Tracey I. From nociception to pain perception: imaging the spinal and supraspinal pathways. J Anat. 2005;207(1):19–33. doi: 10.1111/j.1469-7580.2005.00428.x.
    1. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25(45):10390–10402. doi: 10.1523/JNEUROSCI.3458-05.2005.
    1. Powell A, Dupré J. From molecules to systems: the importance of looking both ways. Studies in History and Philosophy of Biological and Biomedical Sciences. 2009;40:54–64. doi: 10.1016/j.shpsc.2008.12.007.
    1. Lehar J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, Rickles RJ, Short GF III, Staunton JE, Jin X, Lee MS, Zimmermann GR, Borisy AA. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nature Biotechnology. 2009;27:659–666. doi: 10.1038/nbt.1549.
    1. Keith CT, Borisy AA, Stockwell BR. Multicomponent therapeutics for networked systems. Nature Reviews. 2005;4:1–8. doi: 10.1038/nrd1620.
    1. Zimmermann GR, Lehar J, Keith TK. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discovery Today. 2007;12(1/2):34–42. doi: 10.1016/j.drudis.2006.11.008.
    1. WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO Technical Report Series. Geneva; 2005. Annex 5 - Guidelines for registration of fixed-dose combination medicinal products. World Health Organization. No. 929.
    1. Wertheimer AI, Morrison A. Combination drugs: innovation in pharmacotherapy. P&T. 2002;27:44–49.
    1. Prescott LF. In: Paracetamol (acetaminophen) - a critical bibliographic review. Prescott LF, editor. London, Philadelphia: Taylor and Francis; 1996. Pharmacological actions and therapeutic use of Paracetamol; pp. 197–239.
    1. Insel PA. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9. Hardman JG, Limbird LE, editor. New York: Mc-Graw-Hill; 1996. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout; pp. 617–657.
    1. Rainsford KD. In: Ibuprofen - a critical bibliographic review. Rainsford KD, editor. London: Taylor and Francis Ltd, Bristol; 1996. Pharmacology and toxicology of ibuprofen; pp. 143–275.
    1. Sandrini G, Cerbo R, Del Bene E, Ferrari A, Genco S, Grazioli I, Martelletti P, Nappi G, Pinessi L, Sarchielli P, Tamburro P, Uslenghi C, Zanchin G. Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, doubledummy, randomised, parallel group, multicentre study. Int J Clin Pract. 2007;61:1256–1269. doi: 10.1111/j.1742-1241.2007.01458.x.
    1. Galeotti N, Ghelardini C, Grazioli I, Uslenghi C. Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in "in vivo" models of migraine. Pharmacol Res. 2002;46:245–50. doi: 10.1016/S1043-6618(02)00126-3.
    1. Ghelardini C, Galeotti N, Grazioli I, Uslenghi C. Indomethacin, alone and combined with prochlorperazine and caffeine, but not sumatriptan, abolishes peripheral and central sensitization in in vivo models of migraine. J Pain. 2004;5:413–419. doi: 10.1016/j.jpain.2004.06.008.
    1. Ghelardini C, Galeotti N, Vivoli E, Grazioli I, Uslenghi C. The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, prochlorperazine and caffeine, compared to sumatriptan, in an in vivo model. J Headache Pain. 2009;10:435–440. doi: 10.1007/s10194-009-0151-1.
    1. Cerbo R, Centonze V, Grazioli I, Tavolato B, Trenti T, Uslenghi C, Sternieri E. Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine in the treatment of episodic tension-type headache: a double-blind, randomized, nimesulide-controlled, parallel group, multicentre trial. Eur J Neurol. 2005;12:759–767. doi: 10.1111/j.1468-1331.2005.01056.x.
    1. Peroutka SJ. Beyond monotherapy: rational polytherapy in migraine. Headache. 1998;38:18–22. doi: 10.1046/j.1526-4610.1998.3801018.x.
    1. Panconesi A, Pavone E, Franchini M, Mennuti N, Bartolozzi ML, Guidi L, Banfi R. Triptans: low utilization and high turnover in the general population. Cephalalgia. 2010;30:576–581.
    1. Ifergane G, Wirguin I, Shvartzman P. Triptans--Why Once? Headache. 2006;46:1261–1263. doi: 10.1111/j.1526-4610.2006.00435.x.
    1. Krymchantowski AV. Acute treatment of migraine. Breaking the paradigm of monotherapy. BMC Neurol. 2004;4:4. doi: 10.1186/1471-2377-4-4.
    1. Krymchantowski AV, Adriano M, Fernandes D. Tolfenamic acid decreases migraine recurrence when use with sumatriptan. Cephalalgia. 1999;19:186–187. doi: 10.1046/j.1468-2982.1999.1903186.x.
    1. Krymchantowski AV. Naproxen sodium decreases migraine recurrence when administered with sumatriptan. Arq Neuropsiquiatr. 2000;58:428–430. doi: 10.1590/S0004-282X2000000300006.
    1. Smith TR, Sunshine A, Stark SR, Littlefield DE, Spruill SE, Alexander WJ. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache. 2005;45:983–991. doi: 10.1111/j.1526-4610.2005.05178.x.
    1. Brandes JL, Kudrow D, Stark SR, O'Carrol CP, Adelman JU, O'Donnell FJ, Alexander WJ, Spruill SE, Barrett PS, Lener SE. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007;297:1443–1454. doi: 10.1001/jama.297.13.1443.
    1. Lipton RB, Dodick DW, Adelman JU, Kaniecki RG, Lener SE, White JD, Nelsen AC. Consistency of response to sumatriptan/naproxen sodium in a placebocontrolled, crossover study. Cephalalgia. 2009;29:826–836. doi: 10.1111/j.1468-2982.2008.01806.x.
    1. Krymchantowski AV, Barbosa JS. Rizatriptan combined with rofecoxib vs. rizatriptan for the acute treatment of migraine: an open label pilot study. Cephalalgia. 2002;22:309–312. doi: 10.1046/j.1468-2982.2002.00369.x.
    1. Krymchantowski AV, Bigal ME. Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. BMC Neurol. 2004;4:10. doi: 10.1186/1471-2377-4-10.
    1. Krymchantowski AV, Filho PFM, Bigal ME. Rizatriptan vs. rizatriptan plus trimebutine for the acute treatment of migraine: a double-blind, randomized, cross-over, placebo-controlled study. Cephalalgia. 2006;26:871–874. doi: 10.1111/j.1468-2982.2006.01136.x.
    1. Freitag F, Diamond M, Diamond S, Janssen I, Rodgers A, Skobieranda F. Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. Headache. 2008;48:921–930. doi: 10.1111/j.1526-4610.2007.01053.x.
    1. Schoenen J, De Klippel N, Giurgea S, Herroelen L, Jacquy J, Louis P, Monseu G, Vandenheede M. the Belgian Headache Society. Almotriptan and its combination with aceclofenac for migraine attacks: a study of efficacy and the influence of auto-evaluated brush allodynia. Cephalalgia. 2008;28:1095–1105. doi: 10.1111/j.1468-2982.2008.01654.x.
    1. Krymchantowski A, Bigal ME. Rizatriptan in migraine. Expert Rev Neurother. 2005;5:597–603. doi: 10.1586/14737175.5.5.597.
    1. Mannix LK. A review of the 5-HT1B/1D agonist rizatriptan: update on recent research and implications for the future. Expert Opin Pharmacother. 2008;9:1001–1011. doi: 10.1517/14656566.9.6.1001.
    1. Zhang XC, Kainz V, Jakubowski M, Burstein R, Strassman A, Levy D. Localization of COX-1 and COX-2 in the intracranial dura mater of the rat. Neurosci Lett. 2009;452:33–36. doi: 10.1016/j.neulet.2009.01.032.
    1. Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharm Reviews. 1993;45:43–85.
    1. Camann WR, Murray RS, Mushlin PS, Lambert DH. Effects of oral caffeine on postdural puncture headache: a double-blind, placebo-controlled trial. Anesth Analg. 1990;70:181–184. doi: 10.1213/00000539-199002000-00009.
    1. Yücel A, Ozyalcin S, Talu GK, Yücel EC, Erdine S. Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Reg Anesth Pain Med. 1999;24:51–54.
    1. Halker RB, Demaerschalk BM, Wellik KE, Wingerchuk DM, Rubin DI, Crum BA, Dodick DW. Caffeine for the prevention and treatment of postdural puncture headache: debunking the myth. The Neurologist. 2007;13:323–327. doi: 10.1097/NRL.0b013e318145480f.
    1. Ward N, Whitney C, Avery D, Dunner D. The analgesic effects of caffeine in headache. Pain. 1991;44:151–155. doi: 10.1016/0304-3959(91)90129-L.
    1. Myers DE, Shaikh Z, Zullo TG. Hypoalgesic effect of caffeine in experimental ischemic muscle contraction pain. Headache. 1997;37:654–658. doi: 10.1046/j.1526-4610.1997.3710654.x.
    1. Forbes JA, Beaver WT, Jones KF, Kehm CJ, Smith WK, Gongloff CM, Zeleznock JR, Smith JW. Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain. Clin Pharmacol Ther. 1991;49:674–684. doi: 10.1038/clpt.1991.85.
    1. McQuay HJ, Angell K, Carroll D, Moore RA, Juniper RP. Ibuprofen compared with ibuprofen plus caffeine after third molar surgery. Pain. 1996;66:247–251. doi: 10.1016/0304-3959(96)03043-6.
    1. Diamond S, Balm TK, Freitag FG. Ibuprofen plus caffeine in the treatment of tension-type headache. Clin Pharmacol Ther. 2000;68:312–319. doi: 10.1067/mcp.2000.109353.
    1. Dooley JM, Gordon KE, Wood EP, Brna PM, MacSween J, Fraser A. Caffeine as an adjuvant to ibuprofen in treating childhood headaches. Pediatr Neurol. 2007;37:42–46. doi: 10.1016/j.pediatrneurol.2007.02.016.
    1. Peroutka SJ, Lyon JA, Swarbrick J, Lipton RB, Kolodner K, Goldstein J. Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura. A randomized, double-blind, crossover study. Headache. 2004;44:136–141. doi: 10.1111/j.1526-4610.2004.04029.x.
    1. Migliardi JR, Armellino JJ, Friedman M, Gillings DB, Beaver WT. Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther. 1994;56:576–586. doi: 10.1038/clpt.1994.179.
    1. Ali Z, Burnett I, Eccles R, North M, Jawad M, Jawad S, Clarke G, Milsom I. Efficacy of a paracetamol and caffeine combination in the treatment of the key symptoms of primary dysmenorrhoea. Cur Med Res Opinion. 2007;23:841–851. doi: 10.1185/030079907X182239.
    1. Renner B, Clarke G, Grattan T, Beisel A, Mueller C, Werner U, Kobal G, Brune K. Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. J Clin Pharmacol. 2007;47:715–726. doi: 10.1177/0091270007299762.
    1. Iqbal N, Ahmad B, Janbaz KH, Gilant AH, Niazi SK. The effect of caffeine on the pharmacokinetics of acetaminophen in man. Biopharm Drug Dispos. 1995;16:481–487. doi: 10.1002/bdd.2510160606.
    1. Kraetsch HG, Hummel T, Lotsch J, Kussat R, Kobal G. Analgesic effects of propyphenazone in comparison to its combination with caffeine. Eur J Clin Pharmacol. 1996;49:377–382. doi: 10.1007/BF00203781.
    1. Pini LA, Del Bene E, Zanchin G, Sarchielli P, Di Trapani G, Prudenzano MP, LaPegna G, Savi L, Di Loreto G, Dionisio P, Granella F. 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. J Headache Pain. 2008;9:367–373. doi: 10.1007/s10194-008-0071-5.
    1. Forbes JA, Jones KF, Kehm CJ, Smith WK, Gongloff CM, Zeleznock JR, Smith JW, Beaver WT. Evaluation of aspirin, caffeine, and their combination in postoperative oral surgery pain. Pharmacotherapy. 1990;10:387–393.
    1. Schachtel BP, Fillingim JM, Lane AC, Thoden WR, Baybutt RI. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med. 1991;161:733–737. doi: 10.1001/archinte.151.4.733.
    1. Laska EM, Sunshine A, Mueller F, Elvers WB, Siegel C, Rubin A. Caffeine as an analgesic adjuvant. JAMA. 1984;251:1711–1718. doi: 10.1001/jama.251.13.1711.
    1. Bosse K, Kühner A. Behandlung von Kopfschmerzen verschiedenster Genese - Ergebnisse einer Doppelblind-Multicenter-Studie [Treatment of headache of different genesis - results of a double-blind multicenter study -in german] Therapiewoche. 1987;38:3879–3884.
    1. Lipton RB, Stewart WF, Ryan RE, Saper J, Silberstein S, Sheftell F. Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain: three double-blind, randomized, placebo-controlled trials. Arch Neurol. 1998;55:210–217. doi: 10.1001/archneur.55.2.210.
    1. Diener HC, 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 group study. Cephalalgia. 2005;25:776–787. doi: 10.1111/j.1468-2982.2005.00948.x.
    1. Goldstein J, Silberstein SD, Saper JR, Elkind AH, Smith TR, Gallagher RM, Battikha JP, Hoffman H, Baggish J. Acetaminophen, acetylsalicyclic acid, and caffeine versus sumatriptan succinate in the early treatment of migraine: results from the ASSET trial. Headache. 2005;45:973–982. doi: 10.1111/j.1526-4610.2005.05177.x.
    1. Goldstein J, Silberstein SD, Saper JR, Ryan RE Jr, Lipton RB. Acetaminophen, acetylsalicyclic acid, 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;46:444–453. doi: 10.1111/j.1526-4610.2006.00376.x.
    1. Pageler L, Diener HC, Pfaffenrath V, Peil H, Aicher B. Clinical relevance of efficacy endpoints in OTC trials. Headache. 2009;49:646–654. doi: 10.1111/j.1526-4610.2008.01242.x.
    1. Bergmann JF. Self-medication: from European regulatory directives to therapeutic strategy. Fundament Clin Pharmacol. 2003;17:275–280. doi: 10.1046/j.1472-8206.2003.00141.x.
    1. Hersh EV, Moore PA, Ross GL. Over-the-counter analgesics and antipyretics: a critical assessment. Clin Ther. 2000;22:500–548. doi: 10.1016/S0149-2918(00)80043-0.
    1. Bundesgesundheitsamt BGA. Acetylsalicylsäure plus Coffein in fixer Kombination [Acetylsalicylic acid plus caffeine in fixed combination- in german]. Monografie der Aufbereitungskommission B 3 (Neurologie/Psychiatrie) Bundesanzeiger. 1994;46:1247–1249.
    1. Bundesgesundheitsamt BGA. Paracetamol plus Coffein in fixer Kombination [Paracetamol plus caffeine in fixed combination- in german]. Monografie der Aufbereitungskommission B 3 (Neurologie/Psychiatrie) Bundesanzeiger. 1988;40:4778–4779.
    1. Bach PH, Berndt WO, Delzell E, Dubach U, Finn WF, Fox JM, Hess R, Michielsen P, Sandler DP, Trump B, Williams G. A safety assessment of fixed combinations of acetaminophen and acetylsalicylic acid, coformulated with caffeine. Renal Failure. 1998;20:749–762. doi: 10.3109/08860229809045173.
    1. McLaughlin JK, Lipworth L, Chow WH, Blot W. Analgesic use and chronic renal failure: A critical review of the epidemiologic literature. Kidney Int. 1998;54:679–686. doi: 10.1046/j.1523-1755.1998.00043.x.
    1. Feinstein AR, Heinemann LA, Curhan GC, Delzell E, DeSchepper PJ, Fox JM, Graf H, Luft FC, Michielsen P, Mihatsch MJ, Suissa S, van der woude F, Willich S. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy. Relationship between nonphenacetin combined analgesics and nephropathy: A review. Kidney Int. 2000;58:2259–2264. doi: 10.1046/j.1523-1755.2000.00410.x.
    1. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd edition (ICHD-II) Cephalalgia. 2004;24:S9–S160. doi: 10.1111/j.1468-2982.2003.00824.x.
    1. Mihatsch MJ, Khanlari B, Brunner FP. Obituary to analgesic nephropathy--an autopsy study. Nephrol Dial Transplant. 2006;21:3139–3145. doi: 10.1093/ndt/gfl390.
    1. van der Woude FJ, Heinemann LAJ, Graf H, Lewis M, Moehner S, Assmann A, Kühl-Habich D. Analgesics use and ESRD in younger age: a case-control study. BMC Nephrology. 2007;8:15. doi: 10.1186/1471-2369-8-15.
    1. Michielsen P, Heinemann L, Mihatsch M, Schnülle P, Graf H, Koch KM. Non-phenacetin analgesics and analgesic nephropathy. Nephrol Dial Transplant. 2009;24:1253–1259. doi: 10.1093/ndt/gfn643.
    1. Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano JM. Analgesic use and renal function in men. JAMA. 2001;286:315–321. doi: 10.1001/jama.286.3.315.
    1. Hughes JR, Oliveto AH, Helzer JE, Higgins ST, Bickel WK. Should caffeine abuse, dependence, or withdrwal be added to DSM-IV and ICD-10? Am J Psychiatry. 1992;149:33–40.
    1. Dalessio DJ. On the safety of caffeine as an analgesic adjuvant. Headache Quarterly. 1994;5:125–127.
    1. Fox JM, Siebers U. Caffeine as a promoter of analgesic-associated nephropathy - where is the evidence? Fundamental Clin Pharmacol. 2003;17:377–392. doi: 10.1046/j.1472-8206.2003.00174.x.
    1. Murray RM. Genesis of analgesic nephropathy in the United Kingdom. Kidney Int. 1978;13:50–57. doi: 10.1038/ki.1978.7.
    1. Grimlund K. Phenacetin and renal damage at a Swedish factory. Acta Med Scand. 1963;174(Suppl. 405):1–26.
    1. Fox JM. Use of analgesics in self-medication. Therapie. 2002;57:115–118.
    1. Feinstein AR, Heinemann LAJ, Dalessio D, Fox JM, Goldstein J, Haag G, Ladewig D, O'Brien CP. Ad Hoc Review Committee. Do caffeine-containing analgesics promote dependence? A review and evaluation. Clin Pharmacol Ther. 2000;68:457–467. doi: 10.1067/mcp.2000.110974.
    1. Diener HC, Tfelt-Hansen P. In: The Headaches. Olesen J, Tfelt-Hansen P, Welch KMA, editor. New York: Raven Press; 1993. Headache associated with chronic use of substances; pp. 721–727.
    1. Diener HC, Dahlöf CGH. In: The Headaches. 2. Olesen J, Tfelt-Hansen P, Welch KMA, editor. Philadelphia: Williams& Williams; 2000. Headache associated with chronic use of substances; pp. 871–877.
    1. Diener HC, Silberstein SD. In: The Headaches. 3. Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA, editor. Philadelphia: Lippincott Williams& Williams; 2006. Medication overuse headaches; pp. 971–979.
    1. Limmroth V, Katsarava Z. Medication overuse headache. Curr Opin Neurol. 2004;17:301–306. doi: 10.1097/00019052-200406000-00011.
    1. Obermann M, Bartsch T, Katsarava Z. Medication overuse headache. Expert Opin Drug Saf. 2006;5:49–56. doi: 10.1517/14740338.5.1.49.
    1. Haag G. Headache and medication overuse: are clinical case series appropriate to reveal differential risks of different medications? Expert Opin Drug Saf. 2010;9:397–406. doi: 10.1517/14740331003598857.
    1. Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia. 2010;30:321–328. doi: 10.1177/0333102410372426.
    1. Delzell E, Haag G. Comments on results of Scher et al. pertaining to nonprescription caffeine containing combination analgesics. Cephalalgia. 2010;30:1145–1146. doi: 10.1177/0333102410361540.
    1. Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS guideline on the treatment of tension-type headache - report of an EFNS task force. Eur J Neurol. 2010;17:1318–1325.
    1. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48:1157–1168. doi: 10.1111/j.1526-4610.2008.01217.x.
    1. Taubes G. Epidemiology faces its limits. Science. 1995;269:164–169. doi: 10.1126/science.7618077.
    1. Sun-Edelstein C, Bigal ME, Rapoport AM. Chronic migraine and medication overuse headache: clarifying the current International Headache Society classification criteria. Cephalalgia. 2009;29:445–452. doi: 10.1111/j.1468-2982.2008.01753.x.
    1. Haag G. Medication overuse headache - comments on the current International Headache Society classification criteria. Cephalalgia. 2010;30:1409–1410. doi: 10.1177/0333102410365569.
    1. Bigal ME, Sun-Edelstein C, Rapoport A. Medication overuse headache - comments on the current International Headache Society classification criteria - author's reply. Cephalalgia. 2010;30:1410–1411.
    1. Goadsby PJ. Is medication-overuse headache a distinct biological entity? Nature Clin Pract Neurol. 2006;2:401. doi: 10.1038/ncpneuro0236.
    1. Rueda-Sánchez M, Díaz-Martínez LA. Prevalence and associated factors for episodic and chronic daily headache in the Colombian population. Cephalalgia. 2008;28:216–225.
    1. Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature. 1998;395:281–284. doi: 10.1038/26233.
    1. Zeilhofer HU, Brune K. Analgesic strategies beyond the inhibition of cyclooxygenases. Trends Pharmacol Sci. 2006;27:467–474. doi: 10.1016/j.tips.2006.07.007.
    1. Jasmin L, Tien D, Janni G, Ohara PT. Is noradrenaline a significant factor in the analgesic effect of antidepressants? Pain. 2003;106:3–8. doi: 10.1016/j.pain.2003.08.010.
    1. Meves H. The action of prostaglandins on ion channels. Curr Neuropharmacol. 2006;4:41–57. doi: 10.2174/157015906775203048.
    1. Jenkins DW, Feniuk W, Humphrey PP. Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones. Br J Pharmacol. 2001;134:1296–1302. doi: 10.1038/sj.bjp.0704357.
    1. Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol. 2000;129:420–423. doi: 10.1038/sj.bjp.0703110.
    1. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304–1312. doi: 10.1212/01.WNL.0000286940.29755.61.
    1. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12:250–275. doi: 10.1111/j.1527-3458.2006.00250.x.
    1. Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J. 2008;22:383–390. doi: 10.1096/fj.07-8506com.
    1. Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. Proc Natl Acad Sci USA. 2002;99:7130–7135. doi: 10.1073/pnas.102588199.
    1. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12:46–55. doi: 10.1097/00045391-200501000-00008.
    1. Fiebich BL, Lieb K, Hull M, Aicher B, van Ryn J, Pairet M, Engelhardt G. Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells. Neuropharmacology. 2000;39:2205–2213. doi: 10.1016/S0028-3908(00)00045-9.
    1. Miranda HF, Puig MM, Prieto JC, Pinardi G. Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain. Pain. 2006;121:22–28. doi: 10.1016/j.pain.2005.11.012.
    1. Fiebich BL, Biber K, Lieb K, Van Calker D, Berger M, Bauer J, Gebicke-Haerter PJ. Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia. 1996;18:152–160. doi: 10.1002/(SICI)1098-1136(199610)18:2<152::AID-GLIA7>;2-2.
    1. Fernandez-Duenas V, Sanchez S, Planas E, Poveda R. Adjuvant effect of caffeine on acetylsalicylic acid anti-nociception: prostaglandin E2 synthesis determination in carrageenan-induced peripheral inflammation in rat. Eur J Pain. 2008;12:157–163. doi: 10.1016/j.ejpain.2007.03.485.
    1. Cupini LM, Bari M, Battista N, Argiro G, Finazzi-Agro A, Calabresi P, Maccarrone M. Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs. Cephalalgia. 2006;26:277–281. doi: 10.1111/j.1468-2982.2005.01031.x.
    1. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2004;309:56–63. doi: 10.1124/jpet.103.059808.
    1. Patwardhan AM, Jeske NA, Price TJ, Gamper N, Akopian AN, Hargreaves KM. The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci USA. 2006;103:11393–11398. doi: 10.1073/pnas.0603861103.
    1. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol. 2007;573:214–215. doi: 10.1016/j.ejphar.2007.07.012.
    1. Slanina KA, Schweitzer P. Inhibition of cyclooxygenase-2 elicits a CB1-mediated decrease of excitatory transmission in rat CA1 hippocampus. Neuropharmacology. 2005;49:653–659.
    1. Hogestatt ED, Jonsson BA, Ermund A, Andersson DA, Bjork H, Alexander JP. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005;280:31405–31412. doi: 10.1074/jbc.M501489200.
    1. Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol. 2006;531:280–281. doi: 10.1016/j.ejphar.2005.12.015.
    1. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol. 2007;573:214–215. doi: 10.1016/j.ejphar.2007.07.012.
    1. Liu QS, Qiao JT, Dafny N. D2 dopamine receptor involvement in spinal dopamine-produced antinociception. Life Sci. 1992;51:1485–1492. doi: 10.1016/0024-3205(92)90313-E.
    1. Sagen J, Proudfit HK. Evidence for pain modulation by pre- and postsynaptic noradrenergic receptors in the medulla oblongata. Brain Res. 1985;331:285–293. doi: 10.1016/0006-8993(85)91554-9.
    1. Coquoz D, Porchet HC, Dayer P. Central analgesic effects of desipramine, fluvoxamine, and moclobemide after single oral dosing: a study in healthy volunteers. Clin Pharmacol Ther. 1993;54:339–344. doi: 10.1038/clpt.1993.156.
    1. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305. doi: 10.1016/j.pain.2005.08.013.
    1. Dello RC, Boullerne AI, Gavrilyuk V, Feinstein DL. Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production. J Neuroinflammation. 2004;1:9. doi: 10.1186/1742-2094-1-9.
    1. Pini LA, Sandrini M, Vitale G. The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol. 1996;308:31–40. doi: 10.1016/0014-2999(96)00261-0.
    1. Bonnefont J, Daulhac L, Etienne M, Chapuy E, Mallet C, Ouchchane L. Acetaminophen recruits spinal p42/p44 MAPKs and GH/IGF-1 receptors to produce analgesia via the serotonergic system. Mol Pharmacol. 2007;71:407–415. doi: 10.1124/mol.106.025775.
    1. Bonnefont J, Chapuy E, Clottes E, Alloui A, Eschalier A. Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT. Pain. 2005;114:482–490. doi: 10.1016/j.pain.2005.01.019.
    1. Pelissier T, Alloui A, Caussade F, Dubray C, Cloarec A, Lavarenne J, Eschalier A. Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytryptamine3 receptors: In vivo and in vitro evidence. J Pharmacol Exp Ther. 1996;278:8–14.
    1. Pickering G, Loriot MA, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006;79:371–378. doi: 10.1016/j.clpt.2005.12.307.
    1. Dropic AJ, Brailoiu E, Cooper RL. Presynaptic mechanism of action induced by 5-HT in nerve terminals: possible involvement of ryanodine and IP3 sensitive 2+ stores. Comp Biochem Physiol A Mol Integr Physiol. 2005;142:355–361. doi: 10.1016/j.cbpa.2005.08.025.
    1. Bach-Rojecky L. Analgesic effect of caffeine and clomipramine: a possible interaction between adenosine and serotonin systems. Acta Pharm. 2003;53:33–39.
    1. Ghelardini C, Galeotti N, Bartolini A. Caffeine induces central cholinergic analgesia. Naunyn Schmiedebergs Arch Pharmacol. 1997;356:590–595. doi: 10.1007/PL00005094.
    1. Fiebich BL, Candelario-Jalil E, Mantovani M, Heinzmann M, Akundi RS, Hüll M, Knörle R, Schnierle P, Finkenzeller G, Aicher B. Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol, and caffeine. Pharmacol Res. 2006;53:391–396. doi: 10.1016/j.phrs.2006.02.002.
    1. Fanciullacci M, Alessandri M, Del Rosso A. Dopamine involvement in the migraine attack. Funct Neurol. 2000;15(Suppl 3):171–181.
    1. Shioda K, Nisijima K, Nishida S, Kato S. Possible serotonin syndrome arising from an interaction between caffeine and serotonergic antidepressants. Hum Psychopharmacol. 2004;19:353–354. doi: 10.1002/hup.592.
    1. Stovner LJ, Tronvik E, Hagen K. New drugs for migraine. J Headache Pain. 2009;10:395–406. doi: 10.1007/s10194-009-0156-9.
    1. WHO. Cancer pain relief. WHO, Geneva; 1986.
    1. Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J, Price ER, Serbedzija G, Zimmermann GR, Foley MA, Stockwell BR, Keith CT. Systematic discovery of multicomponent therapeutics. PNAS. 2003;100:7977–7982. doi: 10.1073/pnas.1337088100.
    1. Berenbaum MC. The expected effect of a combination of agents: the general solution. J Theor Biol. 1985;114:413–431. doi: 10.1016/S0022-5193(85)80176-4.
    1. Berenbaum MC. What is synergy? Pharmacol Reviews. 1989;41:93–141.
    1. Phero JC, Becker D. Rational use of analgesic combinations. Dent Clin N Am. 2002;46:691–705. doi: 10.1016/S0011-8532(02)00022-8.
    1. Forth W. Risikoabwägung schwachwirksamer Analgetika Paraminiphenol- und Pyrazol-Derivate - Schlussfolgerungen. Münch med Wschr. 1982;124:216–218.
    1. Adam O, Forth W. Coffein. Dt Ärztebl. 2001;98(43A):2816–2818.
    1. Forth W. In: Lehrbuch der Schmerztherapie. Zenz M, Jurna I, editor. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 1993. Sinnvolle Medikamenten-Kombinationen; pp. 187–195.
    1. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage. 2002;23:121–130. doi: 10.1016/S0885-3924(01)00404-3.
    1. Janga SC, Tzakos A. Structure and organization of drug-target networks: insights from genomic approaches for drug discovery. Mol BioSyst. 2009;5:1536–1548. doi: 10.1039/b908147j.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi