Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.
AmeryWK.Brain hypoxia: the turning-point in the genesis of migraine attack?Cephalalgia1982;2:83–109.
2.
DeshmukhSVMeyerJS.Cyclic changes in platelet dynamics and the pathogenesis and prophylaxis of migraine. Headache1977;17:101–8.
3.
WelchKMAChabiENellJHBartoshKCheeANCMathewNTAcharVS.Biochemical comparison of migraine and stroke. Headache1976;16:160–7.
4.
WelchKMAChabiENellJ.BartoshKMeyerJSMathewNT.Similarities in biochemical effects of cerebral ischemia in patients with cerebrovascular disease and migraine. In:Greene Red Current concepts in migraine research.New York:Raven Press,1978;1–9.
5.
BennetAPrattDSangerGJ.Antagonism by fenamates of prostaglandin action in guinea-pig and human alimentary muscle. Br J Pharmacol1980;68:357–62.
6.
GrimmerAJLeathardHLPeatfieldRCRoseFC.The effects of mefenamic acid on tone and evoked responses in human isolated cerebral arteries. Br J Pharmacol1982;75:67P.
7.
SangerGJBennetA.Fenamates may antagonize the actions of prostaglandin endoperoxides in human myometrium. Br J Pharmacol1979;8:479–82.
8.
VapaataloHParantainenJLindénI-BHakkarainenH.Prostaglandins and vascular headache. Action of tolfenamic acid. a new anti-inflammatory analgetic, on migraine. In:Sicuteri Fed Headache, new vistas.Florence:Biomedical Press,1977:287–300.
9.
FerreiraSHVaneJR.New aspects of the mode of action of nonsteroidal anti-inflammatory drugs. Annu Rev Pharmacol1974;14:57–73.
10.
FerreiraSH.Peripheral analgesia: mechanism of the analgesic action of aspirin like drugs and opiate-antagonists. Br J Clin Pharmacol1980;10:2375–2455.
11.
VaneJR.Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature1971;231:232–5.
12.
BruynGW.The biochemistry of migraine. headache1980;20:235–46.
13.
FozardJR.Serotonin. migraine and platelets. In:van ZwietenPASchönbaumE edsDrugs and platelets. Progr Pharmacol1982;4:135–46.
14.
LindénI-BParantainenJVapaataloH.Inhibition of prostaglandin biosynthesis by tolfenamic acid in vitro. Scand J Rheumatol1976;5:129–32.
15.
HeinonenPRadomskiMKangashoMMetsa-KeteläTParantainenJVapaataloH.Inhibition of platelet aggregation by tolfenamic acid.Acta Ther [Suppl]1980;6abstract 32.
16.
HakkarainenHVapaataloHGothoniGParantainenJ.Tolfenamic acid is as effective as ergot-amine during migraine attacks.Lancet1979;2:326–8.
17.
Ala-HurulaVMyllyläVVHokkanenETokolaO.Tolfenamic acid and ergotamine abuse. Headache1981;21:240–2.
18.
MikkelsenBMFalkJW.Prophylactic treatment of migraine with tolfenamic acid. A comparative double-blind cross-over study between tolfenamic acid and placebo.Acta Neurol Scand1982;66:105–11.
19.
NikiforowR.Headache in a random sample of 200 persons: A clinical study of a population in northern Finland. Cephalalgia1981;1:99–107.
20.
WilkinsonM.The treatment of migraine. In:SaxenaPR edMigraine and related headaches.Rotterdam:Erasmus University,1975:141–6.
21.
HarringtonRAHamiltonCWBrogdenRNLinkewichJARomankiewiczJAHeelRC.Metoclopramide. An updated review of its pharmacological properties and clinical use.Drugs1983;25:451–94.
22.
VolansGN.Research review. Migraine and drug absorption.Clin Pharmacokinet1978;3:313–18.
23.
RallTW.The Xanthines: Theophylline, caffeine, and theobromine. In:GilmanAGGoodmanLSGilmanA edsThe pharmacological basis of therapeutics.New York, Toronto, London:Macmillan Publishing Co., Inc.,1980:592–607.
24.
Ad Hoc Committee on Classification of Headache of the NIH.JAMA1962;179:717–18.
25.
DougallJRCunninghamBNimmoWS.Paracetamol absorption from Paramax, Panadol and Solpadeine.Br J Clin Pharmacol1983:15:487–9.
26.
Ross-LeeLMEadieMJHeazlewoodVBochnerFTyrerJH.Aspirin pharmacokinetics in migraine. The effect of metoclopramide.Eur J Clin Pharmacol1983;24:777–85.
27.
SlettnesOSjaastadO.Metoclopramide during attacks of migraine. In:Sicuteri Fed Headache, new vistas.Florence:Biomedical Press,1977:201–4.
28.
BatemanDNKahnCDaviesDS.Concentration effect studies with oral metoclopramide.Br J Clin Pharmacol1979:8:179–82.
29.
BatemanDNKahnCDaviesDS.The pharmacokinetics of metoclopramide in man with observations in the dog. Br J Clin Pharmacol1980;9:371–7.
30.
Over-the-counter drugs: Establishment of a monograph for OTC internal analgesic, antipyretic and antirheumatic products.Fed Reg1977;42(131):35482–5.
31.
SiegersC-P.Effects of caffeine on the absorption and analgesic efficacy of paracetamol in rats. Pharmacology1973;10:19–27.
32.
ReuningRHLevyG.Effect of complex formation on drug absorption VIII. Intestinal transfer characteristics of the salicylamide-caffeine system.J Pharm Sci1968;57:1342–6.
33.
SchmidtRFanchampsA.Effect of caffeine on intestinal absorption of ergotamine in man. Eur J Clin Pharmacol1974;7:213–16.
34.
WeissBHaitWN.Selective cyclic nucleotide phosphodiesterase inhibitors as potential thera peutic agents. Ann Rev Pharmacol Toxicol1977;17:441–77.
35.
SeltzerS.Foods, and food and drug combinations, responsible for head and neck pain.Cephalalgia1982:2:111–24.
36.
CharlesCM.Treatment of hereditary cephalalgia. Postgrad Med1950;7:33–5.
37.
KallósPKallós-DeffnerL.The use of ergot derivatives in prophylaxis and therapy ot migraine. Prog Allergy1952;3:485–99.
MackenzieTBPopkinMK.DziubinskiJ.SheppardJR.Effects of caffeine withdrawal on isoproterenol-stimulated cyclic adenosine mono-phosphate. Clin Pharmacol Ther1981;30:436–8.
40.
GoldsteinAKaizerSWhitbyO.Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee.Clin Pharmacol Ther1969:10:489–97.
41.
HakkarainenHParantainenJGothoniGVapaataloH.Tolfenamic acid and caffeine. A useful combination in migraine.Cephalalgia1982:2:173–7.
42.
LaskaEMSunshineAZighelboimI.RoureCMarreroIWanderlingJOlsonN.Effect of caffeine on acetaminophen analgesia. Clin Pharmacol Ther1983;33:498–509.
43.
WilkinsonM.Treatment of the acute migraine attack-current status. Cephalalgia1983;3:61–7.
44.
TokolaRANeuvonenPJ.Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid.Br J Clin Pharmacol1984:17:67–75.
45.
OlesenJ.KrabbeA Æ.Tfelt-HansenP.Methodological aspects of prophylactic drug trials in migraine. Cephalalgia1981;1:127–41.
46.
HallDW.Migraine. Mefenamic acid (Ponstan) in the treatment of attacks.J Roy Coil Gen Practit1968;15:321–4.
47.
PeatfieldRC.PettyRGRoseFC.Double blind comparison of mefenamic acid and acetaminophen (paracetamol) in migraine.Cephalalgia1983:3:129–34.
48.
RabeyJM.VardiYVan DyckDStreiflerM.Ophthalmoplegic migraine: Amelioration by flufenamic acid, a prostaglandin inhibitor. Ophthalmologica1977;175:148–52.
49.
VardiYRabeyIMStreiflerMSchwartzALindnerHR.ZorU.Migraine attacks. Alleviation by an inhibitor of prostaglandin synthesis and action.Neurology1976;26:447–50.
50.
LindegaardK-FØvrelidLSjaastadO.Naproxen in the prevention of migraine attacks. A double-blind placebo-controlled cross-over study.Headache1980;20:96–8.
