Triptans are used for the treatment of severe migraine attacks or those that do not respond toNSAIDs[5] or otherover-the-counter drugs.[6] Triptans are a mid-line treatment suitable for many migraineurs with typical attacks. They may not work for atypical or unusually severe migraine attacks, transformed migraine, or status migrainosus (continuous migraine).
Triptans are highly effective, reducing the symptoms or aborting the attack within 30 to 90 minutes in 70–80% of patients.[7] A 2024systematic review andnetwork meta analysis compared the effectiveness of medications for acute migraine attacks in adults. It found that triptans were the most effective class of drugs followed by non-steroidal anti-inflammatories.[8][9]
A test measuring a person's skinsensitivity during a migraine may indicate whether the individual will respond to treatment with triptans.[10] Triptans are most effective in those with no skin sensitivity; with skin sensitivity, it is best to take triptans within twenty minutes of the headache's onset.[11]
Triptans should be taken as soon as possible after the onset of pain. In case of migraine withaura they are to be taken after the aura and with the onset of pain.[13] If taken too early, they may not have the full effect on symptom reduction, and in case of an aura, they can worsen the aura. It is assumed that blood vessels areconstricted during the aura phase anddilated during the pain phase, so a constrictive medication like a triptan is not recommended during the aura.[14]
Triptans are effective for the treatment ofcluster headache. This has been demonstrated forsubcutaneous sumatriptan andintranasal zolmitriptan, the former of which is more effective according to a 2013Cochrane review. Tablets were not considered appropriate in this review.[15]
All marketed triptans are available inoral form; some in form ofsublingual tablets.[13]Sumatriptan andzolmitriptan are also available asnasal sprays.[13][17] For sumatriptan, a number of other application forms are marketed:suppositories, a subcutaneous injection,[13] aniontophoretic transdermal patch, which uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes;[18] a drug-device combination containing sumatriptan powder that is "breath powered" allowing the user to blow sumatriptan powder in to their nostrils;[19] as well as a needle-free injection system that works with air pressure.[20]
At least two triptans (sumatriptan and rizatriptan) have been listed under the unacceptable medication by theCanadian Blood Services as a potential risk to the recipient; hence, donors are required not to have taken the medication for the last 72 hours.[26]
Triptans have few side effects if used in correct dosage and frequency. The most common adverse effect is recurrence of migraine. Asystematic review found that "rizatriptan 10 mg was the only triptan with a recurrence rate [the reappearance of moderate to severe pain within 24 hours after the response at 2 hours] greater than that of placebo".[27]
There is a theoretical risk of coronary spasm in patients with established heart disease, and cardiac events after taking triptans may rarely occur.[28]
Combination of triptans with other serotonergic drugs such as ergot alkaloids, monoamine oxidase inhibitors,selective serotonin reuptake inhibitors (SSRIs),serotonin–norepinephrine reuptake inhibitors (SNRIs) orSt John's wort has been alleged to induce symptoms of aserotonin syndrome (a syndrome of changes in mental status, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms),[2][13] whereas scientific studies indicate there is no potential for life-threatening serotonin syndrome in patients taking triptans and SSRI or SNRIs at the same time, although the FDA has officially stated otherwise.[29][30][31][32][33][34][35] Combining triptans with ergot alkaloids is contraindicated because of the danger of coronary spasms.[13]
Pharmacokinetic interactions (for example, mediated byCYP liver enzymes ortransporter proteins) are different for the individual substances; for most triptans, they are mild to absent. Eletriptan blood plasma levels are increased by strong inhibitors ofCYP3A4, and frovatriptan levels byCYP1A2 inhibitors such asfluvoxamine.[13]
5-HT receptors are classified into seven different families named 5-HT1 to 5-HT7. All receptors areG protein coupled receptors with seven transmembrane domains with the one exception of 5-HT3 receptor which is aligand gated ion channel. There is a highhomology in the amino acid sequence within each family. Each family couples to the samesecond messenger systems. Subtypes of 5-HT1 are the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F receptors. All 5-HT1D receptors are coupled to inhibition ofadenylate cyclase. 5-HT1B and 5-HT1D receptors have been difficult to distinguish on a pharmacological basis. After cloning two distinct genes for 5-HT1B and 5-HT1D receptors, a better insight into distribution and expression in different tissues was gained, except in brain tissue where they are overlapping in several areas.[38]
Mostmammalian species, including humans, have 5-HT1D binding sites widely distributed throughout thecentral nervous system. 5-HT1D receptors are found in all areas of the brain but they differ in quantity at each area.[39]An important initiator of head pain is suggested to be the activation oftrigeminovascularafferent nerves which upon activation releases neuropeptides such as CGRP, substance P andneurokinin A. Also they are thought to promote neurogenic inflammatory response important for sensitization ofsensory afferents, and also transmission and generation of head pain centrally. 5-HT1D has been found responsible for inhibition of neurogenic inflammation upon administration with sumatriptan and other related compounds that act on prejunctional 5-HT1D receptors.[38]
All triptans, like the older drugdihydroergotamine, have agonistic effects on the 5-HT1D receptor. Comparison of sumatriptan and dihydroergotamine showed that dihydroergotamine has high affinity and sumatriptan has medium affinity for 5-HT1D.[37] Triptans have at least three modes of action. These antimigraine mechanisms are:
vasoconstriction of pain producing intra cranial extracerebral vessels by a direct effect on vascular smooth muscle. Sumatriptan and rizatriptan have been shown to cause vasoconstriction in the humanmiddle meningeal arteries.
inhibition of vasoactive neuropeptide release by trigeminal terminals innervating intracranial vessels and the dura mater. The trigeminocervical complex has 5-HT1D receptors that bind dihydroergotamine and triptans in humans. Rizatriptan has been shown to block dural vasodilation and plasma protein extravasation by inhibiting the release of CGRP via activation of receptors on preganglionic trigeminal sensory nerver terminals. Sumatriptan is shown to inhibit potassium stimulated CGRP secretion from cultured trigeminal neurons in a dose dependant manner and may also inhibit the release of substance P.
inhibition ofnociceptiveneurotransmission within the trigeminocervical complex in thebrainstem and upper cervical spinal column. Rizatriptan has central trigeminal antinociceptive activity.
Other possibilities of triptans in antimigraine effects are modulation ofnitric oxide dependentsignal transduction pathways, nitric oxide scavenging in the brain, and sodium dependent cell metabolic activity.[40][37]
Most of the triptans, for instancesumatriptan,zolmitriptan, and others, are inactive as serotonin5-HT2A receptoragonists.[41] However, a few triptans, includingdonitriptan,avitriptan, andeletriptan, have been found to act as serotonin 5-HT2A receptor agonists, albeit with one to three orders of magnitude lower activational potency than at the serotonin 5-HT1B and 5-HT1D receptors.[41]
Zolmitriptan is different from the other triptans because it is converted to an activeN-desmethyl metabolite which has higher affinity for the serotonin 5-HT1D and 5-HT1B receptors; both substances have a biological half-life of 2 to 3 hours.[25] In studies, newer triptans are mostly compared to sumatriptan.[24] They are better than sumatriptan for their longer half-life in plasma and higher oralbioavailability,[49] but have a higher potential forcentral nervous side effects.[2]
The history of triptans began with the proposed existence of then unknown serotonin (5-hydroxytryptamine, 5-HT). In the late 1940s two groups of investigators, one in Italy and the other in the United States, identified a substance that was calledserotonin in the US andenteramine in Italy. In the early 1950s it was confirmed that both substances were the same. In the mid-1950s it was proposed that serotonin had a role as aneurotransmitter in the central nervous system (CNS) of animals. Investigations of the mechanism of action were not very successful as experimental techniques were lacking.[49]
Later in the 1960s, studies showed thatvasoconstriction caused by 5-HT,noradrenaline andergotamine could reduce migraine attacks. Patrick P.A. Humphrey among others atGlaxo started researching the 5-HT receptor to discover a more direct 5-HTagonist with fewer side effects.
They continued developing and working on a desirable action on 5-HT by 5-HT1 receptor activation for an anti-migraine drug. Continued work led to thedevelopment of sumatriptan, now known as the first 5-HT1 agonist, selective for the 5-HT1D/B receptors and also the 5-HT1F receptor with less affinity. By 1991 sumatriptan became available in clinical use in the Netherlands and in the US in 1993. However, there was always a debate about its mechanism of action, and it still remains unclear today. Later, Mike Moskowitz proposed a theory about "neuronal extravasation", and this was the first clue that sumatriptan might have a directneuronal effect in migraine attacks.[50]
Sumatriptan became a prototype for other triptans that have been developed for improved selectivity for the 5-HT1D/B receptors.[49]
These drugs have been available only by prescription (US, Canada and UK), but sumatriptan became available over-the-counter in the UK in June 2006.[51] The brand name of the OTC product in the UK is Imigran Recovery. The patent on Imitrex STATDose expired in December 2006, and injectable sumatriptan became available as a generic formula in August 2008.[citation needed] Sumavel Dosepro is a needle-free delivery of injectable sumatriptan that was approved in the US by the FDA in July 2009.[20] Sumatriptan became available as a generic in the US in late 2009. It used to be sold over-the-counter in Romania under the Imigran brand; however, as of August 2014 prescription is required. Zecuity, a sumatriptan transdermal patch, was approved by the US FDA in January 2013.[18] The sumatriptan nasal powder was approved by the FDA in January 2016 and became available in the U.S. May 2016.[52]Naratriptan is available OTC in Germany and Brazil.
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^abcRubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E, Meeus L, Danser AH, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalón CM, MaassenVanDenBrink A (December 2019)."Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan".British Journal of Pharmacology.176 (24):4681–4695.doi:10.1111/bph.14832.PMC6965684.PMID31418454.TABLE 1 Summary of pIC50 (negative logarithm of the molar concentration of these compounds at which 50% of the radioligand is displaced) and pKi (negative logarithm of the molar concentration of the Ki ) values of individual antimigraine drugs at 5‐HT receptors [...] TABLE 2 Summary of pEC50 values of cAMP (5‐HT1A/B/E/F and 5‐HT7), GTPγS (5‐HT1A/B/D/E/F), and IP (5‐HT2) assays of individual antimigraine drugs at 5‐HT receptors [...]
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^abcLippincott, W. W.; Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W. (2013).Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 368–376.
