Triptans are a family of antimigraine drugs used to abort migraines and cluster headaches. While effective at treating individual headaches, they do not provide preventive treatment and are not curative. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain. They are taken orally and by other routes.
The drugs of this class act as agonists for serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors at blood vessels and nerve endings in the brain. Some also activate the 5-HT<sub>1F</sub> receptor. Structurally, triptans are substituted tryptamines or closely related to tryptamines, for instance the psychedelic drug dimethyltryptamine (DMT).
The first clinically available triptan was sumatriptan, which has been marketed since 1991. Subsequently, a variety of other triptans have also been marketed, including zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Triptans have largely replaced ergoline drugs like ergotamine and dihydroergotamine, an older class of medications used to relieve migraine and cluster headaches.
Medical uses
Migraine
Triptans are used for the treatment of severe migraine attacks or those that do not respond to NSAIDs or other over-the-counter drugs. 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. A 2024 systematic review and network 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.
A test measuring a person's skin sensitivity during a migraine may indicate whether the individual will respond to treatment with triptans. 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.
Oral rizatriptan and nasal zolmitriptan are the most used triptans for migraines in children.
Correct timing of intake
Triptans should be taken as soon as possible after the onset of pain. In case of migraine with aura they are to be taken after the aura and with the onset of pain.
Cluster headache
Triptans are effective for the treatment of cluster headache. This has been demonstrated for subcutaneous sumatriptan and intranasal zolmitriptan, the former of which is more effective according to a 2013 Cochrane review. Tablets were not considered appropriate in this review.
Altitude sickness
A single randomized controlled trial found that sumatriptan may be able to prevent altitude sickness.
Available forms
All marketed triptans are available in oral form; some in form of sublingual tablets. Sumatriptan and zolmitriptan are also available as nasal sprays. For sumatriptan, a number of other application forms are marketed: suppositories, a subcutaneous injection, a drug-device combination containing sumatriptan powder that is "breath powered" allowing the user to blow sumatriptan powder in to their nostrils; as well as a needle-free injection system that works with air pressure.
! Tablet
! Oral disintegrating tablets
! Nasal spray
! Subcutaneous injection
! Rectal suppository
|-
| all triptans
| rizatriptan
| sumatriptan
| sumatriptan
| sumatriptan
|-
|
| zolmitriptan
| zolmitriptan
|
|
|}
Contraindications
All triptans are contraindicated in patients with cardiovascular diseases (coronary spasms, symptomatic coronary artery disease, after a heart attack or stroke, uncontrolled hypertension, Raynaud's disease, peripheral artery disease). Most triptans are also contraindicated during pregnancy and breastfeeding and for patients younger than 18; but sumatriptan and zolmitriptan nasal sprays are also approved for youths over 12.
Adverse effects
Triptans have few side effects if used in correct dosage and frequency. The most common adverse effect is recurrence of migraine. A systematic 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".
There is a theoretical risk of coronary spasm in patients with established heart disease, and cardiac events after taking triptans may rarely occur.
Interactions
Combination of triptans with other serotonergic drugs such as ergot alkaloids, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) or St John's wort has been alleged to induce symptoms of a serotonin syndrome (a syndrome of changes in mental status, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms), Combining triptans with ergot alkaloids is contraindicated because of the danger of coronary spasms.
Pharmacokinetic interactions (for example, mediated by CYP liver enzymes or transporter proteins) are different for the individual substances; for most triptans, they are mild to absent. Eletriptan blood plasma levels are increased by strong inhibitors of CYP3A4, and frovatriptan levels by CYP1A2 inhibitors such as fluvoxamine. effects on serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors in blood vessels (causing their constriction) and nerve endings in the brain, and subsequent inhibition of pro-inflammatory neuropeptide release, including CGRP and substance P. Triptans are selective agents for 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub>
5-HT receptors are classified into seven different families named 5-HT<sub>1</sub> to 5-HT<sub>7</sub>. All receptors are G protein coupled receptors with seven transmembrane domains with the one exception of 5-HT<sub>3</sub> receptor which is a ligand gated ion channel. There is a high homology in the amino acid sequence within each family. Each family couples to the same second messenger systems. Subtypes of 5-HT<sub>1</sub> are the 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub>, 5-HT<sub>1E</sub> and 5-HT<sub>1F</sub> receptors. All 5-HT<sub>1D</sub> receptors are coupled to inhibition of adenylate cyclase. 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors have been difficult to distinguish on a pharmacological basis. After cloning two distinct genes for 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors, a better insight into distribution and expression in different tissues was gained, except in brain tissue where they are overlapping in several areas.
Most mammalian species, including humans, have 5-HT<sub>1D</sub> binding sites widely distributed throughout the central nervous system. 5-HT<sub>1D</sub> receptors are found in all areas of the brain but they differ in quantity at each area.
An important initiator of head pain is suggested to be the activation of trigeminovascular afferent nerves which upon activation releases neuropeptides such as CGRP, substance P and neurokinin A. Also they are thought to promote neurogenic inflammatory response important for sensitization of sensory afferents, and also transmission and generation of head pain centrally. 5-HT<sub>1D</sub> has been found responsible for inhibition of neurogenic inflammation upon administration with sumatriptan and other related compounds that act on prejunctional 5-HT<sub>1D</sub> receptors. However, a few triptans, including donitriptan, avitriptan, and eletriptan, have been found to act as serotonin 5-HT<sub>2A</sub> receptor agonists, albeit with one to three orders of magnitude lower activational potency than at the serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors.
Comparison
{| class="wikitable" style="margin: 1em auto 1em auto; font-size: small;"
|+ Comparative pharmacology of marketed triptans in their oral formulations
|-
! Drug !! Brand !! Company !! Targets !! 5-HT<sub>1D</sub><br />affinity (K<sub>i</sub>) !! !! log P !! log D<br /><small>(at pH 7.4)</small> !! T<sub>max</sub> !! T<sub>1/2</sub> !! Metabolism !! Dose
|-
| Sumatriptan
| align="center"| Imitrex
| align="center"|
| align="center"| 5-HT<sub>1B/D</sub>
| align="center"| 3.2–13nM
| align="center"| 14–17%
| align="center"| 0.8
| align="center"| –1.3
| align="center"| 2–2.5h
| align="center"| 2.5h
| align="center"| MAO-A
| align="center"| 25, 50, 100mg
|-
| Zolmitriptan
| align="center"| Zomig
| align="center"| Grünenthal
| align="center"| 5-HT<sub>1B/D</sub>
| align="center"| 0.63nM
| align="center"| 40%
| align="center"| 1.6
| align="center"| –0.7
| align="center"| 1.5–2h
| align="center"| 2–3h
| align="center"| MAO-A <br /> CYP1A2
| align="center"| 2.5, 5mg
|-
| Naratriptan
| align="center"| Amerge
| align="center"|
| align="center"| 5-HT<sub>1B/D</sub>
| align="center"| 5.0nM
| align="center"| 70%
| align="center"| 2.2
| align="center"| –0.2
| align="center"| 2–3h
| align="center"| 6h
| align="center"| Many CYPs <br /> MAO-A
| align="center"| 1, 2.5mg
|-
| Rizatriptan
| align="center"| Maxalt
| align="center"| Merck
| align="center"| 5-HT<sub>1B/D</sub>
| align="center"| 20nM
| align="center"| 45%
| align="center"| 1.4
| align="center"| –0.7
| align="center"| 1–1.5h
| align="center"| 2–2.5h
| align="center"| MAO-A
| align="center"| 5, 10mg
|-
| Almotriptan
| align="center"| Axert
| align="center"| Almirall-<br />Prodesfarma
| align="center"| 5-HT<sub>1B/D</sub> <br /> 5-HT<sub>1F</sub>
| align="center"| 16nM
| align="center"| 70%
| align="center"| 1.6
| align="center"| +0.35
| align="center"| 2.5h
| align="center"| 3.6h
| align="center"| CYP2D6 <br /> CYP3A4 <br /> MAO-A
| align="center"| 6.25, 12.5mg
|-
| Eletriptan
| align="center"| Relpax
| align="center"| Pfizer
| align="center"| 5-HT<sub>1B/D</sub> <br /> 5-HT<sub>1F</sub>
| align="center"| 1.3nM
| align="center"| 50%
| align="center"| 3.9
| align="center"| +0.5
| align="center"| 1–2h
| align="center"| 3.6–5.5h
| align="center"| CYP3A4
| align="center"| 20, 40, 80mg
|-
| Frovatriptan
| align="center"| Frova
| align="center"| Vernalis
| align="center"| 5-HT<sub>1B/D</sub>
| align="center"| 4.0nM
| align="center"| 24–30%
| align="center"| 0.9
| align="center"| –1.53
| align="center"| 2–4h
| align="center"| 26h
| align="center"| CYP1A2
| align="center"| 2.5mg
|}
Zolmitriptan is different from the other triptans because it is converted to an active N-desmethyl metabolite which has higher affinity for the serotonin 5-HT<sub>1D</sub> and 5-HT<sub>1B</sub> receptors; both substances have a biological half-life of 2 to 3 hours. They are better than sumatriptan for their longer half-life in plasma and higher oral bioavailability, Most triptans are simple tryptamines.
History
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 called serotonin in the US and enteramine 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 a neurotransmitter in the central nervous system (CNS) of animals. Investigations of the mechanism of action were not very successful as experimental techniques were lacking.
Later in the 1960s, studies showed that vasoconstriction caused by 5-HT, noradrenaline and ergotamine could reduce migraine attacks. Patrick P.A. Humphrey among others at Glaxo started researching the 5-HT receptor to discover a more direct 5-HT agonist with fewer side effects.
They continued developing and working on a desirable action on 5-HT by 5-HT<sub>1</sub> receptor activation for an anti-migraine drug. Continued work led to the development of sumatriptan, now known as the first 5-HT<sub>1</sub> agonist, selective for the 5-HT<sub>1D/B</sub> receptors and also the 5-HT<sub>1F</sub> 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 direct neuronal effect in migraine attacks.
Sumatriptan became a prototype for other triptans that have been developed for improved selectivity for the 5-HT<sub>1D/B</sub> receptors. 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. Sumavel Dosepro is a needle-free delivery of injectable sumatriptan that was approved in the US by the FDA in July 2009. 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. Naratriptan is available OTC in Germany and Brazil.