triptan

Triptans are used for the treatment of severe migraine attacks or those that do not respond to NSAIDs{{cite journal|vauthors=Brandes JL, Kudrow D, Stark SR, etal |title=Sumatriptan-naproxen for acute treatment of migraine: a randomized trial |journal=JAMA |volume=297 |issue=13 |pages=1443–1454 |year=2007 |pmid=17405970 |doi=10.1001/jama.297.13.1443|doi-access=free }} or other over-the-counter drugs.{{cite journal |vauthors=Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M |title=Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study |journal=Arch. Intern. Med. |volume=160 |issue=22 |pages=3486–92 |year=2000 |pmid=11112243 |doi=10.1001/archinte.160.22.3486|doi-access=free }} 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.{{Cite journal |last1=Sonal Sekhar |first1=M. |last2=Sasidharan |first2=Shalini |last3=Joseph |first3=Siby |last4=Kumar |first4=Anand |date=January 1, 2012 |title=Migraine management: How do the adult and paediatric migraines differ? |journal=Saudi Pharmaceutical Journal |volume=20 |issue=1 |pages=1–7 |doi=10.1016/j.jsps.2011.07.001 |issn=1319-0164 |pmc=3745030 |pmid=23960771}} 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.{{Cite journal |last=Karlsson |first=William K. |last2=Ostinelli |first2=Edoardo G. |last3=Zhuang |first3=Zixuan A. |last4=Kokoti |first4=Lili |last5=Christensen |first5=Rune H. |last6=Al-Khazali |first6=Haidar M. |last7=Deligianni |first7=Christina I. |last8=Tomlinson |first8=Anneka |last9=Ashina |first9=Håkan |last10=Torre |first10=Elena Ruiz de la |last11=Diener |first11=Hans-Christoph |last12=Cipriani |first12=Andrea |last13=Ashina |first13=Messoud |date=2024-09-18 |title=Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis |url=https://www.bmj.com/content/386/bmj-2024-080107 |journal=BMJ |language=en |volume=386 |pages=e080107 |doi=10.1136/bmj-2024-080107 |issn=1756-1833 |pmid=39293828|pmc=11409395 }}{{Cite journal |date=4 April 2025 |title=Which drugs are best for migraine attacks? |url=https://evidence.nihr.ac.uk/alert/which-drugs-are-best-for-migraine-attacks/ |journal=NIHR Evidence}}

A test measuring a person's skin sensitivity during a migraine may indicate whether the individual will respond to treatment with triptans.{{cite journal|year=2004|title=Defeating migraine pain with triptans: A race against the development of cutaneous allodynia|journal=Annals of Neurology|volume=55|issue=1|pages=19–26|pmid=14705108|doi=10.1002/ana.10786|last1=Burstein|first1=R|last2=Collins|first2=B|last3=Jakubowski|first3=M|s2cid=24040813}} 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.{{Cite journal |last2= Jakubowski|first2= Moshe|last3= Rauch|first3= Steven D.|date=2011 |title=The science of migraine |journal=Journal of Vestibular Research: Equilibrium & Orientation |volume=21 |issue=6 |pages=305–314 |doi=10.3233/VES-2012-0433 |issn=0957-4271 |pmc=3690498 |pmid=22348935|last1= Burstein|first1= Rami}}

Oral rizatriptan and nasal zolmitriptan are the most used triptans for migraines in children.{{cite journal|year=2010|title=The use of triptans for pediatric migraines|journal=Paediatr Drugs|volume=12|issue=6|pages=379–389|pmid=21028917|last1=Eiland|first1=L. S.|last2=Hunt|first2=M. O.|s2cid=11187764|doi=10.2165/11532860-000000000-00000}}

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. 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 are constricted during the aura phase and dilated during the pain phase, so a constrictive medication like a triptan is not recommended during the aura.{{Cite journal |last2= Elliott|first2= D.|date=June 6, 2007 |title=Acute migraine: Current treatment and emerging therapies |journal=Therapeutics and Clinical Risk Management |volume=3 |issue=3 |pages=449–459 |issn=1176-6336 |pmc=2386351 |pmid=18488069|last1= Kalra|first1= A. A.}}

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.{{cite journal|title=Triptans for acute cluster headache|journal=The Cochrane Database of Systematic Reviews|volume=7|issue=7|pages=CD008042|pmid=24353996|doi=10.1002/14651858.CD008042.pub3|year=2013|last1=Law|first1=S|last2=Derry|first2=S|last3=Moore|first3=R. A.|pmc=4170909}}

A single randomized controlled trial found that sumatriptan may be able to prevent altitude sickness.{{cite journal |vauthors=Jafarian S, Gorouhi F, Salimi S, Lotfi J |title=Sumatriptan for prevention of acute mountain sickness: randomized clinical trial |journal=Ann. Neurol. |volume=62 |issue=3 |pages=273–7 |year=2007 |pmid=17557349 |doi=10.1002/ana.21162|s2cid=7799716 }}

All marketed triptans are available in oral form; some in form of sublingual tablets.{{cite book|title=Austria-Codex|at=Zomig Rapimelt; Maxalt Rapitab|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=de}} Sumatriptan and zolmitriptan are also available as nasal sprays.{{Cite web|url=https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Imitrex_Nasal_Spray/pdf/IMITREX-NASAL-SPRAY-PI-PIL.PDF|title=Imitrex Nasal Spray package insert|website=GlaxoSmithKline prescribing information|access-date=May 20, 2016|url-status=live|archive-url=https://web.archive.org/web/20150905173656/https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Imitrex_Nasal_Spray/pdf/IMITREX-NASAL-SPRAY-PI-PIL.PDF|archive-date=September 5, 2015}} For sumatriptan, a number of other application forms are marketed: suppositories, a subcutaneous injection, an iontophoretic 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;{{Cite journal|last1=Pierce|first1=Mark|last2=Marbury|first2=Thomas|last3=O'Neill|first3=Carol|last4=Siegel|first4=Steven|last5=Du|first5=Wei|last6=Sebree|first6=Terri|date=2009-06-01|title=Zelrix: a novel transdermal formulation of sumatriptan|journal=Headache|volume=49|issue=6|pages=817–825|doi=10.1111/j.1526-4610.2009.01437.x|issn=1526-4610|pmid=19438727|doi-access=free}} a drug-device combination containing sumatriptan powder that is "breath powered" allowing the user to blow sumatriptan powder in to their nostrils;{{Cite web|url=https://www.pharmacytimes.com/news/onzetra-xsail-approved-as-migraine-treatment|title=Onzetra Xsail Approved as Migraine Treatment|date=February 3, 2016|website=pharmacytimes.com|access-date=October 1, 2019}} as well as a needle-free injection system that works with air pressure.

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).{{cite journal |last1=Dodick |first1=David W. |last2=Shewale |first2=Anand S. |last3=Lipton |first3=Richard B. |last4=Baum |first4=Seth J. |last5=Marcus |first5=Steven C. |last6=Silberstein |first6=Stephen D. |last7=Pavlovic |first7=Jelena M. |last8=Bennett |first8=Nathan L. |last9=Young |first9=William B. |last10=Viswanathan |first10=Hema N. |last11=Doshi |first11=Jalpa A. |last12=Weintraub |first12=Howard |title=Migraine Patients With Cardiovascular Disease and Contraindications: An Analysis of Real-World Claims Data |journal=Journal of Primary Care & Community Health |date=January 2020 |volume=11 |doi=10.1177/2150132720963680 |pmid=33095099 |pmc=7585888 }}{{cite journal |last1=Tepper |first1=Stewart J. |last2=Spears |first2=Roderick C. |title=Acute Treatment of Migraine |journal=Neurologic Clinics |date=May 2009 |volume=27 |issue=2 |pages=417–427 |doi=10.1016/j.ncl.2008.11.008 |pmid=19289223 }} 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. In spite of expert opinion and evidence to the contrary, the FDA and some other drug governance bodies have stated that monoamine oxidase inhibitors are contraindicated for sumatriptan, zolmitriptan and rizatriptan, and combination with ergot alkaloids such as ergotamine for all substances.

At least two triptans (sumatriptan and rizatriptan) have been listed under the unacceptable medication by the Canadian Blood Services as a potential risk to the recipient; hence, donors are required not to have taken the medication for the last 72 hours.{{Cite journal |last1=Gawde |first1=Prathamesh |last2=Shah |first2=Harsh |last3=Patel |first3=Harsh |last4=Bharathi |first4=Koppineedi S |last5=Patel |first5=Neil |last6=Sethi |first6=Yashendra |last7=Kaka |first7=Nirja |title=Revisiting Migraine: The Evolving Pathophysiology and the Expanding Management Armamentarium |journal=Cureus |date=2023 |volume=15 |issue=2 |pages=e34553 |doi=10.7759/cureus.34553 |doi-access=free |issn=2168-8184 |pmc=9985459 |pmid=36879707}}

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".{{cite journal |vauthors=Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jiménez D |title=Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability |journal=Headache |volume=47 |issue=8 |pages=1152–68 |year=2007 |pmid=17883520 |doi=10.1111/j.1526-4610.2007.00849.x|doi-access=free }}

There is a theoretical risk of coronary spasm in patients with established heart disease, and cardiac events after taking triptans may rarely occur.{{cite journal |vauthors=Dahlöf CG, Mathew N |title=Cardiovascular safety of 5HT1B/1D agonists--is there a cause for concern? |journal=Cephalalgia: An International Journal of Headache |volume=18 |issue=8 |pages=539–45 |year=1998 |pmid=9827245 |doi=10.1046/j.1468-2982.1998.1808539.x|s2cid=30125923 }}

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), 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.{{cite journal | last=Rolan | first=Paul E. | title=Drug Interactions with Triptans | journal=CNS Drugs | publisher=Springer Science and Business Media LLC | volume=26 | issue=11 | date=2012-09-25 | issn=1172-7047 | pmid=23018546 | doi=10.1007/s40263-012-0002-5 | pages=949–957| s2cid=43699741 }}{{cite journal|title=The Serotonin Syndrome, Triptans, and the Potential for Drug–Drug Interactions|journal=Headache: The Journal of Head and Face Pain|volume=47|issue=2|pages=266–9|doi=10.1111/j.1526-4610.2006.00691.x|pmid=17300366|year=2007|last1=Shapiro|first1=Robert E.|last2=Tepper|first2=Stewart J.|s2cid=21075435}}{{cite journal|title=The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin-Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper|journal=Headache: The Journal of Head and Face Pain|volume=50|issue=6|pages=1089–99|doi=10.1111/j.1526-4610.2010.01691.x|pmid=20618823|year=2010|last1=Evans|first1=Randolph W.|last2=Tepper|first2=Stewart J.|last3=Shapiro|first3=Robert E.|last4=Sun-Edelstein|first4=Christina|last5=Tietjen|first5=Gretchen E.|s2cid=40713435|doi-access=free}}{{cite journal|title=Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review|last1=Gillman|journal=Headache|volume=50|issue=2|year=2010|pages=264–272|doi=10.1111/j.1526-4610.2009.01575.x|pmid=19925619|s2cid=221752556 |doi-access=free}}{{cite journal|title=The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reports| journal=MedGenMed| volume=9| issue=3| page=48| pmid=18092054| pmc=2100123| year=2007| last1=Evans| first1=R. W.}}{{cite journal|title=Serotonin syndrome risks when combining SSRI/SNRI drugs and triptans: is the FDA's alert warranted?|journal=Annals of Pharmacotherapy|volume=42|issue=11|pages=1692–6|pmid=18957623|year=2008|last1=Wenzel|first1=R. G.|last2=Tepper|first2=S|last3=Korab|first3=W. E.|last4=Freitag|first4=F|doi=10.1345/aph.1L260|s2cid=24942783}}{{cite web|url=https://www.fda.gov/CDER/Drug/InfoSheets/HCP/venlafaxineHCP.htm|title=Information for Healthcare Professionals|last=US Food and Drug Administration|date=2006-07-19|publisher=Food and Drug Administration|access-date=2008-01-10|archive-url=https://web.archive.org/web/20080219184710/https://www.fda.gov/CDER/Drug/InfoSheets/HCP/venlafaxineHCP.htm |archive-date=2008-02-19}} Combining triptans with ergot alkaloids is contraindicated because of the danger of coronary spasms.

In a study from Harvard Medical School and the University of Florida College of Medicine involving 47,968 patients and published on 26 February 2018, concomitant use of a selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor for depression with a triptan for migraine did not demonstrate an increased risk of the serotonin syndrome.{{cite journal|title=Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome |first1=Yulia|last1=Orlova|first2=Paul|last2=Rizzoli|first3=Elizabeth|last3=Loder|date=26 February 2018|journal=JAMA Neurology|volume=75|issue=5|pages=566–572|pmid=29482205|doi=10.1001/jamaneurol.2017.5144|pmc=5885255}}

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.

{{further|Discovery and development of triptans|Serotonin receptor agonist}}

Their action is attributed to their agonist{{Cite journal

| last1 = Tepper | first1 = S. J.

| last2 = Rapoport | first2 = A. M.

| last3 = Sheftell | first3 = F. D.

| title = Mechanisms of action of the 5-HT1B/1D receptor agonists

| journal = Archives of Neurology

| volume = 59

| issue = 7

| pages = 1084–1088

| year = 2002

| pmid = 12117355

| doi=10.1001/archneur.59.7.1084

| doi-access = free

}} effects on serotonin 5-HT_1B and 5-HT_1D 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_1B and 5-HT_1D and have low or even no affinity for other types of 5-HT receptors.{{cite book|author=Brunton, L. |author2=Lazo, J. |author3=Parker, K. |year=2006|title=Goodman & Gilman's The Pharmacological Basis of Therapeutics|edition=11th|publisher=McGraw-Hill Education|pages=305–308}}

5-HT receptors are classified into seven different families named 5-HT₁ to 5-HT₇. All receptors are G protein coupled receptors with seven transmembrane domains with the one exception of 5-HT₃ 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-HT₁ are the 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E and 5-HT_1F receptors. All 5-HT_1D receptors are coupled to inhibition of adenylate cyclase. 5-HT_1B and 5-HT_1D receptors have been difficult to distinguish on a pharmacological basis. After cloning two distinct genes for 5-HT_1B and 5-HT_1D receptors, a better insight into distribution and expression in different tissues was gained, except in brain tissue where they are overlapping in several areas.{{cite journal|author=Hamel, E.|year=1999|title=The biology of serotonin receptors: focus on migraine pathophysiology and treatment|journal=Can J Neurol Sci|at=26 Suppl 3:S2–6|pmid=10563226|volume=26 Suppl 3|issue=3|doi=10.1017/s0317167100000123|doi-access=free}}

Most mammalian species, including humans, have 5-HT_1D binding sites widely distributed throughout the central nervous system. 5-HT_1D receptors are found in all areas of the brain but they differ in quantity at each area.{{cite journal|title=The distribution of 5HT_1D and 5HT_1E binding sites in human brain|author=Lowther, S.|journal=Eur J Pharmacol|year=1992|volume=222|issue=1|pages=137–42|pmid=1468490|doi=10.1016/0014-2999(92)90473-h}}

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_1D has been found responsible for inhibition of neurogenic inflammation upon administration with sumatriptan and other related compounds that act on prejunctional 5-HT_1D receptors.

All triptans, like the older drug dihydroergotamine, have agonistic effects on the 5-HT_1D receptor. Comparison of sumatriptan and dihydroergotamine showed that dihydroergotamine has high affinity and sumatriptan has medium affinity for 5-HT_1D. Triptans have at least three modes of action. These antimigraine mechanisms are:

1. 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 human middle meningeal arteries.
2. inhibition of vasoactive neuropeptide release by trigeminal terminals innervating intracranial vessels and the dura mater. The trigeminocervical complex has 5-HT_1D 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.
3. inhibition of nociceptive neurotransmission within the trigeminocervical complex in the brainstem and upper cervical spinal column. Rizatriptan has central trigeminal antinociceptive activity.

Other possibilities of triptans in antimigraine effects are modulation of nitric oxide dependent signal transduction pathways, nitric oxide scavenging in the brain, and sodium dependent cell metabolic activity.{{cite journal | last1 = Goadsby | first1 = P. J. | year = 1998 | title = Serotonin 5HT_1B/1D receptor agonists in migraine - Comparative pharmacology and its therapeutic implications | journal = CNS Drugs | volume = 10 | issue = 4| pages = 271–286 | doi = 10.2165/00023210-199810040-00005 | s2cid = 68150076 }}

Triptans have a wide variety of pharmacokinetic properties. Bioavailability is between 14% and 70%, biological half-life (T_1/2) is between 2 and 26 hours. Their good ability to cross the blood–brain barrier and the rather long half life of some triptans may result in lower frequencies of migraine recurrence.{{cite journal | last1 = Bigal | first1 = M. E. | last2 = Bordini | first2 = C. A. | last3 = Antoniazzi | first3 = A. L. | last4 = Speciali | first4 = J. G. | year = 2003 | title = The triptan formulations: a critical evaluation | journal = Arquivos de Neuro-Psiquiatria | volume = 61 | issue = 2A | pages = 313–320 | doi = 10.1590/s0004-282x2003000200032 | pmid = 12806521 | doi-access = free }}{{cite journal | last1 = Armstrong | first1 = S. C. | last2 = Cozza | first2 = K. L. | year = 2002 | title = Triptans | journal = Psychosomatics | volume = 43 | issue = 6| pages = 502–504 | doi = 10.1176/appi.psy.43.6.502 | pmid=12444236| doi-access = free }}{{cite journal | last1 = Mathew | first1 = N. T. | last2 = Loder | first2 = E. W. | year = 2005 | title = Evaluating the triptans | doi = 10.1016/j.amjmed.2005.01.017 | pmid = 15841885 | journal = The American Journal of Medicine Supplements | volume = 118 | issue = 1| pages = 28–35 }}

Zolmitriptan is different from the other triptans because it is converted to an active N-desmethyl metabolite which has higher affinity for the 5-HT_1D and 5-HT_1B receptors; both substances have a biological half-life of 2 to 3 hours. In studies, newer triptans are mostly compared to sumatriptan.{{cite journal | last1 = Ferrari | first1 = M. D. | last2 = Goadsby | first2 = P. J. | last3 = Roon | first3 = K. I. | last4 = Lipton | first4 = R. B. | year = 2002 | title = Triptan (serotonin, 5-HT1D/1B agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials | journal = Cephalalgia | volume = 22 | issue = 8| pages = 633–658 | doi = 10.1046/j.1468-2982.2002.00404.x | pmid=12383060| s2cid = 2368571 }} They are better than sumatriptan for their longer half-life in plasma and higher oral bioavailability, but have a higher potential for central nervous side effects.

Donitriptan and avitriptan were never marketed.

{{further|Discovery and development of triptans}}

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.{{cite book|author=Lippincott, W. W. |author2=Lemke, T. L. |author3=Williams, D. A. |author4=Roche, V. F. |author5=Zito, S. W. |year=2013|title=Foye's Principles of Medicinal Chemistry|publisher=Lippincott Williams & Wilkins|pages=368–376}}

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-HT₁ receptor activation for an anti-migraine drug. Continued work led to the development of sumatriptan, now known as the first 5-HT₁ agonist, selective for the 5-HT_1D/B receptors and also the 5-HT_1F 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.{{cite journal | last1 = Humphrey | first1 = P. P. | year = 2007 | title = The discovery of a new drug class for the acute treatment of migraine | doi = 10.1111/j.1526-4610.2007.00672.x | pmid = 17425704 | journal = Headache | volume = 47 | issue = Suppl 1| pages = S10–19 | s2cid = 12201740 | doi-access = free }}

Sumatriptan became a prototype for other triptans that have been developed for improved selectivity for the 5-HT_1D/B receptors.

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.{{cite web

|publisher = BBC News

|date = 2006-05-19

|title = Pharmacies to sell migraine drug

|url = http://news.bbc.co.uk/1/hi/health/4996712.stm

|access-date = 2006-09-05

|url-status = live

|archive-url = https://web.archive.org/web/20060924041401/http://news.bbc.co.uk/1/hi/health/4996712.stm

|archive-date = 2006-09-24

}} 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|date=April 2010}} Sumavel Dosepro is a needle-free delivery of injectable sumatriptan that was approved in the US by the FDA in July 2009.{{cite web|url=http://www.zogenix.com/index.php/news/sumavel-dosepro-sumatriptan-injection-approved-by-fda-for-acute-migraine-and-cluster-headache/|title=Zogenix, Inc. - Therapeutic Solutions for CNS Disorders and Rare Disease|website=www.zogenix.com|access-date=6 May 2018|url-status=live|archive-url=https://web.archive.org/web/20160821125219/http://www.zogenix.com/index.php/news/sumavel-dosepro-sumatriptan-injection-approved-by-fda-for-acute-migraine-and-cluster-headache/|archive-date=21 August 2016}} 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. The sumatriptan nasal powder was approved by the FDA in January 2016 and became available in the U.S. May 2016.{{Cite web|url=http://www.avanir.com/press/avanir-pharmaceuticals-announces-fda-approval-onzetra%E2%84%A2-xsail%E2%84%A2-avp-825-acute-treatment-migraine|title=Avanir's press release: FDA approves Onzetra|date=January 28, 2016|website=Avanir Pharmaceuticals|access-date=May 20, 2016|url-status=live|archive-url=https://web.archive.org/web/20160511232617/http://www.avanir.com/press/avanir-pharmaceuticals-announces-fda-approval-onzetra%E2%84%A2-xsail%E2%84%A2-avp-825-acute-treatment-migraine|archive-date=May 11, 2016}} Naratriptan is available OTC in Germany and Brazil.

;Notes

{{reflist|35em}}

;Sources

• {{Cite journal

| title = The triptans - A summary

| author1=Tepper S. J. |author2=Rapoport A. M. | journal = CNS Drugs

| volume = 12

| issue =5

| pages = 403–417

| year = 1999

| doi = 10.2165/00023210-199912050-00007

| s2cid=72149615 }}

{{Triptans}}

{{Tryptamines}}

Category:5-HT1D agonists