The Pathophysiological and Pharmacological Basis of Current Drug Treatment of Migraine Headache

Doodipala Samba Reddy


Expert Rev Clin Pharmacol. 2013;6(3):271-288. 

In This Article

Triptans: Selective Serotonin 5-HT1-Receptor Agonists

5-HT is a key mediator in the pathogenesis of migraine. 5-HT1-receptor agonists, commonly known as the 'triptans', are the mainstay for acute treatment of migraine headaches. The clinical introduction of sumatriptan in 1992, followed by several other drugs such as zolmitriptan, naratriptan and rizatriptan, has led to major progress in migraine research.[76–78] Various triptans have comparable efficacy in providing relief of migraine headaches.[76,79–86] Triptans are indole derivatives, with substituents on the 3 and 5 positions (Figure 4). Triptan formulations are listed in Table 2.

Figure 4.

Triptans. Triptan antimigraine drugs are indole derivatives with substituents on the 3 and 5 positions.

Sumatriptan (Imitrex®, GlaxoSmithKline) was the first triptan marketed in the USA (1992). It is a selective 5-HT1B and 5-HT1D agonist with a short duration of action. Sumatriptan is highly effective for the treatment of acute migraine.[76] It is available for subcutaneous (sc.) self-injection, as a nasal spray, and for oral administration. Sumatriptan produces relief within 2 h in 60–80% of patients with moderate-to-severe migraine. It is also effective when given at any point during an attack. Sumatriptan is also indicated for acute treatment of cluster-headache episodes. Sumatriptan injections should not be given intravenously because of its potential to cause coronary vasospasm. Sumatriptan suppositories are available in some European countries, but they are not available in the USA.

There are several selective serotonin 5-HT1B/1D-receptor agonists (triptans) approved by the FDA for the acute treatment of migraine. They are similar in efficacy to sumatriptan but differ in pharmacokinetic properties.[76,79–86] In general, triptans have an onset of action ranging from 10 min to 2 h, with an elimination half-life of 2–6 h or longer. Naratriptan has a high oral bioavailability and longer half-life (6 h). Rizatriptan also has high oral bioavailability and early onset of action. Zolmitriptan has early onset of action, higher oral bioavailability and is available as a nasal spray. Almotriptan is well-absorbed and similar to oral sumatriptan. Frovatriptan is less effective than sumatriptan, but has a longer half-life (26 h). It has the longest half-life and a short time to maximal concentration (2–3 h). It has few adverse side effects and limited drug–drug interactions. Eletriptan is the newest triptan with a high efficacy and sustained effect. Eletriptan is metabolized by CYP3A4, therefore must be used in caution with known CYP3A4 inhibitors (such as ketoconazole and clarithromycin).

Pharmacological Effects

The pharmacological effects of triptans are selective at 5-HT1 receptors, suggesting the role of 5-HT1 receptors in the acute relief of migraine attacks. Triptans are more selective agents than ergot alkaloids in that they interact potently with 5-HT1B and 5-HT1D receptors. The selective actions have led to insights into the pathophysiology of migraine.


Clinically effective doses of the triptans correlate well with their affinities for both 5-HT1B and 5-HT1D receptors, which are most likely involved in the mechanism of action of acute antimigraine drugs. 5-HT1B and 5-HT1D receptors are implicated in constriction of intracranial blood vessels. Both 5-HT1B and 5-HT1D receptors serve as presynaptic autoreceptors, modulating neurotransmitter release from neuronal terminals.


Triptans are highly effective for short-term treatment of acute migraine attacks. They are effective in MA or MO, but are not intended for use in prophylaxis of migraine. They also decrease symptoms of nausea and vomiting – a highly desirable feature in migraine therapy. Treatment with triptans should begin as soon as possible after onset of a migraine attack. Frovatriptan is used in short-term prophylaxis for menstrually-associated migraine (see 'Menstrual migraine' section).

Side Effects

A burning sensation at the injection site is common with sc. sumatriptan. Serious but rare cardiac events, including coronary artery vasospasm, transient myocardial ischemia, atrial and ventricular arrhythmias and myocardial infarction have been reported with triptans. Triptans can cause tingling, asthenia, fatigue, flushing, feeling of pressure, tightness or pain in the chest, neck and jaw, drowsiness, dizziness and sweating.


Triptans are contraindicated in patients with cardiovascular diseases and hypertension. Sumatriptan and others are contraindicated in patients taking monoamine oxidase (MAO) inhibitors or within 2 weeks of stopping one. They are deemed pregnancy category C (risk cannot be ruled out).

  • Sumatriptan should not be given to patients with a history, symptoms or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients with other significant underlying cardiovascular diseases should not receive sumatriptan.

  • It should not be given to patients with uncontrolled hypertension.

  • Concurrent administration of MAO-A inhibitors or use within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated. However, the MAO interaction is not clinically significant for sc. sumatriptan and is clinically minimal for oral sumatriptan and almotriptan.

Drug Interactions

A triptan should not be used within 24 h after another triptan or an ergotamine-containing drug is used because vasoconstriction could be additive. Concomitant treatment with triptans with serotonin–norepinephrine reuptake inhibitors (SNRIs; venlafaxine) can cause serious serotonin syndrome.

In July 2006, the FDA issued an alert on "possible life-threatening serotonin syndrome when triptans are used with SSRI or SNRI medicines". A life-threatening condition named 'serotonin syndrome' may occur when triptans, such as sumatriptan, and medicines used to treat depression and mood disorders, called selective serotonin reuptake inhibitors (SSRIs) or SNRIs, are used together. Signs and symptoms of serotonin syndrome include the following: restlessness, diarrhea, hallucinations, coma, loss of coordination, nausea, fast heartbeat, vomiting, increased body temperature, fast changes in blood pressure and overactive reflexes.

The blanket FDA warning about serotonin syndrome has been discussed in the American Headache Society position paper.[87] It is concluded that there is no evidence that this is any more frequent than with SSRIs alone. Therefore, many migraine specialists view that the risk of serotonin syndrome is minimal.[87]


Triptans are available in oral, nasal and injectable formulations (Table 2). Pharmacokinetic features vary with individual triptans. If a triptan is ineffective, a different one should be tried before switching to a different class of drugs. Recent data suggest that a combination of a triptan and an NSAID has increased efficacy.

New Formulations

Treximet, a new combination treatment approved in 2010, contains sumatriptan succinate (a triptan) and naproxen sodium (a NSAID). Each tablet contains 119 mg sumatriptan succinate and 500 mg naproxen sodium. Such a combination is suggested to produce faster and better control of acute migraine. New parenteral systems are developed for delivery of triptans. A needle-free device (Sumavel® DosePro®, Zogenix, CA, USA) uses a small amount of compressed nitrogen gas under high pressure to produce a small hole in the skin for sc. delivery of sumatriptan.[77,78] The formulation, which was introduced in 2010, has a pharmacokinetic profile similar to that of a sc. injection.