Continuing Education Activity

Triptans are a class of medications used in the treatment of migraine headaches. Triptans act as antimigraine agents by selectively binding to the serotonin receptors 5-HT1B and 5-HT1D. Triptan binding to the vascular 5-HT1B receptors leads to vasoconstriction of the cranial arteries, which painfully dilate during a migraine attack. This activity reviews the indications, action, and contraindications for triptans as valuable agents in migraine therapy and also highlights the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for the management team members of patients with migraine.

Objectives:

• Identify the mechanism of action of triptans.
• Describe the potential adverse effects of triptans.
• Review the appropriate monitoring for patients on triptan therapy.
• Summarize interprofessional team strategies for improving care coordination and communication to advance migraine therapy and improve outcomes.

Indications

Triptans are FDA-approved and the first-line agents for treating acute migraine episodes with or without aura.[1][2] There are seven triptans available in the United States in a variety of dosage forms: sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan.[3] In the subcutaneous formulation, sumatriptan is also approved to treat cluster headaches.[1] Almotriptan is the only triptan with an FDA indication for use in adolescents to treat migraines lasting at least 4 hours.[4] Zolmitriptan nasal spray is FDA approved for children 12 years or older; the use of other triptans for children is off-label.[5][4] Frovatriptan, naratriptan, and oral zolmitriptan have an off-label indication for preventing menstrual migraine.[6][7]

Mechanism of Action

Three distinct mechanisms of action of triptans have been described in migraine:

• Vascular mechanism: Vasoconstriction of painfully distended intracranial extracerebral arteries by a direct effect on vascular smooth muscle 
• Trigeminovascular mechanism: Inhibition of nociceptive neurotransmission within the trigeminal nerve in the brainstem and upper spinal cord
• Central mechanism: Inhibition of the release of vasoactive neuropeptides by trigeminal nerve innervating the intracranial vessels and dura mater.[6]

Triptans act as antimigraine agents by selectively binding to the serotonin receptors 5-HT1B and 5-HT1D. Triptan binding to the vascular 5-HT1B receptors leads to vasoconstriction of the cranial arteries, which painfully dilate during a migraine attack. When triptans bind to the neurogenic and central 5-HT1D receptors, they prevent the release of vasoactive neuropeptides by inhibiting trigeminal nerves' activation and blocking the transmission of pain signals to the brain.[8]

Salient Pharmacokinetics of Triptans

The pharmacokinetics of triptans vary widely between individuals and could be explained by the effect of P-glycoprotein efflux transporters, triptan-metabolizing enzymes (CYP450 and MAO), and drug bioavailability.[9]

Sumatriptan: Sumatriptan is available as oral tablets, nasal spray, and subcutaneous injections. Orally administered sumatriptan has a low bioavailability of around 15%, primarily due to pre-systemic metabolism and partly due to incomplete absorption. Despite nasal sprays being faster than oral formulation, their effect is more temporary. Therefore, nasal sprays are an intermediate option for oral triptans and subcutaneous sumatriptan. In vitro studies on human microsomes suggest that sumatriptan is metabolized by the monoamine oxidase (MAO) enzyme, thus prone to serotonin syndrome when administered with other serotonergic drugs. The elimination half-life (t1/2) of sumatriptan is approximately 2.5 hours.

Rizatriptan: Rizatriptan has the fastest onset of action among orally administered triptans (approximately 30 minutes) but with short elimination half-live (2 to 2.5 hours). For this reason, it has the highest recurrence rate at 24 hours (superior to placebo). Hence, rizatriptan seems the better option when attacks are severe with rapid onset but short-lasting. The primary route of rizatriptan metabolism is by MAO-A, which forms the indole acetic acid metabolite. The metabolite is not active at the 5-HT1B/1D receptor. Approximately 14% of an oral rizatriptan dose is excreted in urine as unchanged, while 51% is excreted as indole acetic acid metabolite, proving substantial first-pass metabolism. 

Frovatriptan: The onset of action is delayed, but it has the longest half-life (approximately 26 hours) and the lower recurrence rate at 24 hours (7 to 25%). Frovatriptan is preferred in long-lasting attacks of migraine. In addition, frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes of cytochrome P450. Hence,  it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms. Renal clearance accounted for about 40% and 45% of total clearance in males and females.[10]

Almotriptan: The absolute bioavailability of almotriptan tablets is about 70%, with peak plasma levels occurring 1 to 3 hours post-administration. Food does not affect pharmacokinetics. Almotriptan is the only triptan with an FDA indication for use in adolescents. Almotriptan gets metabolized through two major and one minor pathway. Major routes of metabolism are Monoamine oxidase (MAO)-mediated oxidative deamination (around 27% of the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose), and the minor route of metabolism are flavin monooxygenase. 

Zolmitriptan: Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. This metabolite has 2 to 6 times the potency of the parent compound at 5HT1B/1D receptors; the metabolite contributes a substantial portion of the overall effect. Zolmitriptan is also available as a nasal spray formulation. 

Naratriptan: Naratriptan is better in moderate but long-lasting attacks.

Eletriptan: Eletriptan is preferred in severe, long-lasting attacks because of its long half-life.

Administration

Patients should be instructed to take triptans at the first onset of the headache phase of a migraine attack; they are not effective if taken during the aura phase before the start of the headache.[11] The patient may repeat the dose after 2 hours if needed, but no more than twice a week. "Triptan-overuse headache" is a rebound headache that can occur using triptans for more than ten days per month.[12]

Some of the most commonly prescribed triptan agents are:

• Sumatriptan
• Zolmitriptan
• Frovatriptan
• Eletriptan
• Naratriptan

The above is not an exhaustive list. Triptans are available in multiple dosage forms, such as oral tablets, orally disintegrating tablets, nasal sprays, and subcutaneous injections.[3] Besides oral tablets, formulations make a good alternative for patients with difficulty swallowing. The orally disintegrating tablets are a good option if the patient is not vomiting.[13] The nasal spray and subcutaneous injection dosage forms are options for patients who experience nausea and possibly vomiting before the orally administered medication is absorbed.[14]

The choice of agent should be an individualized therapy. If a patient has no response to one of the triptans after three trials, increasing the dose, switching to a different dosage form of the same agent, or another triptan might work.[12] A nonsteroidal anti-inflammatory drug (NSAID) with a triptan targets a different mechanism and may be more effective than a triptan alone. Sumatriptan is available as an oral tablet combined with the NSAID naproxen.[15]

During a migraine attack, patients may experience a decreased gastric motility, causing a delay in gastric emptying; this may affect the rate and extent of triptan absorption when administered orally. Metoclopramide, an antiemetic agent, exhibits prokinetic activity and is FDA-approved to treat gastric stasis. Metoclopramide can improve the inconsistent absorption of orally administered triptans when taken concomitantly. However, metoclopramide has a boxed warning because of the risk of adverse effects like extrapyramidal symptoms and hyperprolactinemia. Alternatively, an injectable or a nasal triptan formulation is an option, as these formulations bypass the gastrointestinal tract.[16]

A post hoc analysis of five randomized placebo-controlled, double-blind clinical trials compared the efficacy of triptans at relieving nausea associated with migraines two hours after therapy.[17] Patients received rizatriptan 10 mg, sumatriptan (25 mg, 50 mg, or 100 mg), naratriptan 2.5 mg, or zolmitriptan 2.5 mg. Rizatriptan showed a statistically significant improvement in nausea versus sumatriptan and naratriptan. Rizatriptan and zolmitriptan provided similar nausea relief.

To prevent menstrual migraine, patients may initiate frovatriptan or naratriptan two days before menses begin and continue for 5 to 7 days.[18]

Propranolol, which has a role in migraine prophylaxis, increases rizatriptan serum concentrations. Rizatriptan dose should not exceed 5 mg for patients using propranolol.[19]

Adverse Effects

Triptans may cause nausea, dizziness, and coronary vasoconstriction.[20] The most common side effects associated with triptans, such as paresthesia, flushing, tingling, neck pain, and chest tightness, are known as "triptan sensations." These side effects are most pronounced with subcutaneous triptan injections and may be less severe with other formulations. Cardiovascular adverse effects like arrhythmias, myocardial infarctions, and strokes are rare, occurring in less than 1 % of patients on triptans.[3] The severity of adverse effects may differ among triptans.[21]

A post hoc analysis of five randomized placebo-controlled, double-blind clinical trials compared the rate of nausea associated with triptans.[17] The rate of nausea was comparable with rizatriptan 10 mg, sumatriptan (25 mg, 50 mg, or 100 mg), and naratriptan 2.5 mg.

Naratriptan, eletriptan, and frovatriptan are metabolized by cytochrome P-450; therefore, they may have drug-drug interaction with oral contraceptives.

Contraindications

Triptans can cause vasoconstriction of the coronary and limb arteries; therefore, they are contraindicated in patients with a history of myocardial infarction, coronary artery disease, cerebrovascular accidents, hemiplegic migraines, uncontrolled hypertension, or peripheral vascular disease.[2] Other contraindications include severe hepatic or renal failure and the age of 65 years or more. All triptans, except for sumatriptan, are contraindicated in pregnancy and breastfeeding.[3] Based on data from pregnancy registries, sumatriptan is safe during pregnancy and breastfeeding.[22]

Triptans should not be administered with ergot alkaloids or monoamine oxidase inhibitors.[6]

There is not enough evidence that triptans increase the risk of serotonin syndrome either as monotherapy or in patients taking a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin-norepinephrine reuptake inhibitor (SNRI).[23]

Monitoring

Clinicians should monitor for triptan-associated cardiovascular adverse effects in patients taking propranolol. Propranolol is often used for migraine prevention and decreases the metabolism of some triptans like almotriptan and rizatriptan by inhibiting their metabolism via the monoamine oxidase A (MAO-A) pathway. For these patients, lowering the triptan dose or using a triptan that is not metabolized by the MAO-A pathway or other abortive migraine therapy is preferred.[24][19]

Other monitoring parameters include the degree of response to triptan therapy, migraine recurrence, and consistent response to the same triptan. Also, patients review monitoring for nausea, vomiting, sensitivity to light and/or noise, which may occur during a migraine attack, and ultimately, improved ability to function.[6]

Toxicity

Analysis of triptan overdose cases from the National Poison Data System showed a low risk of death. Symptoms of triptan overdose include increased blood pressure, tachycardia, and drowsiness.[25]

Enhancing Healthcare Team Outcomes

A migraine is a common headache that can last for up to 72 hours if left untreated or inappropriately treated. Nausea and/or vomiting may occur along with a migraine attack, thus affecting the patient's ability to function as usual.[26] 

Patient education is essential for successful migraine management plans.[6] It is essential to educate patients about migraine triggers, including stress, skipped meals, disrupted sleep, alcohol, certain types of foods, and menstruation. Keeping a migraine diary may help identify patient-specific triggers. Setting realistic expectations and goals of therapy with the patient is essential, especially since migraine triggers may not always be avoidable.[27]

Some pharmacologic and non-pharmacologic therapies are available for migraine prophylaxis.[27] Prophylactic therapy reduces migraine frequency and severity. Patients should use abortive therapy when a migraine attack occurs. The indication for triptans is abortive migraine therapy.[6]

If the response to triptan therapy does not achieve the desired relief of symptoms, the healthcare team should verify that the patient is taking the triptan as soon as the headache pain begins.[6] Other causes of triptan failure could be due to malabsorption or other patient-related factors. A trial of another triptan may be beneficial in these patients.[28]

Even though the risk of serotonin syndrome is low in patients taking triptans alone or combined with an SSRI or SNRI, health care providers should monitor for signs and symptoms of serotonin syndrome and are encouraged to report such cases to MedWatch.[23]

The interprofessional healthcare team should provide formal counseling to patients being prescribed triptans. Patients should take the triptan as soon as the migraine starts for the best results.[29] The healthcare team should identify patients with headaches due to triptan overuse, defined as taking triptans on ten or more days per month. These patients should receive education to decrease the use of triptans for abortive therapy; they will likely benefit from prophylactic migraine therapy.[30]

Finally, a patient-centered approach is essential in migraine management for prophylactic and abortive treatment. Treatment requires individualization, and the response to treatment is reassessed for the need for change in therapy.[31]

Appropriate use of triptans to treat migraines requires the efforts of an interprofessional healthcare team, including clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all contributing from their specialized areas to enhance patient outcomes while limiting adverse events. [Level 5]