Continuing Education Activity

Zolmitriptan is a medication used in the management and treatment of acute migraine. It is in the triptan class of drugs. This activity describes the indications, action, and contraindications for zolmitriptan as a valuable agent in the treatment of acute migraine. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the treatment of patients with migraine and related conditions.


  • Identify the mechanism of action and administration of zolmitriptan.
  • Describe the adverse effects and contraindications of zolmitriptan.
  • Review the common adverse effects of zolmitriptan and select appropriate monitoring parameters.
  • Outline some interprofessional team strategies for improving care coordination and communication to advance zolmitriptan and improve outcomes.


U.S. Food and Drug Administration (FDA)-approved indications [1]

  • Oral zolmitriptan
    • Acute treatment of migraine with aura in adults 
    • Acute treatment of migraine without aura in adults 
  • Nasal spray zolmitriptan
    • Acute migraine treatment in pediatric patients ages 12 and older and adults 

Off-label Uses [2]

  • Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology
  • Acute treatment of menstrual migraine

Zolmitriptan is efficacious in the acute treatment of migraine headache pain and associated symptoms of nausea, vomiting, phonophobia, and photophobia.[1][3] Zolmitriptan was significantly more effective at helping patients achieve pain-free status at 2 hours, 3 hours, and 4 hours post-treatment compared to placebo.[4][5][6] In a multicenter, randomized placebo-controlled trial, 5.0 mg zolmitriptan nasal spray had a 2-hour headache response rate of 70.3% which was significantly higher than the placebo group.[3]

Mechanism of Action

Zolmitriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist with a weak affinity for the 5-HT 1A receptor subtypes.[7] Its action on 5-HT 1B/1D receptors causes vasoconstriction in intracranial blood vessels; as well it can inhibit the release of pro-inflammatory neuropeptides from trigeminal perivascular nerve endings.[8] It crosses the blood-brain-barrier as evidenced by the presence of radioactive [3H]-zolmitriptan labels within the cells of the trigeminal nucleus caudalis and nucleus tractus solitaries.[9]


Zolmitriptan has a rapid onset of action and has been detected in the brain as early as within 5 minutes of intranasal administration.[10] On average, zolmitriptan has an oral bioavailability of 40%, a mean volume of distribution of 8.3 L/kg after oral administration, and 2.4L/kg after intravenous administration.[11][12]

Zolmitriptan is metabolized into three major metabolites by the human hepatic cytochrome P450 enzymes—primarily CYP1A2. Two-thirds of the parent compound breaks down into the active metabolite N-desmethyl-zolmitriptan (183C91), while the remaining one-third separates into the other two inactive metabolites: zolmitriptan N-oxide and an indole acetic acid derivative. It has an elimination half-life of about three hours before it undergoes renal elimination; its clearance is greater than the glomerular filtration rate suggesting that there is some renal tubular secretion of the compound.[10][11][13][14]


Zolmitriptan is available as an oral tablet, orally-disintegrating tablet, and nasal spray—all of which are available in 2.5mg or 5mg doses. The maximum recommended daily dose is 10mg for adults and pediatric patients ages 12 to 17.[15] This medicine can be taken with food and/or water or while in a fasting state without altering its clinical effect.[11] This is beneficial for those whose migraines can strike at any time day or night.

Hepatic Impairment

Zolmitriptan is metabolized by hepatic enzymes, and consequently, people with severe hepatic impairment should have a reduced daily intake because it has been demonstrated that this condition can alter the pharmacokinetics of zolmitriptan such as decreased metabolism.[11] As a result of decreased metabolism, there was a prolonged half-life and elevated plasma levels of zolmitriptan that could cause more peripheral vasoconstrictive effects such as elevated blood pressure.[16]

Adverse Effects

The most common adverse effect in healthy individuals is dysgeusia, particularly with the nasal spray, which is most likely due to the nature of the drug's administration. Other minor adverse events that have been documented with intranasal zolmitriptan use are nasal passage irritation, dizziness, throat irritation, and fatigue. Additionally, Phase 1 trials of the Real Life Intranasal Zolmitriptan Exposure (REALIZE) study demonstrated that side effects did not cause participants to discontinue the medication.[17] The Treatment of Acute Migraine Headache in Adolescents (TEENZ) was a double-blind, randomized control trial composed of over 700 pediatric participants, and its results further substantiate the trend in adverse events reported in the REALIZE trial with dysgeusia being the most frequent adverse event.[4]

As for cardiovascular side effects, zolmitriptan can increase systolic blood pressure in the elderly and increase diastolic blood pressure in both the elderly and young people. Additionally, there is the side effect of a dose-related increase in sedation.[13] There is a risk of headaches caused by medication withdrawal or medication overuse.[18]

Zolmitriptan has a weak affinity for 5-HT 1A receptors; these receptors have implications in the development of serotonin syndrome.[7] The constellation of autonomic and neuromuscular symptoms that comprise the Serotonin syndrome can occur in response to activation of central and peripheral 5-hydroxytryptamine receptors—mainly the 5-HT 1A and 2A receptor subtypes.[7]

There have been case reports of other rare adverse events associated with zolmitriptan use. There was a case of liver injury associated with zolmitriptan and rizatriptan use and a case report of transient myopia and increased intraocular pressures in a woman who had been using increasing amounts of zolmitriptan over a year.[19][20]

Drug-Drug Interactions

Cimetidine, which is a CYP1A2 inhibitor, increases the levels of zolmitriptan and 183C91 in the systemic circulation, therefore increasing the body's exposure to its vasoconstrictive action; this indicates the need to reduce the total daily dose of zolmitriptan in those taking such inhibitors.[14]

Zolmitriptan did not demonstrate significant interactions with acetaminophen or metoclopramide, which are often part of a regimen to treat headache symptoms.[21] Oral contraceptive use in female study participants did not produce a significant impact on the efficacy or tolerability of the medicine.[11]


Zolmitriptan is contraindicated in patients with cerebrovascular or cardiovascular disease because 5-HT 1B receptors are present in coronary arteries. Such conditions include, but are not limited to, coronary artery disease, stroke, and peripheral vascular disease.[22]

It is also contraindicated in hemiplegic migraine.[22]

Special Populations – Pregnant and breastfeeding mothers

While there are safer alternatives for the treatment of acute migraine in pregnancy, triptans have been viable options in some instances.[23] There is less available data on the safety of zolmitriptan use in human pregnancy, but it may not be unreasonable to assume its effect is likely similar to its fellow 5-HT 1B/1D receptor agonist, sumatriptan. Sumatriptan use in the first trimester of pregnancy was not significantly associated with congenital malformations compared to the general population.[24] On the other hand, Sumatriptan use in the second and third trimesters of pregnancy has correlated with increased odds of an atonic uterus and blood loss during labor.[23] Trace amounts of triptans have appeared in breast milk, but the levels are not high enough to exert a clinical effect in nursing infants.[18]


Blood pressure requires monitoring in all patients taking zolmitriptan because of its vasoconstrictive properties—especially those with hepatic impairment.[16] Some signs that can indicate elevated blood pressure are headaches and palpitations.


In pediatric cases, zolmitriptan toxicity did not result in life-threatening complications; common signs of toxicity were tachycardia, dyspnea, and vomiting.[25] In adults, overdoses in zolmitriptan have resulted in hypertension, tachycardia, and drowsiness.[26] There have been two reported cases of liver toxicity with zolmitriptan.[27] There is the risk of medication overuse headache, which is avoidable when the patients receive education on the proper administration of their medications.[18]

Enhancing Healthcare Team Outcomes

Headache is a widespread neurologic complaint. Health care providers can create an efficacious treatment plan when they partner with their patients to elucidate the qualities of that headache experience better. Triptans have the highest efficacy when taken at the beginning of the headache phase, not the prodrome. Patients that received education on their use of their medication reported a greater understanding of the circumstances for treating their headache pain and contraindications.[28]

Furthermore, providers must consider the ability of patients to afford the medication due to variations in medication coverage by health insurers. Zolmitriptan is the generic formulation of two branded products. Generics are more likely to be covered by both commercial and government health insurers, while brand triptans are more likely to be covered by commercial insurers. Insurance plans can place limits on the type of formulation being used and/or require the meeting of step therapy criteria before covering individual formulations.[29]


In 2006, the FDA issued an alert about serotonin syndrome associated with the concomitant use of triptan drugs with SSRIs or SNRIs; however, many have been skeptical of the actual prevalence of this adverse event [30]. For instance, JAMA Neurology published a secondary data analysis of electronic health record data that evaluated outcomes of patients who had been co-prescribed triptans with SSRIs or SNRIs. Of 19,017 patients, 17 were suspected cases, and two were definite cases that met diagnostic criteria.[30] Also, a review of the 29 cases used by the FDA as the basis for the alert, found that only seven cases met Sternbach criteria, but no instances met the Hunter criteria. Though precipitation of serotonin syndrome appears rare, given the severity of the condition, it is important to be aware of the possibility.[31]

The American Headache Society and the American Academy of Neurology provide evidence-based guidelines on headache treatment that health care providers can use to guide their decisions on treatment. Though the FDA may not currently approve zolmitriptan for the treatment of cluster headaches, the American Academy of Neurology has a Level A recommendation on the use of both oral and intranasal zolmitriptan for the acute treatment of cluster headaches.

Article Details

Article Author

Jasmine Abram

Article Editor:

Priti Patel


9/17/2020 6:07:35 PM

PubMed Link:




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