Pharmacology

A brief account of the pharmacology of sumatriptan is as follows:

Pharmacodynamics. This is a selective agonist of serotonin 5-HT1-like receptors including 5-HT1B/1D subtypes. The drug has no significant activity at 5-HT2 or 5-HT3 receptors or at dopamine, gamma-aminobutyric acid, or adrenoreceptors. Sumatriptan causes vasoconstriction of large cerebral blood vessels, particularly when they are dilated during an acute migraine attack. It can also cause constriction of peripheral and coronary arteries. It blocks neurogenic protein extravasation within the trigeminovascular system and attenuates increased calcitonin gene-related peptide levels in patients with migraine. A randomized, double-blind, placebo-controlled, crossover study in healthy adults showed that forehead dermal blood flow responses to capsaicin, most likely induced by the release of calcitonin gene-related peptide, were attenuated by sumatriptan (11). This model is a biomarker of trigeminovascular effects of antimigraine drugs, including sumatriptan.

A possible mechanism of beneficial effect of sumatriptan in migraine is based on the role of free radicals in migraine, as sumatriptan has direct scavenging activity on free radicals and nitric oxide. Sumatriptan action in migraine may be exerted through presynaptic 5HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. There is an increase in the rate of brain serotonin synthesis during migraine attacks, and triptans exert a negative feedback regulation of brain serotonin synthesis along with modulation of pain pathways. The effect of sumatriptan in migraine depends on the integrity of the blood-brain barrier. Cortical-spreading depression during migraine aura disrupts sodium-hydrogen exchanger type 1 (NHE1), an antiporter, which plays a role in blood-brain barrier integrity and homeostasis of intracellular pH in the brain (17). Although this disruption increases the uptake of sumatriptan into the brain, there may be variations in clinical response. The protective role of NHE1 in the central nervous system suggests that normalization of pH homeostasis by targeting NHE1 function or surface expression could be a unique therapeutic approach to enhance the efficacy of sumatriptan.

Pharmacokinetics. Important features include the following:

Sumatriptan fast disintegrating/rapid release tablet, which is bioequivalent to conventional tablets, has faster absorption and more rapid onset of effect.

Sumatriptan usually does not cross the blood-brain barrier to produce effects on the central nervous system. Animal studies indicate that sumatriptan can cross the blood-brain barrier, and some adverse effects of sumatriptan on the brain may be due to impairment of blood-brain barrier during migraine attack (29).

Therapeutic drug monitoring. A simple and sensitive method of detection coupling ultra-performance liquid chromatography with tandem mass spectrometry has been developed and validated in phase 1 studies to analyze sumatriptan levels in human plasma (24).

Formulations and methods of administration. Sumatriptan is available as oral, intranasal, and subcutaneous injection. An autoinjector has also been developed to fulfill the clinical need for an easy-to-use and rapid-to-administer system that does not require any assembly at the onset of an attack and is preferred by the patients as shown in an open phase 3 trial (14). A needle-free sumatriptan injection, Sumavel® DosePro™ for migraine and cluster headaches, has been approved and available since 2009 (07). Absorption of sumatriptan delivered by self-dissolving microneedles is like that observed after subcutaneous injection and is associated with high bioavailability (approximately 90%), which is much higher than that produced by oral administration (31).

Transdermal delivery of sumatriptan by an iontophoresis patch, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue, has been tested in a phase 1 study (25). A linear relationship was observed between total applied current and sumatriptan delivery to reach therapeutic blood levels. Pharmacokinetic studies have shown that iontophoretic delivery of sumatriptan achieves detectable plasma concentrations 15 minutes after activation with a maximum mean serum concentration of 22 ng/ml (30). Transdermal delivery has several advantages over current formulations, including avoidance of the gastrointestinal tract, controlled and sustained delivery, and convenient administration (22). In 2013, the United States Food and Drug Administration approved sumatriptan iontophoretic transdermal system (Zecuity^®) for the acute treatment of migraine with or without aura in adults. Zecuity^® is a single-use, battery-powered patch that actively delivers sumatriptan through the skin and provides relief of both migraine headache pain and migraine-related nausea. AVP-825 (ONZETRA^® Xsail^®), a breath-powered delivery system for sumatriptan dry powder, has been approved by the Food and Drug Administration for the acute treatment of migraine attacks with or without aura in adults. A single dose of AVP-825 (22 mg) delivers 15 to 16 mg sumatriptan and produces significantly lower exposure than oral or injectable formulations, which may translate into a better safety/tolerability profile (26). It has been shown to have a rapid onset of action and, unlike the traditional nasal sprays, does not drip down into the throat (28). An in situ gel of sumatriptan-loaded nano-transferosomes has been developed as a promising noninvasive drug delivery system for treating migraine by enhancing the bioavailability and sustaining the drug release (20).

Clinical trials

Several randomized, placebo-controlled, double-blind, parallel-group design clinical trials have been conducted with sumatriptan in a total of more than 15,000 patients with moderate to severe migraine using subcutaneous and oral preparations. Some trials have included patients with cluster headaches. Efficacy of intranasal sumatriptan has also been tested in placebo-controlled trials. Results of these trials show:

Indications

Sumatriptan is indicated for use in the following:

Off-label uses

There are few uses of sumatriptan for headaches other than for migraine and cluster headaches. It has been reported to be effective for the treatment of the following types of headaches:

Contraindications

Contraindications of sumatriptan use include the following:

Goals and duration of treatment

Sumatriptan is to be used for termination of acute attacks of migraine when the diagnosis has been clearly established. Recurrence of headache within 24 hours after an initial successful response occurs in 30% to 40% of sumatriptan-treated patients. No evidence exists in controlled trials that a repeat injection produces a benefit to patients who fail to obtain relief after the first injection. A maximum of 2 injections may be given during a 24-hour period.

Dosing

Maximum dose for subcutaneous injection of sumatriptan is 6 mg. However, sumatriptan in doses less than 6 mg can be effective in the acute treatment of cluster headache attacks.

Oral dose of sumatriptan succinate is a single 25-mg tablet, but a maximum of 100 mg may be taken. If no relief is experienced, the dose can be repeated but should not exceed 300 mg in 24 hours.

Special considerations

Anesthesia. No special precautions.

Pregnancy. Sumatriptan is lethal to embryos in experimental animals but teratogenicity has not been demonstrated in humans. The risk of all major birth defects following first-trimester exposure to sumatriptan is reported to be 4.6% (02). Current information is not sufficient to rule out the risk for birth defects with use of sumatriptan, and caution should be exercised in making a recommendation for the use of sumatriptan during pregnancy. Sumatriptan is secreted in human milk, and caution should be exercised when administering sumatriptan to nursing mothers.

Pediatric. Safety in children has not been established.

Geriatric. No information is known about the safety in patients over the age of 65 years because they were excluded from clinical trials.

Interactions

No evidence exists to show that sumatriptan interacts with drugs usually used for prophylaxis of migraine. No interaction is known with naproxen, a nonsteroidal anti-inflammatory drug used for the relief of migraine. Interactions are reported with the following drugs:

The combination of nasally administered sumatriptan and butorphanol, an analgesic used for migraine, is safe. However, if butorphanol nasal spray is administered more than half an hour after sumatriptan nasal spray, the analgesic effect of butorphanol may be diminished due to reduced nasal absorption resulting from transient vasoconstriction of nasal blood vessels by sumatriptan.

Adverse effects

The safety profile of sumatriptan is good with mostly minor adverse reactions. A retrospective study has shown that in well-selected patients with chronic drug-resistant cluster headaches, long-term daily subcutaneous sumatriptan use did not induce serious adverse effects (16). The tolerability profile usually does not change in patients receiving the drug intermittently over a long period. Some of the reported events include the following:

Some patients have reported that they experienced burns or scars on the skin where the transdermal sumatriptan patch (Zecuity^®) was worn, and the United States Food and Drug Administration is investigating. Patients who complain of moderate to severe pain at the application site should be advised to remove the patch immediately and consider switching to a different formulation of sumatriptan or an alternative migraine medicine.

The management of adverse effects is according to the event. The important factors are the prevention of adverse effects and their differentiation from complications of migraine.