General Neurology
Sciatic neuropathy
Jun. 26, 2023
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ISSN: 2831-9125
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Use of sumatriptan evolved due to the role of serotonin (5-hydroxytryptamine, 5-HT) in the pathophysiology of migraine. Vasodilatation within the cerebral circulation was recognized to contribute to the severity of headache. Intravenous serotonin was shown to alleviate migraine headache, although side effects were considerable (12). Sumatriptan resembles serotonin in its structure and, as a 5-HT1 agonist, was developed to stimulate the 5-HT receptors on the blood vessels, reduce vasodilatation, and, thus, reduce headache. Events leading to the development of sumatriptan have been reviewed elsewhere (23). Clinical trials with sumatriptan started around 1989, and the product is now used worldwide. Six other triptan products have received approval from the United States Food and Drug Administration since the 1990s, but sumatriptan remains the most widely prescribed product.
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:
• The bioavailability after subcutaneous administration is 96%. | |
• Following subcutaneous injection, maximum plasma concentration is reached between 17 to 23 hours. | |
• Plasma protein binding is low (14% to 21%). | |
• After absorption, the drug is extensively metabolized to an inactive indoleacetic acid analog that is excreted mainly in the urine. |
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).
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:
• Relief of headache occurred in 50% to 69% of the patients treated with oral sumatriptan compared to relief in 10% to 31% of patients who took placebo. | ||
• Intranasal sumatriptan produced relief in 62% to 78% of patients as compared to relief in 29% to 42% of those who received placebo. Sumatriptan nasal spray is superior to dihydroergotamine nasal spray in the relief of pain and nausea associated with acute migraine headache. | ||
• Rectal sumatriptan was also more effective than placebo in relieving acute migraine. | ||
• Cluster headaches were also relieved in about 75% of the patients treated with sumatriptan. | ||
• Sumatriptan was found to be superior to placebo in reducing productivity loss due to migraine at work. | ||
• Treatment of single-attack migraine at the first sign of pain with sumatriptan, 50- and 100-mg tablets, provides superior pain-free relief at 2 and 4 hours after treatment compared with placebo. | ||
• Fast-disintegrating or rapid-release formulation of sumatriptan tablets was effective for the acute treatment of moderate to severe migraine pain, was generally well tolerated, and achieved an onset of pain relief in as little as 20 minutes. | ||
• Subcutaneous sumatriptan was effective for the treatment of acute migraine attacks and was generally well tolerated. | ||
• Combined sumatriptan/naproxen sodium is more effective in the acute treatment of migraine than sumatriptan alone, naproxen sodium alone, or placebo. | ||
• Patients with migraine and cutaneous allodynia who historically failed to respond to oral triptan medications, 6 mg sumatriptan given subcutaneously proved to be effective. | ||
• Clinical trials have shown that a combination tablet of sumatriptan 85 mg with naproxen sodium 500 mg is more effective for the acute treatment of migraine than either of its components (03). This combination is approved in the United States for treatment of migraine. | ||
• Sumatriptan, administered intranasally by a bi-directional powder delivery device, was found to be effective and safe in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of treatment of a moderate or severe single migraine attack (05). | ||
• A randomized, double-blind, phase 3 study of the NP101, a transdermal patch for delivery of sumatriptan in the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months (27). | ||
• The Cochrane database of systematic reviews of clinical trials concluded the following (04): | ||
(a) Oral, nasal, or subcutaneous sumatriptan is effective as an abortive treatment for migraine attacks, relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events. | ||
(b) Sumatriptan 25 mg, administered rectally, is an effective treatment for acute migraine attacks, but lack of data on relief of headache-associated symptoms or incidence of adverse events limits any conclusions that can be drawn. | ||
• A multicenter, outpatient, single-attack, double-blind, randomized, placebo-controlled, parallel-group study on migrainous children and adolescents in Japan failed to show any significant improvement in pain at 2 hours in the oral sumatriptan group as compared to placebo group (08). There were no significant adverse effects. | ||
• In a randomized, double-blind, placebo-controlled trial, targeted delivery of a low-dose of sumatriptan powder via a closed-palate, breath-powered, intranasal device (AVP-825) provided fast relief of moderate or severe migraine headache in adults (01). | ||
• Pooled data from several randomized trials show that sumatriptan is less effective as acute therapy for migraine attacks with aura compared with attacks without aura (09). | ||
• A systematic review of controlled clinical trials showed that combination sumatriptan/naproxen treatment was effective in the acute treatment of migraine headaches and that the effect was greater than that of the same dose of either sumatriptan or naproxen alone (15). The combination was more effective early in the attack when pain was still mild. | ||
• A multicenter, randomized, double-blind, placebo-controlled efficacy and safety study showed that 3 mg subcutaneous sumatriptan (DFN-11) for the acute treatment of adults with episodic migraine is as effective as the 6 mg dose and more effective than the placebo (13). | ||
• A systematic review of randomized trials of intranasal sumatriptan concluded that sumatriptan is effective for the treatment of acute migraine attacks, but it was associated with a 6-fold increase in the risk of taste disturbance compared to the placebo (18). |
Sumatriptan is indicated for use in the following:
(1) Acute treatment of migraine attacks with and without aura. | |
(2) Acute treatment of cluster headache episodes. |
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:
• High-altitude headache | |
• Post-dural puncture headache | |
• Headache caused by locally invasive head and neck cancer | |
• Severe post-electroconvulsive therapy headache | |
• The headache of subarachnoid hemorrhage. Relief of headache in a mistaken diagnosis of migraine may lead to missed diagnosis of subarachnoid hemorrhage, and danger of inducing vasospasm exists in this situation. | |
• Intranasal sumatriptan for prevention of post-electroconvulsive therapy headaches | |
• Trigeminal neuralgia | |
• In a prospective, double-blind, randomized, placebo-controlled trial, sumatriptan prophylaxis was shown to be effective in prevention of development of acute mountain sickness. | |
• Acute posttraumatic headache | |
• Adult cyclic vomiting syndrome. In an open clinical trial, sumatriptan was administered either subcutaneously or by nasal spray to pediatric patients with cyclic vomiting syndrome (10). The efficacy of sumatriptan was high in attacks that occurred in cases with a family history of migraine compared to those without. There were no adverse effects. | |
• Subcutaneous sumatriptan is safe and effective for postoperative pain management after craniotomy (21). |
Contraindications of sumatriptan use include the following:
• Patients with coronary artery disease or hypertension. | |
• Patients with hemiplegic or basilar artery migraine. | |
• Sumatriptan should not be given intravenously within 24 hours of administration of an ergot compound. | |
• Patients who have demonstrated hypersensitivity to sumatriptan. | |
• Oral, intranasal, and subcutaneous routes of sumatriptan administration are contraindicated in patients with severe hepatic insufficiency. | |
• Patients receiving concurrent MAO type A inhibitors or within 2 weeks of discontinuing an MAO type A inhibitor. | |
• Patients with peripheral vascular disease, cerebrovascular syndromes, or uncontrolled hypertension. |
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.
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.
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.
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:
• Ergot-containing compounds. | |
• Monoamine oxidase inhibitors reduce sumatriptan clearance and increase the serum concentration of sumatriptan. However, if sumatriptan is administered subcutaneously, dominance of the distribution phase and completeness of absorption of sumatriptan explains the trivial effect size of the monoamine oxidase A inhibitor on plasma sumatriptan concentration (06). There are no pharmacokinetic grounds to deter co-administration of a monoamine oxidase A inhibitor and subcutaneous sumatriptan. | |
• Selective serotonin reuptake inhibitors. Serotonin syndrome may result from interactions with other serotonergic drugs. | |
• Calcium channel-blocking antagonists: flunarizine. | |
• Beta blocker: propranolol. |
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.
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:
• The most frequently reported adverse event after sumatriptan nasal spray in clinical trials, in 5% of the patients, is bad or bitter taste. | |
• Chest pain due to myocardial ischemia has been reported as an adverse effect after sumatriptan. | |
• Reversible segmental cerebral arterial vasospasm and cerebral infarction may be associated with excessive use of sumatriptan. | |
• Sumatriptan may activate pain at sites of inflammation, and reaction occurs at a higher rate with the subcutaneous formulation than with the oral preparation. | |
• Sumatriptan-induced ischemic colitis has been reported (19). |
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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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