Sumatriptan in clinical practice: effectiveness in migraine and the problem of psychiatric comorbidity

Abstract

Migraine is a multifactorial and disabling syndrome often in comorbidity with psychiatric illnesses. Triptans are the first-line treatment in acute attacks and the most effective drugs in various types of migraine. Sumatriptan was the first medication of this group. Thanks to multiple types of formulations that greatly increase patient's compliance, sumatriptan is so far the most commonly used drug for moderate-to-severe acute migraine attacks. Although generally safe and well tolerated, sumatriptan has to be carefully administered in patients suffering from various types of medical conditions (such as cardiovascular and cerebrovascular disease and some psychiatric illnesses) and/or treated with various medications (such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). The administration of sumatriptan in some psychiatric condition in which serotonin plays an important role (i.e., major depressive disorder and obsessive-compulsive disorder) has been underestimated so far. In fact, at present, literature studies are few, with non-conclusive and often contrasting findings. Thus, sumatriptan should continue to be used with caution in patients diagnosed with psychiatric illness and/or treated with drugs where serotonin is crucially involved in, until further data demonstrating complete safety become available.

Keywords::

• 5-hydroxytryptamine
• antidepressant
• migraine
• psychiatric comorbidity
• sumatriptan

1. Sumatriptan: molecular characteristics, effectiveness in migraine and tolerability

5-Hydroxytryptamine (5-HT) receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. A subgroup of these receptors, called 5-HT₁, is involved in pathophysiology of migraine. Triptans, which are 5-HT_1B/1D receptor agonists, are effective drugs in the treatment of migraine attacks; among them, the indole derivative sumatriptan was the first anti-migraine medication to exhibit receptor selective properties, with selective agonistic interaction with 5-HT_1B and 5-HT_1D sites [1,2]. It is demonstrated that triptans reduce the vascular inflammation associated with migraine and cause vasoconstriction of the dilated arteries, since their specific receptor subtypes are present on the cranial arteries and veins; moreover, triptans seems to attenuate activation of cyclic adenosine monophosphate response element-binding protein within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization, one of the major features in a migraine attack [3]. Results supporting the effectiveness of sumatriptan in different types of migraine are strong and have been collected over more than 20 years of clinical practice; careful reports have already been made on this topic [1,2] and are beyond the goal of the present paper. Indeed, we aimed to focus on a less-studied topic such as sumatriptan side effects, especially regarding psychiatric comorbidity. In general, the most common adverse events with oral sumatriptan are nausea, vomiting, dizziness, malaise and fatigue. Injection site reactions occur in 10 to 40% of patients receiving the drug subcutaneously and, a bitter taste at the back of the mouth is frequent after intranasal administration. Serious adverse events occur in about 0.14% of patients [2]. A single case of spontaneous splenic infarction has been reported [4]; anyway, since it was a never-replicated finding, it can be supposed that it was probably due to confounding factors than to sumatriptan action. However, the most alarming effect of sumatriptan remains vasoconstriction that can lead to ischemia in different areas. Coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation have been described. As this drug is associated with the possible development of cardiovascular effects, it is contraindicated in patients with a history of cardiovascular disease, cerebrovascular disease, hypertension and hemiplegic or basilar migraine [1,2].

2. Problems in patients with psychiatric comorbidity

Since it cannot be excluded that sumatriptan may cross the blood–brain barrier [5] and may act on central 5-HT₁ receptors, we aimed to investigate the relationship with some psychiatric illnesses (i.e., obsessive-compulsive disorder [OCD]) and medications (i.e., monoamine oxidase inhibitors [MAOIs] and selective serotonin reuptake inhibitors [SSRIs]), in which serotonin is involved. The problem of the coadministration of sumatriptan together with antidepressants is relevant since migraine is often comorbid with depression. Since sumatriptan is metabolized by monoamine oxidase type A (MAO-A) [1,2], simultaneous use of MAOIs would lead to a decrease in the metabolism of the oral sumatriptan as well as an enhancement of its side effects. Anyway, at present, MAOIs are rarely used; thus, studies observing their interaction are few and show contrasting findings [6,7]. Currently, SSRIs are the most common drugs used in the treatment of major depressive episodes, both in major depressive disorder and in bipolar disorder; the frequency of co-prescription with triptans is about 20% [6]. Despite some cases of coadministrations that were almost free of notable side effects [7], many studies demonstrate that the combination of sumatriptan and SSRIs should be used with caution [6,8]. One of the most important risks seems to be serotonin syndrome, a life-threatening condition resulting from increased levels of serotonin in the central nervous system which symptoms include confusion, hallucinations, increased heart rate, fever, nausea, vomiting, sweating and muscle spasms. Although cases of serotonin syndrome caused by coadministration of sumatriptan in patients receiving serotonergic drugs (such as sertraline, paroxetine, lithium, imipramine, amitriptyline) for migraine prophylaxis or for concomitant depression have been reported in literature [2], it is worth noting that, at present, it is not possible to claim a direct link between serotonin syndrome and sumatriptan coadministration. Another important issue is the administration of sumatriptan in individuals suffering from OCD. In fact, although the pathophysiological mechanisms of this disease are still not completely understood, increasing attention has been paid to the putative role of the serotonergic system for two important reasons: first, SSRIs are the most effective drugs in this disease; second, one of the most important genes involved in the pathophysiology of OCD is the 5-HT_1Dβ receptor [9]. Starting from these assumptions, the problem of the administration of sumatriptan in OCD patients is reasonable, although underestimated. The effects of the anti-migraine drug may depend on administration timing: acute administration seems to cause significant exacerbation on obsessive-compulsive symptoms [10] or, conversely, to have no effect on them [11]; on the other hand, in a case series, after continuous administration, three severe and treatment-resistant OCD patients responded with a modest reduction in their obsessive-compulsive symptoms and an improvement in their depression [12]. Although literature findings are still few and further studies are needed to clarify this matter, currently the most reliable hypotheses on OCD pathophysiology concern a dysfunction of specific types of serotonin receptors, an imbalance of serotonin-dopamine pathway and/or a 5-HT_1B/1D receptors supersensitization.

3. Expert opinion

Migraine is a dysfunctional, recurrent and episodic syndrome of the central nervous system, characterized by a very high prevalence in general population and by frequent comorbidity with depression. Migraine causes important disability and, thus, it is an important research focus. Sumatriptan is available in different dosages and formulations (the current ones such as oral, intranasal, rectal, subcutaneous and the future ones such as orally disintegrating tablet, buccal adhesive bilayered patch, lingual spray, transdermal, aerosol particles and nasal mucoadhesive delivery systems) and is currently the only triptans owning the subcutaneous one; this type of formulation, bypassing the hepatic filter, is characterized by a greater effectiveness and a faster onset of action in comparison to the oral one [2]. In particular, in cluster headaches, the subcutaneous formulation seems to decrease pain duration, while other triptans are completely ineffective, with the exception of zolmitriptan. Moreover, sumatriptan is also considered a potential treatment for chronic migraine and refractory chronic migraine, but further studies are needed before its entry in clinical practice [13]. Sumatriptan and other triptans are recommended as first-line therapy for moderate-to-severe migraine both in United States and in Europe [14,15]. Looking at the pharmacokinetic features of sumatriptan, it seems reasonable to make a few remarks concerning its use in patients with psychiatric comorbidity. First, sumatriptan is metabolized by MAO-A and the co-administration with inhibitors of this enzyme (MAOIs) can potentiate the side effects of the anti-migraine agent. Second, sumatriptan is an agonist of 5-HT_1B and 5-HT_1D receptors so that the coadministration of other drugs that act on serotonin pathway (i.e., SSRIs) can excessively increase serotonin level, up to potentially life-threatening events (such as serotonin syndrome). Third, the alteration of serotonin pathway can somehow modify the symptoms of patients with OCD, a disease in which serotonin plays a crucial, even if not completely understood, role. Starting from these speculative considerations, research studies in literature have shown conflicting findings concerning the coadministration of sumatriptan and antidepressant agents [6,7] and concerning the use of sumatriptan in OCD patients [10-12]. In conclusion, since sumatriptan (as triptans in general) acts on a pathway crucially involved in some psychiatric illnesses, in our opinion it should continue to be used with caution in patients taking antidepressants and/or diagnosed with OCD, until further data demonstrating complete safety become available. Nevertheless, since migraine and psychiatric illnesses are frequently comorbid, antidepressants and triptans have been used for > 20 years without relevant safety issues.

Acknowledgment

F Napoletano and L Lionetto have contributed equally to this work.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.