The effect of zolmitriptan on cardiac autonomic modulation in patients with migraine: A double-blind, placebo-controlled, crossover study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.170072
Source of Support: None, Conflict of Interest: None
Background: Triptans, which activate 5-hydroxytryptamine (5-HT)-1B/1D receptors in cerebral arteries, are very effective in aborting attacks of migraine. Although activation of 5-HT-1B/1D receptors diminishes the secretion of noradrenaline from cardiac sympathetic nerves, some studies report that they may cause chest discomfort, myocardial infarction and arrhythmias due to coronary vasospasm. The effect of zolmitriptan on cardiac autonomic modulation has not been evaluated in migraineurs.
Keywords: Cardiac autonomic functions; heart rate variability; migraine; zolmitriptan
Migraine is a complex disease that affects about 15% of the population and can be highly disabling. Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraine and cluster headaches. They were first introduced in the 1990s. While being effective in treating individual headaches, they do not provide preventive treatment and are not considered as curative. Triptans have several advantages over ergotamine and dihydroergotamine in having a selective pharmacology, a well-established safety record, and evidence-based prescribing instructions. Therefore, triptans are often the preferred medications in migraine. Sumatriptan was the first drug in this class and binds to 5-hydroxytryptamine (5-HT)-1B receptors. Zolmitriptan is a new member of triptans and is a serotonin (5-HT) derivative with agonist activity at 5-HT-1B/1D receptors., By activating 5-HT-1B/1D receptors, they lead to vasoconstriction of the cerebral blood vessels, which are dilated during migraine attacks. Moreover, they reduce the secretion of vasoactive peptides and the conduction of painful stimuli in the cerebral cortex. Although triptans exert their therapeutic effect through cerebral vasoconstriction, studies have also documented vasoconstriction in the coronary, pulmonary, and systemic circulation. Triptans are generally better tolerated than ergot alkaloids but chest discomfort can occur as a side effect after administration of triptans. Up to 15% of patients consistently report chest symptoms, including chest pressure, tightness, and discomfort, often mimicking angina pectoris. Fortunately, these are usually transient, mild, and terminate without ischemia. However, a few sporadic ischemic events induced by zolmitriptan have been reported in the literature. It has been shown that triptans constricted the human coronary arteries in vitro. However, apart from avitriptan, therapeutic plasma concentrations of the drugs do not reach levels that are likely to cause myocardial ischemia in individuals with normal coronary circulation.,,,, Rarely, triptans may also cause arrhythmias that can be fatal. Even though the cause of the arrhythmias is not known definitely, it has been considered that they may be associated with coronary vasoconstriction.,, Sumatriptan is, therefore, contraindicated in patients with coronary artery disease.
Heart rate variability (HRV), which can easily be determined non-invasively, has been used to determine risk stratification in cardiological and non-cardiological diseases. Cardiac autonomic dysfunction has been identified with HRV in smokers and in patients with diabetes mellitus or left ventricular dysfunction, as well as in patients after a myocardial infarction.,,,, The risk is estimated with the analysis of frequency and time domain parameters of HRV in short-term recordings (5-min). Different conditions such as an upright position, mental stress, and exercise induced sympathetic stimulation consequently change heart rate and HRV parameters.
The aim of this study was to investigate the effects of zolmitriptan on cardiac autonomic function during rest and mild exercise that cause sympathetic activation, and during controlled respiration that causes parasympathetic activation.
Ten patients (nine female) with migraine, with the mean age being 33 ± 4 years (range: 18–54 years) were included in the study. The single male patient was 35 years old. The average duration of migraine was 5.5 years in the female patients and 6 years in the male patient. Thirty-one percent of female patients had a family history of migraine while the solitary male patient did not. The diagnosis of migraine was established according to the criteria of Headache Classification Committee of the International Headache Society. The participants who had a history of coronary artery disease, or of respiratory, neurological or other systemic disorders that might influence the autonomic function, such as allergy to zolmitriptan, a history of smoking, and the presence of diabetes mellitus, were excluded from the study. Their physical examination, resting 12-lead electrocardiograms, and exercise treadmill tests were in the normal range. Routine laboratory tests including fasting blood glucose, blood urea nitrogen, serum electrolytes, and hemoglobin levels were in the normal range as well. Written informed consent was obtained from all participants, and the Departmental Ethical Committees of Cardiology and Neurology approved the protocol of the study. During the study, we complied with the World Health Organization Declaration of Helsinki and World Psychiatric Association, Good Clinical Practices and Good Laboratory Practice rules.
The participants were involved in a randomized, double-blinded, placebo-controlled, crossover study with two identical experimental sessions conducted at least 5 days apart. They were studied in the morning following at least 8 h of sleep and after having breakfast free of caffeine-containing beverages.
All HRV parameters were recorded in a dimly lighted room with a comfortable temperature (22–24°C). The results were determined by frequency and time domain analysis of HRV in short-term recordings (5-min). As we know, heart rate and HRV parameters change under different conditions such as upright position, mental stress, exercise, and controlled breathing. These conditions cause stimulation of sympathetic or parasympathetic activity. Controlled respiration is used to activate the parasympathetic system, and exercise in an upright position and mental stress are used to activate the sympathetic system. After an adaptation period of at least 15 min rest in supine position, their electrocardiograms were recorded during rest in supine position, controlled respiration (15 breaths/min) in supine position, and during handgrip exercise in sitting position for 5-min intervals. In order to achieve 15 breaths/min, subjects inspired (2-s) and expired (2-s) in synchrony with a metronome. Participants performed an isometric handgrip exercise at 25% of their predetermined maximum voluntary contraction in a manner of 45-s contraction and 15-s resting/min using Jamar hydraulic hand dynamometer (Sammons Preston, Canada). After basal data had been obtained, participants received a single oral dose of 2.5 mg zolmitriptan or placebo with 200 ml water. The order of administration of zolmitriptan or placebo was randomized and participants and operators were blinded to the test. Two hours after taking zolmitriptan or placebo, the participants once again underwent the same procedures as mentioned above. Blood pressure measurements were obtained from the left arm supported at heart level by a trained physician using a sphygmomanometer.
The electrocardiographic data were fed into a personal computer and digitized via an analog-to-digital conversion board (PC-ECG 1200, Norav Medical Ltd., Israel). All recordings were visually examined and manually over-read to verify beat classification. Abnormal beats and artifacts were automatically and manually identified and excluded. HRV analysis was performed by the HRV Software (version 4.2.0, Norav Medical Ltd., Israel). Both time and frequency domain analyses were performed. For the time domain analysis, the mean R-R interval (mean-R-R), the standard deviation of R-R interval (SDNN), and the root mean square of successive R-R interval differences (rMSSD) were measured. For the frequency domain analysis, power spectral analysis based on the fast Fourier transformation algorithm was used. Three components of power spectrum were computed using the following bandwidths: High frequency [HF] (0.15–0.4 Hz), low frequency [LF] (0.04–0.15 Hz), and a detectable part of the very LF spectral band (up to 0.04 Hz). The LF/HF ratio was also calculated.
SPSS computer program (Statistical Package for the Social Sciences version 13.0, SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Data were presented as mean with a standard error of the mean. Dependent variables at basal levels, and after placebo or zolmitriptan administration were tested with Wilcoxon Signed Rank test and P < 0.05 was considered as statistically significant.
All participants well-tolerated the study and no adverse effects such as chest discomfort, palpitation, tremor, headache, and rhythm disturbances were observed. Neither time domain nor frequency domain HRV parameters were different during rest, controlled respiration, and handgrip exercise before administering zolmitriptan versus placebo [Table 1].
Zolmitriptan administration did not change systolic (SBP) and diastolic blood pressures (DBP) compared with placebo, during rest [(SBP) 103 ± (DBP) 7/65 ± (standard deviation) 4 mmHg, placebo: 107 ± 5/73 ± 6 mmHg, P > 0.05), controlled respiration (zolmitriptan: 106 ± 5/68 ± 3 mmHg, placebo: 104 ± 4/70 ± 3 mmHg, P > 0.05), and handgrip exercise (zolmitriptan: 123 ± 5/82 ± 3 mmHg, placebo: 125 ± 4/91 ± 3 mmHg, P > 0.05). Furthermore, there were no significant differences in time and frequency domain HRV parameters obtained during rest, controlled respiration, and handgrip exercise after zolmitriptan administration when compared with placebo [Table 2]. Mean R-R interval and LF/HF ratio after zolmitriptan and placebo administrations are shown in [Figure 1] and [Figure 2].
The results of the present study show that time and frequency domain parameters of HRV did not change after 2.5 mg zolmitriptan administration. In a few studies, it has been shown that there was autonomic dysfunction in patients with migraine.,,,, However, it is not known definitely, whether the autonomic dysfunction occurs as a consequence of, or is the reason for the precipitation of migraine. Both sympathetic and parasympathetic dysfunctions have been observed in patients with migraine.,, Furthermore, dysfunctions of the serotonin and monoamine systems located in the brainstem were shown in patients with migraine.
The effects of triptans are primarily on the serotonin system. The effects of serotonin on the cardiovascular system have been found to be variable in various experimental studies and may include bradycardia-tachycardia, vasodilatation-vasoconstriction, and hypotension-hypertension via different receptors. While bradycardia is mediated by stimulation of 5-HT3 receptors in most of the species, tachycardia can be mediated by stimulation of different receptors.,, Another effect of serotonin on the cardiovascular system is the vasoconstriction of coronary arteries by activation of 5-HT-1B and 5-HT-2A receptors. 5-HT-1B/1D receptors are located in sensory trigeminal fibers of meningeal blood vessels and activation of these receptors by triptans provides pain relief in migraine. 5-HT-1B/1D receptors are also found in different tissues of the cardiovascular system such as human atrium and saphenous vein. The activation of 5-HT-1B/1D receptors in the atrium diminishes the secretion of noradrenaline from noradrenergic axon terminals., It has been shown that sumatriptan also diminishes the secretion of noradrenaline from cardiac sympathetic nerves by activation of 5-HT-1B/1D receptors.
Triptans have been used in aborting attacks of migraine and cluster headache for 24 years. They are more effective than ergot alkaloids in these circumstances and sumatriptan is the most widely used medication. A prevalence of cardiovascular side effects has increased since the drug has started being frequently used. Although it has been reported that sumatriptan caused chest symptoms such as angina pectoris in 15% of patients, recent studies showed that these symptoms were generally not serious and were not explained by ischemia.,,,,,,, Serious cardiovascular events such as myocardial infarction have most often been reported in patients with significant cardiovascular risk or in those with an overt cardiovascular disease. Serious cardiac side effects of sumatriptan limited the administration of new generation triptans in migraineurs with coronary artery disease. Lesser cardiovascular side effects, however, have been observed with new generation triptans. As a matter of fact, the side effects of zolmitriptan have been investigated in 2750 patients with migraine, and no ischemic events and electrocardiographic changes have been detected.
In this study, the effects of zolmitriptan on cardiac autonomic functions were assessed according to changes in HRV. Zolmitriptan did not change the time domain parameters (SDNN, RMSSD, and mean R-R) and frequency domain parameters (LF and HF spectral powers and LF/HF ratio) of HRV when compared with placebo. The results of this study are correlated with another study, which investigated the effect of naratriptan on cardiac autonomic functions. We thought that the decrease of noradrenaline secretion by activation of 5-HT-1B/1D receptors on the atrium, as well as on cardiac sympathetic nerves could cause a sympathetic withdrawal of cardiac autonomic activity or a change of sympathovagal balance.,, However, zolmitriptan administration neither caused sympathetic withdrawal nor changed the sympathovagal balance in our study. A subtle change in parasympathetic activity can affect HRV as mentioned before, but together with the same change in the sympathetic system, may not affect HRV. Therefore, we suggest that small decreases of noradrenaline due to zolmitriptan administration did not affect cardiac autonomic function. However, the possibility remains that the zolmitriptan dose administered in our study might be too low to assess its effect on cardiac autonomic function.
The major limitation of this study was the dose of zolmitriptan administered to the patients. We administered 2.5 mg zolmitriptan to the participants. Some patients with migraine may need more than 2.5 mg zolmitriptan for the alleviation of their symptoms during a migraine attack.
In the present study, we did not observe a significant change in sympathetic or parasympathetic reactivity, and sympathovagal balance after the administration of 2.5 mg zolmitriptan. This observation showed that a single dose, oral administration of 2.5 mg of zolmitriptan did not change cardiac autonomic activity. In light of these findings, zolmitriptan may be preferred in the treatment of migraine especially in individuals having a cardiovascular disease.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]