Abstract
Triptans are effective and well tolerated in the treatment of acute migraine. Chest symptoms are a common adverse effect unrelated to coronary vasoconstriction in most patients. Although the aetiology of chest symptoms remains to be fully defined, pulmonary vasoconstriction is a possible underlying mechanism. Preclinical studies of isolated human blood vessels were used to identify the cerebral selectivity of triptans and ascertain if selectivity vs the pulmonary vasculature predicts a lower rate of chest symptoms. Controlled clinical trials and post-marketing surveillance studies were reviewed to document the incidence of chest symptoms after triptan therapy. In clinical trials, the incidence of chest symptoms at usual therapeutic doses ranged from 1 to 4% depending on the triptan and study design, whereas in post-marketing surveillance studies, up to 41% of patients specifically asked about chest symptoms reported them. A comparative clinical trial showed that almotriptan was associated with lower incidence of chest symptoms than sumatriptan (0.3 vs 2.2%). The intrinsic activity of almotriptan, a second-generation triptan, on human pulmonary arteries and veins was lower than that of sumatriptan. Pre-clinical studies of isolated pulmonary blood vessels may predict the clinical likelihood of chest symptoms; however, additional comparisons are needed.
Introduction
The triptans, selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT1B/1D receptor agonists, are the drugs of choice for treating moderate–severe migraine (1). The first marketed triptan, sumatriptan, which was introduced in 1991, represented a significant advance in migraine treatment and led to the development of a number of second-generation agents, including zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, and eletriptan. Newer triptans offer potential pharmacokinetic advantages relative to sumatriptan in terms of higher oral bioavailability, more-rapid attainment of therapeutic plasma levels and blood–brain barrier penetration (2, 3). Overall, the triptans are generally safe and well tolerated, although patients may experience a variety of mild and short-lived adverse effects, such as paraesthesia, dizziness, and somnolence.
Such ‘chest-related symptoms’ as pressure, heaviness, or discomfort in the chest and arms; shortness of breath; palpitations; and occasionally chest pain occur to a variable extent with all of the triptans. Recent studies suggest that the incidence of chest symptoms associated with almotriptan is significantly lower than that seen with sumatriptan and other second-generation triptans (4, 5, 6).
Because these symptoms can mimic acute angina pectoris and myocardial infarction, and, as rare serious cardiovascular adverse events have been reported in patients receiving sumatriptan (7), chest symptoms are often alarming to patients and physicians. However, given the significant disparity between the prevalence of chest symptoms and lack of associated electrocardiographic or clinical adverse effects, a variety of non-cardiac mechanisms have been proposed to explain the chest symptoms associated with these drugs. This article will review issues related to the cardiovascular safety of the triptans and the evidence that pulmonary vasoconstriction may underlie the chest symptoms associated with these compounds.
Pharmacology and pathophysiology
Pharmacology of triptans
The triptans display high affinity for 5-HT1B and 5-HT1D receptors, and may also interact with varying affinity for other 5-HT1 receptor subtypes, notably 5-HT1F (8). In contrast, they do not have appreciable affinity for 5-HT2, 5-HT3, or non-serotonergic receptors. The exact mechanism of action responsible for the therapeutic efficacy of triptans in migraine remains unclear (2, 8). However, three possible mechanisms have been proposed: (i) vasoconstriction of dilated cranial blood vessels, mediated by activation of vascular 5-HT1B receptors; (ii) inhibition of neurogenic inflammation around the blood vessels, mediated by stimulation of presynaptic 5-HT1D receptors on trigeminal Aα and C fibres, resulting in suppression of calcitonin gene-related peptide, substance P, and neurokinin A release; and (iii) inhibition of neuronal excitability within the trigemal nucleus caudalis, mediated by activation of presynaptic and/or post-synaptic 5-HT1B and 5-HT1D receptors in the brain stem.
Cardiovascular safety issues
Serotonin is a vasoconstrictor in the coronary circulation, an effect mediated predominantly via 5-HT2A receptors and, to a lesser extent, via 5-HT1B receptors (9). In contrast, the serotonergic response in the cerebral vasculature is mediated predominantly by 5-HT1B receptors, thus establishing the basis for the cerebral selectivity of these drugs relative to the coronary circulation. Triptans have the potential to produce a usually mild and short-lived coronary vasoconstriction, due either to a direct effect on the coronary vessels or an indirect effect mediated by small increases in systemic blood pressure. At therapeutic drug levels, however, coronary vasoconstriction is unlikely to cause myocardial ischemia in patients with a normal coronary circulation (10).
Chest symptoms during sumatriptan therapy were not linked to electrocardiogram (ECG) changes, suggesting that coronary vasoconstriction is not the cause in the vast majority of patients (11). In subjects without cardiovascular disease, subcutaneous administration of 6 mg sumatriptan did not affect myocardial perfusion measured by positron emission tomography or produce significant ECG changes (12). Moreover, risk factors for cardiovascular disease were not associated with chest symptoms in a post-marketing study (11). Data from extensive clinical trials, together with information from nearly 10 years of experience in clinical practice, demonstrate that sumatriptan is generally well tolerated, with a favourable risk-benefit ratio when used properly. However, although significant cardiovascular and cerebrovascular events are rare, they have been observed (7). Therefore, the ability of sumatriptan and all other triptans to cause coronary vasoconstriction, albeit usually mild and short-lived, is sufficient reason for contraindicating these drugs in patients with established coronary artery disease (CAD) and adhering to the prescribing recommendations for these drugs.
Etiology of chest symptoms
Because the chest symptoms associated with triptans do not appear to have a cardiovascular origin in the majority of patients, several alternative explanations have been proposed. Oesophageal mechanisms have been hypothesized to underlie the chest symptoms sometimes reported with triptans (13). In support of this hypothesis, a supra-therapeutic 16-mg subcutaneous injection of sumatriptan increased the amplitude and duration of oesophageal contractions as well as abnormal oesophageal motility, but did not cause electrocardiographic abnormalities in 24 healthy volunteers (13). Changes in oesophageal function after sumatriptan injection were observed in every subject in this study. Four of five (80%) subjects reporting chest pain after sumatriptan injection showed clinically abnormal oesophageal motility whereas only eight of 19 (42%) subjects with no chest symptoms showed clinically abnormal motility.
Triptan-associated reductions in the oxygen stores of skeletal muscles has also been suggested to contribute to chest symptoms and similar side-effects such as heaviness of the limbs (14). In a study of the effects of sumatriptan on muscle energy metabolism during isometric exercise, subjects with no side-effects after a 6-mg subcutaneous injection showed no differences from pre- to post-exercise in skeletal muscle energy metabolism, while subjects experiencing side-effects such as heaviness of the limbs showed a transient reduction in oxygen storage as measured by mitochondrial functioning after exercise (14).
Heightened sensory sensitivity may explain the chest symptoms that occur in some patients during migraine. Recent research shows that heightened sensory sensitivity in the form of cutaneous allodynia (i.e. experience of pain to non-painful stimuli) spreads over the course of a migraine from a small, localized cranial area ipsilateral to the headache to other body regions including the contralateral head and the forearms (15). A similar heightened sensitivity to pain has been observed in patients with non-cardiac chest pain, which is similar to anginal pain, but typically originates from the oesophagus. In one study, patients with non-cardiac chest pain compared with healthy volunteers had a lower baseline oesophageal pain threshold and demonstrated more marked and prolonged reductions in upper oesophageal pain threshold in response to acid infusion into the lower oesophagus (16).
A lower pain threshold among migraine sufferers may explain the finding in a pre-triptan era study that, as a group, migraineurs are significantly more likely than non-migraineurs to report chest pain (17). Two cohorts of patients – the first comprising 46 619 patients with a migraine diagnosis based on self-reported symptoms and the second comprising 32 669 patients with a migraine diagnosis based on self-reported physician diagnosis of migraine – who enrolled in the northern California Kaiser Permanente Medical Care Program in 1971 through the first half of 1973 were studied. Presence or absence of chest pain was assessed by asking patients at a health care visit whether they had experienced during the past year pain, pressure, or a tight feeling in their chest that either hurt in the middle under the breastbone or forced them to stop walking. Patients were followed to assess the occurrence of myocardial infarction through 31 December 1987, death, hospitalization for myocardial infarction, or termination of Kaiser Permanente membership, whichever occurred first. The results demonstrated that in both cohorts, chest symptoms were reported significantly more frequently by migraineurs than by enrolees without migraine. Migraineurs were also significantly more likely than non-migraineurs to report other symptoms including stomach pain, heartburn, painful joints, and neck and back pain. Notably, however, the chest symptoms reported by migraineurs in this study did not predict the occurrence of myocardial infarction: migraineurs were no more likely to experience a myocardial infarction than were enrolees without migraine.
Triptan-associated chest symptoms have also been hypothesized to arise from a direct effect on the pulmonary vasculature (18). Little work has been conducted to test this hypothesis, although the demonstration that triptans affect pulmonary arterial pressure and the discovery of 5HT1B/1D receptors on human pulmonary arteries are consistent with the possibility. If pulmonary vasoconstriction were responsible, for example, then triptans with greater selectivity for the cerebral vasculature as compared with the pulmonary vasculature would be expected to cause a lower incidence of chest symptoms than sumatriptan.
Pre-clinical comparisons among triptans on isolated blood vessels
The cerebral selectivity of sumatriptan relative to the coronary vasculature has been evaluated in studies employing isolated tissue techniques. In isolated human basilar and middle meningeal arteries, sumatriptan induced concentration-dependent contractions with pD2 (–log EC50) values of approximately 7.0 and maximal responses (intrinsic activity) similar to those induced by serotonin (19–21). In comparison, sumatriptan was approximately 5–10-fold less potent on isolated coronary arteries, but it caused approximately 20 to 40% of the maximum response elicited by serotonin (10, 19, 21). Thus, the selectivity of sumatriptan for the cerebral vasculature as compared with the coronary vasculature was seen in two ways: greater potency in the cerebral vasculature and lower intrinsic activity in the coronary vasculature relative to serotonin. Similar results have been seen with other triptans (10, 19–23).
If pulmonary vasoconstriction is responsible for triptan-related chest symptoms, then selectivity for the cerebral vasculature relative to the pulmonary vasculature may be more predictive of fewer triptan-induced chest symptoms. Isolated human pulmonary arteries and veins have been shown to contain functional 5-HT1B as well as 5-HT2A receptors (24, 25). In a pre-clinical study, almotriptan was compared with sumatriptan on isolated human pulmonary vessels as well as on human meningeal and coronary arteries (26). Both compounds induced concentration-dependent contractions on each vascular preparation. In the pulmonary artery, both triptans had equal potency, but the intrinsic activity of almotriptan was only 31 and 11% of those of sumatriptan and serotonin, respectively (Table 1). Similar results were found in the pulmonary vein, where the maximal contraction with almotriptan was 21 and 8% of those with sumatriptan and serotonin, respectively. In comparison, almotriptan was approximately 15-fold more potent than sumatriptan on the meningeal artery based on pD2 values, but both agents produced similar maximal responses (26). On the basis of these results, almotriptan appears more selective for the cerebral than pulmonary vasculature, which is particularly evident by its lower intrinsic activity in the pulmonary arteries and veins.
∗The mean pD2 (– log EC50) for each compound was determined on the indicated number of isolated tissue preparations. The maximal contraction for each compound (intrinsic activity) is expressed relative to the maximum for sumatriptan (defined as 1.0). NT, not tested.
In vivo pulmonary, coronary, and systemic vascular effects
The cardiovascular effects of single subcutaneous doses of sumatriptan and naratriptan were evaluated by digital subtraction angiography and invasive haemodynamic monitoring in subjects undergoing diagnostic coronary arteriography (27, 28). Sumatriptan (6 mg) and 1.5 mg naratriptan significantly increased systemic and pulmonary artery pressure and systemic and pulmonary vascular resistance. Sumatriptan caused coronary vasoconstriction, as reflected by 16 and 17% declines in the mean absolute coronary artery diameter at 10 and 30 min after the injection, respectively. In contrast, naratriptan did not cause a significant change in mean coronary artery diameter. How-ever, pulmonary artery pressure changes after naratriptan injection were of a similar magnitude to sumatriptan-induced changes, with a 30 to 40% increase accompanying injection of either agent. As seen with sumatriptan, the relative percentage increase (32%) in pulmonary artery pressure after naratriptan was greater than systemic pressure changes (12%), suggesting the possibility of a greater density of 5-HT1B receptors in the pulmonary circulation or a differential effect on 5-HT1B receptors which is dependent on the vascular bed. Interestingly, four of 10 patients who received naratriptan experienced mild-to-moderate chest discomfort that spontaneously resolved after 10 min (28).
Eletriptan was similarly evaluated following intravenous administration at a dose of 3.33 µg/kg/min to 10 patients without significant obstructive CAD (29). Statistically significant increases in pulmonary capillary wedge pressure, right atrial pressure, and mean pulmonary artery pressure were observed during eletriptan infusion. Pulmonary and systemic vascular resistance increased during drug infusion, reaching statistical significance after infusion. No significant effects were observed on proximal, mild, or distal coronary artery diameter at any time point during or after infusion of eletriptan. Unfortunately, the presence or absence of chest symptoms was not reported, except in one patient who developed segmental constriction of a proximal right coronary artery. Whether this was a drug effect or a result of catheter-induced vasospasm is not clear.
Chest symptoms
The incidence of chest symptoms in controlled clinical trials has been most extensively evaluated for sumatriptan and rizatriptan, but not all trials specifically reported such information. Overall, the incidence of these symptoms appears to be dose-related (Table 2). In placebo-controlled clinical trials of oral sumatriptan, chest symptoms were reported as adverse events in 4% of patients treated with 50 or 100 mg, and in 5% of those given a 300-mg dose (31–33). Similarly, the incidence of chest symptoms in placebo-controlled trials of rizatriptan was 1.5 and 3% with 5- and 10-mg doses, respectively (39, 41), and it ranged from 1 to 6% for zolmitriptan at doses from 2.5 to 10 mg (40). In these studies, the rate of chest symptoms ranged up to 1% in the placebo group. Comparative clinical trials have generally provided consistent results, with most studies using sumatriptan as the comparator. Rizatriptan produced chest symptoms in 1 to 3% at 5 mg and 2 to 4% at 10 mg as compared with 3 to 5% and 6 to 9% for sumatriptan 50 and 100 mg, respectively (30, 34, 35, 42). In a comparative study of eletriptan and sumatriptan, chest and throat symptoms were reported together: 4% for eletriptan 20 mg and 7% for eletriptan 40 and 80 mg and sumatriptan 100 mg, as compared with < 1% for placebo (43). The incidence of chest symptoms was much lower, however, in a comparative study of zolmitriptan 5 mg and sumatriptan 100 mg: 1 and 2%, respectively, which was comparable with the 2% rate seen with placebo (36). Taken together, these results demonstrate that chest symptoms were a relatively common event in the controlled setting of a clinical trial.
Incidence of chest symptoms in placebo-controlled, or comparative, double-blind clinical trials of triptans
Post-marketing surveillance studies suggest that chest symptoms may be even more common than suggested by clinical trials. The Netherlands Centre for Monitoring of Adverse Reactions to Drugs sent a questionnaire to 1727 patients who were prescribed sumatriptan for acute treatment of migraine or cluster headache by general practitioners (44). Of the 1187 patients who returned the questionnaire and had used sumatriptan, 94 (7.9%) reported chest pain. In the majority of patients, chest pain occurred within 1 h of dosing (86%) and more than once (88%). Other chest symptoms reported included a feeling of heaviness (8.0%), pressure in the throat (3.3%), palpitations (2.8%), and dyspnea (2.2%). The number and range of sumatriptan doses were not reported. The Gothenburg Migraine Clinic in Sweden used a 25-item telephone survey of 707 migraine patients being treated with sumatriptan (45). Among those using oral sumatriptan, chest pressure was reported by 11% and pressure in the throat or neck by 7%. Chest pain was not reported.
An 86-item chest symptom questionnaire was mailed to 869 consecutive patients seen in clinical practice in Leiden, the Netherlands (11). Of the 735 patients responding, approximately half had used either oral or subcutaneous sumatriptan for at least five migraine attacks. In this subgroup of 377 patients, 24% receiving oral sumatriptan and 41% receiving the subcutaneous formulation experienced chest symptoms in almost all migraine attacks. In comparison, chest symptoms hardly ever occurred in 58 and 39% of patients taking the oral and subcutaneous preparations, respectively. The most common chest symptoms in this study were heavy arms and chest pressure, which occurred in more than 50% of patients, three-quarters of whom rated them moderate to severe. Shortness of breath, palpitations, and anxiety occurred in 25 to 30% of patients. Chest pain was somewhat less common, occurring in 14% of those receiving the oral formulation, but it also was usually moderate to severe. Sumatriptan was discontinued due to chest symptoms by 9 and 20% of patients taking the subcutaneous and oral formulations, respectively.
If chest symptoms were due primarily to pulmonary vasoconstriction, as postulated, they would be expected to occur at a lower incidence with almotriptan than sumatriptan on the basis of the pre-clinical studies in isolated human blood vessels. In phase 3 clinical studies, chest symptoms occurred in only 0.2% of patients receiving oral almotriptan (4). Moreover, in a multicentre study of 1173 migraine patients, almotriptan 12.5 mg produced a lower incidence of chest symptoms than sumatriptan 50 mg (0.3%vs 2.2%) (5). These findings were confirmed in a recently conducted meta-analysis of 53 randomized controlled triptan clinical trials which demonstrated that that almotriptan was associated with the lowest incidence of chest symptoms, significantly lower than the reference triptan, sumatriptan 100 mg [1.9% CI (1.0–2.7)] (6). If confirmed, these findings are consistent with the hypothesis that pulmonary vasoconstriction may play an important role in causing chest symptoms.
Clinical implications
Controlled clinical trials and post-marketing experience demonstrate that triptans are effective therapeutic agents for acute migraine. However, due to the presence of 5-HT1B receptors in the peripheral vasculature, it is important to recognize that these medications have the potential to precipitate adverse cardiovascular events in patients with pre-existing coronary artery disease, uncontrolled hypertension, Prinzmetal's angina, and cerebrovascular or peripheral vascular disorders. In these groups of patients, triptan therapy is contraindicated.
Once underlying cardiovascular disorders have been excluded, chest symptoms may remain an important consideration in the clinical setting. Although clinical trials of sumatriptan suggest that 4 to 5% of patients experience chest symptoms, post-marketing surveillance studies, in which patients were asked directly about chest symptoms, suggest that more than 24% of patients may experience such symptoms (11). Chest symptoms have been reported with all second-generation triptans, but important differences may exist among individual members of the triptan class, as described in the preceding section.
For the majority of patients, chest symptoms following triptan administration are unlikely due to a coronary vasoconstrictor response, but, rather, may reflect vasoconstriction of the pulmonary vasculature. If this is an important mechanism underlying chest symptoms, triptans with greater selectivity for the cerebral vasculature, as compared with the pulmonary vascular bed, should be associated with a lower incidence of these adverse effects. If additional studies confirm this hypothesis, this would provide a much-needed explanation for the mechanism of triptan-induced chest symptoms and indicate that subtle differences in the pharmacology of the triptans, despite their similar mechanism of action, may have important clinical implications.