Sumatriptan Transdermal System in Patients With Nausea
Nausea is a distinguishing migraine feature, and nearly 50% of migraineurs have clinically significant nausea with most attacks. The timing of nausea relative to headache is variable within and among individuals and the mechanisms are also most likely variable. Potential mechanisms include dysfunction on the central modulation of multisensory afferents as well as autonomic dysfunction, which may be associated with delayed gastric emptying.
Herein, we conducted two different subanalyses. The main focus was on TEN, because evidence suggests that nausea may be a side effect of oral triptans. In clinical trials of oral triptans in general, as well as of sumatriptan in particular, nausea is often among the most common treatment-emergent drug-related adverse events, but the same was not seen with sumatriptan subcutaneous injection. If TEN is a result of oral therapy, we hypothesized that sumatriptan TDS would not induce TEN at rates different from placebo. Different from what we hypothesized, we found that participants receiving sumatriptan TDS were substantially less likely to develop TEN than patients who were treated with placebo. The incidence of TEN with the sumatriptan TDS was lower than with placebo from 1 hour through 24 hours after TDS activation and rates of TEN observed with the sumatriptan TDS were less than half of those reported in studies with oral triptans.
The fact that patients with sumatriptan TDS were less likely to develop TEN relative to placebo may be due to two concurrent effects. First, it may be that that triptan-induced nausea is a local effect of oral administration of the drug; this would explain rates of nausea similar to placebo TDS. But, because triptans treat nausea in patients with migraine, they could also prevent nausea from appearing in the first place if therapeutic levels are achieved before the onset of nausea, due to their central effect. A limitation of our design is the inability to differentiate the degree to which nausea is attributable to oral triptan therapy vs the ongoing migraine attack itself. In future studies, we need to investigate TEN only in patients who achieve pain freedom at 2 hours. In this type of comparison, nausea is less likely to be a residual or emergent symptom of the migraine attack, but rather is likely to be due to the drug administered.
Migraineurs with baseline nausea are less likely to respond to oral triptans, and migraine treatment guidelines recommend non-oral formulations for patients who are nauseated or vomiting. Sumatriptan TDS bypasses the gastric system, being a good choice for those with nausea. We have compared the effectiveness of sumatriptan TDS in migraineurs with or without nausea. We found that those with nausea had more severe headache than those without nausea at baseline. Despite this, the response for pain (including achievement of pain-free and pain relief) and other associated symptoms (photophobia and phonophobia) were remarkably similar in participants with or without nausea receiving sumatriptan TDS. For oral triptans, pretreatment nausea predicts poor response to therapy. This was not true for sumatriptan TDS; nausea did not decrease the beneficial response, and TEN was less likely to happen after its use.
This study has limitations. First, the analyses were "post-hoc" and not a priori defined. Pivotal studies generate a wealth of knowledge and only part of it is considered as being on the primary scope for the trial. Therefore, post-hoc analyses should be seen as an attempt to further expand the knowledge generated by the study. Nonetheless, evidence generated by these analyses need to be further explored by studies primarily designed to test the hypothesis. Second, this study was not powered to conduct multivariate analyses, and therefore confounders may have not been recognized and adjusted. Furthermore, it is important to emphasize that the majority of patients without nausea at baseline did not subsequently develop nausea. Accordingly, the clinical relevance of the findings should be conceptualized. Most individuals with migraine without nausea at time of therapy will not develop nausea. In those receiving placebo, the rate in our study was close to 15% and this likely reflects the outcome of untreated migraine attacks. Studies using oral triptans found that the rates range from 20% to 30%, and in those in our study receiving sumatriptan TDS, the rate was around 9%. Although sumatriptan TDS is associated with very low rates of TEN, the rates are low overall. Finally, although the presence of nausea was meticulously collected, we failed to incorporate assessments that measured the individual contribution of nausea to the burden of migraine attacks.
Strengths of this study include its large size and rigor for regulatory needs. All information was prospectively collected with validated and well-accepted questionnaires and tools.
Sumatriptan TDS is effective for the acute treatment of migraine and is less likely than placebo to induce emergence of nausea in migraineurs without nausea. It is equally effective in participants with or without nausea at the time of treatment.
Discussion
Nausea is a distinguishing migraine feature, and nearly 50% of migraineurs have clinically significant nausea with most attacks. The timing of nausea relative to headache is variable within and among individuals and the mechanisms are also most likely variable. Potential mechanisms include dysfunction on the central modulation of multisensory afferents as well as autonomic dysfunction, which may be associated with delayed gastric emptying.
Herein, we conducted two different subanalyses. The main focus was on TEN, because evidence suggests that nausea may be a side effect of oral triptans. In clinical trials of oral triptans in general, as well as of sumatriptan in particular, nausea is often among the most common treatment-emergent drug-related adverse events, but the same was not seen with sumatriptan subcutaneous injection. If TEN is a result of oral therapy, we hypothesized that sumatriptan TDS would not induce TEN at rates different from placebo. Different from what we hypothesized, we found that participants receiving sumatriptan TDS were substantially less likely to develop TEN than patients who were treated with placebo. The incidence of TEN with the sumatriptan TDS was lower than with placebo from 1 hour through 24 hours after TDS activation and rates of TEN observed with the sumatriptan TDS were less than half of those reported in studies with oral triptans.
The fact that patients with sumatriptan TDS were less likely to develop TEN relative to placebo may be due to two concurrent effects. First, it may be that that triptan-induced nausea is a local effect of oral administration of the drug; this would explain rates of nausea similar to placebo TDS. But, because triptans treat nausea in patients with migraine, they could also prevent nausea from appearing in the first place if therapeutic levels are achieved before the onset of nausea, due to their central effect. A limitation of our design is the inability to differentiate the degree to which nausea is attributable to oral triptan therapy vs the ongoing migraine attack itself. In future studies, we need to investigate TEN only in patients who achieve pain freedom at 2 hours. In this type of comparison, nausea is less likely to be a residual or emergent symptom of the migraine attack, but rather is likely to be due to the drug administered.
Migraineurs with baseline nausea are less likely to respond to oral triptans, and migraine treatment guidelines recommend non-oral formulations for patients who are nauseated or vomiting. Sumatriptan TDS bypasses the gastric system, being a good choice for those with nausea. We have compared the effectiveness of sumatriptan TDS in migraineurs with or without nausea. We found that those with nausea had more severe headache than those without nausea at baseline. Despite this, the response for pain (including achievement of pain-free and pain relief) and other associated symptoms (photophobia and phonophobia) were remarkably similar in participants with or without nausea receiving sumatriptan TDS. For oral triptans, pretreatment nausea predicts poor response to therapy. This was not true for sumatriptan TDS; nausea did not decrease the beneficial response, and TEN was less likely to happen after its use.
This study has limitations. First, the analyses were "post-hoc" and not a priori defined. Pivotal studies generate a wealth of knowledge and only part of it is considered as being on the primary scope for the trial. Therefore, post-hoc analyses should be seen as an attempt to further expand the knowledge generated by the study. Nonetheless, evidence generated by these analyses need to be further explored by studies primarily designed to test the hypothesis. Second, this study was not powered to conduct multivariate analyses, and therefore confounders may have not been recognized and adjusted. Furthermore, it is important to emphasize that the majority of patients without nausea at baseline did not subsequently develop nausea. Accordingly, the clinical relevance of the findings should be conceptualized. Most individuals with migraine without nausea at time of therapy will not develop nausea. In those receiving placebo, the rate in our study was close to 15% and this likely reflects the outcome of untreated migraine attacks. Studies using oral triptans found that the rates range from 20% to 30%, and in those in our study receiving sumatriptan TDS, the rate was around 9%. Although sumatriptan TDS is associated with very low rates of TEN, the rates are low overall. Finally, although the presence of nausea was meticulously collected, we failed to incorporate assessments that measured the individual contribution of nausea to the burden of migraine attacks.
Strengths of this study include its large size and rigor for regulatory needs. All information was prospectively collected with validated and well-accepted questionnaires and tools.
Sumatriptan TDS is effective for the acute treatment of migraine and is less likely than placebo to induce emergence of nausea in migraineurs without nausea. It is equally effective in participants with or without nausea at the time of treatment.