Efficacy and Safety of Orally Inhaled DHE in Treating Migraines
Background.— Central sensitization develops once migraine attacks become established and can be clinically detected by the development of cutaneous allodynia. The efficacy of triptans for migraine resolution has been shown to be markedly reduced when administered in patients with established cutaneous allodynia.
Objective.— The study aimed to evaluate the efficacy and safety of MAP0004, a novel, orally inhaled, form of dihydroergotamine, in patients with and without cutaneous allodynia at the time of treatment.
Methods.— This evaluation was a post hoc subanalysis of a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study. The presence or absence of baseline cutaneous allodynia at the time of drug administration was based on the response to a standard questionnaire. Treatment efficacy at 2 hours posttreatment was compared in patients with and without baseline allodynia.
Results.— At the time of treatment, allodynia was present in 216 patients treated with MAP0004 and 202 patients treated with placebo. MAP0004 treatment efficacy was superior to placebo, as measured by 2-hour pain relief for patients with and without allodynia (P < .0001) and as measured by 2-hour pain freedom for patients with (P < .0001) and without (P < .0002) allodynia. No significant within-treatment differences after treatment with MAP0004 in patients with and without allodynia at baseline were observed. Patients were more likely to be allodynia-free after treatment with MAP0004 compared with placebo (73% vs 66%, P = .0013). Furthermore, treatment with MAP0004 prevented the development of allodynia in patients not experiencing allodynia at baseline (P = .0057). MAP0004 was generally well tolerated.
Conclusions.— This post hoc subanalysis shows that MAP0004 was similarly effective in patients whether or not allodynia was present at treatment baseline. Patients were also more likely to be allodynia-free following treatment of a migraine with MAP0004.
Central sensitization plays an important role in the pathogenesis of migraine. While a throbbing sensation in migraine corresponds to sensitization of peripheral neurons, the development of cutaneous allodynia is indicative of sensitization of central, second-order neurons. Cutaneous allodynia during migraine attacks has been reported by at least 60% of migraineurs attending headache clinics and by more than 50% of patients in several recent treatment studies. The development of allodynia has been linked to increased phonophobia during migraine episodes, which is supportive of the theory that allodynia reflects a broader experience of neural sensitization.
The development of central sensitization has been shown to signify a period of limited or reduced efficacy of sumatriptan. Using an animal model, Burstein and Jakubowski demonstrated that the administration of sumatriptan prior to the onset of central sensitization, as evidenced by the absence of cutaneous allodynia, could effectively block nociceptive transmission at the trigeminal nucleus caudalis. However, after allodynia was established, treatment with sumatriptan failed to block nociceptive stimuli recorded in the thalamus. The clinical relevance of allodynia was also highlighted in a study showing that a pain-free response was achieved by 93% of patients treated with sumatriptan when no allodynia was present compared with only 15% of patients treated with sumatriptan with allodynia present.
Recent studies with almotriptan and rizatriptan have raised questions regarding the necessity of treating patients with triptans prior to the development of allodynia, as no statistically significant differences in efficacy were observed in patients reporting allodynia and those reporting no allodynic symptoms. However, patients in these studies may have been treated merely near the onset of allodynic symptoms rather than during well-established allodynia, when sumatriptan was shown to be ineffective. Whereas it may take up to 4 hours to fully establish allodynia, many of these triptan-treated patients were often treated within 2 hours of migraine onset.
Unlike these triptan results, dihydroergotamine (DHE) may reverse established central sensitization. Using the same animal model as Burstein and Jakubowski, early administration of DHE, as with sumatriptan, was shown to effectively block induction of central sensitization. However, when DHE and zolmitriptan were administered after central sensitization had already been established, DHE reversed the changes in sensory thresholds, whereas zolmitriptan did not. These results are consistent with the earlier work showing sumatriptan to be ineffective in reversing established central sensitization. Furthermore, in a small, open-label study (N = 9), patients with episodic migraine associated with cutaneous allodynia were treated with intramuscular DHE for two headaches. Response was compared among patients treating early (within 2 hours of the onset of throbbing pain) and patients treating late (4 hours after the onset of throbbing pain). While results were similar in both groups, with 2-hour pain relief observed in greater than 55% of patients treating early or late, self-reported cutaneous allodynia began to decrease as soon as 30 minutes after early treatment and 120 minutes after late treatment. While these data support the potential use of DHE for the treatment of migraine with established central sensitization and cutaneous allodynia, the exact mechanisms by which DHE reverses central sensitization are not well established. The effect of DHE on glial cell activity and on the balance between MAP kinases and phosphatases may play an important role in this process, as these are effects that triptans do not exert.
MAP0004 (MAP Pharmaceuticals, Mountain View, CA, USA) is an orally inhaled form of DHE that has been shown to be effective for the acute treatment of migraine with or without aura, with fewer adverse events (AEs) compared with intravenous DHE dosing. This post hoc subanalysis of the efficacy of MAP0004 in patients with established cutaneous allodynia at the time of treatment was designed to expand upon the previously published pilot data supportive of the late treatment of migraine with established allodynia using DHE.
Abstract and Introduction
Abstract
Background.— Central sensitization develops once migraine attacks become established and can be clinically detected by the development of cutaneous allodynia. The efficacy of triptans for migraine resolution has been shown to be markedly reduced when administered in patients with established cutaneous allodynia.
Objective.— The study aimed to evaluate the efficacy and safety of MAP0004, a novel, orally inhaled, form of dihydroergotamine, in patients with and without cutaneous allodynia at the time of treatment.
Methods.— This evaluation was a post hoc subanalysis of a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study. The presence or absence of baseline cutaneous allodynia at the time of drug administration was based on the response to a standard questionnaire. Treatment efficacy at 2 hours posttreatment was compared in patients with and without baseline allodynia.
Results.— At the time of treatment, allodynia was present in 216 patients treated with MAP0004 and 202 patients treated with placebo. MAP0004 treatment efficacy was superior to placebo, as measured by 2-hour pain relief for patients with and without allodynia (P < .0001) and as measured by 2-hour pain freedom for patients with (P < .0001) and without (P < .0002) allodynia. No significant within-treatment differences after treatment with MAP0004 in patients with and without allodynia at baseline were observed. Patients were more likely to be allodynia-free after treatment with MAP0004 compared with placebo (73% vs 66%, P = .0013). Furthermore, treatment with MAP0004 prevented the development of allodynia in patients not experiencing allodynia at baseline (P = .0057). MAP0004 was generally well tolerated.
Conclusions.— This post hoc subanalysis shows that MAP0004 was similarly effective in patients whether or not allodynia was present at treatment baseline. Patients were also more likely to be allodynia-free following treatment of a migraine with MAP0004.
Introduction
Central sensitization plays an important role in the pathogenesis of migraine. While a throbbing sensation in migraine corresponds to sensitization of peripheral neurons, the development of cutaneous allodynia is indicative of sensitization of central, second-order neurons. Cutaneous allodynia during migraine attacks has been reported by at least 60% of migraineurs attending headache clinics and by more than 50% of patients in several recent treatment studies. The development of allodynia has been linked to increased phonophobia during migraine episodes, which is supportive of the theory that allodynia reflects a broader experience of neural sensitization.
The development of central sensitization has been shown to signify a period of limited or reduced efficacy of sumatriptan. Using an animal model, Burstein and Jakubowski demonstrated that the administration of sumatriptan prior to the onset of central sensitization, as evidenced by the absence of cutaneous allodynia, could effectively block nociceptive transmission at the trigeminal nucleus caudalis. However, after allodynia was established, treatment with sumatriptan failed to block nociceptive stimuli recorded in the thalamus. The clinical relevance of allodynia was also highlighted in a study showing that a pain-free response was achieved by 93% of patients treated with sumatriptan when no allodynia was present compared with only 15% of patients treated with sumatriptan with allodynia present.
Recent studies with almotriptan and rizatriptan have raised questions regarding the necessity of treating patients with triptans prior to the development of allodynia, as no statistically significant differences in efficacy were observed in patients reporting allodynia and those reporting no allodynic symptoms. However, patients in these studies may have been treated merely near the onset of allodynic symptoms rather than during well-established allodynia, when sumatriptan was shown to be ineffective. Whereas it may take up to 4 hours to fully establish allodynia, many of these triptan-treated patients were often treated within 2 hours of migraine onset.
Unlike these triptan results, dihydroergotamine (DHE) may reverse established central sensitization. Using the same animal model as Burstein and Jakubowski, early administration of DHE, as with sumatriptan, was shown to effectively block induction of central sensitization. However, when DHE and zolmitriptan were administered after central sensitization had already been established, DHE reversed the changes in sensory thresholds, whereas zolmitriptan did not. These results are consistent with the earlier work showing sumatriptan to be ineffective in reversing established central sensitization. Furthermore, in a small, open-label study (N = 9), patients with episodic migraine associated with cutaneous allodynia were treated with intramuscular DHE for two headaches. Response was compared among patients treating early (within 2 hours of the onset of throbbing pain) and patients treating late (4 hours after the onset of throbbing pain). While results were similar in both groups, with 2-hour pain relief observed in greater than 55% of patients treating early or late, self-reported cutaneous allodynia began to decrease as soon as 30 minutes after early treatment and 120 minutes after late treatment. While these data support the potential use of DHE for the treatment of migraine with established central sensitization and cutaneous allodynia, the exact mechanisms by which DHE reverses central sensitization are not well established. The effect of DHE on glial cell activity and on the balance between MAP kinases and phosphatases may play an important role in this process, as these are effects that triptans do not exert.
MAP0004 (MAP Pharmaceuticals, Mountain View, CA, USA) is an orally inhaled form of DHE that has been shown to be effective for the acute treatment of migraine with or without aura, with fewer adverse events (AEs) compared with intravenous DHE dosing. This post hoc subanalysis of the efficacy of MAP0004 in patients with established cutaneous allodynia at the time of treatment was designed to expand upon the previously published pilot data supportive of the late treatment of migraine with established allodynia using DHE.
SHARE
