A post hoc analysis of migraine-associated symptoms from the phase 3 randomized, double-blind, sham-controlled Trial of External trigeminal nerve stimulation for the Acute treatment of Migraine (TEAM) study

Background: The Trial of External trigeminal nerve stimulation (eTNS) for the Acute treatment of Migraine (TEAM) study demonstrated that eTNS use during active migraine resulted in significantly higher rates of resolution of migraine-associated most bothersome symptom (MBS) compared to sham. However, no previous studies have examined the association between pretreatment MBS subtype and efficacy of eTNS treatment for active migraine. Objective: We conducted a post hoc analysis examining efficacy of eTNS for different pretreatment MBS subtypes using TEAM study data. Methods: Pretreatment MBS subtypes included photophobia (n = 345), nausea (n = 109), phonophobia (n = 73), and vomiting (n = 11). We examined MBS sub-group x treatment group (verum n = 259; sham n = 279) interaction for each post-treatment outcome to explore differential effects conditional on the total sample. We further explored direct, between treatment group comparisons for each MBS subtype, as well as compared treatment outcomes among all MBS subtypes within the sham, verum, and total sample. Finally, clinical heterogeneity of treatment effect (HTE) was assessed using a 1% absolute treatment effect difference as the clinically important threshold. Results: Significant sub-group x treatment interactions were found for resolution of MBS at 2 h (p = 0.008), pain relief at 2 h (p = 0.001), rescue medication between 2 and 24 h (p = 0.012), sustained pain freedom at 24 h (p = 0.033), and sustained pain relief at 24 h (p = 0.003). Significant sub-group x treatment interactions were not found for pain freedom at 2 h (p = 0.054) or absence of all symptoms at 2 h (p = 0.265). Between treatment group comparisons indicated that pain freedom after 2 h of eTNS was not significantly different between the verum and sham groups for any pretreatment MBS. The verum group had a significantly greater proportion of participants who had resolution of nausea MBS after 2 h of treatment compared to sham (37/55 [67.3%] vs. 25/54 [46.3%], respectively; p = 0.028) and resolution of photophobia MBS compared to sham (85/162 [52.5] vs. 71/183 [38.8%], respectively; p = 0.011). There were no significant differences between treatment groups for phonophobia or vomiting. Pain freedom after 2 h of eTNS was not significantly different among pretreatment MBS groups. Within the sham group and total sample, a greater proportion of participants who had vomiting MBS had resolution of their MBS compared to any other pretreatment MBS (p < 0.05 after Bonferroni adjustment). A greater proportion of participants with nausea MBS used rescue medications between 2 and 24 h after eTNS compared to participants with photophobia or phonophobia MBS within the verum and total sample (p < 0.05 after Bonferroni adjustment). No statistical differences were found among MBS groups for any other treatment outcomes. Clinically important HTE was present in vomiting MBS for resolution of MBS and present in nausea MBS for pain freedom and pain relief after 2 h, need for rescue medication, and sustained pain freedom at 24 h post-treatment. There was no clinically relevant HTE in the nausea MBS group for resolution of MBS at 2 h, absence of all migraine-associated symptoms and sustained pain relief at 24 h, or for any endpoint for other MBS subtypes. Conclusion: Our results suggest the presence of both statistically significant HTE as well as clinically meaningful HTE. Statistical differences were primarily found for photophobia MBS, while clinically meaningful HTE was primarily found for nausea MBS. These findings may be clinically relevant for patients and clinicians when developing a treatment plan for acute treatment of migraine. Further studies are needed to elucidate the underlying pathophysiological differences between MBS subtypes and treatment optimization, particularly for patients with nausea MBS subtypes.