Efficacy of ADAM Zolmitriptan for the Acute Treatment of Difficult-to-Treat Migraine Headaches

Stewart J. Tepper, MD; David W. Dodick, MD; Peter C. Schmidt, MD, MSc; Donald J. Kellerman, PharmD


Headache. 2019;59(4):509-517. 

In This Article

Abstract and Introduction


Objective: To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications.

Background: ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention-to-treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients' usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post-dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications.

Methods: The ZOTRIP trial was a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran–Mantel–Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo.

Results: In patients with nausea, 2-hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group (P = .005) (odds ratio = 5.11, 95% CI: 1.96–13.30), and 2-hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo (P = .009) (odds ratio = 2.86, 95% CI: 1.28–6.43). For those with severe pain, corresponding pain-free values were 26% (10/39) and 15% (5/33) (P = .249) (odds ratio = 2.14, 95% CI: 0.60–7.62), and MBS-free values were 64% (25/39) and 42% (14/33) (P = .038) (odds ratio = 2.86, 95% CI: 1.05–7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain-free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively (P = .006) (odds ratio = 4.29, 95% CI: 1.50–12.31), and 72% (26/36) vs 39% (17/44) were MBS-free, respectively (P = .003) (odds ratio = 4.40, 95% CI: 1.61–12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively (P = .017) (odds ratio = 4.33, 95% CI: 1.24–15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group (P = .014) (odds ratio = 3.37, 95% CI: 1.27–8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction.

Conclusion: Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2-hour headache freedom and 2-hour MBS freedom) compared with those who received placebo.


Despite the well-established effectiveness of triptans in the acute treatment of migraine, they elicit a headache response in only 40–70% of patients in clinical trials, and the frequency of achieving complete pain freedom is considerably lower.[1–3] A number of factors are known to contribute to suboptimal acute treatment response. Multiple studies on large numbers of migraine sufferers have found that severe headache pain and nausea are important predictors of response.[4–6]

Early treatment initiation is also a significant predictor of enhanced therapeutic outcome.[7–13] Early treatment can prevent pain from progressing to moderate or severe and lessen the chances of central sensitization. The clinical consequence of central sensitization, allodynia, is itself an independent risk factor for migraine progression.[14] However, early treatment is not always an option, especially in those with rapid pain escalation as well as in the 48% of headaches that develop during sleep ("morning migraine").[15] These are often less responsive to acute treatment with oral therapies.[15–20]

For all migraine headaches, and particularly for these difficult-to-treat headaches, medication should have a fast onset. Guidance from the American Headache Society suggests for migraine headaches that reach maximal intensity rapidly and those associated with nausea and vomiting, non-oral formulations, such as intranasal or injectable treatments, may be more effective,[21] likely due to avoidance (or reduction, in the case of intranasal formulations) of the need for gastrointestinal absorption.

Adhesive Dermally Applied Microarray (ADAM) is a small adhesive device for intracutaneous drug delivery, which allows for rapid absorption. In a study evaluating the pharmacokinetics of zolmitriptan delivered with ADAM, the median tmax in serum was less than 20 minutes, comparable to subcutaneous sumatriptan. Absorption was considerably faster than for oral zolmitriptan, with higher exposure in the first 2 hours.[22] In a pivotal Phase 2b/3 randomized, double-blind, placebo-controlled study (ZOTRIP), ADAM zolmitriptan 3.8 mg met both co-primary endpoints of superior pain freedom and freedom from patients' usual other most bothersome symptom (MBS), compared with placebo at 2 hours post-dose.[23] The frequency of achievement of pain relief as well as lack of recurrence were also superior in the ADAM zolmitriptan 3.8 mg treatment group vs placebo.[23,24]

As ADAM zolmitriptan displays pharmacodynamic properties that may be desirable for use in difficult-to-treat headaches, we have undertaken a post hoc analysis of data from the ZOTRIP trial to examine efficacy in subsets of patients whose headaches had characteristics suggesting potential refractoriness to treatment.

The objective of this post hoc analysis of study data was to determine whether severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or awaking with migraine impacted the efficacy of ADAM zolmitriptan on the co-primary endpoints of the ZOTRIP trial.