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

Disclosures

Headache. 2019;59(4):509-517. 

In This Article

Conclusions and Discussion

Severe pain, delayed treatment, awakening with migraine, and the presence of nausea are established factors that predict a poorer response to acute migraine treatment. In subsets 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.

The single exception was patients with severe pain at the time of treatment. In this subset, MBS freedom was more frequent in the ADAM zolmitriptan group than in the placebo group (P = .038), whereas pain freedom at 2 hours post-dose did not reach significance vs placebo (P = .249). However, the sample size in this group is low, and the percentage of patients (26%) who achieved 2-hour pain freedom was not dissimilar to what has previously been reported (30%) in a meta-analysis of 2657 patients with severe pain and treated with sumatriptan 100 mg.[4] Notably, other studies that have examined the effect of headache severity on triptan efficacy have evaluated the relative treatment effect in those with mild and moderate/severe pain intensity.[4,7,8,10,26] All participants in the ZOTRIP trial were required to have moderate/severe pain, and in aggregate, a clear treatment effect was observed for 2-hour pain freedom.

Migraine headaches peak in intensity within 60 minutes of onset 60–80% of the time,[27] and it is not always possible to treat before headache pain becomes severe. Studies evaluating treatment efficacy as a function of time from onset have often used 1 hour as a cutoff for early vs delayed treatment.[7,8,10,12] In the analysis from the ZOTRIP trial presented here, patients who delayed treatment 2 hours or more after headache onset still responded following ADAM zolmitriptan administration with higher rates of 2-hour pain freedom and 2-hour MBS freedom compared with placebo. Similarly, a significant treatment effect was observed in those who awoke with a migraine headache. The rapid absorption profile of ADAM zolmitriptan[22] may contribute to its ability to provide pain and MBS freedom in patients even when treatment is delayed.

Migraine-associated nausea is a substantial barrier to, and consequence of, taking oral acute therapies.[27,28] ADAM zolmitriptan 3.8 mg was also more effective than placebo in patients who experienced nausea at the time of treatment. Intracutaneous administration may therefore provide an additional advantage in these patients by bypassing the need for swallowing or inhaling medication.

As noted above, these analyses were not pre-specified, and adjustment was not made for multiple subgroup analyses to control for overall type I error, thus P values cannot formally be cited as significant or nonsignificant. For this reason, it is useful to evaluate numerical differences. Every endpoint for every subset was numerically superior in the ADAM zolmitriptan arm than the placebo arm.

Thus, the efficacy results seen in this trial suggest that ADAM zolmitriptan may be more effective than other routes of administration of triptans, particularly oral. The reasons for the improved efficacy are still speculative, but others have reported that efficacy is likely related to the rate of drug absorption.[15] Fast intracutaneous absorption accomplished with ADAM may facilitate rapidly delivering zolmitriptan to the 5-HT1B and 5-HT1D receptors.[29]

The ZOTRIP trial was not designed nor powered to assess treatment efficacy in the subsets of patients examined in these post hoc subgroup analyses. The sample sizes in the subsets were relatively small, which should be taken into consideration in interpreting the results. The fact that treatment effects were seen for the primary endpoints of the study for nearly all the subsets, and the uniform numerical differences in favor of the ADAM zolmitriptan in every subset analysis of each of the endpoints assessed, are noteworthy and suggest that ADAM zolmitriptan 3.8 mg may be an effective alternative for the types of migraine headache that have historically been difficult to treat.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....