Post Hoc Subanalysis of Two Randomized, Controlled Phase 3 Trials Evaluating Diclofenac Potassium for Oral Solution: Impact of Migraine‐Associated Nausea and Prior Triptan Use on Efficacy

Abstract

ObjectiveTo determine whether baseline nausea or prior triptan treatment for migraine impact the effectiveness of diclofenac potassium for oral solution in treating acute migraine.BackgroundA great deal of variability exists in patients' response to migraine medications. Migraine‐associated nausea is common and debilitating and can reduce the effectiveness of oral medications. It may cause patients to delay taking oral medications, which is known to diminish therapeutic outcomes, or to avoid taking them altogether. Gastroparesis, which may be associated with nausea, also inhibits drug absorption, resulting in lower bioavailability. Studies have shown that having nausea at the time of drug administration predicts a poorer response to triptan treatment. It is of interest to understand how effective other migraine medications are in patients with a poor response to triptans.MethodsData from two randomized, double‐blind, placebo controlled trials were pooled and post hoc subgroup analyses were performed in patients with and without nausea at baseline, and in patients with and without prior triptan treatment. Efficacy assessments included the percentage of patients who, at 2 hours postdosing, were headache pain‐free (2hPF, primary endpoint), without photophobia, without phonophobia, without nausea, or without a severe degree of disability. A Cochran–Mantel–Haenszel test, stratified by analysis center was used to evaluate treatment effect. Effects of nausea or prior triptan use were determined using logistic regression with factors of treatment group, analysis center, nausea or prior triptan use at time of dosing, and interaction of treatment group by nausea or prior triptan use at time of dosing.ResultsThe modified intent to treat population consisted of 1272 patients, 644 on active drug and 628 on placebo. The majority of patients (85%) were female. At the time of dosing, 783 (62%) patients reported nausea with the treated attack. Prior triptan use was recorded in 570 (45%). For headache pain, nausea, photophobia, and phonophobia, patients in the active treatment group had a statistically significantly better response than those receiving placebo, regardless of whether they had nausea at baseline. In logistic regression analysis only treatment group predicted a response for these parameters with no detectable group interaction. Baseline nausea, as well as treatment group, predicted whether patients recorded severe disability at 2 hours. While patients in the active treatment group were significantly more likely to be headache pain‐free at 2 hours after dosing, whether or not they had previously been treated with triptan, more triptan‐naïve patients (30%) than triptan‐experienced patients (20%) were headache pain‐free. Interestingly, in the placebo groups, triptan‐naïve patients were also more likely to be PF (14% vs 7%). In the logistic regression analysis, treatment group predicted a headache pain response, triptan use predicted a lack of response, and there was no interaction between the two. Prior triptan use did ...

Efficacy of ubrogepant based on prior exposure and response to triptans: A post hoc analysis

“…However, treatment‐by‐subgroup interaction p values from the logistic regression model, which accounts for all data, found that this pattern was not significant for any of the efficacy outcome measures evaluated. Increased placebo responses in treatment‐naïve participants have been observed in other clinical trials of acute treatment of migraine 22–24 and, although the reasons for this consistent finding are unclear, they may be attributable to a number of factors. It is possible that the diagnosis of migraine was less robustly established in these triptan‐naïve participants and, therefore, this did not lead to prior prescription of a standard migraine‐specific treatment, or that expectation of a new treatment in those who have not had migraine‐specific treatments amplifies the placebo response.…”

STOP 101: A Phase 1, Randomized, Open‐Label, Comparative Bioavailability Study of INP104, Dihydroergotamine Mesylate (DHE) Administered Intranasally by a I123 Precision Olfactory Delivery (POD®) Device, in Healthy Adult Subjects

“…35 Triptans may also cause neurological side effects and a low but increased risk for cardiovascular events. 36,37 Further, 30%-40% of patients 38 experience inadequate pain relief and fail to achieve pain-free status with triptans and may have an increased risk of medication-overuse headache. 39,40 While ergot alkaloids, specifically DHE (first approved in 1946), have been available for decades to treat acute migraine and offer an alternative to triptans, use of existing IV, subcutaneous (SC), intramuscular (IM), and nasal formulations of DHE is limited by patient concerns about ease of use and consistency of response, in addition to safety/tolerability concerns from both patients and health care practitioners.…”

“…Triptans are the standard of care for treating acute episodic migraine, but their oral administration is often hampered by the nausea and vomiting that can accompany migraine . Triptans may also cause neurological side effects and a low but increased risk for cardiovascular events . Further, 30%–40% of patients experience inadequate pain relief and fail to achieve pain‐free status with triptans and may have an increased risk of medication‐overuse headache .…”

Pathophysiology and Therapy of Associated Features of Migraine

“…Nevertheless, acute treatment can be essential in the management of nausea associated with migraine. NSAIDs could be effective in alleviating nausea in patients who have not taken any triptans [ 72 ] and there is a recent meta-analysis that supports gepants as an effective treatment for nausea in patients with episodic migraine [ 73 ]. Special attention must be paid to patients consuming opioids.…”