The burden of medication overuse headache and patterns of switching and discontinuation among triptan users: a systematic literature review

Background A synthesis of real-world discontinuation and switching patterns among triptan users and rates of acute medication use among patients with medication overuse headache (MOH) is needed to better understand the burden among patients with migraine. The study objectives were to: (1) synthesize rates of switching and discontinuation from triptans; (2) characterize acute medication use among patients with MOH; and (3) describe the associated burden. Methods A systematic literature review was conducted, under the Preferred Reporting Items for Systematic Review guidelines, using MEDLINE/EMBASE from database inception to July 2019. The search strategy targeted studies of adults with migraine, and included terms related to migraine and its treatment. Continuous variables were summarized using means, standard deviations, and ranges. Dichotomous and categorical variables were summarized using the number and proportion of individuals. Results Twenty studies were included; seven describing patterns of switching and discontinuation among triptan users, and 13 characterizing triptan overuse among patients with MOH. High rates of switching to non-specific acute medications and low two-year retention rates were reported; among US samples switching to opioids at the first refill (18.2%) or after 1-year (15.5%) was frequent. Compared to persistent use of triptans, switchers experienced greater headache related impact and either no improvement or increased headache-related disability. Rates of medication overuse by agent among patients with MOH varied greatly across the included studies, and only one study described factors associated with the risk of MOH (e.g. duration of medication overuse). Medication agent, increased headache frequency (p = .008), and increased disability (p = .045) were associated with unsuccessful withdrawal; patients overusing triptans were more successful at withdrawal than those overusing opioids or combination analgesics (P < .0001). Conclusions The evidence summarized here highlights that rates of WCS are low and many patients turn to other acute medication at their first refill. Patients may experience no improvement in disability when switching from one triptan agent to another, or experience increasing disability and/or increasing migraine frequency when turning to traditional acute treatment for migraine. Variability in health care settings, patient severity, and study design contributed to heterogeneity across the synthesis.

Ubrogepant to Treat Acute Migraine in Adults

Migraine is a neurobiological headache disorder that affects around 16% of adults in the United States. Medical treatment of mild to moderate migraines include non-prescription non-steroidal anti-inflammatory drugs, acetaminophen, or aspirin and caffeine-containing combination analgesics. Additionally, moderate to severe migraines and those that are mild to moderate that have not responded to analgesics can be treated with triptans, which are drugs specific for migraine treatment. Non-pharmacological treatments include cognitive behavioral therapy and relaxation training. Medications for the prevention of migraines have also been developed since they are more affective in offsetting the symptoms. Ubrogepant’s high specificity and selectivity for calcitonin gene-related peptide (CGRP) sets it apart from certain other drugs, which previously limited the treatment of migraines with or without aura due to their decreased selectivity. The most frequently reported side effects are oropharyngeal pain, nasopharyngitis, and headache. Most studies found that participants receiving Ubrogepant were free from pain within 2 h when compared to placebo. Patients taking Ubrogepant should avoid taking it when pregnant or with end stage renal disease. In summary, Ubrogepant has good tolerability and an overall favorable safety profile. It appears to hold promise for the acute treatment of migraines with or without aura in adults.

Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache

Medication-overuse headaches (MOH) occur with both over-the-counter and pain-relief medicines, including paracetamol, opioids and combination analgesics. The mechanisms that lead to MOH are still uncertain. Here, we show that abnormal activation of Nav1.9 channels by Nitric Oxide (NO) is responsible for MOH induced by triptan migraine medicine. Deletion of the Scn11a gene in MOH mice abrogates NO-mediated symptoms, including cephalic and extracephalic allodynia, photophobia and phonophobia. NO strongly activates Nav1.9 in dural afferent neurons from MOH but not normal mice. Abnormal activation of Nav1.9 triggers CGRP secretion, causing artery dilatation and degranulation of mast cells. In turn, released mast cell mediators potentiates Nav1.9 in meningeal nociceptors, exacerbating inflammation and pain signal. Analysis of signaling networks indicates that PKA is downregulated in trigeminal neurons from MOH mice, relieving its inhibitory action on NO-Nav1.9 coupling. Thus, anomalous activation of Nav1.9 channels by NO, as a result of chronic medication, promotes MOH.