Dodick, David W.

Objective To identify factors associated with triptan discontinuation among migraine patients. Background It is unclear why many migraine patients who are prescribed triptans discontinue this treatment. This study investigated correlates of triptan discontinuation with a focus on potentially modifiable factors to improve compliance. Methods This multicenter cross‐sectional survey (n = 276) was performed at US tertiary care headache clinics. Headache fellows who were members of the American Headache Society Headache Fellows Research Consortium recruited episodic and chronic migraine patients who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years). Univariate analyses were first completed to compare current triptan users to past users for: migraine characteristics, other migraine treatments, triptan education, triptan efficacy, triptan side effects, type of prescribing provider, Migraine Disability Assessment ( MIDAS ) scores and Beck Depression Inventory ( BDI ) scores. Then, a multivariable logistic regression model was selected from all possible combinations of predictor variables to determine the factors that best correlated with triptan discontinuation. Results Compared with those still using triptans (n = 207), those who had discontinued use (n = 69) had higher rates of medication overuse (30 vs 18%, P = .04) and were more likely to have ever used opioids for migraine treatment (57 vs 38%, P = .006) as well as higher MIDAS (mean 63 vs 37, P = .001) and BDI scores (mean 10.4 vs 7.4, P = .009). Compared with discontinued users, current triptan users were more likely to have had their triptan prescribed by a specialist (neurologist, headache specialist, or pain specialist) (74 vs 54%, P = .002) and were more likely to report headache resolution (53 vs 14%, P < .001) or a reduction in pain intensity (71 vs 28%, P < .001) most of the time from their triptan. On a 1‐5 scale (1 = disagree, 5 = agree), triptan users felt they had more: control over their migraine attacks (2.9 vs 2.1), confidence in their prescribing provider (4.5 vs 4.0), and were more educated about triptan use (4.2 vs 3.7) compared with triptan discontinuers ( P < .001 for all comparisons). Although both current and prior users reported similar rates of side effects (48 vs 43%, P = .44), of those who discontinued use, the main reasons were for lack of effect (44%) and side effects (29%). Our multivariable modeling revealed that the strongest correlate of triptan discontinuation was lack of efficacy (odds ratio = 17, 95% confidence interval [8.8, 33.0]). Other factors associated with discontinuation included MIDAS > 24 (2.6, [1.5, 4.6]), BDI >4 (2.5, [1.4, 4.5]), and a history of ever using opioids for migraine therapy (2.2, [1.3, 3.8]). Having a triptan prescribed by a specialist and using at least 1 other abortive medication with the triptan were associated with a decreased likelihood of triptan discontinuation (0.41, [0.2‐0.7] and 0.44 [0.3, 0.8], respectively). Conclusions As expected, discontinuation was most correlated with lack of efficacy, but other important factors associated with those who had discontinued use included greater migraine‐related disability, depression, and the use of opioids for migraine attacks. Compared with patients who had discontinued triptans, current triptan users felt more: educated about their triptan, control over their migraine attacks, and confidence in their prescribing provider. Current triptan users had their triptan prescribed by a specialist and used other abortive medications with their triptan more often compared with patients who had discontinued triptans. Given the cross‐sectional nature of this study, we cannot determine if these factors contributed to triptan discontinuation or reflect the impact of such discontinuation. Interventions that address modifiable risk factors for triptan discontinuation may decrease the likelihood of triptan discontinuation and thus improve overall migraine control. Because lack of efficacy was most strongly associated with triptan discontinuation, future research should determine why triptans are effective for some patients but not others.

Background BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. Methods In this randomized, double-blind, placebo controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg); sumatriptan 100 mg (active comparator); and placebo. Patients were treated for a single migraine attack. The primary endpoint was pain freedom at two hours post-dose. Results Of patients who took the study drug, 799 had one post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, p = 0.002), 150 mg (32.9%, p < 0.001), and 300 mg (29.7%, p = 0.002) groups and the sumatriptan group (35%, p < 0.001) had pain freedom at two hours post-dose versus placebo (15.3%). For the secondary endpoint of sustained pain freedom from two to 24 hours post-dose, BMS-927711 doses (25–600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs. Conclusions BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine ( FHM ). The first FHM gene that was identified is CACNA1A . A second gene, FHM2 , has been mapped to chromosome 1 q 21‐23. The defect is a new mutation in the α 2 subunit of the N a/ K pump ( ATP1A2 ). A third gene ( FHM3 ) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A ( Gln1489Lys ), which encodes an α1 subunit of a neuronal voltage‐gated N a+ channel. Genome‐wide association studies have identified many non‐coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two‐pore domain potassium channel, TWIK ‐related spinal cord potassium channel. TWIK ‐related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.

Significant progress in molecular genetics has advanced our understanding of the genetic basis of migraine. The fundamentals of molecular genetics, and the recent advances in the field, are important for clinicians to understand, as they provide a foundation for critical appraisal of the literature, unprecedented insights into the pathogenesis of the disorder, and reveal promising treatment targets for future drug development. This paper provides a primer of molecular genetics and will be followed by a companion paper on the genetic advances in migraine, the methodology of genome wide association studies, and the potential clinical implications.

Objective Preclinical evaluation of headache by behavioral assessment of reward from pain relief. Methods Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. Results Dural IMs produced long‐lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c‐Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra‐NAc α‐flupenthixol, a dopaminergic antagonist. Intravenous α‐calcitonin gene‐related peptide (αCGRP) (8–37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP (8–37) abolished RVM lidocaine‐induced CPP in IM‐treated rats. Sumatriptan treatment blocked NAc dopamine release in IM‐treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief‐induced CPP in rats with incisional injury. Interpretation Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies. Ann Neurol 2013;74:257–265