Patterns of Perceived Stress Throughout the Migraine Cycle: A Longitudinal Cohort Study Using Daily Prospective Diary Data.

OBJECTIVES: To describe patterns of perceived stress across stages of the migraine cycle, within and between individuals and migraine episodes as defined for this study. METHODS: Individuals with migraine aged ≥18 years, who were registered to use the digital health platform N1-HeadacheTM , and completed 90 days of daily data entry regarding migraine, headache symptoms, and lifestyle factors were eligible for inclusion. Perceived stress was rated once a day at the participant's chosen time with a single question, "How stressed have you felt today?" with response options graded on a 0-10 scale. Days were categorized into phases of the migraine cycle: Ppre  = pre-migraine headache (the 2 days prior to the first day with migraine headache), P0  = migraine headache days, Ppost  = post-migraine headache (the 2 days following the last migraine day with migraine headache), and Pi  = interictal days (all other days). Episodes, defined as discrete occurrences of migraine with days in all 4 phases, were eligible if there was at least 1 reported daily perceived stress value in each phase. Individuals with ≥5 valid episodes, and ≥75% compliance (tracking 90 days in 120 calendar days or less) were eligible for inclusion in the analysis. RESULTS: Data from 351 participants and 2115 episodes were included in this analysis. Eighty-six percent of the sample (302/351) were female. The mean number of migraine days per month was 6.1 (range 2-13, standard deviation = 2.3) and the mean number of episodes was 6.0 (range 5-10, standard deviation = 1.0) over the 90-day period. Only 8 (8/351, 2.3%) participants had chronic migraine (defined as 15 or more headache days per month with at least 8 days meeting criteria for migraine). Cluster analysis revealed 3 common patterns of perceived stress variation across the migraine cycle. For cluster 1, the "let down" pattern, perceived stress in the interictal phase (Pi ) falls in the pre-headache phase (Ppre ) and then decreases more in the migraine phase (P0 ) relative to Pi . For cluster 2, the "flat" pattern, perceived stress is relatively unchanging throughout the migraine cycle. For cluster 3, the "stress as a trigger/symptom" pattern, perceived stress in Ppre increases relative to Pi , and increases further in P0 relative to Pi . Episodes were distributed across clusters as follows: cluster 1: 354/2115, 16.7%; cluster 2: 1253/2115, 59.2%, and cluster 3: 508/2115, 24.0%. Twelve participants (12/351, 3.4%) had more than 50% of their episodes fall into cluster 1, 216 participants (216/351, 61.5%) had more than 50% of their episodes fall into cluster 2, and 25 participants (25/351, 7.1%) had more than 50% of their episodes fall into cluster 3. There were 40 participants with ≥90% of their episodes in cluster 2, with no participants having ≥90% of their episodes in cluster 1 or 3. CONCLUSIONS: On an aggregate level, perceived stress peaks during the pain phase of the migraine cycle. However, on an individual and episode basis, there are 3 dominant patterns of perceived stress variation across the migraine cycle. Elucidating how patterns of perceived stress vary across the migraine cycle may contribute insights into disease biology, triggers and protective factors, and provide a framework for targeting individualized treatment plans.

Evaluating Mean Level and Within-Person Consistency in Migraine Pain Intensity and Migraine-Related Disability for AVP-825 vs Oral Sumatriptan: Results from the COMPASS Study, A Randomized Trial.

BACKGROUND: Consistency of response across multiple attacks is typically measured as the proportion of study participants who achieve a categorical endpoint over a specified number of attacks (ie, 2-hour pain-free response in 2 of 3 attacks). We applied a novel analytic approach for measuring consistency of response in the acute treatment of episodic migraine using data from the COMPASS study. METHODS: The COMPASS study (NCT01667679) was a multiple attack crossover study which compared AVP-825, a Breath Powered® intranasal delivery system for low-dose sumatriptan powder (22 mg), with 100-mg oral sumatriptan tablets in the acute treatment of migraine. Participants were 18-65 years old, met ICHD-2 criteria for migraine with or without aura, and had migraine for ≥1 year prior to screening. They were instructed to treat up to 5 migraine attacks with each treatment and recorded migraine pain intensity and disability data at pre-dose and 10, 15, 30, 45, 60, 90, and 120 minutes post-dose for each attack. We explored the mean level and within-person variability (WPV; a measure of consistency) in migraine pain intensity and migraine-related disability across multiple attacks after treatment with AVP-825 (22 mg) vs oral sumatriptan (100 mg) using location scale mixed-effects models (LSMEMs). LSMEMs controlled for pre-dose pain/disability, demographics, treatment sequence, and treatment period. RESULTS: The mean age was 40 and the sample was 84.6% women. Participants (N = 259) treated an average of 6.8 attacks each during the course of the study. Attacks treated with AVP-825 showed significantly lower mean pain intensity and mean disability from 10 to 90 minutes post-dose (effect sizes ranged from -0.09 to -0.29 and P values ranged from P < .0001 to P = .01). WPV was significantly greater at 10-15 minutes (WPV ratios ranged from 1.20 to 1.58 and P values ranged from P < .0001 to P = .04) but significantly reduced from 45 to 120 minutes for attacks treated with AVP-825 compared to oral sumatriptan (WPV ratios ranged from 0.67 to 0.81 and P values ranged from P < .0001 to P = .03). CONCLUSIONS: LSMEMs demonstrate that treatment with AVP-825 is associated with lower average migraine pain intensity and disability from 10 to 90 minutes and greater within-person consistency across multiple migraine attacks (reduced WPV) from 45 to 120 minutes post-dose compared to oral sumatriptan. These findings may reflect the more rapid and consistent absorption of sumatriptan using AVP-825. Increased WPV with AVP-825 in the first 15 minutes likely reflects the earlier onset of treatment effects with the device compared to oral sumatriptan. LSMEMs show promise as a novel approach for assessing and comparing consistency of treatment response in migraine trials.

AVP-825 (Sumatriptan Nasal Powder) Reduces Nausea Compared to Sumatriptan Tablets: Results of the COMPASS Randomized Clinical Trial.

BACKGROUND: Migraine-related nausea is associated with significant disability, increased burden of disease, and personal distress. Nausea can lead to delays or avoidance of initiating oral migraine treatment, sometimes resulting in treatment failures and poor outcomes. Nausea is often a symptom of migraine, but nausea may also be a consequence of treatment (ie, treatment emergent nausea [TEN]). Relieving nausea and minimizing TEN are important goals in acute migraine therapy. METHODS: We analyzed data from the COMPASS study, a randomized, double blind, double-dummy, comparative efficacy study that contrasted two active treatments, AVP-825 (breath-powered intranasal delivery of powdered sumatriptan 22 mg) and oral sumatriptan tablets (100 mg). Three-level logistic multilevel models were used to examine longitudinal changes in nausea from three distinct perspectives across multiple attacks. Model 1 (Overall Nausea) examined longitudinal change in nausea from pre-dose through 120 minutes post-dose for the entire sample, independent of baseline nausea. Model 2 examined TEN from 10 minutes through 120 minutes post-dose in attacks free of nausea at baseline to investigate whether or not nausea developed following treatment. Model 3 examined Nausea Relief from 10 minutes through 120 minutes post-dose in eligible attacks with nausea at baseline to examine whether or not nausea was relieved over the first 2 hours post-dose. Models tested for differences in rate of change in nausea over time and odds of nausea at specific time-points. RESULTS: Longitudinal nausea trajectories differed for AVP-825 and oral sumatriptan in the Overall Nausea model (Model 1) and TEN model (Model 2), but were more comparable across treatments for the Nausea Relief (Model 3). More specifically, in the Overall Nausea model (Model 1), an individual treating an attack with AVP-825 had a significantly faster decrease in nausea through the first 60 minutes post-dose and reduced odds of nausea at each time-point from 30 minutes through 120 minutes post-dose compared to oral sumatriptan. In Model 2, an individual's risk for TEN increased at a significantly faster rate through the first 45 minutes post-dose when treating an attack with oral sumatriptan, with significantly greater odds of experiencing TEN at 45, 60, and 90 minutes post-dose compared to AVP-825. The Nausea Relief model (Model 3) showed similar rates of change in nausea over time for the two treatments, but there was a constant difference in nausea level leading to reduced odds of nausea when treating with AVP-825 compared to oral sumatriptan. CONCLUSIONS: All three longitudinal models showed that AVP-825 had more favorable nausea outcomes compared to oral sumatriptan. AVP-825 treatment led to more rapid early reductions in Overall Nausea rates during the first hour, reduced odds of nausea from 30 minutes to 2 hours following treatment and reduced risk of TEN compared to oral sumatriptan. These results highlight the importance of separately assessing TEN and Nausea Relief in acute treatment trials of migraine.

Faster Improvement in Migraine Pain Intensity and Migraine-Related Disability at Early Time Points with AVP-825 (Sumatriptan Nasal Powder Delivery System) versus Oral Sumatriptan: A Comparative Randomized Clinical Trial Across Multiple Attacks from the COMPASS Study.

BACKGROUND: Fast relief of migraine pain, associated symptoms, and migraine-related disability are priorities in the acute treatment of migraine. Efforts to improve the pharmacokinetic profiles of acute migraine treatments with the aim of providing faster relief include the development of non-oral routes of administration. AVP-825 (ONZETRA® Xsail® ) is a delivery system containing 22 mg sumatriptan powder that uses a patient's own breath to deliver medication intranasally, targeting the upper posterior nasal cavity beyond the narrow nasal valve, an area lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. While most studies comparing treatments measure differences in proportions of patients achieving a dichotomous endpoint at fixed time intervals, in this study we compare trajectories of migraine pain and disability over time for AVP-825 versus 100 mg oral sumatriptan tablets. METHODS: We used data from the COMPASS study (NCT01667679, clinicaltrials.gov), a double-blind, double-dummy, active-comparator, cross-over study of people with a diagnosis of migraine. Participants treated up to five qualifying migraine attacks within 1 hour of onset with either AVP-825 plus placebo tablets or 100 mg oral sumatriptan tablets plus placebo delivery system during the first of two 12-week treatment periods, and then switched treatment sequences to treat up to five more attacks in the second treatment period. Patients recorded ordinal migraine pain intensity and migraine-related disability before dosing (predose), and at 10, 15, 30, 45, 60, 90 and 120 minutes. Three-level ordinal multilevel models accounted for unique data structure (repeated measures nested within attacks for each patient) and tested for treatment differences in migraine pain and migraine-related disability through the first 2 hours of attacks post dose. RESULTS: Among 259 study participants (mean age 40.0 years, 84.6% female, 78.4% white), there was significant between and within person variability in migraine pain intensity and migraine-related disability. A typical individual showed significantly faster reductions in migraine pain over the first 30 minutes and migraine-related disability over the first 45 minutes when treating with AVP-825 compared with oral sumatriptan. Overall levels of pain and disability also favored AVP-825 over 2 h following treatment. Model-based odds ratios (OR) comparing AVP-825 to oral sumatriptan ranged from 0.38 to 0.76 for pain and 0.37 to 0.65 for disability, with OR <1 indicating reduced pain/disability in the AVP-825 condition. CONCLUSIONS: Compared with 100 mg oral sumatriptan, treatment with AVP-825 was associated with faster reductions in migraine pain intensity and migraine-related disability starting at 10 minutes postdose and continuing through the first 30 minutes for migraine pain intensity and the first 45 minutes for migraine-related disability, resulting in lower overall pain intensity and disability that lasted through the first 2 h following treatment. Both migraine pain intensity and disability varied substantially both across subjects and within subjects across attacks.

Differentiating regressed melanoma from regressed lichenoid keratosis.

BACKGROUND: Distinguishing regressed lichen planus-like keratosis (LPLK) from regressed melanoma can be difficult on histopathologic examination, potentially resulting in mismanagement of patients. OBJECTIVE: We aimed to identify histopathologic features by which regressed melanoma can be differentiated from regressed LPLK. METHODS: Twenty actively inflamed LPLK, 12 LPLK with regression and 15 melanomas with regression were compared and evaluated by hematoxylin and eosin staining as well as Melan-A, microphthalmia transcription factor (MiTF) and cytokeratin (AE1/AE3) immunostaining. RESULTS: (1) A total of 40% of regressed melanomas showed complete or near complete loss of melanocytes within the epidermis with Melan-A and MiTF immunostaining, while 8% of regressed LPLK exhibited this finding. (2) Necrotic keratinocytes were seen in the epidermis in 33% regressed melanomas as opposed to all of the regressed LPLK. (3) A dense infiltrate of melanophages in the papillary dermis was seen in 40% of regressed melanomas, a feature not seen in regressed LPLK. CONCLUSIONS: In summary, our findings suggest that a complete or near complete loss of melanocytes within the epidermis strongly favors a regressed melanoma over a regressed LPLK. In addition, necrotic epidermal keratinocytes and the presence of a dense band-like distribution of dermal melanophages can be helpful in differentiating these lesions.

A Retrospective, Pooled Suicidality Evaluation of Ropinirole Immediate Release and Controlled Release for the Treatment of Restless Legs Syndrome.

PURPOSE: Based on an internal request, GlaxoSmithKline conducted a retrospective pooled analysis of randomized controlled trials to compare suicidality in adult subjects with restless legs syndrome (RLS) who were being treated with ropinirole. The objective was to proactively evaluate the incidence of potentially suicidal thoughts or behaviors (suicidality) among patients with RLS treated with ropinirole immediate release (IR) or controlled release (CR). METHODS: The US Food and Drug Administration approved methods previously used for the retrospective analysis of suicidality with antidepressants and anticonvulsants. Potential cases of suicidal thoughts and behavior were identified from searches of treatment-emergent adverse event preferred and verbatim terms; a review of serious adverse events; and searches of a priori-identified free text comment fields in the case report forms. Blinded case reports for these potential cases, in addition to all serious adverse events, were categorized by using the Columbia Classification Algorithm of Suicide Assessment. FINDINGS: The dataset for this study comprised 1799 patients who received ropinirole (either formulation) and 1258 patients who received placebo. No signal for suicidality was detected for ropinirole in the treatment of patients with RLS. IMPLICATIONS: The pooled datasets in this study were not designed to prospectively assess for suicidal ideation or behavior. Any future studies in this area should include the collection of prespecified, detailed information regarding suicidality.

The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis.

Polymorphic eruption of pregnancy (PEP), formerly known as pruritic urticarial papules and plaques of pregnancy, is a dermatosis of pregnancy that must be distinguished from pemphigoid gestationis (PG). Although this differential diagnosis may be possible on routine histology, an additional biopsy for direct immunofluorescence (DIF) is often needed. Recent studies have demonstrated the utility of anti-C4d or anti-C3d antibodies in the diagnosis of bullous pemphigoid (BP) in formalin-fixed paraffin-embedded tissue (FFPE). We investigated the utility of routine immunohistochemistry (IHC) for anti-C4d in FFPE tissue in the specific differential diagnosis of PEP versus PG in known, DIF-proven cases. We performed C4d IHC on PEP (n = 11), PG (n = 8), DIF-proven BP (n = 12), and other common dermatoses (n = 12) that are typically DIF negative. None of the PEP cases (0/11) or the other common dermatoses (0/12) demonstrated C4d positivity at the basement membrane zone. In comparison, 100% of PG cases (8/8) and 83.3% of BP cases (10/12) showed linear C4d immunoreactant deposition along the basement membrane zone. The results demonstrate the potential utility of C4d IHC in FFPE tissue for distinguishing PEP from PG, thus potentially obviating the need of a repeat biopsy for DIF, particularly in C4d-negative cases where there is a low suspicion of PG on both clinical and histological grounds. Also, patients with positive C4d-positive immunoreactivity may also potentially proceed directly to less invasive serological confirmatory testing, such as BP180 NC16a enzyme-linked immunoabsorbent assay.

Long-term, open-label study of once-daily ropinirole prolonged release in early Parkinson's disease.

Long-term safety and efficacy of once-daily ropinirole prolonged release (PR) were evaluated in subjects with early Parkinson's disease (PD). Subjects (n = 83) who completed one of two studies were enrolled in this open-label, multicenter, extension study, and followed for up to 78 months. Ropinirole PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/day). L-dopa and other non-dopamine agonist PD medications were permitted. Safety outcomes included adverse events (AEs). Efficacy outcomes included Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scores. The median duration of ropinirole PR exposure was 1,069 days. Most subjects (97.6%) reported at least one AE, most commonly (≥ 30%) nausea (42.2%), dizziness (41.0%), peripheral edema (38.6%), back pain (33.7%), and headache (31.3%). Seventeen (20.5%) subjects discontinued due to an AE. UPDRS and CGI scores indicated that the clinical status of subjects was maintained throughout the treatment period. In patients with early PD, long-term treatment with once-daily ropinirole PR was not associated with any new safety concerns, and was effective in maintaining clinical status. These results support the extended use of ropinirole PR for treatment of PD.