Schwedt, Todd J.

Abstract Objective We sought to assess factors associated with the frequency of self‐reported prescription opioid use in persons with migraine, including demographic variables, comorbidities, headache characteristics, and patterns of consultation. Background Despite the dose‐dependent effect of opioids on migraine progression and the association with negative outcomes, migraine treatment often includes opioids. The Migraine in America Symptoms and Treatment Study focuses on individuals with migraine who receive prescription acute medications, including those receiving and those not receiving opioids. Methods This web‐based panel survey identified people in the United States with migraine using a validated screener. This analysis stratified people with migraine into 4 groups based on days of monthly opioid use: non‐opioid users, ≤3 days, 4‒9 days, and ≥10 days per month. Results Of 15,133 respondents with migraine, 4701 (31%) reported acute prescription medication use for headache/migraine in the previous 3 months (mean age 45 years, 71.6% [3367/4701] female), of whom 32.5% (1528/4701) reported opioid use. About one‐third of respondents with primary care or neurology consults in the prior 6 months reported receiving an opioid, and more than half of respondents (209/391, 53.5%) with a pain clinic consultation did so. Models compared those using opioids ≤3 days/month (879/4701, 18.7%), 4‒9 days/month (304/4701, 6.5%), ≥10 days/month (345/4701, 7.3%) to non‐opioid users (3173/4701, 67.5%). Compared to non‐opioid users, infrequent users (≤3 days/month) were more likely to be male and less likely to have chronic migraine or to screen positive for anxiety and depression; and frequent opioid users (the 4‒9 days/month and the ≥10 days/month groups) were more likely to be male, to smoke, to be obese, to report greater pain interference, to have moderate to severe disability, to have symptoms of anxiety and depression, to use fewer triptans and nonsteroidal anti‐inflammatory drugs, and to have poor acute treatment optimization. Conclusion Among prescription medication users, this cross‐sectional analysis shows that increasing use of prescription opioids is associated with male gender, chronic migraine, more severe disability, anxiety and depression, poor acute treatment optimization, and treatment in a pain clinic.

Background Validated chronic migraine biomarkers could improve diagnostic, prognostic, and predictive abilities for clinicians and researchers, as well as increase knowledge on migraine pathophysiology. Objective The objective of this narrative review is to summarise and interpret the published literature regarding the current state of development of chronic migraine biomarkers. Findings Data from functional and structural imaging, neurophysiological, and biochemical studies have been utilised towards the development of chronic migraine biomarkers. These biomarkers could contribute to chronic migraine classification/diagnosis, prognosticating patient outcomes, predicting response to treatment, and measuring treatment responses early after initiation. Results show promise for using measures of brain structure and function, evoked potentials, and sensory neuropeptide concentrations for the development of chronic migraine biomarkers, yet further optimisation and validation are still required. Conclusions Imaging, neurophysiological, and biochemical changes that occur with the progression from episodic to chronic migraine could be utilised for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies. Ultimately, validated biomarkers could move us closer to being able to practice precision medicine in the field and thus improve patient care.

Background/objective Post-traumatic headache is one of the most common and persistent symptoms following mild traumatic brain injury. The objective of this narrative review is to provide an update on the diagnostic criteria, clinical presentation, epidemiology, pathophysiology, and treatment of post-traumatic headache, and to identify future research priorities. Methods This is a narrative review of the literature regarding post-traumatic headache attributed to mild traumatic brain injury. Results Onset of post-traumatic headache within 7 days of injury is the only evidence for a causal relationship between the injury and the headache included in the diagnostic criteria. Post-traumatic headache often resolves within the first few days of onset, whereas it persists for at least 3 months in 30–50%. The majority of insights into post-traumatic headache pathophysiology come from pre-clinical animal studies and human imaging studies, which implicate structural, functional, metabolic, and neuroinflammatory mechanisms for post-traumatic headache. There is a paucity of quality evidence for how to best treat post-traumatic headache. Conclusions Although meaningful progress has been made in the post-traumatic headache field, priorities for future research are numerous, including the optimization of diagnostic criteria, a greater understanding of post-traumatic headache pathophysiology, identifying mechanisms and predictors for post-traumatic headache persistence, and identifying safe, well-tolerated, effective therapies.

Abstract Objective Persistent posttraumatic headache (PPTH), one of the most common symptoms following mild traumatic brain injury, is often associated with substantial functional disability. The objective of this study was to assess the contribution of demographics, headache characteristics, and psychological symptoms to disability associated with PPTH. Methods Participants completed the State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory (BDI), the Pain Catastrophizing Scale (PCS), and the Migraine Disability Assessment (MIDAS) questionnaire. Two linear regression models were formulated to interrogate the relationships between 1) demographics and headache characteristics with the MIDAS questionnaire and 2) demographics, headache characteristics, and psychological symptoms with the MIDAS questionnaire. A two-way stepwise regression using the Akaike information criterion was performed to find a parsimonious model describing the relationships between demographics, headache characteristics, and psychological measures with the MIDAS questionnaire. Results Participants included 58 patients with PPTH and 39 healthy controls (HCs). The median MIDAS score among those with PPTH was 48.0 (first quartile [1Q] = 20.0, third quartile [3Q] = 92.0), indicative of severe disability. Compared with the HCs, those with PPTH had higher scores on the BDI, STAI, and PCS. Older age predicted lower MIDAS scores (age: B=–0.11, P<0.01), whereas higher headache frequency, greater headache intensity, and higher trait anxiety scores predicted higher MIDAS scores in individuals with PPTH (headache frequency: B=0.07, P<0.001; headache intensity: B=0.51, P=0.04; trait anxiety score: B=1.11, P=0.01). Conclusions Individuals with PPTH had substantial psychological symptoms and headache-related disability. Disability was partially explained by age, headache frequency and intensity, and trait anxiety. Holistic management of patients with PPTH to address headaches and psychological symptoms might reduce headache-associated disability.

Background and Objective: Symptoms of persistent post-traumatic headache (PPTH) most often resemble those of migraine, including the presence of photo-, phono-, and cutaneous hypersensitivities. The severity of these hypersensitivity symptoms in those with PPTH compared to those with migraine has yet to be fully elucidated. The objective of this study was to compare symptoms of sensory hypersensitivities between PPTH, migraine, and healthy controls (HCs). Further defining characteristics of PPTH and its similarities to migraine might assist with developing future diagnostic criteria for PPTH and provide insights into PPTH mechanisms. Methods: This analysis included 56 individuals with PPTH attributed to mild traumatic brain injury, 30 with migraine, and 36 HCs. To assess sensory hypersensitivities, all subjects completed the Allodynia Symptom Checklist-12, the Photosensitivity Assessment Questionnaire, and the Hyperacusis Questionnaire. Differences among groups were assessed using Fisher’s exact test, Kruskal–Wallis, or Mann–Whitney U test. Results: PPTH and migraine groups had greater severity of cutaneous, photo-, and phono-hypersensitivity symptoms compared to HCs. There were no statistically significant differences between the PPTH and migraine groups for cutaneous allodynia (median [first quartile, third quartile]; PPTH: 4.0 [2.0, 7.0]; migraine: 5.0 [3.0, 8.0]; p = 0.54) or photosensitivity severity (PPTH: 5.0 [2.0, 7.0]; migraine: 5.0 [2.0, 6.0]; p = 0.53). Those with PPTH had higher hyperacusis scores compared to those with migraine (PPTH: 23.0 [17.0, 31.0]; migraine: 13.5 [9.0, 24.0]; p = 0.001). Conclusion: Sensory hypersensitivity symptoms among individuals with PPTH are at least as severe as those experienced by people with migraine. Results further confirm symptom similarities between PPTH and migraine and could suggest that PPTH and migraine have a partially shared underlying pathophysiology.

Background and Objectives The association between migraine, depression, and anxiety has been established, but the impact of these psychiatric comorbidities on functional impairment in people with migraine has been under‐investigated. The purpose of this cross‐sectional observational study was to investigate the relationship between anxiety and depression symptoms on migraine‐related disability, pain interference, work interference, and career success in a cohort of patients with migraine. Methods This analysis included 567 migraine patients who had been enrolled into the American Registry for Migraine Research (ARMR) between February 2016 and June 2019. Patients completed the Generalized Anxiety Disorder‐7 (GAD‐7) and Patient Health Questionnaire‐2 (PHQ‐2) to measure symptoms of anxiety and depression, respectively. Patients completed the Migraine Disability Assessment Scale (MIDAS), Pain Interference (PROMIS pain short) questionnaire, and Work Productivity and Activity Interference (WPAI) questionnaire to measure levels of functional impairment at work and in daily activities. In addition, patients answered questions designed for ARMR regarding education and career interference. Models were created to describe the relationship between severity of psychiatric symptoms (anxiety and depression), and each outcome of interest (WPAI, MIDAS, pain interference, reporting that migraine had interfered with career success). Each model was controlled for age, sex, headache frequency, years with migraine, and average headache intensity. Results Among the 567 patients with migraine, mean (SD) age was 47.1 (13.7), 87.3% were female, and average headache frequency was 19.1 (9.3) days/month. PHQ‐2 scores were positively associated with scores on MIDAS ( b = 0.06, SE = 0.01, P ≤ .001), pain interference ( b = 1.4, SE = 0.2, P < .001), and WPAI including absenteeism ( b = 0.16, SE = 0.04, P = .007), presenteeism ( b = 2.7, SE = 1.1, P = .012), overall work productivity impairment ( b = 3.7, SE = 1.2, P = .001), and activity impairment ( b = 3.0, SE = 1.2, P = .009). PHQ‐2 scores were also associated with reporting that migraine interfered with career success ( b = 0.34, SE = 0.08, P ≤ .001). GAD‐7 scores were not associated with MIDAS, pain interference, WPAI, or reduced career success. Conclusions Severity of depression symptoms in patients with migraine is associated with migraine‐related disability, work interference, pain interference, and reduced career success. Patients with more severe symptoms of depression are more likely to have greater functional impairment. A management approach that addresses depression in those with migraine may lead to improvements in patient functioning.

Objective To summarize the current literature on non‐steroidal anti‐inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID‐19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. Background The use of non‐steroidal anti‐inflammatory drugs and corticosteroids in patients during the COVID‐19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID‐19 pandemic. Methods A detailed search of the scientific and popular literature was performed. Results There is limited literature pertaining to the safety of non‐steroidal anti‐inflammatory drugs and corticosteroids during the COVID‐19 pandemic. To date, there are no clear scientific data that preclude the use of non‐steroidal anti‐inflammatory drugs in the general population who may acquire COVID‐19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. Conclusion Scientific information regarding the COVID‐19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non‐steroidal anti‐inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID‐19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

Background Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT 1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. Methods Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours. Results Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor. Conclusions In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.