Pilot study evaluating treatment with sumatriptan for moderate to severe post-traumatic headache: A phase 2 open-label study.

OBJECTIVE: Our primary outcome was to determine the feasibility of patients with post-traumatic headache (PTH) keeping a daily headache diary and using sumatriptan as directed. Secondary outcomes include determining if sumatriptan is effective in aborting PTH and whether headache resolution is dependent on PTH phenotype. BACKGROUND: PTH is prevalent and persistent after traumatic brain injury, yet there have been few studies evaluating the effects of pharmacological treatments in individuals with PTH. METHODS: This is a single-arm, prospective, non-randomized phase 2 clinical trial registered at Clinicaltrials.gov (NCT01854385) and conducted from 2013 to 2017. Data analysis was completed in 2022. Of the 299 participants screened, 40 were enrolled in the study. Participants kept a headache diary documenting headache characteristics and severity. Headache characteristics were used to determine PTH phenotypes of migraine-like, probable migraine-like, or non-migraine-like. Participants reported whether sumatriptan was used for their headache, their response to the medication, if a second dose was taken, and their response to the second dose. RESULTS: A total of 15 participants out of the 40 enrolled (mean [SD] age, 41.9 [14.2] years, and 53% [21/40] male), met the criteria for the use of sumatriptan, and completed all assessments. Average headache diary compliance rate for the final month of the study was 80% (372/465). While sumatriptan was used for only 19% (122/654) of all reported headaches, 72% (88/122) of those headaches resolved within 2 h of taking the medication. Resolution of headaches with sumatriptan was not significantly different among headache phenotypes (migraine-like: 22/38 [58%], probable migraine-like: 24/29 [83%], non-migraine-like: 6/15 [40%]; p = 0.154). CONCLUSIONS: A daily headache diary is feasible for tracking headache symptoms. Preliminary results also suggest that sumatriptan, a migraine-specific medication, may be beneficial for the treatment of PTH of different clinical phenotypes. Future studies, such as a phase 3 clinical trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in the treatment of PTH.

A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management.

OBJECTIVE: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug-drug interactions (DDIs) with the use of these therapies in migraine management. BACKGROUND: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. METHODS: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide pathway with medications that may be used for comorbid conditions. RESULTS: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. CONCLUSIONS: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine-specific evidence-based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

Timing and durability of response to erenumab in patients with chronic migraine.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. METHODS: This is a post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). RESULTS: Among the erenumab 140 mg group (n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group (n = 188). CONCLUSION: A majority of erenumab-treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

Use of Amitriptyline in the Treatment of Headache After Traumatic Brain Injury: Lessons Learned From a Clinical Trial.

OBJECTIVES: The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI). BACKGROUND: Despite the fact that headache is the most common and persistent physical symptom after TBI, there has been little research on the longitudinal course or pharmacologic treatment of this disorder. Of those who have headache after injury, about 60% continue to complain of headache at 3 months post injury, with higher levels of disability than those without headache. There have been no prospective, randomized, controlled trials of a pharmacologic agent for headache after TBI. Additionally, a brain-injured population may be more susceptible to side effects of medication. DESIGN: This is a single-center phase II trial of amitriptyline to prevent persistent headache after an mTBI. Medication dose was gradually increased from 10 to 50 mg daily. RESULTS: Fifty participants were enrolled and 33 who completed the 90-day assessment were included in the final analysis. In order to detect a possible cognitive impact of the study drug, 24 participants were randomly assigned to start amitriptyline immediately after study enrollment and 26 were assigned to start 30 days after enrollment. Forty-nine percent (18/37) of those assigned to take medication took none throughout the study period, with less compliance in younger participants with mean ages of 32.7 in those who did not take any medication, 33.4 who were less than 80% compliant, and 42.3 who were compliant (P = .013). Compliance in keeping a daily headache diary was low, with 29/50 participants (58%) meeting daily entry completion, and only 10 participants maintaining 100% diary completion. No differences were found between those who started medication immediately vs at day 30 in headache frequency or severity. CONCLUSIONS: While headache is the most common symptom following mTBI, current evidence does not support a specific treatment. No differences were noted in headache frequency compared to our prior study. However, the current sample had significantly lower headache severity (15% vs 36% with pain rating of 6 or above, P = .015) compared to our prior study. Our current study was not able to determine whether there is any benefit for the use of amitriptyline as a headache preventive because of difficulty with study recruitment and compliance. The challenges with recruitment and retention in the mTBI population were instructive, and future research in this area will need to identify strategies to improve recruitment, diary compliance, and medication adherence in this population.

Posttraumatic Headache: Classification by Symptom-Based Clinical Profiles.

There are currently no accepted therapies for posttraumatic headache (PTH). In order to meet the urgent need for effective therapies for PTH, we must continue to address fundamental gaps in our understanding of the clinical course and impact of PTH. Here we examine the existing schema used to characterize the clinical characteristics of PTH, including the International Classification of Headache Disorders (ICHD). There remain unresolved questions about whether to classify patients based on the extent of brain injury or on clinical symptom profiles. There also remain problematic issues of definition such as continuous headache, and chronic daily headache with features of "embedded" migraine-type within these headaches, which will need to be studied further. We make the case that a symptom-based classification is needed to begin an examination of these unresolved questions, and to establish clinically relevant endpoints for research and clinical trials for effective therapies.

Basic Considerations for the Use of Monoclonal Antibodies in Migraine.

BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.

The Pharmacology of Indomethacin.

BACKGROUND: Over 50 years ago, indomethacin emerged as an extremely potent non-steroidal anti-inflammatory drug (NSAID) during a massive effort to find effective anti-inflammatory and analgesic medications. The 1960s saw acetic acid derivatives developed into indomethacin, diclofenac, and sulindac, and propionic derivatives into ibuprofen, naproxen, and ketoprofen. Indomethacin was likely the most potent of these compounds and one of the earliest to enter clinical trials. It is not surprising that indomethacin was among the first of the NSAID medications to be used in treatment of migraine and for headaches that eventually became known as "indomethacin-responsive" headache disorders. Potential pharmacokinetic and bio-mechanistic differences between indomethacin and other NSAIDs are of great clinical and research interest to explain this observation. METHODS/RESULTS: The present article summarizes pharmacologic properties of indomethacin, including pharmacokinetics with particular attention to its distribution into the central nervous system, adverse effects, drug interactions, and mechanisms of action. Data are emphasized where differences in biomechanisms are found between indomethacin and other NSAIDs. The use of indomethacin in pregnant and lactating women is reviewed. CONCLUSIONS: NSAIDs easily enter the brain, but their high protein binding limits absolute amount of entry. All work similarly as either nonselective or selective cyclooxygenase inhibitors, but indomethacin may have more potent vasoconstrictive activity and unique direct neuronal or nitric oxide-dependent inhibitory pathway activity.

Comorbidity of Headache and Depression After Mild Traumatic Brain Injury.

OBJECTIVE: To examine headache and depression over time in individuals who sustained mild traumatic brain injury (mTBI). Prevalence of headache and depression early after mTBI and at 1 year postinjury as well as the relationship between the two are evaluated. BACKGROUND: Headache is the most common physical symptom and depression is among the most common psychiatric diagnosis after traumatic brain injury regardless of severity. Headache and depression have been found to be two independent factors related to poor outcome after mTBI, yet there appears to be a paucity of research exploring the comorbidity of these two conditions after injury. METHOD/DESIGN: Longitudinal survey design over 1 year of 212 participants with mTBI who were admitted to a Level 1 trauma center for observation or other system injuries. Depression was based on a score ≥10 on the Patient Health Questionnaire-9. Headache was based on participant report of new or worse-than-preinjury headache since hospitalization (baseline) or within the previous 3 months at 1 year postinjury. RESULTS: The prevalence of headache and depression at baseline was 64% (135/212) and 15% (31/212), respectively. The prevalence of headache and depression at 1 year was 68% (127/187) and 27% (50/187), respectively. The co-occurrence of headache and depression increased from 11% (23/212) at baseline to 25% (46/187) at 1 year. At 1 year, the risk ratio of individuals who had headache to be depressed was 5.43 (95% CI 2.05-14.40) compared to those without headache (P < .001). The corresponding risk ratio at baseline was 1.64 (95% CI .77-3.49; P = .23). CONCLUSIONS: While prevalence of headache is consistently high over the first year after injury, rate of depression increased over the first year for those who were followed. Given the high rate of comorbidity, those with headache may develop depression over time. Evaluation for possible depression in those with headache after mTBI should be conducted to address both conditions over the year following injury.

Posttraumatic Headache: Clinical Characterization and Management.

Headache is the most common symptom after traumatic brain injury (TBI). TBI has become a global health concern with an estimated 2.5 million reported TBIs per year in the USA alone. Recent longitudinal studies of posttraumatic headache (PTH) show a high cumulative incidence of 71 % after moderate or severe TBI and an even higher cumulative incidence of 91 % after mild TBI (mTBI) at 1 year after injury. Prevalence remains high at over 44 % throughout the year after moderate or severe TBI and over 54 % after mTBI. A prior history of headache is associated with a higher risk for PTH, whereas older age appears to be protective. Gender does not appear to be a risk factor for PTH. Most PTH has clinical diagnostic criteria meeting that of migraine or probable migraine when primary headache disorder classification criteria are used, followed by tension-type headache. There are no evidence-based treatment guidelines for PTH management; however, expert opinion has suggested treating the PTH using primary headache disorder treatment recommendations according to its type.

A prospective study of prevalence and characterization of headache following mild traumatic brain injury.

BACKGROUND: Headache is one of the most common and persistent symptoms following traumatic brain injury (TBI). The current study examines the prevalence and characteristics of headache following mild TBI (mTBI). METHODS: We prospectively enrolled 212 subjects within one week of mTBI who were hospitalized for observation or other system injuries in a single level 1 US trauma center and followed by telephone at three, six, and 12 months after injury for evaluation of headache. Headaches were classified according to ICHD-2 criteria as migraine, probable migraine, tension-type, cervicogenic, or unclassifiable headache. RESULTS: Subjects were 76% male and 75% white, and 58% were injured in vehicle-related crashes. A follow-up rate of 90% (190/212) occurred at 12 months post-injury. Eighteen percent (38/212) of subjects reported having a problem with headaches pre-injury while 54% (114/210) of subjects reported new or worse headaches compared to pre-injury immediately after injury, 62% (126/203) at three months, 69% (139/201) at six months, and 58% (109/189) at one year. Cumulative incidence was 91% (172/189) over one year. Up to 49% of headaches met criteria for migraine and probable migraine, followed by tension-type headaches (up to 40%). Age (≤ 60) was found to be a risk factor, but no significant difference was found in persistence of new or worse headache compared to pre-injury between males and females. More than one-third of the subjects reported persistent headache across all three follow-up time periods. CONCLUSIONS: Headache after mTBI is very common and persistent across the first year after injury. Assertive, early treatment may be warranted to avoid chronicity and disability. Further research is needed to determine whether post-traumatic headache (PTH) responds to headache treatment used in the primary headache disorders and whether chronic PTH is preventable.

Vascular risk in migraineurs: interaction of endothelial and cortical excitability factors.

BACKGROUND: Migraine is a common primary headache disorder occurring predominantly in a young, relatively healthy population. RESULTS: There is a growing literature on associations between migraine, especially migraine with aura, and ischemic stroke as well as other vascular events. Migraine as a risk factor for vascular disease and connections between migraine and endothelial, structural, and genetic risk are reviewed. CONCLUSION: There may be an interaction between endothelial dysfunction and cortical spreading depression affecting risk. Patient education and treatment of modifiable risk factors may decrease future vascular events.

Medication usage patterns for headache treatment after mild traumatic brain injury.

OBJECTIVE: To describe patient self-report of headache treatment in the first year following mild traumatic brain injury (TBI). BACKGROUND: An understanding of appropriate management of symptoms after mild TBI is crucial for improving acute care and long-term outcomes. This is particularly true for post-traumatic headaches as recent studies suggest that headaches after mild TBI are common with multiple phenotypes. In addition, symptoms such as headache after mild TBI are often managed by primary care providers without specialty training, and often in medically underserved areas. Outside of previous opinion papers, few studies have guided the treatment or examined the effectiveness of the interventions for post-traumatic headache. METHODS: One hundred sixty-seven participants admitted to a level 1 trauma hospital with mild TBI who were prospectively enrolled and reported new or worse headache at 3, 6, or 12 months after injury. RESULTS: Participants were primarily male (75%), white (75%), injured in vehicle crashes (62%), and had completed high school (83%). The majority of headaches met International Classification of Headache Disorders-2nd edition criteria for migraine/probable migraine, followed by tension-type headache. Despite the diverse nature of headaches, more than 70% of those with headache at each time period used acetaminophen or a nonsteroidal anti-inflammatory drug for headache control. Only 8% of those with the migraine/probable migraine phenotype used triptans. Of those individuals who used medication, 26% of those with migraine/probable migraine phenotype and 70% of those with tension headache phenotype endorsed complete relief (vs partial or no relief) because of medication use. The majority of individuals with tension headache reported never taking medication. CONCLUSIONS: Headaches after mild TBI are frequent and are not optimally treated. Results suggest that many individuals with mild TBI may be self-treating their headaches by utilizing over-the-counter pain relief medications. These medications, however, are only providing effective treatment for a minority of this population. Further research must be conducted to develop evidence-guided treatment and educate providers.

Collaborative Care for Chronic Pain After Traumatic Brain Injury: A Randomized Clinical Trial.

Importance: Chronic pain after traumatic brain injury (TBI) is prevalent and associated with poor outcomes. By providing multidisciplinary care through expert consultation, a collaborative care (CC) treatment approach may reduce pain interference. Objective: To compare CC with usual care (UC) in decreasing pain interference. Design, Setting, and Participants: This randomized clinical trial was conducted from July 2018 through April 2021 at 2 hospital-based academic rehabilitation medicine clinics in Seattle, Washington. Participants included adults with mild-to-severe TBI (at least 6 months before enrollment) and chronic pain. Data analysis was performed from March 30, 2022, to August 30, 2023. Intervention: The CC intervention (called TBI Care) included up to 12 in-person or telephone visits over 16 weeks with a care manager (CM) who provided person-centered cognitive behavioral treatment. The CM met weekly with members of the expert team to review participants and discuss recommendations to optimize treatment. Main Outcomes and Measures: The primary outcome was pain interference on the Brief Pain Inventory at treatment conclusion (4 months after randomization). Secondary outcomes included pain interference at 8 months; pain severity; symptoms of depression, anxiety, and sleep disturbance; pain-related emergency department visits; community participation; and participant satisfaction. Linear mixed-effects regression was used for analysis. Results: A total of 1379 individuals were screened for eligibility, and 158 were randomized (79 to CC and 79 to UC). The participants were mostly women (92 participants [58%]) with a mean (SD) age of 46.8 (13.2) years and a mean (SD) of 15.3 (3.0) years of education. TBI occurred a mean (SD) of 4.0 (5.9) years (median [IQR], 1.9 [0.8-4.5] years) before enrollment. All TBI severities were included, and of 149 participants for whom TBI severity was known, the majority (97 participants [65%]) had mild TBI. In the CC group, 71 participants (90%) completed at least 11 sessions, and, at 4 months, this group had significantly lower pain interference scores compared with the UC group (mean [SD], 3.46 [2.17] vs 5.03 [2.28]). This difference was maintained at 8 months after randomization, with mean (SD) TBI care pain interference scores of 3.61 (2.22) for CC vs 4.68 (2.51) for UC. At 4 months, there was significantly lower pain severity in the CC group vs UC group (mean [SD] score, 3.63 [1.95] vs 4.90 [1.96]), as well as symptoms of depression (mean [SD] score, 8.07 [5.34] vs 11.31 [6.37]) and anxiety (mean [SD], 6.20 [5.17] vs 9.58 [6.00]). Satisfaction with pain treatment (mean [SD] score, 2.99 [1.23] vs 2.52 [1.25]), clinical care (mean [SD] score, 3.28 [1.00] vs 2.84 [1.26]), and overall health care (mean [SD] score, 3.25 [0.88] vs 2.82 [1.00]) were significantly higher in the CC group vs the UC group; global impression of change was significantly lower in the CC group vs the UC group (mean [SD] score, 2.74 [1.02] vs 3.47 [1.26]) (lower scores denote a better impression of change). Conclusions and Relevance: In this randomized clinical trial of CC compared with UC for patients with TBI, CC was effective at reducing pain interference and was sustained at 8-month follow-up. Further research is needed to examine the implementation and cost-effectiveness of CC for TBI in other health care settings. Trial Registration: ClinicalTrials.gov Identifier: NCT03523923.

Chronic pain after traumatic brain injury: a collaborative care approach.

Introduction: Chronic pain is common after traumatic brain injury (TBI), frequently limits daily activities, and is associated with negative outcomes such as decreased community participation. Despite the negative impact of chronic pain, few people with TBI receive effective treatment. This paper describes a collaborative care (CC) intervention, TBI Care, adapted specifically to treat chronic pain in people living with TBI, emphasizing expert clinician input, cognitive behavioral therapy (CBT) techniques, and other non-pharmacological approaches for decreasing pain interference. Methods: 79 participants engaged in the CC intervention from two academic medical rehabilitation clinics with weekly assessments of pain intensity, interference, and medication use. Participant feedback on the intervention was gathered by interview with the care manager (CM) at the last treatment session and/or booster session. Provider feedback was gathered by a confidential survey post intervention. Results: Ninety percent of participants received at least 11 of the target 12 sessions with a care manager (CM), the majority occurring over the phone. Participants endorsed an average of 7 pain locations. All participants received pain education, skills in self-monitoring, goal setting/behavioral activation and relaxation training. Pain interference scores (impact on activity and enjoyment), tracked weekly by the CM, significantly decreased across sessions. 89% of participants received recommendations for CBT skills, 65% received referrals for additional treatments targeting pain interference, and 43% received care coordination. 75% of participants reported 6 or more medications/supplements at both the first and last session, with changes recommended primarily for headache treatment. Feedback from participants and providers was positive. Discussion: TBI Care, a novel patient-centered CC approach, was flexibly delivered, tailored to the needs of those living with TBI and chronic pain, with a high level of participant engagement, and satisfaction among participants and providers. This approach, prioritizing pain self-management strategies and other non-pharmacological approaches, along with optimizing pharmacological treatment, led to significant reductions in self-reported pain interference and intensity during the intervention. Using a CC model in TBI is feasible and successfully improved access to evidence-based treatments for chronic pain as well as outcomes for pain interference and intensity. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03523923.

Prediction of headache severity (density and functional impact) after traumatic brain injury: A longitudinal multicenter study.

BACKGROUND: Headache (HA) following traumatic brain injury (TBI) is common, but predictors and time course are not well established, particularly after moderate to severe TBI. METHODS: A prospective, longitudinal cohort study of HA severity post-TBI was conducted on 450 participants at seven participating rehabilitation centers. Generalized linear mixed-effects models (GLMMs) were used to model repeated measures (months 3, 6, and 12 post-TBI) of two outcomes: HA density (a composite of frequency, duration, and intensity) and HA disruptions to activities of daily living (ADL). RESULTS: Although HA density and ADL disruptions were nominally highest during the first three months post-TBI, neither showed significant changes over time. At all time points, history of pre-injury migraine was by far the strongest predictor of both HA density and ADL disruptions (odds ratio (OR) = 8.0 and OR = 7.2, averaged across time points, respectively). Furthermore, pre-injury non-migraine HA (at three and six months post-TBI), penetrating-type TBI (at six months post-TBI), and female sex (at six and 12 months post-TBI) were each associated with an increase in the odds of a more severe HA density. Severity of TBI (post-traumatic amnesia (PTA) duration) was not associated with either outcome. CONCLUSION: Individuals with HA at three months after moderate-severe TBI do not improve over the ensuing nine months with respect to HA density or ADL disruptions. Those with pre-injury HA, particularly of migraine type, are at greatest risk for HA post-TBI. Other independent risk factors are penetrating-type TBI and, to a lesser degree and post-acutely only, female sex. Individuals with these risk factors should be monitored and considered for aggressive early intervention.

Post-traumatic headaches in civilians and military personnel: a comparative, clinical review.

Post-traumatic headache (PTH) is the most frequent symptom after traumatic brain injury (TBI). We review the epidemiology and characterization of PTH in military and civilian settings. PTH appears to be more likely to develop following mild TBI (concussion) compared with moderate or severe TBI. PTH often clinically resembles primary headache disorders, usually migraine. For migraine-like PTH, individuals who had the most severe headache pain had the highest headache frequencies. Based on studies to date in both civilian and military settings, we recommend changes to the current definition of PTH. Anxiety disorders such as post-traumatic stress disorder (PTSD) are frequently associated with TBI, especially in military populations and in combat settings. PTSD can complicate treatment of PTH as a comorbid condition of post-concussion syndrome. PTH should not be treated as an isolated condition. Comorbid conditions such as PTSD and sleep disturbances also need to be treated. Double-blind placebo-controlled trials in PTH population are necessary to see whether similar phenotypes in the primary headache disorders and PTH will respond similarly to treatment. Until blinded treatment trials are completed, we suggest that, when possible, PTH be treated as one would treat the primary headache disorder(s) that the PTH most closely resembles.

Use of common migraine treatments in breast-feeding women: a summary of recommendations.

BACKGROUND: Breast-feeding has important health and emotional benefits for both mother and infant, and should be encouraged. While there are some data to suggest migraine may improve during breast-feeding, more than half of women experience migraine recurrence with 1 month of delivery. Thus, a thorough knowledge base of the safety and recommended use of common acute and preventive migraine drugs during breast-feeding is vital to clinicians treating migraine sufferers. Choice of treatment should take into account the balance of benefit and risk of medication. For some of the medications commonly used during breast-feeding, there is not good evidence about benefits. METHODS: A list of commonly used migraine medications was agreed upon by the 6 authors, who treat migraine and other headaches on a regular basis and are members of the Women's Special Interest Section of the American Headache Society. Each medication was researched by the first author utilizing widely accepted data sources, such as the American Academy of Pediatrics publication "The Transfer of Drugs and Other Chemicals Into Human Milk; Thomas Hale's manual Medications and Mothers Milk; Briggs, Freeman, and Yaffe's reference book Drugs in Pregnancy and Lactation; and the National Library of Medicine's Drugs and Lactation Database (LactMed) - a peer-reviewed and fully referenced database available online. RESULTS: Many commonly used migraine medications may be compatible with breast-feeding based on expert recommendations. Ibuprofen, diclofenac, and eletriptan are among acute medications with low levels in breast milk, but studies of triptans are limited. Toxicity is a concern with aspirin due to an association with Reye's syndrome; sedation or apnea is a concern with opioids. Finally, preventive medications not recommended include zonisamide, atenolol, and tizanidine. CONCLUSIONS: Several excellent resources are available for clinicians making treatment decisions in breast-feeding women. Clinicians treating migraine should discuss both acute and preventive treatment options shortly before and within a few months after delivery, keeping in mind the clinical features of the individual patient, and in consultation with their obstetrician and pediatrician. An awareness of the pharmacological data that are currently available and how to access that data may be helpful in making treatment decisions in this population.

A faster and a stronger defense response: one of the key elements in grapevine explaining its lower level of susceptibility to Esca?

Wood diseases like Esca are among the most damaging afflictions in grapevine. The defense mechanisms in this plant-pathogen interaction are not well understood. As some grapevine cultivars have been observed to be less susceptible to Esca than others, understanding the factors involved in this potentially stronger defense response can be of great interest. To lift part of this veil, we elicited Vitis vinifera plants of two cultivars less susceptible to Esca ('Merlot' and 'Carignan') and of one susceptible cultivar ('Cabernet Sauvignon'), and monitored their defense responses at the leaf level. Our model of elicitation consisted in grapevine cuttings absorbing a culture filtrate of one causal agent of Esca, Phaemoniella chlamydospora. This model might reflect the early events occurring in Esca-affected grapevines. The two least susceptible cultivars showed an earlier and stronger defense response than the susceptible one, particularly with regard to induction of the PAL and STS genes, and a higher accumulation of stilbene compounds and some pathogenesis-related proteins.

Characterization of headache after traumatic brain injury.

BACKGROUND: Headache is a common and persistent symptom following traumatic brain injury (TBI). Headaches following TBI are defined primarily by their temporal association to injury, but have no defining clinical features. To provide a framework for treatment, primary headache symptoms were used to characterize headache. METHODS: Three hundred and seventy-eight participants were prospectively enrolled during acute in-patient rehabilitation for TBI. Headaches were classified into migraine/probable migraine, tension-type, or cervicogenic headache at baseline and 3, 6, and 12 months following TBI. RESULTS: Migraine was the most frequent headache type occurring in up to 38% of participants who reported headaches. Probable migraine occurred in up to 25%, tension-type headache in up to 21%, then cervicogenic headache in up to 10%. Females were more likely to have endorsed pre-injury migraine than males, and had migraine or probable migraine at all time points after injury. Those classified with migraine were more likely to have frequent headaches. CONCLUSIONS: Our data show that most headache after TBI may be classified using primary headache criteria. Migraine/probable migraine described the majority of headache after TBI across one year post-injury. Using symptom-based criteria for headache following TBI can serve as a framework from which to provide evidence-based treatment for these frequent, severe, and persistent headaches.

Aspirin's effect on platelet inhibition in migraineurs.

OBJECTIVE: To assess the effect of aspirin on platelet reactivity in migraineurs. BACKGROUND: Migraineurs, particularly women with aura and high monthly migraine frequency, are at risk for ischemic stroke and myocardial infarction (MI). High on-aspirin platelet reactivity (HAPR), or aspirin resistance, has been reported in females and patients with coronary artery disease, and is associated with adverse outcomes. METHODS: Using a single group, pretest/posttest design, 50 migraineurs without prior history of stroke or MI were prospectively treated for 14 to 21 consecutive days with 325 mg generic enteric-coated aspirin, after undergoing a 14-day aspirin washout. Platelet reactivity was measured after aspirin washout and following aspirin treatment. Subjects were screened for HAPR using the VerifyNow™ Aspirin Assay (Accumetrics, San Diego, CA, USA). HAPR was defined as ≥ 460 Aspirin Reaction Units (ARU; primary endpoint). RESULTS: Fifty subjects, 44 (88%) female, aged (mean ± standard deviation) 43 ± 12 years were enrolled. Twelve (24%; 95% CI 12-36%) subjects, all female, had HAPR and were classified as aspirin resistant. Subjects with HAPR had lower baseline hemoglobin levels than those without HAPR (P = .03). Baseline hemoglobin was significantly correlated with final ARU (r = -0.39, P = .005). CONCLUSIONS: Findings of this exploratory study suggest that migraineurs have a higher prevalence of HAPR than healthy volunteers or patients with coronary artery disease taking aspirin 325 mg. The clinical implications of HAPR in migraine warrant further exploration due to the risk of stroke and MI and the potential need for antiplatelet therapy in this population.