Animal Models of Chronic Migraine

Purpose of Review

Chronic migraine (CM) is a recalcitrant subtype of migraine which causes high degrees of disability, poor treatment responses, and frequent recurrences in sufferers. However, the pathophysiological mechanisms underlying the development and chronification of migraine attacks remain incompletely understood. A validated animal model could help to decipher the pathogenic mechanism of the disease, facilitating the development of possible therapeutic strategies for CM. In this review, we aimed to summarize current animal models of CM and discuss the validity of these models.

Recent Findings

Several methods have been available to induce recurrent headache-like behaviors or biochemical changes in rodents, including repeated dural application of inflammatory soup, chronic systemic infusion of nitroglycerin, repeated administration of acute migraine abortive treatment to simulate medication overuse headache, or genetic modification. These models exhibit some features that are believed to be associated with migraine; however, none of the model can recapitulate all the clinical phenotypes found in humans and each has its own weakness.

Summary

The complex features of CM increase the difficulty of constructing a proper animal model. Nonetheless, currently available models are valid to certain degrees. Future directions might consider simulating the spontaneity and chronicity of migraine by combining known genetic substrates and allostatic loads into the same model.

     

CGRP Monoclonal Antibodies for the Preventative Treatment of Migraine

Purpose of Review

CGRP is a key neuropeptide in migraine pathophysiology. The blockade of the CGRP pathway at the side of the CGRP receptor of the CGRP peptide leads to the interruption of trigeminal nerve system-mediated headache syndromes such as migraine. Monoclonal antibodies (mAbs) targeting the CGRP pathway have been developed and are currently under investigation for episodic (EM) and chronic migraine (CM) prevention. Here, we report data from these clinical trials.

Recent Findings

Placebo-controlled, randomized double-blind phase studies of CGRP mAbs in episodic and chronic migraine have shown that the specific blockade of the peptide or the CGRP receptor are both powerful mechanisms to reduce migraine frequency. Along with the reduction of acute migraine-specific medication intake, early onset of efficacy of mAbs has been demonstrated. Most common adverse events are injection sider reactions. Depending on the mAb, the administration mode is a monthly or even less frequently s.c. or I.V. formulation.

Summary

Phase II studies in EM and CM demonstrate that CGRP mAbs are effective anti-migraine preventatives with a beneficial adverse event profile. Further detailed results from larger phase III clinical trials are expected soon.

     

Impact of migraine on the clinical presentation of insomnia: a population-based study

Background

Insomnia and migraine are closely related; insomnia aggravates migraine symptoms. This study was conducted to investigate the impact of migraine on the clinical presentation of insomnia symptoms.

Methods

The data of the Korean Headache-Sleep Study (KHSS) were used in the present study. The KHSS is a nation-wide cross-sectional population-based survey regarding headache and sleep in Korean adults aged 19 to 69 years. If a participant’s Insomnia Severity Index (ISI) score?≥?10, she/he was classified as having insomnia. The clinical presentation of insomnia symptoms was assessed using total and subcomponent scores of the ISI.

Results

Of 2695 participants, 290 (10.8%) and 143 (5.3%) individuals were assigned as having insomnia and migraine, respectively. The proportions of migraine (12.8% vs. 4.4%, p?<? 0.001) and non-migraine headache (59.0% vs. 39.9%, p?<? 0.001) were higher among individuals with insomnia compared to those without insomnia. Among participants with insomnia, total ISI scores were not significantly different among participants with migraine, non-migraine, and non-headache [median and interquartile range: 13.0 (11.0–17.5) vs. 13.0 (11.0–17.5) vs. 12.0 (11.0–16.0), p?=?0.245]. ISI scores for noticeability of sleep problems to others were significantly higher among participants with migraine [3.0 (2.0–4.0) vs. 2.0 (2.0–3.0), p?=?0.011] and non-migraine headache [3.0 (2.0–4.0) vs. 2.0 (2.0–3.0), p?=?0.001] compared to those without headache history. Other ISI subcomponent scores did not significantly differ between headache status groups.

Conclusions

Participants with insomnia had an increased risk of migraine and non-migraine headache compared to those without insomnia. Among participants with insomnia, overall insomnia severity was not significantly influenced by the headache status.

     

Treatment Update of Chronic Migraine

Purpose of Review

Although chronic migraine (CM) is a common disorder that severely impacts patient functioning and quality of life, it is usually underdiagnosed, and treatment responses often remain poor even after diagnosis. In addition, effective treatment options are limited due to the rarity of randomized controlled trials (RCTs) involving patients with CM. In the present review, we discuss updated pharmacological, non-pharmacological, and neurostimulation treatment options for CM.

Recent Findings

Pharmacological treatments include both acute and preventive measures. While acute treatment options are similar between CM and episodic migraine (EM), preventive treatment with topiramate and botulinum toxin A exhibited efficacy in more than two RCTs. In addition, several studies have revealed that behavioral interventions such as cognitive behavioral therapy, biofeedback, and relaxation techniques are associated with significant improvements in symptoms. Thus, these treatment options are recommended for patients with CM, especially for refractory cases. Neurostimulation procedures, such as occipital stimulation, supraorbital transcutaneous stimulation, non-invasive vagal nerve stimulation, and transcranial direct current stimulation, have shown promising results in the treatment of CM. However, current studies on neurostimulation suffer from small sample size, no replication, or negative results.

Summary

Although CM is less responsive to treatment compared to EM, recent advance in pharmacological, non-pharmacological, and neurostimulation treatments may provide more chance for successful treatment of CM.

     

Is Medication Overuse Drug Specific or Not? Data from a Review of Published Literature and from an Original Study on Italian MOH Patients

Purpose of Review

The aim is twofold. First, to give an insight on the role exerted by different classes of drugs in favouring migraine chronification. Second, to explore the relationship between type and amount of overused medications and history of previous withdrawal treatment and of frequent relapses.

Recent Findings

All drug classes were found to favour migraine chronification. No data are available for the association with relapses into CM-MOH. Our clinical study shows that patients who underwent previous withdrawal treatments were more likely to be overusers of multiple drug classes and overuse higher amounts of symptomatic medications, particularly, indomethacin, eletriptan and tramadol. Frequent relapsers were more likely to be overusers of opioids or ergotamine and caffeine derivates or of multiple classes, particularly acetylsalicylic acid and ergotamine/caffeine derivates.

Summary

The joint results our review and clinical study do not seem to support the idea that MOH is drug-specific: rather, it points out that all drug classes may induce migraine chronification. Those drugs which are at higher risk of overuse are among those preferred by the “worst” patients, i.e. those who needed one or more withdrawal treatments for MOH. Our results reinforce the clinical impression that patients with CM and MOH, and particularly the most difficult to treat for their poor response to withdrawal treatments, are characterised by a particular drive towards the consumption of “whatever is likely to be perceived to provide some relief”, despite these drugs that are perceived as “more powerful”, are often indicated as second- or third-line medications.

     

Triggers,Protectors, and Predictors in Episodic Migraine

Purpose of Review

A wide variety of triggers prompt attacks in episodic migraine. Although experimental triggers such as glyceryl trinitrate reliably produce migraine, natural triggers are much less predictable and vary in importance between individuals. This review describes the most common triggers in episodic migraine and provides strategies for managing them in clinical practice.

Recent Findings

Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned. Clinical studies have verified that fasting, premenstrual periods in women, “letdown” after stress, and most likely low barometric pressures are migraine triggers. Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers.

Summary

Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment. Many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. Healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time.

     

Nonspecific periaqueductal gray lesions on T2WI in episodic migraine

Background

The specific periaqueductal gray (PAG) lesions with migraine-like headache were easily identified on conventional MR images in clinical practice, and the aim of this study is to investigate the nonspecific periaqueductal gray (PAG) lesions in episodic migraine (EM) patients based on T2 weighted imaging (T2WI).

Methods

T2WI images were obtained from 18 EM patients and 18 normal controls (NC) on 3.0 T MR system. The images were observed by two experienced radiologists, and the lesions were identified on T2WI by consensus by 2 experienced neuroradiologists blinded to the patient identity. Chi-Square test was performed for the significance test.

Results

Ring-like hyperintensity lesions (HILs) around the PAG region were observed in 14 EM patients and in 5 NCs on T2WI. Four EM patients and 13 NCs were normal in PAG region. The significance was revealed by Chi-Square test (P?=?0.003).

Conclusion

HIL of PAG may be the direct evidence of the EM genesis, and the further structural and functional study should be performed to elucidate the neuromechanism of migraine pathogenesis.

     

Chronifizierungsmechanismen und Abhängigkeitspotenziale bei Tumorschmerz

Background

Due to advances in oncological therapy options and increasing survival rates, the number of cancer patients with persistant pain, who are in need of analgesic therapy has increased. It has been proven that biopsychosocial mechanisms exist in patients with persistant non-cancer pain leading to chronification. Furthermore, addiction has been identified as a complication of analgesic therapy.

Objective

Can the multidimensional model of chronic pain enhancement and chronification be used for patients with cancer pain, analogue to patients with non-cancer pain? Can addiction sydromes as a result of analgesic treatment be demonstrated?

Material and methods

In this non-systematic review, a literature search was carried out for somatic and psychosocial chronification mechanisms in patients with cancer pain. Indications for potential addiction syndromes in cancer patients are demonstrated based on selected publications. A Medline search provided a number of relevant publications that are listed (see Supplementary Material).

Results and discussion

Somatic chronification mechanisms, such as pain intensity, repetitive algesic stimuli, topical and demographic factors, are found both in persistant non-cancer pain and cancer pain. Cancer-induced peripheral and central sensitization mechanisms that can be due to underlying genetic variations, are specific for cancer pain. With regard to psychosocial determinants for pain chronification, both cancer and non-cancer patients show similar patterns. Furthermore, data from the literature support the existence of addiction in cancer patients.

Conclusion

In order to optimize treatment more attention should be paid to the risk of chronification and addiction in cases of chronic persistant cancer pain.

     

Health Behaviors in Episodic Migraine: Why Behavior Change Matters

Purpose of Review

Episodic migraine is common. Everyday behavioral patterns are associated with migraine attacks and disability. This paper reviews health behaviors that can be targeted in people with episodic migraine to enhance migraine-related outcomes.

Recent Findings

Stressful events and perceived stress have demonstrated associations with migraine attack onset among people with episodic migraine. Consistency in daily patterns (eating, sleeping, exercise, and hydration status) is also associated with migraine activity. Sleep deprivation, fatigue, and poor quality sleep have demonstrated relationships with migraine attack onset, as well as headache frequency and headache-related disability in people with episodic migraine.

Summary

The health behaviors implicated in episodic migraine are part of everyday patterns and can be targeted routinely in clinical practice to improve migraine management. Behavior change is challenging and should ideally be supported by a multidisciplinary team. Future research should focus on evaluating specific behavior change interventions and the relative impact of behavior on migraine outcomes in high- and low-frequency episodic migraine.

     

Sleep disorders in breast cancer survivors

Purpose

The purpose of this study was to evaluate the feasibility, acceptability, and initial results of a structured assessment of sleep disorders in breast cancer survivors (BCS). Our goal was to determine whether the assessment could be easily used and whether it would capture problems suggestive of one or more underlying sleep disorders that require referral to a specialist for diagnostic validation through polysomnography and appropriate specialty treatment.

Methods

A cross-sectional, feasibility study using convenience sampling.

Results

A total of 38 BCS completed the study. Recruitment procedures were adequate in finding eligible BCS, however, procedures used to establish possible patterns of sleep disorders (e.g., interview) were not feasible for screening for sleep disorders in the clinical setting due to the time it took to complete each interview. A total of seven sleep disorder categories were identified in the data with the majority of women having at least one possible sleep disorder.

Conclusions

Study findings suggest that population-based screening for sleep disorders in clinical practice should be a priority for BCS reporting chronic sleep problems.

     

Thalamo-cortical network activity between migraine attacks: Insights from MRI-based microstructural and functional resting-state network correlation analysis

Background

Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks.

Methods

Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores.

Results

In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally.

Conclusions

The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology.

     

Chronische Kiefer- und Gesichtsschmerzen

Background

Psychological factors are associated with the emergence and persistence of pain perception. The aim of this pilot study was to assess the psychological factors relating to pain perception in patients with chronic myofacial pain and to investigate the influence of patient information, education and physiotherapy on pain perception and functional jaw opening examined over a 6-month period.

Patients and methods

In accordance with the research diagnostic criteria for temporomandibular disorders (RDC/TMD), 40 patients (31 females and 9 males, mean age 38.6 years) with chronic myofacial pain were assessed at 3 time points: on admission (T1), after 3 months (T2) and 6 months (T3). The study included a structured interview and five psychological questionnaires. At all time points patients were informed about the development of pain and the relationship between chronification of pain and psychological risk factors.

Results

After 6 months significant improvements in jaw function and quality of life, as well as a decrease in psychological parameters, such as fear and depression were found. Improvement was related to the severity of pain chronification.

Conclusion

The results show the necessity of early identification of patients with severe pain chronification and the need for psychological pain therapy.

     

Neuropeptides as a Marker for Chronic Headache

Purpose of Review

The purpose of this review is to revise current evidence on trigemino-vascular system (TVS) neuropeptides as potential biomarkers for chronic primary headaches, mainly for chronic migraine (CM).

Recent Findings

Within sensory neuropeptides, released by an activated trigeminal nerve, calcitonin gene-related peptide (CGRP) levels seem to be a good biomarker of acute migraine and somewhat sensitive and specific for CM. CGRP, however, is not increased in 20–30% of CM patients, which suggests that CGRP is not the only neuropeptide involved in migraine pain generation and maintenance. Data for other sensory neuropeptides are inconsistent (neurokinin, substance P) or absent (amylin and cholecystokinin-8). Among parasympathetic neuropeptides, vasoactive intestinal polypeptide (VIP) is increased interictally in CM, and in at least some migraine cases ictally, pituitary adenylate cyclase-activating peptide (PACAP) has been shown to be increased ictally in jugular blood, but interictal, peripheral data do not indicate such an increase, and there are no data for other parasympathetic peptides. Finally, S100B, as a potential marker of glial TVS activation, has been studied with inconsistent results in migraine patients.

Summary

Current data on TVS neuropeptides as potential migraine biomarkers must be taken with caution, even for the promising case of CGRP. We do not know with certainty whether increased levels are the reflection of TVS activation, the reliability and homogeneity of the different laboratory tests, or what is the influence on these measurements of the short half-life of many of these peptides or of preventive treatments. One further limitation would be whether the described increases in levels of some neuropeptides such as CGRP are specific for migraine versus other headaches.

     

Emerging Treatments in Episodic Migraine

Purpose of Review

The purpose of this review is to evaluate and describe recent and emerging treatment options for episodic migraine.

Recent Findings

Recent advances have been made in better understanding the pathophysiology of migraine, which has led to further investigation of potential new pharmacologic and non-pharmacologic treatment options.

Summary

A number of new medications are emerging for the acute and preventive treatment of migraine, including CGRP monoclonal antibodies, CGRP receptor antagonists, serotonin 5-HT_1F agonists, and PACAP receptor monoclonal antibodies. Additionally, newer studies on existing non-invasive neuromodulation devices including transcranial magnetic stimulation, supraorbital transcutaneous nerve stimulation, and transcutaneous vagus nerve stimulation have recently received FDA approval for use in migraine. Neuromodulation devices including percutaneous mastoid electrical stimulation, non-painful remote electrical stimulation, and caloric vestibular stimulation are undergoing further investigation and have shown promising results thus far. These new developments are expected to contribute to better treatment and decreased disability in migraine.

     

Positive and negative effects of mechanical ventilation on sleep in the ICU: a review with clinical recommendations

Purpose

Sleep is an essential physiologic process that helps to restore normal body homeostasis. Sleep disturbances have been shown to be associated with poor clinical outcomes, such as a greater risk of cardiovascular disease and increasing mortality. Critically ill patients, particularly those receiving mechanical ventilation, may be more susceptible to sleep disruption.

Methods and Results

Mechanical ventilation is an important factor influencing sleep in critically ill patients as it may have positive or negative effects, depending on patient population, mode, and specific settings. Other causes of sleep disruption include the acute illness itself, the daily routine care, and the effects of medications. Improving sleep in patients admitted to an intensive care unit has the potential to improve both short- and long-term clinical outcomes. In this article we review the specific aspects of sleep in critically ill mechanically ventilated patients, including abnormal sleep patterns and loss of circadian rhythm, as well as the effects of mechanical ventilation and intravenous sedatives on sleep quality and quantity.

Conclusions

We provide recommendations for clinicians regarding optimal ventilatory settings and discuss fields for future research.

     

Alltagsdeutungen und medizinische Deutungen von Kopfschmerzen und Migräne

Background

Every professional segment has its own typical forms of stress, which for members result in patterns of bodily conception and interpretation of pain. The way individuals cope with these typical forms of pain reflects their social identity, social status and group membership. In this study pain was investigated from a sociological perspective as a medium contributing to socialization processes in stress collectives.

Objectives

Cultural conceptions of headache and migraine were investigated in members of blue collar occupations, in service professions and patients in specialized medical pain care.

Materials and methods

In this study 49 qualitative biographical interviews were conducted with patients suffering from headache and migraine. The study population included persons from the general outpatient population and patients recruited from specialized inpatient pain clinics.

Results

Members of blue collar occupations with specific body-oriented, mechanical stress patterns and dominant masculine attitudes, perceived headache and migraine as atypical deviations, which are contextualized as body pain. Professionals in the service sector with specific communicative-emotional work patterns perceived headache and migraine as typical and accepted deviations. Both pain conceptions represent dominant body norms and social commitments in each group; however, in specialized pain care these everyday concepts are transformed by increasing expert knowledge resulting in medicalized life styles and in identity conceptions conforming to the medical imperative.

Conclusion

The success of specialized treatment of headache depends to a certain extent on the ability of patients to impose a medically regulated life style on their significant others; however, this can conflict with the demands of everyday life.

     

Early onset of efficacy with erenumab in patients with episodic and chronic migraine

Background

Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a?≥?50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo.

Methods

There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥?50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data.

Results

In both studies (EM: N?=?955; CM: N?=?667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean [LSM] [95% CI]): placebo, ??0.1 (??0.3, 0.0); erenumab 70 mg, ??0.3 (??0.5, ??0.2) p?=?0.130; erenumab 140 mg, ??0.6 (??0.7, ??0.4) p?<?0.001. For CM the changes were: placebo, ??0.5 (??0.8, ??0.3); erenumab 70 mg, ??0.9 (??1.2, ??0.7) p?=?0.047; erenumab 140 mg, ??0.8 (??1.1, ??0.5) p?=?0.18. Achievement of ≥?50% reduction in WMD was observed as early as Week 1 (adjusted OR [95% CI] erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9) p?=?0.097; erenumab 140 mg, 2.0 (1.4, 2.7) p?<?0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8) p?=?0.011; erenumab 140 mg, 1.9 (1.2, 2.9) p?=?0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR [95% CI]): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0) p?=?0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8) p?=?0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9) p?=?0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0); p?=?0.038.

Conclusion

Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.

     

Prevalence of restless legs syndrome in migraine patients with and without aura: a cross-sectional,case-controlled study

Background

Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura.

Methods

We conducted a cross-sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1–8/month), high-frequency (9–14/month), and chronic (≥15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression.

Results

Univariate analysis revealed an effect of migraine frequency on RLS prevalence (p?=?0.026), though this effect did not persist following adjustment for baseline characteristics (p?=?0.256). The trend was robust in patients whose migraines presented with auras (p _univariate?=?0.002; p _multivariate?=?0.043) but not in those without auras (p _univariate and p _multivariate?>?0.05). Higher anxiety [odds ratio (OR)?=?1.18, p?=?0.019] and sleep disturbance (OR?=?1.17, p?=?0.023) scores were associated with higher RLS prevalence.

Conclusions

Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras.

     

Current Aura Without Headache

Purpose of Review

This review evaluates and explains our current understanding of a rare subtype of migraine, typical aura without headache, also known as migraine aura without headache or acephalgic migraine.

Recent Findings

Typical aura without headache is a known entity within the spectrum of migraine. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. No clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura. Bilateral greater occipital nerve blocks may be helpful in aborting migraine with prolonged aura. Transcranial magnetic stimulation has shown efficacy in aborting attacks of migraine with aura but has not been specifically tested in isolated aura.

Summary

Typical aura without headache occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura. Typical aura without headache commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment.