Refractory Migraine and Chronic Migraine: Pathophysiological Mechanisms

Despite increased understanding of primary headaches and their treatment, the underlying causes of refractory migraine remain unknown. This note considers potential genetic, structural, functional and pharmacological factors that could contribute to this relatively intractable condition. Further understanding of refractory migraine will require the use of medical imaging technologies, clinical experimental medicine studies on novel pharmacological agents and astute observations in clinical practice to direct potential novel therapeutic approaches.     

Refractory chronic migraine: long-term follow-up using a refractory rating scale

Refractory chronic migraine (RCM) is often associated with disability and a low quality of life (QOL). RCM ranges in severity from mild to severe. There would be a benefit both clinically and in research use in categorizing RCM patients according to severity. This study utilized a unique RCM severity rating scale, tracking the clinical course over 10 years. A total of 129 patients, ages 19–72, were assigned a severity rating of 2–10 (10 = worst). Pain level and QOL were assessed. Over the 10 years, 73% of all pts. had a 30% or more decline in pain. Pain levels improved 45% in mild pts., 42% in mod. pts., and 36% in severe pts. Pain was the same, or worse, in 4% of mild, 15% of mod., and 18% of severe pts. QOL in the mild group improved 35% over 10 years. In moderate pts., QOL improved 32%, while for the severe group QOL improved 33%. While pain and QOL improved across all three groups at the end of 10 years, the severe group remained with significantly more pain and decreased QOL than in the milder groups. The medications that helped significantly included: opioids (63% of pts. utilized opioids), frequent triptans (31%), butalbital (17%), onabotulinumtoxinA (16%), stimulants (12%), and other “various preventives” (9%). RCM pts. were rated using a refractory rating scale with the clinical course assessed over 10 years. Pain and QOL improved in all groups. In the severe group, pain and QOL improved, but still lagged behind the mild and moderate groups. Opioids and (frequent) triptans were the most commonly utilized meds.     

Identifying cutaneous allodynia in chronic migraine using a practical clinical method

Cutaneous allodynia is common in migraine. In the majority of previous studies on allodynia in migraine, only patients with episodic migraine (EM) were included. Little is known on patterns of allodynia in chronic migraine (CM). Since the presence of allodynia is associated with a poor response to triptans, a clinically practical method to test migraine patients for allodynia would be useful to the clinician. The aim of this study was to assess the prevalence of dynamic mechanical (brush) allodynia (BA) in CM, using a clinically practical method. Eighty-nine CM patients were prospectively recruited. Patients were given a structured questionnaire regarding demographic data and migraine characteristics. Allodynia was tested using a 10 x 10-cm gauze pad to brush various areas of the skin lightly. The prevalence of BA in the entire study population and in different patient subgroups was calculated. BA was present in 42.7% (38/89) of the patients. The presence of allodynia was unrelated to age, disease duration or to the occurrence of an acute headache exacerbation at the time of testing. Allodynia was positively associated with a history of migraine aura. BA was most common in the cephalic area, but was also seen in cervical dermatomes. BA is common in CM and, unlike in EM, is not significantly affected by the occurrence of an acute headache exacerbation. This suggests that central trigeminovascular neurons are chronically sensitized in patients experiencing migraine headache >15 days per month. The testing of BA in the clinical setting is possible using a simple and brief approach. It allows the clinician to determine whether the patient is sensitized, a diagnosis that affects treatment decisions.     

Refractory chronic migraine: a Consensus Statement on clinical definition from the European Headache Federation

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).     

Defining refractory migraine and refractory chronic migraine: proposed criteria from the Refractory Headache Special Interest Section of the American Headache Society

Certain migraines are labeled as refractory, but the entity lacks a well-accepted operational definition. This article summarizes the results of a survey sent to American Headache Society members to evaluate interest in a definition for RM and what were considered necessary criteria. Review of the literature, collaborative discussions and results of the survey contributed to the proposed definition for RM. We also comment on our considerations in formulating the criteria and any issues in making the criteria operational. For the proposed definition for RM and refractory chronic migraine, patients must meet the International Classification of Headache Disorders, Second Edition criteria for migraine or chronic migraine, respectively. Headaches need to cause significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The definition requires that patients fail adequate trials of preventive medicines, alone or in combination, from at least 2 of 4 drug classes including: beta-blockers, anticonvulsants, tricyclics, and calcium channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE) intranasal or injectable formulation and either nonsteroidal anti-inflammatory drugs (NSAIDs) or combination analgesic, unless contraindicated. An adequate trial is defined as a period of time during which an appropriate dose of medication is administered, typically at least 2 months at optimal or maximum-tolerated dose, unless terminated early due to adverse effects. The definition also employs modifiers for the presence or absence of medication overuse, and with or without significant disability.     

Concepts and mechanisms of migraine chronification

Migraine is a chronic recurrent disorder with episodic manifestations that is progressive in some individuals. Migraine progresses clinically, physiologically, and anatomically. Progression may be a consequence of the mechanisms that generate the migraine attacks (eg, cortical spreading depression) or it may be a function of the activations generated by the attacks (eg, lesions in the periaqueductal gray area), a hypothesis supported by the increase in lesions with attack frequency. Progression may also be partially explained by common genetic or environmental risk factors. Finally, migraine with aura is associated with an elevated Framingham score and with risk factors for cardiovascular disease. Research on this issue is in its infancy and cautions are necessary before extrapolating this information into clinical practice.     

Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study

Background.— Though symptomatic medication overuse is believed to play a major role in progression from episodic to chronic or transformed migraine (TM), population‐based longitudinal data on these agents are limited. Objectives.— To assess the role of specific classes of acute medications in the development of TM in episodic migraine (EM) sufferers after adjusting for other risk factors for headache progression. Methods.— As a part of the American Migraine Prevalence and Prevention study (AMPP), we initially surveyed a population sample of 120,000 individuals to identify a sample of migraineurs to be followed annually over 5 years. Using logistic and linear regression, we modeled the probability of transition from EM in 2005 to TM in 2006 in relation to medication use status at baseline. Adjustments were made for gender, headache frequency and severity, and prevention medication use. Results.— Of 8219 individuals with EM in 2005, 209 (2.5%) had developed TM by 2006. Baseline headache frequency was a risk factor for TM. Using acetaminophen user as the reference group, individuals who used medications containing barbiturates (OR = 2.06, 95%CI = 1.3‐3.1) or opiates (OR = 1.98, 95%CI = 1.4‐2.2) were at increased risk of TM. A dose–response relationship was found for use of barbiturates. Use of triptans (OR = 1.25, 95%CI = 0.9‐1.7) at baseline was not associated with prospective risk of TM. Overall, NSAIDs (OR = 0.85, 95%CI = 0.63‐1.17) were not associated with TM. Indeed, NSAIDs were protective against transition to TM at low to moderate monthly headache days, but were associated with increased risk of transition to TM at high levels of monthly headache days. Conclusion.— EM sufferers develop TM at the rate of 2.5% per year. Any use of barbiturates and opiates was associated with increased risk of TM after adjusting for covariates, while triptans were not. NSAIDs were protective or inducers depending on the headache frequency.     

Iron deposition in pain-regulatory nuclei in episodic migraine and chronic daily headache by MRI

Background.— Progression of migraine toward a more disabling chronic form of at least 15 days/month is linked with frequency of attacks. Magnetic resonance imaging (MRI) findings of iron accumulation in the brain, especially in periaqueductal gray and red nucleus, have been correlated with both duration of illness and frequency of attacks. Methods.— This study therefore evaluated iron deposition as measured with MRI in basal ganglia and pain regulatory nuclei in neurologically healthy control volunteers and in patients with various migraine subtypes: episodic migraine (n = 10) with (n = 4) or without aura (n = 6), and chronic daily headache (n = 11), including medication overuse headache (MOH, n = 8), chronic tension‐type headache (n = 1), and primary chronic migraine (n = 2). The goal was to assess differences in iron deposition among migraine subtypes and controls in the hopes of linking the by‐products of frequent attacks or long duration of illness with these changes. Results.— The study sought to evaluate the tradeoff between sensitivity and specificity in T2 imaging of patients with migraine, and found that only T2 imaging in the globus pallidus was able to distinguish between episodic and chronic migraine, suggesting that this technique may be the most appropriate to assess migraine frequency. Patients with MOH did not demonstrate T2′ shortening. Conclusions.— Because iron accumulation should cause shortening of both T2 and T2′, although the lack of significance in observed T2′ difference could be due to increased variance in T2′ the measurement, these results suggest that a mechanism other than increased iron deposition may play a role in the genesis or pathophysiology of MOH.     

Similarities and differences between chronic migraine and episodic migraine

OBJECTIVE: To quantify and characterize the similarities and the differences between chronic migraine (CM) patients with medication overuse and episodic migraine (EM) patients with only occasional analgesic use. BACKGROUND: Population-level epidemiology, characteristics, mechanisms of chronic daily headache, and medication-overuse headache have been widely studied but patient characteristics have received less attention. Methods.-We compared sociodemographic data, family history, physiological and medical history, health services utilized, drugs taken/prescribed, and outcome of 2 groups of subjects: 150 patients, suffering from CM, complicated by probable medication-overuse headache (CM group), consecutively admitted during 2005 to the inpatients' ward of the Headache Centre of the University Hospital of Modena and Reggio Emilia, Italy, to undergo withdrawal from their overused medications; 100 patients suffering from EM, uncomplicated by medication overuse (EM group), consecutively referred to the outpatients' ward of the Headache Centre during November and December 2005. RESULTS: All sociodemographic characteristics were significantly different between the 2 groups. As a whole, the CM group began to suffer from migraine earlier than the EM group. Drug and/or alcohol abuse was significantly higher among first-degree relatives of CM (19%) than of EM (6%) patients. The most frequent comorbid disorders were psychiatric (67%) and gastrointestinal diseases (43%) in the CM group, and allergies in the EM group (31%). Seventy percent of CM patients and 42% of EM patients were taking daily at least another drug, besides those for headache treatment. Most overused medications in the CM group were triptans (43%); the EM group used above all single NSAIDs (56%). At 3-month follow-up, prophylactic treatments reduced, by at least 50%, the frequency of headache in about three-fourths of patients of both the groups; however, headache remained significantly more frequent in the CM than in EM group: only a minority (15%) of CM patients reverted to a headache frequency comparable to that of the EM group. CONCLUSIONS: CM patients present more multiple comorbid disorders, polypharmacy, and social impediments than EM patients. These associated conditions complicate CM clinical management. Even after withdrawal from medication overuse, CM could not be completely reverted by current prophylactic treatments.     

'Side locked' migraine and trigeminal autonomic cephalgias: evidence for clinical overlap

This paper will discuss evidence which supports a link between 'side locked' migraine (SLM) and the trigeminal autonomic cephalgias (TACs). Recent papers brought strictly unilateral primary headaches into focus, proposing new classification and discussing pathophysiological mechanisms. We reviewed those proposals and present evidence that SLM falls in between the well-defined TACs and side shifting migraine (SSM). It is difficult to differentiate SLM from the recently proposed headache subtype called hemicrania generis incerti (i.e. hemicrania continua unresponsive to indomethacin). We also present cases that may exemplify the considerations made in the paper.     

Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine

BACKGROUND: Chronic migraine is the most common type of chronic daily headache seen in headache tertiary care centers. Most patients with chronic migraine report their ability to function and feeling of well-being as severely impaired. OBJECTIVE: To measure the headache-related disability of patients with chronic migraine using the Migraine Disability Assessment (MIDAS) Questionnaire, comparing it with that obtained in a control group of patients with episodic migraine. METHODS: The clinical records of 703 patients with chronic daily headache treated in a headache specialty clinic were reviewed to identify 182 with chronic migraine who were evaluated using the MIDAS at their initial visit. Our control group consisted of 86 patients with episodic migraine. RESULTS: Of the 182 patients with chronic migraine, 127 (69.8%) were overusing acute-care medication. Patients were predominantly women (72.5%), with a mean age of 38.3 years. The group with episodic migraine consisted of 59 women (68.6%), with a mean age of 36.1 years. No statistically significant demographic differences were observed between the two groups. The group with chronic migraine had more total headache days over 3 months (66.7 versus 15.5, P<.001), missed more days of work or school (5.3 versus 2.3, P =.0007), had more reduced effectiveness days at work or school (11.9 versus 4.6, P =.0001), missed more days of housework (16.5 versus 3.3, P<.0001), and missed more days of family, social, or leisure activities (7.0 versus 5.5, P =.03). The group with chronic migraine was more likely to be in MIDAS grade IV (64.3% versus 43.2%, P =.001), reflecting the great likelihood of severe disability in this group. The average total MIDAS score was 34.9 in the group with chronic migraine versus 19.3 in the group with episodic migraine (P<.001). CONCLUSION: In subspecialty centers, patients with chronic migraine demonstrate remarkable impairment of their daily activities and are severely burdened by their headache syndrome, reflected by their high MIDAS scores. The chronicity and pervasiveness of migraine thus is associated with increased functional impairment as well as increase in headache frequency.     

Sumatriptan in migraine with unilateral cranial autonomic symptoms: an open study

OBJECTIVE: To investigate the response to sumatriptan in migraineurs with unilateral cranial autonomic symptoms such as lacrimation, eye redness, eyelid edema, nasal congestion, and rhinorrhea. BACKGROUND: Given the potential large-scale recruitment of peripheral neurovascular 5-HT1B/1D receptors consequent to the activation of the trigeminal autonomic reflex in such patients, the presence of unilateral cranial autonomic symptoms may predict a positive response to sumatriptan. METHODS: Seventy-two consecutive migraineurs with unilateral cranial autonomic symptoms were given sumatriptan 50-mg tablets to treat 1 migraine attack and were asked to record their clinical response to the drug at different time points. End points were pain-relief and pain-free response at 1 and 2 hours. RESULTS: Pain relief was reported by 47 patients (65.3%) at 1 hour and by 59 (81.9%) at 2 hours. Pain-free response was reported by 22 patients (30.6%) at 1 hour and by 44 (61.1%) at 2 hours. Responsiveness to sumatriptan did not correlate with the type or number of unilateral cranial autonomic symptoms, demographic characteristics, prophylactic treatments, use of contraceptives, or concomitant tension-type headache. CONCLUSIONS: Migraineurs with unilateral cranial autonomic symptoms seem to respond to sumatriptan better than other migraineurs. The presence of unilateral cranial autonomic symptoms may predict a positive response to the triptans.     

Post-traumatic stress disorder in episodic and chronic migraine

OBJECTIVE: To assess and contrast the relative frequency of self-reported post-traumatic stress disorder (PTSD) in patients with episodic migraine and chronic/ transformed migraine. BACKGROUND: Several risk factors have been identified as risk factors for chronification of headache disorders. Childhood abuse has been suggested as a risk factor for chronic pain in adulthood. In addition depression, as well as several other psychiatric disorders, are co-morbid with migraine. Recent data suggest that PTSD may be more common in headache sufferers than in the general population. METHODS: This was a prospective, pilot study conducted at a headache center. Adult subjects with episodic, chronic, or transformed migraine were included. Demographic information, depression history, body mass index (BMI), and headache characteristics were obtained. PTSD was assessed using the life events checklist (LEC) and the PTSD checklist, civilian version (PCL-C). We contrasted the data from episodicmigraineurs and chronic/transformed migraine participants (CM) and conducted multivariate analyses, adjusting for covariates. RESULTS: Of the 60 participants included, 91.7% were female with a mean age of 41.4+/-12.5 years old. EM was diagnosed in 53.3% and CM in 46.7%. The mean BMI was not significantly different between groups. In contrast, the relative frequency of depression was significantly greater in subjects with CM (55.2%) than EM (21.9%, P=.016). There was no significant difference in the percentage of participants reporting at least 1 significant traumatic life event (LE) or in the mean number of traumatic LEs between EM and CM participants. However, the relative frequency of PTSD reported on the PCL in CM (42.9%) was significantly greater as compared to EM (9.4%, P=.0059. After adjusting for depression and other potential confounders, the difference remained significant P=.023). CONCLUSION: PTSD is more common in CM than in episodic migraineurs. This suggests that PTSD may be a risk factor for headache chronification, pending longitudinal studies to test this hypothesis.     

Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part 2

Migraine headache is strongly influenced by reproductive events that occur throughout the lifespan of women. Each of these reproductive events has a different "hormonal milieu," which might modulate the clinical course of migraine headache. Estrogen and progesterone can be preventative or provocative for migraine headache under different circumstances depending on their absolute serum levels, constancy of exposure, and types of estrogen/progesterone derivatives. Attacks of migraine with and without aura respond differently to changes in ovarian hormones. Clearly a greater knowledge of ovarian hormones and their effect on migraine is essential to a greater understanding of the mechanisms and pathogenesis of migraine headache.     

Sumatriptan and corneal reflexes in headache-free migraine patients: a randomized and placebo-controlled crossover study

A temporary sensitization of central trigeminal neurones in migraine patients during acute attacks has been described in previous studies using the electrically evoked nociceptive blink reflex. The cornea is innervated by small myelinated A-delta and unmyelinated C-fibres only. Stimulation with air puffs activates peripheral nociceptors and allows the investigation of peripheral trigeminal nerve structures. Our objective was to investigate whether corneal reflex examinations with air puff stimulation detect abnormalities in migraineurs during their pain-free interval and if the corneal reflex may be modulated by the administration of an oral triptan. After validation of the nociceptive air puff technique by investigating the corneal reflexes before and after a local anaesthesia of the cornea, we recorded corneal reflexes in 25 migraineurs during their pain-free period and 25 healthy controls before and after the oral administration of 100 mg sumatriptan in a randomized, placebo-controlled, crossover study. Baseline response areas under the curve (AUCs) and latencies of the R2 components of the corneal reflexes did not show any significant differences between patients and controls. Patients did not show any significant differences regarding their headache and non-headache side. The use of an oral triptan had no significant influence on latencies or AUCs in both patients and controls. Our data suggest that there is no facilitation of the trigeminal system in the headache-free interval among patients with migraine. The stable corneal reflexes after the oral administration of 100 mg sumatriptan suggest that there was no inhibition of the trigeminal system, both in patients during their headache-free period and in healthy controls.     

Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients

BACKGROUND: Secretion of calcitonin gene-related peptide (CGRP) from trigeminal nerves and vasoactive intestinal peptide (VIP) from parasympathetic nerves is involved in the pathophysiology of migraine and rhinosinusitis. Analysis of these neuropeptides in human saliva samples can be used as markers of trigeminal and parasympathetic nerve activity in patients between and during attacks as well as in response to specific treatments. OBJECTIVE: To compare the amount of trigeminal sensory and parasympathetic nerve activation by measuring CGRP and VIP levels in the saliva of subjects experiencing noninfectious allergic rhinosinusitis, migraine with sinus symptoms, and no symptoms. METHODS: Subjects were enrolled in three groups. Group A: subjects without a history of migraine, "sinus" headache, or allergic rhinosinusitis within the previous 6 months. Group B: subjects with chronic recurrent noninfectious rhinosinusitis and no history of migraine or "sinus" headache. Group C: subjects with self-described "sinus" headaches whose symptoms met International Headache Society diagnostic criteria (1.1 or 1.2) for migraine. The total amount of CGRP and VIP present in saliva collected under normal, pathological, and therapeutic conditions was determined by radioimmunoassay. Neuropeptide levels were normalized to total volume and amount of protein, and levels were correlated to onset and change in clinical symptoms. RESULTS: Total volume, total protein, and CGRP and VIP levels did not significantly change in saliva collected on consecutive days in the clinic and at the subject's home, respectively. No appreciable change in baseline salivary levels of CGRP and VIP was detected in control subjects. However, baseline salivary levels of CGRP and VIP were significantly elevated between attacks in allergic rhinosinusitis and migraine subjects compared to control values. For rhinosinusitis subjects, the amount of CGRP and VIP during attacks returned to baseline values following treatment with pseudoephedrine and relief of symptoms. Similarly, CGRP and VIP levels during a migraine headache were significantly reduced within 2 hours after sumatriptan treatment and reported symptom relief. CONCLUSION: Correlation of CGRP and VIP saliva levels observed in our study supports physiologically coordinated regulation of trigeminal and parasympathetic nerve activation in allergic rhinosinusitis and migraine patients between and during attacks as well as following treatment. Furthermore, our findings demonstrate that analysis of human saliva neuropeptides may provide a semiquantitative index of pathological and therapeutic states and, therefore, function as a clinical model for studying neuronal mechanisms involved in migraine and rhinosinusitis.     

From migraine to chronic daily headache: the biological basis of headache transformation

Migraine headache carries the potential of transforming into chronic daily headache (CDH) over a period of time. Although several risk factors for migraine progression to CDH have been identified, the biological basis of this transformation is unknown. In this review, the consequences of stressful life events and medication overuse, 2 risk factors associated with the development of CDH, on brain processes involved in headache are examined. The extensive overlap in both neural circuitry and cellular events that occur with stress, medication overuse, and migraine provide insight into potential mechanisms that may lead to CDH. Particular attention is devoted to the effect of stress and medication overuse on peripheral and central neuroimmune interactions that can facilitate pain signaling. These interactions include the degranulation of mast cells in the dura, causing the sensitization of primary afferent neurons, as well as the activation of glial cells in the brain that can lead to central sensitization. It is hypothesized that the biological processes involved in migraine headache are directly impacted by stress, medication overuse, and other risk factors, resulting in a reduced threshold for induction of headache and transformation of episodic migraine to CDH.