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ABORTIVE THERAPIES for MIGRAINE: a MECHANISTIC REVIEW
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Abstract and Figures
Migraine is a common primary characteristically lateralizing cephalic painful disorder. The pathogenesis of migraine is not understood. Several theories and mechanisms of possible central brain-related origin of migraine with uncertain trajectories have found favour. Diverse pharmacologic drugs are used to abort acute attacks of migraine headache with varying success. Paradoxically, both vasoconstrictor (triptans) and vasodilator (magnesium) agents have been used. Drugs that do not freely cross the BBB and without definitive neural/neuronal influence (triptans, magnesium) are used to abort migraine attacks. While remaining in the centre stage with undisputed cranial vasoconstrictive action, the triptans offer no support to the currently in-vogue neuronal/neurovascular theory of migraine. Parenteral antiemetic dopaminergic antagonists form the most effective class of migraine abortive agents. Prochlorperazine i.v. is the most effective agent among the dopaminergic antagonists. Metoclopramide i.v. is an effective migraine abortive agent that also releases vasopressin (AVP). AVP offers important analgesic and vasomotor functions. AVP-related vasomotor and analgesic action of metoclopramide is elucidated in this review. Chlorpromazine (CPZ) has a definitive anti-migraine and retrobulbar analgesic action. CPZ blocks the voltage-gated sodium channel human Nav1.7. Less than 50% of patients in clinical trials respond to lasmiditan. There is no dose-response curve with increasing dosages and no clear benefit of a second dose of lasmiditan for rescue treatment. Use of placebo-controls without comparator drugs, as with lasmiditan trials, can be misleading. Analgesics, including NSAIDs, do not support the neuronal/neurovascular theory of origin of migraine. Clinical trials and meta-analyses cannot supplant the need for a reasonable degree of certitude about the nature of migraine. The critical role of the P-value in RCTs is under scrutiny. The site of action of all migraine abortive agents, including analgesics, is empirical and debatable. Emesis frequently aborts acute migraine headache attacks. Nausea/vomiting release AVP. In conjunction with intrinsic brain serotonergic and brain adrenergic activation, AVP release might play an important role in post-psychophysical non-oxidative stress-related migraine attacks as well as the typically delayed onset of headache of migraine. While psychosocial non-oxidative stress is ubiquitous, migraine affects approximately only 1/5 th to 1/6 th of humankind. Vasopressin-serotonergic-adrenergic nexus activation likely keeps migraine at bay in the vast majority of humans. Acute migraine attacks have a subtle onset, and, naturally and unpredictably wane over 4-72 hours. Uncertain decay of protean acute migraine headache attacks complicated by nausea/emesis with adaptive function creates a unique paradigm that complicates traditional studies. Data in migraine research are relatively soft and difficult to replicate precisely. CSD has a well-stablished neuronal as well as vascular protective effect in experimental animals. CSD does not offer any mechanistic insight for current migraine abortive drugs and is an illusory model for future drug development. The concept of adaptive mechanisms rationalizes abortive therapies for acute migraine attacks, and, is a first step in the evolution of a comprehensive pathophysiologic matrix. The future of abortive therapy rests on further evolution of the biology of migraine as well as an exclusive focus on the first (ophthalmic) division of the trigeminal nerve. 4 INDEX Abstract……………………………………………………………………Page 2-3 Introduction………………………………………………………………..Page 5-15
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... Cannabis has been used to cure headaches for hundreds to thousands of years, and medical marijuana users frequently use it today [8]. It has been used for medical purposes since ancient times and has also been recommended by many physicians for many illnesses, especially in the symptomatic and prophylactic treatment of headaches and migraines [9]. Delta-nine-tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the two main bioactive cannabinoids [1]. ...
Medical marijuana treatment for migraine is becoming more common, although the legality and societal acceptance of marijuana for medical purposes in the United States have been challenged by the stigma attached to it as a recreational drug. These substances function to reduce nociception and decrease the frequency of migraine by having an impact on the endocannabinoid system. Our study reviewed the clinical response, dosing, and side effects of marijuana in migraine management. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search in PubMed, Google Scholar, and Science Direct, and nine studies were included in the systematic review. The studies demonstrated that medical marijuana has a significant clinical response by reducing the length and frequency of migraines. No severe adverse effects were noted. Due to its effectiveness and convenience, medical marijuana therapy may be helpful for patients suffering from migraines. However, additional clinical trials and observational studies with longer follow-ups are required to study the efficacy and safety of the drug.
This is the historic beginning of the localization of aberrant neuronal/neural traffic in migraine to the first (ophthalmic) division of the trigeminal nerve, as expostulated as early as 1989/2009.
Till this brave and bold prediction, the V nerve was an omnibus cranial nerve, with no headway being made pathophysiologically since 2 millennia.
This overturns much of the literature of migraine research, substituting dogma and eminence for scientific principles and foundations.
Available at: https://n.neurology.org/content/reader-response-facial-presentations-migraine-tacs-and-other-paroxysmal-facial-pain
Background:
Migraine is a common debilitating condition whose main attributes are severe recurrent headaches with accompanying sensitivity to light and sound, nausea and vomiting. Migraine-related pain is a major cause of its accompanying disability and can encumber almost every aspect of daily life.
Main body:
Advancements in our understanding of the neurobiology of migraine headache have come in large from basic science research utilizing small animal models of migraine-related pain. In this current review, we aim to describe several commonly utilized preclinical models of migraine. We will discuss the diverse array of methodologies for triggering and measuring migraine-related pain phenotypes and highlight briefly specific advantages and limitations therein. Finally, we will address potential future challenges/opportunities to refine existing and develop novel preclinical models of migraine that move beyond migraine-related pain and expand into alternate migraine-related phenotypes.
Conclusion:
Several well validated animal models of pain relevant for headache exist, the researcher should consider the advantages and limitations of each model before selecting the most appropriate to answer the specific research question. Further, we should continually strive to refine existing and generate new animal and non-animal models that have the ability to advance our understanding of head pain as well as non-pain symptoms of primary headache disorders.
Objectives:
To characterize unmet treatment needs in a sample of Migraine in America Symptoms and Treatment (MAST) Study participants using oral, acute prescription migraine medications.
Background:
The MAST Study is a 2017 study of US adults with migraine that profiles current treatment patterns and identifies and quantifies unmet treatment needs.
Methods:
Cross-sectional data from an online survey of US adults meeting ICHD-3 beta criteria for migraine. For inclusion in this paper, respondents self-reported a history of 3 or more monthly headache days (MHDs) in the past 3 months and at least 1 MHD in the past 30 days, and current use of orally administered acute prescription medication for headache. Three domains of unmet need were identified: inadequate treatment response (ie, inadequate 2-hour pain freedom, recurrence within 24 hours of initial relief), demanding attack characteristics (rapid onset of attack, headache associated with sleep), and unique patient characteristics (opioid or barbiturate overuse, cardiovascular comorbidity). Sociodemographics, oral medication use, and coexisting conditions and symptoms (ie, level of treatment optimization, psychological symptoms, attack-related cutaneous allodynia, and migraine symptom severity) were assessed for each domain and by the number of unmet need domains.
Results:
Overall, 15,133 respondents met inclusion criteria, 26.0% (3930/15,133) reported current use of oral acute prescription medication to treat headache. Eligible participants had a mean age of 45.0 years, 73.6% [2892/3930] were women and 81.1% [3186/3930]) were White. A total of 95.8% (3765/3930) of respondents had at least 1 unmet acute treatment need; 89.5% (3516/3930) reported demanding attack characteristics, 74.1% (2912/3930) reported inadequate treatment response, and 16.1% (634/3930) presented with unique patient characteristics. Common areas of unmet need were rapid headache onset (65.3% [2567/3930]), moderate to severe disability (55.6% [2187/3930]), inadequate 2-hours pain freedom (49.0% [1892/3930]), and headache recurrence within 24 hours (38.0% [1493/3930]). An increasing number of unmet treatment need domains was associated with worsening psychological symptoms, attack-related cutaneous allodynia and migraine symptom severity.
Conclusion:
Nearly all MAST Study respondents using acute oral prescription medications for migraine reported at least 1 unmet treatment need. As unmet needs increased, so did coexisting conditions and symptom severity.
Background:
We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.
Methods:
SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan.
Results:
The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo.
Conclusions:
A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo.
Trial registration:
SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].
Migraine is a common headache disorder characterized by often-severe headaches that may be preceded or accompanied by a variety of visual symptoms. Although a typical migraine aura is not difficult to diagnose, patients with migraine may report several other visual symptoms, such as prolonged or otherwise atypical auras, “visual blurring”, “retinal migraine”, “ophthalmoplegic migraine”, photophobia, palinopsia, and “visual snow”. Here, we provide a short overview of these symptoms and what is known about the relationship with migraine pathophysiology. For some symptoms, the association with migraine is still debated; for other symptoms, recent studies indicate that migraine mechanisms play a role.
Objective:
To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine.
Methods:
We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.
Results:
There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia.
Recommendations:
Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counselling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.
Objective To assess the prevalence of facial pain (V2 and/or V3) presentations among nearly 3,000 patients with headache treated in a university tertiary care center.
Methods Between 2010 and 2018, we routinely assessed the prevalence of facial pain presentations of all patients with primary headaches.
Results Of 2,912 patient datasets, 291 patients reported facial pain either as an independent or as an additional symptom. Among patients with migraine, 2.3% (44 of 1,935) reported a facial involvement, most commonly in V2. Of these, 18 patients (40.9%) experienced the pain predominantly in the face. In patients with cluster headache, 14.8% (42 of 283) reported a facial involvement, of which 31.0% perceived the pain predominantly in the face. A facial involvement was seen in 45.0% of patients with paroxysmal hemicrania (9 of 20), 21.4% of patients with hemicrania continua (9 of 42), and 20.0% of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (3 of 15). In addition, we present 6 patients who reported a constant side-locked facial pain with superseded well-defined facial pain attacks of 10- to 30-minute duration that appeared several times per day.
Conclusion Our data suggest that a facial involvement in primary headaches is infrequent but not uncommon. A sole facial presentation of primary headache symptomatology seems to be exceptionally rare. We describe 3 different types of facial pain involvement and, in this context, distinguish patients with paroxysmal orofacial pain syndromes that have not been previously described. These patients may represent a new entity that could tentatively be called constant unilateral facial pain with added attacks.
