Treatment Of Primary Headache Disorders Research Articles

Pituitary cyclase-activating polypeptide targeted treatmentsfor the treatment of primary headache disorders.

Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.

Status of diagnosis and preventative treatment for primary headache disorders: real-world data of unmet needs in China

BackgroundHeadache disorders are widely prevalent and pose a considerable economic burden on individuals and society. Globally, misdiagnosis and inadequate treatment of primary headache disorders remain significant challenges, impeding the effective management of such conditions. Despite advancements in headache management over the last decade, a need for comprehensive evaluations of the status of primary headache disorders in China regarding diagnosis and preventative treatments persists.MethodsIn the present study, we analyzed the established queries in the Survey of Fibromyalgia Comorbidity with Headache (SEARCH), focusing on previous diagnoses and preventative treatment regimens for primary headache disorders. This cross-sectional study encompassed adults diagnosed with primary headache disorders who sought treatment at 23 hospitals across China between September 2020 to May 2021.ResultsThe study comprised 2,868 participants who were systematically examined. Migraine and tension-type headaches (TTH) constituted a majority of the primary headache disorders, accounting for 74.1% (2,124/2,868) and 23.3% (668/2,868) of the participants, respectively. Medication overuse headache (MOH) affected 8.1% (231/2,868) of individuals with primary headache disorders. Over half of the individuals with primary headache disorders (56.6%, 1,624/2,868) remained undiagnosed. The previously correct diagnosis rates for migraine, TTH, TACs, and MOH were 27.3% (580/2,124), 8.1% (54/668), 23.2% (13/56), and 3.5% (8/231), respectively. The misdiagnosis of “Nervous headache” was found to be the most prevalent among individuals with migraine (9.9%, 211/2,124), TTH (10.0%, 67/668), trigeminal autonomic cephalalgias (TACs) (17.9%, 10/56), and other primary headache disorders (10.0%, 2/20) respectively. Only a minor proportion of individuals with migraine (16.5%, 77/468) and TTH (4.7%, 2/43) had received preventive medication before participating in the study.ConclusionsWhile there has been progress made in the rate of correct diagnosis of primary headache disorders in China compared to a decade ago, the prevalence of misdiagnosis and inadequate treatment of primary headaches remains a veritable issue. As such, focused efforts are essential to augment the diagnosis and preventive treatment measures related to primary headache disorders in the future.

Sonographic imaging of the great occipital nerve in the diagnosis and treatment of primary headache disorders

Primary headaches are a type of headache that occurs independently, without any other underlying medical condition or injury. They are a major concern due to their prevalence in the population and their potential to cause significant disruption to daily life. In past years, new techniques have been developed that utilize sonography in diagnosing and treating headache disorders. Some recent publications have appeared on the use of ultrasound in blocks of the greater occipital nerve and the diagnosis of headaches. For a long time, blocks of the nerve have been performed without target visualization, based on exterior landmarks only. New methods may improve the results of performed procedures. Therefore, this study aims to provide an overview of the applications of ultrasound imaging of the greater occipital nerve in clinical practice.

An Asian perspective on complementary and alternative medicine in the treatment of primary headache disorders

An Asian perspective on complementary and alternative medicine in the treatment of primary headache disorders

Non-invasive neuromodulation of the cervical vagus nerve in rare primary headaches.

Primary headache disorders can be remarkably disabling and the therapeutic options available are usually limited to medication with a high rate of adverse events. Here, we discuss the mechanism of action of non-invasive vagal nerve stimulation, as well as the findings of the main studies involving patients with primary headaches other than migraine or cluster headache, such as hemicrania continua, paroxysmal hemicrania, cough headache, or short-lasting neuralgiform headache attacks (SUNCT/SUNA), in a narrative analysis. A bibliographical search of low-prevalence disorders such as rare primary headaches retrieves a moderate number of studies, usually underpowered. Headache intensity, severity, and duration showed a clinically significant reduction in the majority, especially those involving indomethacin-responsive headaches. The lack of response of some patients with a similar diagnosis could be due to a different stimulation pattern, technique, or total dose. The use of non-invasive vagal nerve stimulation for the treatment of primary headache disorders represents an excellent option for patients with these debilitating and otherwise refractory conditions, or that cannot tolerate several lines of preventive medication, and should always be considered before contemplating invasive, non-reversible stimulation techniques.

Current practice for primary headache disorders and perspectives on peripheral nerve blocks among emergency physicians in Canada: A national survey.

This national postal survey aimed to examine Canadian emergency physicians' practice patterns with respect to drug treatment and perspectives on peripheral nerve blocks. The treatment of primary headache disorders in the emergency department is variable. We surveyed 500 emergency physicians listed in the Canadian Medical Directory according to a modified Dillman's method: an initial invitation was followed by up to four reminders to nonresponders. Physicians were asked questions regarding their frequency of medication administration and perspectives toward peripheral nerve blocks. Of 500 mailed surveys, 468 were delivered and 179 physicians responded (response rate = 38.2%). The majority of physicians were men (92/144, 63.9%); 80.6% (116/144) had been in practice for greater than or equal to 10years with 50.7% (75/148) in a community or district general teaching hospital. Commonly used pharmacotherapies for primary headaches were intravenous dopamine receptor antagonists (69%), co-administration of ketorolac and a dopamine receptor antagonist (54.2%), intravenous fluid boluses (54%), nonsteroidal anti-inflammatory drugs (NSAIDs) alone (53.5%), and acetaminophen (51.4%). Only 80 of 144 physicians (55.6%) reported previous experience with peripheral nerve blocks (95% confidence interval [CI] = 48%-65%). The majority (68/80, 85.0%) agreed peripheral nerve blocks are safe and 55.1% (43/78) agreed they are effective. The vast majority (118/140, 84.3%) would consider peripheral nerve blocks as a first-line treatment option given sufficient evidence from a future trial (95% CI = 78%-90%). NSAIDs alone, as well as dopamine receptor antagonists with or without ketorolac are commonly used for primary headache in Canadian emergency departments. A large proportion of physicians have never used a peripheral nerve block in their practice; among those who have experience with peripheral nerve blocks, the majority find them safe and effective. The majority of respondents would consider peripheral nerve blocks as a first-line treatment option given sufficient evidence from a future trial.

Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation

Vagus nerve stimulation (VNS) is a promising neuromodulation approach used in the treatment of migraine, whose therapeutic mechanism is largely unknown. Previous studies suggest that VNS's anti-nociceptive effects may, in part, involve engaging opioidergic mechanisms. We used a validated preclinical model of head pain, with good translational outcomes in migraine, acute intracranial-dural stimulation, which has responded to invasive VNS.We tested the effects of μ (MOR), δ (DOR) and κ (KOR) opioid receptor agonists in this model, and subsequently the effects of opioid receptor antagonists against VNS-mediated neuronal inhibition. MOR, DOR, and KOR agonists all inhibited dural-evoked trigeminocervical neuronal responses. Both DOR and KOR agonists also inhibited ongoing spontaneous firing of dural responsive neurons. Both DOR and KOR agonists were more efficacious than the MOR agonist in this model. We confirm the inhibitory effect of invasive VNS and demonstrate that this effect was prevented by a broad-spectrum opioid receptor antagonist, and by a highly selective DOR antagonist. Our data confirm the role of MOR in dural-trigeminovascular neurotransmission and additionally provide evidence of a role of both DOR and KOR in dural-nociceptive transmission of trigeminocervical neurons. Further, the results here provide evidence of engagement of opioidergic mechanisms in the therapeutic action of VNS in headache, specifically the DOR. These studies provide further support for the important role of the DOR in headache mechanisms, and as a potential therapeutic target. The data begin to dissect the mode of action of the analgesic effects of VNS in the treatment of primary headache disorders.

Noninvasive Neuromodulation in Headache: An Update.

Migraine is a common disabling primary headache condition. Although strives have been made in treatment, there remains an unmet need for safe, effective acute, and preventative treatments. The promising concept of neuromodulation of relevant neuronal targets in a noninvasive fashion for the treatment of primary headache disorders has led to the trial of numerous devices over the years. We aimed to review the evidence on current neuromodulation treatments available for the management of primary headache disorders. Randomized controlled trial as well as open-label and real-world studies on central and peripheral cephalic and noncephalic neuromodulation modalities in primary headaches were critically reviewed. The current evidence suggests a role of single-pulse transcranial magnetic stimulation, supraorbital nerve stimulation, and remote noncephalic electrical stimulation as migraine abortive treatments, with stronger evidence in episodic rather than in chronic migraine. Single-pulse transcranial magnetic stimulation and supraorbital nerve stimulation also hold promising evidence in episodic migraine prevention and initial positive evidence in chronic migraine prevention. More evidence should clarify the therapeutic role of the external vagus nerve stimulation and transcranial direct current stimulation in migraine. However, external vagus nerve stimulation may be effective in the acute treatment of episodic but not chronic cluster headache, in the prevention of hemicrania continua and paroxysmal hemicrania but not of short-lasting neuralgiform headache attacks. The difficulty in setting up sham-controlled studies has thus far prevented the publication of robust trials. This limitation along with the cost of these therapies has meant that their use is limited in most countries. Neuromodulation is a promising nonpharmacological treatment approach for primary headaches. More studies with appropriate blinding strategies and reduction of device cost may allow more widespread approval of these treatments and in turn increase clinician's experience in neuromodulation.

Differential actions of indomethacin: clinical relevance in headache.

Nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide (NO) signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of an NO donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen, and ibuprofen. Administration of indomethacin (5 mg·kg-1), ibuprofen (30 mg·kg-1), or naproxen (30 mg·kg-1) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. By contrast, only indomethacin was able to inhibit NO-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate NO-related signaling as a potential therapeutic approach to these disorders.

A Review of Clinical Research Trends in the Treatment of Primary Headache Disorders with Pharmacopuncture

A Review of Clinical Research Trends in the Treatment of Primary Headache Disorders with Pharmacopuncture

Anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: Update on a Previous Review After the American Headache Society 60th Scientific Meeting, San Francisco, June 2018.

To briefly update and correct the available data on anti-calcitonin gene-related peptide (CGRP) therapies for headache since the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. CGRP is a target for primary headache therapies. The author briefly reviews the new data and publications on gepants and anti-CGRP and anti-CGRP receptor monoclonal antibodies since the writing of his previous review in May 2018, with an emphasis on data provided at the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. The US Food and Drug Administration (FDA) approved erenumab-aooe, an anti-CGRP receptor monoclonal antibody, for the prevention of migraine on May 17, 2018. On September 14, 2018, the FDA approved fremanezumab-vfrm and on September 26, 2018, the FDA approved galcanezumab-gnlm, both anti-CGRP ligand monoclonal antibodies for the prevention of migraine. Galcanezumab showed effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Both galcanezumab and fremanezumab failed to prevent chronic cluster headache. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for the acute treatment of migraine, but have not yet been submitted to the FDA for this indication. A press release with data on the effectiveness of daily atogepant in migraine prevention provides some details. An announcement at the meeting suggests daily rimegepant will be tested for prevention as well. The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

Diagnosis and Treatment of Primary Headache Disorders in Older Adults.

To provide a unique perspective on geriatric headache and a number of novel treatment options that are not well known outside of the headache literature. Review of the most current and relevant headache literature for practitioners specializing in geriatric care. Evaluation and management of headache disorders in older adults requires an understanding of the underlying pathophysiology and how it relates to age-related physiological changes. To treat headache disorders in general, the appropriate diagnosis must first be established, and treatment of headaches in elderly adults poses unique challenges, including potential polypharmacy, medical comorbidities, and physiological changes associated with aging. The purpose of this review is to provide a guide to and perspective on the challenges inherent in treating headaches in older adults. J Am Geriatr Soc 66:2408-2416, 2018.

History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment.

Objective - To briefly describe the history of and available data on anti-calcitonin gene-related peptide (CGRP) therapies for headache. Background - CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti-CGRP treatments. The first anti-CGRP treatment, an intravenous CGRP-receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods - The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti-CGRP and anti-CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti-CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti-CGRP treatments. Results - The US Food and Drug Administration (FDA) approved erenumab, an anti-CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti-CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions - The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

Spotlight on cervical vagus nerve stimulation for the treatment of primary headache disorders: a review.

ObjectivesCervical noninvasive vagus nerve stimulation (nVNS) emerged as an adjunctive neuromodulation approach for primary headache disorders with limited responsiveness to pharmacologic and behavioral treatment. This narrative review evaluates the safety and efficacy of invasive and noninvasive peripheral nerve stimulation of the cervical branch of the vagal nerve (afferent properties) for primary headache disorders (episodic/chronic migraine [EM/CM] and cluster headache [ECH/CCH]) and provides a brief summary of the preclinical data on the possible mechanism of action of cervical vagus nerve stimulation (VNS) and trigemino-nociceptive head pain transmission.Materials and methodsA systematic search of published data was performed in PubMed for randomized controlled trials (RCTs) and prospective cohort clinical studies assessing the efficacy/safety and cost-effectiveness of cervical VNS in primary headache disorders and related preclinical studies.ResultsThree RCTs were identified for ECH/CCH (ACT-1, ACT-2 and PREVA), one RCT for migraine (EVENT) and several prospective cohort studies and retrospective analyses for both headache disorders. In ACT-1, a significantly higher response rate, a higher pain-free rate and a decrease in mean attack duration were found in nVNS-treated ECH/CCH patients compared to sham stimulation. ACT-2 confirmed these findings (e.g., significantly higher pain-free attacks, pain severity decline and increased responder-rate [defined as ≥50% reduction]). The PREVA study demonstrated the superiority of adjunctive nVNS to standard care alone and observed a significantly higher attack reduction (p=0.02) and responder rate (defined as ≥50% reduction). For CM, the EVENT study assessed a significantly higher frequency of decline in the open-label phase. Mostly transient mild/moderate adverse events were recorded, and no severe device-related adverse events occurred.ConclusionCervical nVNS represents a novel, safe and efficient adjunctive treatment option for primary headache disorders. In particular, preliminary observations suggest enhanced nVNS responsiveness in favor of episodic subtypes (EM and ECH). However, preclinical studies are urgently warranted to dissect the mechanism of action.

THE ROLE OF MELATONIN IN THE TREATMENT OF CHRONIC HEADACHE

Melatonin is an endogenous chronobiotic that demonstrated its analgesic potential in an array of experimental and clinical studies. It proved efficient in fibromyalgia, irritable bowel syndrome, back pain and various types of headache. The level of evidence supporting melatonin’s analgesic properties in treating migraine and cluster headache is the highest. This review provides a summary of main papers currently available about the use of melatonin in the treatment of primary headache disorders of various types. It discusses possible mechanisms of melatonin analgesic action and prospects of its use in combination therapy of headache.

Treatment of disabling headache with greater occipital nerve injections in a large population of childhood and adolescent patients: a service evaluation

BackgroundPediatric headache disorders can be extremely disabling, with marked reduction in the quality of life of children and their carers. Evidenced-based options for the treatment of primary headache disorders with preventive medication is limited and clinical outcomes are often unsatisfactory. Greater occipital nerve injections represent a rapid and well-tolerated therapeutic option, which is widely used in clinical practice in adults, and has previously shown a good outcome in a pediatric population.MethodsThis service evaluation reviewed greater occipital nerve injections performed unilaterally with 30 mg 1% lidocaine and 40 mg methylprednisolone, to treat disabling headache disorders in children and adolescents.ResultsWe analyzed a total of 159 patients who received 380 injections. Of the population, 79% had chronic migraine, 14% new daily persistent headache, 4% a trigeminal autonomic cephalalgia, 3% secondary headache and one patient had chronic tension-type headache. An improvement after injection was seen in 66% (n = 105) of subjects, lasting on average 9 ± 4 weeks. Improvement was seen in 68% of patients with chronic migraine, 67% with a trigeminal autonomic cephalalgia and 59% with new daily persistent headache. Side effects were reported in 8% and were mild and transient.Older age, female gender, chronic migraine, increased number of past preventive use, medication overuse and developing side effects were all associated with an increased likelihood of positive treatment outcome.ConclusionsThis large single centre service evaluation confirms that unilateral injection of the greater occipital nerve is a safe, rapid-onset and effective treatment strategy in disabling headache disorders in children, with a range of diagnoses and severity of the condition, and with minimal side effects.

Prochlorperazine/Diphenhydramine Outperforms Ketamine/Ondansetron for Benign Headache Treatment in the ED

Prochlorperazine is a standard agent with well-described effectiveness for treatment of primary headache disorders in the emergency department (ED).

The Role of Melatonin in the Treatment of Primary Headache Disorders.

To provide a summary of knowledge about the use of melatonin in the treatment of primary headache disorders. Melatonin is secreted by the pineal gland; its production is regulated by the hypothalamus and increases during periods of darkness. We undertook a narrative review of the literature on the role of melatonin in the treatment of primary headache disorders. There are randomized placebo-controlled trials examining melatonin for preventive treatment of migraine and cluster headache. For cluster headache, melatonin 10 mg was superior to placebo. For migraine, a randomized placebo-controlled trial of melatonin 3 mg (immediate release) was positive, though an underpowered trial of melatonin 2 mg (sustained release) was negative. Uncontrolled studies, case series, and case reports cover melatonin's role in treating tension-type headache, hypnic headache, hemicrania continua, SUNCT/SUNA and primary stabbing headache. Melatonin may be effective in treating several primary headache disorders, particularly cluster headache and migraine. Future research should focus on elucidating the underlying mechanisms of benefit of melatonin in different headache disorders, as well as clarifying optimal dosing and formulation.

Current Approaches to Neuromodulation in Primary Headaches: Focus on Vagal Nerve and Sphenopalatine Ganglion Stimulation.

Neuromodulation is a promising, novel approach for the treatment of primary headache disorders. Neuromodulation offers a new dimension in the treatment that is both easily reversible and tends to be very well tolerated. The autonomic nervous system is a logical target given the neurobiology of common primary headache disorders, such as migraine and the trigeminal autonomic cephalalgias (TACs). This article will review new encouraging results of studies from the most recent literature on neuromodulation as acute and preventive treatment in primary headache disorders, and cover some possible underlying mechanisms. We will especially focus on vagus nerve stimulation (VNS) and sphenopalatine ganglion (SPG) since they have targeted autonomic pathways that are cranial and can modulate relevant pathophysiological mechanisms. The initial data suggests these approaches will find an important role in headache disorder management going forward.

Transcutaneous and Percutaneous Neurostimulation for Headache Disorders.

Noninvasive and minimally invasive extracranial stimulation has now been widely investigated for the treatment of primary headache disorders, particularly migraine. In this review, we describe methodological challenges in studying occipital and supraorbital stimulation devices. We explore the efficacy and safety of implantable occipital nerve stimulation for primary headache disorders, including the 3 randomized, sham-controlled clinical trials for chronic migraine treatment. We also review noninvasive supraorbital transcutaneous stimulation as a preventive therapy for episodic migraine.