Research Progress on the Experimental Model and Underlying Mechanistic Studies of Tension-Type Headaches.

PURPOSE OF REVIEW: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH. RECENT FINDINGS: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.

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

BACKGROUND: Headache 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: While 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.

Diagnosis and Management of Headache: A Review.

IMPORTANCE: Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide. OBSERVATIONS: Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT1B/D agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene-related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene-related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo. CONCLUSIONS AND RELEVANCE: Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.

[Peppermint oil in the acute treatment of tension-type headache]. / Oleum menthae piperitae (Pfefferminzöl) in der Akuttherapie des Kopfschmerzes vom Spannungstyp.

Tension-type headache is the most frequent form of headache. The local topical treatment with peppermint oil (oleum menthae piperitae) has proven to be significantly more effective than placebo in controlled studies. Peppermint oil targets headache pathophysiology in multiple ways. The efficacy is comparable to that of acetylsalicylic acid or paracetamol. Solutions of 10 % peppermint oil in ethanol are licensed for the treatment of tension-type headache in adults and children above 6 years. It is included in treatment recommendations and guidelines by the respective professional societies and is regarded as a standard treatment for the acute therapy of tension-type headaches.

How to investigate and treat: headache and hyperprolactinemia.

Hyperprolactinemia is a condition characterised by an increase of prolactin blood levels (more than 100-200 ng/ml). It is the most common endocrine disorder of the hypothalamic-pituitary axis. The clinical characteristics of the headache-hyperprolactinemia-hypophyseal-adenoma association are discussed, the various diagnostic and treatment possibilities are explored and the etiology of the headache is considered in the light of several pathogenetic possibilities. We present two cases. (1) A 35-year-old woman suffering from chronic tension-type headache interspersed with occasional episodes of migraine without aura (as defined by the International Headache Society criteria). She had also suffered menstrual cycle alterations since the age of 16. At the age of 30 she developed amenorrhea with hyperprolactinemia. Computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed a median-left intrasellar mass. Treatment with cabergoline resulted in complete resolution of both types of headache and the menstrual cycle and prolactin levels returned to normal. The therapy also reduced the volume of the tumour. (2) The second case relates to a 47-year-old man who had been suffering from tension-type headaches for almost 3 months. The patient had never previously suffered from headaches. CT and MRI scans showed a large sellar and suprasellar lesion with raised serum prolactin levels. Treatment with cabergoline had significantly reduced the prolactin levels and had also improved the patient's headaches. High-resolution CT, with and without contrast, or MRI is necessary to visualise microprolactinomas (and other sellar lesions) and confirm the diagnosis.

P2X7 receptor blockade reverses purinergic facilitation of neck muscle nociception in mice.

INTRODUCTION: Facilitation of neck muscle nociception mediated via purinergic signalling may play a role in the pathophysiology of tension-type headache (TTH). The present study addressed reversal of purinergic facilitation of brainstem nociception via P2X7 antagonist action in anaesthetized mice. METHODS: Following administration of α,ß-meATP (i.m. 20 µL/min, 20 µL each) into semispinal neck muscles, the impact of neck muscle nociceptive input on brainstem processing was monitored by the jaw-opening reflex in anaesthetized mice (n = 20). The hypothesized involvement of the P2X7 receptor in the α,ß-meATP effect was addressed with i.p. (systemic) and i.m. (semispinalis, 20 µL/min, 20 µL each) administration of P2X7 inhibitor A438079 during established facilitation; i.p. saline served as control. RESULTS: α,ß-meATP reliably induced jaw-opening reflex facilitation (256 ± 48% (mean ± SEM), n = 20). I.p. A438079 (150, 300 µmol/kg) completely reversed this α,ß-meATP effect dose-dependently. Neither saline nor intramuscular A438079 (100 µM) altered facilitated brainstem nociceptive processing. DISCUSSION: These data suggest that muscular structures are not directly involved in the P2X7 antagonist-mediated reversal of purinergic facilitation. Instead, involvement of neuronal structures, particularly of the central nervous system, seems more probable. The results from this animal experimental model may point to involvement of purinergic P2X7 receptors in TTH pathophysiology and may suggest potential future targets for its pharmacological treatment.

Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia / Diseño y validación de un diario de cefalea en pacientes con cefalea crónica diaria en Colombia

OBJECTIVE: To devise and test the reliability and validity of a brief headache diary in a series of Colombian patients with chronic daily headache. METHODS: The study was designed in five stages: selection of domains (group of patients and experts); initial devising of the items (writing group); identification of non-understandable items (n=20); assessment of internal consistency (n=100); assessment of validity and assessment of sensitivity to change during seven consecutive days (n=25, 175 observations). RESULTS: Five domains were selected: headache presence, severity and length of pain, analgesics intake, and missing workdays. The headache diary is internally consistent (≈75 percent of rotated variance), correlates with the medical interview (Spearman's rho and Kendall's tau over 0.8 for each domain) and it has an adequate and stable sensitivity and specificity (82 to 96 percent). CONCLUSIONS: This headache diary is a reliable and valid instrument and represents the most important features affecting Colombian patients with chronic daily headache.

OBJETIVO: Diseñar y testar la validez y reproducibilidad de un diario de cefalea en una serie de pacientes Colombianos con cefalea crónica diaria. MÉTODOS: El estudio fue diseñado en cinco fases: selección de los dominios (grupo de pacientes y expertos); diseño inicial de los ítems (grupo redactor); identificación de ítems no comprensibles (n=20); determinación de la consistencia interna (n=100); determinación de la validez y la sensibilidad al cambio durante siete días consecutivos (n=25, 175 observaciones). RESULTADOS: Fueron seleccionados cinco dominios: presencia, severidad y duración del dolor, ingesta de analgésicos y días laborales perdidos. El diario tiene una adecuada consistencia interna (≈75 por ciento de la varianza), se correlaciona con la entrevista médica (rho de Spearman y tau de Kendall >0.8 para cada dominio) y tiene sensibilidad y especificidad estables y satisfactorias (82 a 96 por ciento). CONCLUSIONES: Este diario de cefalea es un instrumento confiable y registra las principales características de las cefaleas en pacientes con cefalea crónica diaria.

Acetylsalicylic acid inhibits α,ß-meATP-induced facilitation of neck muscle nociception in mice--implications for acute treatment of tension-type headache.

Infusion of α,ß-methylene ATP (α,ß-meATP) into murine neck muscle facilitates brainstem nociception. This animal experimental model is suggested to be appropriate for investigating pathophysiological mechanisms in tension-type headache. It was hypothesized that d-lysine acetylsalicylic acid (ASA, aspirin®) reverses this α,ß-meATP effect. Facilitation of neck muscle nociceptive processing was induced via bilateral infusion of α,ß-meATP into semispinal neck muscles (100 nM, 20 µl each) in 42 anesthetized mice. Brainstem nociception was monitored by the jaw-opening reflex elicited via electrical tongue stimulation. The hypothesis was addressed by subsequent (15, 30, 60 mg/kg) and preceding (60 mg/kg) intraperitoneal ASA injection. Saline served as control to ASA solution. Subsequent ASA dose-dependently reversed α,ß-meATP-induced reflex facilitation and was the most prominent with 60 mg/kg. Preceding 60 mg/kg ASA prevented reflex facilitation. Cyclooxygenases are involved in nociceptive transmission. Former experiments showed that unspecific inhibition of cyclooxygenases does not alter the α,ß-meATP effect. This suggests a specific mode of action of ASA. The concept is accepted that neck muscle nociception is involved in the pathophysiology of tension-type headache. Thus, objective proof of ASA effects in this experimental model may emphasize its major role in pharmacological treatment of tension-type headache attacks.

Inhibition of nNOS prevents and inhibition of iNOS reverses α,ß-meATP-induced facilitation of neck muscle nociception in mice.

Infusion of α,ß-methylene ATP (α,ß-meATP) into murine neck muscle facilitates brainstem nociception. Unspecific nitric oxide synthase (NOS) inhibition prevents and reverses this sensitization. It is unclear whether neuronal (nNOS), inducible (iNOS) or endothelial NOS isoenzymes are involved in this α,ß-meATP effect. Hypothesized involvement of nNOS isoenzyme was addressed by preceding (0.5, 1, and 2 mg/kg) and subsequent (2 mg/kg) intraperitoneal injection of the nNOS-inhibitor NPLA. iNOS involvement was addressed by subsequent, intraperitoneal administration of the iNOS-inhibitor 1400 W (2 mg/kg). Brainstem nociception was monitored by the jaw-opening reflex elicited via electrical tongue stimulation in 45 anesthetized mice. Preceding NPLA dose-dependently prevented α,ß-meATP-induced reflex facilitation. Whereas subsequent inhibition of nNOS showed no effect, iNOS inhibition by 1400 W significantly reversed reflex facilitation. Data provide evidence that nNOS plays a major role in induction and iNOS in maintenance of facilitation in neck muscle nociception. Divergent roles of NOS isoenzymes may promote research on target specific treatment for headache and neck muscle pain.

Medication overuse as a cause of chronic headache in shunted hydrocephalus patients.

PURPOSE: To highlight the group of hydrocephalus patients known to have a long history of shunt revisions and refractory chronic headache. When a shunt in perfect working order has no effect on headache, other causes of headache should be investigated. In this paper, patients with medication overuse headache are identified and the positive effect of medication withdrawal are described. MATERIALS AND METHOD: Patients with hydrocephalus and shunt referred from the neurosurgical department to the Danish Headache Centre were identified. In all cases, over- and underdrainage was ruled out prior to referral. Six patients with medication overuse headache were documented and their charts were reviewed retrospectively with specific attention to: shunt revisions, inpatient and outpatient contacts, headache data and medication use before and after withdrawal of analgesic medication overuse. RESULTS: A marked reduction in shunt revisions and inpatient contacts in five out of six patients was found and a reduction in outpatient contacts in four out of six patients. Furthermore, an improvement in headache intensity was found in three out of six patients and a reduction in duration was found in two out of six patients. CONCLUSION: This study indicates that it is important to identify shunt patients with persistent chronic headache from causes other than shunt malfunction. By reducing their analgesic intake, it is possible to reduce headaches, the number of surgical interventions and hospital contacts. Hopefully this will raise awareness and lead to further research on the subject.

Chronic tension-type headache: what is new?

PURPOSE OF REVIEW: This review discusses current data on nosological boundaries related to diagnosis, pathophysiology and therapeutic strategies in chronic tension-type headache (CTTH). RECENT FINDINGS: Diagnostic criteria of CTTH should be adapted to improve its sensitivity against migraine. It seems that mechanical pain sensitivity is a consequence and not a causative factor of CTTH. Recent evidence is modifying previous knowledge about relationships between muscle tissues and CTTH, suggesting a potential role of muscle trigger points in the genesis of pain. An updated pain model suggests that headache perception can be explained by referred pain from trigger points in the craniocervical muscles, mediated through the spinal cord and the trigeminal nucleus caudalis rather than only tenderness of the muscles themselves. Different therapeutic strategies, pharmacological, physical therapy, psychological and acupuncture, are generally used. The therapeutic efficacy of nonsteroidal anti-inflammatory drugs remains incomplete. The tricyclic antidepressants are the most used first-line therapeutic agents for CTTH. Surprisingly, few controlled studies have been performed and not all of them have found an efficacy superior to placebo. Further, there is insufficient evidence to support/refute the efficacy of physical therapy in CTTH. SUMMARY: Although there is an increasing scientific interest in CTTH, future studies incorporating subgroups of patients who will likely to benefit from a specific treatment (clinical prediction rules) should be conducted.

Peppermint oil.

Peppermint leaf and peppermint oil have a long history of use for digestive disorders. Recent evidence suggests that enteric-coated peppermint oil may be effective in relieving some of the symptoms of irritable bowel syndrome. A combination product including peppermint oil and caraway oil seems to be moderately effective in the treatment of non-ulcer dyspepsia. Topical application of peppermint oil may be effective in the treatment of tension headache. Because of its relaxing effects on smooth muscle, peppermint oil given via enema has been modestly effective for relief of colonic spasm in patients undergoing barium enemas. Peppermint oil is well tolerated at the commonly recommended dosage, but it may cause significant adverse effects at higher dosages.

Cefalea recurrente en la consulta de neurología del Hospital Nacional de Niños: 2001-2002: [revisión] / Recurrent headache in the neurology department of Hospital Nacional de Niños: 2001-2002: [review]

Se estudiaron retrospectivamente, 78 pacientes con cefalea recurrente referidos al servicio de Neurología del HNN durante los años 2001 y 2002. 51 por ciento de los pacientes venían referidos por un pediatra, con un tiempo de espera para ser atendidos en el HNN, menor de dos meses (80 por ciento). El grupo representó el 16,5 por ciento de la consulta de pacientes nuevos. 43 varones (55.1 por ciento) y 35 mujeres (44.9 por ciento), de 2 a 13 años de edad (promedio 8), tenían menos de 1 año de evolución de cefalea (50 por ciento), de intensidad moderada (70 por ciento), pulsátil (70 por ciento) y asociada a náuses, vómitos, defectos visuales y fotofobia en 36, 30, 27 y 13 pacientes respectivamente. En 36 niños no se reportó ningún factor desencadenante pero el estrés precipitaba los síntomas en 35 casos. El 72 por ciento tenían el antecedente familiar de migraña. A 61 pacientes se les realizó una tomografía axial computarizada (TAC), que fue normal en 59, uno tenía atrofia cortical y subcortical y otro hallazgos sugestivos de neurocisticercosis. Los diagnósticos principales fueron migraña (95 por ciento) y cefalea tensional (3 por ciento), con respuesta satisfactoria (85 por ciento de los casos) a las recomendaciones, analgésicos o al tratamiento preventivo, permitiendo remitirles (75 por ciento) a sus consultas de origen. Niños con cefalea recurrente y examen neurológico normal deben recibir recomendaciones, información y seguimiento, no siendo generalmente necesario referir a Neurología, hacer exámenes paraclínicos ni hospitalizar.

Cefaléia do tipo tensional crônica: tratamento alternativo com neuroestimulação elétrica transcutâncea / Alternative treatment with the transcutaneous electrical nerve stimulation (TENS)

Resumo: A neuroestimulação elétrica transcutânea foi avaliada no tratamento da cefaléia do tipo tensional crônica para o que foram selecionados 32 pacientes do ambulatório de Cefaléia do HC-UFPE que preenchiam os critérios diagnósticos emitidos pela SIC e que não estavam em uso de medicação profilática. Na consulta inicial lhe era entregue um diário no qual deviam registrar, por 30 dias consecutivos, os dias com dor e a intensidade de suas algias. Retornavam ao fim de 30 dias quando eram computados o número de dias com dor e estabelecido o escore da dor este representado pôr um número obtido da soma das parcelas: (Nº de dias com dor muito forte x 4) + (Nº de dias com dor forte x 3) (+ Nº de dias com dor fraca x 1 ). Iniciavam o tratamento submetendo-se a três sessões de 30 minutos cada e eram revistos após seis (15 dias) e 12 (30 dias) sessões, os dados assinalados no diário eram então computados e cortejados com os registros na fase pré tratamento. Dezoito dos pacientes, por razões várias, foram afastados do estudo. Dos 14 que completaram apenas três obtiveram resultados: satisfatório em dois (melhora de 83,64por cento no nº de dias com dor e em igual percentual no escora da dor); redução de 70por cento no nº de dias com dor e de 77,56por cento no escore da dor) e pouco significativo (redução de 41,18por cento no nº de dias com dor e de 43,34por cento no escore da dor). Em conclusão a neuroestimulação elétrica transcutânea se mostrou ineficaz no tratamento da cefaléia do tipo tensional crônica

The real dimension of analgesic activity of aspirin.

Aspirin, despite being 100-years old, even in the era of evidence-based medicine, remains a valuable analgesic. Results of randomized trials have shown that it is as well effective and safe as other analgesics in relieving mild pain and can be used in the first-line therapy of migraine.

Low-dose diclofenac potassium in the treatment of episodic tension-type headache.

BACKGROUND: Several clinical trials have demonstrated that low doses of non-steroidal anti-inflammatory drugs relieve episodic tension-type headache (ETH). AIMS: The aims of this placebo-controlled study were to determine whether single doses of diclofenac-K 12.5 and 25mg effectively relieve ETH in adults and to compare it to ibuprofen 400mg. METHODS: A single-dose multicentre, randomised, double-blind, double-dummy, clinical trial was conducted at 22 primary care centres in Germany. All subjects had a history of ETH according to the classification of the International Headache Society. Of 684 subjects randomised, 620 used the study drugs for an episode of tension headache occurring within one month after enrolment: diclofenac-K 12.5mg (n=160), diclofenac-K 25mg (n=156), ibuprofen 400mg (n=151) and placebo (n=153). The primary efficacy variable was total pain relief, calculated as the time-weighted sum of the pain relief assessments from baseline to the 3h evaluation time (TOTPAR-3). RESULTS: For TOTPAR-3, all active treatments were superior to placebo; no statistically significant difference between the three active treatments could be detected. A similar pattern was also observed with regard to TOTPAR-6 (6h evaluation time), > or =50%maxTOTPAR at 3 and 6h, weighted pain intensity difference at 3 and 6h (SPID-3; SPID-6), percentage of patients with complete headache relief at 2h, end of study global evaluation and time to rescue medication. The number-needed-to-treat (NNT) at 6h was 4.5 (2.9-9.2) in the ibuprofen 400mg group, 4.0 (2.8-7.3) in the diclofenac-K 12.5mg group and 3.9 (2.7-7.1) in the diclofenac-K 25mg group. These differences were not statistically significant. CONCLUSION: Diclofenac-K, administered as single doses of 12.5 and 25mg effectively relieves ETH and is comparable to ibuprofen 400mg.