Medication-Overuse Headache: Results from a Pain Medicine Clinic Cohort

Background and Objective: Medication-overuse headache (MOH) is a common, disabling, and treatable cause of chronic daily headache. This study evaluates the characteristics of a cohort of patients with MOH seen in a pain medicine clinic. Methods: We conducted a retrospective study of consecutive patients seen by a neurologist in the pain medicine clinic at the University of California, San Diego. Demographics, headache diagnoses, and overused medications were extracted from clinical records from 83 patients ≥ 18 years of age where a diagnosis of MOH was entered into the electronic medical record September 12, 2017-March 30, 2020. Results: Opioids were the most overused medications (42/83, 50.6%) followed by caffeine-containing compounds (20/83, 24.1%), triptans (12/83, 14.5%) and non-steroidal anti-inflammatory drugs (10/83, 12.9%). Chronic migraine was the most common underlying headache syndrome (54/83, 65.1%), followed by secondary headache disorder (13/83, 15.7%) and tension-type headache (8/83, 9.6%). Men were more likely to be overusing opioids (OR 3.3, p = 0.026) while women were more likely to be overusing caffeine-containing compounds (OR 5.4, p = 0.041). Discussion and Conclusions: It is crucial for pain specialists to recognize MOH in the pain clinic setting. Opioid overuse headache is more common among men, likely in part due to migraine being underrecognized in men and therefore men not receiving migraine-specific medications. Caffeine-containing compound overuse is more common among women; these are over-the-counter (OTC) and often do not appear on patients’ medications lists. Pain specialists should specifically ask patients with headache whether they are using OTC caffeine-containing compounds.

Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial

Background Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). Methods RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. Results Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. Conclusions One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. Trial registration This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053.

Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research

Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Comprehensive approach for the treatment of medication-overuse headache

Background: Medication-overuse headache (MOH) is defined by the International Classification of Headache Disorders as a headache in patients with a pre-existing primary headache disorder that occurs on 15 or more days per month for more than 3 months. It is caused by overuse of medication for acute or symptomatic headache treatment. Regular and frequent use of acute or symptomatic medications can worsen headaches and lead to chronic headache or MOH. MOH is a burdensome medical condition that is difficult to treat, and the frequent recurrence of headaches may result in disability in individuals and impair socioeconomic outcomes.Current Concepts: Awareness of MOH and the education of patients, the general population, and healthcare providers are important for the first step of treatment. Scientific research regarding the treatment of MOH has been published in the past few years.Discussion and Conclusion: Physicians should educate and counsel patients to stop or at least reduce the intake of acute or symptomatic medications that can be discontinued abruptly or tapered slowly. During the period after the discontinuation of the overused medications, some withdrawal symptoms including headache might be manageable with bridging therapy. Evidence-based preventive therapies including anticonvulsants (topiramate and divalproex sodium), botulinum toxin A, and medications acting by antagonism of the calcitonin generelated peptide pathway might be helpful in patients with MOH for both avoiding the overused medication and preventing the relapse of overuse. A comprehensive and multidisciplinary approach may improve the outcomes of patients with MOH.

Neurogenic Inflammation: One of the Participants of Migraine and the Contribution of Translational Research

Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Clinical symptoms of androgen deficiency in men with migraine or cluster headache: a cross-sectional cohort study

Background To compare symptoms of clinical androgen deficiency between men with migraine, men with cluster headache and non-headache male controls. Methods We performed a cross-sectional study using two validated questionnaires to assess symptoms of androgen deficiency in males with migraine, cluster headache, and non-headache controls. Primary outcome was the mean difference in androgen deficiency scores. Generalized linear models were used adjusting for age, BMI, smoking and lifetime depression. As secondary outcome we assessed the percentage of patients reporting to score below average on four sexual symptoms (beard growth, morning erections, libido and sexual potency) as these items were previously shown to more specifically differentiate androgen deficiency symptoms from (comorbid) anxiety and depression. Results The questionnaires were completed by n = 534/853 (63%) men with migraine, n = 437/694 (63%) men with cluster headache and n = 152/209 (73%) controls. Responders were older compared to non-responders and more likely to suffer from lifetime depression. Patients reported more severe symptoms of clinical androgen deficiency compared with controls, with higher AMS scores (Aging Males Symptoms; mean difference ± SE: migraine 5.44 ± 0.90, p < 0.001; cluster headache 5.62 ± 0.99, p < 0.001) and lower qADAM scores (quantitative Androgen Deficiency in the Aging Male; migraine: − 3.16 ± 0.50, p < 0.001; cluster headache: − 5.25 ± 0.56, p < 0.001). Additionally, both patient groups more often reported to suffer from any of the specific sexual symptoms compared to controls (18.4% migraine, 20.6% cluster headache, 7.2% controls, p = 0.001). Conclusion Men with migraine and cluster headache more often suffer from symptoms consistent with clinical androgen deficiency than males without a primary headache disorder.

No structural brain alterations in new daily persistent headache – a cross sectional VBM/SBM study

Objective To identify grey matter alterations in patients suffering new daily persistent headache to enrich the pathophysiological concept of this rare headache disorder characterised by a distinct, clearly remembered onset and its instant chronification. Method Magnetic resonance-based voxel-based and surface-based morphometry was used to investigate 23 patients suffering from new daily persistent headache and 23 age- and gender-matched healthy controls with 1.5 Tesla MRI. Independent statistical analysis was performed at three sites using statistical parametric mapping, as well as FSL(FMRIB Software Library)-based approaches. Results No grey matter changes were detected using this sophisticated and cross-checked method. Conclusion The absence of structural brain changes in patients with new daily persistent headache contribute to the recent discussion regarding structural alterations in primary headache disorders in general and does not provide evidence for grey matter changes being associated with the pathophysiology of new daily persistent headache. Future research will have to determine the underlying pathophysiological mechanisms of this disorder.

Serum calcitonin gene related peptide (CGRP) levels in migraine: A study on its clinical correlation and diagnostic efficacy

Migraine is a primary headache disorder marked by recurrent unilateral headache episodes. Calcitonin gene related peptide (CGRP) plays major role in migraine pathophysiology. CGRP is multifunctional, and its vasodilating activity within the central and peripheral blood vessels is one in all its primary functions. The intention is to prove serum calcitonin gene related peptide (CGRP) as an early diagnostic tool for migraine and the novelty is to correlate it with characteristics of migraine so that it helps in early initiation of treatment. Methods. 100 subjects including 90 patients with migraine and 10 with non-headache (NH) age-matched controls were prospectively recruited in our current study. The subjects were aged from 15- 50 years. The clinical assessment was made every month for the three months after the start of therapy. The subjects were compared based on the serum CGRP values. Serum CGRP concentrations were measured by using CGRP ELISA kit. Results. Out of total subjects selected, the maximum (23.3%) subjects were between age 26 and 30 years and least effected age group was 46-50 years (4.44%). Females’ predominance with 82% than males with 18%.Stress was major trigger occurring in 57% of cases. Throbbing pain with elevated CGRP levels 130.44±114.22 and p value (p = 0.01). The average CGRP levels was higher in test group 149.00±93.86 compared to control 61.30±24.37 with p value (p = 0.02). Conclusions. The serum CGRP levels were statistically more in migraine patients correlated with characteristics like throbbing type of pain, stress and inadequate sleep. Hence, the serum CGRP levels estimation can be considered as a diagnostic tool for migraine when the clinical character’s over lap or early in the course of migraine when all criteria for diagnosis are not yet fulfilled.

Evidence That HFE H63D Variant Is a Potential Disease Modifier in Cluster Headache

Cluster headache (CH) is a primary headache disorder with a complex genetic background. Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The HFE gene encodes for a protein involved in iron metabolism, while genetic variants in HFE have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common HFE H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the HFE rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (p > 0.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the HFE gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that HFE H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in HFE gene may be potentially regarded as a disease modifier genetic factor in CH.

Headache in progressive facial hemiatrophy (Parry-Romberg syndrome): A paradigmatic case and systematic review of the literature

Background Parry-Romberg syndrome is a neuro-cutaneous disease characterized by progressive hemifacial atrophy. Although common, headache in this population is scarcely reported in the literature. Objective To evaluate the clinical features of headache in pediatric and adult patients with Parry-Romberg syndrome, and to discuss diagnostic and treatment approaches of headache in Parry-Romberg syndrome. Methods We conducted a systematic review in accordance with PRISMA guidelines. We searched the MEDLINE database to identify eligible studies and identified patients with Parry-Romberg syndrome and headache. We further reported a paradigmatic case with a complex headache disorder and described its management and outcome. Results We identified 74 articles, 41 of which were included in the analysis. A total of 52 patients (55.8% female) were included for data analysis. The main age at onset of headache was 20 years (SD 15.2; range 3–56). A diagnosis of migraine was made in 53.9%. Abnormal brain imaging was found in 82.2% of patients. Conclusion Long-term follow-up of patients is required, because headache may develop (and evolve) at any time over the course of the disease. Primary and secondary headaches often co-occur in patients with Parry-Romberg syndrome. Further research into the underlying etiopathogenesis and therapeutic targets would be recommended.