Medication-overuse headache: a narrative review.

Medication-overuse headache (MOH), which potentially involves 1-2% of the population, is defined as a headache, on ≥ 15 days a month affected, along with overuse of one or other acute attack medications. MOH presents with significant challenges in the headache community, particularly in clinical settings raising various questions about its pathophysiology. Through a review of the current literature and our clinical experience, we have explored the mechanisms through which MOH may occur, provide an understanding of the current state of treatment and detail some possible views on the understanding and treatment of this condition. We evaluate the variations in treatment methods offered globally and understanding of the disorder. Above all interventions, patient education is crucial, which is underscored by an analysis of the academic publications. Given the condition is preventable, early intervention is imperative and patient awareness is highlighted as key. Globally, there is no uniform treatment methodology, which may be advantageous as approaches need to take local circumstances into account.

The effect of anesthetic blockade of greater occipital nerve during the withdrawal period of the medication overuse headache treatment.

Background and purpose:

Discontinua­tion of medication still remains a key element in the treatment of medication overuse headache (MOH), but there is no consensus on the withdrawal procedure. We aimed to share the promising results of anesthetic blockade of greater occipital nerve (GON), which can be an alternative to existing treatments during the early withdrawal period of MOH treatment.

This study was conducted using regular electronic medical records and headache diaries of patients diagnosed with MOH and treated with anesthetic GON blockade with 0.5% bupivacaine solution in a specia­lized headache outpatient clinic. A total of 86 patients who developed MOH while being followed up for chronic migraine were included in the study.

The treatment schemes for MOH are based on expert consensus and withdrawal strategies are the most challenging part of treatment. In our study, numerical rating scale for headache intensity, overused medication consumption per month, headache frequency (day/month) and the duration of each attack (hour/day) decreased significantly in the first month compared to pre-treatment (p < 0.01). 

Conclusion – Our study suggests that GON blockade can be used as a good alternative therapy in the treatment of MOH.

Therapies targeting CGRP signaling for medication overuse headache.

PURPOSE OF REVIEW: Medication overuse headache (MOH) affects more than 60 million individuals worldwide causing enormous personal and social burden. Only repurposed drugs are available for MOH that share limited evidence for efficacy. The preclinical data suggesting that activation of the calcitonin gene-related peptide (CGRP) pathway is involved in headache chronification along with clinical evidence that monoclonal antibodies targeting CGRP (anti-CGRP mAbs) have good efficacy in preventing chronic migraine, triggered this review that aims to summarize the current data on the effectiveness and safety of mAbs against CGRP in MOH. RECENT FINDINGS: Post hoc analyses of phase-3 trials of erenumab, fremanezumab, galcanezumab, and eptinezumab for the prevention of chronic migraine revealed that patients with MOH benefit from the treatment over placebo. Several real-world studies confirm the efficacy of erenumab and galcanezumab in patients with MO. However, all published trials evaluated treatments in patients with chronic migraine with MO collectively, not in patients with MOH exclusively. SUMMARY: The available data indicate that anti-CGRP mAbs represent a good mechanism-based and disease-specific therapeutical option with for MOH as long as detoxification and additional nonpharmaceutical interventions are operated. Future research should focus on long-term-controlled trials in MOH populations exclusively.

Detoxification vs non-detoxification before starting an anti-CGRP monoclonal antibody in medication overuse headache.

BACKGROUND: Medication overuse headache significantly contributes to the chronification process and treatment refractoriness of migraine. Currently, abrupt discontinuation of the overused medication still represents the best management strategy for these patients, challenging public health system resources. METHODS: In this prospective study, chronic migraine and medication overuse headache sufferers with at least 28 days of analgesic consumption per month were included. Assessment of efficacy outcomes at three months were compared among patients who underwent in-hospital abrupt discontinuation of overused acute medication (YES-DETOX group) and patients who did not (NO-DETOX group) before starting an anti-CGRP monoclonal antibody. RESULTS: Of 401 patients who received either erenumab or galcanezumab, 28% (n = 111) satisfied inclusion criteria (YES-DETOX n = 28; NO-DETOX n = 83). After three months of treatment, 59% (n = 65; 47/83 YES-DETOX; 18/28 NO-DETOX) patients reverted from medication overuse headache and 51% (n = 57; 42/83 YES-DETOX; 15/28 NO-DEOTX) achieved ≥50% reduction in monthly headache days; yet no statistical differences were observed between the two groups (p = 0.4788 and p = 0.8393, respectively). Monthly consumption of pain medication was the only baseline prognostic factor in multivariate analysis in the overall cohort (p = 0.016). CONCLUSION: Our results support the emerging evidence that anti-CGRP monoclonal antibodies may be effective in medication overuse headache patients irrespective of detoxification, yet further studies are needed to draw definitive conclusions.

Characteristics and comorbidities of headache in patients over 50 years of age: a cross-sectional study.

BACKGROUND: Although headache is a common complaint in younger individuals, it is one of the most common complaints among persons over the age of 50 and is a significant cause of morbidity. As there are differences in the causes and types of headache, the diagnosis and management of headache in older adults differ from that in younger individuals. METHODS: In this cross-sectional study, 570 patients ≥ 50 years were recruited at a university affiliated tertiary headache center between 2016 and 2019. Demographic data, headache characteristics, and comorbid medical conditions were recorded. The presence of depression was explored using the Beck Depression Inventory. The patients were evaluated using the STOP-BANG scale to determine the risk of obstructive sleep apnea. RESULTS: The mean age of the patients was 57.7 years. Seventy-three percent of the patients had primary headache disorders, with the most prevalent types being migraine, followed by tension-type headache. Secondary headaches were primarily the result of overuse of medication, cervical spine disease, and hypertension. Patients with medication-overuse headache were significantly more likely to suffer from hypothyroidism and gastrointestinal problems such as bleeding/ulcers. Irritable bowel syndrome was also more common in patients with medication-overuse headaches and migraines. The risk for obstructive sleep apnea was intermediate in 45.2% of the patients with hypertension-induced headache, but was lower in the majority of others. There was a high tendency for moderate-to-severe depression in the participants; however, the Beck Depression Inventory scores were significantly higher in medication-overuse headache patients. CONCLUSION: Proper treatment of headache in middle-aged and older adults requires the recognition of secondary causes, comorbid diseases, and drug induced or medication overuse headaches. Special attention should be paid to depression and obstructive sleep apnea in such patients suffering from headache disorders.

Medication overuse headache.

PURPOSE OF REVIEW: Medication overuse headache (MOH)is a disabling problem worldwide with areas of controversy regarding its cause. This article reviews the recent ideas regarding the development of this disorder and its effective management. RECENT FINDINGS: It has been proposed that all acute migraine medications can lead to MOH, with differences in the propensity of different agents to cause the problem. Early data suggests that gepants, which are small-molecule calcitonin gene-related peptide antagonists used for the acute treatment of migraine, may be an exception. Recent studies show that practitioners and the general public are still largely unaware of the problem of medication overuse and its damaging effects. SUMMARY: MOH is an accepted concept of an increase in headaches driven by the frequent administration of acute antimigraine drugs. The impressions of providers, and studies documenting the concept may be flawed. Although it is likely that MOH does occur, and restricting the amount of acute medications is necessary to prevent it, it is also possible that increasing amounts of acute medications are simply a reflection of poorly controlled headaches, rather than a cause. Objective markers need to be developed to identify those who have MOH, which does not include all with chronic migraine, and to use these markers in diagnosis and management, particularly in those patients where the frequent acute drugs might only be a reflection of frequent headaches, rather than a cause.

Use of medicinal plants for headache, and their potential implication in medication-overuse headache: Evidence from a population-based study in Nepal.

BACKGROUND: In Nepal, traditional treatment using medicinal plants is popular. Whereas medication-overuse headache is, by definition, caused by excessive use of acute headache medication, we hypothesized that medicinal plants, being pharmacologically active, were as likely a cause. METHODS: We used data from a cross-sectional, nationwide population-based study, which enquired into headache and use of medicinal plants and allopathic medications. We searched the literature for pharmacodynamic actions of the medicinal plants. RESULTS: Of 2100 participants, 1794 (85.4%) reported headache in the preceding year; 161 (7.7%) reported headache on ≥15 days/month, of whom 28 (17.4%) had used medicinal plants and 117 (72.7%) allopathic medication(s). Of 46 with probable medication-overuse headache, 87.0% (40/46) were using allopathic medication(s) and 13.0% (6/46) medicinal plants, a ratio of 6.7:1, higher than the overall ratio among those with headache of 4.9:1 (912/185). Of 60 plant species identified, 49 were pharmacodynamically active on the central nervous system, with various effects of likely relevance in medication-overuse headache causation. CONCLUSIONS: MPs are potentially a cause of medication-overuse headache, and not to be seen as innocent in this regard. Numbers presumptively affected in Nepal are low but not negligible. This pioneering project provides a starting point for further research to provide needed guidance on use of medicinal plants for headache.

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial.

OBJECTIVE: "Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. METHODS: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. RESULTS: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. CONCLUSIONS: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Secondary headache attributed to exposure to or overuse of a substance.

BACKGROUND: Secondary headaches attributed to exposure to or the overuse of a substance are classified under chapter eight in the International Classification of Headache Disorders 3rd edition. Three distinct sub-chapters consider: 1. Headache attributed to exposure to a substance, 2. Medication overuse headache, and 3. Headache attributed to substance withdrawal. Headache attributed to exposure to a substance refers to a headache with onset immediately or within hours after the exposure, while medication overuse headache is a headache occurring on 15 or more days per month that has developed as a consequence of regular usage of acute headache medication(s) for more than three consecutive months in a patient with a pre-existing primary headache disorder. The withdrawal of caffeine, oestrogen, and opioids is most often associated with the development of headache. DISCUSSION: Despite the current headache classification, there is no certainty of a causal relationship between the use of any substance and the development of headache. Some substances are likely to provoke headache in patients that suffer from a primary headache disorder like migraine, tension-type headache or cluster headache, while others were described to cause headache even in people that generally do not get headaches. Toxic agents, such as carbon monoxide (CO) are difficult to investigate systematically, while other substances such as nitric oxide (NO) were specifically used to induce headache experimentally. If a patient with an underlying primary headache disorder develops a headache, in temporal relation to exposure to a substance, which is significantly worse than the usual headache it is considered secondary. This is even more the case if the headache phenotype is different from the usually experienced headache characteristics. Medication overuse headache is a well-described, distinct disease entity with only marginally understood pathophysiology and associated psychological factors. Managing medication overuse headache patients includes education, detoxification, prophylactic treatments and treating comorbidities, which is reflected in available guidelines. Viewing medication overuse headache as a separate entity helps clinicians and researchers better recognise, treat and study the disorder. CONCLUSION: Identification of substances that may cause or trigger secondary headache is important in order to educate patients and health care professionals about potential effects of these substances and prevent unnecessary suffering, as well as deterioration in quality of life. Treatment in case of medication overuse and other chronic headache should be decisive and effective.

The burden of medication overuse headache and patterns of switching and discontinuation among triptan users: a systematic literature review.

BACKGROUND: A synthesis of real-world discontinuation and switching patterns among triptan users and rates of acute medication use among patients with medication overuse headache (MOH) is needed to better understand the burden among patients with migraine. The study objectives were to: (1) synthesize rates of switching and discontinuation from triptans; (2) characterize acute medication use among patients with MOH; and (3) describe the associated burden. METHODS: A systematic literature review was conducted, under the Preferred Reporting Items for Systematic Review guidelines, using MEDLINE/EMBASE from database inception to July 2019. The search strategy targeted studies of adults with migraine, and included terms related to migraine and its treatment. Continuous variables were summarized using means, standard deviations, and ranges. Dichotomous and categorical variables were summarized using the number and proportion of individuals. RESULTS: Twenty studies were included; seven describing patterns of switching and discontinuation among triptan users, and 13 characterizing triptan overuse among patients with MOH. High rates of switching to non-specific acute medications and low two-year retention rates were reported; among US samples switching to opioids at the first refill (18.2%) or after 1-year (15.5%) was frequent. Compared to persistent use of triptans, switchers experienced greater headache related impact and either no improvement or increased headache-related disability. Rates of medication overuse by agent among patients with MOH varied greatly across the included studies, and only one study described factors associated with the risk of MOH (e.g. duration of medication overuse). Medication agent, increased headache frequency (p = .008), and increased disability (p = .045) were associated with unsuccessful withdrawal; patients overusing triptans were more successful at withdrawal than those overusing opioids or combination analgesics (P < .0001). CONCLUSIONS: The evidence summarized here highlights that rates of WCS are low and many patients turn to other acute medication at their first refill. Patients may experience no improvement in disability when switching from one triptan agent to another, or experience increasing disability and/or increasing migraine frequency when turning to traditional acute treatment for migraine. Variability in health care settings, patient severity, and study design contributed to heterogeneity across the synthesis.

Candidate Genes and Proteomic Biomarkers of Serum and Urine in Medication-Overuse Headache.

Chronic headache is a topical problem of neurology, psychiatry and general practice. The medication-overuse headache (MOH) is one of the leading pathologies in the structure of chronic headache. However, early diagnosis of the MOH is challenging. We analyzed potential proteomic biomarkers of serum and urine in patients with MOH. METHODS: We searched PubMed, Springer, Scopus, Web of Science, ClinicalKey, and Google Scholar databases for English publications over the past 10 years using keywords and their combinations. RESULTS: We found and analyzed seven studies that met the search criteria for the purpose of the review, including 24 serum proteomic biomarkers and 25 urine proteomic biomarkers of MOH. Moreover, the candidate genes and locus of the studied serum (vitamin D-binding protein, lipocalin-type prostaglandin D2 synthase, apolipoprotein E, etc.) and urine proteomic biomarkers (uromodulin, alpha-1-microglobulin, zinc-alpha-2-glycoprotein, etc.) of MOH are presented in this review. CONCLUSIONS: The serum and urine proteomic biomarkers of MOH can potentially help with the identification of patients with MOH development. Due to the relevance of the problem, the authors believe that further investigation of the MOH proteomic biomarkers in different ethnic and racial groups of patients with primary headache is necessary. In addition, it is important to investigate whether medications of different drug classes influence the levels of serum and urine proteomic biomarkers.

Medication overuse headache: Updating of the French recommendations regarding the treatment strategies.

Regular and frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic migraine or medication-overuse headache (MOH). The one-year prevalence of this condition is between 1% and 2% in Europe, provoking substantial burden. MOH is more prevalent in people with comorbid depression, anxiety, and other chronic pain conditions. This paper aims at presenting an updating of French recommendations regarding treatments strategies. Prior French recommendations, published in 2014, were written in French. A literature search in the major medical databases including the terms "medication overuse headache", "symptomatic medication overuse", published between 2010 and 2020 was carried out. Three main strategies can be recommended and conducted in parallel: education and explanations about the negative consequences of overusing acute antimigraine drugs, discontinuation of the overused medication, and finally, preventive drug therapy and non-pharmacological prevention. Medication overuse headache remains a debated problem and evidence for the most effective treatment strategy is needed.

Medication overuse and drug addiction: a narrative review from addiction perspective.

Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH). MOH is a secondary headache caused by overuse of analgesics or other medications such as triptans to abort acute migraine attacks. The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected. MO patients may also develop certain behaviors such as ritualized drug administration, psychological drug attachment, and withdrawal symptoms that have been suggested to correlate with drug addiction. Although several reviews have been performed on this topic, to the authors best knowledge none of them have examined this topic from the addiction point of view. Therefore, we aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications that can cause MOH and those with high risk to produce MO. We further compare differences between sensitization resulting from MO and from drug addiction, the neuronal pathways that may be involved, and the genetic susceptibility that may overlap between the two conditions. Finally, ICHD recommendations to treat MOH will be provided herein.

Medication overuse headache in 787 patients admitted for inpatient treatment over a period of 32 years.

BACKGROUND: Definitions of medication overuse headache have changed over time. OBJECTIVE: To evaluate the clinical characteristics of medication overuse headache patients admitted for inpatient withdrawal therapy over a period of 32 years. METHODS: We included all patients with medication overuse headache treated from 1 January 1984 to 31 December 2015. We obtained all data from the medical reports and defined three periods, P1 (1984-1993), P2 (1994-2003), and P3 (2004-2015). The p-value adjusted for multiple comparisons was set to 0.005. RESULTS: Within 32 years, a total of 787 patients accounted for 904 admissions for MOH. From P1 to P3, the proportion of patients with preexisting migraine increased from 44.3% to 53.3% (chi2 = 9.0, p = 0.01) and that with preexisting tension-type headache decreased from 47.9% to 34.6% (chi2 = 9.3, p < 0.01). The median time since onset of headache and medication overuse headache decreased from 20 to 15 years (p < 0.001) and from 3 to 2 years (p < 0.001). The median cumulative number of single doses decreased from 120 to 90 per month (p = 0.002). Overuse of triptans, non-opioid analgesics, and opioids increased, whereas overuse of ergotamines decreased over time (p < 0.001 for all tests). The use of prophylactic medication before admission increased from 8.3% to 29.9% (chi2 = 89.5, p < 0.001). CONCLUSION: This retrospective study in a large number of patients with medication overuse headache admitted for inpatient withdrawal therapy over a period of 32 years shows a trend towards changes in the preexisting headache type, a decrease in the time since onset of headache and medication overuse headache, a decrease in the number of drug doses used per month, changes in the type of drugs overused, and an increase in, but still low rate, of prophylactic medication prior to admission.

Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache.

BACKGROUND: Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. METHODS: Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours. RESULTS: Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor. CONCLUSIONS: In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.

Cannabinoids induce latent sensitization in a preclinical model of medication overuse headache.

AIM: Evaluation of cannabinoid receptor agonists in a preclinical model of medication overuse headache. METHODS: Female Sprague Dawley rats received graded intraperitoneal doses of WIN55,212-2 or Δ-9-tetrahydrocannabinol (Δ-9-THC). Antinociception (tail-flick test), catalepsy and hypomotility (open field test) and impairment of motor function (rotarod test) were assessed to establish effective dosing. Rats were then treated twice daily with equianalgesic doses of WIN55,212-2 or Δ-9-THC, or vehicle, for 7 days and cutaneous tactile sensory thresholds were evaluated during and three weeks following drug discontinuation. Rats then received a one-hour period of bright light stress (BLS) on two consecutive days and tactile sensory thresholds were re-assessed. RESULTS: WIN55,212-2 and Δ-9-THC produced antinociception as well as hypomotility, catalepsy and motor impairment. Repeated administration of WIN55,212-2 and Δ-9-THC induced generalized periorbital and hindpaw allodynia that resolved within 3 weeks after discontinuation of drug. Two episodes of BLS produced delayed and long-lasting periorbital and hindpaw allodynia selectively in rats previously treated with WIN55,212-2, and Δ-9-THC. INTERPRETATION: Cannabinoid receptor agonists including Δ-9-THC produce a state of latent sensitization characterized by increased sensitivity to stress, a presumed migraine trigger. Overuse of cannabinoids including cannabis may increase the risk of medication overuse headache in vulnerable individuals.

Evidence Regarding Medication Overuse Headache in Children and Adolescents: Protocol for a Systematic Review.

OBJECTIVES: This proposed systematic review will identify the existing evidence on medication-overuse headache in children and adolescents. BACKGROUND: A number of medications have been shown to be effective for acute treatment of migraine in children and adolescents. However, patients may find they need to use their acute medications more frequently when migraine frequency is high. This has led to concern about their potential to develop medication-overuse headache. METHODS: We will search PubMed, Embase, Web of Science, PsycINFO, and Cochrane databases from their inception to present time. We will also search conference proceedings of the last 4 scientific meetings of relevant societies and scan the reference lists of studies identified through the search. Study designs will include case series, cross-sectional, cohort, case-control, and interventional studies. Participants will include children and adolescents under 18 years of age with primary headache disorders. We aim to determine whether frequency of acute medication use is associated with headache frequency in children and adolescents. Outcomes of interest include: (1) headache frequency; (2) change in headache frequency, with time and in relationship to use of acute medications; and (3) headache-related disability. We will also review data addressing treatment/management of medication overuse or medication-overuse headache in children and adolescents. Relevant comparators will be withdrawal vs reduction of acute medication, initiation of preventive therapy vs no initiation with or without withdrawal of acute medication, and initiation of preventive therapy early vs late. Outcomes of interest include (1) days of acute medication use; (2) headache frequency; (3) change in headache frequency; and (4) headache-related disability. After screening for inclusion, 2 team members will independently review and extract relevant data, and any discrepancies will be resolved through discussion and arbitration. We will assess risk of bias using appropriate tools (Cochrane Risk of Bias for randomized controlled trials (RCT) and Newcastle-Ottawa Score for observational studies). Data will be summarized descriptively in text and tables. RESULTS: This systematic review will provide an overview of the available evidence on medication-overuse headache in children and adolescents. CONCLUSIONS: Findings from this review will aid clinicians by clarifying for them the current state of the evidence base, and will inform design of future research on this topic.

The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse.

BACKGROUND: The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT1F receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown. MAIN BODY: Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor expression (lower 5-HT1B/D and higher 5-HT2A expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT1F receptor agonist and gepants are CGRP receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment. CONCLUSION: The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT1F receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT1F receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.

Headache Characteristics and Clinical Features of Elderly Migraine Patients.

OBJECTIVE: To investigate the headache characteristics and clinical features of elderly migraine patients at a tertiary headache center. METHODS: We retrospectively reviewed 239 records of migraine patients, over the age of 64 at the first visit, who had migraine as defined by the International Classification of Headache Disorders 3rd edition (beta version) from 2006 to 2015 based on the Marseille registry at Timone Hospital. RESULTS: 13.8% (33/239) patients had migraine with aura only, 13.0% (31/239) had both diagnoses. Of the patients who presented with migraine with aura, 13.4% (32/239) presented with aura without headache. Unilateral pain location was reported by 58.6% (140/239) of patients and the throbbing type of pain was present in 50.2% (120/239) of our study group. Photo- and phonophobia were observed in 77.4% (185/239) and 79.5% (190/239) of patients. Seventy-nine out of 239 (30.1%) patients were found to have probable medication overuse. Within this group, 31.65% (25/79) overused triptan and 70.9% (56/79) overused combination analgesics. We found higher frequencies of migraine for patients whose age at onset of migraine was younger than 18 years, and low frequency migraine was reported more frequently in the later onset group (P = .0357). DISCUSSION: We assess the headache characteristics of elderly migraine patients who were seen at our tertiary headache center and report the high frequency of probable medication overuse headache in this study group. Finally, we suggest that age of onset is an important factor in the clinical profile of these patients.

Neural hyperactivity in the amygdala induced by chronic treatment of rats with analgesics may elucidate the mechanisms underlying psychiatric comorbidities associated with medication-overuse headache.

BACKGROUND: Patients with medication-overuse headache suffer not only from chronic headache, but often from psychiatric comorbidities, such as anxiety and depression. The mechanisms underlying these comorbidities are unclear, but the amygdala is likely to be involved in their pathogenesis. To investigate the mechanisms underlying the comorbidities we used elevated plus maze and open field tests to assess anxiety-like behavior in rats chronically treated with analgesics. We measured the electrical properties of neurons in the amygdala, and examined the cortical spreading depression (CSD)-evoked expression of Fos in the trigeminal nucleus caudalis (TNC) and amygdala of rats chronically treated with analgesics. CSD, an analog of aura, evokes Fos expression in the TNC of rodents suggesting trigeminal nociception, considered to be a model of migraine. RESULTS: Increased anxiety-like behavior was seen both in elevated plus maze and open field tests in a model of medication overuse produced in male rats by chronic treatment with aspirin or acetaminophen. The time spent in the open arms of the maze by aspirin- or acetaminophen-treated rats (53 ± 36.1 and 37 ± 29.5 s, respectively) was significantly shorter than that spent by saline-treated vehicle control rats (138 ± 22.6 s, P < 0.001). Chronic treatment with the analgesics increased the excitability of neurons in the central nucleus of the amygdala as indicated by their more negative threshold for action potential generation (-54.6 ± 5.01 mV for aspirin-treated, -55.2 ± 0.97 mV for acetaminophen-treated, and -31.50 ± 5.34 mV for saline-treated rats, P < 0.001). Chronic treatment with analgesics increased the CSD-evoked expression of Fos in the TNC and amygdala [18 ± 10.2 Fos-immunoreactive (IR) neurons per slide in the amygdala of rats treated with aspirin, 11 ± 5.4 IR neurons per slide in rats treated with acetaminophen, and 4 ± 3.7 IR neurons per slide in saline-treated control rats, P < 0.001]. CONCLUSIONS: Chronic treatment with analgesics can increase the excitability of neurons in the amygdala, which could underlie the anxiety seen in patients with medication-overuse headache.