The role of caffeine in headache disorders.

Migraine

1. Heidi K. Blume, MD, MPH 1. Division of Pediatric Neurology, Seattle Children’s Hospital and Research Institute, Seattle, WA. * Abbreviations: CSF: : cerebrospinal fluid ICH: : intracranial hemorrhage ICP: : intracranial pressure IIH: : idiopathic intracranial hypertension NDPH: : new daily persistent headache NSAID: : nonsteroidal anti-inflammatory drug SVT: : sinus venous thrombosis TAC: : trigeminal autonomic cephalalgia Headaches are common in children; while most are caused by a benign problem or primary headache disorder, headaches can be a sign of a serious underlying condition. Pediatricians must be aware of the most recent recommendations for evaluating and managing headaches. After reading this article, readers should be able to: 1. Understand the evaluation of a child who has headache. 2. Recognize the diagnostic criteria for pediatric migraine. 3. Recognize “red flags” for elevated intracranial pressure or other underlying conditions in the child who has headache. 4. Discuss treatment strategies for migraine, tension, and chronic headache disorders. Headaches are common in children and adolescents and are a frequent chief complaint in office and emergency department visits. The vast majority of childhood headaches are due to a primary headache disorder, such as migraine, or an acute, relatively benign process, such as viral infection. However, clinicians also need to consider other causes of headaches in children. Even when headaches are benign, they may cause significant dysfunction for the child and family and must be managed appropriately to minimize disability and optimize function. In this review, we discuss the epidemiology of childhood headache, evaluation of the child who has headaches, when to consider secondary headache syndromes, and the diagnosis and management of primary headache disorders such as migraine and tension-type headaches. Acute and chronic headaches are relatively common in children and adolescents, although estimates of the precise prevalence of headache and migraine vary widely. Depending on the study definition of headache, population involved, and time periods studied, 17% to 90% of children report headaches, with an overall prevalence of 58% reporting some form of headache in the past year. (1 …

PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models

Prevention of Migraine in Women Throughout the Life Span

BackgroundMedication 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.MethodsSprague 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.ResultsBoth 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.ConclusionsIn 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.

The frequent or regular intake of medication to treat acute headache episodes can lead to an increase in headache frequency and finally to a transition from episodic to chronic headache. Many patients with chronic headache take abortive medication on a daily basis. 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 (e.g., migraine or tension-type headache) occurring on ≥15 days per month for >3 months. Also, these primary headache disorders occur in association with overuse of medication for acute or symptomatic headache treatment. The prevalence of MOH in the general population is around 1%. MOH is more common in people with chronic migraine and chronic daily headache than in patients with episodic migraine. The phenotype of the headache in MOH depends on the initial primary headache and the type of overused acute medication. Treatment of MOH occurs in three stages. First, we educate patients about the relationship between frequent intake of acute headache medication and MOH to reduce intake of acute medication. In a second step migraine prevention should be initiated in chronic migraine (topiramate or onabotulinumtoxinA in migraine) or amitriptyline in chronic tension-type headache. In patients who fail to cease overuse of overused medication with preventive therapy, then detoxification occurs on an outpatient basis or in a day hospital or inpatient setting, depending on severity and comorbidities. The success rate of treatment is around 50–70%, with higher relapse rates in patients with opioid overuse. Patient education and continuity of care in the follow-up period reduce relapse rates.

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.

To assess whether family history for chronic headache (CH) and drug overuse could represent a risk factor for headache chronification. Among factors investigated as risk factors for chronification of headache disorders, familial liability for CH and drug overuse has been rarely investigated. A total of 105 consecutive patients with daily or nearly daily headache, and 102 consecutive patients with episodic headache matched by age, sex, and type of headache at onset, underwent a structured direct interview about family history for episodic headache, CH with and without medication overuse, substance abuse/dependence, and psychiatric disorders. In total, 80 out of 105 patients with CH received a diagnosis of medication overuse headache (MOH), 21 patients were classified as chronic migraine (CM), and 4 as chronic tension-type headache (CTTH) without drug overuse. Some 38.1% of CH patients reported family history for CH vs only 13.7% of episodic headaches (P = .001). Familiality for CH with medication overuse was reported by 25.7% of cases vs 9.8% of controls (P = .0028). A familial history of substance abuse was reported by 20% of patients vs 5.9% of controls (P = .0026). In all, 28.7% of MOH patients reported family history for CH with medication overuse (P = .0014) and 21.2% for substance abuse (P = .002). Relatives of patients with MOH were more likely than control relatives to suffer from CH (OR = 4.19 [95% CI 2.05-8.53]), drug overuse (OR = 3.7 [95% CI 1.66-8.24]), and substance abuse (OR = 4.3 [95% CI 1.65-11.19]). No differences regarding family history for episodic headache and for psychiatric disorders were found. No differences in family history for CH with drugs overuse and for substance abuse were found between CH patients without overuse and controls. Fifteen CH patients reported family history for alcohol abuse (P = .0003). The significantly increased familial risk for CH, drug overuse, and substance abuse suggests that a genetic factor is involved in the process of headache chronification.

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. 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. 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.

Introduction: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. Methods: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. Results: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01–1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04–3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03–1.24), less than high school (OR, 1.08; 95%, 1.01–1.15), without depression (OR, 1.06; 95%, 1.01–1.12), and without anxiety (OR, 1.06; 95%, 1.01–1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. Conclusion: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

The aim of the present paper is to study which prescription pain medications are most commonly dispensed to people with chronic headache (CH), particularly those with medication-overuse headache (MOH). This cross-sectional study analysed prescription pain medications dispensed within 1 year to 68,518 respondents of a national health survey. Participants with headache ≥ 15 days per month for 3 months were classified as having CH. Those with CH and over-the-counter analgesic use ≥ 15 days per month or purchase of ≥ 20 or ≥ 30 defined daily doses (DDDs) of prescription pain medication per month (depending on the drug) were classified as having MOH. Associations between CH and other chronic pain conditions were analysed by logistic regression. Among those with CH (adjusted prevalence 3.3%, CI 3.2-3.5%), pain medications most commonly dispensed were paracetamol, tramadol, ibuprofen and codeine. CH was associated with osteoarthritis, back pain, and rheumatoid arthritis. Among those with MOH, 32.4% were dispensed an opioid at least once within 1 year. Only 5.1% of people with CH were dispensed triptans. High prevalence of opioid use among people with CH may be due to inappropriate headache treatment or development of MOH among those treated for other pain conditions. While there were cases of triptan overuse, triptans remain underutilized among those with CH, suggesting that migraine may be under-recognized and inappropriately treated, leading to overuse of other medications. Education of physicians on appropriate headache management is essential for MOH prevention. There is a need to increase universal awareness about MOH as an adverse effect of long-term analgesic use.

Objective: to conduct a comparative analysis of factors associated with the development of medication overuse headache (MOH), considering demographic characteristics of patients and comorbid pathology.Material and methods. A prospective study was conducted at "Europe–Asia" International Medical Center. The main group comprised patients with primary headache (HA) aged 18 years and older with MOH, and the control group comprised patients with primary HA without MOH of comparable gender and age. A semi-structured interview was conducted with the patients and additional examinations were performed, including MRI of the brain if indicated. The study included 171 patients with MOH (mean age 43.3 years, 82% women) and 173 patients without MOH (mean age 41.4 years, 75% women).Results. Chronic migraine occurred more frequently in the MOH group (53 and 16%, respectively; p<0.001; OR 5.9; 95% CI 3.6–9.8). One third of patients in both groups suffered from chronic tension-type headache (CTH). Episodic migraine and episodic CTH occurred more frequently in patients without MOH (p<0.001). Patients in the MOH group were more frequently divorced (11.7 and 2.9%, respectively; p=0.002; OR 4.5; 95% CI 1.6–12.2). The majority of patients (76%) in both groups were employed, had a higher education (65% with MOH and 74% without MOH) and were married (63% with MOH and 72% without MOH).The analysis of more than 20 comorbid diseases revealed that three factors were most frequently associated with the development of MOH: chronic insomnia (60.2 and 47.4% respectively; p=0.02; OR 1.7; 95% CI 1.1–2.6), restless legs syndrome (37.4 and 22% respectively; p=0.002; OR 2.1; 95% CI 1.3–3.4) and subjective cognitive impairment (76 and 53.2% respectively; p<0.001; OR 2.8; 95% CI 1.8–4.8).Conclusion. Sleep disturbance, subjective cognitive impairment and marital status of patients are most frequently associated with MOH, indicating the great importance of these factors in the development of MOH and opening new opportunities for its prevention.

Dependence scores predict prognosis of medication overuse headache: A prospective cohort from the Akershus study of chronic headache

Sir, Professor Schoenen and colleagues show reversible metabolic changes in pain processing structures along with persistent orbitofrontal cortex (OFC) hypofunction in patients with medication overuse headache (MOH); these investigators extrapolate these positron emission tomography (PET) findings to both analgesic drug-dependence as well as to the pathogenesis of MOH itself (Fumal et al ., 2005). At the outset, the basic research premise of a causal relation between medication overuse and aggravation or transformation of primary headache disorders is uncertain and likely linked to headache frequency (Tepper and Dodick, 2002; Lipton and Bigal, 2003). The present paper (Fumal et al ., 2005) does not emphasize that: (i) Few migraine patients regularly using analgesics develop chronic daily headache (CDH) or MOH or chronic migraine. This issue needs to be distinguished from the incidence of acute medication overuse in a substantial fraction of patients with chronic headaches seen in prospective studies in specialized headache centres or the general population (Zwart et al ., 2003; Katsarava et al ., 2004). The key pathophysiological concern in MOH is not the incidence of acute medication overuse but its role in transformation of episodic migrainous headache to a more frequent/daily occurrence. Epidemiological evidence is quite unlikely to settle the cause–effect relationship between acute medication overuse and MOH or chronic migraine. (ii) While analgesic abuse is a self-determined unsupervised activity, analgesic withdrawal is a medically controlled activity—supervised analgesic withdrawal involves the placebo effect of the therapist's reassurance. Every therapeutic intervention—including supervised analgesic withdrawal—involves a placebo effect (Bignall, 1994). (iii) Analgesic withdrawal in clinical practice is commonly accompanied by other interventions undertaken simultaneously (Lipton and Bigal, 2003). (iv) No particular temporal pattern has emerged between regular analgesic use and development of daily headache in migraine …

Study Objective: To evaluate the characteristics of patients with medication-overuse headache (MOH) for their further treatment. Study Design: Prospective study. Materials and Methods. Within 12 months, 120 patients (12 men and 108 women, mean age of men — 46.3 ± 3.54 years, of women — 41.3 ± 9.5 years) with primary headache and MOH were followed up. Participants were divided into two groups depending on the diagnosis: group I (n = 44) — patients with chronic forms of primary headache without MOH, group II (n = 76) — patients with chronic forms of primary headache and MOH. The patients filled out special questionnaires for their characterization. Study Results. The study compared groups according to the frequency of taking various types of analgesic drugs. Patients with MOH took pain medications: non-steroidal anti-inflammatory drugs — 15 (19.7%), triptans — 38 (50%), combined drugs — 23 (30.3%); 46 patients chose analgesic drug/s based on the speed of effect, and the preferred characteristics of the drugs were the availability (n = 25) and complete relieve pain (n = 19). The most of participants chose pain medications based on a doctor's recommendation; 44 (57.9%) of MOH patients tried to cancel them on their own, but failed. In people with MOH, the most common behavioral strategies were: taking painkillers to prevent headaches due to fear of pain (34.2%); refusal to discontinue the drug due to fear of increased pain even in the presence of side effects (22.4%); frequent practice of escalating the amount and dose of symptomatic agents in conditions of catastrophic pain (21.1%). The characteristics of our patients and their emotional and behavioral features showed that a more detailed study of these characteristics and features is necessary to develop a further treatment plan. Conclusion. When treating patients with MOH show that a complex approach to a comprehensive analysis of the state of physical and emotional health is needed. The characteristics of our patients once again prove the importance of a dialogue between a doctor and a patient to improve the effectiveness of treatment. A significant role in preventive methods implemented through educational programs are important for improving the quality of their lives. Keywords: medication-overuse headache, chronic primary headache, migraine, tension type headache, behavioral characteristics of patients with chronic headache, educational programs in management of patients with headache.