Diagnostic criteria:
A. Headache occurring on ≥15 days per month in a patient with a preexisting headache disorder
B. Regular overuse for ≥3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache
C. Not better accounted for by another ICHD-3 diagnosis
Table 19.2
Subentities of MOH
8.2 Medication-overuse headache |
8.2.1 Ergotamine-overuse headache |
8.2.2 Triptan-overuse headache |
8.2.3 Analgesic-overuse headache |
8.2.3.1 Paracetamol (acetaminophen)-overuse headache |
8.2.3.2 Acetylsalicylic acid-overuse headache |
8.2.3.3 Other nonsteroidal anti-inflammatory drug (NSAID)-overuse headache |
8.2.4 Opioid-overuse headache |
8.2.5 Combination analgesic-overuse headache |
8.2.6 Medication-overuse headache attributed to multiple drug classes not individually overused |
8.2.7 Medication-overuse headache attributed to unverified overuse of multiple drug classes |
8.2.8 Medication-overuse headache attributed to other medication |
8.3 Headache attributed to substance withdrawal |
8.3.1 Caffeine-withdrawal headache |
8.3.2 Opioid-withdrawal headache |
8.3.3 Estrogen-withdrawal headache |
8.3.4 Headache attributed to withdrawal from chronic use of other substance |
19.2 Clinical Manifestations
Patients with medication-overuse headache are mostly women, on average 40–45 years old. Most of them have migraine, some of them have tension-type headache, or combination of both. On average they suffer from primary headache for 20 years and overuse medication for about 5 years. Simple analgesics or their combination with caffeine is the most frequently overused drug, followed by triptans. In the recant decade, use and overuse of ergots decreased significantly all over the world. In Europe very few patients overuse combination of analgesics with barbiturates, which is much more frequent in the USA [10, 26, 106].
Clinical features of medication-overuse headache seem to depend on the pharmacology of the overused substances. For example, unlike patients who suffer from medication-overuse headaches following ergot or analgesic overuse, migraine patients (but not patients with tension-type headache) who overused triptans did not describe the typical tension-type daily headache but rather a migraine-like daily headache (a unilateral, pulsating headache with autonomic disturbances) or a significant increase in migraine frequency (see the International Headache Society criteria for triptan-induced medication-overuse headache). The delay between the frequent medication intake and the development of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years). Hence, triptans do not only cause a different spectrum of clinical features but are able to cause medication-overuse headache faster and with lower dosages than other substance groups [17, 58].
19.3 Epidemiology
Epidemiological studies on the consumption of analgesics in the general population clearly indicate that antiheadache drugs are widely overused all over the world, in developed as well as developing countries. According to these surveys, between 1 and 3 % of the general population take analgesics on a daily basis, and up to 7 % take them at least once a week [43, 85].
Population-based prevalence studies demonstrate that about 1–2 % of the general population suffer from chronic daily headache combined with overuse of headache medication [13, 15, 56, 59, 69, 73, 92]. Studies in Post-Soviet countries reported a significantly higher prevalence of chronic headache of 10 % and of chronic headache with medication overuse of 6 % [5]. A further study in a population of elderly (65 years or older) Chinese subjects revealed a prevalence of 1.3 % of chronic daily headache in combination with analgesic overuse [100].
Single or combined analgesics are the most frequently overused (71 %) headache drugs all over the world.
Meskunas and colleagues performed a retrospective analysis in order to evaluate the overuse of acute headache drugs in a United States center over the past 15 years. The proportion of subjects with a diagnosis of medication-overuse headache remained stable over the years, varying from 64 % of all cases seen in the center in 1990 to 59.3 % in 2005. The authors found a significant decrease in the relative frequency of probable ergotamine-overuse headache (from 18.6 to 0 %) and in probable combination analgesic-overuse headache (from 42.2 to 13.6 %). The relative frequency increased significantly for the triptans (from 0 to 21.6 %), for simple analgesics (from 8.8 to 31.8 %), and for combinations of acute medications (from 9.8 to 22.7 %). These data indicated that medication-overuse headache remained an important problem in tertiary headache care but that the profile of medication overuse has dramatically changed [60].
Several studies addressed the prevalence of chronic headache in adolescents. One Taiwanese study revealed a prevalence of chronic daily headache in a population of adolescents (12–14 years of age) of 1.5 %. Only 20 % of them overused headache medication, confirming previous findings that medication overuse is less important in children and adolescents [101]. A study from Canada reported a clinical analysis of 1669 children with headache seen in a neurology outpatient clinic. The prevalence of chronic headache was 3 %. The prevalence of medication overuse, however, was significantly higher, about 52 % [61]. Some recent studies report in contrast higher prevalence of pediatric MOH both in GP headache clinic and tertiary headache institutions [71].
19.4 Etiology
The incidence of developing chronic headache for people with episodic headache is about 2–3 % in 1 year [82]. This number, however, is not entirely correct because most of cases resolve spontaneously.
According to the current knowledge, the following risk factors lead to the development of MOH:
19.4.1 Migraine and TTH as Primary Headache
Most headache experts agree that mainly patients with migraine and tension-type headaches have a higher risk to develop medication-overuse headache than patients with no primary headache using analgesics for other diseases. For example, patients who were consuming fairly large amounts of analgesics regularly for arthritis did not show an increased incidence of headache [6, 55]. However, clinical series reported medication-overuse headache in patients with cluster headache [67] and shunted hydrocephalus [23, 105], interestingly in those patients with a positive family history of migraine. In both observations, frequency and intensity of headache decreased after reducing analgesic intake.
19.4.2 Overuse of Any Kind of Acute Headache Medication
A Norwegian study evaluated analgesic use by 32,067 adults in 1984 and again 11 years later. Those who used analgesics daily or weekly at baseline had a higher risk of developing chronic migraine (RR = 13.3), of chronic nonmigraine headache (RR = 6.2), and of chronic neck pain (RR = 2.4) at follow-up [109]. In a subsequent follow-up 10 years later (HEAD HUNT III), the authors were able to estimate the incidence of MOH to be 0.72 per 1000 person-years (95 % confidence interval 0.62–0.81) and the overuse of tranquilizers [odds ratio 5.2 (3.0–9.0)], or a combination of chronic musculoskeletal complaints, gastrointestinal complaints, and Anxiety and Depression [odds ratio 4.7 (2.4–9.0)], Smoking and physical inactivity as the most important risk factors [45]. A population-based study in the USA identified higher headache frequency at baseline and medication overuse as risk factors for developing of chronic headache [82]. A Danish study investigated a population-based sample of 740 people in 1989 and in 2001 and found that daily intake of analgesics and coexistence of migraine and TTH were associated with frequent headache [1]. The incidence of de novo chronic headache was significantly higher (14 %) in a patient population of a specialized headache clinic in Germany. Patients who used acute headache medication frequently (more than 10 days per month) had a 20-fold increased risk for chronic headache than patients who used acute headache medication fewer than 5 days per month. The risk increased to twofold in patients who used two or more different headache drugs simultaneously [50].
A very important question whether use of specific classes of acute headache drugs bears a higher risk for development of MOH was addressed recently in the American Migraine Prevalence and Prevention (AMPP) Study. Of 8219 individuals with episodic migraine, 209 developed chronic headache during the following year. Thus, the incidence of de novo chronic headache was 2.5 %. People using medication containing barbiturates or opiates had a twofold higher risk to develop chronic headache than those using single analgesics or triptans [10]. A large, population-based, case-control study revealed caffeine consumption to be a modest risk factor for chronic daily headache development [81].
19.4.3 Socioeconomic Status and Obesity
Low socioeconomic status is associated with chronic headache and medication-overuse headache in Norway [44, 102] and was even more prominent in countries in transition, e.g., Russia, Republic of Georgia [5, 51]. This observation was supported in immigrant studies. Wiendels and colleagues found a threefold higher prevalence of chronic headache in immigrants than in a Dutch general population [103]. Kavuk and colleagues observed a sevenfold higher prevalence of chronic headache (21 %) in first-generation Turkish immigrants in Germany than in German natives (3.1 %). Interestingly, prevalence of medication-overuse headache in Turkish immigrants of the second generation (i.e., born in Germany) was 3.6 %. This study clearly demonstrated that poor utilization of adequate medical care in first-generation Turkish immigrants in Germany was a major factor leading to high prevalence of medication-overuse headache [53].
Obesity could be another important risk factor for headache chronification. In a longitudinal 1-year population study, Scher et al. demonstrated that obese individuals were five times more likely to develop chronic headache than people with normal weight [82]. Another US study found a significant association of obesity with chronic headache [9].
19.4.4 Psychiatric and Other Comorbidities
Several studies dealt with family history and comorbidities of patients’ MOH. Depression seems to increase the risk of developing chronic headache by 50 % [2]. It seems that patients’ MOH more frequently have a positive family history chronic headache and of substance abuse [14]. Insomnia [80], temporomandibular disorders [20], mood disorders, dependency like behavior [39], or use of psychoactive substances are more frequent in patients with MOH [74], especially in those with preexisting episodic tension-type headache [3].
19.5 Pathogenesis and Pathophysiology
The pathophysiology of medication-overuse headache is unknown. Until now, clarification of the underlying pathophysiology was hampered by the lack of experimental research or suitable animal models. During recent years, however, the number of animal studies has increased significantly demonstrating complex changes in central nervous system following chronic administration of triptans. Reuter and colleagues demonstrated that chronic exposure of triptans causes a downregulation of receptors in trigeminal ganglion and, subsequently, a reduction of receptor function [76]. Chronic administration of sumatriptan and zolmitriptan caused a decrease of the 5-HT synthesis in the dorsal raphe nuclei of the brainstem [30, 97]. Finally, triptan given daily resulted in a sensitization of trigeminal nociception, possibly due to increased expression of neuronal nitric oxide synthase in dural afferents [21]. Chronic application of analgesics resulted in upregulation of pronociceptive 5HT2A receptors of platelets in humans [90], in a significant decrease in the maximum number of 5-HT2A binding sites, and an increase in the maximum number of 5-HT transporter binding sites in the CNS of rats [91].
Genetic studies on medication-overuse headache are ambiguous. Park and colleagues reported an association of a serotonin transporter protein gene polymorphism (short allele) with medication overuse in chronic tension-type headache [68]. In contrast, a recent Italian study did not found significant associations between MOH risk and 5HT2A gene polymorphisms [94]. Another study suggested a possible role of Wolframin His611Arg (WFS1) polymorphism in medication overuse and subsequent medication-overuse headache. Homozygous or compound heterozygous mutations in WFS1 (chromosome 4p16.1) determine Wolfram syndrome, a neurodegenerative disorder associated with diabetes mellitus, diabetes insipidus, hearing loss, progressive blindness, and a heterogenous combination of psychiatric disorders. Heterozygous Wolfram syndrome carriers are prone to develop psychiatric illness or behavioral problems such as impulse control, alcohol, or illicit drug abuse [24].
There is a growing evidence that central sensitization may play an important role in the pathophysiology of chronic headache. A series of investigations using psychophysical and electrophysiological techniques clearly demonstrated a facilitation of trigeminal pain processing in patients with chronic headache. Decreased pain thresholds have been found in patients with chronic tension-type headache [8]. These findings have been confirmed by demonstrating increased amplitudes of laser-evoked cortical potentials in patients with chronic tension-type headache [22]. Ayzenberg and colleagues used a novel technique of simultaneous recording of blink reflex and nociceptive cortical potentials following nociceptive trigeminal stimulation. The authors were able to demonstrate a temporary facilitation of the trigeminal nociceptive system at a supraspinal level that normalized again after withdrawal [4]. Using transcranial magnetic stimulation Curra et al. demonstrated an increase of cortical inhibitory mechanisms in NSAID-induced headache but not in patients overusing triptans [19].
Imaging studies provide further insights into the pathophysiology of medication-overuse headache. The studies are however rather small and findings in details are inconsistent. Overall the available data suggest both structural [77, 83] and functional [32, 36] changes in the pain matrix of the brain. Psychological factors include the reinforcing properties of pain relief by drug consumption, a powerful component of positive conditioning. Many patients report that they take migraine drugs prophylactically because they are worried about missing work or an important social event or they fear an imminent headache. They are often instructed by physicians or by the instructions supplied with the medication to take the migraine drug as early as possible at the start of either the aura or the headache phase of a migraine attack.
Withdrawal headache is an additional factor. When the patient tries to stop or reduce the medication, the preexisting headache worsens. Barbiturates that are contained in drugs used to treat tension-type headache have a high potency for addiction. The stimulating action of analgesics or migraine drugs and their psychotropic side effects, such as sedation or mild euphoria, may lead to drug dependency. Barbiturates, codeine, other opioids, and caffeine are most likely to have this effect. Caffeine increases vigilance, relieves fatigue, and improves performance and mood [41, 42]. The typical symptoms of caffeine withdrawal such as irritability, nervousness, restlessness, and “caffeine-withdrawal headache” [89, 99], which may last for several days, encourage patients to continue their abuse. Despite the fact that caffeine may enhance the analgesic action of acetylsalicylic acid and acetaminophen, caffeine-containing combinations should not be used. Similarly, caffeine and meprobamate, the main metabolite of carisoprodol, should be removed from ergotamine-containing formulations.
Headache patients can develop physical dependence on codeine and other opioids [33, 108]. Although some headache patients have been on codeine for as long as 10 years, no studies have investigated the effects of codeine intake over this time period. It should be remembered that up to 10 % of codeine is metabolized to morphine.
19.6 Differential Diagnosis
All conditions that lead to more than 10–12 headache days per month must be considered in the differential diagnosis of medication-overuse headache. Chronic tension-type headache is a diffuse, dull, nonlocalized headache with or without minimal autonomic features. Headache intensity is lower than that of migraine. Patients find it difficult to describe the character of pain. Sometimes it is described as a feeling of a metal band around the head or a feeling of increased pressure. Many patients with chronic tension-type headache complain of mild autonomic disturbances such as nausea, photophobia, or phonophobia. Chronic tension-type headache with medication overuse can be differentiated from chronic tension-type headache without medication overuse only after drug withdrawal or a drug holiday. If the headache persists, responsibility for chronic headache cannot be attributed to the analgesic intake.
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
