INTRODUCTION — Chronic daily headache is a descriptive term that encompasses several different specific headache diagnoses. Primary chronic daily headache types of long duration (ie, four hours or more) include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. Medication overuse headache (MOH), a secondary headache disorder, frequently complicates management of primary headache disorders and other secondary headache disorders. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)
Although not a primary type of chronic daily headache, MOH frequently coexists with primary chronic daily headache and other secondary headaches. MOH is among the top 20 causes of disability worldwide [1].
This topic will review the etiology, clinical features, and diagnosis of MOH. The treatment and prognosis of MOH is discussed separately. (See "Medication overuse headache: Treatment and prognosis".)
DEFINITION AND TERMINOLOGY — Medication overuse headache (MOH) is the term applied to headache occurring on 15 or more days per month developing as a consequence of regular overuse of acute headache medication for more than three months [2]. It usually, but not invariably, resolves after the overuse is stopped. MOH has also been termed analgesic rebound headache, drug-induced headache, and medication-misuse headache. The frequency of headache medication intake that constitutes overuse is defined by the diagnostic criteria for MOH, as listed in the table (table 1).
PATHOPHYSIOLOGY — Available evidence suggests many drugs used for the acute symptomatic treatment of headache can cause medication overuse headache (MOH) in individuals with primary or other secondary headache disorders [3,4]. The precise mechanisms that lead to MOH are still uncertain. However, multiple factors seem to play a role, including the presence of a baseline headache disorder, genetic predisposition, central sensitization, and biobehavioral factors.
Association with primary headache disorders — Various studies and clinical observations suggest that MOH is restricted to individuals who already have other headache disorders [3]. MOH does not develop de novo in individuals with no previous headache history [5].
In a study of 103 patients using daily analgesics for arthritic pain but not for headache, only 8 patients (8 percent) had chronic daily headache, each of whom reported a previous history of episodic migraine [6]. This study supports the hypothesis that patients with previous episodic headaches may be susceptible to developing MOH and that analgesics may merely be a cofactor to the development of chronic daily headache in a genetically vulnerable individual.
Patients with migraine and tension-type headache seem to have the highest potential for MOH [7]. However, MOH has also been described in cluster headache [8] and in hemicrania continua [9].
Genetic predisposition — Limited data suggest a genetic component of MOH. In a 2018 systematic review, 33 genes with 50 polymorphisms were associated with an increased risk of MOH [10].
Central sensitization — Investigations demonstrating facilitation of trigeminal pain processing in patients with chronic headache have suggested that central sensitization, the same process that occurs in migraine, can lead to MOH [4,7,11]. Daily exposure to some triptans can downregulate serotonin receptor subtypes 5-HT 1B and 5-HT 1D, and influence serotonin synthesis in the rat central nervous system [3,12].
In humans, chronic exposure to triptans and other analgesics could lead to downregulation of serotonin receptors and changes in central inhibitory pathways that translate to an impairment of antinociceptive activity and a permanent feeling of head pain [3]. In support of this argument, neurophysiologic studies have shown facilitation of trigeminal and somatic nociceptive systems in MOH primarily mediated at a supraspinal level [13]. Another study in rats found that sustained or repeated triptan treatment induced pro-nociceptive neural adaptations and enhanced responses to nitric oxide, a known trigger of migraine headache in humans [14]. In addition, a report that measured glucose metabolism in migraineurs with MOH using 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated reversible metabolic change in pain processing structures and persistent orbitofrontal hypofunction [15].
Exposure to opiates also causes changes in the nervous system. Peripherally, the chronic administration of morphine results in increased expression of calcitonin gene-related peptide in primary afferent neurons [16]. Centrally, prolonged exposure to this opiate leads to increased descending facilitation from the rostral ventromedial medulla and increased excitatory neurotransmission at the level of the dorsal horn [16]. The combination of these may result in MOH [16].
Biobehavioral factors — It has been proposed that MOH is a biobehavioral disorder [17]. Some patients may have compulsive drug seeking and drug taking behavior despite negative consequences, as the basis of MOH. Other patients may use opiates or other drugs with sedative/anxiolytic effects to treat both pain and a coexistent anxiety disorder [17].
Behaviors that may be particularly important in prompting and sustaining the overuse of medication include fear of headache, anticipatory anxiety, drug-taking behavior, and psychologic drug dependence [17]. In a prospective population-based longitudinal study of 32,067 adults from Norway, individuals using analgesics daily or weekly at baseline had a significantly increased risk of chronic pain 11 years later compared with those who never used analgesics [18]. People with chronic migraine had the highest risk (relative risk 13.3, 95% CI 9.3-19.1).
Further evidence that MOH is part of the spectrum of addictive disorders comes from the following observations:
●In a case-control study, patients with MOH derived from migraine (n = 41) had a significantly greater risk of substance-related disorders than those with episodic migraine (n = 41) (odds ratio 7.6, 95% CI 2.2-26) [19].
●In a prospective study of 1861 patients with chronic daily headache, 895 met criteria for probable MOH [20]. Substance dependence was significantly more frequent in patients with MOH than those without MOH (68 versus 20 percent).
●In research imaging studies, MOH is associated with atypical structure and function of brain regions that are commonly implicated in addiction, including regions of the mesocorticolimbic dopamine system [21].
EPIDEMIOLOGY AND RISK FACTORS — The prevalence of medication overuse headache (MOH) in the general population is approximately 1 to 2 percent in most studies, and is higher in females than males [3,4,11,22-28]. Among patients who are seen at specialized headache centers, the prevalence of MOH is near 50 percent.
Migraine is the most common primary headache disorder associated with MOH. In a meta-analysis of 29 studies that included a total of 2612 patients with chronic MOH, the underlying primary headache type was migraine, tension-type, or mixed/other in 65, 27, and 8 percent, respectively [29].
In addition to medication overuse, history of substance disorders, anxiety, and depression may be risk factors for the evolution of migraine into MOH [19,30]. (See 'Biobehavioral factors' above.)
Lower educational attainment and income may also be risk factors for the development of MOH in patients with migraine [31].
Among those with migraine, the odds of medication overuse are increased with older age, smoking, symptoms of anxiety and depression, cutaneous allodynia, greater migraine symptom severity, and more intense head pain [32].
CAUSAL MEDICATIONS — Many acute symptomatic medications used to treat headaches have the potential for causing MOH [3]. However, the degree of risk differs depending upon the specific medication or class of medications [33]. The risk of MOH appears to be highest with opioids, butalbital-containing combination analgesics, and acetaminophen-aspirin-caffeine combinations [11,34]. The frequency of headache medication intake that constitutes overuse is defined by the diagnostic criteria for medication overuse headache (MOH), as listed in the table (table 1).
Opioids and barbiturates — A longitudinal population-based study that included 8219 subjects with episodic migraine (from a population sample of 120,000) showed that use of barbiturates (including butalbital) or opiates was associated with an approximate doubled risk of transformation from episodic to chronic migraine compared with patients taking acetaminophen [35]. A 2008 review of clinic-based and population studies found that, for opiates, the increased risk was more pronounced in males, and the critical dose of exposure was approximately eight days a month [35,36]. For barbiturates, the critical dose of exposure was approximately five days a month and the effect appeared greater in females.
Butalbital-containing combination analgesic products are among the most common medications associated with MOH [37]. In a report of 169 patients from a tertiary headache center in New York who were followed for five years, butalbital-containing combination products were the most often associated with MOH, reported in 48 percent [38].
Other analgesics — The risk of MOH appears to be high with other combination analgesic medications, including acetaminophen-aspirin-caffeine combinations [11,34]. Simple analgesic medications are also among the most common medications associated with MOH, likely related to the frequency of use. In a trial that enrolled 610 patients with chronic migraine, the most commonly overused medications were simple analgesics (62 percent) and combination analgesics (41 percent), followed by triptans (21 percent) [39]. Patients taking opioids or butalbital-containing products were excluded. Similar results were found in a large cross-sectional study of more than 16000 patients with migraine, including nearly 3000 patients who met criteria for MOH [40]. Simple and combination analgesics were associated with MOH in 65 and 34 percent of cases, respectively.
Nonsteroidal antiinflammatory medications — There are conflicting data regarding nonsteroidal antiinflammatory drugs (NSAIDs), with the estimated risk of MOH from NSAIDs being low in most but not all studies [35,36,38,41]. Some studies have suggested that NSAIDs are protective against the development of chronic migraine for patients who have less than 10 headache days per month [42].
Ergotamines — The risk of MOH with ergotamines varies but appears to be decreasing due to decreased use associated with the introduction of new acute headache medications over time [3]. Until the mid-1990s, combination analgesics with codeine or caffeine or with ergots combined with caffeine were the most frequently overused drugs associated with MOH in many European countries [27]. In a review of patients seen at a single headache center in the United States from 1990 to 2005, MOH secondary to ergotamine decreased while MOH secondary to triptans increased [43].
The risk of MOH with ergotamines may also reflect varying prescription patterns from country to country. In an analysis of 669 individuals with MOH in Europe and Latin America, ergotamines were overused by 4 percent of Europeans and 72 percent of Latin Americans [44].
Triptans — The estimated risk for MOH with triptans has varied among different studies, ranging from intermediate to low [41]. In a 2002 prospective German study of 98 patients with MOH, including 70 patients with migraine as the underlying primary headache type, overuse of triptans led to MOH sooner than overuse of ergots or analgesics and did so at a lower frequency of use [45]. The mean interval until onset of MOH was shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (codeine, barbiturates, caffeine combinations; 4.8 years) [45].
Medications with uncertain risk
●CGRP antagonists – Experience and data with calcitonin gene-related peptide (CGRP) antagonists are limited. However, preliminary data suggest CGRP antagonists are unlikely to cause MOH [46,47].
●Ditans – The risk of MOH associated with selective serotonin 1F receptor agonists is uncertain, but experimental data suggest it may be similar to the risk associated with triptans [46,48].
Multiple medications — It is often difficult to identify a single causal substance for MOH, since many patients are overusing more than one drug [3,38]. In the Brazilian study of 133 patients with chronic migraine and symptomatic medication overuse, the frequencies of patients overusing one, two, or three medication categories were 55, 41, and 4 percent, respectively [49].
CLINICAL FEATURES
●Preceding episodic headache disorder treatment – The development of medication overuse headache (MOH) is typically preceded by an episodic headache disorder, typically migraine or tension-type headache, that has been treated frequently with acute symptomatic medications [11]. Acute symptomatic treatment only provides transient relief, which leads to more acute symptomatic medication use. Insufficient symptomatic therapy leads to a gradual or abrupt increase in headache frequency, which in turn leads to an increased intake of analgesics, eventually resulting in MOH superimposed upon the initial headache disorder. At this stage, patients may find themselves taking daily or frequent analgesics merely to prevent a disabling analgesic withdrawal headache [3].
●MOH headache features – The severity, location, and type of head pain with MOH can vary significantly among different individuals, but headache commonly occurs daily or nearly daily [11]. Nausea, asthenia, difficulty concentrating, memory problems, and irritability can accompany MOH [11].
To some extent, the clinical features of MOH may depend upon the type of headache medication that is overused [45]. In a prospective study of 98 patients with MOH, which included a majority of patients (71 percent) having migraine as the underlying type of headache, patients overusing ergots and analgesics (codeine, barbiturates, caffeine combinations) typically had a daily tension-type headache phenotype, while those with triptan-induced MOH were more likely to describe a daily migraine-like phenotype or an increase in migraine frequency [45].
DIAGNOSIS — The diagnosis of medication overuse headache (MOH) is based upon clinical impression. The course of the headache disorder and the history of drug intake and intake frequency are the only available methods of diagnosis. A history of analgesic use averaging more than two to three days per week in association with chronic daily headache supports the diagnosis of MOH. The diagnosis is made when there is a pattern of frequent headaches that fulfill diagnostic criteria for MOH listed below. (See 'Diagnostic criteria' below.)
Other disorders causing secondary headache must be excluded. (See 'Differential diagnosis' below.)
In practice, some patients may be reluctant to fully disclose their medication history, particularly with regard to the frequency and amount consumed. In addition, it is not uncommon for patients to report their use of prescription medications but not over-the-counter analgesics. In order to improve the accuracy of the medication history, it may be helpful to explain the concept of MOH to the patient, including the critical importance of medication use to development, diagnosis, and treatment of the disorder [3].
Diagnostic criteria — The diagnostic criteria for MOH (table 1) from the International Classification of Headache Disorders, 3rd edition (ICHD-3) are as follows [2]:
●Headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder
●Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:
•Regular intake, for ≥10 days per month for >3 months, of ergotamines, triptans, opioids, or combination analgesics, or any combination of ergotamines, triptans, simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids without overuse of any single drug or drug class alone or when the pattern of overuse cannot be reliably established
•Regular intake, for ≥15 days per month for >3 months, of simple analgesics (ie, acetaminophen, aspirin, or NSAID)
●Not better accounted for by another ICHD-3 diagnosis
Patients who meet criteria for both medication overuse headache and chronic migraine are given both diagnoses [2]. (See "Chronic migraine", section on 'Diagnosis'.)
Patients with fewer than 15 headache days per month who meet other diagnostic criteria may have medication overuse, even if they would not be diagnosed with MOH. Such patients may be at risk for medication adverse effects or toxicities, chronification of the headache disorder, and development of MOH [40]. Management should be geared to reduce medication overuse and identify more effective treatment strategies for the underlying headache disorder.
Differential diagnosis — Any form of chronic daily headache, whether primary or secondary, needs to be considered in the differential diagnosis of MOH. Primary headache subtypes of chronic daily headache with long-duration attacks include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. (See "Chronic migraine" and "Tension-type headache in adults: Etiology, clinical features, and diagnosis" and "Hemicrania continua" and "New daily persistent headache".)
Appropriate diagnostic testing should be undertaken if clinical evaluation indicates the possibility of a secondary headache disorder suggestive of a serious medical or neurologic condition. (See "Evaluation of headache in adults" and "Evaluation of the adult with nontraumatic headache in the emergency department".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Headaches in adults (The Basics)")
●Beyond the Basics topics (see "Patient education: Headache causes and diagnosis in adults (Beyond the Basics)")
SUMMARY
●Definition – Medication overuse headache (MOH) is a headache occurring on 15 or more days per month developing as a consequence of regular overuse of acute or symptomatic headache medication for more than 3 months. It usually, but not invariably, resolves after the overuse is stopped. (See 'Definition and terminology' above.)
●Pathophysiology – The precise mechanisms that lead to MOH are still uncertain. However, multiple factors seem to play a role. These include (see 'Pathophysiology' above):
•Presence of a baseline headache disorder
•Genetic predisposition
•Central sensitization of trigeminal pain processing
•Biobehavioral factors
●Epidemiology – The prevalence of MOH in the general population is approximately 1 to 2 percent and is higher in females than males. Migraine is the most common primary headache disorder associated with MOH. (See 'Epidemiology and risk factors' above.)
●Causal medications – Many acute symptomatic medications used to treat headaches have the potential for causing MOH. Estimates of the risk for MOH have varied across studies, but can be summarized as follows (see 'Causal medications' above):
•Highest with opioids, butalbital-containing analgesics, and combination analgesics (eg, acetaminophen-aspirin-caffeine combinations)
•Intermediate to low with triptans
•Likely low with NSAIDs, although some studies suggest the risk could be high
•Uncertain but may be low risk with the calcitonin gene-related peptide antagonists and lasmiditan
●Clinical features – The development of MOH is typically preceded by an episodic headache disorder, usually migraine or tension-type headache, that has been treated with frequent amounts of acute symptomatic medications. MOH commonly occurs daily or nearly daily. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of MOH is based upon clinical impression. A history of symptomatic medication use averaging more than two to three days per week in association with chronic daily headache is suggestive. The diagnosis is made when the pattern of frequent headaches fulfills the diagnostic criteria for MOH (table 1). (See 'Diagnosis' above.)
●Management – The management of MOH is discussed separately. (See "Medication overuse headache: Treatment and prognosis".)
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