Medication Overuse Headaches
Hans-Christoph Diener
Stephen D. Silberstein
INTERNATIONAL HEADACHE SOCIETY CLASSIFICATION AND DEFINITION
Frequent intake of analgesics leads to chronic headache. This was probably first observed in Switzerland, where workers in the pharmaceutical industry were given free samples of the analgesic phenacetin (48). Peters and Horton (53) observed the same phenomenon in patients with excessive use of ergotamine preparations and later described 52 patients who took ergotamine on a daily basis, developed daily headache, and significantly improved after ergotamine was withdrawn (32). The literature up to 1988 is summarized by Diener and Wilkinson (16) and up to 2004 by Diener and Limmroth (15). Just 1 year after their introduction in 1993, it became evident that excessive triptan (5-HT1B/D agonists) use, like all other drugs for the treatment of headache, could lead to medicationoveruse headache (MOH), but may cause a “pure” increase in migraine frequency (37,40) as well.
Many terms have served to describe this entity, which was first defined as drug-induced headache by The International Headache Society (IHS) in 1988 (27). This term has been criticized since the single intake of several drugs such as nitrates may also lead to headache. To emphasize the regular intake of drugs as the basis of this headache form the new name medication-overuse headache has now been introduced with the new IHS classification from 2004 (28). The new classification further extends the definition according to different clinical symptoms caused by different drugs (see Table 118-1).
DRUGS THAT MAY CAUSE MEDICATION-OVERUSE HEADACHE
There is now substantial evidence that all drugs used for the treatment of headache may cause MOH in patients with primary headache disorders. The use of drugs that lead to chronic MOH varies considerably from country to country and is influenced by cultural factors. In many patients it is difficult to identify a single “responsible” substance, since 90% of patients take more than one compound at a time and since each component contained in antimigraine drugs can potentially induce headache. This has been shown even for substances such as acetylsalicylic acid (ASA) and paracetamol (56).
Six studies have been performed to investigate the incidence of MOH with various drugs (3,4,10,46,47,58). Combination analgesics containing butalbital (short-acting barbiturate), caffeine, and ASA with or without codeine were the leading candidates for MOH in the American studies (4,46). Until the mid 1990s, combination analgesics with codeine or caffeine, or ergots combined with codeine were most frequently (mis)used in many European countries (3,10,47,58). The introduction of triptans and the fact that ergots have recently been withdrawn from some markets (e.g., in Germany) is now changing the picture. Sumatriptan-induced MOH was first observed in patients who abused ergotamine previously (7,37). De novo cases, however, were later reported (21,22,54). Reports of patients who developed MOH from naratriptan, zolmitriptan, or rizatriptan usually were published 1 year after a drug had been approved (34,40). Today, all available triptans undoubtedly cause MOH. Due to the delay between frequent triptan intake and the development of MOH, similar cases will probably be observed in the future, since other triptans (eletriptan, frovatriptan, and almotriptan) have been approved. Headache patients who have a previous history of analgesic and/or ergotamine misuse are at higher risk. It will be interesting to observe whether new treatment principles such as calcitonin gene-related peptide (CGRP) antagonism (51) will also lead to MOH once introduced into the treatment of migraine attacks.
TABLE 118-1 Diagnostic Criteria of Medication-Overuse Headache According to the Second Classification of Headache Disorders (ICHD-II, Code 8.2, ICD 10: G44.4 or G44.83) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CLINICAL MANIFESTATION
Despite the IHS classification (28) and the fact that the diagnosis of MOH does not require any additional examinations (only to exclude symptomatic forms of chronic headache) and is based on the patient’s history and the clinical presentation only, MOH is frequently overlooked. Almost no experimental work has been done in this field, and the following is based mainly on clinical series describing patients presenting at headache clinics with this problem, with subsequent treatment and follow-up. Several clinical characteristics may help identify MOH in patients with primary headache disorders (Table 118-2) (46).
A prospective study of 96 patients investigated the characteristics of MOH with regard to different substances (14,34). In this study, which was conducted between 1999 and 2001, triptan overuse outnumbered ergot overuse by far. This reflects that despite high costs, triptans have become widely used (and overused) and suggests that triptans are about to become the most important group to cause MOH. Unlike patients who suffer from MOH following ergot or analgesic overuse, migraine patients (but not tension-type headache [TTH] patients) with triptan-induced headache did not describe the typical tension-type daily headache, but rather a migrainelike daily headache (a unilateral, pulsating headache with autonomic disturbances) or a significant (and pure) increase in migraine attack frequency. Furthermore, the delay between the frequent medication intake and the development of daily headache was shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years). The intake frequency (single dosages per month) was lowest for triptans (18 single dosages per month), higher for ergots (37 single dosages per month), and highest for analgesics (114 single dosages per month). Hence, triptans do not only cause a different spectrum of clinical features, but are able to cause MOH faster and with lower dosages compared with other substance groups.
Diener and Dahlöf performed a meta-analysis summarizing 29 studies comprising a total of 2612 patients with chronic medication-overuse headache (11). Sixty-five percent of the patients reported migraine as their primary headache, 27% of patients reported TTH as their primary headache, and 8% of patients reported mixed or other headaches as their primary headache. Women were
more prone to MOH than men (3.5:1; 1533 women, 442 men). This ratio is slightly higher than would be expected from the gender differences in frequency of migraine. The mean duration of primary headache was 20.4 years. The mean admitted time of frequent drug intake was 10.3 years and the mean duration of daily headache was 5.9 years. Results from headache diaries show that the number of tablets or suppositories taken per day averages 4.9 (range 0.25 to 25). Patients take on average 2.5 to 5.8 different pharmacologic components simultaneously (range 1 to 14) (11). As seen in the recent study by Katsarava et al., the number of doses per day is much smaller in patients who abuse triptans (34).
more prone to MOH than men (3.5:1; 1533 women, 442 men). This ratio is slightly higher than would be expected from the gender differences in frequency of migraine. The mean duration of primary headache was 20.4 years. The mean admitted time of frequent drug intake was 10.3 years and the mean duration of daily headache was 5.9 years. Results from headache diaries show that the number of tablets or suppositories taken per day averages 4.9 (range 0.25 to 25). Patients take on average 2.5 to 5.8 different pharmacologic components simultaneously (range 1 to 14) (11). As seen in the recent study by Katsarava et al., the number of doses per day is much smaller in patients who abuse triptans (34).
TABLE 118-2 Clinical Characteristics of Medication-Overuse Headache | ||||||||||||||||||
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ETIOLOGY AND PATHOPHYSIOLOGY
The cause of MOH is still widely unknown. Several mechanisms, however, appear to play an important role:
A. Genetic disposition: The association between analgesic overuse and headache has been studied in conditions other than primary headache disorders. Chronic overuse of analgesics does not cause increased headache in nonmigraineurs. For example, patients who were consuming fairly large amounts of analgesics regularly for arthritis did not show an increased incidence of headache (39). In patients with cluster headache, who consume often large amounts of analgesics, MOH is not reported. In contrast, it has recently been shown that patients with migraine who are forced to take analgesics for the treatment of other pain conditions than headache are significantly more likely to develop MOH than nonmigraineurs (2). The conclusion drawn from various clinical observations and studies is that MOH may be restricted to individuals who are already headache sufferers. The basis for this could either be genetic or the fact that migraine pain is more severe than, for example, joint pain.
B. Receptor and enzyme physiology and regulation: There is no doubt that the regular exposure to the same substance will induce substantial changes regarding expression and sensitization of receptors as well as changes for the threshold of receptor activation. The extent of these changes and the velocity in which these changes occur depend on the receptor type (e.g., ion channels or G-protein-coupled receptors) and the duration and concentration of drug exposure. Recently, it has been shown in rats that the regular (daily) exposure to triptans such as sumatriptan or zolmitriptan causes a significant downregulation of these receptors in various cortical regions, the extrapyramidal system, and the brainstem and influences the synthesis rate of serotonin (17,59). Moreover, from in vivo studies it is well known that downregulation of 5-HT receptors may occur as early as 24 to 96 hours following chronic exposure (62). Chronic or frequent exposure to 5-HT1B/D agonists in humans may lead to a downregulation of 5-HT receptors and change central inhibitory pathways significantly. The same mechanisms account for the regulation of enzymes such as cyclo-oxygenase I and II, which are the main pharmacologic targets of analgesics such as ASA or ibuprofen. Enzyme regulation, however, is slower and needs longer exposure time and higher drug concentration (72). These theoretical aspects, however, are well in line with clinical experience and a recently conducted trial on withdrawal symptoms (35) showing that MOH will develop faster with triptan than with analgesic misuse but that intensity and duration of withdrawal symptoms will be significantly milder and shorter when triptans had been misused. Thus, it is tempting to hypothesize that the downregulation of 5-HT receptors and/or prostaglandin-synthesizing enzymes within anatomic structures involved in the transmission or modulation of nociceptive signals such as the periaquiductal grey (PAG) (which exhibits serotonergic descending inhibitory pathways mainly to trigeminal nuclei) may lead to an impairment of antinociceptive activity and subsequently result in a permanent feeling of head pain.
C. Psychologic and behavioral mechanisms: Psychologic factors include the reinforcing properties of pain relief by drug consumption, a very 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. Early treatment also bears the danger of patients consuming more medication than necessary and thereby steadily increasing their intake frequency even for headache attacks that would not have been treated otherwise. This model behavior can be relevant in families as children may learn the early and low-threshold consumption of analgesic from their parents.
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. Early treatment also bears the danger of patients consuming more medication than necessary and thereby steadily increasing their intake frequency even for headache attacks that would not have been treated otherwise. This model behavior can be relevant in families as children may learn the early and low-threshold consumption of analgesic from their parents.
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