Headache syndromes secondary to various medications and substances form a diverse and complex set of conditions. Medications inducing such headaches may be, in fact, used for headache therapy, or may be used in entirely separate conditions. Other substances capable of inducing headache range from foods and food additives to toxic exposures. A greater understanding of headache syndromes secondary to medications and substances may permit further understanding of the mechanisms leading to primary headaches.
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• Headache is listed in the adverse event profile of many medications, although some therapeutic agents (eg, nitrates) are far more likely to induce headache than others, particularly in susceptible individuals.
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• Recurrent exposure to analgesics, even if not used for headache pain, is often overlooked as a cause for refractory headache.
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• Environmental and toxic exposures, illicit substances, and foods and food additives should also be considered as potential contributors to headache.
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• The mechanisms underlying these disorders involve a complex interplay of the triggering and modulation of nociception and are still only partly understood.
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• Management revolves around eliminating exposure to the offending agent, which can be challenging in the case of medication overuse headache.
Historical note and terminology
Headache induced by medication ingestion was first reported in a scientific manner in 1936, when O'Sullivan described her own experience using ergotamine tartrate for migraine. She described a patient who developed increased migraine frequency after starting the medication, and later went on to describe 2 other patients (165). Silfverskiold also described ergotamine tartrate (Gynergen) abuse in 1947 (206), commenting that 7 patients developed "migraine status" with almost daily attacks. Following World War II, headache secondary to medication use was reported frequently in Switzerland (205). In 1955, Lippman first characterized recurrent headaches resulting from prolonged ergotamine use (132). A series of 52 patients with excessive ergotamine use and typical symptoms of ergotamine withdrawal was described by Peters and Horton (174; 98). In the 1950s, it was recognized that nonprescription preparations containing phenacetin led to chronic headaches in more than 30% of female factory workers (111). It was another 30 years, however, before neurologists recognized frequent ergotamine and analgesic use as a common cause of chronic refractory headaches (118). Currently, this phenomenon is termed “medication overuse headache.”
The classification system developed by the International Headache Society (IHS) in 1988 has assisted considerably the study and understanding of headache (92). In 2004, the Headache Classification Committee of the IHS updated its classification, demonstrating greater diversity and encompassing more headache syndromes. In particular, this revision has extensively examined exposure to agents and medications as contributors to headache (93). The third edition was released in beta form in June 2013 (94), and the final form was published in 2018 (95). It includes some updates to the chapter on headache attributable to a substance or its withdrawal (163).
The International Headache Society defines headache associated with substances or their withdrawal under section 8. Subsections include headache due to use of or exposure to a substance (8.1), headache due to medication overuse (8.2), and headache due to substance withdrawal (8.3). Despite this categorization, headache due to medications or substances remains an extensive topic with great diversity. A large number of medications or other substances have been noted to cause specific or nonspecific headache or have headache as a side effect. In this updated version, it is recommended that when a primary headache disorder worsens due to substance exposure or withdrawal, both the primary headache diagnosis and the secondary headache diagnosis be ascribed. Many of the headache syndromes reported in the scientific literature or medical textbooks to be due to medications or substances may also represent de novo idiopathic headache syndromes, such as tension-type headache and migraine headache; however, this is not always determinable unless the diagnostic criteria for acute or chronic substance exposure are followed for each case. It must be kept in mind that drug use with headache does not prove causality, as headache due to other causes frequently coexists. For example, most physicians are aware of patients who say they get a headache after ingesting chocolate, but in controlled trials, headache occurred as frequently after ingesting carob placebo (143).
Headache can also be part of another syndrome itself induced by medications or substances, such as aseptic meningitis, encephalopathy, or intracranial hypertension.
A shorter review of this topic has been published and covers the history of this phenomenon in greater detail (220).