Medications and substances causing headache

Stephanie J Nahas MD (Dr. Nahas of Thomas Jefferson University received honorariums from Allergan, Amgen, Electrocore, Eli Lilly, and Supernus for consulting work, and from Amgen for speaking engagements.)
Stephen D Silberstein MD, editor. (

Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, receives honorariums from Allergan, Avanir Pharmaceuticals, Curelator, Depomed, Dr. Reddy's Laboratories, eNeura,  INSYS Therapeutics, Lilly USA, Supernus Pharmacerticals,  Thernica and Trigemina for consulting. He is also the  principal investigator for a clinical trials conducted by Alder Biopharmaceuticals, Amgen, electroCore Medical, Lily USA and Teva.

Originally released December 19, 2002; last updated October 8, 2017; expires October 8, 2020


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.

Key points


• 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.


• Excessive use of analgesics, even if not taken for headache pain, is often overlooked as a cause for refractory headaches.


• Environmental and toxic exposures, illicit substances, and foods and food additives should also be considered as potential contributors to headaches.


• The mechanisms underlying these disorders involve a very complex interplay of the triggering and modulation of nociception, and are still only partly understood.


• 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 with ergotamine tartrate for migraine headaches. She described a patient who developed increased migraine frequency after starting the medication, and later went on to describe 2 other patients (Boes and Capobianco 2005). Silfverskiold also described ergotamine tartrate (Gynergen) abuse in 1947 (Boes and Capobianco 2005), commenting that 7 patients developed a sort of "migraine status" with almost daily attacks. Following World War II, headache secondary to medication use was frequently reported in Switzerland (Silberstein and Lipton 1997). In 1955, Lippmann first characterized recurrent headaches resulting from prolonged ergotamine use (Lippmann 1955). A large series of 52 patients with excessive ergotamine use and typical symptoms of ergotamine withdrawal was described by Peters and Horton (Peters and Horton 1951; Horton and Peters 1963). In the 1950s, it was recognized that nonprescription preparations containing phenacetin led to chronic headaches in more than 30% of female factory workers (Boes and Capobianco 2005). It was another 30 years, however, before neurologists recognized frequent ergotamine and analgesic overuse as a common cause of chronic refractory headaches (Kudrow 1982). Currently, this phenomenon is termed “medication overuse headache.”

The classification system developed by the International Headache Society (IHS) in 1988 has considerably assisted the study and understanding of headache (Anonymous 1988). 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 (Anonymous 2004). The third edition, currently in beta version, was released in June 2013 and includes some updates to the chapter on headache attributable to a substance or its withdrawal (Headache Classification Committee of the International Headache Society (IHS) 2013).

The IHS defines headaches associated with substances or their withdrawal under section 8. Subsections include headaches due to use of or exposure to a substance (8.1), headaches due to medication overuse (8.2), and headaches due to substance withdrawal (8.3). Despite this categorization, headaches due to medications or substances remain an extensive topic with great diversity. A large number of medications or other substances have been noted to cause specific or nonspecific headaches 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 headaches reported in the scientific literature or medical textbooks to be due to medications or substances may also represent de novo idiopathic headaches, 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 with carob placebo (Marcus et al 1997).

Headaches can also be part of a syndrome, such as aseptic meningitis, encephalopathy, or benign intracranial hypertension, induced by medications or substances.

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