Medications and substances causing headache …

Headache & Pain

Updated 11.04.2024
Released 12.19.2002
Expires For CME 11.04.2027

Medications and substances causing headache

Authors: Brittany Heckel MD, Stephanie J Nahas MD

See Contributor Disclosures

Editor: Stephen D Silberstein MD

Medications and substances causing headache

In This Article

Quick Link

Introduction

Overview

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 food 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.
	• Recurrent exposure to analgesics, even if not used for headache pain, is often overlooked as a cause for refractory headache.
	• Environmental and toxic exposures, illicit substances, foods, and food additives should also be considered as potential contributors to headache.
	• The mechanisms underlying these disorders involve a 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 using ergotamine tartrate for migraine. She described a patient who developed an increased migraine frequency after starting the medication, and later went on to describe two other patients (171). Silfverskiold also described ergotamine tartrate (Gynergen) abuse in 1947 (212), commenting that seven patients developed "migraine status" with almost daily attacks. Following World War II, headache secondary to medication use was reported frequently in Switzerland (211). In 1955, Lippman first characterized recurrent headaches resulting from prolonged ergotamine use (136). A series of 52 patients with excessive ergotamine use and typical symptoms of ergotamine withdrawal was described by Peters and Horton (180; 99). In the 1950s, it was recognized that nonprescription preparations containing phenacetin led to chronic headaches in more than 30% of female factory workers (112). It was another 30 years, however, before neurologists recognized frequent ergotamine and analgesic use as a common cause of chronic refractory headaches (120). Currently, this phenomenon is termed “medication overuse headache.” Medication overuse headache is thought to be responsible for approximately 1% of all chronic headache forms (164).

The classification system developed by the International Headache Society (IHS) in 1988 has assisted considerably with the study and understanding of headache (93). 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 (94). The third edition was released in beta form in June 2013 (95), and the final form was published in 2018 (96). It includes some updates to the chapter on headache attributable to a substance or its withdrawal (169).

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 (147).

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 (226).

Clinical manifestations

Presentation and course

Clinical manifestations vary depending on the exposure to or withdrawal of each individual medication or substance. Although many reports of headache induced by medication or substance in the literature do not use ICHD diagnostic criteria, their use is important to prove association.

The clinical manifestations of these headache syndromes can be summarized by considering the diagnostic criteria that describe each syndrome. These criteria are as follows:

A. Headache fulfilling criterion C
B. Use of, exposure to, or withdrawal from a substance known to be able to cause headache
C. Evidence of causation demonstrated by two of the following:
	1. Headache has developed in temporal relation to use of or exposure to the substance
	2. Either of the following:
		a. Headache has significantly improved or resolved in close temporal relation to cessation of use of or exposure to the substance
		b. Headache has significantly improved or resolved within a defined period after withdrawal from the substance
	3. Headache has characteristics typical for use of, exposure to, or withdrawal from the substance
	4. Other evidence exists of causation
D. Not better accounted for by another ICHD-3 diagnosis

The IHS Classification Committee stated that double-blind, placebo-controlled experiments that demonstrate a greater incidence of headache after active drug compared to placebo are the only true basis for attributing headache as a side effect to the medication.

Although many reports of medication-induced or substance-induced headache exist, a consistent clinical profile of these syndromes does not always exist. Although some medications (eg, cyclosporine, dipyridamole, niacin) typically induce headache with migraine phenotype, others (eg, nitroglycerin, calcitonin gene-related peptide, and ethanol) may induce headache with a range of features or tend to precipitate the primary headache type a person typically experiences. Other medications and substances (eg, heroin) may have tension-type headache associated with their use.

Prognosis and complications

Discontinuing the substance exposure or the medication believed to be causing the headache leads to headache termination. Exposure to particular substances, such as cocaine or carbon monoxide, may leave persisting neurologic dysfunction after the acute neurologic syndrome and accompanying headache have resolved.

Headache-related disability in people with medication overuse headache is higher than in people with other headache types. Persons with medication overuse headache are likely to suffer during nonworking days with total or significant disability and to have significantly reduced effectiveness on days spent at work (122).

Clinical vignette

A 39-year-old woman presented with headache occurring at least 6 days per week for the past 4 years. She experienced migraine without aura as a teenager. These attacks resolved by 20 years of age, and she reported only occasional “stress headaches” that were consistent with episodic tension-type headache during her 20s. At 35 years of age, she noted recurrence of her prior migraine attacks and the onset of headache consistent with chronic tension-type headache. No provocation was identified. Initially, over-the-counter medications, including acetaminophen and ibuprofen, controlled the headache. During the next 12 months, the patient’s headache increased in severity, and her intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen increased to as many as eight tablets per day on a daily basis. Her headache severity fluctuated, with headache duration always greater than 8 hours, and averaging 12 hours, each day. The headache was described as holocephalic, with pain described as nonthrobbing and achy in nature. Over the next 3 years, headache severity and frequency increased, and on presentation, the patient was ingesting approximately four different headache medications, including a caffeine-containing compound and a butalbital-containing compound. In the prior year, she used prescription medications twice, for several months each time; these included meperidine and a codeine-containing compound. She even tried marijuana at the insistence of a friend, and initially found relief from her tension-type headache for several hours after smoking it. However, after a few months of marijuana use, she found that her headaches intensified slightly while smoking, and she also reported redness of her eyes, dryness of her mouth, and a warm feeling over her body. She discontinued marijuana use, and the symptoms resolved. The patient’s headaches caused her to miss 5 days of work per month and had caused difficulties with her domestic situation.

Neurologic examination, including funduscopy, was normal. Magnetic resonance imaging of the brain was unremarkable, and routine blood studies were normal.

The patient was hospitalized. The Raskin protocol, using consecutive and recurrent doses of intravenous dihydroergotamine preceded by metoclopramide, was used for 4 days. After several doses without a clinical response, intravenous chlorpromazine was added to the regimen, replacing metoclopramide. After minimal response, intravenous methylprednisolone was also added to the regimen, and the patient became headache-free 6 days after admission. Discharge medications included amitriptyline 10 mg at bedtime to be titrated upwards as tolerated for prevention, naproxen sodium 550 mg up to twice per day as needed for moderate attacks, and rizatriptan 10 mg up to twice per day as needed for severe attacks, with naproxen and rizatriptan usage limited to 10 days per month total. Control was moderately successful over the next 9 months, with headache still occurring 8 to 10 days per month. Her work productivity improved, and she required infrequent over-the-counter analgesics one year after her initial visit, with headache frequency reduced to 5 to 6 days per month.

Biological basis

Etiology and pathogenesis

Alcohol (IHS 8.1.4). Alcohol may provoke headache within 30 to 45 minutes of ingestion. This correlates with peak blood alcohol levels, which suggests that headache is probably not caused by intracranial vasodilation due to this latency period (189). The mechanism by which alcohol causes headache is not fully understood but is felt to be complex and likely involves cortical, subcortical, and brainstem structures (172). The mechanism of “hangover headache” has been debated and is complex. Animal data suggest that the formation of acetate as a result of ethanol metabolism is key (153).

Wine has been noted as a cause of migraine in different parts of the world, with red wine being a more common migraine trigger than white wine in England, and white wine being a more common migraine trigger than red wine in France and Italy (149). White wine with red color added is more likely to induce headaches (149). In a study, people with migraine who reported red wine to be a trigger were challenged with red wine or vodka; red wine provoked headache in 82% as compared to none who were given vodka; however, neither form of alcohol provoked headache in controls nor in persons with migraine who had not described red wine as a trigger for headache (141). Phenolic flavonoids may be the ingredient in red wine that may trigger a migraine attack (140). Given the inconsistency of alcohol as a trigger (or nontrigger), variability of resultant headaches, cultural factors, and unclear pathogenesis, Dueland concluded in a 2015 review that there appears to be no reason to recommend that patients with headache should avoid alcohol in general; an individualized approach is preferred (56). A web survey of 2197 persons with migraine revealed that 35.6% report alcohol as a trigger, and 25% avoid alcohol altogether due to presumed triggering effects. The most commonly reported trigger was wine, particularly red wine, at 77.8%, but red wine led to acute attacks consistently for only 8.8% of them (170).

Table 1. IHS Diagnostic Criteria for Alcohol and Alcoholic Beverage-Induced Headache: Immediate or Delayed

8.1.4 Alcohol-induced headache
	A. Any headache fulfilling criterion C B. Alcohol has been ingested C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 3 hours of alcohol ingestion 2. Headache has resolved within 72 hours after alcohol ingestion has ceased 3. Headache has at least one of the following three characteristics:
			a. Bilateral b. Pulsating quality c. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis
8.1.4.2 Delayed alcohol-induced headache
	A. Any headache fulfilling criterion C B. Alcohol has been ingested C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 5 to 12 hours after ingestion of alcohol 2. Headache has resolved within 72 hours of onset 3. Headache has at least one of the following three characteristics:
			a. Bilateral b. Pulsating quality c. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis

Antihistamines and histamine (IHS 8.1.7). A number of antihistamines have been associated with headache with migraine features (25). Second-generation antihistamines, such as fexofenadine, (levo)cetirizine, and (des)loratadine are commonly associated with the adverse event of headache (160). Histamine has also been shown to trigger headache with migraine features (13; 25) and cluster features (61). Histamine infusion may cause hypotension followed by a severe, short-lasting headache that is believed to be due to intracranial vasodilation (157).

Histamine inhalation leads to headache that resembles migraine without aura in both persons prone to migraine and controls (128). Histamine may trigger headache via endogenous formation of nitric oxide by vascular endothelial nitric oxide synthase (NOS) (43). It is believed that the H3 receptor plays a major role in histamine and headache (246). IHS criteria for histamine-induced headache are listed in Table 2.

Table 2. IHS Diagnostic Criteria for Histamine-Induced Headache

8.1.7.1 Immediate histamine-induced headache
	A. Any headache fulfilling criterion C B. Histamine has been administered C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 1 hour of histamine absorption 2. Headache has resolved within 1 hour after absorption of histamine has ceased 3. Headache has at least one of the following four characteristics:
			a. Bilateral b. Mild to moderate intensity c. Pulsating quality d. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis
8.1.7.2 Delayed histamine-induced headache
	A. Headache, in a person affected by a primary headache disorder and with the characteristics of that headache type, fulfilling criterion C B. Histamine has been administered C. Evidence of causation demonstrated by both of the following:
			1. Headache has developed within 2 to 12 hours after administration of histamine 2. Headache has resolved within 72 hours after administration of histamine
	D. Not better accounted for by another ICHD-3 diagnosis.

Caffeine (IHS 8.3.1). Diagnostic criteria for caffeine-withdrawal headache are presented in Table 3.

Table 3. IHS Diagnostic Criteria for Caffeine-Withdrawal Headache

8.3.1 Caffeine-withdrawal headache
	A. Headache fulfilling criterion C B. Caffeine consumption of more than 200 mg/day for more than 2 weeks, which has been interrupted or delayed C. Evidence of causation demonstrated by both of the following:
		1. Headache has developed within 24 hours after last caffeine intake 2. Either or both of the following:
			a. Headache is relieved within 1 hour by intake of caffeine 100 mg b. Headache has resolved within 7 days after total caffeine withdrawal
	D. Not better accounted for by another ICDH-3 diagnosis

Caffeine is a cerebral vasoconstrictor, and its withdrawal probably leads to vasodilation with vascular congestion (50). In a double-blind study, patients who normally had moderate caffeine intake were given either placebo or caffeine. Fifty percent of the patients who were given placebo had headaches compared to 6% of the patients who were given caffeine (213). Seventy-five percent of caffeine-dependent teenagers develop caffeine-withdrawal headache (165). Cola intake in children and adolescents has been blamed for daily or near-daily headache. In a study, gradual withdrawal from cola drinks led to complete cessation of all headaches in more than 90% of subjects (98). Next to simple analgesics, caffeine and caffeine-containing tablets are the second most commonly overused drugs in chronic daily headache (119). Caffeine-withdrawal headache may not always be related to high consumption or variation in consumption (214).

Caffeine withdrawal has been blamed for perioperative headache as well. Headache secondary to caffeine withdrawal due to cessation of intake prior to and during the surgical event has been implicated in a review of 287 patients who underwent minor surgical procedures under general anesthesia (83).

Transcranial Doppler measurements of cerebral blood flow velocities demonstrate significant increases in velocity following caffeine withdrawal periods, with subsequent decreases seen within a half hour of caffeine intake. Whether blood flow derangements may play a role in caffeine withdrawal headache or are epiphenomena remains to be elucidated (45).

Caffeine is associated with headache due not only to its withdrawal, but also with regular use, which may be related to its mild analgesic properties, or possibly via mechanisms related to adenosine (209). Caffeine consumption is much higher in patients with chronic daily headache than in population controls prior to the onset of chronic daily headache (202) but not during chronic daily headache. This is particularly true of young women with chronic episodic headaches (202). This may suggest that caffeine intake is a risk factor for development of chronic daily headache or, alternatively, that a drop in caffeine intake after development of chronic daily headache may be associated with a continuing headache syndrome. A population study showed that high dietary caffeine consumption is associated with a modest increase in headache prevalence (87).

Two reviews detail the role caffeine may play in headache, especially migraine (04; 162).

Nitric oxide (NO) donor-induced headache (IHS 8.1.1). Nitroglycerin has been described as a well-known cause of headache, as have amyl nitrate and isosorbide dinitrate (13). The use of endocervical isosorbide dinitrate gel solution for treatment of missed abortion has been associated with development of headache in 60% of patients, compared to 17% of patients receiving misoprostol (12). Exposure to nitroglycerin in the form of dynamite led to headache in munitions workers (205). Fifty percent of patients taking nitroglycerin have noted headache, which may reflect the development of tolerance (46). Nitroglycerin-induced headache has features similar to those of migraine without aura. Nitroglycerin also has induced attacks of cluster headache (61). In persons with cluster headache, cluster attacks may be induced by nitroglycerin during a cluster period (100). Nitric oxide seems to be the key chemical leading to headache, and the reasons for this have been reviewed extensively (169). Functional neuroimaging of migrainous headaches triggered by nitroglycerin revealed that the premonitory phase of the attack was associated with activations in posterior hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortices (145). IHS criteria for nitric oxide donor headache are listed below, with both immediate and delayed forms.

Table 4. IHS Diagnostic Criteria for Nitrate- and Nitrite-Induced Headache

8.1.1.1 Immediate nitric oxide donor-induced headache
	A. Any headache fulfilling criterion C B. Absorption of a nitric oxide donor has occurred C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 1 hour after absorption of the nitric oxide donor 2. Headache has resolved within 1 hour after release of nitric oxide has ended 3. Headache has at least one of the following four characteristics:
			a. Bilateral b. Mild to moderate intensity c. Pulsating quality d. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis
8.1.1.2 Delayed nitric oxide donor-induced headache
	A. Headache, in a person affected by a primary headache disorder and with the characteristics of that headache type, fulfilling criterion C B. Absorption of a nitric oxide donor has occurred C. Evidence of causation demonstrated by both of the following:
		1. Headache has developed within 2 to 12 hours after exposure to the nitric oxide donor and after nitric oxide is cleared from the blood 2. Headache has resolved within 72 hours after exposure
	D. Not better accounted for by another ICHD-3 diagnosis

Foods and additives. Many foods and additives have been causally linked to headache, specifically migraine. Many people prone to headache are able to produce a list of foods that they avoid because they fear getting an attack. However, only a few studies have examined food and food additives, and most of these have been strictly observational. Criteria have been created for headache associated with food components and additives.

Common foods and food additives believed to induce headache have included citrus fruits, chocolate (147), dairy products (177), tyramine (90; 25), sodium chloride (33), sodium nitrate (97), monosodium glutamate (200), aspartame (103), and sucralose (23; 175). This is based mostly on anecdotal case reports, though some diary studies and double-blind, placebo-controlled trials have been conducted. Such studies of chocolate have revealed no statistically significant association with any form of headache (159; 79). The notion that true food allergies may also trigger migraine remains suspected but unproven; however, IgG testing may be of some clinical utility (76).

Monosodium glutamate, commonly found in soy sauces and food additives, has been described as a cause of the so-called “Chinese restaurant syndrome” in as many as 30% of people (193; 13). It has been noted to cause a diffuse, throbbing headache within 30 minutes of ingestion, associated with tightness and burning sensations over the face and chest. A dull, nonthrobbing headache may also occur (193; 249). Similar symptoms have occurred with intravenous injection of monosodium glutamate, and placebo-controlled studies have shown a variety of symptoms in one third of people receiving monosodium glutamate (110; 109). A placebo-controlled, double-blinded study confirmed the phenomenon of the monosodium glutamate symptom complex, a triad consisting of facial pressure, chest pain, and burning in the head and upper trunk (249). A systematic review of available trials concluded that evidence is insufficient to deem a causal relationship given difficulties with blinding and inconsistent results among studies (163). The mechanism of monosodium glutamate-induced symptoms is unknown.

The so-called “hot dog headache” occurs shortly after eating frankfurters or cured meat. Nitrites, added to meat to give a red color, have been implicated as the cause. “Hot dog headaches” are typically bitemporal, nonthrobbing, and moderately severe, often associated with facial flushing (97). IHS criteria place hot dog headache under nitrate- and nitrite-induced headache (IHS 8.1.1).

The synthetic sweetener aspartame, potential etiology of “chewing gum headache” (26), was studied in a double-blind manner and shown not to be associated with headache (203), whereas a similar double-blind study suggested susceptibility to aspartame in patients who self-report it (220). Aspartame has been noted to block the normal response in brain tryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid after carbohydrate ingestion, which may explain its ability to induce headache (203; 115), and 8% of migraineurs report aspartame as a migraine trigger (139).

Monoamine oxidase inhibitors have been associated with headache under certain circumstances. When these agents are combined with amphetamines, selective serotonin reuptake inhibitors, ephedrine, other sympathomimetic agents, or foods that have a high tyramine level, they have induced severe headache in addition to hypertension (25).

Hormonal agents. Oral contraceptives and other female hormonal preparations can exacerbate a previously existing headache syndrome (usually migraine) or cause headache (02). Although it has been previously reported that women may develop new-onset migraine, an exacerbation of migraine, or a change in the pattern of migraine during oral contraceptive use and that the attacks frequently remit when the oral contraception is terminated (19), a systematic review was more controversial regarding any association between oral contraceptives and migraine. There was no consistent relationship between oral contraceptive use and headache except in those women with a prior history or family history of migraine. Also, there is no evidence for a dose effect of estrogens on headache. For those women who note headache beginning or worsening in the first month of oral contraceptive use, headache prevalence seems to fall during the second (one in three), third (one in 10), and subsequent months (142).

The pathophysiology of estrogen-induced migraine is unclear, but it may relate to estrogen’s actions on vascular smooth muscle or modulation of vasoactive neuropeptides and neurotransmitters at the intracranial neurovascular junction (19). In addition, disruptions in central prostaglandins, serotonin, and prolactin metabolism may lead to alterations in vasoregulation within the brainstem and changes in cerebrovascular tone, lowering the “threshold” for migraine in prone individuals (204). Data suggest there is interplay of several complex mechanisms modulating nociception (86). Oral contraceptives, estrogen preparations, and progesterone preparations have also been associated with idiopathic intracranial hypertension (80), as has the gonadotrophin analogue leuprorelin acetate (11). The association of oral contraceptives with idiopathic intracranial hypertension remains controversial, but patients reported by Davidson were slim females in contrast to the usual body morphology of obesity in idiopathic intracranial hypertension (51; 22). The mechanism of oral contraceptive-induced idiopathic intracranial hypertension may relate to impaired venous sinus drainage due to occult thrombosis, as cases of venous sinus thrombosis have been reported with oral contraceptive therapy and hormonal replacement therapy (187; 219; 173). Another theory of oral contraceptive-induced idiopathic intracranial hypertension is increased salt and water retention (52).

In addition to headaches induced by its use, estrogen withdrawal following cessation of exogenous estrogens (such as during the pill-free interval of combined oral contraceptives or following a course of replacement or supplementary estrogen) may also induce headache and migraine (19).

Table 5. IHS Diagnostic Criteria for Estrogen Withdrawal Headache

8.3.3 Estrogen-withdrawal headache
	A. Headache or migraine fulfilling criterion C B. Daily use of exogenous estrogen for at least 3 weeks, which has been interrupted C. Evidence of causation demonstrated by both of the following:
		1. Headache or migraine has developed within 5 days after the last use of estrogen 2. Headache or migraine has resolved within 3 days of its onset
	D. Not better accounted for by another ICHD-3 diagnosis

The antiestrogen tamoxifen, used frequently to treat breast cancer, has shown conflicting effects, either alleviating (166) or worsening (150) migraine. It is suspected that the reason for amelioration of migraine in those who benefit from tamoxifen is calcium uptake inhibition or decreased levels of prostaglandin E (166).

Although danazol has been used successfully in the management of catamenial headaches (36; 232), it has also been described as a cause of idiopathic intracranial hypertension (208).

Cocaine (and other illicit drugs) (IHS 8.1.6 and IHS 8.3.2). As many as 60% to 75% of cocaine users report severe headaches related to cocaine use (54). Cocaine has a number of potential side effects, including intracerebral infarction or hemorrhage, tremor, and headache (134; 133; 107; 132; 217). The “crack” form of cocaine has also been associated with headache and with cerebrovascular complications (132). Headache patterns associated with cocaine include a bitemporal, pulsating, short-duration headache that appears soon after cocaine use, a migraine-like headache with binging cocaine use, and chronic daily headache with cocaine withdrawal (139; 54). A hemiplegic migraine syndrome can also occur after cocaine use (139). Severe occipital headache due to subarachnoid hemorrhage secondary to ecstasy use has been reported (15). The basis of headache associated with cocaine and cocaine preparations is probably secondary to sympathomimetic vasoconstrictive effects (54); however, metabolic alterations, including abnormal cerebral glucose metabolism (234) and reduced levels of dopamine D2 receptors (233), have been described. Cocaine withdrawal headache may be due to disrupted serotonin metabolism (54). Rare cases of cocaine-induced vasculitis have been associated with headache (118; 156; 35). Headache in cocaine users has been reviewed (17).

Headache due to illicit drugs may have more specific etiologies. Cocaine- and amphetamine-induced headaches may be related to a rapid cocaine surge, leading to a rapid block of presynaptic norepinephrine reuptake with potent sympathomimetic effects and acute vasoconstriction. Dysfunction of norepinephrine and vasomotor control may also play a role (54). Prolonged cocaine use may lead to secondary presynaptic serotonin depletion, leading to increased severity of headache with cocaine use. Illicit drug-withdrawal headaches may result from a rebound of central functions after CNS depression of various physiologic systems initially modified by the drug (101).

Table 6. IHS Diagnostic Criteria for Cocaine-Induced Headache

8.1.5 Cocaine-induced headache
	A. Any headache fulfilling criterion C B. Cocaine has been administered by any route C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 1 hour of cocaine administration 2. Headache has resolved within 72 hours after cocaine administration 3. Headache has at least one of the following four characteristics:
			a. Bilateral b. Mild to moderate intensity c. Pulsating quality d. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis

Withdrawal from cocaine (54; 234) and amphetamines (54; 25) can lead to migraine-like headache.

Methamphetamine injection can lead to either ischemic or hemorrhagic forms of stroke, which are frequently associated with symptoms of headache. Although uncertain, injection of methamphetamine may produce delayed stroke secondary to vasculitis, which may present with concurrent symptoms of headache (168). Methamphetamine-induced hemorrhagic stroke does not demonstrate any pathological evidence of vasculitis or aneurysm formation (155). Additionally, chemicals and solvents used in the manufacturing of methamphetamine in clandestine drug labs can cause headache in roughly 31% of exposed individuals (116). These chemicals can leach into nearby apartments/structures and remain present in structures even after the manufacturing of the drugs have ceased.

Heroin-induced cerebral arteritis is rare but has been associated with headache (113). A headache that resembles tension-type headache with a diffuse, continuous, and persisting presentation may follow heroin intake.

Opioid withdrawal can be associated with a frontotemporal, pulsating, long-lasting migraine-like headache (53).

Table 7. IHS Diagnostic Criteria for Headache Attributed to Opioid Withdrawal

8.3.2 Opioid-withdrawal headache
	A. Headache fulfilling criterion C B. Opioid intake daily for more than 3 months, which has been interrupted C. Evidence of causation demonstrated by both of the following:
		1. Headache has developed within 24 hours after last opioid intake 2. Headache has resolved within 7 days after total opioid withdrawal
	D. Not better accounted for by another ICHD-3 diagnosis

Sixty-five percent of marijuana-addicted headache sufferers experience pain relief when they smoke marijuana at headache onset (07). Coital headache and stroke related to cannabis use is rare (06). Mild frontal headaches related to marijuana use are reported along with conjunctival irritation, paresthesia, mouth dryness, and sensations of warmth (62).

In a report, psilocybin was reported to cause delayed, transient headaches in nonheadache volunteers in a dose-dependent fashion (105). Psilocybin is a traditional hallucinogen chemically related to LSD (lysergic acid diethylamide), which incidentally was discovered in the process of engineering new migraine medications). Interestingly, it has been reported to be of potential benefit in cluster headache. In this study, not originally intended to examine headache as an adverse event of psilocybin, the researchers noted that delayed headache was frequent (in about 50% to 90% of subjects, dose-dependently), tended to occur around 8 hours after dose administration, and was more intense with higher doses of psilocybin. Very few of the 18 participants had any headache history (one with one to two migraine attacks per month, one with one to five headache attacks per year, two with a few headache attacks associated with perimenopause, and one with a remote history of a 6-month headache). A mechanism for the headache remains speculative, but given the timing may involve NO, histamine, or calcitonin-gene related peptide (CGRP) (known to cause both immediate and delayed headaches), or may be serotonergic in nature.

Toxic gases (eg, carbon monoxide) (IHS 8.1.3). Carbon monoxide poisoning may occur in warehouse workers (63) and divers (41); sources in the home can include the kitchen and the bathroom (57). Both carbon monoxide and carbon dioxide poisoning have been associated with early nonspecific symptoms of headache, irritability, poor concentration, and poor judgment. Chronic carbon monoxide exposure has occurred when faulty heaters or a snow-impeded gas exchange has caused poor ventilation. Headaches associated with carbon monoxide have been described as typically frontal (66%), dull (72%), and constant (74%) and have shown improvement with normobaric oxygen administration (89). One speculated mechanism of headache in this situation is vascular dilation of cerebral venous structures. Head pain correlates with the concentration of carbon monoxide.

Air pollution has also been linked to headaches (161). Although cigarette smoking has been associated with cluster headache, a causal relationship has not been established. However, subsequent data from a survey study revealed that secondhand cigarette smoke exposure during childhood may be linked to the later development of cluster headache (197). Still, the nature of this association has yet to be elucidated and may be due to shared genetic factors. Many with migraine also report sensitivity to tobacco smoke.

Table 8. IHS Diagnostic Criteria for Carbon Monoxide (CO)-Induced Headache

8.1.3 Carbon monoxide (CO)-induced headache
	A. Bilateral headache fulfilling criterion C B. Exposure to carbon monoxide (CO) has occurred C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 12 hours of exposure to CO 2. Headache intensity varies with the severity of CO intoxication 3. Headache has resolved within 72 hours of elimination of CO
	D. Not better accounted for by another ICHD-3 diagnosis

Acetanilid, in excessive amounts, has caused headache due to hypoxemia, as it converts hemoglobin to methemoglobin (25). Nitrous oxide is also a possible cause of idiopathic intracranial hypertension (25).

Acute poisoning with ethyl alcohol, carbon tetrachloride, benzene, arsenic, lead, anticholinesterases, and insecticides has induced headaches of unknown mechanism (210).

Phosphodiesterase inhibitors (8.1.2). Sildenafil, vardenafil, and tadalafil, used to treat erectile dysfunction, act by inhibiting phosphodiesterase 5, an enzyme that degrades cyclic guanosine monophosphate (cGMP). Common adverse effects of sildenafil are headache and flushing, which occur in 16% of men using the sexual enhancement drug (37; 148; 251). Cilostazol, a phosphodiesterase 3 inhibitor, also induces delayed migraine-like headache, purportedly via cAMP release (24; 85).

Table 9. IHS Diagnostic Criteria for Phosphodiesterase (PDE)-Induced Headache

8.1.2 Phosphodiesterase inhibitor-induced headache
	A. Any headache fulfilling criterion C B. A single dose of a phosphodiesterase (PDE) inhibitor has been taken C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 5 hours of intake of the PDE inhibitor 2. Headache has resolved within 72 hours of onset 3. Headache has at least one of the following four characteristics:
			a. Bilateral b. Mild to moderate intensity c. Pulsating quality d. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis

Calcitonin-gene related peptide (CGRP) likely plays a role in the pathogenesis of primary migraine. Infusion of CGRP is noted to trigger immediate or delayed headache in those with migraine, with or without aura (127; 91; 84).

Table 10. IHS Diagnostic Criteria for Calcitonin Gene-Related Peptide (CGRP)-Induced Headache

8.1.7.1 Immediate CGRP-induced headache
	A. Any headache fulfilling criterion C B. Calcitonin gene-related peptide (CGRP) has been administered C. Evidence of causation demonstrated by all of the following:
		1. Headache has developed within 1 hour of CGRP absorption 2. Headache has resolved within 1 hour after absorption of CGRP has ceased 3. Headache has at least one of the following four characteristics:
			a. Bilateral b. Mild to moderate intensity c. Pulsating quality d. Aggravated by physical activity
	D. Not better accounted for by another ICHD-3 diagnosis
8.1.7.2 Delayed CGRP-induced headache
	A. Headache, in a person affected by a primary headache disorder and with the characteristics of that headache type, fulfilling criterion C B. CGRP has been administered C. Evidence of causation demonstrated by both of the following:
		1. Headache has developed within 2 to 12 hours after administration of CGRP 2. Headache has resolved within 72 hours after administration of CGRP has ceased
	D. Not better accounted for by another ICHD-3 diagnosis

Another vasoactive peptide, pituitary adenylate cyclase activating peptide-38 (PACAP38), also has been shown to trigger migraine-like attacks in persons with migraine and in healthy controls. The headache tends to be delayed in those with migraine (206). Prostacyclin also has vasoactive properties and is reported to cause both immediate and delayed headache (not necessarily migraine-like) in those with migraine, cluster headache, or no headache history. Activation and sensitization of sensory afferents around extracranial arteries may underlie this phenomenon (176; 240). Another vasoactive prostanoid, prostaglandin E2, also can induce immediate or delayed dull or migraine-like headache in subjects with and without migraine (241; 10), and other prostanoids are reported to have similar, varying effects (242; 243).

Headache due to other substances listed under miscellaneous are also classified as listed in Table 11.

Table 11. IHS Diagnostic Criteria for Headaches Due to Medications Used for Other Indications

8.1.10 Headache attributed to long-term use of nonheadache medication
	A. Headache present on 15 days per month and fulfilling criterion C B. Long-term use of a medication taken for purposes other than the treatment of headache C. Evidence of causation demonstrated by at least two of the following:
		1. Headache has developed in temporal relation to the commencement of medication intake 2. One or more of the following:
			a. Headache has significantly worsened after an increase in dosage of the medication b. Headache has significantly improved or resolved after a reduction in dosage of the medication
		3. The medication is recognized to cause headache, in at least some people, during long-term use
	D. Not better accounted for by another ICHD-3 diagnosis
8.1.11 Headache attributed to use of or exposure to other substance
	A. Any headache fulfilling criterion C B. Exposure to a substance other than those described above C. Evidence of causation demonstrated by both of the following:
		1. Headache has developed within 12 hours of exposure 2. Headache has resolved within 72 hours after exposure
	D. Not better accounted for by another ICHD-3 diagnosis

Anesthetic agents. Nitrous oxide may precipitate or exacerbate pain in sinus or ear structures during surgical interventions (196). Ketamine and nitrous oxide have been associated with the development of idiopathic intracranial hypertension (102). When patients undergoing sinus and ear surgeries are given nitrous oxide, headache may occur. This may be due to increased pressure, as nitrous oxide equilibrates with air in the sinuses and the ear (196). Intrathecal administration of anesthetic agents has led to aseptic meningitis (102).

Anticonvulsants. The anticonvulsant carbamazepine has been noted rarely as a cause of aseptic meningitis (102). In an open-label study of beaded carbamazepine oral therapy in patients with bipolar disorder, headache was the most commonly noted side effect (111). The similar compound oxcarbazepine was reported to cause refractory headache in three patients with epilepsy and migraines who were transitioned off carbamazepine; the headaches abated after discontinuation of oxcarbazepine (181). Valproate withdrawal, but not induction, has been associated with exacerbation of migraine (52).

Gabapentin, an anticonvulsant used in headache prophylaxis, was reported to be associated with headache in 21% of epilepsy patients in an open-label study (20). Lamotrigine, a drug used for bipolar disorder, had headache as its most common adverse effect (31). One report attributed aseptic meningitis with severe headache to anticonvulsant sensitivity syndrome due to lamotrigine (144). The agents lacosamide, rufinamide, and perampanel list headache as a common adverse event (44; 03; 114).

Antibiotics and antimalarials. A number of antibiotics have been implicated in idiopathic intracranial hypertension, including tetracycline (236; 13; 52), trimethoprim sulphamethoxazole, nalidixic acid, ofloxacin, nitrofurantoin (13), minocycline, doxycycline (74), and ampicillin (25).

Drug-induced aseptic meningitis has been associated with cotrimoxazole (117; 81; 25), sulfasalazine, penicillin, amoxicillin, isoniazid, pyrazinamide, ciprofloxacin (81), and cephalosporins (48). The topic has been reviewed in more detail (250).

Linezolid, an antibiotic within the oxazolidinone class of drugs, was associated with headache in a review of trials using the medication (178). Other antibiotics and antimalarials associated with headache include amphotericin, griseofulvin, chloroquine, and ethionamide (210).

Mefloquine syndrome, a posthepatic syndrome due to the antimalarial drug mefloquine, has been associated with a number of nonspecific features that include headache (49).

Anti-parkinsonian agents. Both bromocriptine and dopamine have been associated with migraine-like headaches (52; 25; 69), particularly with higher doses of levodopa. Pramipexole is associated with an increased incidence of headache compared to placebo; this may be due to increased central monoamine sensitivity interfering with antinociceptive processes (182).

Asthmatic agents. Antiasthmatic agents have been implicated as a cause of migraine-like headaches in numerous references. In particular, theophylline, aminophylline, and terbutaline have been noted as a cause of headaches with vascular features (189). However, in a randomized study, the incidence of headache associated with aminophylline use was similar to that of placebo (58). In a randomized controlled trial of beclomethasone and theophylline for mild to moderate chronic asthma, theophylline caused significantly more headaches (191). In a randomized controlled trial, headache was noted to be a common side effect of budesonide, an inhaled corticosteroid (248). One report described three patients who used budesonide for the treatment of Crohn disease and developed idiopathic intracranial hypertension (131). An agent in asthma therapy, zafirlukast, a leukotriene antagonist, was associated with headache in 13% of patients (215). Omalizumab, a humanized monoclonal antibody that prevents binding of IgE to mast cells and other effector cells, was associated with side effects, including ill-described headache, in 15% of patients studied (16).

Cardiovascular agents. Antihypertensive agents associated with headache include atenolol, hydralazine, prazosin (also used in prostatic hypertrophy) (13), and calcium channel blockers, such as nifedipine (25; 247), mibefradil (65), and nitrendipine (77). An open-label study of nifedipine preparations were associated with headache in 20% of patients (247). Nifedipine’s headache-inducing ability is probably due to vasodilation, with potent relaxation of vascular smooth muscle (253). Sudden withdrawal of clonidine, propranolol, or labetalol has precipitated both hypertension and headache (18). Antiplatelet agents and blood flow agents, including dipyridamole and pentoxifylline, have been associated with migraine-like headache and also are suspected to cause headache through a vasodilatory mechanism (25). Amiodarone is a rare cause of idiopathic intracranial hypertension (71). There is a case report of long-duration hypnic headache (a rare disorder affecting older individuals, characterized by regular nighttime attacks of short-lasting, featureless headaches) precipitated by lisinopril withdrawal and reversed after resuming lisinopril (59). Niacin, a lipid-lowering agent, has also caused acute vasodilation and migrainous headache (189). Other lipid-lowering agents from various classes also have headache as a reported adverse event (221). Monoamine oxidase inhibitors have been associated with headache when combined with amphetamines, selective serotonin reuptake inhibitors, ephedrine, other sympathomimetic agents, or foods having high tyramine levels (25).

Gastrointestinal agents. Agents used to treat peptic ulcer disease and gastroesophageal reflux disease, including the histamine receptor (H2 receptor) blockers cimetidine (08) and ranitidine (52), and proton pump inhibitors omeprazole (125) and lansoprazole (52), have been associated with particularly severe, persisting headaches with migraine features. In a double-blind multicenter trial, cimetidine was associated with headache in 5% of patients, significantly more than placebo (08). Famotidine and ranitidine are rarely reported etiologies of aseptic meningitis (13).

Isosorbide-5-mononitrate, used in therapy of gastroesophageal varices and ulcers in cirrhotic patients, was associated with a significantly increased incidence of headache compared to placebo (75).

Wood creosote, an herbal antidiarrheal and antispasmodic agent, was associated with mild headache in 13% of normal volunteers (121).

Immunomodulatory agents. Vaccination has been reported to be a migraine trigger or an exacerbating factor, particularly in those with existing migraine disease. Vaccinations for polio, measles, mumps, rubella, and hepatitis B have been implicated as etiologies of aseptic meningitis (25). Vaccination against SARS-CoV-2 is associated with a two-fold increased risk of headache within seven days of vaccination (38). This appears to be true across the various vaccine types, suggesting that the etiology of this headache is secondary to a systemic immune response (38).

Intravenous immunoglobulin may trigger migraine, usually in those with migraine disease, but it has more commonly been associated with aseptic meningitis (21).

Cyclosporine as a cause of headache has been described under oncologic agents.

Azathioprine may be a rare cause of aseptic meningitis (13).

Corticosteroids, including withdrawal from corticosteroid therapy, have often been described as causing idiopathic intracranial hypertension (25); they have occasionally been described as causing aseptic meningitis with intravenous methylprednisolone (21). Intranasal corticosteroids may trigger migraine-like headache (183). Withdrawal from corticosteroids can lead to worsening of existing headache syndromes or the development of a new headache syndrome (25).

Headache is a common side effect of interferons used in the treatment of hepatitides and multiple sclerosis; this is often worse in the first month of therapy (192). As many as 40% of patients using pegylated interferon alpha-2b for treatment of hepatitis B complain of headache (230). Ribavirin use has also been found to be associated with headache (167), as has the use of FK-506 and thalidomide (207).

Neuropsychiatric agents. Headache was an uncommon side effect of selective serotonin reuptake inhibitors in a meta-analysis (60). A metabolite of trazodone, M-chlorophenylpiperazine, activates 5-hydroxytryptamine 2B and 2C receptors. Similar activation with selective serotonin reuptake inhibitors may explain headache that occurs with their initiation and withdrawal (IHS 8.4.3) (34). Rapid venlafaxine withdrawal may be associated with severe headache (154).

Benzodiazepines, particularly the shorter-acting ones, can trigger headache (189). In a small, placebo-controlled study, a small number of patients noted headache with preoperative midazolam and lorazepam given nocturnally; however, preoperative anxiety may have played a role in this (152). A possible association between idiopathic intracranial hypertension and lithium has been noted (198). In an open-label study of lithium in children and adolescents with bipolar disorder, 74% of patients noted headache (174).

Sodium oxybate, a central nervous system depressant used to treat narcolepsy, causes headache in approximately one quarter of individuals (129; 123). Development of headache is typically dose-dependent and related to initiation of the medication (129).

Oncologic agents. A number of agents used in cancer therapy have been described as a cause of headache. These included retinoic acid, trimethoprim-sulfamethoxazole (13), cimetidine (08), corticosteroids and their withdrawal (25), and tamoxifen.

Cyclosporine, an antineoplastic agent most commonly used for immunomodulation, caused neurologic side effects in 15% to 40% of patients (106). Cyclosporine neurotoxicity, a form fruste of hypertensive encephalopathy, has been correlated with headache, posterior encephalopathy syndrome, visual dysfunction, and changes in level of consciousness (80; 244). The headache induced by cyclosporine often has migrainous features, but a syndrome resembling idiopathic intracranial hypertension has been reported (102). The neurotoxicity associated with cyclosporine is nearly completely reversible with termination of the drug (106).

Tacrolimus, similar to cyclosporine in its immunomodulation, has side effects similar to cyclosporine (106; 157). However, tacrolimus was more commonly associated with the development of headache than cyclosporine in a systematic meta-analysis (237). One third of patients who received parenteral tacrolimus developed headache, whereas oral administration was only rarely associated with headache (73). Tacrolimus-induced encephalopathy may occur in as many as 20% of patients receiving stem cell transplantation, and headache is often a prominent symptom (108).

OKT3 is another immunosuppression agent that has side effects similar to cyclosporine (27). OKT3 has been associated with four different headache syndromes: (1) cytokine release syndrome, a dose-dependent syndrome that occurs within 1 hour of OKT3 administration; it lasts several hours and has clinical features of headache, fever, dyspnea, nausea, vomiting, and chills (185); (2) aseptic meningitis, which occurs in 3% to 5% of patients within 3 days of OKT3 initiation (70); (3) a nonspecific, unclassified headache (27); and (4) the syndrome of headache, neurologic deficit, and cerebrospinal fluid lymphocytosis (HaNDL) (223).

Anagrelide, an agent used to decrease platelet counts and the risk of thrombosis in myeloproliferative disorders, has headache as a side effect; this is hypothesized to be due to vasodilatory effects (179). Capecitabine and 5-fluorouracil can both cause headaches, possibly due to their known propensity to induce vasospasm. The calcium channel blocker diltiazem was reported to abolish capecitabine-induced headache, which may substantiate this theory (188).

The use of 9-cis-retinoic acid, a high-affinity ligand for retinoid X receptors and retinoic acid receptors in the treatment of Kaposi sarcoma and cervical dysplasia, has been associated with intolerable headache at doses greater than 100 mg/m² per day (01; 05).

Three chemotherapeutic agents (methotrexate, cytarabine, and diaziquone) have been described as a cause of aseptic meningitis (30; 102). Intraventricular gentamicin and antineoplastic infusions have been associated with aseptic meningitis as well.

Intrathecal delivery of liposomal cytarabine in children has led to development of arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain. Headache is dose limiting in up to 25% of patients, although concurrent dexamethasone may be beneficial in limiting development of arachnoiditis (28).

Radiographic contrast agents. A large number of idiosyncratic reactions have been noted with the use of ionic contrast agents in diagnostic radiographic procedures. One of the more uncommon side effects is headache; more common reactions include anaphylactoid-like reactions and cardiovascular, flushing, and gastrointestinal complications (40).

Intrathecal contrast media has rarely been associated with aseptic meningitis (102).

Oral cholecystographic media, including iopanoic acid and ipodate, may induce gastrointestinal side effects, dysuria, skin rash, and headache (40).

Topical ophthalmic therapy. Phenylephrine, a sympathomimetic agent used to dilate the pupil, has associated side effects of headache, hypertension, tremor, and diaphoresis (130; 82; 238).

A small study of topical prostaglandin F2 alpha for use in glaucoma found that 50% of patients had mild ocular pain or headache (64).

The use of latanoprost 0.005% plus timolol 0.5% in open-angle glaucoma therapy has headache as the most common adverse effect (146).

Vitamins or related agents. Etretinate (29) and retinoids, including isotretinoin, have been associated with idiopathic intracranial hypertension (25), as have both an excess and a deficiency of vitamin A (52). An excess of vitamin A can cause both acute and chronic headache (189). Acute headaches occur 4 to 8 hours after massive ingestion of vitamin A (78). Excessive vitamin A can be caused by ingestion of large amounts of polar bear liver, either as a food fad or as treatment for dermatological conditions. Daily intake in excess of 7.5 mg of retinol (less in children and infants) has led to neurotoxicity. The most common association with headache is idiopathic intracranial hypertension, particularly in infancy (25; 225).

Miscellaneous agents. Perhexiline, benzene hexachloride (218; 231), beta-human chorionic gonadotropin hormone, growth hormone, synthetic luteinizing hormone-releasing hormone, anabolic steroids, and thyroxine (229) have been described as rare causes of idiopathic intracranial hypertension.

Allopurinol, muromonab CD-3, and phenazopyridine may have a role in aseptic meningitis (13).

Methoxamine, a selective alpha-1-adrenoceptor agonist used in urinary stress incontinence, showed a significant incidence of headache in a randomized controlled trial (186). Another urological agent, tolterodine, was associated with headache in a systematic analysis examining randomized trials with the medication (47).

In a small study of primary dysmenorrhea with an open-label, crossover, controlled design, glyceryl trinitrate was associated with a significantly greater incidence of headache than the NSAID diclofenac, with 33% of patients discontinuing therapy with glyceryl trinitrate due to headache (68). The etiology has been related to vasodilation due to the vasorelaxation effects of nitric oxide. Headache associated with glyceryl trinitrate tends to be immediate, along with a delayed migraine attack (228).

Carmustine administration has been associated with headache and flushing, suggesting a vasodilatory effect leading to headache (52).

Intrathecal injection of baclofen is a rare cause of aseptic meningitis (13). Withdrawal of various agents, including prothipendyl, octreotide (252), or benzodiazepines (25), has also precipitated or worsened migraine, with some of these headaches due to medication overuse.

Development of headache following the use of an extended-release dipyridamole and aspirin combination is common (33% to 39%), although these are self-limited, with a demonstrated 69% placebo efficacy at 2 hours (135; 137). Twenty-six percent of patients taking dipyridamole cannot tolerate the therapy, usually due to headache (66). It is possible that headache due to dipyridamole may be dose-related, and smaller doses may produce less common and less severe headache, perhaps increasing compliance (135). In fact, regular dosing of dipyridamole (200 mg orally twice a day) is associated with higher prevalence of headache (39%) when compared to once-daily dosing for up to 14 days followed by twice daily dosing (39).

A study noted that essential oils (camphor, clove, eucalyptus, fennel, sage, tea tree oil, and thujone) in toothpaste caused new onset cluster headache in five individuals; cluster headache resolved after stopping the use of toothpaste with essential oils (151). It is postulated that the mechanism of action for this is stimulation of a receptor, which then results in the release of calcitonin gene-related peptide (CGRP) from the trigeminal nerves (151). This is similar to the mechanism of action suspected after exposure to the Umbellularia californica, also known as the “headache tree,” which induces cluster headache through umbellu-lone contained in its leaves (151).

An Iranian dried flower extract, Echium amoenum (Boraginaceae) has been used in the treatment of anxiety and depression and was associated with development of headache in a small placebo-controlled study (199).

Agents used for obesity management, such as sibutramine (216) and lorcaserin (222), have headache as a commonly reported side effect. Semaglutide, a drug used for both diabetes and weight loss, was shown to cause headache in 15.2% of study participants (245).

Naltrexone, an opioid antagonist, has been associated with headache and somnolence at a dose of 100 mg (104).

Teriparatide is a drug used for osteoporosis that reproduces the 34 N-terminal amino acids of parathormone. It may be associated with headache development in one study (09).

Headache was reported as a delayed (up to 2 days later) adverse reaction in 10 of 50 patients receiving intravenous iron polymaltose (88). In most cases, the headache was at least moderate in intensity with migrainous features, and in some cases, the headache was disabling for several days.

The smoking cessation agent varenicline should be used with caution in persons with migraine, particularly those with underlying mood disturbances because not only can it induce headache, it can have serious neuropsychiatric consequences, including suicidal ideation (92).

Peripheral sensitization with altered neurotransmitter sensitivity may play a role in the mechanisms of headache development due to substance exposure, as may central sensitization to certain substances. Altered pain regulation systems in chronic substance use may play a role in withdrawal headache syndromes. Resetting of the pain control mechanisms may occur with continuous high doses of a substance in headache-prone patients, and subsequent withdrawal may lead to enhanced nociception. Alterations in gene expression, such as with c-fos with intense neuronal stimulation, may lead to enhanced pain perception with substance exposure. Alterations in c-fos, an intermediate gene product, may lead to further changes in other gene products, including neurotransmitters, neuropeptides, and receptors (184).

Nitric oxide-associated headaches may be partly due to the sensitization of perivascular sensory nerve endings via neurogenic inflammation or free radical formation (42). Nitric oxide may also interact with N-methyl-D-aspartate (NMDA) receptors, leading to hyperalgesia (224). Ketamine, an NMDA antagonist, and fentanyl may be beneficial in treating and preventing headaches induced by intravenous nitroglycerin in cardiac patients. Also, a nitric oxide synthase inhibitor was associated with headache relief during spontaneous migraine attacks in a placebo-controlled study (126). Nitroglycerin-induced histamine release may also play a role in migraine development; however, nitroglycerin-induced headache fails to respond to mepyramine, a histamine antagonist (100).

Epidemiology

In general, the epidemiology of medication- or substance-induced headache depends on the substance and the type of headache. Medication as a cause of headache is likely unrecognized and may be the cause of headache in as many as 8% of patients with headache (67; 252). In a German clinical trial center, all adverse events occurring in healthy volunteers over 1 year among all clinical studies were recorded, and headache (2.23%) was the most common adverse event reported (143). In Europe, the incidence of drug-induced headache has been reported as being 5% to 10% of all headaches (158). A random telephone survey conducted in Canada suggested that 1.5% of persons with migraine had medication overuse headache due to analgesics (195). One of the major problems with defining the epidemiology of medication- or substance-induced headache is the inability to prove an association between substance and headache in many cases. Fisher actually refuted the idea of medication-induced headache, but the patients he documented were taking pain-relief medications for arthritis, suggesting that medication-induced headache tends to occur in headache-prone patients (72). The fact that placebo can also induce headache indicates that headache can sometimes occur with the expectation of side effects of a therapy (147). Headache itself is also common, with one study suggesting a one-day point prevalence of 11% of men and 22% of women, so its occurrence with a particular substance may often be coincidental (190). Similarly, primary chronic daily headache occurs in 4% to 5% of the general population, and nearly one third of the population with chronic daily headache had migrainous features suggestive of chronic migraine (201). Despite these problems, some epidemiological data do emerge.

Most headache experts agree that people with migraine and tension-type headache have a greater risk for drug-induced headache. Patients who use dihydroergotamine daily for arterial hypotension or NSAIDs daily for musculoskeletal difficulties, prophylaxis of stroke, or myocardial infarction have a 2% to 5% risk of developing chronic headache (32; 124). Of patients who present with headache secondary to medication overuse, the initial headache syndrome that led to the medication use is most commonly migraine without aura (71%), followed by migraine without aura coexistent with tension-type headache (11%), migraine with and without aura (10%), and episodic tension-type headache (8%) (194). One predictor of medication overuse headache in patients with chronic migraine is the previous overuse of analgesics, even a decade earlier (254).

Medication overuse headache affects approximately 1.5% of the general population, mostly women. In specialized headache centers in Europe, 4% to 10% of patients have it, and in the United States, it affects 50% to 80% of patients in tertiary centers. Community sampling reveals 18% of patients with chronic tension-type headache and 32% of patients with chronic migraine from acute overuse of medication (55).

Patients with medication overuse headache may have a shorter mean duration of education than patients with uncomplicated migraine, with an inverse association between extent of education and duration of medication overuse headache (14). Low socioeconomic status may also be associated with development of medication overuse headache (14).

In a study, only 8% of children with chronic daily headache could be classified as having probable medication overuse headache, although 16% used analgesics daily and difficulty attaining precise classification may have underestimated analgesic overuse (239).

In a large health maintenance organization, 21% of headache patients managed by primary care physicians were chronic or frequent (more than 14 days per month) users of symptomatic headache medications (235). In this same study, chronic use of over-the-counter medication (15.9%) was twice that of chronic use of prescription medication (7.7%). Chronic medication use was best predicted by the number of headache days at baseline. Using IHS criteria, 90% of persons with migraine reported the use of over-the-counter drugs, and 1.5% of persons with migraine had medication overuse headache resulting from ergotamine tartrate or analgesics (195).

Kulkarni and colleagues also reviewed the topic of medication overuse headache (122).

As many as 60% to 75% of cocaine users report severe headaches related to cocaine use (54).

Carbon monoxide poisoning occurs in warehouse workers (63) and divers (41); sources in the home can include the kitchen and the bathroom (57).

References

01: Aboulafia DM, Norris D, Henry D, et al. 9-cis-retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial. Arch Dermatol 2003;139(2):178-86. PMID 12588223
02: Allais G, Gabellari IC, Airola G, Borgogno P, Schiapparelli P, Benedetto C. Headache induced by the use of combined oral contraceptives. Neurol Sci 2009;30(Suppl 1):S15-7. PMID 19415419
03: Alsaad AM, Koren G. Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: A meta-analysis of randomized, placebo-controlled trials. Br J Clin Pharmacol 2014;78(6):1264-71. PMID 25132372
04: Alstadhaug KB, Andreou AP. Caffeine and primary (migraine) headaches—friend or foe? Front Neurol 2019;10:1275. PMID 31849829
05: Alvarez RD, Conner MG, Weiss H, et al. The efficacy of 9-cis-retinoic acid (aliretinoin) as a chemopreventive agent for cervical dysplasia: results of a randomized double-blind clinical trial. Cancer Epidemiol Biomarkers Prev 2003;12(2):114-9. PMID 12582020
06: Alvaro LC, Iriondo I, Villaverde FJ. Sexual headache and stroke in a heavy cannabis smoker. Headache 2002;42(3):224-6. PMID 11903547
07: Amenta V, Pitari GM, Caff M, et al. An epidemiological study on the activity of cannabis in idiopathic headache. Cephalalgia 1996;16:377.
08: Anonymous. Comparison of two doses of cimetidine and placebo in the treatment of duodenal ulcer: a multicenter trial. Gut 1979;20(1):68-74. PMID 367885
09: Anonymous. Teriparatide: new preparation. Osteoporosis: less well evaluated than alendronic acid. Prescrire Int 2005;14(75):5-9. PMID 15747448
10: Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandin E2 induces immediate migraine-like attack in migraine patients without aura. Cephalalgia 2012;32(11):822-33. PMID 22718556
11: Arber N, Shirin H, Fadila R, Melamed E, Pinkhas J, Sidi Y. Pseudotumor cerebri associated with leuprorelin acetate. Lancet 1990;335(8690):669. PMID 1969048
12: Arteaga-Troncoso G, Villegas-Alvarado A, Belmont-Gomez A, Martinez-Herrera FJ, Villagrana-Zesati R, Guerra-Infante F. Intracervical application of the nitric oxide donor isosorbide dinitrate for induction of cervical ripening: a randomised controlled trial to determine clinical efficacy and safety prior to first trimester surgical evacuation of retained products of conception. BJOG 2005;112(12):1615-9. PMID 16305563
13: Askmark H, Lundberg PO, Olsson S. Drug-related headache. Headache 1989;29:441-4. PMID 2759851
14: Atasoy HT, Unal AE, Atasoy N, Emre U, Sumer M. Low income and education levels may cause medication overuse and chronicity in migraine patients. Headache 2005;45(1):25-31. PMID 15663609
15: Auer J, Berent R, Weber T, Lassnig E, Eber B. Subarachnoid haemorrhage with "Ecstasy" abuse in a young adult. Neurol Sci 2002;23(4):199-201. PMID 12536290
16: Bang LM, Plosker GL. Omalizumab: a review of its use in the management of allergic asthma. Treat Respir Med 2004;3(3):183-99. PMID 15219177
17: Barbanti P, Cafforio G, Fofi L. Headache in cocaine users: epidemiology, clinical features, and putative pathophysiological mechanisms. In: Preedy V, editor. The neuroscience of cocaine: mechanisms and treatment. Academic Press, 2017:363-74.
18: Bayne L, McLeod PJ, Oglivie RI. Antihypertensive drugs. In: Dukes MG, editor. Meyer’s side effects of drug. 9th ed. Amsterdam: Excerpta Medica, 1980:317.
19: Becker WJ. Use of oral contraceptives in patients with migraine. Neurology 1999;53:S19-25. PMID 10487509
20: Beran R, Berkovic S, Black A, et al. AUStralian study of titration to effect profile of safety (AUS-STEPS): high-dose gabapentin (neurontin) in partial seizures. Epilepsia 2001;42(10):1335-9. PMID 11737169
21: Bertorini TE, Nance AM, Horner LH, Greene W, Gelfand MS, Jaster JH. Complications of intravenous gammaglobulin in neuromuscular and other diseases. Muscle Nerve 1996;19:388-91. PMID 8606709
22: Bickerstaff ER. Neurological complications of oral contraceptives. Oxford: Clarendon Press, 1975.
23: Bigal ME, Krymchantowski AV. Migraine triggered by sucralose – case report. Headache 2006;46(3):515-7. PMID 16618274
24: Birk S, Kruuse C, Petersen KA, Tfelt-Hansen P, Olesen J. The headache-inducing effect of cilostazol in human volunteers. Cephalalgia 2006;26(11):1304-9. PMID 17059437
25: Blain PG, Stewart-Wynne E. Neurological disorders. In: Davies DM, Ferner RE, de Glanville H, editors. Textbook of adverse drug reactions. 5th ed. New York: Chapman and Hall, 1998.
26: Blumenthal HJ, Vance DA. Chewing gum headaches. Headache 1997;37(10):665-6. PMID 9439090
27: Bock HA, Gallati H, Zurcher RM, et al. A randomized prospective trial of prophylactic immunosuppression with ATG-Fresenius versus OKT3 after renal transplantation. Transplantation 1995;59(6):830-40. PMID 7701577
28: Bomgaars L, Geyer JR, Franklin J, et al. Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis. J Clin Oncol 2004;22(19):3916-21. PMID 15459213
29: Bonnetblanc JM, Hugon J, Dumas M, Rupin D. Intracranial hypertension with etretinate. Lancet 1983;2(8356):974. PMID 6138537
30: Boogerd W. Neurological complications of chemotherapy. In: deWolff FA, editor. Handbook of Clinical Neurology. Amsterdam: Elsevier Science, 1995:527.
31: Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003;60(4):392-400. PMID 12695317
32: Bowdler I, Kilian J. The association between analgesic abuse and headache--coincidental or causal. Headache 1988;28(7):494. PMID 3243712
33: Brainard JB. Salt load as a trigger for migraine. Minn Med 1976;59:232-3. PMID 1272213
34: Brewerton TD, Murphy DL, Mueller EA, Jimerson DC. Induction of migraine-like headaches by the serotonin agonist m-chlorophenylpiperazine. Clin Pharmacol Ther 1988;43(6):605. PMID 3378382
35: Brust JC. Vasculitis owing to substance abuse. Neurol Clin 1997;15:945-57. PMID 9367974
36: Calton GJ, Burnett JW. Danazol and migraine. N Engl J Med 1984;310(11):721-2. PMID 6700650
37: Carson CC. Long-term use of sildenafil. Expert Opin Pharmacother 2003;4(3):397-405. PMID 12614192
38: Castaldo M, Waliszewska-Prosół M, Koutsokera M, et al. Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis. J Headache Pain 2022;23(1):41. PMID 35361131
39: Chang YJ, Ryu SJ, Lee TH. Dose titration to reduce dipyridamole-related headache. Cerebrovasc Dis 2006;22(4):258-62. PMID 16788299
40: Chen MY, Ansell G, Ott DJ. Complications of diagnostic studies of the gastrointestinal tract. In: Ansell EG, Bettman, MA, Kaufman JA, et al, editors. Complications in Diagnostic Imaging and Interventional Radiology. 3rd ed. Cambridge: Blackwell Science, 1996.
41: Cheshire WP, Ott MC. Headache in divers. Headache 2001;41:235-47. PMID 11264683
42: Christiansen I, Iversen H, Olesen J. Headache characteristics during the development of tolerance to nitrates: pathophysiological implications. Cephalalgia 2000b;20(5):437-44. PMID 11037739
43: Christiansen I, Iversen H, Olesen J. Induction of nitrate tolerance is not a useful treatment in cluster headache. Cephalalgia 2000a;20(5):444-54. PMID 11037740
44: Chung S, Ben-Menachem E, Sperling MR, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010;24(12):1041-54. PMID 21090838
45: Couturier EG, Laman DM, van Duijn MA, van Duijn H. Influence of caffeine and caffeine withdrawal on headache and cerebral blood flow velocities. Cephalalgia 1997;17(3):188-90. PMID 9170342
46: Cowan JC. Nitrate tolerance. Int J Cardiol 1986;12:1-19. PMID 3089947
47: Crandall C. Tolterodine: a clinical review. J Womens Health Gend Based Med 2001;10:735-43. PMID 11703885
48: Creel G, Hurtt M. Cephalosporin-induced recurrent aseptic meningitis. Ann Neurol 1995;37:815-7. PMID 7778857
49: Croft A, Herxheimer A. Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement. BMC Public Health 2002;2:6. PMID 11914150
50: Dalessio DJ, Silberstein SD, editors. Wolff's headache and other head pain. New York: Oxford University Press, 1993.
51: Davidson SI. Reported adverse effects of oral contraceptives on the eye. Trans Ophthalmol Soc U K 1971;91:561-74. PMID 5291550
52: Davies DM, Ferner RE, de Glanville H, editors. Textbook of Adverse Drug Reactions. 5th ed. New York: Chapman and Hall, 1998.
53: De Marinis M, Janiri L, Agnoli A. Headache in the use and withdrawal of opiates and other associated substances of abuse. Headache 1991;31:159-63. PMID 2071394
54: Dhuna A, Pascual-Leone A, Belgrade M. Cocaine-related vascular headaches. J Neurol Neurosurg Psychiatry 1991;54:803-6. PMID 1955899
55: Dodick D, Freitag F. Evidence-based understanding of medication-overuse headache: clinical implications. Headache 2006;46(SUPPL 4):S202-11. PMID 17078852
56: Dueland AN. Headache and alcohol. Headache 2015;55(7):1045-9. PMID 26121267
57: Duenas-Laita A, Ruiz-Mambrilla M, Gandia F, et al. Epidemiology of acute carbon monoxide poisoning in a Spanish region. J Toxicol Clin Toxicol 2001;39(1):53-7. PMID 11327227
58: Duffy N, Walker P, Diamantea F, Calverley PM, Davies L. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Thorax 2005;60(9):713-7. PMID 15939732
59: Eccles MJ, Gutowski NJ. Precipitation of long duration hypnic headaches after ACE inhibitor withdrawal. J Neurol 2007;254(11):1597-8. PMID 17965960
60: Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57(4):507-33. PMID 10235690
61: Ekbom K. Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 1968;19:487-93. PMID 4971733
62: el-Mallakh RS. Marijuana and migraine. Headache 1987;27(8):442-3. PMID 3667262
63: Ely EW, Moorehead B, Haponik EF. Warehouse workers' headache: emergency evaluation and management of 30 patients with carbon monoxide poisoning. Am J Med 1995;98:145-55. PMID 7847431
64: Erkilic K, Ekinciler OF, Mirza GE, Dogan H, Cagil N. Effects of topically applied prostaglandin F2 alpha on normotensive human eyes. Ophthalmic Res 1996;28(6):351-5. PMID 9032793
65: Ernst ME, Kelly MW. Mibefradil, a pharmacologically distinct calcium antagonist. Pharmacotherapy 1998;18:463-85. PMID 9620098
66: ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367(9523):1665-73. PMID 16714187
67: Evers S, Suhr B, Bauer B. A retrospective long-term analysis of the epidemiology and features of drug-induced headache. J Neurol 1999;246:802-9. PMID 10525978
68: Facchinetti F, Sgarbi L, Piccinini F, Volpe A. A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Gynecol Endocrinol 2002;16(1):39-43. PMID 11915580
69: Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351(24):2498-508. PMID 15590952
70: Figg WD. Aseptic meningitis associated with muromonab-CD3. DICP 1991;25(12):1395. PMID 1815441
71: Fikkers BG, Bogousslavsky J, Regli F, Glasson S. Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psychiatry 1986;49(5):606. PMID 3711927
72: Fisher CM. Analgesic rebound headache refuted. Headache 1988;28:666. PMID 3229998
73: Freise CE, Rowley H, Lake J, Hebert M, Ascher NL, Roberts JP. Similar clinical presentation of neurotoxicity following FK 506 and cyclosporine in a liver transplant recipient. Transplant Proc 1991;23(6):3173. PMID 1721397
74: Friedman DI, Gordon LK, Egan RA, et al. Doxycycline and intracranial hypertension. Neurology 2004;62(12):2297-9. PMID 15210900
75: Garcia-Pagan JC, Morillas R, Banares R, et al. Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT. Hepatology 2003;37(6):1260-6. PMID 12774003
76: Geiselman JF. The clinical use of IgG food sensitivity testing with migraine headache patients: a literature review. Curr Pain Headache Rep 2019;23(11):79. PMID 31456119
77: Gennari C, Nami R, Pavese G, Gragnani S, Bianchini C, Buracchi P. Calcium-channel blockade (nitrendipine) in combination with ACE inhibition (captopril) in the treatment of mild to moderate hypertension. Cardiovasc Drugs Ther 1989;3 Suppl 1:319-25. PMID 2487803
78: Gerber A, Raab AP, Sobel AE. Vitamin A poisoning in adults. Am J Med 1954;16:729-45. PMID 13148217
79: Gibb CM, Davies PT, Glover V, Steiner TJ, Rose F, Sandler M. Chocolate is a migraine-provoking agent. Cephalalgia 1991;11:93-5. PMID 1860135
80: Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999;246:339-46. PMID 10399863
81: Gordon MF, Allon M, Coyle PK. Drug-induced meningitis. Neurology 1990;40:163. PMID 2296366
82: Grant WM, Schuman JS. Toxicology of the Eye. 4th ed. Springfield: Charles Thomas, 1993.
83: Griffiths RR, Bigelow GE, Liebson IA. Human coffee drinking: reinforcing and physical dependence producing effects of caffeine. J Pharmacol Exp Ther 1986;230:416-25. PMID 3772801
84: Guo S, Christensen AF, Liu ML, Janjooa BN, Olesen J, Ashina M. Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine. Cephalalgia 2017;37(2):114-24. PMID 26994300
85: Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 2014;137(11):2951-9. PMID 25161294
86: Gupta S, Mehrotra S, Villalón CM, Perusquía M, Saxena PR, MaassenVanDenBrink A. Potential role of female sex hormones in the pathophysiology of migraine. Pharmacol Ther 2007;113(2):321-40. PMID 17069890
87: Hagen K, Thoresen K, Stovner LJ, Zwart JA. High dietary caffeine consumption is associated with a modest increase in headache prevalence: Results from the head-HUNT study. J Headache Pain 2009;10(3):153-9. PMID 19308315
88: Haines ML, Gibson PR. Delayed adverse reactions to total-dose intravenous iron polymaltose. Intern Med J 2009;39(4):252-5. PMID 19402865
89: Hampson NB, Hampson LA. Characteristics of headache associated with acute carbon monoxide poisoning. Headache 2002;42(3):220-3. PMID 11903546
90: Hanington E, Harper AM. The role of tyramine in the etiology of migraine, and related studies on the cerebral and extracerebral circulations. Headache 1968;8:84-97.
91: Hansen JM, Hauge AW, Olesen J. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30:1179-86. PMID 20855363
92: Hays JT, Ebbert JO. Adverse effects and tolerability of medications for the treatment of tobacco use and dependence. Drugs 2010;70(18):2357-72. PMID 21142259
93: Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8 Suppl 7:1-96. PMID 3048700
94: Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders. Cephalalgia 2004;24:1-160.
95: Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808. PMID 23771276
96: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1-211. PMID 29368949
97: Henderson WR, Raskin NH. "Hot-dog" headache: individual susceptibility to nitrite. Lancet 1972;2:1162-3. PMID 4117590
98: Hering-Hanit R, Gadoth N. Caffeine-induced headache in children and adolescents. Cephalalgia 2003;23(5):332-5. PMID 12780761
99: Horton B, Peters G. Clinical manifestations of excessive use of ergotamine preparations and manifestations of withdrawal effect: report of 52 cases. Headache 1963;2:2214-27. PMID 13964041
100: Iversen HK. Nitric oxide and migraine. Cephalalgia 1997;17:144.
101: Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Rall TW, Nies AS, editors. Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Pr, 1990:485-521.
102: Jain KK. Drug-induced neurological disorders. Seattle: Hogrefe and Huber Publishers, 1996.
103: Johns DR. Migraine provoked by aspartame. N Engl J Med 1986;315:456. PMID 3736626
104: Johnson BA, O'Malley SS, Ciraulo DA, et al. Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003;23(3):281-93. PMID 12826990
105: Johnson MW, Andrew Sewell, R, Griffiths RR. Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Dependence 2012;123(1-3):132-40 PMID 22129843
106: Kahan BD. Cyclosporine. N Engl J Med 1989;321:1725. PMID 2687689
107: Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990;113:821. PMID 2240897
108: Kanekiyo T, Hara J, Matsuda-Hashii Y, et al. Tacrolimus-related encephalopathy following allogeneic stem cell transplantation in children. Int J Hematol 2005;81(3):264-8. PMID 15814339
109: Kenney RA. Placebo-controlled studies of human reaction to oral monosodium L-glutamate. In: Filer Jr LJ, Garrantini S, Kare MR, et al, editors. Glutamic Acid: Advances in Biochemistry and Physiology. New York: Raven Press, 1979:363-73.
110: Kenney RA, Tidball CS. Human susceptibility to oral monosodium L-glutamate. Am J Clin Nutr 1972;25:140-6. PMID 5009781
111: Ketter TA, Kalali AH, Weisler RH; SPD417 Study Group. A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004;65(5):668-73. PMID 15163253
112: Kielholz P. Abuse & addiction with phenacetin-containing preparations. Schweiz Med Wochenschr 1957;87(35-36):1131-4. PMID 13467193
113: King J, Richards M, Tress B. Cerebral arteritis associated with heroin abuse. Med J Aust 1978;2:444-5. PMID 732746
114: Ko D, Yang H, Williams B, Xing D, Laurenza A. Perampanel in the treatment of partial seizures: time to onset and duration of most common adverse events from pooled phase III and extension studies. Epilepsy Behav 2015;48:45-52. PMID 26057204
115: Koehler SM, Glaros A. The effect of aspartame on migraine headache. Headache 1991;28:10-3. PMID 3277925
116: Koppen A, Wijnands-Kleukers APG, Gresnigt FMJ, de Lange DW. Clinical toxicology of exposures to chemicals from clandestine drug laboratories: a literature review. Clin Toxicol (Phila) 2022;60(5):559-70. PMID 35191346
117: Kremer I, Ritz R, Brunner F. Aseptic meningitis as an adverse effect of co-trimoxazole. N Engl J Med 1983;308:1841. PMID 6602292
118: Krendel DA, Ditter SM, Frankel MR, Ross WK. Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology 1990;40:1092. PMID 2356010
119: Krymchantowski AV. Overuse of symptomatic medications among chronic (transformed) migraine patients: profile of drug consumption. Arq Neuropsiquiatr 2003;61(1):43-7. PMID 12715017
120: Kudrow L. Paradoxical effects of frequent analgesic use. Adv Neurol 1982;33:335-41. PMID 7055014
121: Kuge T, Shibata T, Willett MS. Wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medicine: a single-dose, dose-escalation safety and pharmacokinetic study. Pharmacotherapy 2003;23(11):1391-400. PMID 14620385
122: Kulkarni GB, Mathew T, Mailankody P. Medication overuse headache. Neurol India 2021;69(Supplement):S76-82. PMID 34003151
123: Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. Sleep 2022;45(6):zsab200. PMID 34358324
124: Lance F, Parkes C, Wilkinson M. Does analgesic abuse cause headaches de novo. Headache 1988;28:61-2. PMID 3343127
125: Langtry HD, Wilde MI. Omeprazole. A review of its use in Helicobacter pylori infection, gastro-esophageal reflux disease and peptic ulcers induced by non-steroidal anti-inflammatory drugs. Drugs 1998;56:447-86. PMID 9777317
126: Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 1998;18(1):27-32. PMID 9601621
127: Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia 2002;22(1):54-61. PMID 11993614
128: Lassen LH, Heinig JH, Oestergaard S, Olesen J. Histamine inhalation is a specific but insensitive laboratory test for migraine. Cephalalgia 1996;16(8):550-3. PMID 8980857
129: Lemon MD, Strain JD, Farver DK. Sodium oxybate for cataplexy. Ann Pharmacother 2006;40(3):433-40. PMID 16507620
130: Leroy MP, Cantineau D, Brasdefer D, Courteville H. [Adverse effects of neosynephrine]. Bull Soc Ophtalmol Fr 1989;89(2):243-5. PMID 2805195
131: Levine A, Watemberg N, Hager H, Bujanover Y, Ballin A, Lerman-Sagie T. Benign intracranial hypertension associated with budesonide treatment in children with Crohn’s disease. J Child Neurol 2001;16(6):458-61. PMID 11417618
132: Levine SR, Brust JC, Futrell N, et al. Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 1990;323(11):669-704. PMID 2388668
133: Levine SR, Welch KM. Cocaine and stroke. Stroke 1988;19:779-83. PMID 3076698
134: Lichtenfeld PJ, Rubin DB, Feldman RS. Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 1984;41:223. PMID 6691830
135: Lindgren A, Husted S, Staaf G, Ziegler B. Dipyridamole and headache--a pilot study of initial dose titration. J Neurol Sci 2004;223(2):179-84. PMID 15337620
136: Lippman C. Characteristic headache resulting from prolonged use of ergot derivatives. J Nerv Ment Dis 1955;121(3):270-3. PMID 14381915
137: Lipton RB, Bigal ME, Kolodner KB, et al. Acetaminophen in the treatment of headaches associated with dipyridamole-aspirin combination. Neurology 2004;63(6):1099-101. PMID 15452309
138: Lipton RB, Mazer C, Newman LC, Solomon S. Sumatriptan relieves migraine-like headaches associated with carbon monoxide exposure. Headache 1997;37:392-5. PMID 9237414
139: Lipton RB, Newman LC, Cohen JS, Solomon S. Aspartame as a dietary trigger of headache. Headache 1989;29(2):90-2. PMID 2708042
140: Littlewood JT, Gibb C, Glover V, et al. Red wine as a migraine trigger. In: Rose FC, editor. Advances in Headache Research. London: John Libbey, 1990:123-7.
141: Littlewood JT, Gibb C, Glover V, Sandler M, Davies PT, Rose FC. Red wine as a cause of migraine. Lancet 1988;1(8585):558-9. PMID 2894493
142: Loder EW, Buse DC, Golub JR. Headache as a side effect of combination estrogen-progestin oral contraceptives: a systematic review. Am J Obstet Gynecol 2005;193(3 Pt 1):636-49. PMID 16150254
143: Lutfullin A, Kuhlmann J, Wensing G. Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects. Int J Clin Pharmacol Ther 2005;43(5):217-26. PMID 15906587
144: Maniyar F, Rooney C, Lily O, Bazaz R. Anticonvulsant hypersensitivity syndrome presenting as aseptic meningitis. J Neurol 2009;256(7):1190-1. PMID 19330481
145: Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 2014;137(1):232-41. PMID 24277718
146: Manni G, Centofanti M, Parravano M, Oddone F, Bucci MG. A 6-month randomized clinical trial of bimatoprost 0.03% versus the association of timolol 0.5% and latanoprost 0.005% in glaucomatous patients. Graefes Arch Clin Exp Ophthalmol 2004;242(9):767-70. PMID 15241611
147: Marcus DA, Scharff L, Turk D, Gourley LM. A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia 1997;17(8):855-62. PMID 9453274
148: Markou S, Perimenis P, Gyftopoulos K, Athanasopoulos A, Barbalias G. Vardenafil (Levitra) for erectile dysfunction: a systematic review and meta-analysis of clinical trial reports. Int J Impot Res 2004;16(6):470-8. PMID 15229625
149: Masyczek R, Pugh CS. The “red wine” reaction. Ann J Enol Vitic 1983;34:260-4.
150: Mathew P, Fung F. Recapitulation of menstrual migraine with tamoxifen. Lancet 1999;353:467. PMID 9989725
151: Mathew T, John SK, Javali M, Vasireddy M, Nadig R, Sarma GRK. Substance use related cluster headache: A case series. Headache 2022;62(7):908-10. PMID 35856604
152: Mattila MA, Salmela J, Vaananen A, Kylmamaa T. Midazolam vs. lorazepam and placebo as hypnotic premedication before surgery. A controlled, double-blind study. Drugs Exp Clin Res 1985;11:841. PMID 2873011
153: Maxwell CR, Spangenberg RJ, Hoek JB, Silberstein SD, Oshinsky ML. Acetate causes alcohol hangover headache in rats. PLoS One 2010;5(12). PMID 21209842
154: Mayr BJ, Bonelli RM. Severe headache with venlafaxine withdrawal. Ann Pharmacother 2003;37(7-8):1145-6. PMID 12841832
155: McGee SM, McGee DN, McGee MB. Spontaneous intracerebral hemorrhage related to methamphetamine abuse: autopsy findings and clinical correlation. Am J Forensic Med Pathol 2004;25(4):334-7. PMID 15577524
156: Merkel PA, Koroshetz WJ, Irizarry MC, Cudkowicz ME. Cocaine-associated cerebral vasculitis. Semin Arthritis Rheum 1995;25:172-83. PMID 8650587
157: Meyer JS, Dalessio DJ. Headache associated with chemicals, toxins, systemic infections, and metabolic disorders (toxic vascular headache). In: Wolff's Headache and Other Head Pain. 6th ed. New York: Oxford University Press, 1993.
158: Micieli G, Manzoni GC, Granella F, et al. Clinical and epidemiological observations on drug abuse in headache patients. In: Diener HC, Wilkinson M, editors. Drug-Induced Headache. Berlin: Springer-Verlag, 1988:20-8.
159: Moffett AM, Swash M, Scott DF. Effect of chocolate in migraine: a double-blind study. J Neurol Neurosurg Psychiatry 1974;37:445-8. PMID 4838915
160: Motala C. H1 antihistamines in allergic disease. Current Allergy and Clinical Immunology 2009;22(2):71-4.
161: Mukamal KJ, Wellenius GA, Suh HH, Mittleman MA. Weather and air pollution as triggers of severe headaches. Neurology 2009;72(10):922-7. PMID 19273827
162: Nowaczewska M, Wiciński M, Kaźmierczak W. The ambiguous role of caffeine in migraine headache: from trigger to treatment. Nutrients 2020;12(8):2259. PMID 32731623
163: Obayashi Y, Nagamura Y. Does monosodium glutamate really cause headache? A systematic review of human studies. J Headache Pain 2016;17:54. PMID 27189588
164: Obermann M, Katsarava Z. Headache attributed to a substance or its withdrawal. Neurol Clin 2024;42(2):497-506. PMID 38575262
165: Oberstar JV, Bernstein GA, Thuras PD. Caffeine use and dependence in adolescents: one-year follow-up. J Child Adolesc Psychopharmacol 2002;12(2):127-35. PMID 12188981
166: O’Dea JP, Davis EH. Tamoxifen in the treatment of menstrual migraine. Neurology 1990;40:1470. PMID 2392241
167: Odievre M, Gros-Desormeaux A, Jouannault S, Tison M. Headache: an unrecognized risk of ribavirin in infants. Arch Pediatr 1998;5(3):347. PMID 10328015
168: Ohta K, Mori M, Yoritaka A, Okamoto K, Kishida S. Delayed ischemic stroke associated with methamphetamine use. J Emerg Med 2005;28(2):165-7. PMID 15707812
169: Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 2008;120(2):157-71. PMID 18789357
170: Onderwater GLJ, van Oosterhout WPJ, Schoonman GG, Ferrari MD, Terwindt GM. Alcoholic beverages as trigger factor and the effect on alcohol consumption behavior in patients with migraine. Eur J Neurol 2019;26(4):588-95. PMID 30565341
171: O'Sullivan ME. Termination of one thousand attacks of migraine with ergotamine tartrate. JAMA 1936;107(15):1208-12.
172: Panconesi A. Alcohol-induced headaches: evidence for a central mechanism? J Neurosci Rural Pract 2016;7(2):269-75. PMID 27114660
173: Partziguian T, Camerlingo M, Castro L, et al. Cerebral venous thrombosis in young adults. Experience in a stroke unit, 1988-1994. Ital J Neurol Sci 1996;17(6):419. PMID 8978448
174: Patel NC, DelBello MP, Bryan HS, et al. Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry 2006a;45(3):289-97. PMID 16540813
175: Patel RM, Sarma R, Grimsley E. Popular sweetner sucralose as a migraine trigger. Headache 2006b;46(8):1303-4. PMID 16942478
176: Peatfield RC, Gawel MJ, Rose FC. The effect of infused prostacyclin in migraine and cluster headache. Headache 1981;21(5):190-5. PMID 7026501
177: Peatfield RC, Glover V, Littlewood JT, Sandler M, Clifford Rose F. The prevalence of diet-induced migraine. Cephalalgia 1984;4(3):179-83. PMID 6498931
178: Perry CM, Jarvis B. Linezolid: a review of its use in the management of serious gram-positive infections. Drugs 2001;61:525. PMID 11324682
179: Pescatore SL, Lindley C. Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother 2000;1(3):537-46. PMID 11249536
180: Peters G, Horton B. Headache: with special reference to excessive use of ergotamine preparations and withdrawal effects. Mayo Clin Proc 1951;276:153-61. PMID 14827944
181: Piovesan EJ, Teive HG, de Paola L, et al. Uncontrolled headache induced by oxcarbazepine. J Headache Pain 2007;8(5):301-5. PMID 17955169
182: Pogarell O, Gasser T, van Hilten JJ, et al. Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. J Neurol Neurosurg Psychiatry 2002;72(6):713-20. PMID 12023411
183: Pokladnikova J, Meyboom RH, Vlcek J, Edwards RI. Can intranasal corticosteroids cause migraine-like headache. Cephalalgia 2009;29(3):360-4. PMID 19175775
184: Post RM, Silberstein SD. Shared mechanisms in affective illness, epilepsy and migraine. Neurology 1994;44:S37-47. PMID 7969945
185: Radhakrishnan J, Cohen DJ. Cytokine-release syndrome: general risk-factor modification--preparation of high-risk patients for use of OKT3. Transplant Proc 1993;25(2 Suppl 1):60-2. PMID 8465429
186: Radley SC, Chapple CR, Bryan NP, Clarke DE, Craig DA. Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study. Neurourol Urodyn 2001;20:43-52. PMID 11135381
187: Rahman NU, Al-Tahan AR. Deep venous thrombosis in oral contraceptive use. Stroke 1995;46:633.
188: Raman AK, Fakih MG. Capecitabine-induced headache responding to diltiazem. Chemotherapy 2007;53(4):306-8. PMID 17536204
189: Raskin NH. Headache. New York: Churchill Livingstone, 1988.
190: Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general population – a prevalence study. J Clin Epidemiol 1991;44:1147. PMID 1941010
191: Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman D. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma, and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101(1 Pt 1):14-23. PMID 9449495
192: Reess J, Haas J, Gabriel K, Fuhlrott A, Fiola M. Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy. Mult Scler 2002;8(1):15-8. PMID 11936482
193: Reif-Lehrer L. A questionnaire study of the prevalence of Chinese restaurant syndrome. Fed Proc 1977;36:1617-23. PMID 844607
194: Relja G, Granato A, Maria Antonello R, Zorzon M. Headache induced by chronic substance use: analysis of medication overused and minimum dose required to induce headache. Headache 2004;44(2):148-53. PMID 14756853
195: Robinson RG. Pain relief for headaches. Is self-medication a problem. Can Fam Physician 1993;39:867-8, 871-2. PMID 8495144
196: Rosenberg H, Clofine R, Bialik O. Neurologic changes during awakening from anesthesia. Anesthesiology 1981;54(2):125-30. PMID 7469090
197: Rozen TD. Childhood exposure to second-hand tobacco smoke and the development of cluster headache. Headache 2005;45(4):393-4. PMID 15836583
198: Saul RF, Hamburger HA, Selhorst JB. Pseudotumor cerebri secondary to lithium carbonate. JAMA 1985;253:2869-70. PMID 3921728
199: Sayyah M, Sayyah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(1):166-9. PMID 16309809
200: Schaumburg HH, Byck R, Gerstl R, Mashman JH. Monosodium L-glutamate: its pharmacology and role in the Chinese restaurant syndrome. Science 1969;163:826-8. PMID 5764480
201: Scher AI, Stewart WF, Liberman J, Lipton RB. Wolff Award 1998. Prevalence of frequent headache in a population sample. Headache 1998;38(7):497-506. PMID 15613165
202: Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology 2004;63(11):2022-7. PMID 15596744
203: Schiffman SS, Buckley CE 3rd, Sampson HA, et al. Aspartame and susceptibility to headache. N Engl J Med 1987;317(19):1181-5. PMID 3657889
204: Schipper HM. Neurology of sex steroids and oral contraceptives. Neurol Clin 1986;4(4):721. PMID 3025581
205: Schwartz AM. The cause, relief, and prevention of headaches arising from contact with dynamite. N Engl J Med 1946;306:541-4. PMID 21000388
206: Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009;132(1):16-25. PMID 19052139
207: Shah A, Lisak RP. Neurological complications of immunomodulating therapy. In: deWolff FA, editor. Handbook of Clinical Neurology. Amsterdam: Elsevier Science, 1995:547.
208: Shah A, Roberts T, McQueen IN, Graham JG, Walker K. Danazol and benign intracranial hypertension. BMJ 1987;294(6583):1323. PMID 3109637
209: Shapiro RE. Caffeine and headaches. Curr Pain Headache Rep 2008;12(4):311-5. PMID 18625110
210: Silberstein SD. Drug-induced headache. Neur Clin 1998;16(1):107. PMID 9421543
211: Silberstein SD, Lipton RB. Chronic daily headache. In: Goadsby PJ, Silberstein SD, editors. Headache. Blue Books of Practical Neurology. Vol. 17. Boston: Butterworth-Heinemann, 1997:201-25.
212: Silfverskiold BP. Gynergen abuse in cases of migraine. Acta Psychiatr Scand 1947;22:281-5.
213: Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992;327(16):1109-14. PMID 1528206
214: Sjaastad O, Bakketeig LS. Caffeine-withdrawal headache. The Vaga study of headache epidemiology. Cephalalgia 2004;24(4):241-9. PMID 15030532
215: Spector SL. Safety of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol 2001;86(6 Suppl 1):18-23. PMID 11426912
216: Stavchansky MM, Wilson JP. FDA adverse event reports on use of sibutramine: An exploratory analysis. J Pharm Technol 2004;20(6):323-8.
217: Stein MD. Medical consequences of substance abuse. Psychiatr Clin North Am 1999;22(2):351-70. PMID 10385938
218: Stephens WP, Eddy JD, Parsons LM, Singh SP. Raised intracranial pressure due to perhexiline maleate. BMJ 1978;1(6104):21. PMID 620132
219: Strachan R, Hughes D, Cowie R. Thrombosis of the straight sinus complicating hormone replacement therapy. Br J Neurosurg 1995;9:805-8. PMID 8719840
220: Strong FC. Why do some dietary migraine patients claim they get headaches from placebos. Clin Exp Allergy 2000;30(5):739-43. PMID 10792367
221: Strony J, Hoffman R, Hanson M, Veltri E. Tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin for twelve months: results from two open-label extension studies in hypercholesterolemic patients. Clin Ther 2008;30(12):2280-97. PMID 19167588
222: Taylor JR, Dietrich E, Powell J. Lorcaserin for weight management. Diabetes Metab Syndr Obes 2013;6:209-16. PMID 23788837
223: Thomas MC, Walker R, Wright A. HaNDL syndrome after "benign" OKT3-induced meningitis. Transplantation 1999;67(10):1384-5. PMID 10360598
224: Thomsen LL, Iversen HK, Lassen LH, et al. The role of nitric oxide in migraine pain. Therapeutic implications. CNS Drugs 1994;2:417-22.
225: Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by all-trans retinoic acid: a case report. J Med Assoc Thai 2000;83(11):1420-3. PMID 11215876
226: Toom K, Braschinsky M, Obermann M, Katsarava Z. Secondary headache attributed to exposure to or overuse of a substance. Cephalalgia 2021;41(4):443-52. PMID 32819151
227: Toth CC, Burak K, Becker W. Recurrence of migraine with aura due to tacrolimus therapy in a liver transplant recipient successfully treated with sirolimus substitution. Headache 2005;45(3):245-6. PMID 15836601
228: Tvedskov JF, Thomsen LL, Thomsen LL, et al. The effect of propranolol on glyceryltrinitrate-induced headache and arterial response. Cephalalgia 2004;24(12):1076-87. PMID 15566422
229: Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308(18):1076-80. PMID 6835321
230: van Zonneveld M, Flink HJ, Verhey E, et al. The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther 2005;21(9):1163-71. PMID 15854180
231: Vespignani H, Lepori JC, Gehin P, Barroche G, Raspiller A, Weber M. Benign intracranial hypertension: apropos of 4 drug-induced cases. Rev Oto Neuro Ophthalmol 1984;56:277-86. PMID 6209770
232: Vincent FM. Migraine responsive to danazol. Neurology 1985;35(4):618. PMID 3982663
233: Volkow ND, Fowler JS, Wang GJ, et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 1993;14(2):169-77. PMID 8101394
234: Volkow ND, Fowler JS, Wolf AP. Changes in brain glucose metabolism in cocaine dependence and withdrawal. Am J Psychiatry 1991;148(5):621-6. PMID 2018164
235: Von Korff M, Galer BS, Stang P. Chronic use of symptomatic headache medications. Pain 1995;62:179-86. PMID 8545143
236: Walters BN, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. BMJ 1981;282:19. PMID 6449976
237: Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005;331(7520):810. PMID 16157605
238: Wheatcroft S, Sharma A, McAllister J. Reduction in mydriatic drop size in premature infants. Br J Ophthalmol 1993;77(6):364-5. PMID 8318484
239: Wiendels NJ, van der Geest MC, Neven AK, Ferrari MD, Laan LA. Chronic daily headache in children and adolescents. Headache 2005;45(6):678-83. PMID 15953300
240: Wienecke T, Olesen J, Oturai PS, Ashina M. Prostacyclin (epoprostenol) induces headache in healthy subjects. Pain 2008;139(1):106-16. PMID 18450380
241: Wienecke T, Olesen J, Oturai PS, Ashina M. Prostaglandin E2 (PGE2) induces headache in healthy subjects. Cephalalgia 2009;29(5):509-19. PMID 19187340
242: Wienecke T, Olesen J, Ashina M. Prostaglandin I2 (epoprostenol) triggers migraine-like attacks in migraineurs. Cephalalgia 2010;30(2):179-90. PMID 19614689
243: Wienecke T, Olesen J, Ashina M. Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D2 (PGD2). Cephalalgia 2011;31(1):65-76. PMID 20974593
244: Wijdicks EF. Neurological manifestations of immunosuppressive agents. In: Widjicks EF, editor. Neurological Complications in Organ Transplant Recipients. Boston: Butterworth-Heinemann, 1999.
245: Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384(11):989-1002. PMID 33567185
246: Worm J, Falkenberg K, Olesen J. Histamine and migraine revisited: mechanisms and possible drug targets. J Headache Pain 2019;20(1):30. PMID 30909864
247: Wurdeman RL, Mooss AN, Mohiuddin SM, Lucas BD Jr, Ryschon KL, Hilleman DE. Comparison of 24-hour ambulatory blood pressure data in hypertensive patients switched from nifedipine-GITS to nifedipine-CC. Pharmacotherapy 1999;19(1):94-100. PMID 9917082
248: Yang WH, Dolovich J, Drouin MA, Keith P, Haddon J, Jennings B. Comparison of budesonide Turbohaler with budesonide aqua in the treatment of seasonal allergic rhinitis. Rhinocort Study Group. Can Respir J 1998;5(6):455-60. PMID 10070173
249: Yang WH, Drouin MA, Herbert M, Mao Y, Karsh J. The monosodium glutamate symptom complex: assessment in a double-blind, placebo-controlled, randomized study. J Allergy Clin Immunol 1997;99:757-62. PMID 9215242
250: Yelehe-Okouma M, Czmil-Garon J, Pape E, Petitpain N, Gillet P. Drug-induced aseptic meningitis: a mini-review. Fundam Clin Pharmacol 2018;32(3):252-60. PMID 29364542
251: Young JM, Feldman RA, Auerbach SM, et al. Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: US trial. J Androl 2005;26(3):310-8. PMID 15866997
252: Zed PJ, Loewen PS, Robinson G. Medication-induced headache: overview and systematic review of therapeutic approaches. Ann Pharmacother 1999;33(1):61-72. PMID 9972386
253: Zsoter TT, Church JG. Calcium antagonists. Pharmacodynamic effects and mechanism of action. Drugs 1983;25(2):93-112. PMID 6131809
254: Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J. Analgesic use: a predictor of chronic pain and medication overuse headache: the Head-HUNT Study. Neurology 2003;61(2):160-4. PMID 12874392

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Brittany Heckel MD

Dr. Heckel of Thomas Jefferson University Hospitals received a consulting fee from AbbVie.
See Profile
Stephanie J Nahas MD

Dr. Nahas of Thomas Jefferson University received honorariums from Allergan/AbbVie, Amneal, Axsome, Eli Lilly, Lundbeck, Pfizer, and Tonix as consultant.
See Profile

Editor

Stephen D Silberstein MD

Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University has no relevant financial relationships to disclose.
See Profile

Former Authors

Cory Toth MD BSc

Patient Profile

Age range of presentation: 2 to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD-10: Headache: R51
ICD-11: Headache, not elsewhere classified: MB4D

Other specified secondary headache: 8A84.Y

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Medications and substances causing headache

Associated Disorders

Analgesic abuse headache
Analgesic headache
Analgesic-induced chronic headache
Analgesic-induced headache
Analgesic rebound headache
- Chinese restaurant headache
- Chronic refractory headache
- Drug dependence headache
- Drug-induced refractory headache
- Ergotamine-induced headache
- Medication misuse headache
- Rebound headache
- Refractory headache
- Substance use headache
- Sumatriptan-induced daily headache

Differential Diagnosis

primary headache syndromes
other causes of secondary headache syndromes
other headache syndromes
intracranial hemorrhage
stroke
- endocarditis
- brain abscess

Also Relevant

Activity-related headache
Alternative therapies
Headache associated with illicit drug use
Lamotrigine
Medication overuse headache
- Serotonin syndrome

Medications and substances causing headache

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. IHS Diagnostic Criteria for Alcohol and Alcoholic Beverage-Induced Headache: Immediate or Delayed

Table 2. IHS Diagnostic Criteria for Histamine-Induced Headache

Table 3. IHS Diagnostic Criteria for Caffeine-Withdrawal Headache

Table 4. IHS Diagnostic Criteria for Nitrate- and Nitrite-Induced Headache

Table 5. IHS Diagnostic Criteria for Estrogen Withdrawal Headache

Table 6. IHS Diagnostic Criteria for Cocaine-Induced Headache

Table 7. IHS Diagnostic Criteria for Headache Attributed to Opioid Withdrawal

Table 8. IHS Diagnostic Criteria for Carbon Monoxide (CO)-Induced Headache

Table 9. IHS Diagnostic Criteria for Phosphodiesterase (PDE)-Induced Headache

Table 10. IHS Diagnostic Criteria for Calcitonin Gene-Related Peptide (CGRP)-Induced Headache

Table 11. IHS Diagnostic Criteria for Headaches Due to Medications Used for Other Indications

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Metal neurotoxicity

Primary cough headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Mercury neuropathy

This is an article preview.
Start a Free Account
to access the full version.