Clinical manifestations

Presentation and course

The clinical manifestations of these headaches are variable and depend on factors; the substance, dose, and duration of exposition. The key features for headache attributed to substance use are classified are as follows:

	(1) Headache features, which vary with the substance.
	(2) Documented administration of the substance known to be able to cause headache.
	(3) Headache developing in close temporal proximity relation to ingestion or exposure.
	(4) Headache significantly improving or resolving after exposure ceases.

The same substances can trigger attacks of pre-existing migraine or tension-type headache. A causal relationship is supported by the fact that provoked attacks and nonprovoked attacks are phenotypically identical. However, if the phenotype is clearly different from the previously experienced attacks, it is more likely that the current headache episode is not directly related to the underlying primary headache and represents a new acute secondary headache attributed to the substance (35).

Nitric oxide donor-induced headache. Headache is a side effect of therapeutic use of nitroglycerine and other nitric oxide donors. This headache has been associated with nitroglycerine’s potent vasodilator effects. With chronic use, tolerance develops, and nitroglycerine-induced headache disappears in most patients. Currently, two types of nitrate-induced headache have been recognized:immediate headache that develops within the first hour of application, which is usually mild to moderate in intensity and is without characteristic migrainous features. The other is delayed headache, which tends to be moderate or severe migraine-type headache developing 3 to 6 hours after the intake of nitrates with accompanying nausea, vomiting, photophobia, or phonophobia. The delayed headache occurs mainly in subjects with a personal or family history of migraine (03). The ability of nitroglycerine to trigger migraine-like attacks, often described as identical to spontaneously occurring migraine attacks, makes it a reliable clinical model to investigate the underlying pathophysiological mechanisms of migraine (32).

Phosphodiesterase inhibitor-induced headache. Phosphodiesterase inhibitors used for pulmonary hypertension or erectile dysfunction can induce headache. Phosphodiesterase inhibitor-induced headache is defined as any headache developed within five hours of intake of the phosphodiesterase inhibitor. Headache is usually tension-type-like and resolves spontaneously within 72 hours; however, in people with migraine history, use of phosphodiesterase inhibitor may provoke migraine-like headache (19).

Carbon monoxide-induced headache. The headache accompanying acute carbon monoxide poisoning is extremely variable in nature. Head pain has been described as frontal or bitemporal and can be dull sharp or throbbing. Typically, carboxyhemoglobin levels of 10% to 20% cause a mild headache without gastrointestinal or neurologic symptoms, levels of 20% to 30% cause a moderate pulsating headache and irritability, and levels of 30% to 40% cause a severe headache with nausea, vomiting, and blurred vision (16). Provocation models showed that nontoxic concentrations of carbon monoxide did not provoke migraine-like attacks (14).

Alcohol-induced headache. Alcohol-induced headache is classified into immediate or delayed alcohol-induced headache in the third edition (beta version) of the International Classification of Headache Disorders (19). Immediate alcohol-induced headache occurs within three hours of ingestion. The effective dose of alcohol to induce headache is variable but could be lower for patients with migraine, which explains the inverse association between the prevalence of migraine and alcohol consumption (26), which is much more rarely seen than the delayed type. Delayed alcohol-induced headache, also named hangover headache, is one of the commonest secondary headaches. Pressing or pulsatile bilateral headache aggravated by physical activity is the most common phenotype. Headache duration correlates with the total grams of alcohol consumed (12). It occurs from 54 to 1224 hours after the end of drinking alcohol ingestion. Headache characteristics are unspecific but, in patients with migraine, headaches after alcohol intake often have similar qualities as their usual migraine attacks. In fact, it can cause migraine-like symptoms, including unilateral throbbing pain with photophobia in migraineurs. Both forms resolve within 72 hours of onset (05).

Cocaine-induced headache. Headache is one of the most common symptoms after cocaine use. Cocaine-induced headache is defined by ICHD-3 as a headache that develops within an hour after cocaine use, manifesting with at least one of the following symptoms: bilaterality, frontotemporal location, pulsating quality, and worsening with physical activity. Chronic cocaine use frequently seems to worsen or induce headache with migraine or migraine-like characteristics (10). Cocaine consumers can suffer from throbbing frontal headache that progressively worsens with continued drug abstinence and is associated with photophobia, nausea, and vomiting (09).

Histamine-induced headache. Similar to other substances, histamine can cause immediate headache in most people, but it can also cause a delayed headache in people with primary headaches as migraine or tension-type headache. Delayed headache phenomenologically resembles primary headache (19).

Calcitonin gene-related peptide-induced headache. Calcitonin gene-related peptide is a key molecule in migraine pathogenesis and has been used to experimentally induce migraine attacks. Intravenous calcitonin gene-related peptide infusion triggers immediate headache, but it can also cause delayed migraine-like attacks in 66% of migraine patients (02).

Headache attributed to occasional use of non-headache medication. Headache attributed to occasional use of non-headache medication has been reported as an adverse event after use of many drugs. The following are the most commonly incriminated: atropine, digitalis, disulfiram, hydralazine, imipramine, nicotine, nifedipine, and nimodipine. The headache characteristics are not very well defined in the literature, and probably depend on the drug, but in most cases headache is dull, continuous, diffuse, and of moderate to severe intensity (19).

Headache attributed to long-term use of non-headache. Headache attributed to long-term use of non-headache medication subsumes headache developing as an adverse event during hormone therapy, taken usually for contraception or as hormone replacement therapy. Oral contraceptives have been associated with both migraine and nonmigraine headaches and have been related to estrogen use (develops or worsens within three months of commencing exogenous hormones) or withdrawal (typically during the free-pill week) (19).

Headache attributed to use of or exposure to other substance. Headache attributed to use of or exposure to other substance includes headache caused by herbal, animal, or other organic or inorganic substances given by physicians or non-physicians with medicinal intent although not licensed as medicinal products. It has been reported after exposure to a number of other organic and inorganic substances. The following are most commonly incriminated: inorganic compounds—arsenic, borate, bromate, chlorate, copper, iodine, lead, lithium, mercury, and tolazoline hydrochloride; and organic compounds—aniline, balsam, camphor, carbon disulfide, carbon tetrachloride, chlordecone, EDTA, heptachlor, hydrogen sulfide, kerosene, long-chain alcohols, methyl alcohol, methyl bromide, methyl chloride, methyl iodine, naphthalene, and organophosphorous compounds (parathion, pyrethrum). The characteristics are not well defined in the literature and almost certainly vary with the agent. In most cases it is dull, diffuse, continuous, and of moderate to severe intensity (19).

Finally, headache has been reported after exposure to a number of other organic and inorganic substances. Food and dietary substances have classically been described to trigger headache or migraine in susceptible individuals. Interestingly, despite being such a common belief, most of the clinical studies have shown conflicting results. Premonitory symptoms of migraine attack include food cravings or increased feeling of hunger that are then misinterpreted as the initial cause of the migraine attack (20).

Prognosis and complications

Headache attributed to substance use consists of acute headache developed in temporal relation to use of a substance that frequently improves or resolves after substance withdrawal (19). If the patient stops using the substance causing the headache, the headache should improve without complications. The exception is carbon monoxide poisoning that can cause permanent neurologic damage, particularly in the occipital areas or cerebellum, with permanent neurologic dysfunction and headache.

Biological basis

Etiology and pathogenesis

There is no single, unifying, etiologic explanation for substance-use headache. Substance-use headache in patients who normally suffer from migraine or cluster headache is an area of active research that aims to improve experimental migraine provocation models in animal or human subjects. Migraine pathophysiological-based hypotheses involving serotonin 5-HT-2B/2C receptors (11) or nitric oxide (29) have been advanced with a considerable scientific underpinning (15) in contrast to nonmigraine-type headache.

Headache pathophysiology depends on the trigger substance, so the understanding of substance-use headache etiology has not significantly progressed. It is likely that at least some substance-use headaches may have a direct effect on trigeminal afferents, ie, chemically mediated irritative effects, whereas others might act on central mechanisms including triggers that increase excitation of cortical excitability or neurons and cause withdrawal of pain descending modulatory systems of sensory inhibition originating in the brainstem (24). Nonetheless, these hypotheses require further investigation.

A useful way to understand the pathogenesis of substance-use headaches is to study the headache phenotype provoked by each substance.

Nitric oxide donor-induced headache. Probably, the most well understood substance-use headache is nitrates-induced headache. Currently, two types of nitrate-induced headache have been recognized. One is immediate headache that develops within the first hour of application, which is usually mild to moderate in intensity and without characteristic migrainous features. The other is delayed headache, which tends to be moderate or severe migraine-type headache developing 3 to 6 hours after the intake of nitrates, with accompanying nausea, vomiting, photophobia, or phonophobia. The delayed headache occurs mainly in subjects with a personal or family history of migraine (03). Immediate headache is generally considered to be related to nitric oxide-mediated vasodilatation, whereas delayed migraines are triggered by the release of calcitonin gene-related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S-nitrosylation (03).

Nitric oxide is a small lipophilic molecule released from endothelial cells and stimulates cGMP synthesis via activation of soluble guanylate cyclase, causing smooth muscle relaxation and vasodilation. In the middle of the 19th century, when nitrates were introduced for the acute treatment of angina, it became clear that these compounds could induce headache (02). Glyceryl trinitrate, a nitric oxide donor, and PDE5 inhibitors (sildenafil and dypiridamol) that lead to accumulation of cGMP similar to that caused by nitric oxide signaling have been proven to trigger headache and migraine-like attacks in human provocation models (21; 23; 22). In healthy subjects, sublingual nitroglycerin can induce changes in trigeminal nociceptive reflex and evoked cortical response resembling those found immediately before and during a migraine attack, which might partially explain the attack-triggering effect of nitroglycerin in migraineurs (07). Considering its headache-provoking effect, the nitroglycerin headache model has been employed to explore the pathophysiological mechanisms of migraine and cluster headache in both humans and animals (21; 34; 28; 01). Based on current evidence, it is conceivable that nitric oxide could be a crucial molecule in primary headaches; blockade of the nitric oxide-cyclic guanosine monophosphate pathway may be a novel target for antimigrainous therapy (33). Selective and nonselective nitric oxide synthase inhibitors have been tested as an antimigraine agent, and preclinical results showed that they could be effective acute and preventative therapies against spontaneous migraine attacks (02).

Carbon monoxide-induced headache. Carbon monoxide had been considered to be a toxic gas, and hypoxia was previously thought to be the sole mechanism behind carbon monoxide-induced headache. However, carbon monoxide-induced headache may also appear after exposure to nontoxic doses. Interestingly, carbon monoxide is nowadays known to be an important endogenously produced signaling molecule involved in multiple biological processes such as nociceptive processing or regulation of cerebral arterial tone.

Controversially, some authors argue that nitroglycerin provocation headache in normal subjects is not an ideal human migraine model (36). One trial demonstrated that CGRP receptor antagonist olcegepant does not prevent glyceryl trinitrate-induced migraine, suggesting that nitric oxide does not induce migraine by liberating CGRP (37). A gap between animal and human study remains to be filled.

Alcohol-induced headache. Alcohol-induced headache is classified into immediate or delayed alcohol-induced headache (19). Immediate alcohol-induced headache occurs within three hours of ingestion, and delayed alcohol-induced headache, much more frequent and also named hangover headache, occurs from 4 to 24 hours after drinking. Alcohol can cause migraine-like symptoms, including unilateral throbbing pain with photophobia in migraineurs and is frequently incriminated as a trigger for cluster headache attacks during bouts (13). Alcohol-induced headache is thought to be by other compounds of alcoholic beverages rather than alcohol in susceptible individuals. Biogenic amines, sulphites, flavonoid phenols, 5-hydroxytryptamine mechanisms, and vasodilating effects have all been considered possible contributing factors for alcohol-induced headache (30). In one animal study, it was demonstrated that acetate might be responsible for the hangover headache (27).

Cocaine-induced headache. Acute cocaine administration blocks monoamine reuptake, inducing increased dopaminergic and serotoninergic activity with potent sympathomimetic effects and acute vascular smooth muscle constriction (06). Chronic cocaine use is associated with a reduced dopamine D2 receptor binding potential and, consequently, decreased dopamine transmission related to a downregulation connected to dopaminergic pathway supersensitivity (38). There are many pathophysiological impacts caused by cocaine consumption, including increment in oxidative stress, platelet activation, production and activation of prostaglandins, sympathetic activity, and endothelial dysfunction (09).

Histamine-induced headache. In vitro experiments have indicated that histamine may dilate primate cerebral arteries via an endothelial H1 receptor due to endothelial nitric oxide synthase activation with subsequent nitric oxide formation. Histamine-induced immediate headache, delayed migraine, and arterial dilatation are elicited via the H1 receptor because these can be almost completely prevented by the H1-receptor-antagonist mepyramine. Thus, it seems likely that histamine may induce migraine indirectly via increased production of nitric oxide (25).

Calcitonin gene-related peptide-induced headache. Calcitonin gene-related peptide is located in the trigeminal nerve fibers surrounding human cerebral arteries and is a strong vasodilator. Calcitonin gene-related peptide activates adenylate cyclase and consequently increases formation of intracellular cAMP in vascular smooth muscle cells of cerebral arteries. Is has also been suggested that calcitonin gene-related peptide modulates nociceptive transmission in headache and possibly nonheadache pain conditions. Evidence from experimental studies in humans supports the hypothesis that calcitonin gene-related peptide has an important role in initiating migraine attacks and supports the development of calcitonin gene-related peptide-based migraine treatment (02).

Epidemiology

There is a lack of specific epidemiological data about headache attributed to substance use, and it depends on the exposure dose. According to clinical studies, nitrate-induced headache varies between 20% and 82% (03). Although carbon monoxide intoxication is not frequent, headache is the most common symptom among individuals with symptomatic carbon monoxide exposure and is referred by 90% of patients (16). Delayed alcohol-induced headache (hangover) is probably one of the most common types of secondary headache reported. It depends on alcohol amount and duration exposure, but epidemiological studies reported 64% to 84% lifetime prevalence (31). Headache is also one of the most common symptoms after cocaine use. After acute cocaine use, 90% of users reported headache attacks (10).

Prevention

Substance-use headaches are prevented by avoiding the use of the offending substances. Patients with primary headaches like migraine or cluster headache are at a higher risk of suffering also from substance-induced headache. Considering the lifetime prevalence of migraine in the general population and given the migraine-inducing effects of nitrates or phosphodiesterase inhibitors and hormonal treatments, migraine patients should be made aware of the risk of inducing a migraine attack.

The shortest lasting phosphodiesterase inhibitors (avanafil, vardenafil, or sildenafil) in the lowest doses should be used first (08). Possible contraceptive strategies to reduce headache include extended-cycle combined hormonal contraception, progesterone-only contraception, or new generation hormones like estradiol valerate/dienogest (04).

Differential diagnosis

Headache attributed to use or exposure to a substance is an exclusion diagnosis. Substance-use headaches must be differentiated initially from secondary and then from primary headache syndromes. Other secondary causes must be excluded. The major diagnostic points are the absolute link of the headache and the the substance exposure together with the resolution after substance withdrawal or avoidance. Patients suffering from primary headaches such as migraine, cluster headache, or tension-type headache should receive both the primary headache and the substance-induced headache diagnose.

Diagnostic workup

There are no specific clinical diagnostic data for headache attributed to substance use other than the temporal relationship between exposure and the headache onset. Routine complementary examinations are normal, except for the case of carbon monoxide poisoning, where carboxyhemoglobin levels higher than 10% or bilateral ischemic lesions of the basal ganglia are diagnostic.

Management

Headache resolves after substance withdrawal. Therefore, substance avoidance or a cautious risk-benefit evaluation of medications that induce headache should be performed. Carbon monoxide poisoning is often treated with hyperbaric oxygen therapy. If not possible, the treatment of substance-use headache consists of simple analgesics.

Special considerations

Pregnancy

The majority of the substances that induces headache are not recommended during pregnancy.