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.
