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, aiming to improve experimental migraine provocation models in animal or human subjects. Migraine pathophysiological-based hypotheses involving serotonin 5-HT-2B/2C receptors (23) or nitric oxide (59) have been advanced with a considerable scientific underpinning (27) in contrast to nonmigraine-type headache.
The headache pathophysiology depends on the trigger substance, so the understanding of their etiology has not progressed greatly. 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 (43). Nonetheless, these hypotheses require further investigation.
A useful way to understand the pathogenesis and pathophysiology of substance-use headaches is to deal with substances and the types of headache they produce. Some of these substances have been specifically coded by the Headache Classification Committee of the International Headache Society, and others have not.
The first of these headache-inducing substances is nitrites. Headaches caused by nitrite ingestion sometimes have been called "hot dog headaches" because sodium nitrite is employed as a food coloring and preservative in processed and cured meats and fish, such as frankfurters (“hot dogs”), bacon, ham, bologna, salami, pepperoni, sausages, corned beef, pastrami, and lox. Ingestion of either hot dogs or 10 mg of sodium nitrite (but not 10 mg of sodium bicarbonate) can produce headache (36). This headache has been described as bitemporal, nonthrobbing, moderately severe pains associated with facial flushing. Susceptible individuals need no family history of headache, although it is interesting that increased plasma nitrites can be seen in migraineurs (12).
Currently, 2 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, and/or phonophobia. The delayed headache occurs mainly in subjects with a personal or family history of migraine (05).
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 (05).
Nitric oxide donor-induced headache. Nitric oxide is a small lipophilic molecule that is 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 (03). 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 proved to trigger headache and migraine-like attacks in human provocation models (38; 42; 41). 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 (15). 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 (38; 73; 52; 01). Compelling evidence was observed in animal models. For example, infusion of a nitric oxide donor could result in increase of CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion (16) and CGRP release and c-fos expression within trigeminal nucleus caudalis (57). In addition, it was found that systemic infusion or topical application of nitric oxide donors could lead to phosphorylation of extracellular signal-regulated kinase (ERK) in meningeal arteries and a delayed increase in the mechanosensitivity of meningeal nociceptors (81). However, previous studies in anesthetized or in awake rodents tended to use glyceryl trinitrate with doses 1000 to 10,000 times higher than that used in humans, which is far beyond clinical and pharmacological relevance. A neutralistic dose (8 times higher than in humans) of glyceryl trinitrate in an awake rat model that could effectively upregulate c-FOS mRNA in trigeminal nucleus caudalis might be more rational (64). 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 (72). 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 (03). A study found that blockers of CGRP, nNOS, or neurokinin-1 receptors could inhibit glyceryl trinitrate induced Fos activation, suggesting their potential role as migraine therapeutics (65). CGRP antagonists could also decrease spinal trigeminal activity and hyperalgesia induced by nitroglycerin infusion (19; 29). Pituitary adenylate cyclase-activating polypeptide, which was a pivotal mediator in nitroglycerol-induced trigeminovascular activation and meningeal dilatation in mice, or meningeal ERK phosphorylation, are also potential novel targets for anti-migraine therapy (49; 81).
Carbon monoxide-induced headache. Carbon monoxide was previously considered to just be a toxic gas. Hypoxia was previously thought to be the sole mechanism behind carbon monoxide-induced headache, but carbon monoxide-induced headache may also appear after exposure to nontoxic doses. Interestingly, carbon monoxide is now known to be an important endogenously produced signaling molecule involved in multiple biological processes such as nociceptive processing or regulation of cerebral arterial tone.
However, some argue that nitroglycerin provocation in normal subjects is perhaps not an ideal human migraine model (74). 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 (75). A gap between animal and human study remains to be filled.
Perhaps the best known cause of substance-use headache is monosodium glutamate, which causes "Chinese restaurant headache." Publication of a placebo-controlled, double-blinded study has clearly established that monosodium glutamate is the cause of this syndrome (79). The syndrome, which consists of a triad of facial pressure, chest pain, and burning in the head and upper trunk, is now more correctly called the monosodium glutamate symptom complex, although another unrecognized substance may contribute to the syndrome (28). The headache may be migrainous, but a dull, nonthrobbing headache is sometimes reported. The latter might be characterized as a tension-type headache in a phenomenological sense, and this, in itself, exposes the lack of detailed work in this field. Some migraineurs develop intense, throbbing, unilateral or bilateral headaches 15 to 30 minutes after eating a food flavored with even a small amount of monosodium glutamate. The amounts of monosodium glutamate that produce headaches in susceptible migraineurs are generally insufficient to produce the complete Chinese restaurant headache. In a double-blinded, placebo-controlled, crossover study, systemic monosodium glutamate (MSG) (75 or 150 mg/kg) significantly increased headache and pericranial tenderness in comparison with placebo (NaCl 24 mg/kg) (04). In another study, 5 daily sessions of MSG intake (150 mg/kg) were also found to cause headache, elevation of salivary glutamate, and mechanical sensitization in masseter muscle (69). Whatever the headache, it seems monosodium glutamate avoidance is helpful in patients who report the association (68) and can be usefully recalled in pediatric practice in addition to aspartame in this group (53). A study demonstrated that monosodium glutamate could induce a dose-dependent swelling and death of mature neurons (12 to 14 days in culture), and it was postulated that this might partially account for the mechanism of its side effect (78). The study disclosed that addition of vitamin C or preexposure to low-dose monosodium glutamate could provide significant protection against monosodium glutamate-mediated toxicity, which deserves further exploration in vivo.
Carbon monoxide has long been recognized as a cause of headache (22) and can be an indication for hyperbaric treatment (30), as it may be seen after diving (10; 09). A carefully collected series showed that 71% (n = 100) of patients had dull pain, whereas only 41% reported throbbing (31). It was concluded that no specific phenotype for carbon monoxide-induced headache exists. The onset of the headache is usually masked by clouding of consciousness that is often associated with carbon monoxide inhalation. It settles rapidly with hyperbaric treatment (Goadsby, unpublished observations). A more insidious form of headache may be associated with pollution in cities and may be more directly related to nitrogen dioxide (56). A large-scale episode was reported after an ice storm (11). Attempts to reduce carbon monoxide by increasing methyl tertiary butyl ether in gasoline have not reduced headache and other symptoms (20). It is interesting that the classical symptoms of carbon monoxide toxicity can be reproduced in a situation of mass psychogenic illness (39). The management of carbon monoxide poisoning has been well reviewed (40). One report presents a comparison of a cohort of 38 male army recruits with 46 unexposed controls (37). Headache was seen in 87% of army recruits and 39% of controls. Headache was among the slowest symptoms to resolve. A comprehensive review summarized the potential mechanisms of carbon monoxide-induced headaches, which include hypoxia, nitric oxide signalling, cyclic guanosine monophosphate pathways, cerebral vasodilation, and oxidative stress pathways, amongst others (02). Carbon monoxide decreases the oxygen-carrying capacity and impairs oxygen release to the tissues so that during exogenous carbon monoxide exposure, tissues will eventually become hypoxic. Besides, carbon monoxide is also synthesized endogenously by the enzyme heme-oxygenase, which is widely expressed in important nociceptive structures of the peripheral nervous system such as trigeminal cells, sphenopalatine ganglion, and superior cervical and dorsal root ganglia, where carbon monoxide is likely to act as a nociceptive neurotransmitter. Other mechanisms include activation of cyclic guanosine monophosphate pathways, cerebral vasodilatation, interaction with nitric oxide, and oxidative stress (58).
Alcohol-induced headache. There is still no study of alcohol and headache that demonstrates which compound of alcohol beverages is responsible for triggering headaches. The alcohol in itself does not seem to be the main trigger for headache and compounds such as histamine, sulfites, tyrine, and tannins may contribute to headaches but are not able to provoke headache alone (13). Meningeal nociceptors activation through inflammatory/vasodilatatory mechanism is suggested to be responsible for migraine pain. Alcohol may have an action similar to other strong vasodilators such histamine, calcitonin gene-related peptide, and glyceryl trinitrate, which trigger migraine. However, disagreement between cranial vasodilatation and drug-provoked headache suggests that vasodilatation per se could not explain the induced headache. Moreover, acute intake of ethanol acts as a central nervous system depressant and at cortical level, alcohol is reported to reduce cortical excitability or facilitate the activity of cortical inhibitory circuits (60; 61).
Alcohol-induced headaches are classified into immediate or delayed alcohol-induced headache in the third edition (beta version) of the International Classification of Headache Disorders (Headache Classification Subcommittee of the International Headache Society 2013). Immediate alcohol-induced headache occurs within 3 hours of ingestion, which is much more rarely seen than the delayed type. Delayed alcohol-induced headache, also named hangover headache, occurs from 4 to 24 hours after the end of drinking. It can cause migraine-like symptoms, including unilateral throbbing pain with photophobia in migraineurs. This headache type is thought to be primarily related to substances other than alcohol (48) and may be determined by various phenolsulphotransferase phenotypes in susceptible individuals (66). Biogenic amines, sulphites, flavonoid phenols, 5-hydroxytryptamine mechanisms, and vasodilating effects have all been considered as possible contributing factors for alcohol-induced headache (60). In 1 animal study, it was demonstrated that acetate might be responsible for the hangover headache (51). One recent study demonstrated that the His allelic variant of alcohol dehydrogenase 2 (ADH2), Arg48His polymorphism, was associated with risks of migraine attack after alcohol consumption. In a Japanese study using facial flushing as a clinical surrogate of the presence of inactive ADH2, it was found that the sensitivity to alcohol may partly explain the alcohol consumption behaviors in headache patients (80). For example, male migraineurs, especially flushers, would avoid alcohol drinking more than men with tension-type headache or other headaches. Alcohol is frequently incriminated as a trigger for cluster headache (24). A genetic association study also disclosed that the carriage of the AA genotype of the rs1126671 polymorphism of the alcohol dehydrogenase 4 (ADH4) gene was associated with a significantly increased disease risk in comparison with remaining genotypes (OR = 2.33) (63).
Migraineurs and nonmigraineurs (and their physicians) hold strong views on chocolate. Two double-blind, placebo-controlled studies of chocolate in headache have been performed. There was no statistically significant association of chocolate ingestion with any form of headache in either study, although the clinical impression of an association continues to be reported (54; 25). Of interest is Peatfield's careful dissection of a possible association with sensitivity to cheese (62). This question requires larger blinded studies. By contrast, an animal study found that cocoa-enriched diets could enhance expression of phosphatases and decrease expression of inflammatory molecules in trigeminal ganglion neurons, suggesting a potentially beneficial effect of cocoa in migraine (08).
Other substances that have been associated with headache include the synthetic sweetener aspartame (07). Aspartame has been studied in a double-blind manner and shown not to produce headache (67), although the issue has been revisited. By selecting patients who self-report aspartame-related headache, a double-blind crossover study demonstrated susceptibility to headache in those patients who were "very sure" of the association prior to the study (76). A similar double-blind study has confirmed this susceptibility in those who recognize it (71). It seems prudent to advise such patients accordingly (53) while cases, such as those of chewing gum headache (06), continue to be reported.
Cocaine-induced headache. Acute cocaine administration blocks monoamine reuptake, inducing increased dopaminergic and serotoninergic activity with potent sympathomimetic effects and acute constriction of vascular smooth muscle (14). Chronic cocaine use is associated with a reduced dopamine D2 receptor binding potential and, consequently, with decreased dopamine transmission, related to a downregulation connected to dopaminergic pathway supersensitivity (77).
Histamine-induced headache. In vitro experiments have indicated that histamine may dilate primate cerebral arteries via an endothelial H1 receptor due to activation of endothelial nitric oxide synthase with subsequent formation of nitric oxide. 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 (44).
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 in initiating migraine attacks and supports the development of calcitonin gene-related peptide-based migraine treatment (03).
