Headache Associated with Acute Substance Use or Exposure

José M. Pereira Monteiro

Stewart Tepper

Robert E. Shapiro

INTRODUCTION

Since Hippocrates (460 B.C.) and Cornelius Celsus (25-50 A.D.), we have known of substances that are able to induce headaches, especially in susceptible persons. The substances involved are many: drugs, chemical products, alcoholic drinks, vapors, and others. Drugs are the most widely cited, and their effects have been studied the most thoroughly. The descriptions of headaches induced by substances are generally not very precise. The headaches are often generalized, persistent, and at times throbbing, and increase in intensity with increased dosage of substances.

In particular, as noted in the first edition of the International Classification of Headache Disorders (ICHD) (27), “migraineurs are physiologically and perhaps psychologically hyper-responsive to a variety of internal and external stimuli. Alcohol, food and food additives, chemical and drug ingestion … have all been reported to provoke or activate migraine in susceptible individuals.” Headaches attributed to substances reflect the chemical sensitivity of the headache-prone brain, and migraine is a state of hypersensitivity to physical and chemical exposures.

In evaluating patients with headaches related to substance exposures, the first question is whether the headaches are primary or secondary. The ICHD-II (28) gives qualitative guidance on this issue: when a preexisting headache disorder occurs in temporal relation to substance exposure, it may be coded as a primary or secondary headache. The factors in favor of secondary causation include close temporal association, marked worsening of pre-existing headache, “very good evidence” that the substance can aggravate the primary headache, and improvement of headache on termination of the substance.

EPIDEMIOLOGY

There are no population-based prospective epidemiologic data on the incidence of substance-induced headaches, but certain substances have been studied (4,23,62). The major study was the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring of 27 countries that gathered 10,506 reports of drug-induced headaches from 1972 to 1987. Of these headaches, 9733 were unclassified headaches, 611 were migraine-type headaches or worsening of a pre-existing migraine, and 162 were due to intracranial hypertension. The 10 most reported drugs associated with headaches were indomethacin, nifedipine, cimetidine, atenolol, trimethoprim-sulphamethoxazole, zimelidine, glyceryl trinitrate, isosorbide dinitrate, zomepirac, and ranitidine. The majority of the drugs were nonsteroidal antiinflammatory drugs (NSAIDs), peripheral vasodilators, calcium channel blockers, β-receptor blockers, histamine receptor blockers, or angiotensin-converting enzyme (ACE) inhibitors. Oral contraceptives were the most common cause of migraine. Other common precipitants of migraine-type headaches were atenolol, cimetidine, danazol, diclofenac, ethinylestradiol, indomethacin, nifedipine, and ranitidine. Tetracyclines, isotretinoin, and trimethoprim-sulphamethoxazole were the most frequently reported as causing intracranial hypertension (61,62,63).

PATHOPHYSIOLOGY

Substance-induced headache has variable mechanisms. Vasodilation is the oldest concept (77). Schumacher et al. (71) showed that intracranial vasodilation was responsible for headaches induced by histamine and that trigeminal
nerve section blocked the occurrence of histaminic headache but only along the trigeminal nerve. Dhuna et al. described noradrenergic alteration in vessel tone due to cocaine (14); however, the drugs most frequently implicated in the origin of headaches do not penetrate the blood-brain barrier. Toth speculated that “cocaine- and amphetamine-induced headaches may relate to a rapid cocaine surge, leading to a rapid block of presynaptic norepinephrine reuptake with potent sympathomimetic effects and acute vasoconstriction. Prolonged cocaine use may lead to secondary presynaptic serotonin depletion, leading to increased severity of headache with cocaine use” (83).

Headaches also occur in situations associated with cerebral edema, such as hypertensive encephalopathy (75,79) and mountain sickness (38). Drugs that cause some degree of cerebral edema and intracranial hypertension include beclomethasone, cimetidine, indomethacin, isotretinoin, monocycline, methylprednisolone, nalidixic acid, nitrofurantoin, prednisolone, tamoxifen, tetracycline, and trimethoprim-sulphamethoxazole (4,23).

However, NSAIDs, hormones, and other substances do not have vascular effects and do not cause cerebral edema. Since medications such as cimetidine, indomethacin, and ranitidine can cause headache, some substance-induced headaches may be the result of a primary cerebral neuronal action, possibly triggering a vascular reaction, which by its nature or intensity may bring on the headache. The possibility of substance-use headaches as a result of direct chemically mediated irritative effects on trigeminal afferents has also been suggested (23).

Toth speculated that “peripheral sensitization with altered neurotransmitter sensitivity may play a role, as central sensitization may occur due to certain substances” (83). Post and Silberstein noted that c-fos is immediately expressed after medication delivery, which may be a signal of altered pain modulation (65).

CAUSATION

Headaches can be induced by acute or delayed exposure to a substance, or from its withdrawal. The immediate headache is closely temporally related to the exposure, while the delayed headache occurs many hours to days after the immediate headache has resolved (Table 117-1).

A causal relationship between headache and acute use or exposure to a specific substance often is difficult to determine and requires well-conducted controlled studies.

It has been stated that “a diagnosis of Headache attributed to a substance usually becomes definite only when the headache resolves or greatly improves after termination of exposure to the substance.… The fact that these stimuli are associated with headache does not prove causation or eliminate the need to consider other aetiologies.… Because common events happen commonly, the association between a headache and an exposure to a substance may be mere coincidence. Headache can occur just on the basis of chance.” (62).

TABLE 117-1 2004 International Classification of Headache Disorders (ICHD-II) Classification of Headache Attributed to a Substance or Its Withdrawal

8.1 Headache induced by acute substance use or exposure
	8.1.1 Nitric oxide (NO) donor-induced headache
		8.1.1.1 Immediate NO donor-induced headache
		8.1.1.2 Delayed NO donor-induced headache
	8.1.2 Phosphodiesterase (PDE) inhibitor-induced headache
	8.1.3 Carbon monoxide-induced headache
	8.1.4 Alcohol-induced headache
		8.1.4.1 Immediate alcohol-induced headache
		8.1.4.2 Delayed alcohol-induced headache
	8.1.5 Headache induced by food components and additives
		8.1.5.1 Monosodium glutamate-induced headache
	8.1.6 Cocaine-induced headache
	8.1.7 Cannabis-induced headache
	8.1.8 Histamine-induced headache
		8.1.8.1 Immediate histamine-induced headache
		8.1.8.2 Delayed histamine-induced headache
	8.1.9 Calcitonin gene-related peptide (CGRP)-induced headache
		8.1.9.1 Immediate CGRP-induced headache
		8.1.9.2 Delayed CGRP-induced headache
	8.1.10 Headache as an acute adverse event attributed to medication used for other indications
	8.1.11 Headache induced by other acute substance use or exposure
8.2 Medication-overuse headache (not covered in this chapter)
8.3 Headache as an adverse event attributed to chronic medication (not covered in this chapter)
8.4 Headache attributed to substance withdrawal (not covered in this chapter)
From ref. 22: Giuseffi V, Michel W, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudo-tumor cerebri) a case-control study. Neurology 1991;41:239-244.

The ICHD-II lists the following as contributing to headache after acute exposure (28) (Table 117-2). Immediate acute substance-induced headaches (Table 117-3) and delayed substance-induced headaches (Table 117-4) often are different. Therefore, they are described separately.

TABLE 117-2 Substances Causing Headache After Acute Exposure

8.1.1 Nitric oxide (NO) donor (immediate and delayed)

8.1.2 Phosphodiesterase (PDE) inhibitor

8.1.3 Carbon monoxide

8.1.4 Alcohol (immediate and delayed)

8.1.5 Food components and additives (e.g., monosodium glutamate [MSG])

8.1.6 Cocaine

8.1.7 Cannabis

8.1.8 Histamine-induced (immediate and delayed)

8.1.9 Calcitonin gene-related peptide (CGRP) (immediate and delayed)

TABLE 117-3 Immediate Headaches Induced by Acute Substance Use or Exposure (8.1)

*IHS Diagnosis*	*8.1.1*	*8.1.2*	*8.1.3*	*8.1.4.1*	*8.1.5*	*8.1.6*	*8.1.7*	*8.1.8.1*	*8.1.9.1*
Headache-associated substance	NO donor	PDE inhibitors	Carbon monoxide	Alcohol	Food additives	Cocaine	Cannabis	Histamine	CGRP
Headache onset postexposure	Within 10 minutes	Within 5 hours	Within 12 hours	Within 3 hours	Within 12 hours (MSG 1 hour)	Within 1 hour	Within 12 hours	Within 10 minutes	Within 10 minutes
Headache resolution postexposure	Within 1 hour	Within 72 hours	Within 72 hours	Within 72 hours	Within 72 hours	Within 72 hours	Within 72 hours	Within 1 hour	Within 1 hour
Headache features	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Depends on extent of exposure	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Bilateral ▶Stabbing or pulsating ▶“Pressure”	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity
CGRP = calcitonin gene-related peptide; MSG, monosodium glutamate; NO, nitric oxide; PDE, phosphodiesterase. From ref. 22: Giuseffi V, Michel W, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudo-tumor cerebri) a case-control study. Neurology 1991;41:239-244.

TABLE 117-4 Delayed Headaches Induced by Acute Substance Use or Exposure

*IHS Diagnosis*	*8.1.1.2*	*8.1.4.2*	*8.1.8.2*	*8.1.9.2*
Headache-associated substance	NO donor	Alcohol	Histamine	CGRP
Headache onset postexposure	▶Migraineurs and tension-type HA: 5-6 hours ▶Cluster HA: 1-2 hours	After alcohol cleared from the blood	▶Migraineurs and tension-type HA: 5-6 hours ▶Cluster HA: 1-2 hours	▶Migraineurs and tension-type HA: 5-6 hours ▶Cluster HA: 1-2 hours
Headache resolution postexposure	Within 72 hours	Within 72 hours	Within 72 hours	Within 72 hours
Headache features	▶Migraineurs: migraine without aura ▶Tension-type HA: tension-type HA ▶Cluster HA: cluster HA	▶Bilateral ▶Frontotemporal ▶Pulsating ▶↑with activity	▶Migraineurs: migraine without aura ▶Tension-type HA: tension-type HA ▶Cluster HA: cluster HA	▶Migraineurs: migraine without aura ▶Tension-type HA: tension-type HA ▶Cluster HA: cluster HA
CGRP, calcitonin gene-related peptide; HA, headache.
From ref. 22: Giuseffi V, Michel W, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudo-tumor cerebri) a case-control study. Neurology 1991;41:239-244.

IMMEDIATE HEADACHES INDUCED BY SUBSTANCES

Nitric Oxide Donor

International Headache Society (IHS) code and diagnosis: 8.1.1.1 Immediate nitric oxide donor-induced headache

WHO code: G44.400

This type of headache includes those associated with the contact or use of nitroglycerine (NTG), (nitroglycerine headache or dynamite headache) and nitrates or nitrites (hot-dog headache).

Nitroglycerine

Nitroglycerine serves as a nitric oxide (NO) donor and its ingestion causes immediate headache in most people. The headaches are nonspecific and may be due to cyclic guanine monophosphate (cGMP) activation (74,82).

NTG was first recognized to induce headache after observing complaints of workers in factories manufacturing explosives (e.g., dynamite) (72). It was later noted that the minimum dose of NTG needed to bring on a headache could be rapidly reduced while simultaneously consuming alcohol (72). Also, migraine sufferers are known to be more susceptible to NTG, as are cluster headache sufferers during cluster episodes (16).

Nitrates and Nitrites

Some people describe variable intensity headaches minutes or hours after eating sausages or other cured meats and fish such as frankfurters, bacon, ham, salami, pepperoni, corned beef, pastrami, and lox. This type of headache has become known as the “hot-dog headache” and is related to the nitrates or nitrites that are added to foods for food coloring, to impart a cured flavor, and to prevent botulism (30). Nitrates normally become toxic only under conditions in which they are, or may be, reduced to nitrites (56). Toxicity of nitrites is due primarily to their interaction with blood pigment to produce methemoglobinemia (3).

Authorities limit the use of nitrites in cured meat (to 200 mg/kg), and the storing and cooking of the food further reduces the nitrite content (to 50 to 130 mg/kg) (30,56). Other substances in the same group, such as cyclandelate, dipyridamole, erythrityl tetranitrate, isosorbide dinitrate, mannitol hexanitrate, nimodipine, papaverine hydrochloride, pentaerythritol tetranitrate, tolazoline hydrochloride, and trolnitrate phosphate, can also bring on nitrite headaches, particularly in susceptible patients (56).

Immediate NO donor-induced headache diagnostic criteria (ICHD-II) are as follows:

A. Headache with at least one of the following characteristics and fulfilling criteria C and D:

1. Bilateral

2. Frontotemporal location

3. Pulsating quality

4. Aggravated by physical activity

B. Absorption of NO donor

C. Headache develops within 10 minutes after absorption of NO donor.

D. Headache resolves within 1 hour after release of NO has ended.

Phosphodiesterase Inhibitor

IHS code and diagnosis: 8.1.2 Phosphodiesterase (PDE) inhibitor-induced headache

WHO code: G44.40

PDE-induced headache is migrainous in quality, except for being bilateral, and monophasic in temporal sequence, unlike NO donor headache. PDEs are enzymes that metabolize cGMP and cyclic adenosine monophosphate (cAMP), and the erectile dysfunction medications such as sildenafil, vardenafil, and tadalafil are examples. They inhibit cGMP-specific PDE5, thereby increasing levels of cGMP. Since cGMP likely mediates the nonspecific immediate headaches post-NTG, and because PDE-induced headache is more common in migraine similar to NO-induced headache, it is plausible that PDE-induced headache is NO-mediated. According to prescribing information, headache occurs in between 11% and 15% of patients treated with tadalafil, and in 16% of sildenafil patients, compared to about 5% with placebo (64). PDE-induced headache occurs in 14% of migraine patients.

PDE inhibitor-induced headache diagnostic criteria (ICHD-II) are as follows:

A. Headache with at least one of the following characteristics and fulfilling criteria C and D:

1. Bilateral

2. Frontotemporal location

3. Pulsating quality

4. Aggravated by physical activity

B. A single dose of a PDE inhibitor has been given.

C. Headache develops within 5 hours of PDE inhibitor intake.

D. Headache resolves within 72 hours.

Carbon Monoxide

IHS code and diagnosis: 8.1.3 Carbon monoxide-induced headache

WHO code: G44.401

Previously used term: warehouse workers’ headache

Headache caused by carbon monoxide (CO) is often a dull, continuous bilateral discomfort, with character and intensity related to the severity of CO intoxication (Table 117-5). Slight headache or dizziness may occur in heavy smokers or those using gas for cooking food or exposed to car exhaustion (29,50,55,86,88).

CO-induced headache diagnostic criteria (ICHD-II) are as follows:

A. Bilateral and/or continuous headache, with quality and intensity that may be related to severity of carbon monoxide intoxication, fulfilling criteria C and D.

B. Exposure to CO.

C. Headache develops within 12 hours of exposure

D. Headache resolves within 72 hours after elimination of CO.

Alcohol

IHS code and diagnosis: 8.1.4.1 Immediate alcohol-induced headache

TABLE 117-5 Relationship Between Carbon Monoxide (CO) Blood Levels, Headache Type and Severity, and Emergence of Associated Symptoms

*CO level (%)*	*Headache Type and Severity*	*Associated Symptoms*
10-20	Dull, mild	None
>20-30	Moderate, pounding	Irritability
>30-40	Severe, pounding	Nausea, vomiting, blurred vision
>40-50		Confusion
>50-60		Coma
80		Death
CO, Carbon monoxide.
From ref. 22: Giuseffi V, Michel W, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudo-tumor cerebri) a case-control study. Neurology 1991;41:239-244.