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  • Updated 12.03.2019
  • Released 08.17.1995
  • Expires For CME 12.03.2022

Headache associated with acute substance use or exposure


This article includes discussion of headache associated with acute substance use or exposure, headache associated with acute substance use, substance-use headache, nitric oxide (NO) donor-induced headache, phosphodiesterase (PDE) inhibitor-induced headache, carbon monoxide (CO)-induced headache, cocaine-induced headache, histamine-induced headache, calcitonin gene-related peptide (CGRP)-induced headache, alcohol-induced headache, carbon monoxide-induced headache, Chinese restaurant headache, hot dog headache, monosodium glutamate-induced headache, and nitrate-induced headache. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Substance headache is a headache that develops de novo with the use or exposure of a substance. The clinical manifestations of substance-induced headache are variable. In this article, the authors update the current evidence regarding the clinical manifestations and pathophysiology of headache associated with the acute use or exposure of certain substances, with specific focus on nitric oxide donor, and carbon monoxide and calcitonin gene-related peptide, which provides a better understanding of headache biology.

Key points

• The clinical manifestations of headache associated with the use or exposure of substances are variable.

• Headache attributed to substances is currently placed under Section 8 of the International Classification of Headache Disorders, 3rd edition (2018).

• Nitric oxide and calcitonin gene-related peptides are crucial components in the pathophysiology of primary headache disorders and they have been used to experimentally trigger headache attacks.

• Headache is the most common symptom among individuals with symptomatic carbon monoxide exposure. Headache attributed to monosodium glutamate might be associated with its dose-dependent neuronal toxicity.

• Alcohol, cocaine, and histamine can cause immediate headache after exposure and delayed headache in predisposed individuals. Subjects vulnerable to alcohol-induced migraine or cluster headache could have a genetic predisposition.

Historical note and terminology

The codification of headache diagnosis by the International Headache Society in 1988 had a considerable impact on the study and understanding of headache (32). The second edition of the classification revised section 8: headache attributed to a substance or its withdrawal (33). The committee took the view that if a headache develops de novo with the use of a substance, it should be coded as being secondary to that substance; however, if the sufferer has already had the headache type and it is triggered by the substance, “judgment is required,” and it may be classified as the primary headache type. In the third edition (beta version) of the International Classification of Headache Disorders, the definition was slightly modified (35). When a headache occurs de novo in close temporal relation to exposure of a substance, it remains true to code, the headache as a secondary headache attributed to exposure to that substance. However, when there is a pre-existing headache with characteristics of a primary headache disorder and that headache becomes chronic or significantly worse in close temporal relation to exposure to a substance, both the initial headache diagnosis and a diagnosis of “Headache attributed to a substance” should be given.

This article deals with section 8.1 headache attributed to use of or exposure to a substance of the IHCD-3 and includes discussion about clinical manifestations and pathophysiological mechanisms of: 8.1.1 nitric oxide (NO) donor-induced headache, 8.1.2 phosphodiesterase (PDE) inhibitor-induced headache, 8.1.3 carbon monoxide (CO)-induced headache, 8.1.4 alcohol-induced headache, 8.1.5 cocaine-induced headache, 8.1.6 histamine-induced headache, and 8.1.7 calcitonin gene-related peptide (CGRP)-induced headache. In this review we do not cover headache attributed to exogenous acute pressor agent, nonheadache medication or other substance, medication overuse headache, or headache attributed to substance withdrawal.

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