Headache associated with acute substance use

Shih-Pin Chen MD PhD (Dr. Chen of the National Yang-Ming University School of Medicine has no relevant financial relationships to disclose.)
Shuu-Jiun Wang MD, editor. (

Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, received consulting fees from Eli Lilly, Daichi-Sankyo, and Novartis.

Originally released August 17, 1995; last updated March 1, 2018; expires March 1, 2021

This article includes discussion of alcohol-induced headache, substance-use 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 author updates 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, 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 (beta version) (2013).


• Nitric oxide is a crucial component in the pathophysiology of primary headache disorders.


• Headache attributed to monosodium glutamate might be associated with its dose-dependent neuronal toxicity.


• 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 (Headache Classification Committee of the International Headache Society 1988). The second edition of the classification revised section 8: headache attributed to a substance or its withdrawal (Headache Classification Committee of The International Headache Society 2004). 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 (Headache Classification Committee of the International Headache Society 2013). 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 review deals with section 8.1.1 (nitric oxide donor-induced headache), 8.1.3 (carbon monoxide-induced), 8.1.4 (alcohol-induced), 8.1.5 (food or additive-induced), and 8.1.13 (other substance-induced). Not covered are phosphodiesterase inhibitor-induced headaches (Kruuse et al 2003), histamine-induced headaches (Lassen et al 1995), calcitonin gene-related peptide-induced headaches (Lassen et al 2002), drug-overuse (illicit and prescribed) headaches, opioid-withdrawal headaches, medication overuse headaches, and hormone-induced headaches.

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