Caffeine is an antagonist of adenosine A1, A2A and A2B receptors, which are localized at multiple sites such as the spinal cord, the thalamus and other supraspinal site. Its analgesic properties seem to be mainly based on interaction with these receptors. In higher concentrations, which normally cannot be reached through normal dietary intake, further pharmacological actions can be triggered such as inhibition of phosphodiesterase, Ca2+ release and block of GABAA receptors.
Caffeine as an antagonist of adenosine is known to have a major influence on sleep from daily experience. Adenosine is a purine nucleoside that is localized in all cells [34]. It is a key signaling molecule for sleep induction and interacts mainly with the cerebral adenosine A2A receptor. (Holle & Obermann, 2012)
Chronic consumption of caffeine promotes a pro-nociceptive state of cortical hyperexcitability that can intensify a primary headache or trigger a headache. (Espinosa et al, 2017)
Caffeinated headache medications, either alone or in combination with other treatments, are widely used by patients with headache. Compared with analgesic medication alone, combinations of caffeine with analgesic medications, including acetaminophen, acetylsalicylic acid, and ibuprofen, showed significantly improved efficacy in the treatment of patients with TTH or migraine, with favorable tolerability in the vast majority of patients. (Lipton et al, 2017)
Caffeine overuse may lead to migraine chronification, and sudden caffeine withdrawal may trigger migraine attacks. Migraine sufferers should be aware of the amount of caffeine they consume and not exceed 200 mg daily. (Nowaczewska et al, 2020)
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