Caffeine as Headache Trigger and Treatment: Two Sides of the Same Coin

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While caffeine use and withdrawal are headache precipitators, caffeine can also be an effective headache treatment.
While caffeine use and withdrawal are headache precipitators, caffeine can also be an effective headache treatment.

The relationship between caffeine and headache is complex. Caffeine has been implicated as a trigger in multiple types of headache, including migraine and tension-type headache (TTH), and yet it is also effective as an adjuvant therapy to common analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Three factors need to be considered when looking at the influence of caffeine in headache:

  1. It is a purine alkaloid substance occurring natively in coffee and tea plants, frequently used in hot and cold beverages (including many non-cola sodas), and found in cocoa solids used in the making of chocolate;
  2. It is known to trigger rebound headaches, particularly migraine; and
  3. It is also effective when used properly to reduce pain from headache.

Mechanisms of Caffeine

As one of several nonselective adenosine receptor blockers, caffeine plays multiple roles in the mediation of central and peripheral pain. Caffeine is a competitive antagonist of the neurotransmitter adenosine on adenosine receptors that interacts with multiple enzymes, including acetylcholinesterase, monoamine oxidase, phosphodiesterase, and ryanodine receptors.1,2 In this capacity, caffeine is responsible for direct vasoconstriction of the blood vessels in the brain. Acute withdrawal of caffeine is likely to cause rebound vasodilation, producing a rebound headache that diminishes slowly over a 2-week washout period.3

In the cosmetics industry, commercially available topical formulations promoted for the reduction of cellulite often contain 3% caffeine, due to its effects on preventing excessive accumulation of fat in cells and stimulating the degradation of fats during lipolysis through inhibition of phosphodiesterase activity.4 Additional properties include potent antioxidant effects that help protect skin cells from ultraviolet radiation, slow down photoaging, and stimulate microvessels under the skin.4

OTC Use for Headache

An estimated 11% of people worldwide have migraine, while 40% experience tension-type headache (TTH).5 Over-the-counter (OTC) medications are widely used by 57% of people with migraine and more than 80% of those with TTH to treat their headache pain.5 The main reasons for choosing OTC medications are the significant cost savings over prescription medications, the lessened concern regarding potential adverse effects, and the availability of OTC agents without requiring an office visit with a clinician.

Caffeine has initial stimulant effects on blood pressure, heart rate, diuresis, adrenaline and noradrenaline levels, renin activity, and sleep that occur within the first few days of use and generally subside as tolerance develops.5 Overuse of caffeine can create a physical dependence with OTC medication use, particularly when used chronically and in combination with food, beverages, and other products containing caffeine.5 Caffeine withdrawal syndrome upon sudden discontinuation can lead to rebound headache, nausea, vomiting, and decreases in cognition in about half of people who use it chronically.5

Caffeine for Treatment of Tension-Type Headache

A 2014 pooled analysis by Diener et al6 of 4 identical randomized controlled trials found that in 6861 TTH episodes treated with OTC headache medications, including 2215 severe headache episodes, caffeine added to either aspirin or acetaminophen was effective, well tolerated, and significantly better than acetaminophen alone for episodic TTH.

Derry and colleagues6 compared the addition of caffeine (≥100 mg) to a standard dose of commonly used analgesics for pain from postoperative dental work, postpartum pain, and primary headache, identifying a small proportion of patients who experienced substantial pain relief. Most studies used paracetamol or ibuprofen with the addition of caffeine 100 mg to 130 mg. At doses of 100 mg or more, caffeine provided a small but significant benefit independent of type of pain and analgesic. Approximately 5% to 10% more participants achieved a level of pain relief deemed “good” (at least 50% of the pain peak over 4 to 6 hours).

Role of Caffeine in Migraine

Lipton and colleagues8 first established the efficacy of acetaminophen, aspirin, and caffeine at a dose of 130 mg (AAC-130) in 1220 patients with migraine in 3 parallel, double-blind, randomized, placebo-controlled trials conducted in 1998. Results of these trials showed that 21% of participants were pain free 2 hours after administration compared with 7% of participants receiving placebo, and 59% (vs 33% taking placebo) had pain reduction from severe or moderate to mild or none. At 6 hours, the percentage of patients who were pain free increased to 51% compared with 24% receiving placebo, while pain reduction improved in 79% receiving AAC-130 vs 52% receiving placebo.

Intravenous (IV) caffeine citrate has also been used in the emergency department for acute relief of severe migraine. A recent comparison by Baratloo et al9 indicated that IV caffeine citrate 60 mg was effective although slightly inferior to IV magnesium sulfate in the same setting.

Caffeine is also considered a trigger for migraine, and chronic caffeine consumption at high levels has been suggested as a contributing factor in chronic migraine, although this is yet unproven.3

Judicious use of caffeine as adjuvant therapy to OTC pain relievers can improve or relieve pain for patients with migraine and TTH. Although dosing has not been clearly established, some studies have suggested that a dosage of 130 mg/d may be the most therapeutically beneficial.5 However, careful attention must be paid to prevent overuse and dependence.


  1. Pohanka M. The perspective of caffeine and caffeine derived compounds in therapy. Bratisl Lek Listy. 2015;116(9):520-530.
  2. Pohanka M. The effects of caffeine on the cholinergic system. Mini Rev Med Chem. 2014(6);14:543-549.
  3. Lee MJ, Choi HA, Choi H, Chung CS. Caffeine discontinuation improves acute migraine treatment: a prospective clinic-based studyJ Headache Pain. 2016;17(1):71.
  4. Herman A, Herman AP. Caffeine's mechanisms of action and its cosmetic use. Skin Pharmacol Physiol. 2013;26(1):8-14.
  5. Lipton RB, Diener H-C, Robbins MS, Garas SY, Patel K. Caffeine in the management of patientswith headache. J Headache Pain. 2017;18(1):107.
  6. Diener H-C, Gold M, Hagen M. Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies. J Headache Pain. 2014;15(1):76.
  7. Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane Database Syst Rev. 2014;(12):CD009281.
  8. Lipton RB, Stewart WF, Ryan RE, Saper J, Silbrstein S, Sheftell F. Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain: three double-blind, randomized, placebo-controlled trials. Arch Neurol. 1998;55(2):210-217.
  9. Baratloo A, Mirbaha S, Delavar Kasmaej H, Payandemehr P, Elmaraezy A, Negida A. Intravenous caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a prospective quasi-experimental study. Korean J Pain. 2017;30(3):176-182.

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