Alcohol-Induced Headache: A Narrative Review Based on Migraine Pathophysiology

1. Immediate alcohol-induced headache (International Classification of Headache Disorders, 3rd edition code 8.1.4.1)

Immediate AIH, also referred to as “cocktail headache,” is defined by the ICHD-3 diagnostic criteria shown in Table 1.7 This headache can occur rapidly, within 3 hours, even after small amounts of alcohol (e.g., one or two glasses of wine). The pain is typically bilateral and pulsating and is aggravated by physical activity. Affected individuals often prefer to lie down, a behavior that may reflect difficulty maintaining cerebral perfusion pressure secondary to alcohol-induced cerebral vasodilation.14

Table 1.

ICHD-3 criteria for immediate alcohol-induced headache (8.1.4.1)

2. Delayed alcohol-induced headache (International Classification of Headache Disorders, 3rd edition code 8.1.4.2)

Delayed AIH, commonly referred to as “alcohol hangover headache,” develops 5–12 hours after heavy alcohol consumption and is defined by the ICHD-3 criteria summarized in Table 2.7 Duration and severity of headache may correlate with the amount of alcohol intake.15 Patients with delayed AIH also frequently report orthostatic headaches. In contrast to immediate AIH, delayed AIH occurs as part of a broader hangover syndrome and is accompanied by a cluster of autonomic, gastrointestinal, sleep-related, and cognitive symptoms.16 A characteristic feature of delayed AIH typically emerges when blood alcohol concentration (BAC) is declining or has returned to near zero (Figure 1).17 Experimental studies suggest that a peak BAC of at least 0.1% is generally required for a clinically relevant hangover to occur.18 According to Widmark’s equation,19 this corresponds approximately to the BAC reached 90 minutes after a 60-kg adult consumes one bottle of soju.

Table 2.

ICHD-3 criteria for delayed alcohol-induced headache (8.1.4.2)

Figure 1.

Schematic illustration of the temporal characteristics of alcohol-induced headache based on blood alcohol concentration.

The time-based distinction between immediate and delayed AIH in ICHD-3 is primarily operational and reflects consistent clinical observations rather than established mechanistic thresholds. To date, no definitive physiological evidence has validated a specific biological boundary underlying the 3-hour versus 5–12-hour cut-offs, and this classification should be interpreted as a pragmatic framework for clinical and research purposes.

3. Distinguishing alcohol-triggered migraine from alcohol-induced headache

According to a cohort study in Korea, alcohol consumption was associated with an odds ratio (OR) of 2.5 for attack occurrence in episodic migraine.20 However, as discussed above, the current ICHD-3 framework does not clearly distinguish alcohol-triggered migraine from AIH in individuals with migraine. When patients present with recurrent headaches following alcohol consumption, we suggest that diagnosis should simultaneously consider temporal profile, headache phenotype, and individual susceptibility (Table 3). The most critical factor is whether the patient’s habitual migraine phenotype is faithfully reproduced after alcohol intake. This includes classical migraine features such as unilateral pain, nausea or vomiting, photophobia, and phonophobia. If these features are present, the headache should be classified as alcohol-triggered migraine. Conversely, when headache is accompanied by symptoms commonly associated with hangover, such as thirst, impaired concentration, apathy, diarrhea, anorexia, and autonomic symptoms, it should be classified as delayed AIH. However, despite this approach, many patients may exhibit overlapping or inconsistent clinical phenotypes. In such cases, we recommend assigning alcohol-triggered migraine as the primary diagnosis for clinical practicality, while interpreting non-headache symptoms and residual complaints as part of the hangover spectrum.

Table 3.

Clinical characteristics of alcohol-related headaches

1. Central mechanisms: trigeminovascular activation and calcitonin gene-related peptide signaling

AIH was historically attributed primarily to peripheral vasodilation.34 However, accumulating evidence now indicates that activation of the trigeminovascular system and enhanced CGRP signaling represent central mechanisms directly linked to migraine pathophysiology.13,35,36 Migraine pain originates from activation of trigeminal afferents innervating the meninges and perivascular structures.37,38 Following alcohol consumption, ethanol is metabolized to acetaldehyde, which directly stimulates this system and activates trigeminal afferents.

Experimental animal models have demonstrated that gastrointestinal administration of alcohol activates members of the transient receptor potential (TRP) ion channel family, including transient receptor potential cation channel subfamily V member 1 (TRPV1) and Transient receptor potential cation channel, subfamily A, member 1 (TRPA1), leading to increased CGRP release.14,32 CGRP released from trigeminal nerve terminals acts on neurons and satellite glial cells within the trigeminal ganglion, promoting peripheral sensitization, while simultaneously activating second-order nociceptive neurons in the brainstem to induce central sensitization.37 These mechanisms provide a biological explanation for why AIH frequently manifests not only as pain but also with migraine-like extracranial features such as cutaneous allodynia and photophobia.32,39 Notably, these alcohol-induced effects are attenuated by CGRP antagonists, such as olcegepant, or by silencing receptor activity–modifying protein 1, a key component of the CGRP receptor complex, in animal model.32 Together, these findings suggest that anti-CGRP therapies may be effective in suppressing the clinical expression of AIH.

2. Peripheral mechanisms: nitric oxide signaling, vascular reactivity, and inflammation

Both animal and human studies consistently demonstrate that alcohol induces complex and bidirectional changes in NO signaling.12,39,40 Acute or low-dose alcohol exposure activates endothelial NO synthase, resulting in increased NO production and vasodilation. NO promotes cerebral blood flow while activating cyclic guanosine monophosphate signaling pathways that facilitate CGRP release from trigeminal nerve terminals.37 In contrast, chronic exposure to high-dose alcohol leads to depletion of NO bioavailability and antioxidant defenses through oxidative stress.12,33 Although this mechanism contributes to hypertension in chronic alcoholism, it may also offer insight into the paradoxically lower headache frequency reported in long-term heavy drinkers. Importantly, the delayed nature of NO-induced headache provides a plausible explanation for why delayed AIH is not strictly dose dependent and why headache frequently emerges during the declining phase of BAC.41

In parallel, alcohol consumption elicits systemic and central inflammatory responses. Elevated levels of cytokines, including interleukin-10, interleukin-12, and interferon-γ, as well as increased prostaglandin production, have been consistently observed during alcohol hangover.16,42 These inflammatory mediators are related to headache, nausea, and malaise and overlap substantially with pathways implicated in migraine-related neuroinflammation.43

3. Metabolic and behavioral modifiers

The metabolic consequences of alcohol consumption are broad and help explain why certain individuals are particularly prone to migraine. Alcohol increases the production of reactive oxygen species and reactive nitrogen species, inducing oxidative stress within the trigeminovascular system.44,45 This mechanism is well recognized in alcohol-related cardiovascular disease and may also be relevant to migraine biology. In migraine, thiobarbituric acid–reactive substances have been proposed as potential biomarkers, and preliminary studies suggesting therapeutic effects of antioxidants support a shared oxidative stress pathway linking AIH and migraine.44,46 Alcohol also inhibits diamine oxidase, the primary enzyme responsible for histamine degradation, thereby increasing endogenous histamine levels.47 Elevated histamine exerts vasodilatory effects and represents another potential mechanism contributing to migraine susceptibility following alcohol intake.43

Furthermore, alcohol disrupts sleep architecture and increases sleep fragmentation, while also elevating next-day anxiety levels.48,49 These behavioral and neuropsychological effects may lower the migraine threshold and place susceptible individuals in a state that favors headache generation.

1. Current evidence

To date, no clinical trial has specifically evaluated AIH as a primary outcome. Instead, most interventional studies have focused on the prevention or treatment of alcohol hangover as a broader syndrome.50 Based on randomized controlled trials, the following agents have demonstrated some efficacy in reducing hangover symptoms: clovinol,51 tolfenamic acid,52 pyritinol,53 Hovenia dulcis extract,54 L-cysteine combined with vitamins B and C,55 red ginseng,56 Korean pear juice,57 and HK-GCM-H01.58 Notably, four of these eight agents were evaluated in studies conducted in Korea. These compounds have been proposed to act through anti-inflammatory or prostaglandin-related pathways, or through antioxidant and metabolic mechanisms.50 In contrast, medications commonly considered anti-migraine agents, such as naproxen or propranolol,59,60 have not demonstrated benefit.

However, important limitations prevent us from extrapolating these findings directly to AIH. A 2022 systematic review of seven of the eight agents listed above found that all randomized trials were rated as having “very low quality” according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.50 This was largely due to small sample sizes and substantial selection bias.

A more fundamental limitation lies in the heterogeneity of hangover definitions and outcome measures. Most studies assessed hangover severity using composite scores derived from multiple symptoms, such as fatigue, thirst, sweating, and headache. These scales were often investigator-developed, insufficiently validated, and remain controversial in the literature.61 No single agent improved all symptom domains. Headache severity was usually evaluated using binary outcomes or simple numeric rating scales. These methodological issues substantially limit the applicability of existing hangover trials to AIH.

2. Interface with migraine treatment and the potential role of calcitonin gene-related peptide-pathway–based therapies

In clinical practice, when alcohol-triggered migraine is suspected, standard acute migraine treatments, such as triptans, are frequently used and appear effective. Most established acute migraine therapies can be considered in this setting, and there is currently no evidence suggesting clinically relevant drug–alcohol interactions for triptans.

In patients who experience migraine attacks with high probability following alcohol consumption, a strategy of mini-prophylaxis may be considered. For example, administration of a long-acting triptan, such as frovatriptan, at bedtime after alcohol intake may be conceptually analogous to mini-prophylaxis used for menstrual migraine.62 More recently, Lipton and colleagues63 introduced the concept of “situational prevention,” in which imegepant is used for prophylactic purpose during periods with increased risk of migraine attacks. AIH is a prototypical example of such a high-risk situation, in which pharmacological prevention may be considered in the setting of anticipated alcohol exposure, such as wine consumption during travel.

Although current evidence remains limited, CGRP-targeted therapies represent the most biologically plausible candidate for AIH prevention from a migraine-based perspective.13 Rimegepant, a CGRP receptor antagonist with both acute and preventive indications, is particularly attractive, as it may theoretically provide benefit in alcohol-triggered migraine as well as in immediate and delayed AIH.64 Nevertheless, important safety considerations remain. While imegepant has demonstrated minimal hepatotoxicity with short-term use,65 its safety profile when administered in the context of recent alcohol consumption, including repeated or situational use, remains insufficiently studied.

3. Key considerations for future clinical trials of calcitonin gene-related peptide antagonists in alcohol-induced headache

Several methodological issues must be addressed in future trials evaluating CGRP antagonists for the prevention or treatment of AIH. First, reproducibility of AIH must be ensured. AIH exhibits marked interindividual variability, and even within the same individual, identical alcohol exposure may or may not result in headache. A randomized, crossover trial design would therefore be optimal to control for this variability. Second, phenotypes of AIH should be clearly distinguished rather than pooled. For example, trials should separately evaluate migraineurs with reproducible alcohol-triggered migraine and non-migraineurs with reproducible delayed AIH. Third, alcohol exposure must be standardized. Target exposure should be defined by BAC rather than by beverage volume alone, for example aiming for a peak BAC of ≥0.1%. Verification can be achieved using breath analyzers or blood sampling. Fourth, confounding hangover-related factors, including sleep quality, mood, gastrointestinal symptoms, and hydration status, should also be measured and controlled. Finally, ethical considerations exist. Investigators must carefully assess whether study designs inadvertently encourage alcohol consumption and must adhere strictly to institutional review board standards regarding participant safety.