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Editor: Patrick M. Zito Updated: 11/12/2023 10:12:42 PM


The FDA recognized the combination of acetylsalicylic acid (250 mg), acetaminophen (250 mg), and caffeine (65 mg) as safe and effective in treating acute headaches, especially migraine, and was considered effective also by the American Headache Society.[1][2] This combination is well-tolerated in episodic tension-type headaches and is considered superior to acetaminophen monotherapy.[3] All components of this combination are considered safe during breastfeeding and can be taken orally for acute migraine attacks.[4][5]

This combination may have other benefits according to the components.


Caffeine is legal, cheap, and not regulated in almost all parts of the world; it can be found as over-the-counter (OTC) medication or in other sources such as coffee, tea, sodas, gum, and candy.


Besides migraines and tension-type headaches, caffeine is considered effective for other types of headaches, like post-dural puncture headaches and hypnic headaches, which can present with cranial autonomic features.

Clinical studies showed that caffeine citrate (intravenous [IV]) might be used alone in acute migraine attacks, but it might be inferior to magnesium sulfate (IV) in moderate-to-severe migraines. Early administration of ergotamine/caffeine compounds may also be effective.

A clinical study showed that discontinuing caffeine before a migraine attack can increase the efficacy of acute treatment.

Physical performance

Caffeine improved high-intensity exercise tolerance with less fatigue but no change in power. Therefore, athletes use it as an ergogenic aid to increase physical performance.


Adding 100 mg or more caffeine to a standard dose of commonly used analgesics provides a small but significant increase in pain relief in postoperative procedures[6]. Adding 100 mg of caffeine to 400 mg of ibuprofen demonstrated more efficacy than ibuprofen alone following dental extraction. A study also showed that introducing caffeine after general anesthesia enhanced the recovery from the anesthesia, but further studies are needed.

Premature babies

Caffeine has a significant role in treating and preventing further damage in premature babies younger than 32 weeks and with very low birth weight (500 to 1250 g). Caffeine is used as therapy for apnea of prematurity, decreases the risk of developing bronchopulmonary dysplasia, and decreases brain damage in hypoxic brain injury. Furthermore, the drug has a role in reducing the rate of patent ductus arteriosus requiring treatment and decreases the likelihood of discharging home with oxygen. Caffeine can help shorten the time of mechanical ventilation in premature babies who develop acute respiratory distress syndrome, which may reduce the risk of lung injury. Other clinical studies showed decreases in bilirubin neurotoxicity after introducing caffeine to rats.

Habitual caffeine consumption may demonstrate benefits in other fields, such as neurodegenerative disorders, dementia in Alzheimer disease, and Parkinson disease, and improve neurobehavioral performance without changing the subjective assessment of sleepiness and fatigue.


Acetaminophen, or paracetamol, is the most commonly used analgesic and antipyretic drug worldwide. The drug may be used without a prescription and is the drug of choice in patients who cannot have treatment with non-steroidal anti-inflammatory drugs (NSAIDs) as well as those patients with bronchial asthma, peptic ulcer disease, hemophilia, salicylate-sensitized people, children under 12 years of age, and pregnant or breastfeeding women.

Acetaminophen is used alone or combined with other medications to treat acute primary headaches; it is combined with aspirin and caffeine for migraine, tension-type headaches, and tramadol for cluster headaches.

Other uses 

  • First-line treatment for pain associated with osteoarthritis 
  • Chronic pain (safer to use than opioids)
  • APAP may be used orally to close the patent ductus arteriosus by decreasing prostacyclin synthesis without peripheral vasoconstrictive effect in infants with contraindications to NSAIDs

Some studies showed the association of acetaminophen use with:

  • Inhibition of cell proliferation in pancreatic cancer cells when used with metamizole
  • When used orally is more effective than deferoxamine injections in the treatment of iron overload and associated cardiac complications
  • Improve the healing of the tendon in tendinopathy when combined with NO by decreasing the water content and enhancing the collagen content of the injured tendon

Acetylsalicylic Acid

Acetylsalicylic Acid, aspirin, is metabolized into salicylic acid (SA) and used at doses of less than or equal to 325 mg per day to reduce the risk of cardiovascular events, whereas it is used at higher doses (500 to 1000 mg as a single dose and 3000 to 4000 mg per day) to reduce pain, fever, and inflammation.

Used alone or combined with other drugs, aspirin 500 to 1000 mg is a first-line therapy for moderate to severe primary headaches. ASA may be combined with ibuprofen 400 mg for a tension-type headache or metoclopramide 10 mg for acute migraines. It may also be used as a prophylactic treatment of migraine with aura.

Intravenous aspirin administration for inpatient management of a headache is considered safe, effective, and useful, and in migraine headaches, it is considered superior to sumatriptan with minor possible adverse effects.

Acetylsalicylic acid is contraindicated in children under the age of 12 because of the risk of Reye syndrome, except in Kawasaki disease, when used with intravenous immunoglobulin.

Aspirin is used as an antiplatelet drug at lower doses (75 to 325 mg) to reduce cardiovascular events in high-risk patients.

The drug has anti-inflammatory properties. Therefore, aspirin can be used in an exercise-induced inflammatory response, chronic pain, or inflammation-induced cancers. Other studies showed an association between the use of aspirin with a preventive and therapeutic role in the following cancers:

  • Breast cancer
  • Esophageal adenocarcinoma
  • Colorectal cancer
  • Pancreatic cancer
  • Glioma
  • Mesothelioma

Aspirin has been used to decrease the nocturnal pain in osteoid osteoma. Aspirin may have a neuroprotective role in peripheral nerve injuries and Alzheimer disease.

Mechanism of Action

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Mechanism of Action

The mechanism of action of this combination is from the accumulation of the components' effects; each component has a different mechanism of action.[7][8]


Caffeine has anti-oxidant, anti-inflammatory, anticholinesterase, and anti-TLR-4 properties. Studies on rats showed that these properties play an essential role in sleep deprivation-induced inflammatory response and anxious behavior.

Caffeine is a methylxanthine that antagonizes adenosine receptors (eg, A1, A2A, A2B, and A3) non-selectively. These receptors appear in high concentrations in the nucleus accumbens, which modulates behavioral activation and effort-based-decision making. This effect may modulate the work effort of those who are not intrinsically motivated, although there are individual differences in the energizing effects of caffeine.

A clinical study showed that antagonizing the adenosine receptor (A2A) can reverse the behavioral effect of dopamine (D2) antagonists (eg, haloperidol). Another clinical study showed mild, partial reversal effects on the D1 antagonist. These findings can have implications for treating psychiatric symptoms (psychomotor slowing and fatigue) that are observable in depressed patients.

Continued caffeine consumption does not lead to consistent changes in the functional availability of cerebral adenosine receptor A1.

Caffeine reduces the cerebral blood flow in the brain but with an increase in brain entropy, which reflects the information processing capacity, especially in the lateral prefrontal cortex. Caffeine also increases the oxygen extraction fraction as compensation for reducing cerebral blood flow, and no significant changes occur in the whole brain's cerebral metabolic rate of oxygen or electrical brain activity. Researchers noticed variations in the change of cerebral blood flow between the regions of the brain. The decrease in cerebral blood flow was smaller in the posterior cingulate cortex and superior temporal region, whereas it was more significant in the dorsolateral prefrontal cortex and medial frontal cortex.

One may conclude that caffeine's effect on vasculature may be region-specific and can result from the spatial distribution of the adenosine receptors. Another study showed that caffeine might stimulate ketone production as an alternative fuel for the brain during decreased concentrations of glucose (aging or Alzheimer disease), but the ketogenic effect or the effect on medium-chain triglycerides is still unknown. Caffeine can affect the quality of sleep and increase performance in sleep deprivation. EEG showed that it reduces slow-wave sleep and slow-wave activities, increasing stage-1 wakefulness and arousal.

Caffeine down-regulates the calmodulin-dependent protein kinase II (CaMKII) and phosphorylated and total CREB (cAMP response element-binding protein). This association plays a vital role in learning and memory. A clinical study on mice showed that caffeine reduces amyloid-beta concentrations in the brain, which accumulate during Alzheimer disease.

Caffeine metabolism is affected by many factors (age, gender, hormones, liver disease, obesity, smoking, and diet). CYP1A2 isoform of cytochrome P450 mainly metabolizes the drug. Polymorphism at the level of this isoform explains the variability of pharmacokinetics among individuals. Research has located several loci involved in caffeine consumption, which affect sleep, anxiety, and neurodegenerative/psychiatric disorders.

Caffeine as therapy can be taken intravenously (IV) or orally.


Acetaminophen inhibits central and may weakly inhibit peripheral cyclooxygenase (COX), strongly inhibits prostacyclin synthesis, and increases nitric oxide (NO) synthesis. However, NO synthesis is not affected at pharmacologically relevant concentrations. There is experimental evidence that acetaminophen inhibits cyclooxygenase-3 in the CNS, accounting for its analgesic and antipyretic effects while explaining its lack of anti-inflammatory effects in the periphery.

A study showed that caffeine induces faster absorption and prolonged half-life of acetaminophen, and this effect is profound in hepatic patients.

At the genetic level, acetaminophen increases the expression of the gene GRIN2C, which encodes the N-methyl-D-aspartate receptor 2C subunit.


Aspirin is a non-steroidal anti-inflammatory drug (NSAID) that irreversibly inhibits cyclooxygenase-1 and 2 (COX-1 and COX-2), thus suppressing prostaglandin E2. Aspirin stimulates the regulatory braking signals such as lipoxin, resulting in decreased concentrations of:

  • C-reactive protein
  • Tumor necrosis factor-alpha
  • IL-6

However, the concentrations of regulatory cytokines (IL-4 and IL-10) will not decrease; TGF-beta is a possible target for acetylsalicylic acid.

Chronic, high-dose aspirin intake inhibited the terminal differentiation of dendritic cells. This inhibition is observable by the suppressed levels of CD83 and the secreted p40 unit of IL-12, which are markers of mature dendritic cells.

Analgesic effects of aspirin were found in primary and secondary somatosensory cortices and anterior parts of the anterior cingulate cortex, whereas the antihyperalgesic effects mainly appeared in the primary somatosensory area, parietal association cortices and anterior portions of the anterior cingulate cortex. Aspirin attenuated glutamate, which may play a role in its neuroprotective effect.

Aspirin's protective effects on tumors and inflammation may be demonstrated by inhibiting mTOR, which leads to an inhibitory effect on tumor angiogenesis. Also, the drug is biotransformed into salicylic acid, which binds to human high mobility group box1 (HMGB1), which is an inflammatory molecule.


Acetaminophen/aspirin/caffeine is available in an oral tablet of 250 mg/250 mg/65 mg, respectively. This dose form is available OTC. The typical dosage is 2 tablets orally once every 24 hours as needed for migraine headaches. Do not exceed 1 g/h or 4g/day acetaminophen.

Special Populations

Renal impairment: For patients with CrCl <10, consider alternatives, although dose adjustment is not possible with the fixed-dose combination.

Hepatic impairment: Consider decreasing the dose based on acetaminophen.

Pregnancy considerations: Acetaminophen is the pain reliever and antipyretic of choice during pregnancy. No known risk of fetal harm is known. Aspirin may be used in low doses during pregnancy. Weigh the risks and benefits of full-dose aspirin at 20 to 29 weeks gestation and avoid full-dose aspirin after 30 weeks gestation. Caffeine may be used during pregnancy with no known risk of fetal harm. A possible risk to the fetus has been observed at dosages greater than 200 mg daily.

Breastfeeding considerations: Acetaminophen is a pain reliever and antipyretic of choice while breastfeeding. No known risk of fetal harm based on human data is known. Aspirin may be used in low doses during pregnancy. Avoid full-dose aspirin when breastfeeding. Caffeine may be consumed when breastfeeding. Monitor infants during high-dose or long-term use.

Pediatric considerations: This medication is not recommended for children younger than 12.

Older patients: Adjust dosage per hepatic and renal parameters if necessary.

Adverse Effects


A double-blinded, randomized, and placebo-controlled trial in 13 academic hospitals in 4 countries showed that caffeine did not affect general intelligence, attention, and behavior and was safe for use.[9][10]

As a treatment for acute primary headaches, patients may develop several adverse effects:

  • Nervousness
  • Nausea
  • Abdominal pain/discomfort
  • Dizziness[11]

Nervousness was the most frequently reported adverse effect.

Although caffeine is an acute treatment for migraine pain, it is a known trigger for migraines. One clinical study on mice showed that acute and chronic effects of caffeine could potentially be an underlying reason for the aura of a migraine, and another study showed that patients who take aspirin and caffeine experience headaches more than patients who take aspirin only.

Studies showed that caffeine use has a neutral effect on hypertension and heart failure, but further studies are needed to determine the association with arrhythmias.

Sleep and Habitual Use

Habitual daily use of caffeine may cause other adverse effects, such as the following:

  • Daytime sleepiness and worsening sleep quality
  • Osteopenia in infants may lead to spontaneous rib fracture and increased risk of fracture in women
  • Increasing the risk of low birth weight and pre-term labor when used in pregnant women
  • Worsening the symptoms of restless leg syndrome and physiological tremor
  • Physical and emotional dependence, which may cause a withdrawal syndrome (flu-like symptoms, low alertness, mood distributions, reduced motivation to work, nausea, and headache); in one study, withdrawal syndrome caused reversible cerebral vasoconstriction syndrome (presented with thunderclap-headache).


  • A medication-overuse headache: Incapacitating headache from the chronic, daily treatment with acetaminophen increases the excitability of the neurons of the amygdala and may cause anxiety along with a headache, although it may result from the overuse of other migraine treatments and may be associated with insomnia, non-restorative sleep, and psychological distress.
  • Nephropathy: APAP may cause allergic tubular interstitial nephritis, and an association with chronic kidney disease is suspected.
  • A study showed that prolonged use might correlate with metabolic acidosis with an increased anion gap.
  • When used at high doses, it appears to change semen quality (morphology) by suppressing testosterone synthesis and provoking apoptosis of spermatocytes.
  • Acetaminophen is considered safe for use in pregnancy, although some studies showed an association with ADHD with long-term use even after adjusting the other risk factors.
  • Reduction of primordial follicles, irregular menstrual cycle, the premature absence of corpus luteum, and reduced fertility in female offspring to acetaminophen-exposed mothers
  • Liver damage
  • Renal damage

Acetylsalicylic Acid/Aspirin

Aspirin is associated with Reye syndrome when used in children younger than age 12. The syndrome presents with different degrees of encephalopathy with severe brain edema, hyperammonemia, and hypoglycemia.

After using high-dose aspirin, the most well-known adverse effects are abdominal pain and peptic ulcers. In contrast, low-dose aspirin may be associated with dyspeptic symptoms and gastrointestinal (GI) bleeding. Studies showed that the effect on the GI system is dose-dependent.

Other Adverse Effects

  • Bloating
  • Hepatotoxicity with high doses
  • Acute kidney injury with high doses
  • Metabolic acidosis and metabolic encephalopathy after long-term use
  • Iron deficiency with chronic consumption (undetermined association)
  • Some patients may experience aspirin resistance, especially when using aspirin for its anti-platelet effects

A review suggests that exposure to aspirin during the first trimester of pregnancy may be associated with an increased risk of gastroschisis. Acetaminophen can also increase the risk of gastroschisis.

Some experiments suggest combining aspirin with ascorbic acid makes COX-2 inhibition more sensitive. This may achieve anti-inflammatory purposes with lower doses and avoid the adverse effects of high-dose aspirin treatment.

Patients with gout may experience recurrent gout attacks with aspirin use. Therefore, urate-lowering therapy in these patients needs to be adjusted.


The combination is contraindicated if the patient has a contraindication to any individual component.


Caffeine use requires caution under the following conditions:

  • When used with isoflurane in premature infants, a clinical study on mice showed that caffeine increases the toxicity of isoflurane when used together.
  • When used with adolescents at high risk of repetitive mild traumatic brain injury, a study showed that chronic caffeine consumption might alter the recovery from the condition.
  • When used in people who have a positive family history of Meniere disease, a study showed that caffeine might lower the age of onset of symptoms in this disease.


Acetaminophen should be used cautiously and in reduced doses (2 to 3 grams per day) in patients with hepatic impairment for a period not exceeding a few days.

Patients with chronic hepatitis C infection are predisposed to developing liver failure after acetaminophen overdose. Also, acetaminophen showed a dose-dependent enhancement of the anticoagulant effect of warfarin, although studies in healthy volunteers have shown no such effect. Competition for CYP1A2 and CYP3A4 metabolic activity, but conditions such as aging and tissue hypoxia alter the action of these pathways in human studies. Acetaminophen still is the analgesic and antipyretic of choice in patients taking warfarin. Still, patients should avoid excessive amounts and prolonged administration (greater than 1.3 grams daily for 2 weeks).


Aspirin is contraindicated in:

  • Children younger than 12 because of the risk of Reye syndrome, except those with Kawasaki disease
  • An aspirin-exacerbated respiratory disease is a form of chronic rhinosinusitis, nasal polyps, asthma, and acute reaction after aspirin ingestion. However, when aspirin is necessary as a therapy, aspirin desensitization is the most relevant therapeutic approach that improves nasal symptoms and appears to stabilize intrinsic asthma.
  • In patients with peptic ulcer disease, aspirin harms the mucosa of the stomach and duodenum by inhibiting prostaglandin synthesis. Patients who need aspirin should use it cautiously, and a proton pump inhibitor is an option during treatment.



When treating acute primary headaches, doses greater than 130 mg enhance the analgesia in a tension-type headache, and doses greater than 100 mg enhance the analgesia in a migraine headache. 

Mild, transient, and reversible cardiovascular symptoms may result from doses exceeding 600 mg daily.

Consuming caffeine at 200 mg in one sitting or 400 mg daily is not considered harmful.


When used regularly and in large doses (more than 4 grams per day), a risk of serious adverse effects may arise. Patients with cirrhosis or on warfarin require reduced doses: 2 to 3 grams per day for a few days in cirrhosis and less than 1.3 grams per day for no more than 2 weeks in patients who take warfarin.

Acetylsalicylic Acid 

When given with glyburide or other sulfonylureas, aspirin increases the risk of hypoglycemia. The explanation for hypoglycemia may be synergetic inhibition of K(ATP) activity.



Very high doses of caffeine can cause various supraventricular and ventricular arrhythmias. Therefore, caffeine dosing should be optimized in patients who experience heart disease, but this is a prudent measure even in other patients.


In many countries, acetaminophen overdose is the leading cause of drug-induced acute liver failure. Liver intoxication initiates by metabolizing acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), depleting cellular glutathione and forming protein adducts on mitochondrial proteins; this leads to the activation of the apoptosis cascade. Intoxication differs between the individuals according to some factors, specifically, decreased P53 that shows a protective role in regulating the metabolism of acetaminophen, increased protein kinase (cAMP-dependent) inhibitor alpha, deficiency of interleukin 15, and deficiency of prostaglandin E2.

Acetaminophen stimulates Kupffer cells to form peroxynitrite, which is a potent oxidant and leads to the accumulation of neutrophils.

Lower acetaminophen (150 mg/kg) causes reversible mitochondrial dysfunction and fat droplet formation in hepatocytes without ALT release or necrosis.


Acetylcysteine is known as a scavenger of reactive oxygen species. This drug can be used with no contraindications, orally within 8 to 10 hours of the overdose, and intravenously in patients more than 10 hours after the overdose or in patients with conditions preventing taking it orally. Acetylcysteine has a limited therapeutic window. There is a need to develop interventions for late-presenting patients.

Up to 10% of patients with acetaminophen overdose may experience acute kidney injury; some patients may rarely present with acute pancreatitis and hepatic failure.


Acute ingestion of more than 150 mg/kg or 6.5 g of aspirin or ingestion of more than a lick or taste of wintergreen (98% methyl salicylate) by children younger than age 6 or 4 mL of oil of wintergreen by patients aged 6 or older, warrants referral to an emergency department.

The potentially chronic clinical manifestations of salicylate toxicity include:

  • Hematemesis
  • Tachypnea
  • Hyperpnea
  • Dyspnea
  • Tinnitus
  • Deafness
  • Lethargy
  • Seizures
  • Severe weakness
  • Complete heart block or confusion

Patients with such symptoms and signs should receive a referral to the emergency department. Infants initially diagnosed with neonatal sepsis due to metabolic acidosis, tachypnea, and hypoglycemia who failed to respond to therapy should undergo further investigation to exclude salicylate toxicity, especially in infants whose mothers took aspirin throughout the pregnancy.

Laboratory results will show respiratory alkalosis, metabolic acidosis, and elevated salicylate concentration. Patients may develop renal tubular acidosis during treatment, which causes normal anion gap metabolic acidosis.

Metabolic findings in salicylate toxicity may be explainable by the following:

  • Stimulation of the respiratory center of the brain, leading to respiratory alkalosis
  • Uncoupling of oxidative phosphorylation, leading to an increase in glyconeogenesis and an increase in heat production
  • Inhibition of Krebs cycle enzymes, leading to an increase in organic acids
  • Alterations in lipid metabolism and amino acid metabolism, enhancing metabolic acidosis
  • Increasing fluid and electrolytes losses, leading to dehydration, depletion of sodium, potassium depletion, and loss of buffer capacity

Salicylate toxicity may be acquired in multiple ways: oral route, intravenously, or excessive application of topical agents. Methyl salicylate is absorbable through intact skin, where the scrotal skin can have up to 40-fold greater absorption compared to dermal regions.

Patients with salicylate toxicity should not have vomiting induced for acute ingestion of toxic doses. Out-of-hospital administration of activated charcoal should merit consideration in the following conditions:

  • The patient is not vomiting
  • No delay in transportation to administer activated charcoal

For asymptomatic patients with dermal exposures to methylsalicylate of salicylic acid, the skin should be washed with soap and water. The patient can undergo observation at home for the development of symptoms.

For chronic topical poisoning, modern high-flux, intermittent hemodialysis is an effective method for removing salicylates.

For ocular exposure, the affected eye requires irrigation with room-temperature tap water for 15 minutes and referral for an ophthalmological examination if the patient has pain, decreased visual acuity, or persistent irritation.

For oral or intravenous ingestion, fluid resuscitation and sodium bicarbonate infusion should be initiated with an administration of glucose; a patient with severe toxicity should undergo hemodialysis, and mechanical ventilation is recommended.

Complicated outcomes of salicylic poisoning are associated with the following conditions and populations:

  • Chronic poisoning
  • Advanced age
  • Infants younger than 12 months
  • Concurrent medical diseases
  • Neurological symptoms
  • Low standard HCO3
  • Increased respiratory rate
  • Initial serum lactate
  • Hemodialysis not performed

Initial salicylate concentration alone is not predictive.

Enhancing Healthcare Team Outcomes

All healthcare professionals should be aware of the adverse effects of the combination of acetylsalicylic acid (250 mg),  acetaminophen (250 mg), and caffeine (65 mg). While the treatment is effective for migraine and tension headaches, the patient must understand the importance of medication adherence.[12] Each visit should include a query regarding the patient's adverse effects. Finally, to prevent drug toxicity, the medication must be stored away from the reach of children.[13][14][15]

The use of this combination medication requires an interprofessional team approach. Regardless of discipline, the prescriber should work with the pharmacist to rule out drug interactions and account for all possible sources of acetaminophen and NSAIDs to prevent toxicity. Nurses should be familiar with the adverse events of all 3 components and report any concerns observed to the prescriber. This strategy relies on open communication channels between the various clinical disciplines so all interprofessional team members operate from the same data, and appropriate action can be taken in the patient's case if necessary. Shared decision-making is crucial to effective interprofessional teamwork. This coordinated interprofessional methodology optimizes therapeutic results while limiting adverse effects and interactions, resulting in better patient outcomes.



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