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 (Level A). This combination is well-tolerated in episodic tension-type headache and considered superior to acetaminophen. All components of this combination are considered safe during breastfeeding and can be taken orally for acute migraine attacks.[1][2]

This combination may have other benefits according to the components.

Caffeine

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.

Headaches

Besides migraines and tension-type headaches, caffeine is considered effective for other types of headaches like post-dural puncture headache 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 showed an improvement in high-intensity exercise tolerance and less fatigue but no change in power. It is therefore used as an ergogenic aid in athletes to increase physical performance.

Pain

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. Adding 100 mg of caffeine to 400 mg of ibuprofen showed more efficacy than ibuprofen alone after dental extraction. A study also showed that introducing caffeine after general anesthesia enhanced the recovery from the anesthesia, but further studies are needed.

Other Uses

Premature Babies

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

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

Acetaminophen

Acetaminophen is also known as paracetamol, and it is the most commonly used analgesic and antipyretic drug around the world. It 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 a migraine and tension-type headache and combined with tramadol for a cluster headache.

Other Uses 

• First-line treatment for pain associated osteoarthritis 
• Chronic pain (safer to use than opioids)
• 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 (Aspirin)

Asprin 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 in moderate to severe primary headaches. It may be combined with ibuprofen 400 mg for a tension-type headache, or with metoclopramide 10 mg for acute migraines, and also it may be used as a prophylactic treatment of migraine with aura.

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

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

It has anti-inflammatory properties so that it can be used in an exercise-induced inflammatory response, chronic pain, or even in 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

It has been used to decrease the nocturnal pain in osteoid osteoma.

Aspirin may have a neuroprotective role in peripheral nerve injuries and Alzheimer disease.

The mechanism of action of this combination is from the accumulation of the components effect; each component has a different mechanism of action.[3][4]

Caffeine

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, which antagonizes adenosine (A1, A2A, A2B, and A3) non-selectively. These receptors appear in high concentrations in nucleus accumbens, which modulates the behavioral activation and effort-based-decision making. This effect may modulate the work effort in 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 A(2A) can reverse the behavioral effect of dopamine (D2) antagonist (haloperidol). Another clinical study showed mild, partial, reversal effects on the D1 antagonist. These findings can have implications for the treatment of 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. It also increases the oxygen extraction fraction as compensation for the reduction of cerebral blood flow, and no significant changes occur in the whole brain 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 are 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 with an increase in stage-1 wakefulness and arousals.

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

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

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

Acetaminophen

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 which accounts 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

Aspirin is a non-steroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX)-1 and COX-2 irreversibly, thus resulting in a suppression of prostaglandin E2. It stimulates the regulatory braking signals such as lipoxin, resulting in decreased levels 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 showed an inhibition of 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 showed an attenuation of glutamate, which may play a role in its neuroprotective effect.

Protective effects of aspirin on tumors and inflammation may be demonstrated by inhibiting mTOR, which leads to an inhibitory effect on tumor angiogenesis. Also, it metabolizes to 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 in the following strength 250 mg, 250 mg, and 65 mg, respectively. This dosage form is available OTC. The usual dose is 2 tablets po once every 24 hours prn for migraine headache.

Caffeine

A double-blinded, randomized, and placebo-controlled trial in 13 academic hospitals in four countries showed that caffeine does not affect general intelligence, attention, and behavior, and was safe for use.[5][6]

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

• Nervousness
• Nausea
• Abdominal pain/discomfort
• Dizziness

Nervousness was the most frequently reported side 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 headache episodes more than patients who take aspirin only.

Studies showed that taking caffeine 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 side effects such as the following:

• Daytime sleepiness and worsening the sleep quality
• Osteopenia in infants which may lead to spontaneous rib fracture and increased risk of fracture 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).

Acetaminophen

• A medication-overuse headache: Incapacitating headache from the chronic, daily treatment with acetaminophen which 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: It 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 spermatocyte.
• Acetaminophen is regarded as safe to 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

Acetylsalicylic Acid/Aspirin

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

The most well-known side effects after the use of high-dose aspirin are abdominal pain and peptic ulcer, whereas 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 side effects are:

• 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 as anti-platelets

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 that the combination of aspirin with ascorbic acid makes the COX-2 inhibition more sensitive, and this may allow achieving anti-inflammatory purposes with lower doses and avoiding the side 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.

If the patient has a contraindication to one component, then the combination is contraindicated.

Caffeine

Should be used in caution with 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 it.
• 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 with caution 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 have a predisposition 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 hypothesizes it, but conditions such as aging and tissue hypoxia alter the activity of these pathways in human studies. Acetaminophen still is the analgesic and antipyretic of choice in patients who take warfarin, but patients should avoid excessive amounts and prolonged administration (greater than 1.3 grams per day for two weeks).

Aspirin

Contraindicated in:

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