FDA recognized the combination of acetylsalicylic acid (250 mg), acetaminophen (250 mg) and caffeine (65 mg) as safe and effective in treating acute headache, 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, and all components of this combination are considered safe during breastfeeding and can be taken orally for acute migraine attacks.
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 headache and hypnic headaches which can be presented with cranial autonomic features.
Clinical studies showed that caffeine citrate (intravenous [IV]) may 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 the acute treatment.
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 the physical performance.
Adding 100 mg or more caffeine to a standard dose of commonly used analgesics provides a small, but important, an increase in pain relief in postoperative procedures. Adding 100 mg of caffeine to 400 mg of ibuprofen showed more efficacy that 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.
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 the brain damage in hypoxic brain injury. Furthermore, it has a role in decreasing the rate of patent ductus arteriosus requiring treatment and decreasing the likelihood of discharging home with oxygen. It can be used 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 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 be treated 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.
Some studies showed the association of acetaminophen use with:
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 considered as 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 a 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 it is used with intravenous immunoglobulin.
At lower doses (75 to 325 mg) aspirin is used as an antiplatelet drug to reduce the cardiovascular events in high-risk patients.
It has anti-inflammatory properties so it can be used in 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:
It has been used to decrease the nocturnal pain in osteoid osteoma.
Aspirin may have a neuroprotective role in peripheral nerves injuries and Alzheimer disease.
Caffeine has anti-oxidant, anti-inflammatory, anticholinesterase, and anti-TLR-4 properties. Studies on rats showed that these properties play an important role in sleep deprivation-induced inflammatory response and anxious behavior.
Caffeine is methylxanthine which antagonizes adenosine (A1, A2A, A2B, and A3) non-selectively. These receptors are highly concentrated 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 treatment of psychiatric symptoms (psychomotor slowing and fatigue) that can be observed 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. This 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 are noticed in the whole brain cerebral metabolic rate of oxygen or electrical brain activity. Variations in the change of cerebral blood flow between the regions of the brain were noticed. The decrease in cerebral blood flow was less in the posterior cingulate cortex and superior temporal region; whereas, it was greater in the dorsolateral prefrontal cortex and medial frontal cortex. It may be concluded that caffeine's effect on vasculature may be region-specific and can be caused by the spatial distribution of the adenosine receptors. Another study showed that caffeine might stimulate ketone production as an alternative fuel for the brain during a decreased level 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 the sleep and increase the 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 an important 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. Several loci have been identified 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 inhibits central and peripheral cyclooxygenase (COX), strongly inhibits prostacyclin synthesis, and increase nitric oxide (NO) synthesis. However, NO synthesis is not affected at pharmacologically relevant concentrations.
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 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:
However, the levels of regulatory cytokines (IL-4 and IL-10) will not be decreased; 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 can be observed 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 were mainly detected in the primary somatosensory area, parietal association cortices, and anterior parts 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 is metabolized to salicylic acid which binds to human high mobility group box1 (HMGB1), which is an inflammatory molecule.
A double-blinded, randomized, and placebo-controlled trials study in 13 academic hospitals in 4 countries showed that caffeine does not affect general intelligence, attention, and behavior. It can be used safely.
As a treatment for acute primary headaches, patients may develop several side effects:
Nervousness was the most frequently reported side effect.
Although caffeine is used as 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 are thought to 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:
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:
A review suggests that exposure to aspirin during the first trimester of pregnancy may be associated with an increased risk of gastroschisis.
Some experiments suggest that combination of aspirin with ascorbic acid makes the COX-2 inhibition more sensitive, and this may allow achieving the 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, the urate-lowering therapy in these patients needs to be adjusted.
If the patient has a contraindication to one component, then the combination is contraindicated.
Should be used in caution with the following conditions:
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 develop 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 3A4 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 excessive amounts and prolonged administration (greater than 1.3 grams per day for 2 weeks) should be avoided.
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 be caused by doses greater than 600 mg per day.
It is considered not harmful to consume caffeine at levels of 200 mg in one sitting or 400 mg daily.
When used regularly and in large doses (more than 4 grams per day), a risk of serious side effects may arise. In patients with cirrhosis or patients on warfarin, reduced doses are needed: 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.
Aspirin will have an increased risk of hypoglycemia when given with glyburide or sulfonylurea. The hypoglycemia may be explained by synergetic inhibition of K(ATP) activity.
Very high doses of caffeine can cause various supraventricular and ventricular arrhythmias. Therefore, caffeine should be used in optimal doses in patients who experience heart diseases or even in normal patients.
Acetaminophen overdose is the leading dose of drug-induced acute liver failure in many developed countries. Liver intoxication is initiated by metabolizing acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This leads to activation of 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.
Also, acetaminophen stimulates Kupffer cells to form peroxynitrite, a potent oxidant, and leads to 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 and 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. The use of it is narrow because of the 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, and rarely, some patients may present with acute pancreatitis along with hepatic failure.
Acute ingestion of more than 150 mg/kg or 6.5 g of aspirin or ingestion of greater than a lick or taste of wintergreen (98% methyl-salicylate) by children younger than the age of 6, or 4 mL of oil of wintergreen by patients who are 6 years of age or older warrant a referral to an emergency department.
Clinical manifestations of salicylate toxicity which may be chronic are: hematemesis,
Patients with such symptoms and signs should be referred to the emergency department. Infants who were diagnosed initially with neonatal sepsis due to metabolic acidosis, tachypnea, and hypoglycemia, and 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. During treatment, patients may develop renal tubular acidosis which causes normal anion gap metabolic acidosis.
Metabolic findings in salicylate toxicity may be explained by the following:
Salicylate toxicity may be acquired in multiple ways: oral, intravenous or excessive application of topical agents. Methyl salicylate can be absorbed through an intact skin, where the scrotal skin can have up to 40-fold greater absorption compared to dermal regions.
Patient with salicylate toxicity should not be induced to vomit for acute ingestion of toxic doses. Out-of-hospital administration of activated charcoal should be considered in the following conditions:
For asymptomatic patients with dermal exposures to methylsalicylate of salicylic acid, the skin should be washed with soap and water, and the patient can be observed 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 should be irrigated with room-temperature tap water for 15 minutes, and referral for an ophthalmological examination is indicated if the patient is having 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:
Initial salicylate concentration alone is not predictive.
All healthcare workers including nurse practitioners, the primary care provider and the neurologist should be aware of the side effects of the combination acetylsalicylic acid (250 mg), acetaminophen (250 mg) and caffeine (65 mg). While the treatment is effective for migraine and tension headaches, the patient must be educated on the importance of medication compliance. At each visit, the patient's side effects should be recorded. Finally, to prevent drug toxicity, the medication needs to be stored away from the reach of children.
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