Acetaminophen, Butalbital and Caffeine

What it is

A prescription tablet or capsule that holds three separate drugs at once. The widely used tablet strength contains butalbital 50 mg, acetaminophen 325 mg and caffeine 40 mg. Butalbital is a barbiturate (5-allyl-5-isobutylbarbituric acid); acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic; caffeine is 1,3,7-trimethylxanthine. The product is controlled in the United States because the barbiturate component is habit-forming.

What the research says

The evidence is thin and old for the one thing it is approved for, and essentially absent for the thing it is most often used for. Placebo-controlled trials in episodic tension-type headache did favour butalbital combinations, but those trials are decades old and were summarised rather than pooled; the label itself states that evidence for repeated use in recurrent headache is unavailable. For migraine there is no placebo-controlled evidence of benefit, and in the one modern placebo-controlled crossover trial the butalbital combination did not separate from placebo on sustained pain freedom. Against that sit three well-documented harms: acetaminophen is the leading cause of acute liver failure in the United States, barbiturate use is associated with roughly double the risk of episodic migraine turning into chronic migraine, and butalbital produces tolerance, dependence and a withdrawal syndrome that can include seizures.

Evidence grade: Disputed.

How it works

Drug class: Fixed-dose combination of a short- to intermediate-acting barbiturate (butalbital), a non-opioid analgesic and antipyretic (acetaminophen) and a methylxanthine central nervous system stimulant (caffeine); US Schedule III

Butalbital is a barbiturate: barbiturates bind an allosteric site on the GABA-A receptor-chloride channel complex and increase the inhibitory effect of GABA, which produces sedation and relaxation. Acetaminophen relieves pain and lowers fever by a mechanism that is still incompletely characterised. Caffeine blocks adenosine signalling and stimulates the central nervous system, and adding 100 mg or more of caffeine to a standard analgesic gives a small measurable increase in pain relief. The label is explicit that how the three together relieve tension headache is not understood. (Source 1)

Boxed warning

HEPATOTOXICITY ACETAMINOPHEN HAS BEEN ASSOCIATED WITH CASES OF ACUTE LIVER FAILURE, AT TIMES RESULTING IN LIVER TRANSPLANT AND DEATH. MOST OF THE CASES OF LIVER INJURY ARE ASSOCIATED WITH THE USE OF ACETAMINOPHEN AT DOSES THAT EXCEED 4000 MILLIGRAMS PER DAY, AND OFTEN INVOLVE MORE THAN ONE ACETAMINOPHEN-CONTAINING PRODUCT.

(Source 2)

What it is used for

• This is the only approved use. A 2001 review of the butalbital literature concluded the combinations beat placebo in episodic tension-type headache trials, but those trials are old, were not pooled, and the FDA label states outright that evidence for using the product for repeated headaches is unavailable. For the acetaminophen component on its own, a Cochrane review of 23 trials put the number needed to treat for being pain-free at two hours at 22 for paracetamol 1000 mg, and found 500 to 650 mg was not better than placebo - each tablet of this combination contains only 325 mg. Evidence: limited. (Source 3)
• Not an approved use, yet butalbital combinations have been among the most commonly prescribed acute migraine drugs in the United States. A qualitative systematic search found no evidence of benefit over other agents or placebo, and the US Headache Consortium guidelines discourage their use. In a 442-subject double-blind placebo-controlled crossover trial in people who were already satisfied butalbital users, sustained pain freedom was 6% with the butalbital combination versus 3% with placebo, a difference the study did not detect at the 0.05 level. Evidence: not-supported. (Source 4)
• The label says evidence for safety and efficacy in multiple recurrent headaches is unavailable and that extended use is not recommended. Prospective population data found that people using barbiturate-containing acute medication had about twice the odds of progressing from episodic to transformed (chronic) migraine over one year compared with acetaminophen users, with a dose-response relationship. Evidence: not-supported. (Source 5)
• The label states safety and effectiveness below age 12 have not been established. A paediatric headache programme commentary records that butalbital-containing medicines kept their place in US prescribing despite limited evidence on safety or efficacy and bans in Germany and other European countries; no placebo-controlled paediatric trial was identified. Evidence: unknown. (Source 6)

Interactions

• Alcohol (drinking alcohol) (label): Alcohol adds to the sedation from butalbital. The label says the combination should be avoided with alcohol, and that the lethal dose of a barbiturate is far lower when alcohol is also taken. (Source 7)
• Alcohol (chronic or heavy use, with acetaminophen) (case reports): People who developed liver injury after taking more than 10 g of acetaminophen a day for pain were alcohol users; the label also states the risk of acute liver failure is higher in people who drink while taking acetaminophen. (Source 8)
• Fasting or skipped meals (case reports): Recent fasting was more common than alcohol use among people who developed acetaminophen liver injury at 4 to 10 g a day, so going without food appears to lower the dose at which the acetaminophen component becomes hepatotoxic. (Source 8)
• Warfarin (clinical trial): In a randomised double-blind crossover trial, paracetamol 4 g a day raised INR within a week in people on stable warfarin, alongside falls in the vitamin K-dependent clotting factors II, VII, IX and X. (Source 9)
• Warfarin (high weekly acetaminophen intake) (case reports): In a case-control study of outpatients on warfarin, acetaminophen intake was dose-dependently associated with an INR above 6.0, a level carrying a high bleeding risk. (Source 10)
• Vitamin K (from supplements or leafy green foods), in people taking warfarin (case reports): The acetaminophen-warfarin interaction runs through vitamin K-dependent clotting factors. In the same case-control study, a higher vitamin K intake was associated with a lower risk of an INR above 6.0, so vitamin K intake and acetaminophen use push INR in opposite directions. (Source 10)
• Caffeine from coffee, tea, energy drinks and caffeine-containing supplements (clinical trial): Each tablet adds 40 mg of caffeine to whatever is already being consumed, and the label lists dependence, tremor and irritability among caffeine's potential effects. Caffeine withdrawal headache has been produced experimentally by stopping doses as low as 100 mg a day, so a dose from tablets plus drinks can become a dose that is itself withdrawn from. (Source 11)
• Monoamine oxidase inhibitors (label): The label states that MAO inhibitors may enhance the central nervous system effects of butalbital. (Source 7)
• Opioids, sedatives, tranquillisers and general anaesthetics (label): The label states the combination may enhance the effects of other central nervous system depressants, causing increased CNS depression. (Source 7)
• Other acetaminophen-containing medicines (including over-the-counter cold and pain products) (label): Because one tablet already contains 325 mg of acetaminophen, taking another acetaminophen product alongside it is the commonest route to unintentional overdose; the label instructs patients to check labels for acetaminophen or APAP. (Source 12)

Stopping it

• After heavy or prolonged use, stopping a barbiturate abruptly can cause major withdrawal including convulsions and delirium. The label places onset within 16 hours of the last dose, with symptoms lasting up to five days and declining over about 15 days. (Source 13)
• The label's stated approach to barbiturate dependence is gradual dose reduction rather than abrupt stopping, starting at the person's usual dose and decreasing it as tolerated. (Source 13)
• The published method with the most supporting data is substituting long-acting phenobarbital, whose long half-life produces a self-tapering withdrawal. In a retrospective chart review of 18 inpatients withdrawn from butalbital combinations, all were withdrawn without serious adverse events, but the number of doses needed varied widely and could not be predicted from the person's prior intake. (Source 14)
• An earlier published inpatient protocol tapered phenobarbital and caffeine over several days in three patients who had been taking between 150 and 420 tablets a month for 2 to 15 years; one of the three restarted after eight months. This is case-series evidence only. (Source 15)
• Stopping also removes a daily caffeine dose. Experimentally, caffeine withdrawal headache begins 12 to 24 hours after the last dose, peaks at 20 to 51 hours and lasts 2 to 9 days, which can be mistaken for the headache returning. (Source 11)
• The reason given in the butalbital literature for limiting and monitoring use at all is the combination of overuse, medication-overuse headache and withdrawal. (Source 3)

What goes wrong

In a prospective population cohort, people using barbiturate-containing acute headache medication had roughly double the odds of progressing from episodic to transformed (chronic) migraine within a year, with a dose-response relationship. (Source 16)

• Cohort study, Moderate certainty.
• Size: 8219 individuals with episodic migraine in 2005, drawn from a population sample of 120,000.
• Who: US adults with episodic migraine followed annually in the American Migraine Prevalence and Prevention study.
• How long: 1 year transition (2005 to 2006) within a 5-year cohort.
• Result: 209 of 8219 (2.5%) developed transformed migraine in a year; barbiturates OR 2.06 (95% CI 1.3-3.1) and opiates OR 1.98 (1.4-2.2) versus acetaminophen users; triptans OR 1.25 (0.9-1.7), not significant; dose-response found for barbiturates.
• Funding: not stated in the abstract.

Using acetaminophen user as the reference group, individuals who used medications containing barbiturates (OR = 2.06, 95%CI = 1.3-3.1) or opiates (OR = 1.98, 95%CI = 1.4-2.2) were at increased risk of TM.

Acetaminophen was responsible for 42% of acute liver failure cases in a US multicentre prospective study, and almost half of those overdoses were unintentional in people treating pain. (Source 17)

• Cohort study, Moderate certainty.
• Size: 662 consecutive patients with acute liver failure at 22 US tertiary centres; 275 acetaminophen-related.
• Who: US patients meeting standard criteria for acute liver failure (coagulopathy and encephalopathy)
• How long: 6 years of prospective enrolment.
• Result: 275 of 662 (42%) acetaminophen-related, rising from 28% of cases in 1998 to 51% in 2003; median dose 24 g; 131 of 275 (48%) unintentional; 65% survived, 27% died without transplant, 8% transplanted.
• Funding: not stated in the abstract.

Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury.

In the same study, unintentional acetaminophen liver failure clustered in people taking more than one acetaminophen-containing product, which is the specific hazard of a combination tablet. (Source 17)

• Cohort study, Moderate certainty.
• Size: 131 unintentional cases among 275 acetaminophen-related acute liver failures.
• Who: US patients with acetaminophen-related acute liver failure.
• How long: 6 years.
• Result: 38% of unintentional cases took two or more acetaminophen preparations simultaneously; 63% used narcotic-containing compounds; 81% were taking acetaminophen or other analgesics for acute or chronic pain.
• Funding: not stated in the abstract.

In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds.

Acetaminophen liver injury at doses between 4 and 10 g a day was associated with recent fasting, and at doses above 10 g a day with alcohol use. (Source 8)

• Case series, Low certainty.
• Size: 49 patients with acetaminophen hepatotoxicity identified from 126,779 discharge summaries; 21 had taken it for therapeutic purposes.
• Who: hospital inpatients at the University of Pittsburgh Medical Center, 1987 to 1993.
• How long: retrospective over 6.5 years.
• Result: all patients with hepatotoxicity exceeded 4 g/day; recent fasting more common than recent alcohol use in the 4-10 g/day group (P = .02); recent alcohol use more common above 10 g/day (P = .004)
• Funding: not stated in the abstract.

Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use.

Butalbital produces intoxication, tolerance, dependence and, at higher doses, a withdrawal syndrome, and can itself cause drug-induced headache. (Source 3)

• Expert review, not systematic, Low certainty.
• Size: not stated; narrative review of the butalbital literature.
• Who: people using butalbital-containing analgesics for headache.
• How long: not stated.
• Result: no rates given; the review reports intoxication clinically indistinguishable from alcohol, tolerance, dependence, drug-induced headache and withdrawal syndromes at higher doses.
• Funding: not stated.

Barbiturates can produce intoxication, hangover, tolerance, dependence, and toxicity. Butalbital can result in intoxication that is clinically indistinguishable from that produced by alcohol. Butalbital-containing analgesics can produce drug-induced headache in addition to tolerance and dependence.

The label's own list of the most frequent adverse reactions is dominated by sedation and central nervous system effects, with no placebo comparison given. (Source 18)

• Official position, Certainty not rated.
• Size: not stated in the label.
• Who: people prescribed butalbital, acetaminophen and caffeine tablets.
• How long: not stated.
• Result: no frequencies or placebo rates are given; drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain and intoxicated feeling are listed as most frequent.
• Funding: not applicable; manufacturer label.

The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling.

Caffeine withdrawal is itself a validated cause of headache, which is relevant when a caffeine-containing headache tablet is stopped. (Source 11)

• Systematic review, Moderate certainty.
• Size: 57 experimental and 9 survey studies meeting inclusion criteria.
• Who: humans abstaining from habitual caffeine.
• How long: symptoms typically 2 to 9 days.
• Result: incidence of headache 50%; clinically significant distress or functional impairment 13%; onset 12-24 h after abstinence, peak 20-51 h; symptoms produced by abstinence from doses as low as 100 mg/day.
• Funding: not stated in the abstract.

In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%.

In a propensity-matched retrospective cohort of adults with tension-type headache, butalbital was prescribed to 3.8% of patients not receiving spinal manipulation over two years and medication-overuse headache was recorded in 1.2%. (Source 19)

• Cohort study, Low certainty.
• Size: 3116 patients per cohort after propensity matching, from a US academic medical records database 2013-2024.
• Who: adults with tension-type headache, excluding inpatient and emergency settings and other headache diagnoses.
• How long: 2 years.
• Result: butalbital prescription 1.7% with spinal manipulation versus 3.8% without, RR 0.46 (95% CI 0.33-0.63, p < 0.001); medication-overuse headache 0.5% versus 1.2%, RR 0.44 (0.25-0.80, p < 0.001)
• Funding: not stated in the abstract; the study was conducted by chiropractic researchers, so the comparator is not neutral.

Limit of this finding: The published abstract reports the medication-overuse headache result as a risk ratio of 0.44 with a 95% confidence interval of 0.25 to 0.80 and p < 0.001. Those two numbers do not fit together: an interval that reaches as far as 0.80 corresponds to a p-value of roughly 0.006, not below 0.001. The p-value as printed cannot be relied on. What a reader can take from this study is the recorded difference in prescribing and in recorded medication-overuse headache between the two matched groups, and not the strength of statistical evidence implied by that p-value. This is also a retrospective records comparison, so it cannot show that one treatment caused the other outcome.

Butalbital is an acute headache medication commonly prescribed for tension-type headache (TTH), although discouraged by guidelines due to a risk of medication overuse headache (MOH).

What the evidence supports

A review of the butalbital literature concluded that butalbital combinations outperformed placebo in episodic tension-type headache trials, but found no placebo-controlled migraine trials at all. (Source 3)

• Expert review, not systematic, Low certainty.
• Size: not stated; a narrative review of the butalbital literature.
• Who: adults with episodic tension-type headache and with migraine.
• How long: not stated.
• Result: no pooled effect size reported; the review reports the direction of the placebo-controlled tension-type headache trials only.
• Funding: not stated.

The butalbital-containing compounds are efficacious in placebo-controlled trials among patients with episodic tension-type headaches. Despite their frequent clinical use for migraine, they have not been studied in placebo-controlled trials among patients with migraine.

In that same trial, adverse-event rates were similar for the butalbital combination, the active comparator and placebo. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 442 subjects.
• Who: adults with migraine who were existing butalbital users.
• How long: single-attack dosing, 3 attacks.
• Result: adverse event incidence 9% butalbital combination, 12% sumatriptan-naproxen, 10% placebo; nausea most frequent at under 1% versus 2% and 2%.
• Funding: not stated in the abstract.

Adverse event incidence was similar for all treatments (10%, 12%, and 9% for placebo, SumaRT/Nap, and BCM, respectively).

For the acetaminophen component alone, a Cochrane review found a small absolute benefit in episodic tension-type headache: 1000 mg gave a number needed to treat of 22 for being pain-free at two hours. (Source 21)

• Systematic review, High certainty.
• Size: 23 studies, 8079 participants enrolled; 5890 participants in the pain-free at 2 hours analysis.
• Who: adults with frequent episodic tension-type headache and moderate or severe pain at baseline.
• How long: single acute attack.
• Result: NNT 22 (95% CI 15 to 40) for pain-free at 2 hours; NNT 10 (7.9 to 14) for pain-free or mild pain at 2 hours; no difference from placebo at 1 hour.
• Funding: not stated in the abstract; Cochrane review.

For the IHS preferred outcome of being pain free at two hours the NNT for paracetamol 1000 mg compared with placebo was 22 (95% confidence interval (CI) 15 to 40) in eight studies (5890 participants; high quality evidence), with no significant difference from placebo at one hour.

The caffeine in the combination has a small measurable analgesic contribution at doses of 100 mg or more, which is more than the 40 mg in one tablet. (Source 22)

• Systematic review, High certainty.
• Size: 20 studies, 7238 participants in valid comparisons; 4262 participants in the caffeine analyses.
• Who: adults with acute pain, most commonly postoperative dental pain, postpartum pain and headache.
• How long: four to six hours after a single dose.
• Result: about 5% to 10% more participants reached at least 50% of maximum pain relief with added caffeine; NNT about 14 (high quality evidence); most studies used 100 mg to 130 mg caffeine.
• Funding: not stated in the abstract; the authors note around 25 further studies with almost 12,500 participants whose data they could not obtain.

About 5% to 10% more participants achieve a good level of pain relief (at least 50% of the maximum over four to six hours) with the addition of caffeine, giving a NNT of about 14 (high quality evidence).

Barbiturates act by enhancing the inhibitory effect of GABA at the GABA-receptor chloride channel, which is the molecular basis of butalbital's sedative effect; this is laboratory binding and electrophysiology work, not a human finding. (Source 23)

• Lab study in cells, Low certainty.
• Size: not applicable; radioligand binding and ion-flux assays.
• Who: not applicable; brain membrane and solubilised receptor preparations.
• How long: not applicable.
• Result: no clinical effect size; barbiturates allosterically enhance GABA-regulated chloride channels and show mutual allosteric interaction with GABA, benzodiazepine and picrotoxin sites in the same receptor complex.
• Funding: not stated.

These receptors are defined by sensitivity to the agonist muscimol and the antagonist bicuculline, and are also subject to indirect allosteric inhibition by picrotoxin-like convulsants and enhancement by the clinically important drugs, the benzodiazepines and the barbiturates.

What the evidence does not support

A qualitative systematic search of the literature and of the US Headache Consortium guidelines found no evidence that butalbital-containing products benefit migraine more than other agents or placebo. (Source 4)

• Systematic review, Low certainty.
• Size: MEDLINE January 1966 to November 2001; only one controlled trial of these drugs for migraine was identified.
• Who: adults with migraine.
• How long: not applicable.
• Result: the single identified controlled trial found butalbital-containing products inferior to butorphanol.
• Funding: not stated.

Although butalbital-containing products commonly are prescribed for migraine, no evidence in the literature demonstrates their benefit over other agents or placebo.

In a modern double-blind placebo-controlled crossover trial, butalbital 50 mg / acetaminophen 325 mg / caffeine 40 mg did not separate from placebo on sustained pain freedom in migraine. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 442 subjects treated at least one attack, pooled from 2 identical crossover studies.
• Who: adults with migraine, 88% of whom were current butalbital users and 82% satisfied with it.
• How long: 3 attacks, each treated with one of the 3 study treatments.
• Result: sustained pain-free 2-24 hours without rescue: 8% sumatriptan-naproxen, 6% butalbital combination, 3% placebo; no difference detected at the 0.05 level.
• Funding: not stated in the abstract; the comparator was a branded sumatriptan-naproxen product, so an industry sponsor is likely.

This study did not detect a difference at the nominal 0.05 level in percent sustained pain-free between SumaRT/Nap (8%), BCM (6%), and placebo (3%).

In that same trial the butalbital combination lost to sumatriptan-naproxen on pain freedom, pain relief and migraine freedom at almost every timepoint measured. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 442 subjects treated at least one attack, pooled from 2 identical crossover studies.
• Who: adults with migraine, 88% of whom were current butalbital users and 82% satisfied with it.
• How long: 3 attacks, each treated with one of the 3 study treatments.
• Result: sumatriptan-naproxen superior to the butalbital combination for pain free at 2, 4, 6, 8, 24 and 48 hours (P≤.044), pain relief at the same timepoints (P≤.01), sustained pain relief 2-24 hours (P<.001), migraine free at 4, 6, 8, 24 and 48 hours (P≤.046) and complete symptom free at 4, 6, 8 and 48 hours (P≤.031); the authors also report less rescue medication use and a longer time to rescue with sumatriptan-naproxen.
• Funding: not stated in the abstract; the comparator was a branded sumatriptan-naproxen product, so an industry sponsor is likely.

SumaRT/Nap was superior to BCM for pain free at 2, 4, 6, 8, 24, 48 hours (P≤.044); pain relief (mild or no pain) at 2, 4, 6, 8, 24, 48 hours (P≤.01); sustained pain relief 2-24 hours (P<.001)

The same Cochrane review found acetaminophen 500 to 650 mg was not superior to placebo for tension-type headache, which matters because each tablet of this combination contains only 325 mg. (Source 21)

• Systematic review, Low certainty.
• Size: limited data within the 23 included studies.
• Who: adults with frequent episodic tension-type headache.
• How long: single acute attack.
• Result: paracetamol 500 mg to 650 mg not superior to placebo; paracetamol 1000 mg not different from ketoprofen 25 mg or ibuprofen 400 mg (low quality evidence)
• Funding: not stated in the abstract; Cochrane review.

On limited data, the efficacy of paracetamol 500 mg to 650 mg was not superior to placebo, and paracetamol 1000 mg was not different from either ketoprofen 25 mg or ibuprofen 400 mg (low quality evidence).

Where the research disagrees

Whether butalbital-containing analgesics should still be prescribed for headache at all

• Seymour Solomon, arguing the “No” side of a published point/counterpoint (Current Pain and Headache Reports, 2002), one side of a published point/counterpoint debate, written to argue against withdrawing these agents from the market; no stated search method and no new data: Butalbital compounds are of proven efficacy in the treatment of tension headache. Decades of experience have established their value in the treatment of other mild-to-moderate headaches. (Source 24)
• Authors arguing against their use in migraine (Pharmacotherapy, 2002), qualitative systematic search of MEDLINE plus review of the US Headache Consortium evidence-based guidelines: The consortium's guidelines specifically discourage administration of butalbital-containing products for migraine. (Source 4)
• Caruso and colleagues at the Pediatric Headache Program, Boston Children’s Hospital (Headache, 2015), commentary stating one centre’s practice recommendation, with no stated method and no new data; the authors themselves describe the evidence on safety and efficacy as limited: Despite limited evidence from the literature surrounding safety or efficacy, butalbital-containing medicines (BCMs) have maintained their rank as "go-to" prescribed migraine and headache relief drugs in the United States, despite bans on these barbiturates in Germany and other European countries. (Source 6)

How much

• Reference intake: There is no reference intake for a drug. Dosing is set by the prescriber. As a position, the FDA label of 10 December 2025 states the dose as one or two tablets every four hours as needed. (Source 25)
• Upper limit: As a position, the same label caps the dose at 6 tablets in 24 hours (equivalent to acetaminophen 1950 mg, butalbital 300 mg and caffeine 240 mg) and separately instructs that no more than 4000 mg of acetaminophen be taken per day from all sources. (Source 25)
• Studied: The 2012 placebo-controlled crossover trial used a single dose of butalbital 50 mg, acetaminophen 325 mg and caffeine 40 mg per migraine attack. (Source 20)
• Studied: The Cochrane tension-type headache trials of the acetaminophen component used single doses of 1000 mg, and 500 mg to 650 mg. (Source 21)
• Studied: The caffeine adjuvant trials pooled by Cochrane mostly used 100 mg to 130 mg of caffeine added to paracetamol or ibuprofen. (Source 22)

A common belief, and what the research shows

The belief: It is a stronger, prescription version of paracetamol for bad headaches, and because it is prescribed it must be better evidenced than over-the-counter painkillers.

What the research shows: The acetaminophen dose in one tablet is 325 mg, and a Cochrane review found that "the efficacy of paracetamol 500 mg to 650 mg was not superior to placebo" for tension-type headache. For migraine, the use it is most often prescribed for, "no evidence in the literature demonstrates their benefit over other agents or placebo". The label itself states that "Evidence supporting the efficacy and safety of this combination product in the treatment of multiple recurrent headaches is unavailable." Meanwhile the barbiturate component is habit-forming and barbiturate use carried an odds ratio of 2.06 for progression from episodic to chronic migraine.

Questions and answers

What is it?

It is one tablet or capsule holding three different drugs: butalbital, a barbiturate; acetaminophen, a non-opioid painkiller and fever reducer; and caffeine. The common tablet strength is butalbital 50 mg, acetaminophen 325 mg and caffeine 40 mg. It is a prescription-only controlled medicine in the United States because the barbiturate is habit-forming. (Source 1)

What does it do in the body?

Butalbital increases the inhibitory signalling of GABA in the brain, which makes people drowsy and relaxed. Acetaminophen reduces pain and fever. Caffeine stimulates the central nervous system and adds a small amount of pain relief when used at 100 mg or more. How the three together relieve a tension headache has never been worked out; the manufacturer's own label says so. (Source 1)

Is it good or bad for you?

It depends heavily on how often it is used. For an occasional tension headache the placebo-controlled trials were positive and the short-term adverse event rate in a modern trial was no higher than placebo. Used regularly it becomes harmful: barbiturate use roughly doubled the odds of episodic migraine turning chronic, the barbiturate causes tolerance, dependence and withdrawal, and the acetaminophen component is the leading cause of acute liver failure in the United States. The butalbital literature positions these products as a fallback rather than a first choice. (Source 3)

How do you get more of it?

This question does not apply in the way it does to a nutrient. It is a prescription-only controlled medicine; there is no food or supplement source and no reason to seek more of it. The amount a person takes is set by the prescriber, and the label caps the total at 6 tablets in 24 hours. (Source 25)

If it is harmful, what reduces it?

In an acute overdose, the recognised treatment for the acetaminophen component is N-acetylcysteine, given as early as possible, with activated charcoal to limit absorption. For the barbiturate component, the published approach is not elimination but gradual withdrawal, often by substituting long-acting phenobarbital and letting its long half-life taper the dose. (Source 25)

Why might someone be low in it or missing it?

Being without it is not a deficiency. The reasons people end up off it are the opposite problem: it is contraindicated in porphyria and in acetaminophen allergy, it is not recommended for extended use, and prescribers withdraw it when it starts to cause medication-overuse headache or dependence. (Source 3)

Which whole foods contain it or feed it?

No whole food contains butalbital or acetaminophen. One component, caffeine, is in coffee, tea, cocoa, cola and energy drinks, so dietary caffeine adds to the 40 mg per tablet; this matters because stopping a habitual caffeine dose as low as 100 mg a day can itself produce headache. (Source 11)

What happens if you do not have it?

Nothing happens from never taking it; there is no deficiency state, and other treatments for tension-type headache and migraine have better evidence. What does happen is withdrawal after heavy use: stopping abruptly can cause convulsions and delirium within 16 hours. (Source 13)

How can you test for it?

There is no blood test to monitor ordinary use. In suspected overdose, a serum acetaminophen level drawn at least four hours after ingestion is the test that guides treatment; levels drawn earlier can mislead. The label also advises serial liver and kidney function tests in people with severe liver or kidney disease. (Source 25)

References

1. DailyMed (US National Library of Medicine), label of Chartwell RX, LLC. Butalbital, Acetaminophen and Caffeine Tablets, USP (C-III) 50 mg/325 mg/40 mg - FDA label, revised 08/2023, DailyMed version published 10 Dec 2025 - CLINICAL PHARMACOLOGY section. 2025. Read the source
2. DailyMed (US National Library of Medicine), label of Chartwell RX, LLC. Butalbital, Acetaminophen and Caffeine Tablets, USP (C-III) 50 mg/325 mg/40 mg - FDA label, revised 08/2023, DailyMed version published 10 Dec 2025 - BOXED WARNING section. 2025. Read the source
3. Headache. Butalbital in the treatment of headache: history, pharmacology, and efficacy.. 2001. PMID 11903523, DOI 10.1046/j.1526-4610.2001.01189.x. Read the source
4. Pharmacotherapy. Do butalbital-containing products have a role in the management of migraine?. 2002. PMID 12173787, DOI 10.1592/phco.22.12.1029.33595. Read the source
5. DailyMed (US National Library of Medicine), label of Chartwell RX, LLC. Butalbital, Acetaminophen and Caffeine Tablets, USP (C-III) 50 mg/325 mg/40 mg - FDA label, revised 08/2023, DailyMed version published 10 Dec 2025 - INDICATIONS AND USAGE section. 2025. Read the source
6. Headache. Butalbital and pediatric headache: stay off the downward path.. 2015. PMID 25532552, DOI 10.1111/head.12484. Read the source
7. DailyMed (US National Library of Medicine), label of Chartwell RX, LLC. Butalbital, Acetaminophen and Caffeine Tablets, USP (C-III) 50 mg/325 mg/40 mg - FDA label, revised 08/2023, DailyMed version published 10 Dec 2025 - Information for Patients / Drug Interactions section. 2025. Read the source
8. JAMA. Association of acetaminophen hepatotoxicity with fasting and ethanol use.. 1994. PMID 7990219, DOI 10.1001/jama.1994.03520230055038. Read the source
9. Haematologica. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study.. 2006. PMID 17145598. Read the source
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