It consists of a fixed combination of butalbital, acetaminophen, and caffeine. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood.

Pharmacokinetics

The behavior of the individual components is described below.

Butalbital

Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.

Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose), 5-isobutyl-5-(2, 3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated.

The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity, indicating that there is no preferential distribution of butalbital into either plasma or blood cells.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

Caffeine

Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.

Caffeine is cleared through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug.

Following an acute overdosage of butalbital, acetaminophen, and caffeine, toxicity may result from the barbiturate or the acetaminophen. Toxicity due to caffeine is less likely, due to the relatively small amounts in this formulation.

Signs and Symptoms
Toxicity from barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock.

In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necroses, hypoglycemic coma, and thrombocytopenia may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. In adults hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams, or fatalities with less than 15 grams.

Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia and extrasystoles.

Treatment
A single or multiple overdose with this combination product is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.

Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Pressors should be avoided. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary, to provide assisted respiration. If renal function is normal, forced diuresis may aid in the elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital.

Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously.

If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible. Serum acetaminophen levels should be obtained, since levels four or more hours following ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before initiating treatment. Hepatic enzymes should be obtained initially, and repeated at 24-hour intervals.

Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include insomnia, restlessness, tremor, dizziness, drowsiness, diarrhea, increased sweating, shallow breathing, confusion, uneven heartbeats, seizure (convulsions), or coma.

Pain-Relievers 

• Mixed analgesics – These medicines are pain-relievers that contain more than one active ingredient. For example, Excedrin contains acetaminophen, aspirin and caffeine, and Fiorinal contains butalbital and aspirin. You may take these if mild analgesics are not strong enough to relieve your headache pain or if you headache is more severe. Some

Preventive medications
Certain medications taken at regular intervals may reduce the frequency and severity of attacks. Your doctor may prescribe these if you have frequent headaches or have tension headaches that aren’t relieved by acute medication and nondrug therapy such as stress management. Your doctor also may recommend preventive medication if your headache pain becomes disabling or causes you to overuse acute medication, or if you can’t take acute medication because of other medical conditions.

Doctors may prescribe antidepressants to prevent tension headache, especially the chronic form. These drugs aren’t painkillers. Rather, they work to stabilize the levels of brain chemicals such as serotonin, which may be involved in the development of a headache. You don’t have to have depression in order to use these drugs.

Preventive medications may include:

• Tricyclic antidepressants. Tricyclic antidepressants, including amitriptyline and nortriptyline (Pamelor), are the most commonly used medications to prevent tension headache. They’re effective against both the episodic and chronic forms. Side effects of these medications may include weight gain, drowsiness and dry mouth.
• Selective serotonin reuptake inhibitors (SSRIs). Antidepressants such as paroxetine (Paxil), venlafaxine (Effexor) and fluoxetine (Prozac, Sarafem) produce fewer side effects than do the tricyclic antidepressants but generally aren’t considered effective for tension headaches.
• Other medications. Other medications that may prevent tension headache include anticonvulsants, such as topiramate (Topamax) and gabapentin (Neurontin), and muscle relaxants, such as tizanidine (Zanaflex).

Preventive medications may require several weeks or more to build up in your nervous system before they take effect. So don’t get frustrated if you haven’t seen improvements shortly after you begin taking the drug — it may take a couple of months or longer. Also be aware that overusing caffeine or painkillers for acute relief may reduce the effect of a preventive drug.

To obtain the greatest benefit from preventive medication, keep your use of acute pain relievers to a minimum. Your doctor will monitor your treatment to see how the preventive medication is working. If your headaches are under control, your dose of medication may be reduced gradually over time.

Preventive, or “prophylactic,” medicines are taken every day to prevent headaches from starting. They are used to treat chronic headaches that occur more than twice a week and/or are extremely painful. They are also prescribed when other headache medicines or remedies do not work or cannot be used. More commonly-used medicines include:

• Tricyclic anti-depressants (TCAs) – These medicines were originally used to treat depression and related disorders. However, headache experts have learned that TCAs can also help prevent and relieve chronic TTH. A TCA such as amitriptyline (Elavil) is often the first medicine of choice for preventing chronic TTH. TCAs are often begun at lower doses and are slowly increased. In addition to relieving pain, TCAs may improve sleep and decrease depression in people who have it. Other TCAs given for chronic TTH include nortriptyline (Pamelor), desipramine (Norpramin), doxepin (Sinequan) and clomipramine (Anafranil).

• Anti-convulsants – These medicines were originally used to treat seizures (convulsions or epilepsy). Now, certain anti-convulsants are also used to help prevent chronic TTH. Your health care provider may give you an anti-convulsant if TCAs failed to relieve your headaches. Examples include valproic acid (Depakote), gabapentin (Neurontin) and topiramate (Topamax).

Other Medicines

• Muscle relaxants – These medicines are also called “anti-spasmodics.” They given to relax tight muscles. They may be given alone, but medical research shows that they are more effective when given together with a medicine such as a TCA. Examples of muscle relaxants are tizanidine (Zanaflex) and metaxalone (Skelaxin). More research needs to be done on the effectiveness of muscle relaxants as a treatment for TTH.

Drug therapy for migraine is divided into acute and preventive treatment. Acute or “abortive” medications are taken as soon as symptoms occur to relieve pain and restore function. Preventive treatment involves taking medicines daily to reduce the severity of future attacks or keep them from happening. The U.S. Food and Drug Administration (FDA) has approved a variety of drugs for these treatment methods. Headache drug use should be monitored by a physician, since some drugs may cause side effects.

Acute treatment for migraine may include any of the following drugs.

• Triptan drugs increase levels of the neurotransmitter serotonin in the brain. Serotonin causes blood vessels to constrict and lowers the pain threshold. Triptans-the preferred treatment for migraine-ease moderate to severe migraine pain and are available as tablets, nasal sprays, and injections.
• Ergot derivative drugs bind to serotonin receptors on nerve cells and decrease the transmission of pain messages along nerve fibers. They are most effective during the early stages of migraine and are available as nasal sprays and injections.
• Non-prescription analgesics or over-the-counter drugs such as ibuprofen, aspirin, or acetaminophen can ease the pain of less severe migraine headache.
• Combination analgesics involve a mix of drugs such as acetaminophen plus caffeine and/or a narcotic for migraine that may be resistant to simple analgesics.
• Nonsteroidal anti-inflammatory drugs can reduce inflammation and alleviate pain.
• Nausea relief drugs can ease queasiness brought on by various types of headache.
• Narcotics are prescribed briefly to relieve pain. These drugs should not be used to treat chronic headaches.

Taking headache relief drugs more than three times a week may lead to medication overuse headache (previously called rebound headache), in which the initial headache is relieved temporarily but reappears as the drug wears off. Taking more of the drug to treat the new headache leads to progressively shorter periods of pain relief and results in a pattern of recurrent chronic headache. Headache pain ranges from moderate to severe and may occur with nausea or irritability. It may take weeks for these headaches to end once the drug is stopped.

Everyone with migraine needs effective treatment at the time of the headaches. Some people with frequent and severe migraine need preventive medications. In general, prevention should be considered if migraines occur one or more times weekly, or if migraines are less frequent but disabling. Preventive medicines are also recommended for individuals who take symptomatic headache treatment more than three times a week. Physicians will also recommend that a migraine sufferer take one or more preventive medications two to three months to assess drug effectiveness, unless intolerable side effects occur.

Several preventive medicines for migraine were initially marketed for conditions other than migraine.

• Anticonvulsants may be helpful for people with other types of headaches in addition to migraine. Although they were originally developed for treating epilepsy, these drugs increase levels of certain neurotransmitters and dampen pain impulses.
• Beta-blockers are drugs for treating high blood pressure that are often effective for migraine.
• Calcium channel blockers are medications that are also used to treat high blood pressure treatment and help to stabilize blood vessel walls. These drugs appear to work by preventing the blood vessels from either narrowing or widening, which affects blood flow to the brain.
• Antidepressants are drugs that work on different chemicals in the brain; their effectiveness in treating migraine is not directly related to their effect on mood. Antidepressants may be helpful for individuals with other types of headaches because they increase the production of serotonin and may also affect levels of other chemicals, such as norepinephrine and dopamine. The types of antidepressants used for migraine treatment include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants (which are also used to treat tension-type headaches).

Natural treatments for migraine include riboflavin (vitamin B2), magnesium, coenzyme Q10, and butterbur.

Non-drug therapy for migraine includes biofeedback and relaxation training, both of which help individuals cope with or control the development of pain and the body’s response to stress.

Lifestyle changes that reduce or prevent migraine attacks in some individuals include exercising, avoiding food and beverages that trigger headaches, eating regularly scheduled meals with adequate hydration, stopping certain medications, and establishing a consistent sleep schedule. Obesity increases the risk of developing chronic daily headache, so a weight loss program is recommended for obese individuals.

Physical Therapies

Bracing yourself for the next headache attack can result in tight, tense muscles. Your health care provider may suggest physical therapy (PT) if you have problems with muscle tension. A therapist may use techniques to relax your muscles and increase normal movement. These include:

• Electrotherapy such as TENS 
• Heat and cold treatments
• Manual (“hands on”) therapy such as head and neck massage
• Stretching exercises

Exercising at home or at the local gym can also be an important part of your headache treatment program. Exercise can include aerobic reconditioning and stretching exercises. Regular aerobic exercise may help decrease how severe and how often people get headaches such as migraine. Muscle tightness and tenderness that bothers many people with chronic headache can be decreased with stretching exercises.

arteriovenous malformation-a tangle of veins and arteries that can disrupt the normal flow of blood and is frequently associated with episodic headache.

aura-a warning of a migraine headache. Usually visual, it may appear as flashing lights, zigzag lines, or a temporary loss of vision, along with numbness or trouble speaking.

autonomic-occurring involuntary. Autonomic nervous system dysfunction is frequently associated with various types of migraine.

basilar-type migraine-a type of migraine, occurring primarily in young women, causing symptoms of abnormal brain stem functioning such as double vision, loss of peripheral vision, numbness, imbalance, or loss of consciousness.

benign intracranial hypertension-increased pressure within the brain that causes severe headaches. It can be caused by clotting in the major cerebral veins or from certain medications (including some antibiotics, human growth hormone replacement, and vitamin A and related compounds).

biofeedback-a process that increases an individual’s voluntary control of physiologic states such as blood pressure and pain response.

cephalgia-head pain.

cervical arterial dissection-a tear in an artery wall that can lead to stroke or transient ischemic attacks.

cervicogenic headache-a type of headache caused by structural irregularities in either the neck or head.

chronic headache-headache that occurs 15 or more days a month over a 3-month period.

cluster headache-sudden, extremely painful headaches that occur in a closely grouped pattern several times a day and at the same times over a period of weeks.

computed tomography (CT)-a type of diagnostic imaging that uses X-rays and computer technology to produce two-dimensional images of organs, bones, and tissues.

cortical spreading depression-a wave of increased brain activity that slowly spreads from the back toward the front of the brain’s surface and may be the basis for migraine aura.

epidural hematoma-bleeding between the brain’s protective coating and the skull.

episodic-comes and goes.

ergot derivative drugs-drugs that bind to the neurotransmitter serotonin and help to decrease the transmission of pain messages along nerve fibers.

hemicrania continua-one-sided headaches that are chronic or continuous and respond to indomethacin treatment.

hemiplegic migraine-a type of migraine causing temporary paralysis on one side of the body.

hypnic headache-a rare form of headache that awakens individuals at night (also called “alarm-clock headache”).

ice cream headache-a painful headache brought on by changes in blood flow that result from a sudden chilling of the roof of the mouth.

ischemic stroke-stroke caused by a clot that blocks blood flow to the brain.

medication overuse headache-caused by the overuse of drugs (more than 3 times weekly) to treat headache. While the medication may help to relieve the headaches temporarily, over time the underlying headache becomes worse and occurs more frequently, creating a vicious cycle of medication use and head pain. The pain improves when the medication is stopped.

meninges-the three layers of membrane that cover the brain and spinal cord.

menstrually-related migraine-a migraine that affects women around the time of their period.

migraine-headaches that are usually pulsing or throbbing and occur on one or both sides of the head. They are moderate to severe in intensity, associated with nausea, vomiting, sensitivity to light and noise, and worsen with routine physical activity.

new daily persistent headache-a type of treatment-resistant chronic headache marked by daily pain that can last for years.

neurotransmitters-chemicals in the brain that helps nerve cells communicate with each other.

nociceptors-nerve fiber endings that receive and transmit pain signals.

ophthalmoplegic migraine-an uncommon form of migraine featuring a droopy eyelid, large pupil, and double vision that may last for weeks after the headache pain is gone.

paroxysmal hemicrania-a rare form of headache that usually begins in adulthood and is marked by one-sided attacks that typically occur 5 to 40 times a day.

postdrome-the period following the headache.

premonitory-meaning before. Some individuals with migraine experience premonitory symptoms up to 24 hours prior to headache pain.

primary exertional headache-headache brought on by fits of coughing or sneezing, or by intense physical activity such as running or lifting.

primary headaches-headaches that occurs on their own with no detectable underlying cause, such as migraine, tension-type headache, and the trigeminal autonomic cephalgias.

primary stabbing headache-also called “ice pick headache” or “jabs and jolts” headache for its extremely intense pain that develops suddenly and generally lasts 1 to 10 seconds.

retinal migraine-a type of migraine that is characterized by attacks of visual loss or disturbances in one eye.

reversible vasoconstriction syndrome-a narrowing of the arteries in the brain that can cause sudden, “thunderclap” headache that may be brought on by bleeding in or around the brain.

secondary headaches-headaches that are caused by an underlying condition or disease.

serotonin-a neurotransmitter present throughout the body and brain that plays an important role in headache and migraine, mood disorders, regulating body temperature, sleep, vomiting, sexuality, and appetite.

status migrainosus-migraine lasting more than 72 hours.

subdural hematoma-bleeding between the brain and its protective membrane covering.

SUNCT (Short-lasting, Unilateral, Neuralgiform headache attacks with Conjunctival injection and Tearing)-a rare form of headache marked by brief recurrent bursts of moderate to severe burning, stabbing, or throbbing pain, usually on one side of the head and around the eye or temple, accompanied by symptoms including watery, reddish eyes, and runny nose.

tension-type headache-a primary headache that is band-like or squeezing and does not worsen with routine activity. It may be brought on by stress.

transient ischemic attack-a strokes that last only a few minutes but signals a subsequent and more severe stroke.

trigger-something that brings about a disease or condition.

triptans-a family of drugs used to treat migraines and cluster headaches by preventing or stopping nerve tissue inflammation and resulting changes in blood vessels.

vascular-refers to blood vessels or the flow of blood.

venous sinus thrombosis-a form of stroke caused by a clot that blocks blood flow in the brain’s veins.