Butalbital

Butalbital
Systematic (IUPAC) name
5-(2-methylpropyl)-5-(2-propenyl)-
2,4,6(1H,3H,5H)-pyrimidinetrione
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a601009
  • US: C (Risk not ruled out)
oral
Pharmacokinetic data
Bioavailability 20-45%
Metabolism hepatic mainly CYP3A4
Half-life 35 hours [1]
Excretion renal
Identifiers
77-26-9 Yes
None
PubChem CID 2481
DrugBank DB00241 Yes
ChemSpider 2387 Yes
UNII KHS0AZ4JVK Yes
KEGG D03182 Yes
ChEBI CHEBI:102524 Yes
ChEMBL CHEMBL454 Yes
Chemical data
Formula C11H16N2O3
224.256
 Yes (what is this?)  (verify)

Butalbital is a barbiturate with an intermediate duration of action. Butalbital is often combined with other medications, such as acetaminophen (paracetamol) or aspirin, and is commonly prescribed for the treatment of pain and headache. The various formulations combined with codeine are FDA-approved for the treatment of tension headaches. Butalbital has the same chemical formula as talbutal but a different structure—one that presents as 5-allyl-5-isobutylbarbituric acid.[2]

Preparations

Combinations include:

Contraindications

Butalbital is not suggested as a first-line treatment for headache because it impairs alertness, brings risk of dependence and addiction, and increases the risk that episodic headaches will become chronic.[3] Opioids also can cause heightened sensitivity to headache pain.[3] When other treatments fail or are unavailable, butalbital may be appropriate for treating headache if the patient can be monitored to prevent the development of chronic headache.[3]

There are specific treatments which are appropriate for targeting migraines and headaches which are preferable to butalbital when available as an option.[4] It is a least preferable option to be used if other available treatments fail.[4]

Side effects

Side effects for any psychoactive drug are difficult to predict, but commonly reported side effects for butalbital include:

Fioricet (50/40/325)

Rare side-effects include Stevens–Johnson syndrome, an adverse reaction to barbiturates, and anaphylaxis.

Butalbital has a very long half-life and accumulates in the body following repeated doses, although therapeutic effects tend to wear off after a few hours the risk of side effects following repeated doses increases with each subsequent dose, as does the severity of side effects which have already presented. Sedation, memory loss, and ataxia are very common after taking fioricet multiple times in one day. The long half-life also means that side effects can persist for hours or days after the last dose and care must be taken when returning to normal activities after each use, motor impairment may be present even after other effects such as sedation have worn off.

The risk and severity of all side effects is greatly increased when butalbital (or butalbital-based medications, such as Fioricet) are combined with other sedatives (ex. ethanol, opiates, benzodiazepines, antihistamines), and other side effects, which are not typically associated with butalbital, may occur. Inhibitors of the hepatic enzyme CYP3A4 may also increase the risk, severity, and duration of side effects, many drugs inhibit this enzyme as do some foods such as grapefruit and the blood orange. Taking butalbital-based medications with some other drugs may also increase the side effects of the other medication.

Dangers and risks

Butalbital is a physically and psychologically addictive barbiturate. Mixing with alcohol increases the risk of intoxication, increases respiratory depression, and increases liver toxicity when it is a butalbital combination including paracetamol (acetaminophen). Many opioid-dependent persons frequently use barbiturates as a potentiator to their normal dose of opiates in order to increase the effects, or with a less than normal dose as means of conserving their supply. Especially when used with the stronger narcotics, suicide or accidental death occurs much more frequently than first reported with one drug alone. Use of alcohol, benzodiazepines, and other CNS-depressants often also contribute to respiratory depression, coma, and in extreme cases fatality.

When benzodiazepines are co-administered with barbiturates, the sum effect of the drugs is far greater than would be expected considering the effect of both drugs separately. This is due to complimentary mechanisms at the GABAA receptor, where benzodiazepines increase the rate of chloride channel opening while barbiturates increase the duration. A dose of a benzodiazepine causes a channel which normally opens once every 30 seconds to open 3 times faster, while a barbiturate causes the channel to pass three chloride ions per opening instead of the normal one. When combined, the channel is now passing nine ions every 30 seconds instead of one, a 9-fold increase in activity.

As with most barbiturates, butalbital is a general inducer of P450 enzymes in both rodents and humans, particularly CYP3A4 (hence inducing its own metabolism), CYP2D6, and CYP2C9, although its P450 enzyme induction capability is far less than that of equivalent doses of phenobarbital or secobarbital (the most potent known enzyme inducers in the barbiturate molecular family). At very high doses it has also been demonstrated to induce glutathione S-transferase A1/glutathione S-transferase A2 in rats, although the doses required to achieve this effect to a clinically significant degree fall within the range of butalbitals LD50, making its use for this purpose impractical and highly dangerous (this effect has not yet been tested in human models, it is therefor unknown whether or not GS-T induction plays a significant role in butalbital's effects in humans, or even occurs at all).

References

  1. ↑ http://www.drugs.com/pro/butalbital-and-acetaminophen.html
  2. ↑ DE Patent 526854
  3. ↑ 3.0 3.1 3.2 American Headache Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Headache Society), retrieved 10 December 2013, which cites
    • Bigal, M. E.; Lipton, R. B. (2009). "Excessive opioid use and the development of chronic migraine". Pain 142 (3): 179–182. doi:10.1016/j.pain.2009.01.013. PMID 19232469.
    • Bigal, M. E.; Serrano, D.; Buse, D.; Scher, A.; Stewart, W. F.; Lipton, R. B. (2008). "Acute Migraine Medications and Evolution from Episodic to Chronic Migraine: A Longitudinal Population-Based Study". Headache: the Journal of Head and Face Pain 48 (8): 1157–1168. doi:10.1111/j.1526-4610.2008.01217.x. PMID 18808500.
    • Scher, A. I.; Stewart, W. F.; Ricci, J. A.; Lipton, R. B. (2003). "Factors associated with the onset and remission of chronic daily headache in a population-based study". Pain 106 (1–2): 81–89. doi:10.1016/S0304-3959(03)00293-8. PMID 14581114.
    • Katsarava, Z.; Schneeweiss, S.; Kurth, T.; Kroener, U.; Fritsche, G.; Eikermann, A.; Diener, H. C.; Limmroth, V. (2004). "Incidence and predictors for chronicity of headache in patients with episodic migraine". Neurology 62 (5): 788–790. doi:10.1212/01.WNL.0000113747.18760.D2. PMID 15007133.
  4. ↑ 4.0 4.1 American Academy of Neurology (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Academy of Neurology), retrieved August 1, 2013, which cites
      • Silberstein, S. D. (2000). "Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 55 (6): 754–762. doi:10.1212/WNL.55.6.754. PMID 10993991.
      • Evers, S.; Afra, J.; Frese, A.; Goadsby, P. J.; Linde, M.; May, A.; Sándor, P. S.; European Federation of Neurological Societies (2009). "EFNS guideline on the drug treatment of migraine - revised report of an EFNS task force". European Journal of Neurology 16 (9): 968–981. doi:10.1111/j.1468-1331.2009.02748.x. PMID 19708964.
      • Institute for Clinical Systems Improvement (2011), Headache, Diagnosis and Treatment of, Institute for Clinical Systems Improvement

External links

"Butalbital". On-line Medical Dictionary. Retrieved June 26, 2005. "Butalbital and Acetaminophen (Systemic)". MedicinePlus Drug Information. Archived from the original on December 30, 2006. Retrieved December 31, 2006. "Controlled Substances in Schedule III". Drug Enforcement Administration. 2007. Retrieved 2007-01-13.