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Editor: Sara Abdijadid Updated: 6/25/2023 7:58:52 AM


Barbiturates are a group of sedative-hypnotic medications used for treating seizure disorder, neonatal withdrawal, insomnia, preoperative anxiety, and induction of coma for increased intracranial pressure. They are also useful for inducing anesthesia. Thiopental was introduced in 1934 for induction of anesthesia for general anesthesia.[1] Thiopental was the predominant IV anesthetic induction agent until its replacement by propofol.[2] In refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for controlling seizure activity.[3] Because of its use in lethal injection protocols, the major supplier of thiopental in the US elected to discontinue production in 2011, and it is unavailable in the USA.[4] FDA-approved barbiturates in clinical use are as below. 

  • Phenobarbital: Phenobarbitone has extensive use as an antiepileptic drug in the neonatal and pediatric population. It is the most cost-effective drug treatment for epilepsy in adults in low-resource countries.[5] Intravenous barbiturates have been used for neurosurgery due to reduced cerebral metabolic rate of oxygen consumption.[6] For individuals with severe traumatic brain injury (TBI), high-dose barbiturates may be a consideration but are not indicated for prophylactic administration.[7] In a review of practice in five European countries, about 20% of patients received barbiturates.[8] In refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for controlling seizure activity.[3]
  • Methohexital: Methohexital has demonstrated safety and efficacy for procedural sedation of short duration for cardioversion and pediatric outpatient surgery.[9][10] Methohexital can be used for fracture reduction in the emergency department and sedation for elective intubation in neonates.[11][12] Methohexital has preferential use in electroconvulsive therapy due to its longer seizure duration.[6]
  • Butalbital: Butalbital is used primarily for the treatment of headache disorders.[13]
  • Pentobarbital: Pentobarbital is used as a  pre-anesthetic medication and status epilepticus.[14] Pentobarbital is used off-label for traumatic brain injury associated with refractory elevated intracranial pressure.[15]
  • Primidone: Primidone is used for seizure disorders. According to the American academy of neurology, depending on comorbidities and potential ADR, primidone(barbiturate) or propranolol can be used for essential tremors.[16]
  • Amobarbital: Amobarbital has a labeled indication for insomnia, but the American Association of Sleep Medicine does not endorse its use.[17]

Mechanism of Action

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Mechanism of Action

Barbiturates cause postsynaptic enhancement of GABA, interacting with alpha and beta subunits of the GABA-A receptor.[18] Barbiturates increase chloride ion flux, resulting in postsynaptic hyperpolarization and CNS depression. Phenobarbital and pentobarbital affect the GABA-A receptors with a dose-dependent response. These drugs activate chloride channels at higher micromolar concentrations associated with anesthetic levels.[19] Both barbiturates and benzodiazepines interact with GABA-A receptors. Still, barbiturates are unique because they potentiate GABA-A receptors while increasing chloride ion influx even with very low concentrations of the GABA neurotransmitter.[20]

Structure-Activity Relationships: The German chemist Adolf von Baeyer synthesized barbituric acid (malonylurea)in 1864.[19] The date of this discovery was December 4, the feast day of Saint Barbara, which was the inspiration for the compound’s name.[21] Barbituric acid was the basis of many other formulations patented by the Bayer company. Due to its lack of lipophilicity, barbituric acid had no innate central nervous system activity. A lipophilic derivative of barbituric acid was developed (barbital: 5,5-diethylbarbituric acid) and successfully induced sleep in dogs.[19] 

Amylobarbitone became the first intravenous anesthetic used in 1928. The formulation of parenteral dosage forms came with the addition of sodium at the C2 position.[21] Lipophilicity was enhanced by Volviler and Tabern with the addition of a sulfur group while replacing an oxygen atom, creating the thiobarbiturates in 1934.[21] In 1957 Methohexital was created by Stoelting with the addition of an aliphatic side chain at carbon 5, along with methylation of the nitrogen atom.[20] The R(+) isomer of many barbiturates produces excitatory effects, while the S(-) isomers produce more depressant effects.[22] Barbiturate classification is according to the duration of their action. The short and intermediate-acting have an effect lasting 2 to 6 hours. Long-acting barbiturates have an effect of longer than 6 hours.[23][24]

Ultra Short-Acting Barbiturates

  • Methohexital
  • Thiopental

 Short-Acting Barbiturates

  • Pentobarbital
  • Secobarbital

Intermediate-acting barbiturates

  • Amobarbital
  • Butalbital

Long-acting Barbiturates

  • Phenobarbital
  • Primidone


Absorption: Phenobarbital is rapidly absorbed with a time-to-peak concentration in 2-4 hours. The bioavailability of phenobarbital is approximately 90% in adults and less in neonatal populations.[25] Sodium salts of barbiturates are absorbed more rapidly, and the presence of food delays the onset of action of orally administered barbiturates. The intravenous route is usually reserved for managing status epilepticus (phenobarbital sodium) or the induction or maintenance of general anesthesia (e.g., methohexital or thiopental). Thiopental observes first-order kinetics in low doses of 5 mg/kg boluses. In high-dose or prolonged infusions, non-linear kinetics will occur due to the progressive saturation of enzyme systems.[26]

Distribution: Highly lipid-soluble barbiturates cross the blood-brain barrier rapidly, but there is rapid redistribution from the CNS to peripheral tissues.[24] Thiopental and methohexital undergo rapid redistribution after intravenous injection into less-vascular tissues, particularly muscle and fat, decreasing the concentration of barbiturates in the plasma and brain. Terminating the effect of a single bolus IV injection of thiopental occurs by redistribution from the central compartment to peripheral compartments.[27]

Metabolism: The oxidation of barbiturates is the most important biotransformation that terminates biological activity. In addition, n-glycosylation is important for the metabolism of phenobarbital. Phenobarbital is metabolized extensively by the cytochrome P450, and the maturation of this enzyme family mainly occurs during the neonatal period.[28][29] Repeated administration of phenobarbital decreases the half-life due to the induction of microsomal enzymes. The self-induced increase in barbiturate metabolism partially accounts for tolerance to barbiturates. In addition, with chronic administration, there is an increase in ALA synthetase enzymes. The effect of barbiturates on ALA synthetase can cause dangerous disease exacerbations in patients with porphyria. Primidone is metabolized to phenylethylmalonamide and phenobarbital; the effectiveness of primidone on essential tremor is independent of its phenobarbital metabolite.[16]

Excretion: About 25% of phenobarbital is excreted unchanged in the urine. The renal excretion can be increased by osmotic diuresis or alkalinization of the urine. The metabolic elimination of barbiturates is more rapid in young people than in the elderly and infants. Age-related changes have been demonstrated in pharmacokinetics due to slower clearance in the elderly, resulting in higher serum concentrations with smaller drug doses.[30] In children, a shorter elimination half-time occurs due to greater clearance.[27] The half-life of phenobarbital decreases by approximately 4.6 hours per day on chronic administration.[31]


Barbiturates are administered in oral and parenteral forms (IM and IV). Intramuscular injections of solutions of the sodium salts such as phenobarbital or amobarbital should be administered in large muscle masses to avoid potential necrosis at superficial sites.

  • Phenobarbital: According to the American Epilepsy Society guidelines, phenobarbital 15 mg/kg in a single dose is suggested for status epilepticus (parenteral benzodiazepines are the first line choice).[32] When administered as an antiepileptic drug for pediatric patients, phenobarbital may be given as an IV loading dose, followed by IV or oral administration.[33] In neonates, the loading dose of phenobarbital is 20 mg/kg intravenously, and the maintenance dose is 3 to 4 mg/kg by mouth. Nonresponders should be administered additional doses of 5 to 10 mg/kg till seizure control. The indication for use typically determines the route of administration for adults. Maintenance therapy for antiepileptic drugs in adults is typically the oral route; other first-line drugs have replaced phenobarbital.[34]
  • Methohexital: Methohexital and thiopental may be administered rectally in pediatrics, particularly if the child cannot cooperate with IV needle administration. This method is best suited in procedures of short duration, such as radiology or dentistry. The usual dose for methohexital is 1 to 1.5 mg/kg for induction. Barbiturates administered for the induction of anesthesia in adults are most commonly given as an IV bolus for a rapid and pleasant loss of consciousness.[35][36]
  • Thiopental: When using the IV route of administration in pediatrics, wide variation in the required dose has been noted. Cote recommended a higher dose range for unpremeditated children.[37] Thiopental was removed from the US market in 2011 largely based on the diversion of the drug within the USA as a lethal injection drug.[38]
  • Pentobarbital: Pentobarbital is administered by IM and IV routes. Pentobarbital is administered by intramuscular route 150 to 200 mg as a single dose pre-anesthetic medication. For status epilepticus, pentobarbital is given as a 5 to 15 mg/kg IV loading dose followed by a continuous infusion of 0.5 to 5 mg/kg/hour. It is important to recognize that continuous infusion dosing of pentobarbital is titrated to EEG (Neurocritical Care Society guidelines).[14]
  • Butalbital: Butalbital is used with aspirin/acetaminophen/caffeine for migraine and tension headaches. American academy of neurology doesn't endorse its use for a long time due to the risk of dependence and medication overuse headaches.[13]
  • Primidone: The usual starting dose of primidone is 100 to 125 mg at bedtime for seizure control in treatment-naive patients. The regular maintenance beyond ten days is 250 mg three times a day. The total daily dose of primidone should not exceed 2000 mg. Primidone is also used to treat essential tremors; the suggested starting dose is 25 mg daily, increasing by 25 or 50 mg per month as tolerated.[39]
  • Amobarbital: The sedative dose of amobarbital is 30 mg to 50 mg, given 2 or 3 times daily. The hypnotic dose is 65 mg to 200 mg at bedtime. Amobarbital is a DEA-scheduled II substance, and agents with better safety profiles should be used due to misuse potential.[40]

Use in Specific Patient Populations

  • Patients with Renal Impairment: No dose adjustment has been provided for methohexital. The use of thiopental is relatively contraindicated in renal disease. Dose reduction is recommended in phenobarbital. Nephrotoxicity is reported with an overdose of phenobarbital.[41]
  • Patients with Hepatic Impairment: No dose adjustment has been provided for methohexital. As phenobarbital undergoes extensive hepatic metabolism, dose reduction is advised.[42]
  • Pregnancy Considerations: The placental transfer occurs within 1 minute of administration.[20] Neonatal depression may occur if thiopental is used as an induction agent for cesarean section. Methohexital can also cross the placental barrier. For general anesthesia, drugs other than methohexital are recommended by ACOG (American College of Obstetricians and Gynecologists).[43] The use of phenobarbitone is associated with major malformations. Antiepileptic agents, lamotrigine and levetiracetam, are preferred during pregnancy.[44][45]
  • Breastfeeding Considerations: Clinical data on the effects of phenobarbital indicates that there is inter and intrapatient variability of excretion in breast milk. Phenobarbital can cause drowsiness in infants, especially when used with other sedating drugs. In a series of breastfeeding infants, for each mg/kg of phenobarbital taken by mothers, the infant's serum concentration increased by 2 to 5 mg/L. Several case reports exist of infant sedation occurring in mothers treated with phenobarbital.[46] Consequently, monitor the infant for drowsiness, and weight gain, especially in younger, exclusively breastfed infants. If there is excessive sedation, discontinuation of breastfeeding is suggested.[46] Concerning the short-acting IV barbiturates, mothers who received methohexital were found in breastmilk at the highest concentrations 1 to 2 hours after an IV dose and undetectable 24 to 48 hours after an IV dose.[47] For thiopental, when used for induction of anesthesia for cesarean section, the highest concentration of thiopental in breast milk was in the first nursing after anesthesia, about 0.9 mg/L.[48] Breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia. However, if a combination of drugs is used during the procedure, follow the standard operating procedure considering the elimination half-life of each agent.[48]

Adverse Effects

For women taking phenobarbital as monotherapy, the drug correlates with congenital defects in exposed infants.[5]

When given in IV anesthetics, barbiturates will produce a reduction in blood pressure and an increase in heart rate. Respiratory depression and apnea may occur.[20]

Thiopental and thiamylal have been shown to release histamine, while methohexital and pentobarbital have minimal histamine release.[49]

Extravasation of thiopental (a vesicant) may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine.[50] Case reports of successful treatment also include the topical application of a eutectic mixture of local anesthetics (EMLA) and the local injection of lidocaine.[51]

Barbiturates such as butalbital can lead to withdrawal symptoms, including seizures. The recommended risk mitigation strategy is to taper off barbituates gradually under supervision.[52]

Hepatotoxicity: Barbiturates can cause allergic reactions and skin rashes associated with mild liver injury. Phenobarbital is predominantly linked with drug-induced liver injury. Phenobarbital-induced serious adverse drug reactions are DRESS (Drug reaction with eosinophilia and systemic symptoms), Stevens-Johnson syndrome, and toxic epidermal necrolysis.[53]

Drug-drug Interactions 

  • Phenobarbital is known to be an inducer of the cytochrome enzyme system, specifically the CYP1A2, 2B6, 2C9, and 3A4/5 isozymes that will reduce the efficacy of warfarin, steroids, psychoactive drugs, and immunosuppressants.
  • Phenobarbital will also lower the plasma concentrations of other antiepileptic drugs, such as lamotrigine, oxcarbazepine, phenytoin, tiagabine, and valproate.[54]
  • Contraceptive failure can occur when systemic hormonal contraception drugs are administered with enzyme inducers like phenobarbital.[55]
  • Phenobarbital is a strong CYP3A4 inducer; avoid combination with hepatitis C drugs paritaprevir/ritonavir, ombitasvir, and dasabuvir.[56]
  • Primidone is also a CYP3A4 inducer; combination with apremilast should be avoided.[57]
  • Barbiturates combined with other CNS depressants like benzodiazepines and opioids can cause oversedation and severe respiratory depression.[58][59]


Absolute contraindications for any barbiturate include status asthmaticus and acute and intermittent variegate porphyria.[20] Hypersensitivity to barbiturates or excipients is a contraindication to their use. Hypersensitivity reactions, including anaphylaxis, have been reported. Barbiturates can trigger hypersensitivity reactions by direct histamine release or IgE-mediated mechanisms.[60]


Monitoring for Misuse: Due to the abuse potential of barbiturates, restricted access started with the passage of the Federal Comprehensive Drug Abuse and Control Act of 1970. Barbiturates are classified as Schedule II-IV based on their abuse potential.[61]

Evaluation and monitoring for anesthesia: Preanesthetic evaluation is required when barbiturates are used for general anesthesia. RCRI (Revised Cardiac Risk Index for Pre-Operative Risk) can estimate the risk of cardiac complications after noncardiac surgery.[62] During anesthesia American Society of Anesthesiologists (ASA) guidelines recommend monitoring oxygenation, ventilation, circulation, and temperature. (Standards for Basic Anesthetic Monitoring). According to the American Society of Anesthesiologists Task Force on postanesthetic care, mental status, patient temperature, pain, nausea/vomiting, and volume status should be monitored.[63]

Development of Tolerance and Dependence: Tolerance is a gradual loss of effectiveness such that the dose has to be increased to maintain the same effect.[23] This effect is partly explained by enzyme induction in the liver. Animal models have demonstrated tolerance. Withdrawal symptoms may occur: nervousness, tremor, agitation, and hypotension may develop 2 to 8 days after the abrupt discontinuation of barbiturates. Additionally, the patient may develop delirium or grand mal seizures.[23] Phenobarbital has a narrow therapeutic range of 10 to 30 mg/L, with 80 mg/L reported as being fatal.[64] A Cochrane review found no clear evidence of a benefit to routine serum monitoring drug concentrations for antiepileptic drugs. Dose titration to control seizures was found to be effective.[65]


Acute barbiturate toxicity may result from an intentional or unintentional overdose. Barbiturates have a history of abuse; New York City Health Department data showed 8469 cases of barbiturate poisoning in the period between 1957 through 1963.[66]  Overdosage of phenobarbital symptoms includes CNS depression, respiratory failure, and hemodynamic instability. No antidote exists. Treatment of an overdose includes supportive care and urinary alkalinization.[64] 

A systematic review demonstrates the efficacy of multiple-dose activated charcoal for phenobarbital and primidone overdose. Haemodialysis and haemoperfusion may be considered in patients having life-threatening barbiturate toxicity.[67] Extracorporeal clearance with dialysis can augment drug elimination in cases of severe butalbital overdose.[68] During recovery, patients with chronic barbiturate misuse can present with seizures and autonomic instability.[52]

Enhancing Healthcare Team Outcomes

Barbiturates have historically been a widely prescribed class of drugs in outpatient and inpatient settings. Barbiturates are controlled substances; thus, all DEA prescription requirements must be met. The prescription drug monitoring program(PDMP) can identify potential misuse and abuse.[69] Benzodiazepines have largely replaced them when used for anti-anxiety or insomnia. IV anesthetic uses of barbiturates are minimal for two reasons:

  • After 2011, major manufacturers no longer produced thiopental or methohexital
  • the preferred routine IV anesthetic induction agent has become propofol due to its availability, rapid onset, and offset

Phenobarbital continues to be used as a second-line antiepileptic drug in the US and has frequent use in low-resource countries as a first-line drug due to its low cost. All healthcare workers, including physicians, and nurse practitioners who prescribe these agents, must be fully aware of the adverse drug reactions, misuse, drug-drug interactions, and the potential to develop physical dependence. When barbiturates are used in anesthesia, supervision by anesthetics and certified registered nurse anesthetists (CRNAs) is necessary. Movement disorder specialists should oversee the use of primidone for essential tremors. Given the potential for severe adverse events, including death, a pharmacist should verify the dosing and perform a thorough medication reconciliation to ensure no drug interactions, particularly additive CNS depressing effects.

The healthcare team must know how to resuscitate the patient in case of an overdose; MICU-level care and consultation with a critical care physician are often required. A toxicologist should be consulted in case of severe overdose. A psychiatrist should be consulted once the patient has recovered in case of an overdose. Prescribing barbiturates and follow-up monitoring requires an interprofessional team approach, including clinicians (MD, DO, NP, PA), specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient outcomes related to barbiturate therapy. [Level 5]


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Barbituric acid
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Sneyd JR, Thiopental to desflurane - an anaesthetic journey. Where are we going next? British journal of anaesthesia. 2017 Dec 1;     [PubMed PMID: 29161390]


Brown TC, Thiopentone and its challengers. Paediatric anaesthesia. 2013 Oct;     [PubMed PMID: 23216953]


Prabhakar H,Kalaivani M, Propofol versus thiopental sodium for the treatment of refractory status epilepticus. The Cochrane database of systematic reviews. 2017 Feb 3;     [PubMed PMID: 28155226]

Level 1 (high-level) evidence


Ruble JH, The     [PubMed PMID: 25121632]


Brodie MJ,Kwan P, Current position of phenobarbital in epilepsy and its future. Epilepsia. 2012 Dec;     [PubMed PMID: 23205961]

Level 1 (high-level) evidence


Kadiyala PK,Kadiyala LD, Anaesthesia for electroconvulsive therapy: An overview with an update on its role in potentiating electroconvulsive therapy. Indian journal of anaesthesia. 2017 May;     [PubMed PMID: 28584345]

Level 3 (low-level) evidence


Haddad SH,Arabi YM, Critical care management of severe traumatic brain injury in adults. Scandinavian journal of trauma, resuscitation and emergency medicine. 2012 Feb 3;     [PubMed PMID: 22304785]


Majdan M,Mauritz W,Wilbacher I,Brazinova A,Rusnak M,Leitgeb J, Barbiturates use and its effects in patients with severe traumatic brain injury in five European countries. Journal of neurotrauma. 2013 Jan 1;     [PubMed PMID: 22950895]


Wood J,Ferguson C, Best evidence topic report. Procedural sedation for cardioversion. Emergency medicine journal : EMJ. 2006 Dec;     [PubMed PMID: 17130605]


Jones NE,Kelleman MS,Simon HK,Stockwell JA,McCracken C,Mallory MD,Kamat PP, Evaluation of methohexital as an alternative to propofol in a high volume outpatient pediatric sedation service. The American journal of emergency medicine. 2017 Aug;     [PubMed PMID: 28330689]


Miner JR,Biros M,Krieg S,Johnson C,Heegaard W,Plummer D, Randomized clinical trial of propofol versus methohexital for procedural sedation during fracture and dislocation reduction in the emergency department. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2003 Sep;     [PubMed PMID: 12957974]

Level 1 (high-level) evidence


Naulaers G,Deloof E,Vanhole C,Kola E,Devlieger H, Use of methohexital for elective intubation in neonates. Archives of disease in childhood. Fetal and neonatal edition. 1997 Jul;     [PubMed PMID: 9279186]


Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015 Jan:55(1):3-20. doi: 10.1111/head.12499. Epub     [PubMed PMID: 25600718]


Brophy GM,Bell R,Claassen J,Alldredge B,Bleck TP,Glauser T,Laroche SM,Riviello JJ Jr,Shutter L,Sperling MR,Treiman DM,Vespa PM,Neurocritical Care Society Status Epilepticus Guideline Writing Committee., Guidelines for the evaluation and management of status epilepticus. Neurocritical care. 2012 Aug     [PubMed PMID: 22528274]


Bernstein JE,Ghanchi H,Kashyap S,Podkovik S,Miulli DE,Wacker MR,Sweiss R, Pentobarbital Coma With Therapeutic Hypothermia for Treatment of Refractory Intracranial Hypertension in Traumatic Brain Injury Patients: A Single Institution Experience. Cureus. 2020 Sep 22     [PubMed PMID: 33110727]


Shanker V, Essential tremor: diagnosis and management. BMJ (Clinical research ed.). 2019 Aug 5;     [PubMed PMID: 31383632]


Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2017 Feb 15:13(2):307-349. doi: 10.5664/jcsm.6470. Epub 2017 Feb 15     [PubMed PMID: 27998379]

Level 1 (high-level) evidence


Chau PL, New insights into the molecular mechanisms of general anaesthetics. British journal of pharmacology. 2010 Sep;     [PubMed PMID: 20735416]

Level 3 (low-level) evidence


Löscher W,Rogawski MA, How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. 2012 Dec;     [PubMed PMID: 23205959]

Level 3 (low-level) evidence


Martone CH,Nagelhout J,Wolf SM, Methohexital: a practical review for outpatient dental anesthesia. Anesthesia progress. 1991 Nov-Dec;     [PubMed PMID: 1842156]


Cozanitis DA, One hundred years of barbiturates and their saint. Journal of the Royal Society of Medicine. 2004 Dec;     [PubMed PMID: 15574863]


Ho IK,Harris RA, Mechanism of action of barbiturates. Annual review of pharmacology and toxicology. 1981;     [PubMed PMID: 6263177]

Level 3 (low-level) evidence


Devenyi P,Wilson M, Barbiturate abuse and addiction and their relationship to alcohol and alcoholism. Canadian Medical Association journal. 1971 Feb 6;     [PubMed PMID: 4924250]


Zhang Q,Yu Y,Lu Y,Yue H, Systematic review and meta-analysis of propofol versus barbiturates for controlling refractory status epilepticus. BMC neurology. 2019 Apr 6     [PubMed PMID: 30954065]

Level 1 (high-level) evidence


Jalling B, Plasma concentrations of phenobarbital in the treatment of seizures in newborns. Acta paediatrica Scandinavica. 1975 May;     [PubMed PMID: 1155069]


Stanski DR,Mihm FG,Rosenthal MH,Kalman SM, Pharmacokinetics of high-dose thiopental used in cerebral resuscitation. Anesthesiology. 1980 Aug;     [PubMed PMID: 7416528]


Sorbo S,Hudson RJ,Loomis JC, The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology. 1984 Dec;     [PubMed PMID: 6507924]


Stanski DR,Maitre PO, Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology. 1990 Mar;     [PubMed PMID: 2310020]


Burch PG,Stanski DR, The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology. 1983 Feb;     [PubMed PMID: 6824168]


Homer TD,Stanski DR, The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology. 1985 Jun;     [PubMed PMID: 4003792]


Pacifici GM, Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Current pediatric reviews. 2016     [PubMed PMID: 26496779]


Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016 Jan-Feb:16(1):48-61. doi: 10.5698/1535-7597-16.1.48. Epub     [PubMed PMID: 26900382]

Level 1 (high-level) evidence


Moffett BS,Weingarten MM,Galati M,Placencia JL,Rodman EA,Riviello JJ,Kayyal SY, Phenobarbital population pharmacokinetics across the pediatric age spectrum. Epilepsia. 2018 Jul;     [PubMed PMID: 29897629]


Nevitt SJ,Sudell M,Weston J,Tudur Smith C,Marson AG, Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. The Cochrane database of systematic reviews. 2017 Jun 29;     [PubMed PMID: 28661008]

Level 1 (high-level) evidence


Hunter MJ,Griswold JD,Rosenberg M, Administration of methohexital for pediatric outpatient dentistry. Anesthesia progress. 1990 Sep-Oct;     [PubMed PMID: 2096749]


Carrel R,Binns WH Jr, Rectal pentothal sedation for selected patients. Anesthesia progress. 1975 Sep-Oct;     [PubMed PMID: 1060389]


Coté CJ,Goudsouzian NG,Liu LM,Dedrick DF,Rosow CE, The dose response of intravenous thiopental for the induction of general anesthesia in unpremedicated children. Anesthesiology. 1981 Dec;     [PubMed PMID: 7305061]


American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists., Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002 Apr     [PubMed PMID: 11964611]

Level 1 (high-level) evidence


Lenka A,Louis ED, Primidone Intolerance in Essential tremor: Is it More than Just Age? Tremor and other hyperkinetic movements (New York, N.Y.). 2021     [PubMed PMID: 35070493]


Caulkins JP,Goyeneche LA,Guo L,Lenart K,Rath M, Outcomes associated with scheduling or up-scheduling controlled substances. The International journal on drug policy. 2021 May     [PubMed PMID: 33476862]


Mahmoud SH,Zhou XY,Ahmed SN, Managing the patient with epilepsy and renal impairment. Seizure. 2020 Feb 10     [PubMed PMID: 32087549]


Patsalos PN,Spencer EP,Berry DJ, Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update. Therapeutic drug monitoring. 2018 Oct;     [PubMed PMID: 29957667]


American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 209: Obstetric Analgesia and Anesthesia. Obstetrics and gynecology. 2019 Mar:133(3):e208-e225. doi: 10.1097/AOG.0000000000003132. Epub     [PubMed PMID: 30801474]


Gedzelman E,Meador KJ, Antiepileptic drugs in women with epilepsy during pregnancy. Therapeutic advances in drug safety. 2012 Apr     [PubMed PMID: 25083227]

Level 3 (low-level) evidence


Patel SI,Pennell PB, Management of epilepsy during pregnancy: an update. Therapeutic advances in neurological disorders. 2016 Mar     [PubMed PMID: 27006699]

Level 3 (low-level) evidence


Phenobarbital 2006;     [PubMed PMID: 30000331]


Methohexital 2006;     [PubMed PMID: 30000358]


Thiopental 2006;     [PubMed PMID: 30000360]


Hirshman CA,Edelstein RA,Ebertz JM,Hanifin JM, Thiobarbiturate-induced histamine release in human skin mast cells. Anesthesiology. 1985 Oct;     [PubMed PMID: 2412468]


Le A,Patel S, Extravasation of Noncytotoxic Drugs: A Review of the Literature. The Annals of pharmacotherapy. 2014 Jul;     [PubMed PMID: 24714850]


Mao CC,Hsieh YC,Hseu SS,Tsai SK,Lee TY, EMLA cream and lidocaine local injection in the treatment of extravenous thiopental injection--a case report. Acta anaesthesiologica Sinica. 1997 Jun;     [PubMed PMID: 9293651]

Level 3 (low-level) evidence


Rodulfo A,Augsten A,Wainwright E,Abramovici G, A Case of Severe Fioricet Withdrawal Presenting During Admission to an Inpatient Psychiatric Unit. Case reports in psychiatry. 2021;     [PubMed PMID: 34790421]

Level 3 (low-level) evidence


Barbiturates LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012     [PubMed PMID: 31643584]


Brodie MJ,Mintzer S,Pack AM,Gidal BE,Vecht CJ,Schmidt D, Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013 Jan;     [PubMed PMID: 23016553]


Anderson S,Mauskopf J,Talbird SE,White A,Srinivasan M, Antiseizure medications and oral contraceptives: Impact of enzyme inducers on pregnancy outcomes and costs. Epilepsy & behavior : E&B. 2021 Dec     [PubMed PMID: 34775242]


Menon RM,Badri PS,Wang T,Polepally AR,Zha J,Khatri A,Wang H,Hu B,Coakley EP,Podsadecki TJ,Awni WM,Dutta S, Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. Journal of hepatology. 2015 Jul     [PubMed PMID: 25646891]

Level 1 (high-level) evidence


Liu Y,Zhou S,Wan Y,Wu A,Palmisano M, The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers. British journal of clinical pharmacology. 2014 Nov;     [PubMed PMID: 24962564]


Savelloni J,Gunter H,Lee KC,Hsu C,Yi C,Edmonds KP,Furnish T,Atayee RS, Risk of respiratory depression with opioids and concomitant gabapentinoids. Journal of pain research. 2017;     [PubMed PMID: 29180889]


Abrahamsson T,Berge J,Öjehagen A,Håkansson A, Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug and alcohol dependence. 2017 May 1     [PubMed PMID: 28315808]


Montañez MI,Mayorga C,Bogas G,Barrionuevo E,Fernandez-Santamaria R,Martin-Serrano A,Laguna JJ,Torres MJ,Fernandez TD,Doña I, Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis. Frontiers in immunology. 2017     [PubMed PMID: 28611774]


Gabay M, The federal controlled substances act: schedules and pharmacy registration. Hospital pharmacy. 2013 Jun;     [PubMed PMID: 24421507]


Roshanov PS,Walsh M,Devereaux PJ,MacNeil SD,Lam NN,Hildebrand AM,Acedillo RR,Mrkobrada M,Chow CK,Lee VW,Thabane L,Garg AX, External validation of the Revised Cardiac Risk Index and update of its renal variable to predict 30-day risk of major cardiac complications after non-cardiac surgery: rationale and plan for analyses of the VISION study. BMJ open. 2017 Jan 9     [PubMed PMID: 28069624]

Level 1 (high-level) evidence


Apfelbaum JL, Silverstein JH, Chung FF, Connis RT, Fillmore RB, Hunt SE, Nickinovich DG, Schreiner MS, Silverstein JH, Apfelbaum JL, Barlow JC, Chung FF, Connis RT, Fillmore RB, Hunt SE, Joas TA, Nickinovich DG, Schreiner MS, American Society of Anesthesiologists Task Force on Postanesthetic Care. Practice guidelines for postanesthetic care: an updated report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. Anesthesiology. 2013 Feb:118(2):291-307. doi: 10.1097/ALN.0b013e31827773e9. Epub     [PubMed PMID: 23364567]

Level 1 (high-level) evidence


Hoyland K,Hoy M,Austin R,Wildman M, Successful use of haemodialysis to treat phenobarbital overdose. BMJ case reports. 2013 Nov 21;     [PubMed PMID: 24265338]

Level 3 (low-level) evidence


Tomson T,Dahl ML,Kimland E, Therapeutic monitoring of antiepileptic drugs for epilepsy. The Cochrane database of systematic reviews. 2007 Jan 24;     [PubMed PMID: 17253477]

Level 1 (high-level) evidence




Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning - a systematic review. Clinical toxicology (Philadelphia, Pa.). 2011 Jan:49(1):2-12. doi: 10.3109/15563650.2010.550582. Epub     [PubMed PMID: 21288146]

Level 1 (high-level) evidence


Poyant JO,Albright R,Clain J,Pandompatam G,Barreto EF, Extracorporeal elimination of butalbital in acute aspirin-butalbital-caffeine-codeine (Fiorinal with Codeine) poisoning. Clinical toxicology (Philadelphia, Pa.). 2018 Jun     [PubMed PMID: 29124988]


Weaver MF, Prescription Sedative Misuse and Abuse. The Yale journal of biology and medicine. 2015 Sep     [PubMed PMID: 26339207]