Barbiturate Toxicity

Continuing Education Activity

Barbiturates are a class of sedative-hypnotic drugs. They are commonly used as antiepileptics (phenobarbital) and for the induction of general anesthesia (thiopental). This activity illustrates the evaluation and management of barbiturate toxicity and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the epidemiology of barbiturate toxicity.
• Review the symptoms of withdrawal in the physical examination of patients with barbiturate toxicity.
• Explain the use of immunoassays (EIA) in the detection of the drug in patients with barbiturate toxicity.
• Describe the importance of the interprofessional team in educating patients to prevent further cases of barbiturate toxicity.

Introduction

Barbiturates are a class of sedative-hypnotic drugs. They are commonly used as antiepileptics (phenobarbital) and for the induction of general anesthesia (thiopental). Some states administer barbiturates for physician-assisted suicide/euthanasia and use them for capital punishment by lethal injection. Their use in clinical practice has largely been replaced by benzodiazepines such as alprazolam, diazepam, and lorazepam due to the lower risk of overdose and available antidote to reverse toxicity. Barbiturates are used as a laboratory buffer and can be found in clinical and research laboratories.[1][2]

Barbiturates are controlled substances that pose a high risk for abuse, given their psychoactive effects. Restrictions on access to barbiturates have caused the number of overdoses to decline. Common barbiturates include the following:

• Methohexital and thiopental are used as anesthetics
• Phenobarbital and primidone are used in the treatment of seizures
• Amobarbital is used as an investigative agent in the Wada test (neurological assessment of cerebral hemispheres) 
• Butalbital, in combination with other medications, is used for headaches and muscle pain

Etiology

Barbiturate overdose can be intentional or unintentional. Decreased use of this controlled substance has led to a decrease in barbiturate-related fatalities. However, this medication should still be considered in cases of suspected overdose in patients with respiratory depression. A study in 2016 described two cases of intentional barbiturate overdose with medication purchased over the internet. These medications also can be obtained in laboratory settings as they are often used as buffers. Intentional overdose is closely related to the epidemiology of depression and the presence of coexisting medical conditions such as anxiety and other mood disorders. Unintentional overdose often results when patients co-ingest substances, such as alcohol and benzodiazepines, that have additive effects that result in sedation and decreased respiration.[3][4]

Epidemiology

Barbiturate abuse was popular in the 60s and 70s, but strict guidelines and the advent of newer sedative-hypnotics, like benzodiazepines, have led to a decrease in barbiturate availability. Currently, deaths from drug overdose have become the leading cause of death in the United States for individuals under the age of 50 years, with opioid poisonings topping the list. Sedative-hypnotic agents, as a group, comprise the fifth leading cause of reported fatalities according to the 2012 National Poison Data System Database, with pentobarbital being the most common barbiturate used.[5]

Pathophysiology

Barbiturates act on GABA-A receptors by increasing the amount of time the chloride ion channel is opened, which increases the affinity of the receptor for GABA. GABA is the primary inhibitory neurotransmitter of the central nervous system, which acts to reduce neuronal activity. In contrast to benzodiazepines, they also act to increase chloride influx in the absence of GABA, which accounts for their ability to significantly depress the central nervous system and contribute to their toxicity.[6]

The toxic dose of barbiturates varies. However, an oral dose of one gram for most barbiturates can cause significant poisoning in an adult. Fatal cases of ingestion have occurred with doses ranging between 2.0 and 10.0 grams; the usual lethal blood level ranges from 40 to 80 mcg/mL.

Toxicokinetics

Barbiturates have various onsets of action, durations, half-lives, and toxic levels, depending on the lipid solubility and rate of metabolic inactivation. The onset of action for oral administration ranges from 20 to 60 minutes, and intravenous administration can range from almost immediate to 5 minutes. High lipid-solubility in some (amobarbital, pentobarbital, and thiopental) allow them to be well absorbed and rapidly redistributed. Most are rapidly metabolized to inactive compounds before they are excreted in the urine. However, phenobarbital is only partially converted and can be found unchanged in the urine. Phenobarbital is a long-acting, polar drug that is slowly absorbed and slowly redistributed, contributing to its longer duration of action. Barbiturates easily cross the placenta and are excreted into breast milk.

Barbiturates are also hepatic enzyme inducers which means that they will induce the metabolism of other medications, including other barbiturates. Pentobarbital and phenobarbital have increased the clearance rate and reduced the plasma concentrations of some beta-blockers. Abrupt cessation of these barbiturates while taking a beta-blocker could increase the effect of the beta-blocker or cause frank toxicity.[7]

History and Physical

Patient history should focus on determining the exact type and amount of medication taken and whether there has been co-ingestion of other substances. Symptoms of barbiturate toxicity vary from case to case but commonly include difficulty thinking, decreased level of consciousness, bradycardia or rapid and weak pulse, poor coordination, vertigo, nausea, muscle weakness, thirst, oliguria, decreased temperature, and dilated or contracted pupils. Fatal cases are marked by coma, hypotension (low blood pressure), and respiratory depression (decreased efforts to breathe), evidenced by cyanosis and hypotension. Pulmonary edema is another complication associated with barbiturate toxicity and contributing to respiratory depression and death.  It is also important to determine if the individual has taken other substances that may have additive effects, such as ethanol (alcohol), benzodiazepines, and opiates.  

Chronic abusers can develop severe withdrawal symptoms within 8 to 15 hours of cessation.  Symptoms include restlessness, tremors, hyperthermia, sweating, insomnia, anxiety, seizures, circulatory failure, and potentially death.

Physical examination should include serial mental status, vital signs, and neurologic examinations conducted at regular intervals. Barbiturates also have been associated with thrombocytopenia and pulmonary eosinophilia (with febarbamate).

Evaluation

As with most drug and medication-related toxicities, evaluation often includes a qualitative assessment of the amount of drug taken with a plasma or urine screening test. Plasma barbiturate concentration and ingested dose have been implicated as the most important correlates of toxicity. Immunoassays (EIA) can provide a cost-effective and sensitive method to detect barbiturates and other substances in the body. Another method often used is gas chromatography/mass spectrometry (GC/MS), which can further identify and confirm the presence of a particular barbiturate.

Treatment / Management

Treatment of barbiturate toxicity remains supportive as there is no specific antidote for overdose. The first step in treatment, as with any overdose, is assessing the patient’s airway, breathing, and circulation. With significant sedation and respiratory depression, intubation and mechanical ventilation may become necessary. Early treatment with activated charcoal may be useful and can be given via nasogastric tube. Patients will likely need to be admitted or observed. During recovery, the patient should receive counseling about the dangers of barbiturate misuse. Long-term barbiturate use can cause tolerance and physical dependence. Therefore, withdrawal symptoms can occur with abrupt discontinuation.[8][1]

Other options for managing barbiturate toxicity include forced alkaline diuresis and hemodialysis for severe cases. Bemegride (Megimide) is a central nervous system stimulant that increases respiration and can be used as a treatment for depressant toxicity. It is, however, an emetic that raises the concern of emesis and aspiration.

Management of long-term use involves restoring central nervous system (CNS) inhibitory tone. Abrupt cessation can lead to severe withdrawal symptoms; therefore, discontinuance of barbiturates should be a gradual taper using medications that demonstrate cross-tolerance, with the first line being benzodiazepines.

Differential Diagnosis

The differential diagnosis should include intoxication by other substances with sedative effects, such as benzodiazepines, anticonvulsants (carbamazepine), alcohols (ethanol, ethylene glycol, methanol), opioids, carbon monoxide, sleep aids, and gamma-Hydroxybutyric acid (GHB – a known date rape drug). Natural diseases that can result in disorientation may be in the differential, including hypoglycemia and myxedema coma. In the right setting, hypothermia should be ruled out. 

Prognosis

Individuals suffering from barbiturate overdose typically do well if they receive prompt medical treatment and are otherwise healthy. The patient outcome depends on the amount of barbiturate taken, the specific barbiturate used, other drugs that were ingested or injected, promptness of medical care, and comorbidities. Individuals with other significant health conditions, such as heart and pulmonary disease, may have a more complicated clinical course. For example, an individual with coronary artery atherosclerosis and/or cardiomegaly (an enlarged heart) will be already prone to suffering a myocardial infarction. Respiratory depression or hypotension from a depressant drug (like a barbiturate) will further decrease the amount of oxygen reaching the heart. An individual with a chronic obstructive pulmonary disease (COPD) or another pulmonary disease will have an increased risk for complications since their respiratory drive is compromised with barbiturate toxicity.

Complications

Complications include hypotension, coma, and respiratory depression.  It is important to maintain the respiratory and cardiovascular status, as failure to do so can result in hypoxic brain injury and death. Rarely, phenobarbital has been associated with Steven-Johnson syndrome, a medical emergency that results in blisters (especially mucous membranes), fever, and widespread pain.

Long-term abuse has been associated with depression, loss of appetite, achiness, and rarely liver damage. As previously discussed, withdrawal symptoms can be severe, and the patient should be monitored carefully and treated accordingly. 

Deterrence and Patient Education

It is essential to determine whether the overdose was accidental or deliberate. The former requires patient counsel on proper dosing or a switch to a different, less toxic agent. Deliberate overdose treatment after stabilization starts with psychological counseling and evaluation, along with a switch in agents.[9]

Enhancing Healthcare Team Outcomes

Barbiturate toxicity is not very common today because this class of drugs is less frequently prescribed. However, it is important for all healthcare workers to understand the toxicity of the drug and how to manage it. Despite the lack of an antidote, survival with supportive therapy is excellent. Mortality rates associated with barbiturate toxicity are less than 2%. However, the management of the patient is usually in the ICU with very close monitoring. The key to preventing morbidity and mortality from barbiturate overdose is patient education. The parents should be asked to store the drug in a locked cabinet away from the easy reach of children. Any patient who intentionally takes an overdose of barbiturate should be referred to a mental health counselor prior to discharge. Patients with a drug addiction should be referred to a drug rehabilitation center.[10][11]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 15, 2023. Phenobarbital. [PubMed: 30000331]

2.

Agulnik A, Kelly DP, Bruccoleri R, Yuskaitis C, Ebrahimi-Fakhari D, Sahin M, Burns MM, Kohane DS. Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose. Pediatrics. 2017 May;139(5) [PMC free article: PMC9923579] [PubMed: 28557718]

3.

Hassanian-Moghaddam H, Ghadiri F, Shojaei M, Zamani N. Phenobarbital overdose presenting with status epilepticus: A case report. Seizure. 2016 Aug;40:57-8. [PubMed: 27348061]

4.

Crellin SJ, Katz KD. Pentobarbital Toxicity after Self-Administration of Euthasol Veterinary Euthanasia Medication. Case Rep Emerg Med. 2016;2016:6270491. [PMC free article: PMC4735920] [PubMed: 26881149]

5.

El Moheb M, Herrera-Escobar JP, Breen K, Orlas C, Haynes AN, Levy-Carrick NC, Nehra D, Sanchez SE, Salim A, Velmahos G, Kaafarani HMA. Long-term outcomes of psychoactive drug use in trauma patients: A multicenter patient-reported outcomes study. J Trauma Acute Care Surg. 2021 Feb 01;90(2):319-324. [PubMed: 33264267]

6.

Tachibana K, Hashimoto T, Kato R, Tsuruga K, Ito R, Morimoto Y. Long-lasting effects of neonatal pentobarbital administration on spatial learning and hippocampal synaptic plasticity. Brain Res. 2011 May 04;1388:69-76. [PubMed: 21385570]

7.

Fletcher ML, Sarangarm P, Nash J, Smolinske SC, Alunday RL, Seifert SA, Warrick BJ. A systematic review of second line therapies in toxic seizures. Clin Toxicol (Phila). 2021 Jun;59(6):451-456. [PubMed: 33755521]

8.

Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning - a systematic review. Clin Toxicol (Phila). 2011 Jan;49(1):2-12. [PubMed: 21288146]

9.

Miller TR, Swedler DI, Lawrence BA, Ali B, Rockett IRH, Carlson NN, Leonardo J. Incidence and Lethality of Suicidal Overdoses by Drug Class. JAMA Netw Open. 2020 Mar 02;3(3):e200607. [PMC free article: PMC7090840] [PubMed: 32202643]

10.

Forrester MB. Human exposures to pentobarbital-phenytoin combination veterinary drugs. Hum Exp Toxicol. 2017 Jul;36(7):755-761. [PubMed: 27465984]

11.

Yerby MS. Pregnancy, teratogenesis, and epilepsy. Neurol Clin. 1994 Nov;12(4):749-71. [PubMed: 7845341]

12.

Sae-Heng T, Rajoli RKR, Siccardi M, Karbwang J, Na-Bangchang K. Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria. CPT Pharmacometrics Syst Pharmacol. 2022 Jan;11(1):104-115. [PMC free article: PMC8752110] [PubMed: 34730282]

Disclosure: Jolee Suddock declares no relevant financial relationships with ineligible companies.

Disclosure: Kristen Kent declares no relevant financial relationships with ineligible companies.

Disclosure: Matthew Cain declares no relevant financial relationships with ineligible companies.