Benzodiazepine overdose is a common cause of hospitalization in the United States, associated with about 30% of overdose cases. Such incidences fixedly increase in quantity and are important to consider when dealing with patients who have a history of drug abuse or predisposing factors for a possible overdose. These comprise e.g. psychological disorders, post-traumatic stress syndrome in patients with a military background, depressive or suicidal states.

Benzodiazepines are a class of medication with anxiolytic, analgesic, sedative and hypnotic features marking them a target of drug abuse and subsequent overdose [1]. Illegitimate practices and 'doctor shopping', involving patients visiting multiple doctors, lead to the unreasonable prescription of benzodiazepines and consecutive abuse [2]. Psychiatric patients, on the other hand, are known to use benzodiazepines in an attempt of suicide or intentional self-harm [3].

Often, polydrug users execute the administration of benzodiazepines in combination with alcohol, antidepressants or opioids giving rise to the failure of cardiovascular and respiratory systems [4]. Other complications include neurological, renal impairment, muscular complications like hypotonia, and possible hearing loss.

Acute manifestations in overdosed patients usually involve collapse with seizures, cyanosis due to respiratory failure, loss of consciousness, coma and possible cardiac arrest [5]. On examination of the eyes, the patient might have fixed miosis or pinpoint pupil.

• Unconsciousness

  Although most benzodiazepine overdoses are known to be safe and nonfatal without coingestions, morbidity or mortality after benzodiazepine overdose is closely related with the duration of unconsciousness or depth of compromised airway. [ncbi.nlm.nih.gov]

  A 67-year-old woman came to our hospital unconscious 19.5 hours after clonazepam overdose, due to delayed detection. The chest x-ray showed focal segmental atelectasis on the left lung field. [jstage.jst.go.jp]

  Flumazenil, which is a competitive antagonist of GABA receptors, can help to confirm a suspected diagnosis of benzodiazepine overdose in unconsciousness poisoned patients. The management of acute benzodiazepine poisoning is mainly supportive. [dlib.si]

  […] is already unconscious – to make sure that none of these symptoms threatens the person’s life or health. [deserthopetreatment.com]

  A magnetic resonance imaging (MRI) of the brain is a necessity if the patient appears unconscious, comatose and with a possible risk of acidosis. [symptoma.com]

• Hypothermia

  Hypothermia may occur. Serious complications are more likely when newer short-acting agents are involved or when other depressant drugs have been ingested. Diagnosis usually is based on the history of ingestion ... [accessmedicine.mhmedical.com]

  3.7 Overdose Overdose with a benzodiazepine can cause drowsiness, dysarthria and nystagmus ; very large overdose may cause hypothermia and rhabdomyolysis. [mhra.gov.uk]

  Apnoea indicated airway obstruction Large ingestions can rarely cause hypothermia, bradycardia and hypotension. [lifeinthefastlane.com]

  […] been abusing these substances begins showing any of the signs listed below, seek immediate medical attention: Loss of balance Delirium Hallucinations Loss of consciousness Coma Double vision Labored or otherwise impaired breathing Irregular heart rate Hypothermia [longleafhospital.com]

• Gastric Lavage

  The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. [ncbi.nlm.nih.gov]

  Initiate gastric lavage for clinically significant recent ingestions (ie, within 30 minutes). Ensure/monitor airway patency/protective reflexes during the above treatments. [anesth.unboundmedicine.com]

  Lyons, Juan Ochoa and Christopher King, Hypothermia: An Unusual Indication for Gastric Lavage, The Journal of Emergency Medicine, 40, 2, (176), (2011). T. [doi.org]

  Occasionally, gastric lavage and administration of activated charcoal is indicated, but only if the patient is awake and potentially sensitive to benzodiazepines and if a large dose has been ingested within the last 1 to 2 hours. [link.springer.com]

  Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. [inchem.org]

• Malaise

  Less commonly, patients may also experience nausea, malaise, blurred vision, sweating, nightmares, depression, muscle coordination problems,tremors, and muscle twitching or spasms. [rxlist.com]

  […] antihypertensives (labetalol - need alpha-1 blockade) vitamin C - promotes excretion non-pharmacologic do not restrain patients may result in rhabdomyolysis Withdrawal presentation severe depression and suicidality hyperphagia, hypersomnolence, fatigue, malaise [step2.medbullets.com]

• Aspiration

  […] demonstrates, careful attention and repetitive evaluations before and after use of flumazenil may be needed in benzodiazepine overdose because resedation occurs in approximately 30% of total flumazenil-treated cases, which suggests that the risk of aspiration [ncbi.nlm.nih.gov]

  Oral benzodiazepine (BZD) overdoses, without co-ingestions, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. In mixed overdoses, they can potentiate the effect of alcohol or other sedative-hypnotics. [emedicine.medscape.com]

  However, careful attention and repetitive evaluations before and after flumazenil administration may be needed in benzodiazepine overdose because resedation occurs in approximately 30% of total flumazenil-treated cases, which suggests that the risk of aspiration [jstage.jst.go.jp]

• Respiratory Insufficiency

  The level of consciousness and respiratory insufficiency on the scene were assessed by responsiveness to a verbal stimulus and pulse oximetry. [ncbi.nlm.nih.gov]

  In the case by Łukasik-Głębocka et al, 4 respiratory insufficiency returned 30 minutes after receiving flumazenil. [mhc.cpnp.org]

• Dyspnea

  Note: preexisting conditions that compromise respiratory function such as chronic obstructive pulmonary disease, sleep apnea, asthma, or pneumonia clinical indicators of changes in respiratory function, such as respiratory rate, dyspnea, hypoxemia, and [mdedge.com]

• Hypotension

  Although rare, this may result in hypotension, cardiac dysrhythmias, lactic acidosis, seizures, or coma. [emedicine.medscape.com]

  Coma, life-threatening hypotension, bradycardia and clinically significant respiratory depression are rare if only a benzodiazepine has been taken. [mhra.gov.uk]

  Aggressive/expectant airway management for frank/anticipated inadequacy of protective airway reflexes Supine/Trendelenburg positioning and aggressive IV fluid therapy for hypotension GI decontamination Activated charcoal 1 g/kg PO or per NG tube is effective [anesth.unboundmedicine.com]

  Clinical features : CNS depressio n : lethargy, somnolence, hyporeflexia Respiratory depression Mild hypotension Ataxia Slurred speech Carbamazepine and oxcarbazepine: possibly SIADH Diagnostics Routine urine screening for benzodiazepine metabolites [amboss.com]

• Suggestibility

  […] overdose.However, as the case we present demonstrates, careful attention and repetitive evaluations before and after use of flumazenil may be needed in benzodiazepine overdose because resedation occurs in approximately 30% of total flumazenil-treated cases, which suggests [ncbi.nlm.nih.gov]

  This suggests that benzodiazepine use is not implicated in the overdose. However there is evidence to suggest that benzodiazepines potentiate the effects of methadone, with several theories as to why. [bestbets.org]

  Many published articles suggest that flumazenil may have some effect in clearing hepatic encephalopathy. [pharmacyjoe.com]

  Thus the importance of monitoring the affected patient is suggested. Urine sample analysis may expose high levels of benzodiazepines. [symptoma.com]

  Researchers suggest emphasizing the danger of overdose when taking benzodiazepines with opioid painkillers or with alcohol, along with suggesting talk therapy as an alternative to benzos for treating anxiety. Source: Bachhuber M, Starrels J, et al. [medicaldaily.com]

• Confusion

  Other effects can include: confusion dizziness jitteriness/excitability slurred speech loss of coordination impaired judgement difficulty in thinking clearly memory loss mood swings and aggressive behaviour. [mydr.com.au]

  In long-term users who have developed dependence, cessation of BZDs can result in a withdrawal syndrome, with manifestations including anxiety, irritability, confusion, seizures, and sleep disorders. [1] Alprazolam withdrawal syndrome may be especially [emedicine.medscape.com]

  Extreme drowsiness or trouble staying awake Slurred speech or confusion Agitation Lack of muscle coordination Coma How is a benzodiazepine overdose diagnosed? Your healthcare provider will ask about the medicines you take. [drugs.com]

  The signs and symptoms of benzodiazepine overdose are: Somnolence Confusion Diminished reflexes Respiratory depression Apnea Respiratory arrest Cardiac arrest The treatment for benzodiazepine overdose is: Discontinue dental treatment Call for assistance [dentalcare.com]

  A higher dose of benzodiazepines can make you feel drowsy, confused, aggressive, and uncoordinated. Benzodiazepine withdrawal symptoms include headaches, heart palpitations, nausea, sweating and shakiness. [drugfoundation.org.nz]

• Slurred Speech

  Other effects can include: confusion dizziness jitteriness/excitability slurred speech loss of coordination impaired judgement difficulty in thinking clearly memory loss mood swings and aggressive behaviour. [mydr.com.au]

  Other effects may include slurred speech, loss of motor coordination, weakness, headache, lightheadedness, blurred vision, dizziness, nausea, vomiting, low blood pressure, and slowed breathing. [www1.nyc.gov]

  Clinical features : CNS depressio n : lethargy, somnolence, hyporeflexia Respiratory depression Mild hypotension Ataxia Slurred speech Carbamazepine and oxcarbazepine: possibly SIADH Diagnostics Routine urine screening for benzodiazepine metabolites [amboss.com]

  Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Generally, patients with benzodiazepine-induced coma have hyporeflexia and midposition or small pupils. Hypothermia may occur. [accessmedicine.mhmedical.com]

  Signs of an Overdose on Xanax, Valium, or Klonopin Symptoms of overdose on Xanax, Valium, or Klonopin include: Drowsiness or extreme fatigue Confusion, agitation, anxiety, and mood changes Dizziness Slurred speech or acting drunk Amnesia Physical weakness [americanaddictioncenters.org]

• Agitation

  Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. [ncbi.nlm.nih.gov]

  Findings on physical examination may include the following: Nystagmus Hallucinations Slurred speech Ataxia Coma Hypotonia Weakness Altered mental status, impairment of cognition Amnesia Paradoxical agitation Respiratory depression Hypotension See Presentation [emedicine.medscape.com]

  You feel extremely agitated. When should I contact my healthcare provider? You have questions or concerns about your condition or care. Care Agreement You have the right to help plan your care. [drugs.com]

   BZDs commonly are used for a variety of situations that include 1. seizure control 2. anxiety 3. alcohol withdrawal 4. insomnia 5. control of drug-associated agitation 6. muscle relaxants 7. preanesthetic agents. 8. [slideshare.net]

• Amnesia

  BACKGROUND: A prospective study was conducted to investigate the presence of anterograde amnesia in those who attempted suicide by benzodiazepine overdose and to study the correlation with sedation. [ncbi.nlm.nih.gov]

  It provides anxiolysis, sedation, hypnosis, skeletal muscle relaxation, anterograde amnesia, respiratory depression and an anticonvulsant effect but has no analgesic properties. [dentalcare.com]

  One hundred and thirty patients responded positively to flumazenil, characterized by improved response to painful stimuli, and decreased amnesia. [mjiri.iums.ac.ir]

  Important adverse effects include confusion, impaired motor coordination, amnesia, drowsiness, and respiratory depression. [amboss.com]

  Calming, euphoria Vivid or disturbing dreams Amnesia, hostility, irritability Overdose may be fatal. [getsmartaboutdrugs.gov]

• Ataxia

  Ataxia was the most common clinical finding following benzodiazepine ingestion in this series. Flumazenil appeared beneficial for the treatment of severe benzodiazepine toxicity in only two patients. [doi.org]

  Disposition Most children can be observed at home unless there is significant ataxia or drowsiness. [lifeinthefastlane.com]

  Patients with a mild benzodiazepine overdose display drowsiness, dysarthria and ataxia. In large doses, benzodiazepine can cause coma and respiratory depression, and death. [dlib.si]

  Clinical features : CNS depressio n : lethargy, somnolence, hyporeflexia Respiratory depression Mild hypotension Ataxia Slurred speech Carbamazepine and oxcarbazepine: possibly SIADH Diagnostics Routine urine screening for benzodiazepine metabolites [amboss.com]

  Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Generally, patients with benzodiazepine-induced coma have hyporeflexia and midposition or small pupils. Hypothermia may occur. [accessmedicine.mhmedical.com]

Benzodiazepine overdose is managed according to possible complications.

A magnetic resonance imaging (MRI) of the brain is a necessity if the patient appears unconscious, comatose and with a possible risk of acidosis. The MRI will expose herniations, edema and diffuse white matter injury (leukoencephalopathy) relatively excluding the lesions of the gray matter. The white matter injury may also be of connection with the use of chemotherapy agents and exposure to toxins e.g. carbon monoxide. Signs of edema and herniation may evolve and be the cause of death if not handled or monitored appropriately [6] [7].

A computed tomography (CT) examination findings include hypodensity in the affected area of the white brain matter, correlating to the clinical picture found in MRI. Reports suggest that early in the disease, the imaging of the patient's brain can appear normal which leads to discharge from the hospital. After about two weeks, a rapid deterioration of the white matter precedes and involves serious changes in consciousness, behavior, gait, parasympathetic system, etc., advancing to dramatic complications like coma or quadriparesis. Thus the importance of monitoring the affected patient is suggested [8].

Urine sample analysis may expose high levels of benzodiazepines [6].

Lumbar puncture with a collection of the cerebrospinal fluid is useful to exclude other diagnoses e.g. herpes simplex virus infection, Epstein-Barr virus disease or other infections associated with brain tissues that cause similar radiologic findings. The analysis includes cell count, protein, and glucose level determination [9].

Electroencephalography (EEG) is optional and used to discover electrical potential abnormalities if the patient experienced neurologic signs e.g. seizures. The EEG might reveal slowing of background in low frequencies [6].

It is a viable alternative to inpatient treatment for those who have home, work, or school obligations to fulfill. Cognitive behavioral therapy (CBT). This is a treatment approach that may be used in both inpatient and outpatient treatment programs. [drugabuse.com]

Amy has completed the American Psychiatric Nurses Association’s course on Effective Treatments for Opioid Use Disorder and continuing education on Screening, Brief Intervention and Referral to Treatment (SBIRT). [drugrehab.com]

[…] to speak to a treatment support advisor, who can help you find the right treatment program for your needs. [recovery.org]

Three Part Question [In adults with acute opiate overdose] is [concomitant use of benzodiazepines] associated with a [poorer prognosis in terms of death aspiration, admission to ITU] Clinical Scenario A 27 year old man comes into the emergency department [bestbets.org]

Please find relevant information on First Aid for Benzodiazepine Overdose regarding cause, signs & symptoms, administration of first aid treatment, prognosis, preventive measures, and additional resources HERE. [dovemed.com]

With good supportive care prognosis is excellent. Toxic Mechanism: Simple mechanism, they enhance the inhibitory neurotransmitter GABA by increasing the opening frequency of chlorine. [lifeinthefastlane.com]

The prognosis depends on how quickly the diagnosis is made and the treatment administered. [ncbi.nlm.nih.gov]

9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis [inchem.org]

Acute poisoning with benzodiazepines and other hypnotics: etiologic cause, sex/age distribution and clinical outcome. J of IMAB. 2016 Oct-Dec;22(4):1371-1374. DOI: 10.5272/jimab.2016224.1371. [journal-imab-bg.org]

Etiology 4. Clinical Course IV. Benzodiazepine Withdrawal 1. Signs and Symptoms 2. Treatment V. Benzodiazepine Overdose 1. Clinical Presentation 2. Treatment VI. Case Study: Benzodiazepine Drug-Drug Interaction VII. [ce4less.com]

This activity reviews the pathophysiology, presentation, and etiology of benzodiazepine toxicity and highlights the role of the interprofessional team in the management of these patients. [ncbi.nlm.nih.gov]

Gökel, Etiological and demographical characteristics of acute adult poisoning in Adana, Turkey, Human & Experimental Toxicology, 26, 5, (401), (2007). M. Schmidt, Benzodiazepine, Suchtmittel in der AINS, 10.1007/978-3-540-33734-8_5, (79-89), (2007). [doi.org]

Use of flumazenil in the diagnosis and treatment of patients with coma of unknown etiology. Crit Care Med 1993; 21: 538–42 PubMed CrossRef Google Scholar 63. Skeie B, Emhjellen S, Wickstrom E, et al. [link.springer.com]

International Journal of Epidemiology, 22, 838 – 847. Shader, I. R. & Greenblat, D. J. ( 1993 ) Use of benzodiazepines in anxiety disorders. New England Journal of Medicine, 328, 1398 – 1405. [doi.org]

Epidemiology of acute drug poisoning in a tertiary center from Iasi Country, Romania. Hum Exp Toxicol. 2011 Dec;30(12):1896-903. [ PubMed ] 13. Hutton J, Dent A, Buykx P, Burgess S, Flander L, Dietze P. [journal-imab-bg.org]

Thus the prevalence of an isolated benzodiazepine use disorder is difficult to determine from epidemiologic studies. [ncbi.nlm.nih.gov]

Unfortunately, this syndrome remains of an unclear pathophysiology and with no successful treatment. [ncbi.nlm.nih.gov]

Pharmacotherapy: A Pathophysiologic Approach, 9th edition. Chapter 53: Anxiety Disorders I; Generalized Anxiety, Panic, and Social Anxiety Disorders. Access Pharmacy [online]. DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach, 9th edition. [rxlist.com]

Pharmacotherapy: A Pathophysiologic Approach. 8th ed. http://accesspharmacy.com/content.aspx?aid=7987346. Accessed June 9, 2012. [accesspharmacy.mhmedical.com]

"Though broad efforts are underway to prevent overdose from opioid painkillers, there is another class of prescription drugs that require attention—benzodiazepines," she said. [forbes.com]

Vancouver’s Overdose Prevention Society says there were 16 overdoses in the city over two days last week. [globalnews.ca]

Centers for Disease Control and Prevention. National Vital Statistics System. Multiple Cause of Death 1999-2013. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2014. [doi.org]

We examined data from the Medical Expenditure Panel Survey and multiple-cause-of-death data from the Centers for Disease Control and Prevention. [ncbi.nlm.nih.gov]

“Moving forward, policy interventions should focus on preventing concurrent exposure instead of simply reducing the length of time patients use both drugs.” [upmc.com]

1. Bachhuber MA, Hennessy S, Cunningham CO, Starrels JL. Increasing Benzodiazepine Prescriptions and Overdose Mortality in the United States, 1996–2013. Am J Public Health. 2016;106(4):686-688.
2. Peirce GL, Smith MJ, Abate MA, Halverson J. Doctor and pharmacy shopping for controlled substances. Med Care. 2012;50:494–500.
3. Shin HI, Lin MC, Lin CC, et al. Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments—a population-based nested case-control study. Psychopharmacology (Berl). 2013;229:665–71.
4. Slavova S, Bunn TL, Talbert J. Drug Overdose Surveillance Using Hospital Discharge Data. Public Health Rep. 2014;129(5):437-445.
5. Martins SS, Sampson L, Cerdá M, Galea S. Worldwide Prevalence and Trends in Unintentional Drug Overdose: A Systematic Review of the Literature. Am J Public Health. 2015;105(11):e29-e49.
6. Aljarallah S, Al-Hussain F. Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature. BMC Neurol. 2015;15:69.
7. Kim JH, Chang KH, Song IC, et al. Delayed encephalopathy of acute carbon monoxide intoxication: diffusivity of cerebral white matter lesions. AJNR Am J Neuroradiol. 2003;24(8):1592–7.
8. Chang WL, Chang YK, Hsu SY, Lin GJ, Chen SC. Reversible delayed leukoencephalopathy after heroin intoxication with hypoxia: a case report. Acta Neurologica Taiwanica. 2009;18(3):198–202.
9. Wallace IR, Dynan C, Esmonde T. One confused patient, many confused physicians: a case of delayed post-hypoxic leucoencephalopathy. QJM Monthly J Assoc Physicians. 2010;103(3):193–4.