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.

• 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]

  […] possible dose per kg of each drug Co-ingestants e.g. paracetamol Examination CNS depression Neurologic – confusion, dysarthria, nystagmus, lethargy, ataxia, areflexia, hypotonia, seizure Respiratory – depression Cardiovascular – hypotension Metabolic – hypothermia [rch.org.au]

• 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]

  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]

  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]

  It is recommended only if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination.[44] Gastric lavage (stomach pumping) or whole bowel irrigation are also not recommended.[44] Enhancing elimination of the [en.wikipedia.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]

• Food Poisoning

  poisoning ) Fish / seafood Shellfish poisoning ( Paralytic shellfish poisoning, Diarrheal shellfish poisoning, Amnesic shellfish poisoning, Neurotoxic shellfish poisoning ) · Ciguatera · Ichthyoallyeinotoxism · Scombroid · Haff disease Other vertebrates [psychology.wikia.com]

• Hypotension

  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]

  […] anxiety, and mood changes Dizziness Slurred speech or acting drunk Amnesia Physical weakness or lack of coordination Hypotonia (lack of muscle tone) Blurry vision Difficulty breathing or depressed breathing Stupor or unresponsiveness Hallucinations Hypotension [americanaddictioncenters.org]

  Tachycardia, with concomitant hypotension, is more often reported. 2,5 The patient in this case denied taking any medications that would reduce his HR and he had no known cardiac history. [mhc.cpnp.org]

  In addition to excessive sedation, potential symptoms of a typical benzodiazepine overdose include hypotension (low blood pressure), diminished respiratory function (shallow breathing) and a condition called nystagmus, which involves rapid, involuntary [drugaddictiontreatment.com]

• Musculoskeletal Pain

  Trends in opioid prescribing and co-prescribing of sedative hypnotics for acute and chronic musculoskeletal pain: 2001-2010. Pharmacoepidemiol Drug Saf. 2015 ;24: 885 – 892. Crossref, Medline, Google Scholar 9. [doi.org]

• Confusion

  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]

  Some people exhibit mental confusion and slurred speech, but vital signs are often normal. [drugrehab.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]

  Some of the signs of acute toxicity or overdose are: Drowsiness Confusion Dizziness Blurred vision Weakness Poor judgment and decision making Slurred speech Lack of coordination Difficulty breathing Coma Death from respiratory arrest (ceased breathing [arizonadetoxhelpline.com]

• Slurred Speech

  The most common symptoms of overdose include the central nervous system (CNS); depression and intoxication with impaired balance, and slurred speech. Severe symptoms include coma and respiratory depression. [healthguidance.org]

  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]

  Some of the signs of acute toxicity or overdose are: Drowsiness Confusion Dizziness Blurred vision Weakness Poor judgment and decision making Slurred speech Lack of coordination Difficulty breathing Coma Death from respiratory arrest (ceased breathing [arizonadetoxhelpline.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]

• 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]

  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]

• 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]

  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]

  Initial signs and symptoms include intoxication, somnolence, diplopia, impaired balance, impaired motor function, anterograde amnesia, ataxia, and slurred speech. [en.wikipedia.org]

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

• Stupor

  Drowsiness or extreme fatigue Confusion, agitation, anxiety, and mood changes Dizziness Slurred speech or acting drunk Amnesia Physical weakness or lack of coordination Hypotonia (lack of muscle tone) Blurry vision Difficulty breathing or depressed breathing Stupor [americanaddictioncenters.org]

  These were identical with those described by McCarron et al for assessing the severity of barbiturate intoxication. 7 A 7 point scale of conscious state (alert, drowsy, stuporous, coma 1–4) was used. [doi.org]

  Below are the symptoms of benzos overdose: Difficulty in breathing Fingernails and lips appear bluish Mentally disturbed or confused Feeling dizzy Blurred vision or double vision Feeling weak Tremors Lack of coordination of muscle movements Stupor Coma [addictionresource.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].

• Atelectasis

  The chest x-ray showed focal segmental atelectasis on the left lung field. Before flumazenil administration, we examined the patient’s airway and assessed the presence of contraindications for flumazenil administration. [jstage.jst.go.jp]

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.