Benzodiazepine poisoning and withdrawal
- Howard Greller, MD
Howard Greller, MD
- Associate Professor of Emergency Medicine
- Hofstra North Shore/LIJ School of Medicine
- Amit Gupta, MD
Amit Gupta, MD
- Clinical Assistant Professor of Emergency Medicine
- New York Downstate Medical Center/Staten Island University Hospital
Benzodiazepines (BZD) are sedative-hypnotic agents that have been in clinical use since the 1960s. The first benzodiazepine, chlordiazepoxide, was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach. Three years later, it was marketed as a therapeutic medication under the brand name Librium. Following chlordiazepoxide in 1963, diazepam was released followed by multiple other compounds over subsequent years.
BZDs are used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and drug-associated agitation. They are frequently combined with other medications for procedural sedation. Due to their many uses, BZDs are widely prescribed and nearly 50 different agents are available worldwide. The high incidence of BZD overdose mirrors their widespread use and availability [1,2].
The diagnosis and management of acute benzodiazepine poisoning will be reviewed here. A general approach to the poisoned patient and the management of poisonings involving other agents with sedative properties are discussed elsewhere. (See "General approach to drug poisoning in adults" and "Ethanol intoxication in adults" and "Acute opioid intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)
PHARMACOLOGY AND CELLULAR TOXICITY
Benzodiazepines (BZD) are organic bases with a benzene ring and a seven member diazepine moiety; various side chains determine the potency, duration of action, metabolite activity, and rate of elimination for specific agents . BZDs exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system.
The GABA-A receptor is composed of five subunits (alpha, beta, and gamma) arranged in various combinations [4-9]. The composition of subunits determines the affinity of the various xenobiotics that bind to the receptor. Benzodiazepines bind at the interface of the alpha and gamma subunits and, once bound, lock the GABA-A receptor into a conformation that increases its affinity for GABA. BZDs do not alter the synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions by augmenting receptor binding. This binding increases the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization and a decreased ability to initiate an action potential. The low incidence of respiratory depression with orally ingested BZDs appears to be related to the low density of binding sites in the brainstem respiratory center .
- Drug Abuse Warning Network: The DAWN Report. April 2004. Benzodiazepine in Drug-Abuse Related Emergency Department Visits: 1995-2002. www.oas.samhsa.gov/2k4benzodiazepinesTrends.pdf (Accessed on May 04, 2009).
- Lader M. Benzodiazepines revisited--will we ever learn? Addiction 2011; 106:2086.
- Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol 1999; 19:533.
- Hevers W, Lüddens H. The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol 1998; 18:35.
- Smith TA. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment. Br J Biomed Sci 2001; 58:111.
- Ali NJ, Olsen RW. Chronic benzodiazepine treatment of cells expressing recombinant GABA(A) receptors uncouples allosteric binding: studies on possible mechanisms. J Neurochem 2001; 79:1100.
- Olsen RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 1981; 37:1.
- Potokar J, Coupland N, Wilson S, et al. Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines. Psychopharmacology (Berl) 1999; 146:180.
- Snead OC 3rd, Nichols AC, Liu CC. gamma-Hydroxybutyric acid binding sites: interaction with the GABA-benzodiazepine-picrotoxin receptor complex. Neurochem Res 1992; 17:201.
- Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther 2007; 32:333.
- Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38:41.
- Greenblatt DJ, Shader RI, Divoll M, Harmatz JS. Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol 1981; 11 Suppl 1:11S.
- Wynn G, Oesterheld J, Cozza K, Armstong G. Clinical manual of drug interaction principles for medical practice. Chapters 2, 3, 19. American psychiatric publishing Inc, Washington, DC 2009.
- Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 1997; 15:357.
- Bauer TM, Ritz R, Haberthür C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 1995; 346:145.
- Höjer J, Baehrendtz S, Gustafsson L. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226:117.
- Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ 1995; 310:219.
- Isbister GK, O'Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004; 58:88.
- Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy 2005; 25:8S.
- Garzone PD, Kroboth PD. Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 1989; 16:337.
- Blank A, Hellstern V, Schuster D, et al. Efavirenz treatment and false-positive results in benzodiazepine screening tests. Clin Infect Dis 2009; 48:1787.
- Weinbroum AA, Flaishon R, Sorkine P, et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf 1997; 17:181.
- Seger DL. Flumazenil--treatment or toxin. J Toxicol Clin Toxicol 2004; 42:209.
- Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center's ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med 2012; 43:677.
- Shalansky SJ, Naumann TL, Englander FA. Effect of flumazenil on benzodiazepine-induced respiratory depression. Clin Pharm 1993; 12:483.
- Romazicon package insert. Roche Pharmaceuticals. www.dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6844 (Accessed on May 05, 2009).
- Maxa JL, Ogu CC, Adeeko MA, Swaner TG. Continuous-infusion flumazenil in the management of chlordiazepoxide toxicity. Pharmacotherapy 2003; 23:1513.
- Höjer J, Baehrendtz S, Magnusson A, Gustafsson LL. A placebo-controlled trial of flumazenil given by continuous infusion in severe benzodiazepine overdosage. Acta Anaesthesiol Scand 1991; 35:584.
- Marriott S, Tyrer P. Benzodiazepine dependence. Avoidance and withdrawal. Drug Saf 1993; 9:93.
- Hood HM, Metten P, Crabbe JC, Buck KJ. Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes Brain Behav 2006; 5:1.
- Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr 2009; 67:408.
- Pétursson H. The benzodiazepine withdrawal syndrome. Addiction 1994; 89:1455.
- Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria? Acta Psychiatr Scand 1990; 82:165.
- Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19.
- Voshaar RC, Couvée JE, van Balkom AJ, et al. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry 2006; 189:213.
- Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution--a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010; 105:1870.
- Parr JM, Kavanagh DJ, Cahill L, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction 2009; 104:13.
- Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother 2006; 40:441.
- Denis C, Fatséas M, Lavie E, Auriacombe M. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev 2006; :CD005194.
- Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry 1991; 48:448.
- PHARMACOLOGY AND CELLULAR TOXICITY
- CLINICAL FEATURES OF OVERDOSE
- Benzodiazepine poisoning
- Propylene glycol poisoning
- DIFFERENTIAL DIAGNOSIS
- LABORATORY EVALUATION
- Testing for benzodiazepine toxicity
- General diagnostic testing
- Initial treatment
- Antidote (flumazenil)
- Mechanism, signs, and prevention
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS