Authier N, Boucher A, Lamaison D, et al. Second meeting of the French CEIP (Centres d’Evaluation et d’Information sur la Pharmacodépendance). Part II: benzodiazepine withdrawal. Therapie. 2009;64(6):365-70. Abstract

Ballenger JC. Medication discontinuation in panic disorder. J Clin Psychiatry. 1992;53 Suppl:26-31. Abstract

DuPont RL. A physician’s guide to discontinuing benzodiazepine therapy. West J Med. 1990;152(5):600-3. Article

DuPont RL. A practical approach to benzodiazepine discontinuation. J Psychiatr Res. 1990;24 Suppl 2:81-90. Abstract

DuPont RL. Thinking about stopping treatment for panic disorder. J Clin Psychiatry. 1990;51 Suppl A:38-45. Abstract

Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria? Acta Psychiatr Scand. 1990;82(2):165-8. Abstract

Lader M. Coming off tranquilizers: a Sisyphean toil. Addiction. 2009;104(1):25-6. Link

Landry MJ, Smith DE, McDuff DR, Baughman OL. Benzodiazepine dependence and withdrawal: identification and medical management. J Am Board Fam Pract. 1992;5(2):167-75. Abstract

Nyström C. Effects of long-term benzodiazepine medication. A prospective cohort study: methodological and clinical aspects. Nord J Psychiatry. 2005;59(6):492-7. Abstract

Sep-Kowalikowa B, Czucha M. Dependence on benzodiazepine and treatment of withdrawal syndrome. Psychiatr Pol. 2002;36(6 Suppl):347-57. Abstract

Rickels K, Schweizer E. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol. 1998;18(6 Suppl 2):12S-18S. Abstract

Guidelines

Guaiana G, Barbui C. Discontinuing benzodiazepines: best practices. Epidemiol Psychiatr Sci. 2016;25(3):214-6. Abstract

Meta-Analyses

Parr JM, Kavanagh DJ, Cahill L, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24. Abstract

Voshaar RC, Couvée JE, van Balkom AJ, et al. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry. 2006;189:213-20. Article

Reviews

Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408-13. Abstract

Chouinard G, Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65 Suppl 5:7-12. Abstract

Lader M, Kyriacou A. Withdrawing benzodiazepines in patients with anxiety disorders. Curr Psychiatry Rep. 2016;18(1):8. Abstract

Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34. Article

Lapierre YD, Benzodiazepine withdrawal. Can J Psychiatry. 1981;26(2):93-5. Abstract

MacKinnon GL, Parker WA, Benzodiazepine withdrawal syndrome: a literature review and evaluation. Am J Drug Alcohol Abuse. 1982;9(1):19-33. Abstract

Mezciems PE. Withdrawal strategies for outpatients. Alcohol, benzodiazepine, barbiturate, and opiate addictions. Can Fam Physician. 1996;42:1745-52. Article

Noyes R, Garvey MJ, Cook BL, Perry PJ. Benzodiazepine withdrawal: a review of the evidence. J Clin Psychiatry. 1988;49(10):382-9. Abstract

Onyett SR. The benzodiazepine withdrawal syndrome and its management. J R Coll Gen Pract. 1989;39(321):160-3. Article

Pelissolo A, Bisserbe JC. Dependence on benzodiazepines. Clinical and biological aspects. Encephale.1994;20(2):147-57. Abstract

Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-9. Abstract

17.2 Terminology

Other names known for this syndrome include:

Prolonged Withdrawal Syndrome
Chronic Withdrawal Syndrome
Extended Withdrawal Syndrome
Lingering Withdrawal Symptoms
Post Withdrawal Syndrome
Late Withdrawal
Postuse Syndrome
Protracted Abstinence
Sobriety Symptoms
Subacute Withdrawal Syndrome
Post Acute Withdrawal Syndrome (PAWS – Note: this term actually represents a shorter time frame directly after cessation of the drug; usually about 3 weeks to a month or so).

17.3 Animal Studies

Allison C, Pratt JA. Differential effects of two chronic diazepam treatment regimes on withdrawal anxiety and AMPA receptor characteristics. Neuropsychopharmacology. 2006;31(3):602-19. Article

Baldwin HA, Hitchcott PK, File SE. Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity. Pharmacol Biochem Behav. 1989;34(4):931-3. Abstract

Baldwin HA, File SE. Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor. Brain Res Bull. 1988;20(5):603-6. Abstract

Begg DP, Hallam KT, Norman TR. Attenuation of benzodiazepine withdrawal anxiety in the rat by serotonin antagonists. Behav Brain Res. 2005;161(2):286-90. Abstract

Cabral A, De Ross J, Castilho VM, et al. Glutamate receptor antagonism in inferior colliculus attenuates elevated startle response of high anxiety diazepam-withdrawn rats. Neuroscience. 2009;161(3):707-17. Abstract

Das P, Zerda R, Alvarez FJ, Tietz EI. Immunogold electron microscopic evidence of differential regulation of GluN1, GluN2A, and GluN2B, NMDA-type glutamate receptor subunits in rat hippocampal CA1 synapses during benzodiazepine withdrawal. J Comp Neurol. 2010;518(21):4311-28. Article

Das P, Lilly SM, Zerda R, et al. Increased AMPA receptor GluR1 subunit incorporation in rat hippocampal CA1 synapses during benzodiazepine withdrawal. J Comp Neurol. 2008;511(6):832-46. Article

De Ross J, Castilho VM, Brandão ML, Nobre MJ. Analysis of the chronic intake of and withdrawal from diazepam on emotional reactivity and sensory information processing in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):794-802. Abstract

Earl DE, Das P, Gunning WT, Tietz EI. Regulation of Ca²⁺/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal. Neural Plast. 2012;2012:405926. Article

File SE, Andrews N. Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal. Psychopharmacology (Berl). 1991;105(4):578-82. Abstract

Lopez F, Miller LG, Greenblatt DJ, et al. Chronic administration of benzodiazepines. V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam. Neuropharmacology. 1990;29(3):237-41. Abstract

Martijena ID, Lacerra C, Molina VA. Carbamazepine normalizes the altered behavioral and neurochemical response to stress in benzodiazepine-withdrawn rats. Eur J Pharmacol. 1997;330(2-3):101-8. Abstract

Martijena ID, Tapia M, Molina VA. Altered behavioral and neurochemical response to stress in benzodiazepine-withdrawn rats. Brain Res. 1996;712(2):239-44. Abstract

Martin WR, Sloan JW, Wala E. Precipitated abstinence in orally dosed benzodiazepine-dependent dogs. J Pharmacol Exp Ther. 1990;255(2):744-55. Abstract

Raffa RB, Cavallo F, Capasso A. Flumazenil-sensitive dose-related physical dependence in planarians produced by two benzodiazepine and one non-benzodiazepine benzodiazepine-receptor agonists. Eur J Pharmacol. 2007;564(1-3):88-93. Article

Shen G, Tietz EI. Down-regulation of synaptic GluN2B subunit-containing N-methyl-D-aspartate receptors: a physiological brake on CA1 neuron α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hyperexcitability during benzodiazepine withdrawal. J Pharmacol Exp Ther. 2011;336(1):265-73. Article

Toki S, Saito T, Hatta S, Takahata N. Diazepam physical dependence and withdrawal in rats is associated with alteration in GABAA receptor function. Life Sci. 1996;59(19):1631-41. Abstract

Van Sickle BJ, Xiang K, Tietz EI. Transient plasticity of hippocampal CA1 neuron glutamate receptors contributes to benzodiazepine withdrawal-anxiety. Neuropsychopharmacology. 2004;29(11):1994-2006. Article

Xiang K, Tietz EI. Benzodiazepine-induced hippocampal CA1 neuron alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptor plasticity linked to severity of withdrawal anxiety: differential role of voltage-gated calcium channels and N-methyl-D-aspartic acid receptors. Behav Pharmacol. 2007;18(5-6):447-60. Abstract

17.4 Neuro Physiology of Withdrawal

Andrews N, File SE. Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioral evidence. Psychopharmacology (Berl). 1993;112(1):21-5. Abstract

File SE, Andrews N. Benzodiazepine withdrawal: behavioral pharmacology and neurochemical changes. Biochem Soc Symp. 1993;59:97-106. Abstract

Miller LG, Lumpkin M, Greenblatt DJ, Shader RI. Accelerated benzodiazepine receptor recovery after lorazepam discontinuation. FASEB J. 1991;5(1):93-7. Abstract

Nutt DJ. Pharmacological mechanisms of benzodiazepine withdrawal. J Psychiatr Res. 1990;24 Suppl 2:105-10. Abstract

Tsuda M, Shimizu N, Suzuki T. Contribution of glutamate receptors to benzodiazepine withdrawal signs. Jpn J Pharmacol. 1999;81(1):1-6. Article

Brain Loci

Calixto E, López-Colomé AM, Casasola C, et al. Neocortical hyperexcitability after GABA withdrawal in vitro. Epilepsy Res. 2000;39(1):13-26. Abstract

Casasola C, Montiel T, Calixto E, Brailowsky S. Hyperexcitability induced by GABA withdrawal facilitates hippocampal long-term potentiation. Neuroscience. 2004;126(1):163-71. Abstract

Casasola C, Bargas J, Arias-Montaño JA, et al. Hippocampal hyperexcitability induced by GABA withdrawal is due to down-regulation of GABA(A) receptors. Epilepsy Res. 2001;47(3):257-71. Abstract

Endogenous Substances

Rada P, Hoebel BG. Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency. Eur J Pharmacol. 2005;508(1-3):131-8. Abstract

Neuro-Hormonal

Skelton KH, Gutman DA, Thrivikraman KV, et al. The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal. Psychopharmacology (Berl). 2007;192(3):385-96. Abstract

Wichniak A, Brunner H, Ising M, et al. Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression. Psychoneuroendocrinology. 2004;29(9):1101-8. Abstract

Receptor Effect

Calixto E. GABA withdrawal syndrome: GABAA receptor, synapse, neurobiological implications and analogies with other abstinences. Neuroscience. 2016;313:57-72. Abstract

Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal of tranquilizing drugs: is there a common neurochemical mechanism? Lancet. 1982;2(8294):360-2. Abstract

Das P, Lilly SM, Zerda R, et al. Increased AMPA receptor GluR1 subunit incorporation in rat hippocampal CA1 synapses during benzodiazepine withdrawal. J Comp Neurol. 2008;511(6):832-46. Abstract

Koff JM, Pritchard GA, Greenblatt DJ, Miller LG.The NMDA receptor competitive antagonist CPP modulates benzodiazepine tolerance and discontinuation. Pharmacology. 1997;55(5):217-27. Abstract

Listos J, Talarek S, Fidecka S. Adenosine receptor agonists attenuate the development of diazepam withdrawal-induced sensitization in mice. Eur J Pharmacol. 2008;588(1):72-7. Abstract

Shen G, Van Sickle BJ, Tietz EI. Calcium/calmodulin-dependent protein kinase II mediates hippocampal glutamatergic plasticity during benzodiazepine withdrawal. Neuropsychopharmacology. 2010;35(9):1897-909. Article

Song J, Shen G, Greenfield LJ, Tietz EI. Benzodiazepine withdrawal-induced glutamatergic plasticity involves up-regulation of GluR1-containing alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in Hippocampal CA1 neurons. J Pharmacol Exp Ther. 2007;322(2):569-81. Article

Tsuda M, Shimizu N, Suzuki T. Contribution of glutamate receptors to benzodiazepine withdrawal signs. Jpn J Pharmacol. 1999;81(1):1-6. Abstract

Wafford KA. GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr Opin Pharmacol. 2005;5(1):47-52. Abstract

Tolerance

17.5 Withdrawal Symptoms

Aches and pains
Agitation and restlessness
Akathisia
Anxiety, possible terror and panic attacks
Blurred vision
Chest pain
Depersonalization
Depression (can be severe), possible suicidal ideation
Derealisation (feelings of unreality)
Diarrhea
Dilated pupils
Dizziness
Double vision
Dry mouth
Dysphoria
Electric shock sensations
Elevation in blood pressure
Fatigue and weakness
Flu-like symptoms
gastrointestinal problems
Hearing impairment
Headache
Hot and cold spells
Hyperosmia
Hypertension
Hypnagogia-hallucinations
Hypochondriasis
Increased sensitivity to touch
Increased sensitivity to sound
Increased urinary frequency
Indecision
Insomnia
Impaired concentration
Impaired memory and concentration
Loss of appetite and weight loss
Metallic taste
Mild to moderate Aphasia
Mood swings
Muscular spasms, cramps or fasciculations
Nausea and vomiting
Nightmares
Numbness and tingling
Obsessive compulsive disorder
Paraesthesia
Paranoia
Perception that stationary objects are moving
Perspiration
Photophobia
Postural hypotension
REM sleep rebound
Restless legs syndrome
Sounds louder than usual
Stiffness
Taste and smell disturbances
Tachycardia
Tinnitus
Tremor
Visual disturbances

Rapid discontinuation may result in a more serious syndrome

Catatonia, which may result in death
Confusion
Convulsions, which may result in death
Coma (rare)
Delirium tremens
Delusions
Hallucinations
Hyperthermia
homicidal ideation
Mania
Neuroleptic malignant syndrome-like event (rare)
Organic brain syndrome
Post-traumatic stress disorder
Psychosis
Suicidal ideation
Suicide
Urges to shout, throw, break things or harm someone
Violence

Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1-2):19-28. Abstract

Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsych. 2004;19(3):437-54. Abstract

Burrows GD, Norman TR, Judd FK, Marriott PF. Short-acting versus long-acting benzodiazepines: discontinuation effects in panic disorders. J Psychiatr Res. 1990;24 Suppl 2:65-72. Abstract

Curran HV, Collins R, Fletcher S, et al. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med. 2003;33(7):1223-37. Abstract

Herman JB, Brotman AW, Rosenbaum JF. Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry. 1987;48 Suppl:22-8. Abstract

Pecknold JC. Discontinuation reactions to alprazolam in panic disorder. J Psychiatr Res. 1993;27 Suppl 1:155-70. Abstract

Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-9. Abstract

Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47(10):899-907. Abstract

Risse SC, Whitters A, Burke J, et al. Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder. J Clin Psychiatry. 1990;51(5):206-9. Abstract

Seivewright N, Dougal W. Withdrawal symptoms from high dose benzodiazepines in poly drug users. Drug Alcohol Depend. 1993;32(1):15-23. Abstract

Străulea AO, Chiriţă V. The withdrawal syndrome in benzodiazepine dependence and its management. Rev Med Chir Soc Med Nat Iasi. 2009;113(3):879-84. Abstract

Tata PR, Rollings J, Collins M, et al. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203-13. Abstract

Uhlenhuth EH, Starcevic V, Qualls C, et al. Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs. J Clin Psychopharmacol. 2006;26(5):519-23. Abstract

Vikander B, Koechling UM, Borg S, et al. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010;64(4):273-82. Abstract

Zalsman G, Hermesh H, Munitz H. Alprazolam withdrawal delirium: a case report. Clin Neuropharmacol. 1998;21(3):201-2. Abstract

Mortality

Lann MA, Molina DK. A fatal case of benzodiazepine withdrawal. Am J Forensic Med Pathol. 2009;30(2):177-9. Abstract

17.6 Withdrawal Symptoms By Organ System

Atopy

Hematologic

Cancer

Immunologic

Ferrarese C, Appollonio I, Frigo M, et al. Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment. Acta Psychiatr Scand. 1990;82(2):169-73. Abstract

Dermatologic

HEENT

Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J Clin Psychopharmacol. 1988;8(5):359-62. Abstract

Respiratory

Cardiovascular

Kulkarni SK, Kaushal A, Dhir A. Effect of withdrawal of diazepam or morphine treatment on gastric motility (charcoal meal test) in mice: possible role of different central and peripheral receptors. Indian J Exp Biol. 2007;45(7):642-8. Abstract

Gyn

Obstetric

Teratogenic Potential

Musculoskeletal

Endocrine

Neurologic

Seizure

Breier A, Charney DS, Nelson JC. Seizures induced by abrupt discontinuation of alprazolam. Am J Psychiatry. 1984;141(12):1606-7. Abstract

Fialip J, Aumaitre O, Eschalier A, et al. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol. 1987;10(6):538-44. Abstract

Franson KL, Hay DP, Neppe V, et al. Drug-induced seizures in the elderly. Causative agents and optimal management. Drugs Aging. 1995;7(1):38-48. Abstract

Hu X. Benzodiazepine withdrawal seizures and management. J Okla State Med Assoc. 2011;104(2):62-5. Abstract

Lee KC, Finley PR, Alldredge BK. Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings. Expert Opin Drug Saf. 2003;2(3):233-47. Abstract

Levy AB. Delirium and seizures due to abrupt alprazolam withdrawal: case report. J Clin Psychiatry. 1984;45(1):38-9. Abstract

Martínez-Cano H, Vela-Bueno A, de Iceta M, et al. Benzodiazepine withdrawal syndrome seizures. Pharmacopsychiatry. 1995;28(6):257-62. Abstract

Noyes R, Perry PJ, Crowe RR, et al. Seizures following the withdrawal of alprazolam. J Nerv Ment Dis. 1986;174(1):50-2. Abstract

Rosenberg HC. Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment. Pharmacol Biochem Behav. 1995;51(2-3):363-8. Abstract

Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther. 1992;14(2):292-305. Abstract

Ward BO, Stephens DN. Sensitization of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity. Psychopharmacology (Berl). 1998;135(4):342-52. Abstract

Psychiatric

Lader M. Anxiety or depression during withdrawal of hypnotic treatments. J Psychosom Res. 1994;38 Suppl 1:113-23; discussion 118-23. Abstract

O’Connor KP, Marchand A, Bélanger L, et al. Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication. Addict Behav. 2004;29(3):583-93. Abstract

Rosebush PI, Mazurek MF. Catatonia after benzodiazepine withdrawal. J Clin Psychopharmacol. 1996;16(4):315-9. Abstract

Anxiety

Fontaine R, Beaudry P, Beauclair L, Chouinard G. Comparison of withdrawal of buspirone and diazepam: a placebo controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11(2-3):189-97. Abstract

Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and rebound anxiety: a review. Pharmacology. 1983;26(3):121-37. Abstract

Mandos LA, Rickels K, Cutler N, et al. Placebo-controlled comparison of the clinical effects of rapid discontinuation of ipsapirone and lorazepam after 8 weeks of treatment for generalized anxiety disorder. Int Clin Psychopharmacol. 1995;10(4):251-6. Abstract

Pourmotabbed T, Mcleod DR, Hoehn-Saric R, et al. Treatment, discontinuation, and psychomotor effects of diazepam in women with generalized anxiety disorder. J Clin Psychopharmacol. 1996;16(3):202-7. Abstract

Vgontzas AN, Kales A, Bixler EO. Benzodiazepine side effects: role of pharmacokinetics and pharmacodynamics. Pharmacology. 1995;51(4):205-23. Abstract

Delusion

Keshavan MS, Moodley P, Eales M, et al. Delusional depression following benzodiazepine withdrawal. Can J Psychiatry. 1988;33(7):626-7. Abstract

Depression

Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use: a report of four cases. Psychol Med. 1984;14(4):937-40. Abstract

Mania

Lapierre YD, Labelle A. Manic-like reaction induced by lorazepam withdrawal. Can J Psychiatry. 1987;32(8):697-8. Abstract

Rigby J, Harvey M, Davies DR. Mania precipitated by benzodiazepine withdrawal. Acta Psychiatr Scand. 1989;79(4):406-7. Abstract

Turkington D, Gill P. Mania induced by lorazepam withdrawal: a report of two cases. J Affect Disord. 1989;17(1):93-5. Abstract

Psychosis

Sleep

Gillin JC, Spinweber CL, Johnson LC. Rebound insomnia: a critical review. J Clin Psychopharmacol. 1989;9(3):161-72. Abstract

Hajak G, Clarenbach P, Fischer W, et al. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci. 1998;248(3):148-56. Abstract

Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and rebound anxiety: a review. Pharmacology. 1983;26(3):121-37. Abstract

Lader M, Lawson C. Sleep studies and rebound insomnia: methodological problems, laboratory findings, and clinical implications. Clin Neuropharmacol. 1987;10(4):291-312. Link

Merlotti L, Roehrs T, Zorick F, Roth T. Rebound insomnia: duration of use and individual differences. J Clin Psychopharmacol. 1991;11(6):368-73. Abstract

Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation. Psychopharmacology (Berl). 1992;108(1-2):67-71. Abstract

17.7 Withdrawal Outcomes: Executive Function

Chronic Cognitive Effects

Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsych. 2004;19(3):437-54. Abstract

Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34. Article

Tata PR, Rollings J, Collins M, et al. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203-13. Abstract

Tsunoda K, Uchida H, Suzuki T, et al. Effects of discontinuing benzodiazepine-derivative hypnotics on postural sway and cognitive functions in the elderly. Int J Geriatr Psychiatry. 2010;25(12):1259-65. Abstract

Chronic Psychomotor Effects

Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34. Article

Tata PR, Rollings J, Collins M, et al. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203-13. Abstract

Chronic Psychomotor Effects: Driving

17.8 Withdrawal Assessment

Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol. 1989 ;9(6):412-6. Astract

Couvée JE, Zitman FG. The Benzodiazepine Withdrawal Symptom Questionnaire: psychometric evaluation during a discontinuation program in depressed chronic benzodiazepine users in general practice. Addiction. 2002;97(3):337-45. Abstract

Mol AJ, Voshaar RC, Gorgels WJ, et al. Development and psychometric evaluation of the Benzodiazepine Craving Questionnaire. Addiction. 2003;98(8):1143-52. Abstract

Tyrer P, Murphy S, Riley P. The benzodiazepine withdrawal symptom questionnaire. Journal of Affective Disorders. 1990;19(1):53-61. Abstract

Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)

Physician Withdrawal Checklist (PWC-20)

Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol. 2008;28(4):447-51. Abstract

Clinical Institute Withdrawal Assessment – Benzodiazepine (CIWA-B)

Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol. 1989;9(6):412-6. Abstract

17.9 Withdrawal Treatment

Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005 May;18(3):249-55. Article

Gould RL, Coulson MC, Patel N, et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry. 2014;204(2):98-107. Article

Knoop H, Kan CC, Mickers FC, Barnhoorn D. Predicting the success of a benzodiazepine discontinuation program: myths or clinical wisdom? Tijdschr Psychiatr. 2006;48(9):695-703. Abstract

Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34. Abstract

Lader M, Kyriacou A. Withdrawing benzodiazepines in patients with anxiety disorders. Curr Psychiatry Rep. 2016;18(1):8. Abstract

Oude Voshaar RC, Gorgels WJ, Mol AJ, et al. Treatment methods for discontinuation of long-term benzodiazepine use. Ned Tijdschr Geneeskd. 2001;145(28):1347-50. Abstract

Parr JM, Kavanagh DJ, Cahill L, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24. Abstract DARE Summary

Pollmann AS, Murphy AL, Bergman JC, Gardner DM. Deprescribing benzodiazepines and Z-drugs in community-dwelling adults: a scoping review. BMC Pharmacol Toxicol. 2015;16:19. Article

Treatment Epidemiology

Under – Treatment

Over – Treatment

Treatment Barriers

Bias: Patient

Bias: Provider

Bias: Public

Economic

Legal / Regulatory

Principles of Treatment

Diaper AM, Law FD, Melichar JK. Pharmacological strategies for detoxification. Br J Clin Pharmacol. 2014;77(2):302-14. Article

17.10 Treatment: Modalities

Alternative / Complementary

Cialdella P, Boissel JP, Belon P. Homeopathic specialties as substitutes for benzodiazepines: double-blind vs. placebo study. Groupe de recherche ASTRHO. Therapie. 2001;56(4):397-402. Abstract

Brief Intervention

Bashir K, King M, Ashworth M, Controlled evaluation of brief intervention by general practitioners to reduce chronic use of benzodiazepines. Br J Gen Pract. 1994;44(386):408-12. Abstract

Cormack MA, Owens RG, Dewey ME. The effect of minimal interventions by general practitioners on long-term benzodiazepine use. J R Coll Gen Pract. 1989;39(327):408-11. Article

Linden M, Bär T, Geiselmann B. Patient treatment insistence and medication craving in long-term low-dosage benzodiazepine prescriptions. Psychol Med. 1998;28(3):721-9. Abstract

Niessen WJ, Stewart RE, Broer J, Haaijer-Ruskamp FM, Reduction in the consumption of benzodiazepines due to a letter to chronic users from their own general practitioner. Ned Tijdschr Geneeskd. 2005;149(7):356-61. Abstract

Vicens Caldentey C, Fiol Gelabert F, González Garrido E, et al. Long-term effectiveness of an intervention to discontinue chronic benzodiazepine use. Actas Esp Psiquiatr. 2008;36(5):295-8. Abstract

Diet / Nutrition / Weight Management

Faith-Based

Mind-Body Therapies

Biofeedback

Nathan RG, Robinson D, Cherek DR, et al. Alternative treatments for withdrawing the long-term benzodiazepine user: a pilot study. Int J Addict. 1986;21(2):195-211. Abstract

Hypnosis

Imagery

Meditative Movement

Meditation

Mindfulness Meditation

Music

Relaxation

Lichstein KL, Peterson BA, Riedel BW, et al. Relaxation to assist sleep medication withdrawal. Behav Modif. 1999;23(3):379-402. Abstract

Mutual Help Programs

Tattersall ML, Hallstrom C. Self-help and benzodiazepine withdrawal. J Affect Disord. 1992;24(3):193-8. Abstract

Psychotherapeutic Modalities

Elsesser K, Sartory G, Maurer J. The efficacy of complaints management training in facilitating benzodiazepine withdrawal. Behav Res Ther. 1996;34(2):149-56. Abstract

Spiegel DA. Psychological strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol. 1999;19(6 Suppl 2):17S-22S. Abstract

Acceptance and Commitment Therapy (ACT)

Cognitive Behavioral Therapy (CBT)

Otto MW, McHugh RK, Simon NM, et al. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation. Behav Res Ther. 2010;48(8):720-7. Abstract

Otto MW, Hong JJ, Safren SA. Benzodiazepine discontinuation difficulties in panic disorder: conceptual model and outcome for cognitive-behavior therapy. Curr Pharm Des. 2002;8(1):75-80. Abstract

Otto MW, Pollack MH, Sachs GS, et al. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Am J Psychiatry. 1993;150(10):1485-90. Abstract

Otto MW, Pollack MH, Meltzer-Brody S, Rosenbaum JF. Cognitive-behavioral therapy for benzodiazepine discontinuation in panic disorder patients. Psychopharmacol Bull. 1992;28(2):123-30. Abstract

Parr JM, Kavanagh DJ, Young RM, Mitchell G. Acceptability of cognitive-behavior therapy via the Internet for cessation of benzodiazepine use. Drug Alcohol Rev. 2011;30(3):306-14. Abstract

Spiegel DA, Bruce TJ, Gregg SF, Nuzzarello A. Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? Am J Psychiatry. 1994;151(6):876-81. Abstract

Physical Modalities

Acupuncture

Balneotherapy

De Maricourt P, Gorwood P, Hergueta T, et al. Balneotherapy together with a psychoeducation program for benzodiazepine withdrawal: a feasibility study. Evid Based Complement Alternat Med. 2016;2016:8961709. Article

Exercise

Massage

17.11 Treatment: Modality Combinations

17.12 Treatment: Modality v Modality Comparisons

17.13 Treatment: Medications

Perry PJ, Alexander B. Sedative/hypnotic dependence: patient stabilization, tolerance testing, and withdrawal. Drug Intell Clin Pharm. 1986;20(7-8):532-7. Abstract

Rickels K, DeMartinis N, Rynn M, Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol. 1999;19(6 Suppl 2):12S-16S. Abstract

Rickels K, Case WG, Schweizer E, et al. Benzodiazepine dependence: management of discontinuation. Psychopharmacol Bull. 1990;26(1):63-8. Abstract

Smith DE, Landry MJ. Benzodiazepine dependency discontinuation: focus on the chemical dependency detoxification setting and benzodiazepine-polydrug abuse. J Psychiatr Res. 1990;24 Suppl 2:145-56. Abstract

Anti-Epileptic Medications

Zullino DF, Khazaal Y, Hättenschwiler J, et al. Anticonvulsant drugs in the treatment of substance withdrawal. Drugs Today (Barc). 2004;40(7):603-19. Abstract

Carbamazepine

Denis C, Fatséas M, Lavie E, Auriacombe M. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev. 2006;(3):CD005194. Abstract

Galpern WR, Miller LG, Greenblatt DJ, et al. Chronic benzodiazepine administration. IX. Attenuation of alprazolam discontinuation effects by carbamazepine. Biochem Pharmacol. 1991;42 Suppl:S99-104. Abstract

Garcia-Borreguero D, Bronisch T, Apelt S, et al. Treatment of benzodiazepine withdrawal symptoms with carbamazepine. Eur Arch Psychiatry Clin Neurosci. 1991;241(3):145-50. Abstract

Keck PE, McElroy SL, Friedman LM. Valproate and carbamazepine in the treatment of panic and posttraumatic stress disorders, withdrawal states, and behavioral dyscontrol syndromes. J Clin Psychopharmacol. 1992;12(1 Suppl):36S-41S. Abstract

Kaendler SH, Volk S, Pflug B. Benzodiazepine withdrawal with carbamazepine. Nervenarzt. 1996;67(5):381-6. Abstract

Kornowski J. The comparison of tianeptine and carbamazepine in benzodiazepines withdrawal symptoms. Psychiatr Pol. 2002;36(6 Suppl):311-8. Abstract

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(5):448-52. Abstract

Oxcarbazine

Croissant B, Grosshans M, Diehl A, Mann K. Oxcarbazepine in rapid benzodiazepine detoxification. Am J Drug Alcohol Abuse. 2008;34(5):534-40. Abstract

Croissant B, Grosshans M, Klein O, et al. Scheme-based benzodiazepine detoxification with oxcarbazepine – a case report. Pharmacopsychiatry. 2005;38(5):222-3. Abstract

Valproate

Harris JT, Roache JD, Thornton JE. A role for valproate in the treatment of sedative-hypnotic withdrawal and for relapse prevention. Alcohol Alcohol. 2000;35(4):319-23. Abstract

Roy-Byrne PP, Ward NG, Donnelly PJ. Valproate in anxiety and withdrawal syndromes. J Clin Psychiatry. 1989;50 Suppl:44-8. Abstract

Rickels K, Schweizer E, Garcia España F, et al. Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome. Psychopharmacology (Berl). 1999;141(1):1-5. Abstract

Starer J, Chang G. Hyperammoneic encephalopathy, valproic acid, and benzodiazepine withdrawal: a case series. Am J Drug Alcohol Abuse. 2010;36(2):98-101. Abstract

Barbiturates

Benzer D, Cushman P. Alcohol and benzodiazepines: withdrawal syndromes. Alcohol Clin Exp Res. 1980;4(3):243-7. Abstract

Phenobarbital

Kawasaki SS, Jacapraro JS, Rastegar DA. Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. J Subst Abuse Treat. 2012;43(3):331-4. Abstract

Ravi NV, Maany I, Burke WM, et al. Detoxification with phenobarbital of alprazolam-dependent polysubstance abusers. J Subst Abuse Treat. 1990;7(1):55-8. Abstract

Benzodiazepine-GABA Receptor Agents

Benzodiazepine Tapering

BZ taper Water titration

BZ taper Water titration Multiple dose

BZ taper Water titration spreadsheet

Alexander B, Perry PJ. Detoxification from benzodiazepines: schedules and strategies. J Subst Abuse Treat. 1991;8(1-2):9-17. Abstract

Fontaine R, Chouinard G, Annable L. Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Am J Psychiatry. 1984;141(7):848-52. Abstract

Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI. Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med. 1987;317(12):722-8. Abstract

Hajak G, Clarenbach P, Fischer W, et al. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci. 1998;248(3):148-56. Abstract

Lader M, Morton S. Benzodiazepine problems. Br J Addict. 1991;86(7):823-8. Abstract

Laughren TP, Battey Y, Greenblatt DJ, Harrop DS. A controlled trial of diazepam withdrawal in chronically anxious outpatients. Acta Psychiatr Scand. 1982;65(3):171-9. Abstract

McDuff DR, Schwartz RP, Tommasello A, et al. Outpatient benzodiazepine detoxification procedure for methadone patients. J Subst Abuse Treat. 1993;10(3):297-302. Abstract

McGregor C, Machin A, White JM. In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods. Drug Alcohol Rev. 2003;22(2):175-80. Abstract

Murphy SM, Tyrer P. A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence. Br J Psychiatry. 1991;158:511-6. Abstract

Pecknold JC, Swinson RP, Kuch K, Lewis CP. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Arch Gen Psychiatry. 1988;45(5):429-36. Abstract

Rickels K, Schweizer E, Weiss S, Zavodnick S. Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper. Arch Gen Psychiatry. 1993;50(1):61-8. Abstract

Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation. Psychopharmacology (Berl). 1992;108(1-2):67-71. Abstract

Schweizer E, Rickels K, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry. 1990;47(10):908-15. Article

Sellers EM. Alcohol, barbiturate and benzodiazepine withdrawal syndromes: clinical management. CMAJ. 1988;139(2):113-20. Abstract

Tolbert D, Harris SI, Bekersky I, et al. Withdrawal-related adverse events from clinical trials of clobazam in Lennox-Gastaut syndrome. Epilepsy Behav. 2014;37:11-5. Abstract

Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after long-term therapy. Lancet. 1983;1(8339):1402-6. Abstract

Vicens C, Fiol F, Llobera J, et al. Withdrawal from long-term benzodiazepine use: randomised trial in family practice. Br J Gen Pract. 2006;56(533):958-63. Abstract

Vikander B, Koechling UM, Borg S, et al. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010;64(4):273-82. Abstract

Clonazepam

Albeck JH. Withdrawal and detoxification from benzodiazepine dependence: a potential role for clonazepam. J Clin Psychiatry. 1987;48 Suppl:43-9. Abstract

Connor KM, Davidson JR, Potts NL, et al. Discontinuation of clonazepam in the treatment of social phobia. J Clin Psychopharmacol. 1998;18(5):373-8. Abstract

Patterson JF. Withdrawal from alprazolam dependency using clonazepam: clinical observations. J Clin Psychiatry. 1990;51 Suppl:47-9; discussion 50-3. Abstract

Chlordiazepoxide

Diazepam

Laughren TP, Battey Y, Greenblatt DJ, Harrop DS. A controlled trial of diazepam withdrawal in chronically anxious outpatients. Acta Psychiatr Scand. 1982;65(3):171-9. Abstract

McGregor C, Machin A, White JM. In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods. Drug Alcohol Rev. 2003;22(2):175-80. Abstract

Murphy SM, Tyrer P. A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence. Br J Psychiatry. 1991;158:511-6. Abstract

Sellers EM. Alcohol, barbiturate and benzodiazepine withdrawal syndromes: clinical management. CMAJ. 1988;139(2):113-20. Abstract

Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after long-term therapy. Lancet. 1983;1(8339):1402-6. Abstract

Zitman FG, Couvée JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group. Br J Psychiatry. 2001;178:317-24. Article

Flumazenil

Dunton AW, Schwam E, Pitman V, et al. Flumazenil: US clinical pharmacology studies. Eur J Anaesthesiol Suppl. 1988;2:81-95. Abstract

File SE, Hitchcott PK. A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena. Psychopharmacology (Berl). 1990;101(4):525-32. Abstract

Gerra G, Zaimovic A, Giusti F, et al. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol. 2002;7(4):385-95. Abstract

Gerra G, Giucasto G, Zaimovic A, et al. Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal. Int Clin Psychopharmacol. 1996;11(2):81-8. Abstract

Hood SD, Norman A, Hince DA, et al. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol. 2014;77(2):285-94. Article

Lader MH, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol. 1992;6(3):357-63. Abstract

Mintzer MZ, Stoller KB, Griffiths RR. A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. Psychopharmacology (Berl). 1999;147(2):200-9. Abstract

Moore PW, Donovan JW, Burkhart KK, et al. Safety and efficacy of flumazenil for reversal of iatrogenic benzodiazepine-associated delirium toxicity during treatment of alcohol withdrawal, a retrospective review at one center. J Med Toxicol. 2014;10(2):126-32. Article

Ngo AS, Anthony CR, Samuel M, et al. Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation. 2007;74(1):27-37. Abstract

Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse events associated with flumazenil treatment for the management of suspected benzodiazepine intoxication – a systematic review with meta-analyses of randomised trials. Basic Clin Pharmacol Toxicol. 2016;118(1):37-44. Abstract

Saxon L, Borg S, Hiltunen AJ. Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil. Pharmacol Biochem Behav. 2010;96(2):148-51. Abstract

Saxon L, Hiltunen AJ, Hjemdahl P, Borg S. Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study. Psychopharmacology (Berl). 2001;153(2):231-7. Abstract

Saxon L, Hjemdahl P, Hiltunen AJ, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal – a double-blind pilot study. Psychopharmacology (Berl). 1997;131(2):153-60. Abstract

Weinbroum AA, Flaishon R, Sorkine P, et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf. 1997;17(3):181-96. Abstract

Beta Blockers

Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet. 1981 Mar 7;1(8219):520–522. Abstract

Calcium Channel Agents

Gabapentin

Bramness JG, Sandvik P, Engeland A, Skurtveit S. Does Pregabalin (Lyrica(®) ) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. Basic Clin Pharmacol Toxicol. 2010;107(5):883-6. Abstract

Himmerich H, Nickel T, Dalal MA, Müller MB. Gabapentin treatment in a female patient with panic disorder and adverse effects under carbamazepine during benzodiazepine withdrawal. Psychiatr Prax. 2007;34(2):93-4. Abstract

Mariani JJ, Malcolm RJ, Mamczur AK, et al. Pilot trial of gabapentin for the treatment of benzodiazepine abuse or dependence in methadone maintenance patients. Am J Drug Alcohol Abuse. 2016;42(3):333-40. Abstract

Pregabalin

Bobes J, Rubio G, Terán A, et al. Pregabalin for the discontinuation of long-term benzodiazepines use: an assessment of its effectiveness in daily clinical practice. Eur Psychiatry. 2012;27(4):301-7. Abstract

Oulis P, Kalogerakou S, Anyfandi E, et al. Cognitive effects of pregabalin in the treatment of long-term benzodiazepine-use and dependence. Hum Psychopharmacol. 2014;29(3):224-9. Abstract

Oulis P, Masdrakis VG, Karakatsanis NA, et al. Pregabalin in the discontinuation of long-term benzodiazepine use: a case-series. Int Clin Psychopharmacol. 2008;23(2):110-2. Abstract

Oulis P, Konstantakopoulos G, Kouzoupis AV, et al. Pregabalin in the discontinuation of long-term benzodiazepines’ use. Hum Psychopharmacol. 2008;23(4):337-40. Abstract

Rubio G, Bobes J, Cervera G, et al. Effects of pregabalin on subjective sleep disturbance symptoms during withdrawal from long-term benzodiazepine use. Eur Addict Res. 2011;17:262–70. Abstract

Hormones

Progesterone

Schweizer E, Case WG, Garcia-Espana F, et al. Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome. Psychopharmacology (Berl). 1995;117(4):424-9. Abstract

Melatonergic Drugs

Melatonin

Baandrup L, Fagerlund B, Glenthoj B. Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo. Eur Arch Psychiatry Clin Neurosci. 2017;267(2):163-171. Abstract

Baandrup L, Glenthøj BY, Jennum PJ. Objective and subjective sleep quality: Melatonin versus placebo add-on treatment in patients with schizophrenia or bipolar disorder withdrawing from long-term benzodiazepine use. Psychiatry Res. 2016;240:163-9. Abstract

Baandrup L, Fasmer OB, Glenthøj BY, Jennum PJ. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial. BMC Psychiatry. 2016;16(1):348. Article

Baandrup L, Fagerlund B, Jennum P, et al. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial – the SMART trial protocol. BMC Psychiatry. 2011;11:160. Article

Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med. 1999;159(20):2456-60. Abstract

Wright A, Diebold J, Otal J, et al. The effect of melatonin on benzodiazepine discontinuation and sleep quality in adults attempting to discontinue benzodiazepines: a systematic review and meta-analysis. Drugs Aging. 2015;32(12):1009-18. Abstract

Mono-Amine Reuptake Inhibitors

Gorgels WJ, Oude Voshaar RC, Mol AJ, et al. Consequences of a benzodiazepine discontinuation program in family practice on psychotropic medication prescription to the participants. Fam Pract. 2007;24(5):504-10. Article

Tyrer P, Ferguson B, Hallström C, et al. A controlled trial of dothiepin and placebo in treating benzodiazepine withdrawal symptoms. Br J Psychiatry. 1996;168(4):457-61. Abstract

Imipramine

Rickels K, DeMartinis N, García-España F, et al. Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J Psychiatry. 2000;157(12):1973-9. Abstract

Rynn M, García-España F, Greenblatt DJ, et al. Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy. J Clin Psychopharmacol. 2003;23(5):505-8. Abstract

Paroxetine

Nakao M, Takeuchi T, Nomura K, et al. Clinical application of paroxetine for tapering benzodiazepine use in non-major-depressive outpatients visiting an internal medicine clinic. Psychiatry Clin Neurosci. 2006;60(5):605-10. Abstract

Plant-Based Products

Cannabinoids

Bluelight thread 1: CB for BZ WD

Bluelight thread 2: CB for BZ WD

Bluelight thread: CBD for BZ WD

Bluelight thread: Using BZ to quit CB

Blog. Warning about Using CB to get off BZ

Kava

Malsch U, Kieser M. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (Berl). 2001;157(3):277-83. Abstract

Valarian

Poyares DR, Guilleminault C, Ohayon MM, Tufik S. Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(3):539-45. Abstract

Seratonin Receptor Agents

Buspirone

Ashton CH, Rawlins MD, Tyrer SP. A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry. 1990;157:232-8.

Delle Chiaie R, Pancheri P, Casacchia M, et al. Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder, shifting to buspirone from prior treatment with lorazepam: a placebo-controlled, double-blind study. J Clin Psychopharmacol. 1995;15(1):12-9. Abstract

Lader M, Olajide D. A comparison of buspirone and placebo in relieving benzodiazepine withdrawal symptoms. J Clin Psychopharmacol. 1987;7(1):11-5. Abstract

Lemoine P, Rouillon F, Pouget D. Efficacy and withdrawal of clobazam, lorazepam and buspirone in the treatment of anxiety disorders. Encephale. 1996;22(6):461-7. Abstract

Morton S, Lader M. Buspirone treatment as an aid to benzodiazepine withdrawal. J Psychopharmacol. 1995;9(4):331-5. Abstract

Schweizer E, Rickels K, Failure of buspirone to manage benzodiazepine withdrawal. Am J Psychiatry. 1986;143(12):1590-2. Abstract

Captodiamine

Mercier-Guyon C, Chabannes JP, Saviuc P. The role of captodiamine in the withdrawal from long-term benzodiazepine treatment. Curr Med Res Opin. 2004;20(9):1347-55. Abstract

Hydroxyzine

Lemoine P, Touchon J, Billardon M. Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo. Encephale. 1997;23(4):290-9. Abstract

Ondansetron

Prather PL, Rezazadeh SM, Lane JD, et al. Conflicting evidence regarding the efficacy of ondansetron in benzodiazepine withdrawal. J Pharmacol Exp Ther. 1993;264(2):622-30. Abstract

Romach MK, Kaplan HL, Busto UE, et al. A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation. J Clin Psychopharmacol. 1998;18(2):121-31. Abstract

Trazodone

Bossini L, Casolaro I, Koukouna D. Off-label uses of trazodone: a review. Expert Opin Pharmacother. 2012;13(12):1707-17. Abstract

Funk S. Pharmacological treatment in alcohol-, drug- and benzodiazepine-dependent patients – the significance of trazodone. Neuropsychopharmacol Hung. 2013;15(2):85-93. Abstract

Stimulants

17.14 Treatment: Medication Combinations

Lemoine P, Touchon J, Billardon M. Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo. Encephale. 1997;23(4):290-9. Abstract

17.15 Treatment: Medication Comparisons

Lemoine P, Touchon J, Billardon M. Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo. Encephale. 1997;23(4):290-9. Abstract

Barbiturate v Benzodiazepine Taper

Perry PJ, Stambaugh RL, Tsuang MT, Smith RE. Sedative-hypnotic tolerance testing and withdrawal comparing diazepam to barbiturates. J Clin Psychopharmacol. 1981;1(5):289-96. Abstract

Sullivan M, Toshima M, Lynn P, Roy-Byrne P. Phenobarbital versus clonazepam for sedative-hypnotic taper in chronic pain patients. A pilot study. Ann Clin Psychiatry. 1993;5(2):123-8. Abstract

Flumazenil v Benzodiazepine Taper

Imipramine v Buspirone

17.16 Treatment: Medication + Modality

CBT + Benzodiazepine Taper

Gosselin P, Ladouceur R, Morin CM, et al. Benzodiazepine discontinuation among adults with GAD: A randomized trial of cognitive-behavioral therapy. J Consult Clin Psychol. 2006;74(5):908-19. Abstract

Gosselin P, Ladouceur R, Morin CM, et al. Benzodiazepine withdrawal in patients with generalized anxiety disorder: efficiency of a behavioral and cognitive intervention. Sante Ment Que. 2003;28(2):59-86. Abstract

Morin CM, Bastien C, Guay B, et al. Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. Am J Psychiatry. 2004;161(2):332-42. Abstract

O’Connor K, Marchand A, Brousseau L, et al. Cognitive-behavioral, pharmacological and psychosocial predictors of outcome during tapered discontinuation of benzodiazepine. Clin Psychol Psychother. 2008;15(1):1-14. Abstract

Voshaar RC, Gorgels WJ, Mol AJ, et al. Tapering off long-term benzodiazepine use with or without group cognitive-behavioral therapy: three-condition, randomised controlled trial. Br J Psychiatry. 2003;182:498-504. Abstract

17.17 Treatment: Relapse

Risk Factors

Mol AJ, Oude Voshaar RC, Gorgels WJ, et al. The role of craving in relapse after discontinuation of long-term benzodiazepine use. J Clin Psychiatry. 2007;68(12):1894-900. Abstract

Triggers

17.18 Withdrawal Treatment: Outcomes

Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. Br J Addict. 1987;82(6):665-71. Link

Belleville G, Morin CM. Hypnotic discontinuation in chronic insomnia: impact of psychological distress, readiness to change, and self-efficacy. Health Psychol. 2008;27(2):239-48. Abstract

Bourin M, Malinge M. Controlled comparison of the effects and abrupt discontinuation of buspirone and lorazepam. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19(4):567-75. Abstract

Browne JL, Hauge KJ. A review of alprazolam withdrawal. Drug Intell Clin Pharm. 1986;20(11):837-41. Abstract

Bruce TJ, Spiegel DA, Gregg SF, Nuzzarello A. Predictors of alprazolam discontinuation with and without cognitive behavior therapy in panic disorder. Am J Psychiatry. 1995;152(8):1156-60. Abstract

Couvée JE, Timmermans MA, Zitman FG. The long-term outcome of a benzodiazepine discontinuation program in depressed outpatients. Dutch Chronic Benzodiazepine Working Group. J Affect Disord. 2002;70(2):133-41. Abstract

de Gier NA, Gorgels WJ, Lucassen PL, et al. Discontinuation of long-term benzodiazepine use: 10-year follow-up. Fam Pract. 2011;28(3):253-9. Abstract

DuPont RL, Swinson RP, Ballenger JC, et al. Discontinuation of alprazolam after long-term treatment of panic-related disorders. J Clin Psychopharmacol. 1992;12(5):352-4. Abstract

Joester J, Vogler CM, Chang K, Hilmer SN. Hypnosedative use and predictors of successful withdrawal in new patients attending a falls clinic: a retrospective, cohort study. Drugs Aging. 2010;27(11):915-24. Abstract

Joughin N, Tata P, Collins M, et al. In-patient withdrawal from long-term benzodiazepine use. Br J Addict. 1991;86(4):449-55. Abstract

Kales A, v. Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects. J Clin Psychopharmacol. 1983;3(2):140-50. Abstract

Kan CC, Mickers FC, Barnhoorn D. Short- and long-term results of a systematic benzodiazepine discontinuation program for psychiatric patients. Tijdschr Psychiatr. 2006;48(9):683-93. Abstract

Knoop H, Kan CC, Mickers FC, Barnhoorn D. Predicting the success of a benzodiazepine discontinuation program: myths or clinical wisdom? Tijdschr Psychiatr. 2006;48(9):695-703. Abstract

Liebrenz M, Gehring MT, Buadze A, Caflisch C. High-dose benzodiazepine dependence: a qualitative study of patients’ perception on cessation and withdrawal. BMC Psychiatry. 2015;15:116. Article

Martin-Kleisch A, Zulfiqar AA. Retrospective study of the assessment and management of benzodiazepine withdrawal syndrome in hospital between 2000 and 2015. Ann Pharm Fr. 2016 Dec 22. pii: S0003-4509(16)30134-1. [Epub ahead of print] Abstract

Mol AJ, Oude Voshaar RC, Gorgels WJ, et al. The absence of benzodiazepine craving in a general practice benzodiazepine discontinuation trial. Addict Behav. 2006;31(2):211-22. Abstract

Morin CM, Belanger L, Bastien C, Vallieres A. Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse. Behav Res Ther. 2005;43(1):1-14. Abstract

Oude Voshaar RC, Gorgels WJ, Mol AJ, et al. Long-term outcome of two forms of randomised benzodiazepine discontinuation. Br J Psychiatry. 2006;188:188-9. Abstract

Parr JM, Kavanagh DJ, Cahill L, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13-24. Abstract

Poyares D, Guilleminault C, Ohayon MM, Tufik S. Chronic benzodiazepine usage and withdrawal in insomnia patients. J Psychiatr Res. 2004;38(3):327-34. Abstract

Rickels K, Case WG, Schweizer E, et al. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry. 1991;148(6):757-61. Abstract

Roy-Byrne P, Russo J, Pollack M, et al. Personality and symptom sensitivity predictors of alprazolam withdrawal in panic disorder. Psychol Med. 2003;33(3):511-8. Abstract

Schmauss C, Apelt S, Emrich HM. Characterization of benzodiazepine withdrawal in high- and low-dose dependent psychiatric inpatients. Brain Res Bull. 1987;19(3):393-400. Abstract

Schweizer E, Rickels K, De Martinis N, et al. The effect of personality on withdrawal severity and taper outcome in benzodiazepine dependent patients. Psychol Med. 1998;28(3):713-20. Abstract

Schweizer E, Rickels K, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry. 1990;47(10):908-15. Abstract

Thorel M, Fummi C, Gras V, Masmoudi K. Benzodiazepine or non-benzodiazepine hypnotics withdrawal syndrome during hospitalization: a series of 22 cases. Therapie. 2016 Jun;71(3):323-8. Abstract

Veronese A, Garatti M, Cipriani A, Barbui C. Benzodiazepine use in the real world of psychiatric practice: low-dose, long-term drug taking and low rates of treatment discontinuation. Eur J Clin Pharmacol. 2007;63(9):867-73. Abstract

Vicens C, Bejarano F, Sempere E, et al. Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care. Br J Psychiatry. 2014;204(6):471-9. Article

Vorma H, Naukkarinen H, Sarna S, Kuoppasalmi K. Symptom severity and quality of life after benzodiazepine withdrawal treatment in participants with complicated dependence. Addict Behav. 2004;29(6):1059-65. Abstract

Voshaar RC, Gorgels WJ, Mol AJ, et al. Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program. Can J Psychiatry. 2006;51(7):445-52. Abstract

Cognition

Craving

Mol AJ, Oude Voshaar RC, Gorgels WJ, et al. The absence of benzodiazepine craving in a general practice benzodiazepine discontinuation trial. Addict Behav. 2006;31(2):211-22. Abstract

Predictors of Discontinuation

Bish A, Golombok S, Hallstrom C, Fawcett S. The role of coping strategies in protecting individuals against long-term tranquilizer use. Br J Med Psychol. 1996;69 ( Pt 2):101-15. Abstract

Gorgels WJ, Oude Voshaar RC, Mol AJ, et al. Predictors of discontinuation of benzodiazepine prescription after sending a letter to long-term benzodiazepine users in family practice. Fam Pract. 2006;23(1):65-72. Article

Knoop H, Kan CC, Mickers FC, Barnhoorn D. Predicting the success of a benzodiazepine discontinuation programme: myths or clinical wisdom? Tijdschr Psychiatr. 2006;48(9):695-703. Abstract

Psychomotor

Rickels K, Lucki I, Schweizer E, et al. Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. J Clin Psychopharmacol. 1999;19(2):107-13. Abstract

17.19 Comparison Withdrawal from other Agents

SSRI

Lader M. Dependence and withdrawal: comparison of the benzodiazepines and selective serotonin re-uptake inhibitors. Addiction. 2012;107(5):909-10. Link

Nielsen M, Hansen EH, Gøtzsche PC. What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction. 2012;107(5):900-8. Abstract

17.20 Benzodiazepine Withdrawal by Subpopulation

Armed Services / Veterans

Addiction

Cancer

Cardiovascular Disease

Care Facilities

Emergency Department

Hospital: See also Pediatric below

Joughin N, Tata P, Collins M, et al. In-patient withdrawal from long-term benzodiazepine use. Br J Addict. 1991;86(4):449-55. Abstract

Străulea AO, Chiriţă V. The withdrawal syndrome in benzodiazepine dependence and its management. Rev Med Chir Soc Med Nat Iasi. 2009;113(3):879-84. Abstract

Thorel M, Fummi C, Gras V, Masmoudi K. Benzodiazepine or non-benzodiazepine hypnotics withdrawal syndrome during hospitalization: a series of 22 cases. Therapie. 2016 Jun;71(3):323-8. Abstract

Long-Term Care Facilities

Bourgeois J, Elseviers MM, Van Bortel L, et al. Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study. Eur J Clin Pharmacol. 2014;70(10):1251-60. Abstract

Cognitive Dysfunction

Criminal Justice

Elderly

Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf. 2014;13(7):919-34. Abstract

Petrovic M, Pevernagie D, Mariman A, et al. Fast withdrawal from benzodiazepines in geriatric inpatients: a randomized double-blind, placebo-controlled trial. Eur J Clin Pharmacol. 2002;57(11):759-64. Abstract

Petrovic M, Pevernagie D, Van Den Noortgate N, et al. A program for short-term withdrawal from benzodiazepines in geriatric hospital inpatients: success rate and effect on subjective sleep quality. Int J Geriatr Psychiatry. 1999;14(9):754-60. Abstract

Schweizer E, Case WG, Rickels K. Benzodiazepine dependence and withdrawal in elderly patients. Am J Psychiatry. 1989;146(4):529-31. Abstract

Wolter DK. Discontinuation of benzodiazepines in old age: When and if so, how? Z Gerontol Geriatr. 2017;50(2):115-122. Abstract

Yokoi Y, Misal M, Oh E, et al. Benzodiazepine discontinuation and patient outcome in a chronic geriatric medical/psychiatric unit: a retrospective chart review. Geriatr Gerontol Int. 2014;14(2):388-94. Abstract

Ethnicity

African-American

Asian

Caucasian

Hispanic

Native American

Pacific Island

Health Care Providers

Hepatic Disease

HIV / AIDS

LGBT

Men

Pain

Pediatric

Best KM, Boullata JI, Curley MA. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model. Pediatr Crit Care Med. 2015;16(2):175-83. Article

Birchley G. Opioid and benzodiazepine withdrawal syndromes in the pediatric intensive care unit: a review of recent literature. Nurs Crit Care. 2009;14(1):26-37. Abstract

da Silva PS, Reis ME, Fonseca TS, Fonseca MC. Opioid and benzodiazepine withdrawal syndrome in PICU patients: which risk factors matter? J Addict Med. 2016;10(2):110-6. Abstract

Ducharme C, Carnevale FA, Clermont MS, Shea S. A prospective study of adverse reactions to the weaning of opioids and benzodiazepines among critically ill children. Intensive Crit Care Nurs. 2005;21(3):179-86. Abstract

Ista E, de Hoog M, Tibboel D, et al. Psychometric evaluation of the Sophia Observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med. 2013;14(8):761-9. Abstract

Ista E, van Dijk M, Gamel C, et al. Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation. Crit Care Med. 2008;36(8):2427-32. Abstract

Ista E, van Dijk M, Gamel C, et al. Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: a literature review. “Assessment remains troublesome”. Intensive Care Med. 2007;33(8):1396-406. Abstract

Newborn

Bläser A, Pulzer F, Knüpfer M, et al. Drug withdrawal in newborns – clinical data of 49 infants with intrauterine drug exposure: what should be done? Klin Padiatr. 2008;220(5):308-15. Abstract

Levy M, Spino M. Neonatal withdrawal syndrome: associated drugs and pharmacologic management. Pharmacotherapy. 1993;13(3):202-11. Abstract

Uzun S, Kozumplik O, Jakovljević M, Sedić B, Side effects of treatment with benzodiazepines. Psychiatr Danub. 2010;22(1):90-3. Article

Psychiatric Disease

Anxiety

Depression

Psychosis

Suicidality

Renal Disease

Sleep Disorders

Sleep Apnea

Surgery

Swallowing Disorders

Women

Perinatal

Nursing

Library 17 Benzodiazepine: Withdrawal

17 Benzodiazepine: Withdrawal

17.1 Reviews

17.2 Terminology

17.3 Animal Studies

17.4 Neuro Physiology of Withdrawal

17.5 Withdrawal Symptoms

17.6 Withdrawal Symptoms By Organ System

17.7 Withdrawal Outcomes: Executive Function

17.8 Withdrawal Assessment

17.9 Withdrawal Treatment

17.10 Treatment: Modalities

17.11 Treatment: Modality Combinations

17.12 Treatment: Modality v Modality Comparisons

17.13 Treatment: Medications

17.14 Treatment: Medication Combinations

17.15 Treatment: Medication Comparisons

17.16 Treatment: Medication + Modality

17.17 Treatment: Relapse

17.18 Withdrawal Treatment: Outcomes

17.19 Comparison Withdrawal from other Agents

17.20 Benzodiazepine Withdrawal by Subpopulation

Related Posts

Register Now: Free CME Benzo Webinar Series

Do you know anyone interested in serving on a public health board?

Farewell to Dr. Steven Wright