Withdrawal from Benzodiazepines

Editor’s note: We know that our reviews of the withdrawal literature are incomplete, and we urge readers to help us add to them. Please send study citations that are relevant to the withdrawal literature for benzodiazepines to [email protected].

Introduction

Benzodiazepines have a sedating effect due to agonism of certain subtypes of GABA receptors in the amygdala. Studies have focused on involvement of the hypothalamic-pituitary-adrenocortical (HPA) system, glutaminergic strength, NMDA, and serotonin.

Biology of Withdrawal Effects

1. Wichniak A, Brunner H, Ising M, Gil FP, Holsboer F, Friess E. Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression. Psychoneuroendocrinology (2004) Oct 31;29(9):1101-8. PubMed link

This study found that benzodiazepine withdrawal may be due to disinhibiting the hypothalamic-pituitary-adrenocortical (HPA) system.

2) Song J, Shen G, Greenfield LJ, Tietz EI. Benzodiazepine withdrawal-induced glutamatergic plasticity involves up-regulation of GluR1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in hippocampal CA1 neurons. Journal of Pharmacology and Experimental Therapeutics (2007) Aug 1;322(2):569-81. PubMed link

Researchers found that benzodiazepine withdrawal leads to an increase in glutaminergic strength and excitability of CA1 in the brain, and that these changes can underlie the mechanism of physiological adaptations to drug withdrawal.

3) Xiang K, Tietz EI. Benzodiazepine-induced hippocampal CA1 neuron α-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. Behavioural Pharmacology. 2007 Sep 1;18(5-6):447-60. PubMed link

These authors showed that increased AMPAR activity during benzodiazepine withdrawal contributes to anxiety experienced when people withdraw from benzodiazepines, and that NMDAR activity is downregulated. The authors speculate that increased plasticity of glutamate receptors and certain types of receptor signaling may underlie withdrawal anxiety and substance dependence.

4) 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. Journal of Pharmacology and Experimental Therapeutics. 2011 Jan 1;336(1):265-73. PubMed link

Researchers suggest that a subtype of NMDA receptor (GluN2B) may modulate the strength of the gluteminergic synapse during benzodiazepine withdrawal (because there is neuronal hyperactivity resulting from withdrawal, which may cause anxiety), and thus may be an attempt to achieve homeostasis.

5) Benyamina A, Naassila M, Bourin M. Potential role of cortical 5-HT 2A receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal. Psychiatry Research. 2012 Jul 30;198(2):307-12. PubMed link

This study found that the anxiety-reducing effect of cyamemazine in withdrawal from benzodiazepines is likely due to serotonin receptor antagonistic activity in the cortex.

6) Preskorn SH. A Way of Conceptualizing Benzodiazepines to Guide Clinical Use. Journal of Psychiatric Practice. 2015 Nov 1;21(6):436-41. PubMed link

This article divides benzodiazepines into 4 classes depending on their characteristics on a continuum along 2 dimensions: length of half-life and potency of affinity for the binding site (low to high) and proposes using medications for different clinical indications depending on their classification.

Animal Research

Animal research has focused on anxiety as a withdrawal symptom of benzodiazepines. Increased serotonin release is hypothesized to play a role in this increased anxiety. Sudden withdrawal from alprazolam was associated with HPA axis activation, decrease in food consumption, and decrease in body weight.

7) File SE, Pellow S. Chlordiazepoxide enhances the anxiogenic action of CGS 8216 in the social interaction test: evidence for benzodiazepine withdrawal? Pharmacology Biochemistry and Behavior. 1985 Jul 1;23(1):33-6. PubMed link

This study found that chlordiazepoxide made animals less socially interactive (a measure of increased anxiety) in the presence of a compound CGS 8216 after both acute and chronic treatment, which was a surprising finding given that it is typically anxiety-reducing. The authors speculate this effect may be due to withdrawal from the high dose.

8) 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. Pharmacology Biochemistry and Behavior. 1989 Dec 31;34(4):931-3. PubMed link

In this study, researchers administered chlordiazepoxide to rats and then put them in a maze 24-30 hours after the last dose. Anxiety was measured by the percentage of time rats spent in each arm of the maze. Researchers found that rats withdrawing from CDP spent less time in the open arms of the maze, indicating anxiety. Clonidine and DL-propranolol did not reverse these effects, indicating that there is likely not noradrenergic involvement in the anxiety component of benzodiazepine withdrawal.

9) Nutt DJ. Pharmacological mechanisms of benzodiazepine withdrawal. Journal of Psychiatric Research. 1990 Dec 31;24:105-10. PubMed link

This author discusses the role of receptors in benzodiazepine withdrawal, stating that a shift in efficacy occurs at different receptor sites (attenuation of agonist receptors and enhancement of inverse agonist receptors) in the brain. The author states that treatment with flumazenil has been shown in rats to prevent or reverse the efficacy shift.

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

This study sought to investigate whether increased release of 5-HT in the hippocampus during benzodiazepine withdrawal can be linked to anxious behaviors in animals. A group of rats who did not show an anxious response also did not have increases in 5-HT release, which corroborated the hypothesis, but the authors did not establish causality.

11) Goudie AJ, Harrison AA, Leathley MJ. Evidence for a dissociation between benzodiazepine withdrawal signs. NeuroReport. 1993 Mar 1;4(3):295-8. PubMed link

This study found that chlordiazepoxide-withdrawal-induced weight loss occurred after just 10 days of treatment, and that the severity of weight loss is proportional to the length of treatment.

12) Pires JP, Monteiro KC, Alvarenga SO, Costa MG. Evidence suggesting that gonadal hormones influence benzodiazepine withdrawal-induced weight loss in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 1998 Feb 28;22(2):425-33. PubMed link

The authors found that surgically castrated rats had a statistically significant weight loss when compared with rats withdrawing from benzodiazepines who were not castrated and rats not withdrawing from benzodiazepines.

13) Pokk P, Zharkovsky A. Small platform stress attenuates the anxiogenic effect of diazepam withdrawal in the plus-maze test. Behavioural Brain Research. 1998 Dec 1;97(1):153-7. PubMed link

Mice were withdrawn from benzodiazepines and then subjected to stress by standing on a small platform surrounded by water for 24 hours. These mice were then placed into a maze, as were mice who were not subjected to stress. The researchers found that benzodiazepine withdrawal induced anxiety and small platform stress inhibited anxiety; they state that the effect of stress on withdrawal symptoms thus depends on the type and length of stress.

14) Metten P, Crabbe JC. Genetic determinants of severity of acute withdrawal from diazepam in mice: commonality with ethanol and pentobarbital. Pharmacology Biochemistry and Behavior. 1999 Jul 31;63(3):473-9. PubMed link

This study found that there are likely common genetic factors contributing to seizures upon withdrawal from diazepam, ethanol, and pentobarbital. The researchers speculate that a common neural mechanism involved in actions of all three drugs are the GABA/benzodiazepine receptor/chloride ionophore complex (GRC).

15) Stock H, Ford K, Biscardi R, Wilson MA. Lack of sex differences in anxiety behaviors during precipitated benzodiazepine withdrawal in rats. Physiology & Behavior. 1999 Mar 31;66(1):125-30. PubMed link

In this study, the researchers induced benzodiazepine withdrawal with flumazenil and measured length of time spent in the open arms of a maze to ascertain anxiety. They found that rats withdrawing from benzodiazepines spent less time in the open arms of the maze, but that there was also less activity overall. The authors conclude that anxiety behaviors do not tend to increase upon precipitated withdrawal from benzodiazepines and that there is no hormonal influence.

16) Elliot EE, White JM. Precipitated and spontaneous withdrawal following administration of lorazepam but not zolpidem. Pharmacology Biochemistry and Behavior. 2000 Jun 30;66(2):361-9. PubMed link

Researchers administered Lorazepam, zolpidem, or placebo to rats for 12 days and found that there was no evidence of withdrawal syndrome in the zolpidem group despite the fact that tolerance developed, but that there was evidence of withdrawal in the lorazepam groups both after administration of flumazenil and in spontaneous cessation. However, the results of this study contradict studies in baboons and humans.

17) Nath C, Saxena RC, Gupta MB. Effect of dopamine agonists and antagonists on the lorazepam withdrawal syndrome in rats. Clinical and Experimental Pharmacology and Physiology. 2000 Mar 11;27(3):167-71. PubMed link

This study investigated the effect of dopaminergic agonists and antagonists in withdrawal from lorazepam in rats by administering these compounds to rats after withdrawing them from lorazepam and measuring withdrawal symptoms. The authors conclude that dopamine D2 receptors (and partially dopamine D1 receptors) are facilitators concerning benzodiazepine withdrawal syndrome.

18) Nath C, Gupta MB. Role of central histaminergic system in lorazepam withdrawal syndrome in rats. Pharmacology Biochemistry and Behavior. 2001 Apr 30;68(4):777-82. PubMed link

This study investigated the effect of histaminergic agonists and antagonists in withdrawal from lorazepam in rats by administering these compounds to rats after withdrawing them from lorazepam and measuring withdrawal symptoms. Histamine-N-methyl, which is an agonist of the H3 receptor, as well as the H1 receptor antagonists promethazine and pheniramine, blocked all of the withdrawal symptoms. The authors conclude that histamine H1 receptors are facilitators and H3 receptors are inhibitors concerning benzodiazepine withdrawal syndrome.

19) Isoardi NA, Martijena ID, Carrer HF, Molina VA. Increased fear learning coincides with neuronal dysinhibition and facilitated LTP in the basolateral amygdala following benzodiazepine withdrawal in rats. Neuropsychopharmacology. 2004 Oct 1;29(10):1852-64. PubMed link

This study found that when exposed to a stimulus previously paired with an electric shock to the foot, rats that were withdrawn from benzodiazepines experienced significantly more freezing (fear conditioning) than control rats. The researchers think this could be due to depressed GABAergic activity in rats withdrawn from benzodiazepines.

20) Skelton KH, Nemeroff CB, Owens MJ. Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression. The Journal of Neuroscience. 2004 Oct 20;24(42):9303-12. PubMed link

This study found that sudden withdrawal from alprazolam was associated with HPA axis activation, decrease in food consumption, and decrease in body weight, as well as increased corticotropin-releasing factor mRNA expression and is likely to play a role in benzodiazepine withdrawal though the behavioral expression of this is unclear.

21) Rada P, Hoebel BG. Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency. European Journal of Pharmacology. 2005 Jan 31;508(1):131-8. PubMed link

The authors build upon the finding that diazepam is addictive and that unlike other addictive drugs, it decreases dopamine levels, by finding that it decreases acetylcholine levels as well when administered in rats. The administration of flumazenil increases both of these neurotransmitters and shows that acetylcholine may play a role in benzodiazepine withdrawal.

22) Begg DP, Hallam KT, Norman TR. Attenuation of benzodiazepine withdrawal anxiety in the rat by serotonin antagonists. Behavioural Brain Research. 2005 Jun 20;161(2):286-90. PubMed link

This study showed that when diazepam was abruptly withdrawn, rodents developed symptoms of anxiety such as decreased social interaction and decreased exploration of open arms of a maze compared to diazepam-treated and control rodents. Administration of serotonin receptor antagonists ritanserin and mitanserin led to a reduction in these anxious behaviors in the withdrawn animals, indicating that blocking post-synaptic 5-HT2 receptors may assist in alleviating anxiety associated with benzodiazepine withdrawal.

23) Fontanesi LB, Ferreira R, Cabral A, Castilho VM, Brandão ML, Nobre MJ. Brainstem areas activated by diazepam withdrawal as measured by Fos-protein immunoreactivity in rats. Brain Research. 2007 Aug 29;1166:35-46. PubMed link

This study used a technique to detect Fos immunoreactivity in certain brain structures when rats were withdrawn from benzodiazepines and found that benzodiazepine withdrawal activates the same brain structures (midbrain tectum) as those activated when exposed to dangerous situations.

24) Souza-Pinto LF, Castilho VM, Brandão ML, Nobre MJ. The blockade of AMPA-kainate and NMDA receptors in the dorsal periaqueductal gray reduces the effects of diazepam withdrawal in rats. Pharmacology Biochemistry and Behavior. 2007 Jul 31;87(2):250-7. PubMed link

This study investigated the effect of administering AMPA-kainate and NMDA receptor antagonists to the dorsal periaqueductal gray (dPAG) on symptoms of anxiety in rats withdrawing from benzodiazepines and found that inhibition of glutamatergic neurotransmission in the dPAG reduces symptoms of benzodiazepine withdrawal.

25) Das P, Lilly SM, Zerda R, Gunning WT, Alvarez FJ, Tietz EI. Increased AMPA receptor GluR1 subunit incorporation in rat hippocampal CA1 synapses during benzodiazepine withdrawal. Journal of Comparative Neurology. 2008 Dec 20;511(6):832-46. PubMed link

This study showed a significant increase in AMPAR GluR1-mediated glutamatergic neurotransmission in excitatory synapses on hippocampal CA1 neurons during benzodiazepine withdrawal, which gives insight into the physiological mechanisms underlying benzodiazepine-induced withdrawal anxiety.

26) 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. Journal of Comparative Neurology. 2010 Nov 1;518(21):4311-28. PubMed link

This study extends prior research into the role of Nmethyl-D-aspartate receptor (NMDAR) in anxiety during withdrawal from benzodiazepines and proposes a benzodiazepine withdrawal model.

27) Divljaković J, Milić M, Namjoshi OA, Tiruveedhula VV, Timić T, Cook JM, Savić MM. βCCT, an antagonist selective for α 1 GABA A receptors, reverses diazepam withdrawal-induced anxiety in rats. Brain Research Bulletin. 2013 Feb 28;91:1-7. PubMed link

Researchers treated rats with diazepam for 21 days and found after abrupt cessation, rats displayed anxiety-like behaviors. They found that both flumazenil and βCCT, an antagonist selective for α 1 GABA A receptors, alleviated the anxiety symptoms. This implies that antagonism at the GABA A receptors to reduce anxiety from benzodiazepine withdrawal involves the α 1 subunits of these receptors.

Withdrawal Symptoms

Benzodiazepine withdrawal has been characterized as a distinct syndrome consisting of symptoms such as severe anxiety, heightened sensitivity, weight loss, insomnia, and perceptual changes. It is protracted in nature and may last 5-54 days. Sudden cessation of benzodiazepines may result in seizures. It is both a physical and psychological experience that may warrant care from other providers in addition to the primary care provider.

28) Hallstrom C, Lader MH. Benzodiazepine withdrawal phenomena. International Pharmacopsychiatry. 1981. PubMed link

This study describes a withdrawal syndrome as benzodiazepines were withdrawn in 10 patients who stated they were unable to discontinue benzodiazepines. Symptoms included severe anxiety, heightened sensitivity, weight loss, and perceptual changes.

29) Ashton H. Benzodiazepine withdrawal: an unfinished story. British Medical Journal (Clinical research ed.). 1984 Apr 14;288(6424):1135. PubMed link

This paper outlines distinct symptoms of benzodiazepine withdrawal and describes it as being protracted in nature lasting anywhere from 5-54 days, though in some cases recovery may take six months to a year or more. The paper also describes it as a “severe illness” that is readily dismissed by medical providers as being anxiety-related, though the symptoms are distinct from anxiety.

30) Ayd FJ. Benzodiazepine Withdrawal Phenomena-New Insights. Psychiatric Annals. 1984 Feb 1;14(2):133-4.

This study reviews the results of a double-blind study of benzodiazepine withdrawal in 41 long-term benzodiazepine users conducted in Great Britain by Tyrer, Owen, and Dawling. One group consisted of early withdrawers and the other of late withdrawers. Between 44% and 50% of patients developed withdrawal symptoms included anxiety, restlessness, anorexia, low mood, depression, insomnia, and heightened sensitivity to light, touch, noise, and smell despite gradual reduction in use. After stopping, clients became more vulnerable to stress and illness, and symptoms were so distressing that 15 of 41 patients were again taking benzodiazepines at six-month follow-up and 7 were taking other psychotropic medication.

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

The authors demonstrate that all patients who experienced rebound anxiety in a double-blind RCT with placebo had received benzodiazepines. There was a significant difference in dropout rates between the abrupt withdrawal group and placebo.

32) Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. British Journal of Addiction. 1987 Jun 1;82(6):665-71. PubMed link

This study examined clinical outcomes in 50 patients who had been taking benzodiazepines anywhere from 1-22 years. Almost half of clients (48%) were classified as fully recovered 10-42 months later following withdrawal; 6% were no better, and younger age was significantly associated with favorable outcomes.

33) Noyes R, Garvey MJ, Cook BL, Perry PJ. Benzodiazepine withdrawal: a review of the evidence. Journal of Clinical Psychiatry. 1988 Oct. PubMed link

The authors review studies of benzodiazepines and benzodiazepine withdrawal and recommend gradual discontinuation lasting anywhere from 4-16 weeks with dose decreases not exceeding thresholds from 2.5 mg to 5 mg. Clinicians should watch for complications such as increase in alcohol use and depression, and be prepared to treat anxiety emerging.

34) Onyett SR. The benzodiazepine withdrawal syndrome and its management. JR Coll Gen Pract. 1989 Apr 1;39(321):160-3. PubMed link

This author describes benzodiazepine withdrawal as both a physical and psychological experience and discusses the importance of structured withdrawal and provider-client communication realistic expectations of the withdrawal experience. In some cases, support from other practitioners, including mental health practitioners, is warranted.

35) Schweizer E, Case WG, Rickels K. Benzodiazepine dependence and withdrawal in elderly patients. Am J Psychiatry. 1989 Apr 1;146(4):529-31. PubMed link

This study found that older patients had a less severe withdrawal experience than younger patients when tapering benzodiazepines; however, only 50% of each group remained free of benzodiazepines after 4 weeks.

36) DuPont RL. Thinking about stopping treatment for panic disorder. Journal of Clinical Psychiatry. 1990 Dec. PubMed link

This article differentiates chemical dependence from physical dependence and outlines a four-step tapering strategy applicable for patients with both types: gradual discontinuation, substitution of a different medication, use of medication to suppress withdrawal symptoms, and inpatient treatment and a 12-step program.

37) Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria?. Acta Psychiatrica Scandinavica. 1990 Aug 1;82(2):165-8. PubMed link

The authors administered psychophysiological tests to patients diagnosed with anxiety or conversion disorder and normal controls and found no evidence that withdrawal syndrome could be due to anxiety or conversion disorder and is likely an iatrogenic condition resulting from treatment with benzodiazepines.

38) Joughin N, Tata P, Collins M, Hooper C, Falkowski J. In‐patient withdrawal from long‐term benzodiazepine use. British Journal of Addiction. 1991 Apr 1;86(4):449-55. PubMed link

This study found that 38% of patients who completed an inpatient followed by outpatient program to withdraw from benzodiazepines achieved a good outcome, with younger patients faring better than older patients and those diagnosed with anxiety faring better than those with depressive disorder.

39) Neiman J, Persson H, Bergman H. Early benzodiazepine withdrawal in benzodiazepine-dependent subjects: a pilot study. Nordic Journal of Psychiatry. 1994 Jan 1;48(1):19-25. PubMed link

The authors compared six women withdrawing from benzodiazepines and six healthy controls and found that those withdrawing from benzodiazepines experienced higher anxiety, depressivity, fatigue, and confusion and lower “vigor” than controls.

40) Petursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994 Nov 1;89(11):1455-9. PubMed link

This author describes symptoms of the benzodiazepine withdrawal syndrome including insomnia, panic attacks, increases in anxiety, hand tremor, sweating, tension, difficulty concentrating, dry heaving and nausea, weight loss, headache, muscle tension and stiffness, perceptual changes, and seizures and psychosis at high doses. The author differentiates symptom patterns and discusses risk factors for withdrawal syndrome as well.

41) Martinez-Cano H, Vela-Bueno A, De Iceta M, Pomalima R, Martinez-Gras I. Benzodiazepine withdrawal syndrome seizures. Pharmacopsychiatry. 1995 Nov;28(06):257-62. PubMed link

This study is a case presentation of five seizures occurring after withdrawal from benzodiazepines (3% of a sample of 153 in a larger study) and found that sudden cessation and high-dose use increased risk.

42) Cassano GB, Petracca A, Borghi C, Chiroli S, Didoni G, Garreau M. A randomized, double-blind study of alpidem vs placebo in the prevention and treatment of benzodiazepine withdrawal syndrome. European Psychiatry. 1996 Dec 31;11(2):93-9. PubMed link

The authors found that withdrawal syndrome occurred in 31% of patients taking alpidem after abrupt withdrawal of benzodiazepines compared to 44% of the placebo group; severe withdrawal occurred in 11.1% of patients in the alpidem group and 31.6% of patients in the placebo group. Alpidem was withdrawn from the market in France in 1993 due to suspected liver toxicity.

43) Vorma H, Naukkarinen H, Sarna S, Kuoppasalmi K. Symptom severity and quality of life after benzodiazepine withdrawal treatment in participants with complicated dependence. Addictive Behaviors. 2004 Aug 31;29(6):1059-65. PubMed link

This study examined self-rated quality of life, as well as psychopathology as assessed by the Symptom Checklist 90 and Visual Analogue Scales after benzodiazepine withdrawal treatment in people with complicated dependence, defined as those with co-occurring harmful alcohol use or high doses of benzodiazepines. The study found that for the whole sample, symptoms and quality of life improved following withdrawal; for those with clinically significant dose decreases, symptoms and self-rated quality of life improved more than those who decreased doses less, though there were no statistically significant differences between groups.

44) Mol AJ, Gorgels WJ, Voshaar RC, Breteler MH, van Balkom AJ, van de Lisdonk EH, Kan CC, Zitman FG. Associations of benzodiazepine craving with other clinical variables in a population of general practice patients. Comprehensive Psychiatry. 2005 Oct 31;46(5):353-60. PubMed link

This study examined craving of benzodiazepines in a sample of primary care patients attempting to discontinue use and found that patients reporting craving were more dependent on benzodiazepines, psychopathology, negative mood, and personality factors such as negativism, somatization, and psychopathology.

45) Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A. Benzodiazepine dependence: focus on withdrawal syndrome. In Annales Pharmaceutiques Francaises 2009 Nov 30 (Vol. 67, No. 6, pp. 408-413). Elsevier Masson. PubMed link

This article examines the literature to determine patients most vulnerable to withdrawal symptoms (older adults, pregnant women, children, people with comorbid mental health conditions or alcohol/substance use disorder). It briefly discusses the lack of understanding of biological mechanisms behind benzodiazepine withdrawal, reviews how providers may have withdrawal conversations with clients, and finally concludes that there is not currently evidence that when tapering, substitutive pharmacotherapy improves outcomes compared to gradual reduction in use.

46) Saxon L, Borg S, Hiltunen AJ. Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil. Pharmacology Biochemistry and Behavior. 2010 Aug 31;96(2):148-51. PubMed link

This study found a decrease in hostility and aggression among people withdrawing from benzodiazepines who were treated with flumazenil, and the opposite effect among controls.

47) Dell’Osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. European Psychiatry. 2013 Jan 31;28(1):7-20. PubMed link

The authors discuss the utility of benzodiazepines as treatment for mental health conditions. In discussing withdrawal, the authors note that medication substitution has little evidence for efficacy when withdrawing, and that tapering rates are recommended based on clinical experience and not empirical evidence.

48) Tolbert D, Harris SI, Bekersky I, Lee D, Isojarvi J. Withdrawal-related adverse events from clinical trials of clobazam in Lennox–Gastaut syndrome. Epilepsy & Behavior. 2014 Aug 31;37:11-5. PubMed link

This study examined adverse event data from Phase I (abrupt stopping) and Phase III trials (gradual tapering) after clobazam withdrawal among patients with Lennox-Gastaut syndrome. No withdrawal-related AEs were noted after tapering, while after abrupt stoppage 193 adverse events occurred in 68 patients including headache, insomnia, tremor, and anxiety.

49) Yokoi Y, Misal M, Oh E, Bellantoni M, Rosenberg PB. Benzodiazepine discontinuation and patient outcome in a chronic geriatric medical/psychiatric unit: A retrospective chart review. Geriatrics & Gerontology International. 2014 Apr 1;14(2):388-94. PubMed link

This study found in a retrospective chart review comparing older adults who discontinued benzodiazepines to older adults who continued upon discharge that discontinuers had a shorter length of stay and lower levels of depression. There was no evidence of withdrawal syndrome, though there was a non-significant trend toward increase in agitation among discontinuers.

50) 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 May 13;15(1):1. PubMed link

This was a qualitative study of 41 patients who were dependent on benzodiazepines or had engaged in problematic use. They found that health concerns, feelings of being addicted, and social factors were motivations to stop and withdrawal “is difficult and unpredictable, with lots of complications.”

Protracted Withdrawal Symptoms

Studies focused on protracted withdrawal have focused on symptoms such as tinnitus, cognitive function, and life satisfaction.

51) Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. Journal of Clinical Psychopharmacology. 1988 Oct 1;8(5):359-62. PubMed link

This study describes persistent tinnitus in three former benzodiazepine users after withdrawal, and evidence of strong likelihood that the tinnitus was related to the benzodiazepine withdrawal.

Lagnaoui R, Bégaud B, Moore N, Chaslerie A, Fourrier A, Letenneur L, Dartigues JF, Moride Y. Benzodiazepine use and risk of dementia: A nested case–control study. Journal of Clinical Epidemiology. 2002 Mar 31;55(3):314-8. PubMed link

This study found that former and ever-use of benzodiazepines was associated with a significantly higher risk of developing dementia in adults aged 65 and older. There was no elevated risk associated with current use of benzodiazepines.

52) Vorma H, Naukkarinen H, Sarna S, Kuoppasalmi K. Long-term outcome after benzodiazepine withdrawal treatment in subjects with complicated dependence. Drug and Alcohol Dependence. 2003 Jun 5;70(3):309-14. PubMed link

This study compared treatment outcomes in people withdrawing from benzodiazepines. One group had a cognitive-behavioral intervention and the other group was treatment as usual. There were no between-group differences in outcomes, but lower initial benzodiazepine dose, zero previous attempts to withdraw, and life satisfaction predicted success in avoiding relapse.

53) Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Archives of Clinical Neuropsychology. 2004 Apr 30;19(3):437-54. PubMed link

This meta-analysis found that many benzodiazepine users show improvements in cognitive functioning after withdrawal, but that impairments compared to controls or normative data remain in most areas of cognitive functioning. There was not full restoration of cognitive functioning within the first 6 months after discontinuation and there may be aspects of cognitive functioning that are permanently impaired or take longer than 6 months to recover.

54) O’Connor KP, Marchand A, Bélanger L, Mainguy N, Landry P, Savard P, Turcotte J, Dupuis G, Harel F, Lachance L. Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication. Addictive Behaviors. 2004 May 31;29(3):583-93. PubMed link

This study assessed psychosocial factors associated with relapse of benzodiazepine use after a 20-week withdrawal program. Higher dose was associated with greater numbers of withdrawal symptoms, as well as poorer outcomes. Successful withdrawal was associated with low neuroticism, low behavioral inhibition, higher numbers of positive events, and higher levels of satisfaction with social support.

54) Morin CM, Bélanger L, Bastien C, Vallières A. Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse. Behaviour Research and Therapy. 2005 Jan 31;43(1):1-4. PubMed link

The authors examined time to relapse and relapse rate among benzodiazepine users who were in a supervised taper group (Taper), a cognitive-behavioral therapy group (CBT), and a Combined group receiving both interventions. Participants in the Combined and Taper groups relapsed significantly less than those in the CBT group. Medication-free time was significantly longer for both the Taper and Combined groups than the CBT group.

55) Mura T, Proust-Lima C, Akbaraly T, Amieva H, Tzourio C, Chevassus H, Picot MC, Jacqumin-Gadda H, Berr C. Chronic use of benzodiazepines and latent cognitive decline in the elderly: results from the Three-city study. European Neuropsychopharmacology. 2013 Mar 31;23(3):212-23. PubMed link

This study assessed whether benzodiazepine use is associated with an acceleration in cognitive decline in adults age 65 years and older. Researchers found that chronic benzodiazepine use was associated with poorer cognitive performance, but was not associated with acceleration in cognitive decline.

Withdrawal Tapering Protocols

Different approaches to tapering benzodiazepines have been attempted: tapering (with dose equivalents for each benzodiazepine and the tapering speed provided in a table), phenobarbital substitution when more rapid detoxification is required, sedative tolerance testing in situations where estimating the dose of phenobarbital or tapering is not recommended such as an unclear history of taking sedatives, and benzodiazepine substitution. Many different medications have been tested as an assist to tapering benzodiazepines. The latest evidence, however, suggests an 8-12 week tapering schedule with the aim of complete cessation in under 6 months; schedules should be slowed if withdrawal symptoms become overly distressing, and switching to diazepam may help in some cases where the process is more difficult.

56) Lader MH, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. Journal of Psychopharmacology. 1992 May 1;6(3):357-63. PubMed link

This was a study of flumazenil in the treatment of acute symptoms of benzodiazepine withdrawal. The authors found evidence of effectiveness with many symptoms, but that symptoms did return in most cases with a range of severity, indicating that follow-up doses would be needed.

57) Gabe J. Promoting benzodiazepine withdrawal. Addiction. 1994 Nov 1;89(11):1497-504. PubMed link

This author uses a prevention framework to discuss promotion of benzodiazepine withdrawal and outlines four strategies that could be used: health persuasion, personal counselling, state action, and community development. He advocates for greater involvement of state action in enacting policies.

58) Benzer DG, Smith DE, Miller NS. Detoxification from benzodiazepine use: Strategies and schedules for clinical practice. Psychiatric Annals. 1995 Mar 1;25(3):180-5. PubMed link

This article outlines four different strategies to stop benzodiazepine use and when each is appropriate: tapering (with dose equivalents for each benzodiazepine and the tapering speed provided in a table), phenobarbital substitution when more rapid detoxification is required, sedative tolerance testing in situations where estimating the dose of phenobarbital or tapering is not recommended such as an unclear history of taking sedatives, and benzodiazepine substitution, in which patients taking short- to medium-acting benzodiazepines are switched to a long-acting benzodiazepine.

59) Morton S, Lader M. Buspirone treatment as an aid to benzodiazepine withdrawal. Journal of Psychopharmacology. 1995 Jul 1;9(4):331-5. PubMed link

This study evaluated the use of buspirone in benzodiazepine withdrawal compared to placebo. Six of 12 patients in each group successfully withdrew, but anxiety levels were lower in those in the buspirone group. Higher benzodiazepine usage as measured by lifetime mean dose by duration was related to poorer outcome.

60) Schweizer E, Case WG, Garcia-Espana F, Rickels K, Greenblatt DJ. Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome. Psychopharmacology. 1995 Feb 1;117(4):424-9. PubMed link

Researchers found no difference between progesterone treatment and placebo in severity of benzodiazepine withdrawal symptoms, and no difference in cessation between the two groups at 12 weeks after tapering.

61) Elsesser K, Sartory G, Maurer J. The efficacy of complaints management training in facilitating benzodiazepine withdrawal. Behaviour Research and Therapy. 1996 Feb 29;34(2):149-56. PubMed link

This study compared two different interventions to manage benzodiazepine tapering over a 4-week gradual withdrawal period: complaints management training (CMT) and anxiety management training (AMT). Though CMT was initially more successful than AMT in terms of depression, anxiety, number of severe withdrawal symptoms reported, and abstinence, at 6 months there was no significant difference between the two interventions.

62) Saxon L, Hjemdahl P, Hiltunen AJ, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal–a double-blind pilot study. Psychopharmacology. 1997 May 1;131(2):153-60. PubMed link

This study found that flumazenil reduced withdrawal symptoms in patients withdrawing from benzodiazepines and increased negative experiences in controls who were not taking benzodiazepines.

63) Connor KM, Davidson JR, Potts NL, Tupler LA, Miner CM, Malik ML, Book SW, Colket JT, Ferrell F. Discontinuation of clonazepam in the treatment of social phobia. Journal of clinical psychopharmacology. 1998 Oct 1;18(5):373-8. PubMed link

This was a study of clonazepam for social phobia where after an initial 6-month period on the medication, patients were assigned to continuation therapy for 5 months or discontinuation taper of .25 mg per week every two weeks with double-blind placebo substitution. 21.1% of patients in the discontinuation group relapsed; 12.5% of patients in the continuation group and 27.7% of patients in the discontinuation group had withdrawal symptoms. At the end of the 11-month study, continuation therapy patients tapered for 3 weeks (considered “rapid”) and patients who underwent this rapid tapering showed more withdrawal symptoms than the clients who had gradually tapered.

64) Rickels K, DeMartinis N, Rynn M, Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment. Journal of Clinical Psychopharmacology. 1999 Dec 1;19(6):12S-6S. PubMed link

This study found that a variety of medications were useful for improving the rate of tapering benzodiazepine use, but not in mitigating severity of withdrawal symptoms. This study also suggests a 4-step approach to tapering including establishing a patient-physician relationship, treat any anxiety and depression while patient is still on benzodiazepines, taper patients who are taking more than 10 mg of diazepam or equivalent only after sufficient treatment and to 10 mg per day, and then maintain this level of use for several months before final taper.

65) Saxon L, Hiltunen AJ, Hjemdahl P, Borg S. Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study. Psychopharmacology. 2001 Jan 1;153(2):231-7. PubMed link

This was a study of gender-specific differences in response to placebo injections among the participants in a study of flumazenil for benzodiazepine withdrawal (people who had previously taken benzodiazepines and controls.) The study showed that females were more affected by placebo injections.

66) Zitman FG, Couvee JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off. The British Journal of Psychiatry. 2001 Apr 1;178(4):317-24. PubMed link

This study had chronic benzodiazepine users switch to diazepam and found that after treatment for depression with paroxetine vs. placebo, approximately 2/3 were successful in tapering from benzodiazepines and 13% of all patients in the study remained benzodiazepine-free three years later.

67) Oude Voshaar RC, Gorgels WJ, Mol AJ, Van Balkom AJ, Van de Lisdonk EH, Breteler MH, Van Den Hoogen HJ, Zitman FG. Tapering off long-term benzodiazepine use with or without group cognitive–behavioural therapy: three-condition, randomised controlled trial. The British Journal of Psychiatry. 2003 Jun 1;182(6):498-504. PubMed link

This study examined benzodiazepine taper in two groups: taper only and CBT group plus taper, and compared this to usual care. The findings were that tapering was more successful than usual care and that CBT had no added benefit and that success and intervention type had no association with measures of psychological functioning.

68) Morin CM, Bastien C, Guay B, Radouco-Thomas M, Leblanc J, Vallières A. Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. American Journal of Psychiatry. 2004 Feb 1;161(2):332-42. PubMed link

This study consisted of three interventions in older adults: a supervised withdrawal taper, cognitive-behavioral therapy for insomnia, or taper plus CBT. More patients who received taper plus CBT were benzodiazepine-free at the end of the initial intervention than patients with either tapering or CBT alone, though all three groups reduced the quantity and frequency of benzodiazepine use.

69) Mol AJ, Voshaar RO, Gorgels WJ, Breteler MH, Van Balkom AJ, Van de Lisdonk EH, Kan CC, Mulder J, Zitman FG. The absence of benzodiazepine craving in a general practice benzodiazepine discontinuation trial. Addictive Behaviors. 2006 Feb 28;31(2):211-22. PubMed link

The authors conducted a 21-month study of benzodiazepine craving in benzodiazepine users undergoing three interventions: a letter from their primary care provider, a supervised discontinuation involving the primary care provider combined with CBT groups, and usual care. They ound that the craving severity had decreased for all groups, patients still using benzodiazepines reported more craving than patients who had successfully quit during the study, and that the way in which patients quit benzodiazepines did not affect craving severity, though patients who received an additional tapering-off intervention reported more severe craving. This suggests that people attempting to quit benzodiazepines who are reporting a more severe craving may need more intense interventions.

70) Nakao M, Takeuchi T, Nomura K, Teramoto T, Yano E. Clinical application of paroxetine for tapering benzodiazepine use in non‐major‐depressive outpatients visiting an internal medicine clinic. Psychiatry and Clinical Neurosciences. 2006 Oct 1;60(5):605-10. PubMed link

This study found that, among three groups of non-depressed clients (one using SSRIs during benzodiazepine taper, one doing benzodiazepine taper without SSRIs, and one not reducing use of benzodiazepines) that the use of SSRI predicted becoming benzodiazepine-free after adjusting for age, gender, length of benzodiazepine use, and baseline HAM-A and HAM-D scores.

71) Vicens C, Fiol F, Llobera J, Campoamor F, Mateu C, Alegret S, Socías I. Withdrawal from long-term benzodiazepine use: randomised trial in family practice. Br J Gen Pract. 2006 Dec 1;56(533):958-63. PubMed link

This study found that an intervention consisting of standardized advice given by a primary care doctor combined with a tapering schedule and biweekly follow-up visits were five times as likely as patients receiving usual care to discontinue their use of benzodiazepines.

72) O’Connor K, Marchand A, Brousseau L, Aardema F, Mainguy N, Landry P, Savard P, Leveille C, Lafrance V, Boivin S, Pitre D. Cognitive–behavioural, pharmacological and psychosocial predictors of outcome during tapered discontinuation of benzodiazepine. Clinical Psychology & Psychotherapy. 2008 Jan 1;15(1):1-4. PubMed link

This study examined benzodiazepine withdrawal in three groups (CBT plus taper, group support plus taper, or taper only) and found that outcomes in the CBT and group support groups were equivalent.

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

This study reviews different withdrawal strategies for benzodiazepines in a primary care setting. They suggest that most clients can be withdrawn on a schedule 8-12 weeks in length, but for clients who have tried previously and unsuccessfully to stop a schedule as long as 26 weeks could be necessary.

74) Otto MW, McHugh RK, Simon NM, Farach FJ, Worthington JJ, Pollack MH. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation. Behaviour Research and Therapy. 2010 Aug 31;48(8):720-7. PubMed link

This study examined benzodiazepine taper in three groups: taper only, CBT plus taper, and relaxation plus taper and found that CBT had a significantly larger effect size than either of the other two groups at a six-month follow-up.

75) Parr JM, Kavanagh DJ, Young R, Mitchell G. Acceptability of cognitive‐behaviour therapy via the Internet for cessation of benzodiazepine use. Drug and Alcohol Review. 2011 May 1;30(3):306-14. PubMed link

This was a study of the acceptability of CBT delivered over the Internet (consisting of completing online assessments and reading newsletters, with therapist contact via email) for cessation of benzodiazepines and found that 8 of 14 reduced intake by half according to self-report, and five stopped use entirely.

76) Bobes J, Rubio G, Teran A, Cervera G, López-Gómez V, Vilardaga I, Pérez M. Pregabalin for the discontinuation of long-term benzodiazepines use: an assessment of its effectiveness in daily clinical practice. European Psychiatry. 2012 May 31;27(4):301-7. PubMed link

This was a prospective, uncontrolled, observational study of the use of pregabalin for benzodiazepine withdrawal in people age 18 and older. Success was being free of benzodiazepines according to a urine screen at 12 weeks. Though pregablin showed promise in alleviating anxiety and other withdrawal symptoms, the authors state that a placebo-controlled study should be conducted and that long-term maintenance of these results, withdrawal from pregabalin, and appropriate withdrawal schedules have yet to be investigated.

77) Furuya M, Miyaoka T, Wake R, Nagahama M, Kawano K, Yamashita S, Ieda M, Ezoe S, Horiguchi J. Possibility of early withdrawal of benzodiazepine hypnotics by combination with ramelteon for the treatment of insomnia: A pilot study. Sleep and Biological Rhythms. 2013 Jan 1;11(1):55-61. PubMed link

This prospective observational study examined the effectiveness of ramelteon, a melatonin receptor agonist, on insomnia related to benzodiazepine withdrawal. They found that sleep-related scores improved after beginning ramelteon and that there were no adverse-related sleep effects such as rebound insomnia that occurred with tapering of benzodiazepine hypnotics as ramelteon was used.

78) Gould RL, Coulson MC, Patel N, Highton-Williamson E, Howard RJ. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. The British Journal of Psychiatry. 2014 Feb 1;204(2):98-107. PubMed link

This study was a systematic review and meta-analysis of 10 studies of benzodiazepine withdrawal strategies in older adults. The most successful intervention was supervised withdrawal with psychotherapy and withdrawal with prescribing interventions compared to treatment as usual, education placebo, withdrawal with or without drug placebo, and psychotherapy alone. Multifaceted prescribing interventions were also significant compared to control consisting of treatment as usual or placebo.

79) Baandrup L, Fagerlund B, Jennum P, Lublin H, Hansen JL, Winkel P, Gluud C, Oranje B, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial-the SMART trial protocol. BMC psychiatry. 2011 Oct 5;11(1):160. PubMed link

This study found that after 24 weeks of tapering, the melatonin group had similar rates of benzodiazepine dosage and similar rates of cessation to controls, and thus that melatonin does not appear to assist with cessation of benzodiazepine use.

80) 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 Research. 2016 Jun 30;240:163-9. PubMed link

This study found that after 24 weeks of tapering, melatonin had no added effect on sleep quality, and that decreased benzodiazepine use at 24 weeks was associated with decreased stage 2 sleep.

81) Lader M, Kyriacou A. Withdrawing Benzodiazepines in Patients With Anxiety Disorders. Current Psychiatry Reports. 2016 Jan 1;18(1):1-8. PubMed link

This article states that available evidence suggests an 8-12 week tapering schedule with the aim of complete cessation in under 6 months; schedules should be slowed if withdrawal symptoms become overly distressing.

Brain Changes

The GABAA receptors have been investigated as playing a key role in benzodiazepine dependence. Cognitive impairment compared with normative data was still present after benzodiazepine tapering among some clients, though cognitive performance improved after withdrawal.

82) Wafford KA. GABA A receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Current Opinion in Pharmacology. 2005 Feb 28;5(1):47-52. PubMed link

This article concludes that future research with subtype-insensitive mice may play a role in further research about how GABA A receptor subtypes contribute to benzodiazepine dependence, as well as the use of subtype-selective drugs.

83) Licata SC, Rowlett JK. Abuse and dependence liability of benzodiazepine-type drugs: GABA A receptor modulation and beyond. Pharmacology Biochemistry and Behavior. 2008 Jul 31;90(1):74-89. PubMed link

The authors examine the literature concerning neurobiological mechanisms of physical dependence on and withdrawal from benzodiazepines, and call for more research into this issue to inform development of safer and more effective medications.

84) Heberlein A, Lenz B, Muschler M, Frieling H, Buechl R, Gröschl M, Kornhuber J, Bleich S, Hillemacher T. BDNF plasma levels decrease during benzodiazepine withdrawal in patients suffering from comorbidity of depressive disorder and benzodiazepine dependence. Psychopharmacology. 2010 Apr 1;209(2):213-5. PubMed link

This study found that brain-derived neuronal factor plasma levels were significantly increased in benzodiazepine-dependent patients compared to age- and sex-matched controls and decreased significantly due to benzodiazepine withdrawal, which indicates that benzodiazepines may work according to a similar neurological mechanism to antidepressant medications.

85) Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABAA receptor modulators?. Advances in pharmacological sciences. 2012 Mar 29;2012. PubMed link

The authors review the different neurobiological processes by which people may develop tolerance to benzodiazepines and recommend that a potential solution to developing tolerance may be a varied dosing schedule including placebos, as development of tolerance is a process that differs across individuals and drugs.

86) 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. European Archives of Psychiatry and Clinical Neuroscience. 2016 Jul 11:1-9. PubMed link

This study found that, among 80 patients with schizophrenia or bipolar disorder, cognitive impairment compared with normative data was still present after benzodiazepine tapering, though cognitive performance improved after tapering. The addition of melatonin did not affect cognition, well-being, or psychosocial functioning.