Withdrawing Benzodiazepines in Patients With Anxiety Disorders

Anxiety Disorders (A Pelissolo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Anxiety Disorders

Abstract

The large class of CNS-depressant medications—the benzodiazepines—have been extensively used for over 50 years, anxiety disorders being one of the main indications. A substantial proportion (perhaps up to 20–30 %) of long-term users becomes physically dependent on them. Problems with their use became manifest, and dependence, withdrawal difficulties and abuse were documented by the 1980s. Many such users experience physical and psychological withdrawal symptoms on attempted cessation and may develop clinically troublesome syndromes even during slow tapering. Few studies have been conducted to establish the optimal withdrawal schedules. The usual management comprises slow withdrawal over weeks or months together with psychotherapy of various modalities. Pharmacological aids include antidepressants such as the SSRIs especially if depressive symptoms supervene. Other pharmacological agents such as the benzodiazepine antagonist, flumazenil, and the hormonal agent, melatonin, remain largely experimental. The purpose of this review is to analyse the evidence for the efficacy of the usual withdrawal regimes and the newer agents. It is concluded that little evidence exists outside the usual principles of drug withdrawal but there are some promising leads.

Keywords

Benzodiazepines Dependence Withdrawal Clinical risks Abuse Flumazenil Circadin 

Notes

Compliance with Ethical Standards

Conflict of Interest

Malcolm Lader and Andri Kyriacou declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    D’Hulst C, Atack J, Kooy R. The complexity of the GABAA receptor shapes unique pharmacological profiles. Drug Discov Today. 2009;14(17–18):866–75.CrossRefPubMedGoogle Scholar
  2. 2.
    Lader M. Benzodiazepines revisited-will we ever learn? Addiction. 2011;106(12):2086–109.CrossRefPubMedGoogle Scholar
  3. 3.
    O’Brien C. Benzodiazepine use, abuse and dependence. J Clin Psychiatry. 2005;66:28–33.CrossRefPubMedGoogle Scholar
  4. 4.
    Donoghue J, Lader M. Usage of benzodiazepines: a review. Int J Psychiatry Clin Pract. 2010;14(2):78–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Locke A, Kirst N, Shultz C. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2015;91:617–24.PubMedGoogle Scholar
  6. 6.
    Cloos J, Ferreira V. Current use of benzodiazepines in anxiety disorders. Curr Opin Psychiatry. 2009;22(1):90–5.CrossRefPubMedGoogle Scholar
  7. 7.•
    Baldwin D, Aitchison K, Bateson A, Curran H, Davies S, Leonard B, et al. Benzodiazepines: risks and benefits. A reconsideration. J Psychopharmacol. 2013;27(11):967–71. A reconsideration of the risk/benefit of benzodiazepines.CrossRefPubMedGoogle Scholar
  8. 8.
    Rcpsych.ac.uk. Benzodiazepines [Internet]. 2015 [cited 19 June 2015]. Available from: http://www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/benzodiazepines.aspx.
  9. 9.
    Mehdi T. Benzodiazepines revisited. Br J Med Pract Manage. 2012;5(1):a501.Google Scholar
  10. 10.
    Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249–55.CrossRefPubMedGoogle Scholar
  11. 11.
    Petursson H, Lader M. Dependence on tranquillizers. Oxford: Oxford University Press; 1984.Google Scholar
  12. 12.
    Tvete I, Bjorner T, Aursnes I, Skomedal T. A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing. BMJ Open. 2013;3(10):e003296.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Vinkers C, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABAA receptor modulators? Adv Pharm Sci. 2012;2012:1–19.CrossRefGoogle Scholar
  14. 14.•
    Manthey L, Lohbeck M, Giltay E, van Veena T, Zitman F, Penninx B. Correlates of benzodiazepine dependence in the Netherlands study of depression and anxiety. Addiction. 2012;107(12):2173–82. Presents predictive data on dependence liability.CrossRefPubMedGoogle Scholar
  15. 15.
    Cuevas C, Sanz E, Fuente J, Padilla J, Berenguer J. The severity of dependence scale (SDS) as screening test for benzodiazepine dependence: SDS validation study. Addiction. 2000;95(2):245–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Schweizer E, Rickels K. Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Acta Psychiatr Scand. 1998;98(s393):95–101.CrossRefGoogle Scholar
  17. 17.
    Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria? Acta Psychiatr Scand. 1990;82(2):165–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Hallstrom C, Lader M. Benzodiazepine withdrawal phenomena. Int Pharmacopsychiatry. 1981;16:235–44.PubMedGoogle Scholar
  19. 19.
    Lader M. Long-term anxiolytic therapy: the issue of drug withdrawal. J Clin Psychiatry. 1987;1(48 Suppl):12–6.Google Scholar
  20. 20.
    Vikander B, Koechling U, Borg S, Tönne U, Hiltunen A. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010;64(4):273–82.CrossRefPubMedGoogle Scholar
  21. 21.
    Russell J, Lader M. Guidelines for the prevention and treatment of benzodiazepine dependence. London: The Mental Health Foundation; 1994.Google Scholar
  22. 22.
    Mcgregor C, Machin A, White J. In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods. Drug Alcohol Rev. 2003;22(2):175–80.CrossRefPubMedGoogle Scholar
  23. 23.
    Kan C, Breteler M, Zitman F. High prevalence of benzodiazepine dependence in out-patient users, based on the DSM-III-R and ICD-10 criteria. Acta Psychiatr Scand. 1997;96(2):85–93.CrossRefPubMedGoogle Scholar
  24. 24.
    de Gier N, Gorgels W, Lucassen P, Oude Voshaar R, Mulder J, Zitman F. Discontinuation of long-term benzodiazepine use: 10-year follow-up. Fam Pract. 2010;28(3):253–9.CrossRefPubMedGoogle Scholar
  25. 25.••
    Lingford-Hughes A, Welch S, Peters L, Nutt D. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol. 2012;26(7):899–952. An authoritative review on the features and management of various types of addiction.CrossRefPubMedGoogle Scholar
  26. 26.
    Ashton C. Benzodiazepines: how they work & how to withdraw. Newcastle: University of Newcastle; 2001.Google Scholar
  27. 27.
    Higgitt A, Lader M, Fonagy P. Clinical management of benzodiazepine dependence. BMJ. 1985;291(6503):1202.PubMedCentralCrossRefGoogle Scholar
  28. 28.
    Voshaar R. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry. 2006;189(3):213–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Denis D, Fatseas M, Lavie E, Auriscombe M. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev. 2007. CD005194.Google Scholar
  30. 30.
    Murphy S, 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(4):511–6.Google Scholar
  31. 31.
    Voshaar R, Gorgels W, Mol A, Van Balkom A, Mulder J, Van De Lisdonk E, et al. Long-term outcome of two forms of randomised benzodiazepine discontinuation. Br J Psychiatry. 2006;188(2):188–9.CrossRefGoogle Scholar
  32. 32.
    Podhorna J. The experimental pharmacotherapy of benzodiazepine withdrawal. Curr Pharm Des. 2002;8(1):23–43.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    Kawasaki S, Jacapraro J, Rastegar D. Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. J Subst Abus Treat. 2012;43(3):331–4.CrossRefGoogle Scholar
  35. 35.
    Schweizer E. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Arch Gen Psychiatry. 1991;48(5):448.CrossRefPubMedGoogle Scholar
  36. 36.
    Efficacy of drug treatments for Generalised Anxiety Disorder: systematic review and meta-analysis. BMJ. 2011;342(mar16 2):d1718-d1718.Google Scholar
  37. 37.••
    Baldwin D, Anderson I, Nutt D, Allgulander C, Bandelow B, den Boer J, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403–39. An authoritative survey of the treatments available to treat various anxiety disorders.CrossRefPubMedGoogle Scholar
  38. 38.
    Baldwin D, Ajel K. Role of pregabalin in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat. 2007;3(2):185–91.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Hadley S, Mandel F, Schweizer E. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol. 2011;26(4):461–70.CrossRefPubMedGoogle Scholar
  40. 40.
    Crockford D, White W, Campbell B. Gabapentin use in benzodiazepine dependence and detoxification. Can J Psychiatr. 2001;46:287.Google Scholar
  41. 41.
    Chessick C, Allen M, Thase M. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2015;3, CD006115.Google Scholar
  42. 42.
    Ashton C, Rawlins M, Tyrer S. A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry. 1990;157(2):232–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database Syst Rev. 2010;12. CD006815.Google Scholar
  44. 44.
    Gao K, Sheehan D, Calabrese J. Atypical antipsychotics in primary generalized anxiety disorder or comorbid with mood disorders. Expert Rev Neurother. 2009;9(8):1147–58.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Vulink N, Figee M, Denys D. Review of atypical antipsychotics in anxiety. Eur Neuropsychopharmacol. 2011;21(6):429–49.CrossRefPubMedGoogle Scholar
  46. 46.
    Srinivasan V, Brzezinski A, Pandi-Perumal S, Spence D, Cardinali D, Brown G. Melatonin agonists in primary insomnia and depression-associated insomnia: are they superior to sedative-hypnotics? Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(4):913–23.CrossRefGoogle Scholar
  47. 47.
    Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin. Arch Intern Med. 1999;159(20):2456.CrossRefPubMedGoogle Scholar
  48. 48.
    Peles E, Hetzroni T, Bar-Hamburger R, Adelson M, Schreiber S. Melatonin for perceived sleep disturbances associated with benzodiazepine withdrawal among patients in methadone maintenance treatment: a double-blind randomized clinical trial. Addiction. 2007;102(12):1947–53.CrossRefPubMedGoogle Scholar
  49. 49.
    Clay E, Falissard B, Moore N, Toumi M. Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and z-drugs consumption in nine European countries. Eur J Clin Pharmacol. 2012;69(4):1–10.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Rickels K, DeMartinis N, Rynn M, Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol. 1999;19:12S–6S.CrossRefPubMedGoogle Scholar
  51. 51.
    Tyrer P, Ferguson B, Hallstrom C, Michie M, Tyrer S, Cooper S, et al. A controlled trial of dothiepin and placebo in treating benzodiazepine withdrawal symptoms. Br J Psychiatry. 1996;168(4):457–61.CrossRefPubMedGoogle Scholar
  52. 52.
    Zitman FG, Couveé 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(4):317–24.CrossRefPubMedGoogle Scholar
  53. 53.
    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 Clin Neurosci. 2006;60(5):605–10.CrossRefPubMedGoogle Scholar
  54. 54.
    Spiegel D. Psychological strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol. 1999;19:17S–22S.CrossRefPubMedGoogle Scholar
  55. 55.
    Voshaar R, Gorgels W, Mol A, Van Balkom A, Van de Lisdonk E, Breteler M, et al. Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial. Br J Psychiatry. 2003;182(6):498–504.CrossRefPubMedGoogle Scholar
  56. 56.
    Gosselin P, Ladouceur R, Morin C, Dugas M, Baillargeon L. Benzodiazepine discontinuation among adults with GAD: a randomized trial of cognitive-behavioral therapy. J Consult Clin Psychol. 2006;74(5):908–19.CrossRefPubMedGoogle Scholar
  57. 57.
    Baillargeon L, Landreville P, Verreault R, Beauchemin J, Gregoire J, Morin C. Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering; a randomized trial. Can Med Assoc J. 2003;169:1015–20.Google Scholar
  58. 58.
    Ten Wolde G, Dijkstra A, van Empelen P, van den Hout W, Knuistingh Neven A, Zitman F. Long-term effectiveness of computer-generated tailored patient education on benzodiazepines: a randomized controlled trial. Addiction. 2008;103(4):662–70.CrossRefPubMedGoogle Scholar
  59. 59.
    Parr J, Kavanagh D, Cahill L, Mitchell G, Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009;104(1):13–24.CrossRefPubMedGoogle Scholar
  60. 60.
    Smith A, Tett S. Improving the use of benzodiazepines—is it possible? A non-systematic review of interventions tried in the last 20 years. BMC Health Serv Res. 2010;10(1):321.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Gould R, Coulson M, Patel N, Highton-Williamson E, Howard R. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry. 2014;204(2):98–107.CrossRefPubMedGoogle Scholar
  62. 62.
    Hood S, Norman A, Hince D, Melichar J, Hulse G. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol. 2014;77(2):285–94.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Gerra G, Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, et al. Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal. Int Clin Psychopharmacol. 1996;11(2):81–8.PubMedGoogle Scholar
  64. 64.
    Griffiths R, Evans S, Guarino J. Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal. J Pharmacol Exp Ther. 1993;265:1163–74.PubMedGoogle Scholar
  65. 65.
    Mintzer M, Stoller K, Griffiths R. A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. Psychopharmacology. 1999;147(2):200–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Lader M, Morton S. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol. 1992;6(3):357–63.CrossRefPubMedGoogle Scholar
  67. 67.
    Saxon L, Hjemdahl P, Hiltunen A, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal—a double-blind pilot study. Psychopharmacology. 1997;131(2):153–60.CrossRefPubMedGoogle Scholar
  68. 68.
    Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol. 2002;7(4):385–95.Google Scholar
  69. 69.
    Hood S, O’Neil G, Hulse G. The role of flumazenil in the treatment of benzodiazepine dependence: physiological and psychological profiles. J Psychopharmacol. 2009;23(4):401–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Quaglio G, Pattaro C, Gerra G, Mathewson S, Verbanck P, Des Jarlais D, et al. High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. Psychiatry Res. 2012;198(3):457–62.CrossRefPubMedGoogle Scholar
  71. 71.
    Hulse G, O’Neil G, Morris N, Bennett K, Norman A, Hood S. Withdrawal and psychological sequelae, and patient satisfaction associated with subcutaneous flumazenil infusion for the management of benzodiazepine withdrawal: a case series. J Psychopharmacol. 2012;27(2):222–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19.CrossRefPubMedGoogle Scholar
  73. 73.
    Parr J, Kavanagh D, Young R, Mitchell G. Acceptability of cognitive-behaviour therapy via the internet for cessation of benzodiazepine use. Drug Alcohol Rev. 2011;30(3):306–14.CrossRefPubMedGoogle Scholar
  74. 74.
    Vorma H, Naukkarinen H, Sarna S, Kuoppasalmi K. Treatment of out-patients with complicated benzodiazepine dependence: comparison of two approaches. Addiction. 2002;97(7):851–9.CrossRefPubMedGoogle Scholar
  75. 75.•
    Lugoboni F, Quaglio G. Exploring the dark side of the moon: the treatment of benzodiazepine tolerance. Br J Clin Pharmacol. 2014;77(2):239–41. An expert account of the management of benzodiazepine dependence and withdrawal.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Barker M. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol. 2004;19(3):437–54.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.National Addiction Centre, Addictions Department, Institute of Psychiatry, Psychology and NeurosciencesKing’s College LondonLondonUK

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