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Anxiolytics: Misuse, Dependence, and Withdrawal Syndromes

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NeuroPsychopharmacotherapy

Abstract

The use of anxiolytic medications requires a careful assessment of the risk for misuse, dependence, and withdrawal. Clinicians should be aware of the range of presentations for misuse and dependence, which includes non-medical use, diversion, self-medication, inappropriate prescription, and behavioral and psychological syndromes of addictive disorders. In comparison to other anxiolytics, benzodiazepines pose the greatest risks for misuse, dependence, and withdrawal. A strong association between benzodiazepine misuse with other sedating drugs such as opioids has been reported and is associated with increased overdose deaths. Careful monitoring is needed for benzodiazepine withdrawal, which can be severe, and gradual tapers with psychological support should be offered. Cognitive behavioral therapy has evidence for efficacy through the stages of benzodiazepine discontinuation and relapse prevention. Although reports of gabapentinoid misuse, dependence, and withdrawal have been increasing in the literature over the years, the numbers involved are small relative to the large number of individuals who have been exposed to the drugs, and true population-based prevalence rates remain poorly characterized. However, randomized controlled trials involving discontinuation in people with anxiety disorders do not show evidence for any significant withdrawal potential. Azapirone anxiolytics including buspirone and tandospirone likely have negligible pharmacological potential for misuse, dependence, and withdrawal. While there may be a gradient of risk for misuse and dependence from benzodiazepines, having the highest, through gabapentinoids to azapirones, having the least, the greatest risk factor by far with all anxiolytic drug classes is the presence of other substance use disorders. This suggests that the pre-existing characteristics of individuals using a medication may contribute as much if not more than the pharmacology of specific drugs in determining the likelihood of misuse and dependence.

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References

  • Abrahamsson T, Berge J, Öjehagen A, Håkansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment – a nation-wide register-based open cohort study. Drug Alcohol Depend. 2017;174:58–64.

    CAS  PubMed  Google Scholar 

  • Airagnes G, Pelissolo A, Lavallée M, Flament M, Limosin F. Benzodiazepine misuse in the elderly: risk factors, consequences, and management. Curr Psychiatry Rep. 2016;18(10):89.

    PubMed  Google Scholar 

  • Alessi-Severini S, Bolton JM, Enns MW, Dahl ME, Chateau D, Collins DM, Sareen J. Sustained use of benzodiazepines and escalation to high doses in a Canadian population. Psychiatr Serv. 2016;67(9):1012–8.

    PubMed  Google Scholar 

  • Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010;3:CD005063.

    Google Scholar 

  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Text revision: DSM-1V-TR. 4th ed. Washington, DC: American Psychiatric Association; 2004.

    Google Scholar 

  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC: American Psychiatric Association; 2013.

    Google Scholar 

  • Andrews G, Bell C, Boyce P, Gale C, Lampe L, Marwat O, Rapee R, Wilkins G. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018;52(12):1109–72.

    Google Scholar 

  • Argyropoulos S, Nutt D. The use of benzodiazepines in anxiety and other disorders. Eur Neuropsychopharmacol. 1999;9:S407–12.

    CAS  PubMed  Google Scholar 

  • Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abus Treat. 1991;8(1–2):19–28.

    CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Asomaning K, Abramsky S, Liu Q, Zhou X, Sobel R, Watt S. Pregabalin prescriptions in the United Kingdom: a drug utilisation study of The Health Improvement Network (THIN) primary care database. Int J Clin Pract. 2016;70(5):380–8.

    CAS  PubMed  Google Scholar 

  • Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi A, Vennat B, Llorca P-M, Eschalier A. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408–13.

    CAS  PubMed  Google Scholar 

  • Baandrup L, Lindschou J, Winkel P, Gluud C, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: a randomised, placebo-controlled, blinded trial. World J Biol Psychiatry. 2016;17(7):514–24.

    PubMed  Google Scholar 

  • Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Grégoire JP, Morin CM. Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial. CMAJ. 2003;169(10):1015–20.

    PubMed  PubMed Central  Google Scholar 

  • Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: a survey among substance misusers. Eur Addict Res. 2014;20(3):115–8.

    PubMed  Google Scholar 

  • Baldwin DS, Aitchison K, Bateson A, Curran HV, Davies S, Leonard B, Nutt DJ, Stephens DN, Wilson S. Benzodiazepines: risks and benefits. A reconsideration. J Psychopharmacol. 2013;27(11):967–71.

    CAS  PubMed  Google Scholar 

  • Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, Christmas DM, Davies S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O’Neill C, Scott J, van der Wee N, Wittchen H-U. 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.

    PubMed  Google Scholar 

  • Bandelow B, Zohar J, Hollander E, Kasper S, Möller H-J, WFSBP. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision. World J Biol Psychiatry. 2008;9(4):248–312.

    PubMed  Google Scholar 

  • Barrueto F, Green J, Howland MA, Hoffman RS, Nelson LS. Gabapentin withdrawal presenting as status epilepticus. J Toxicol Clin Toxicol. 2002;40(7):925–8.

    PubMed  Google Scholar 

  • Bastiaens L, Galus J, Mazur C. Abuse of gabapentin is associated with opioid addiction. Psychiatry Q. 2016;87(4):763–7.

    Google Scholar 

  • Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des. 2002;8(1):5–21. https://doi.org/10.2174/1381612023396681.

    Article  CAS  PubMed  Google Scholar 

  • Bernik M, Gorenstein C, Vieira Filho A. Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users. J Psychopharmacol. 1998;12(2):146–50.

    CAS  PubMed  Google Scholar 

  • Bodén R, Wettermark B, Brandt L, Kieler H. Factors associated with pregabalin dispensing at higher than the approved maximum dose. Eur J Clin Pharmacol. 2014;70(2):197–204.

    PubMed  Google Scholar 

  • Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol. 2017;27(12):1185–215.

    CAS  PubMed  Google Scholar 

  • Bonnet U, Strasser JC, Scherbaum N. Screening for physical and behavioral dependence on non-opioid analgesics in a German elderly hospital population. Addict Behav. 2019;90:265–71.

    PubMed  Google Scholar 

  • Boyd CJ, Austic E, Epstein-Ngo Q, Veliz PT, McCabe SE. A prospective study of adolescents’ nonmedical use of anxiolytic and sleep medication. Psychol Addict Behav. 2015;29(1):184.

    PubMed  Google Scholar 

  • Boyd C, West B, McCabe S. Does misuse lead to a disorder? The misuse of prescription tranquilizer and sedative medications and subsequent substance use disorders in a US longitudinal sample. Addict Behav. 2018;79:17–23.

    CAS  PubMed  Google Scholar 

  • Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med. 1986;315(14):854–9.

    CAS  PubMed  Google Scholar 

  • Cai K, Nanga RP, Lamprou L, Schinstine C, Elliott M, Hariharan H, Reddy R, Epperson CN. The impact of gabapentin administration on brain GABA and glutamate concentrations: a 7T 1H-MRS study. Neuropsychopharmacology. 2012;37(13):2764–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Calandre EP, Rico-Villademoros F, Slim M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother. 2016;16(11):1263–77.

    CAS  PubMed  Google Scholar 

  • Chen KW, Berger CC, Forde DP, D’Adamo C, Weintraub E, Gandhi, D. Benzodiazepine use and misuse among patients in a methadone program. BMC Psychiatry. 2011;11:90.

    Google Scholar 

  • Chessick CA, Allen MH, Thase ME, da Cunha AABM, Kapczinski F, de Lima MS, dos Santos Souza JJ. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006;3:CD006115.

    Google Scholar 

  • Chiappini S, Schifano F. A decade of gabapentinoid misuse: an analysis of the European Medicines Agency’s “Suspected Adverse Drug Reactions” database. CNS Drugs. 2016;30(7):647–54.

    PubMed  Google Scholar 

  • Chouinard G, Chouinard V-A. New classification of selective serotonin reuptake inhibitor withdrawal. Psychother Psychosom. 2015;84(2):63–71.

    PubMed  Google Scholar 

  • Cloos J-M, Ferreira V. Current use of benzodiazepines in anxiety disorders. Curr Opin Psychiatry. 2009;22(1):90–5.

    PubMed  Google Scholar 

  • Cole JO. Assessment of the abuse liability of buspirone in recreational sedative users. J Clin Psychiatry. 1982;43(12):69–75.

    CAS  PubMed  Google Scholar 

  • Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend. 2006;83(Suppl 1):S4–7. https://doi.org/10.1016/j.drugalcdep.2005.10.020.

    Article  CAS  PubMed  Google Scholar 

  • Cosci F, Chouinard G. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom. 2020;89(5):283–306.

    PubMed  Google Scholar 

  • Darker CD, Sweeney BP, Barry JM, Farrell MF, Donnelly-Swift E. Psychosocial interventions for benzodiazepine harmful use, abuse or dependence. Cochrane Database Syst Rev. 2015;5:CD009652.

    Google Scholar 

  • Del Paggio D. Psychotropic medication abuse by inmates in correctional facilities. Ment Health Clin. 2012;1(8):187–8.

    Google Scholar 

  • Demyttenaere K, Bonnewyn A, Bruffaerts R, De Girolamo G, Gasquet I, Kovess V, Haro JM, Alonso J. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Affect Disord. 2008;110(1–2):84–93.

    PubMed  Google Scholar 

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

    Google Scholar 

  • Dooley DJ, Mieske CA, Borosky SA. Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett. 2000;280(2):107–10.

    CAS  PubMed  Google Scholar 

  • Du YT, Roberts AP, Torpy DJ. Seizure induced by sudden cessation of pregabalin in a patient with chronic kidney disease. BMJ Case Rep. 2017;2017:bcr-2016-219158.

    PubMed  Google Scholar 

  • el-Guebaly N, Sareen J, Stein MB. Are there guidelines for the responsible prescription of benzodiazepines? Can J Psychiatr. 2010;55(11):709–14.

    Google Scholar 

  • Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Özkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA. Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139(2):380–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Evans SM, Griffiths RR, De Wit H. Preference for diazepam, but not buspirone, in moderate drinkers. Psychopharmacology. 1996;123(2):154–63.

    CAS  PubMed  Google Scholar 

  • Evoy KE, Covvey JR, Peckham AM, Ochs L, Hultgren KE. Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: an analysis of the Food and Drug Administration Adverse Events Reporting System (FAERS). Res Soc Adm Pharm. 2019;15(8):953–8.

    Google Scholar 

  • Feltner D, Wittchen H-U, Kavoussi R, Brock J, Baldinetti F, Pande AC. Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol. 2008;23(1):18–28.

    PubMed  Google Scholar 

  • Fenton MC, Keyes KM, Martins SS, Hasin DS. The role of a prescription in anxiety medication use, abuse, and dependence. Am J Psychiatry. 2010;167(10):1247–53.

    PubMed  PubMed Central  Google Scholar 

  • Fialip J, Aumaitre O, Eschalier A, Maradeix B, Dordain G, Lavarenne J. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol. 1987;10(6):538–44.

    CAS  PubMed  Google Scholar 

  • Fruensgaard K. Withdrawal psychosis: a study of 30 consecutive cases. Acta Psychiatr Scand. 1976;53(2):105–18.

    CAS  PubMed  Google Scholar 

  • Funderburk FR, Griffiths RR, McLeod DR, George E. Relative abuse liability of lorazepam and diazepam: an evaluation in “recreational” drug users. Drug Alcohol Depend. 1988;22(3):215–22.

    CAS  PubMed  Google Scholar 

  • Gahr M, Freudenmann RW, Hiemke C, Kölle MA, Schönfeldt-Lecuona C. Pregabalin abuse and dependence in Germany: results from a database query. Eur J Clin Pharmacol. 2013;69(6):1335–42.

    PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case–control study. PLoS Med. 2017;14(10):e1002396.

    PubMed  PubMed Central  Google Scholar 

  • Gosselin P, Ladouceur R, Morin CM, Dugas MJ, Baillargeon L. Benzodiazepine discontinuation among adults with GAD: a randomized trial of cognitive-behavioral therapy. J Consult Clin Psychol. 2006;74(5):908.

    PubMed  Google Scholar 

  • 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. Br J Psychiatry. 2014;204(2):98–107.

    PubMed  Google Scholar 

  • Greenblatt HK, Greenblatt DJ. Gabapentin and pregabalin for the treatment of anxiety disorders. Clin Pharmacol Drug Dev. 2018;7(3):228–32.

    CAS  PubMed  Google Scholar 

  • Greist JH, Liu-Dumaw M, Schweizer E, Feltner D. Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled 26-week study. Int Clin Psychopharmacol. 2011;26(5):243–51.

    PubMed  Google Scholar 

  • Grosshans M, Mutschler J, Hermann D, Klein O, Dressing H, Kiefer F, Mann K. Pregabalin abuse, dependence, and withdrawal: a case report. Am J Psychiatry 2010;167(7):869.

    Google Scholar 

  • Hadley SJ, Mandel FS, Schweizer E. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol. 2012;26(4):461–70.

    CAS  PubMed  Google Scholar 

  • Häkkinen M, Vuori E, Kalso E, Gergov M, Ojanperä I. Profiles of pregabalin and gabapentin abuse by postmortem toxicology. Forensic Sci Int. 2014;241:1–6.

    PubMed  Google Scholar 

  • Hamik A, Oksenberg D, Fischette C, Peroutka SJ. Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites. Biol Psychiatry. 1990;28(2):99–109.

    CAS  PubMed  Google Scholar 

  • Hallström C. Benzodiazepine dependence: Avoidance and withdrawal. Int J Psychiatry Clin Pract. 1998;2(1):31–4.

    Google Scholar 

  • Holroyd S, Duryee JJ. Substance use disorders in a geriatric psychiatry outpatient clinic: prevalence and epidemiologic characteristics. J Nerv Ment Dis. 1997;185(10):627–32.

    CAS  PubMed  Google Scholar 

  • Huang X, Li C, Li W-H, Luo Y-L, Wang B, Zhang W, Gan J-J, Ji J-L. Clinical evaluation of the efficacy and safety of tandospirone versus sertraline monotherapy for social anxiety disorder: a randomized open-label trial. Hum Psychopharmacol. 2013;28(6):594–9.

    CAS  PubMed  Google Scholar 

  • Hughes A, Williams M, Lipari R, Bose J, Copello E, Kroutil L. Prescription drug use and misuse in the United States: results from the 2015 National Survey on Drug Use and Health. NSDUH Data Rev. 2016;2016:A1–A24.

    Google Scholar 

  • Isacson D. Long-term benzodiazepine use: factors of importance and the development of individual use patterns over time – a 13-year follow-up in a Swedish community. Soc Sci Med. 1997;44(12):1871–80.

    CAS  PubMed  Google Scholar 

  • Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med. 2018;178(2):292–4.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Kapil V, Green J, Le Lait C, Wood D, Dargan P. Misuse of benzodiazepines and Z-drugs in the UK. Br J Psychiatry. 2014a;205(5):407–8.

    CAS  PubMed  Google Scholar 

  • Kapil V, Green JL, Le Lait M-C, Wood DM, Dargan PI. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Br J Clin Pharmacol. 2014b;78(1):190.

    CAS  PubMed  Google Scholar 

  • Kasper S, Iglesias-García C, Schweizer E, Wilson J, DuBrava S, Prieto R, Pitman VW, Knapp L. Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder. Int J Neuropsychopharmacol. 2014;17(5):685–95.

    CAS  PubMed  Google Scholar 

  • Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University, Antony MM, Bouchard S, Brunet A, Flament M, Grigoriadis S, Mendlowitz S, O’Connor K, Rabheru K, Richter PMA, Robichaud M, Walker JR. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1. https://doi.org/10.1186/1471-244X-14-S1-S1.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  • Kuerbis A, Sacco P, Blazer DG, Moore AA. Substance abuse among older adults. Clin Geriatr Med. 2014;30(3):629–54.

    Google Scholar 

  • Lader M. Assessing the potential for buspirone dependence or abuse and effects of its withdrawal. Am J Med. 1987;82(5):20–6.

    CAS  PubMed  Google Scholar 

  • Lader M. Benzodiazepines revisited – will we ever learn? Addiction. 2011;106(12):2086–109.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lan L, Chen Y-L, Zhang H, Jia B-L, Chu Y-J, Wang J, Tang S-X, Xia G-D. Efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea and anxiety. World J Gastroenterol. 2014;20(32):11422.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin J, Su Y, Wang C, Yang F, Xu Y, Yuan Y, Yuan Y, Wang X, Yu X, Si T. Effects of tandospirone augmentation in major depressive disorder patients with high anxiety: a multicenter, randomized, parallel-controlled, open-label study. J Psychiatr Res. 2018;99:104–10.

    PubMed  Google Scholar 

  • Linsen S, Zitman F, Breteler M. Defining benzodiazepine dependence: the confusion persists. Eur Psychiatry. 1995;10(6):306–11.

    CAS  PubMed  Google Scholar 

  • Loane C, Politis M. Buspirone: what is it all about? Brain Res. 2012;1461:111–8.

    CAS  PubMed  Google Scholar 

  • McAnally H, Bonnet U, Kaye AD. Gabapentinoid benefit and risk stratification: mechanisms over myth. Pain Ther. 2020;9(2):441–52.

    PubMed  PubMed Central  Google Scholar 

  • McCabe SE. Correlates of nonmedical use of prescription benzodiazepine anxiolytics: results from a national survey of US college students. Drug Alcohol Depend. 2005;79(1):53–62.

    PubMed  PubMed Central  Google Scholar 

  • McCabe SE, Veliz P, Boyd CJ, Schulenberg JE. Medical and nonmedical use of prescription sedatives and anxiolytics: adolescents’ use and substance use disorder symptoms in adulthood. Addict Behav. 2017;65:296–301.

    PubMed  Google Scholar 

  • McHugh RK, Geyer R, Karakula S, Griffin ML, Weiss RD. Nonmedical benzodiazepine use in adults with alcohol use disorder: the role of anxiety sensitivity and polysubstance use. Am J Addict. 2018;27(6):485–90.

    PubMed  Google Scholar 

  • Mersfelder TL, Nichols WH. Gabapentin: abuse, dependence, and withdrawal. Ann Pharmacother. 2016;50(3):229–33.

    CAS  PubMed  Google Scholar 

  • Mezher AW, McKnight CA, Caplan JP. Buspirone abuse: no safe haven. Psychosomatics. 2019;60(5):534.

    PubMed  Google Scholar 

  • Miller LG, Greenblatt DJ, Barnhill J, Shader RI. Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther. 1988;246(1):170–6.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Möhler H, Fritschy J, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300(1):2–8.

    PubMed  Google Scholar 

  • Montastruc F, Loo SY, Renoux C. Trends in first gabapentin and pregabalin prescriptions in primary care in the United Kingdom, 1993–2017. JAMA. 2018;320(20):2149–51.

    PubMed  PubMed Central  Google Scholar 

  • Mugunthan K, McGuire T, Glasziou P. Minimal interventions to decrease long-term use of benzodiazepines in primary care: a systematic review and meta-analysis. Br J Gen Pract. 2011;61(590):e573–8.

    PubMed  PubMed Central  Google Scholar 

  • Murphy S, Owen R, Tyrer P. Withdrawal symptoms after six weeks treatment with diazepam. Lancet. 1984;324(8416):1389.

    Google Scholar 

  • Nagy LM, Krystal JH, Woods SW, Charney DS. Clinical and medication outcome after short-term alprazolam and behavorial group treatment in panic disorder: 2.5-year naturalistic follow-up study. Arch Gen Psychiatry. 1989;46(11):993–9.

    CAS  PubMed  Google Scholar 

  • Neutel CI, Skurtveit S, Berg C. What is the point of guidelines? Benzodiazepine and z-hypnotic use by an elderly population. Sleep Med. 2012;13(7):893–7.

    PubMed  Google Scholar 

  • Nishitsuji K, To H, Murakami Y, Kodama K, Kobayashi D, Yamada T, Kubo C, Mine K. Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression. Clin Drug Investig. 2004;24(2):121–6.

    CAS  PubMed  Google Scholar 

  • Nutt D, Mandel F, Baldinetti F. Early onset anxiolytic efficacy after a single dose of pregabalin: double-blind, placebo-and active-comparator controlled evaluation using a dental anxiety model. J Psychopharmacol. 2009;23(8):867–73.

    CAS  PubMed  Google Scholar 

  • O’Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry. 2005;66(Suppl 2):28–33.

    PubMed  Google Scholar 

  • Oaklander AL, Buchbinder BR. Pregabalin-withdrawal encephalopathy and splenial edema: a link to high-altitude illness? Ann Neurol. 2005;58(2):309–12.

    PubMed  Google Scholar 

  • Ojanperä I, Kriikku P, Vuori E. Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database. Int J Legal Med. 2016;130(5):1209–16.

    PubMed  Google Scholar 

  • Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiat. 2015;72(2):136–42.

    Google Scholar 

  • Orzack MH, Friedman L, Dessain E, Bird M, Beake B, McEachern J, Cole JO. Comparative study of the abuse liability of alprazolam, lorazepam, diazepam, methaqualone, and placebo. Int J Addict. 1988;23(5):449–67.

    CAS  PubMed  Google Scholar 

  • Otto C, Crackau B, Löhrmann I, Zahradnik A, Bischof G, John U, Rumpf H-J. Brief intervention in general hospital for problematic prescription drug use: 12-month outcome. Drug Alcohol Depend. 2009;105(3):221–6.

    PubMed  Google Scholar 

  • 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. Behav Res Ther. 2010;48(8):720–7.

    PubMed  PubMed Central  Google Scholar 

  • Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH, Sutherland SM. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341–8.

    CAS  PubMed  Google Scholar 

  • Paulose-Ram R, Safran MA, Jonas BS, Gu Q, Orwig D. Trends in psychotropic medication use among US adults. Pharmacoepidemiol Drug Saf. 2007;16(5):560–70.

    PubMed  Google Scholar 

  • Peckham AM, Fairman KA, Sclar DA. Prevalence of gabapentin abuse: comparison with agents with known abuse potential in a commercially insured US population. Clin Drug Investig. 2017;37(8):763–73.

    CAS  PubMed  Google Scholar 

  • Peckham AM, Ananickal MJ, Sclar DA. Gabapentin use, abuse, and the US opioid epidemic: the case for reclassification as a controlled substance and the need for pharmacovigilance. Risk Manag Healthc Policy. 2018;11:109.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Petracca A, Nisita C, McNair D, Melis G, Guerani G, Cassano G. Treatment of generalized anxiety disorder: preliminary clinical experience with buspirone. J Clin Psychiatry. 1990;51:31.

    PubMed  Google Scholar 

  • Petursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455–9.

    CAS  PubMed  Google Scholar 

  • Pittenger C, Desan PH. Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clin Psychiatry. 2007;68(3):483.

    PubMed  Google Scholar 

  • Pollack MH, Otto MW, Tesar GE, Cohen LS, Meltzer-Brody S, Rosenbaum JF. Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder. J Clin Psychopharmacol. 1993;13(4):257–63.

    CAS  PubMed  Google Scholar 

  • Pottie K, Thompson W, Davies S, Grenier J, Sadowski CA, Welch V, Holbrook A, Boyd C, Swenson R, Ma A, Farrell B. Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline. Can Fam Physician. 2018;64(5):339–51.

    PubMed  PubMed Central  Google Scholar 

  • Preskorn SH, Denner LJ. Benzodiazepines and withdrawal psychosis: report of three cases. JAMA. 1977;237(1):36–8.

    CAS  PubMed  Google Scholar 

  • Reccoppa L, Malcolm R, Ware M. Gabapentin abuse in inmates with prior history of cocaine dependence. Am J Addict. 2004;13(3):321–3.

    PubMed  Google Scholar 

  • Riblet LA, Taylor DP, Eison MS, Stanton HC. Pharmacology and neurochemistry of buspirone. J Clin Psychiatry. 1982;43(12 Pt 2):11–8.

    CAS  PubMed  Google Scholar 

  • Rickels K, Case WG, Downing RW, Winokur A. Long-term diazepam therapy and clinical outcome. JAMA. 1983;250(6):767–71.

    CAS  PubMed  Google Scholar 

  • Rickels K, Case WG, Schweizer E, Garcia-Espana F, Fridman R. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry. 1991;148(6):757–61.

    CAS  PubMed  Google Scholar 

  • Ryu JH, Lee PB, Kim J, Do S, Kim C. Effects of pregabalin on the activity of glutamate transporter type 3. Br J Anaesth. 2012;109(2):234–9.

    CAS  PubMed  Google Scholar 

  • Sannerud CA, Ator NA, Griffiths RR. Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination. Drug Alcohol Depend. 1993;32(3):195–208.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Schepis TS, Hakes JK. Dose-related effects for the precipitation of psychopathology by opioid or tranquilizer/sedative nonmedical prescription use: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Addict Med. 2013;7(1):39–44.

    CAS  PubMed  Google Scholar 

  • Schifano F, D’Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Furia LD, Farre M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Sherbaum N. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom. 2011;80(2):118–22.

    PubMed  Google Scholar 

  • Schjerning O, Pottegård A, Damkier P, Rosenzweig M, Nielsen J. Use of pregabalin – a nationwide pharmacoepidemiological drug utilization study with focus on abuse potential. Pharmacopsychiatry. 2016;49(4):155–61.

    CAS  PubMed  Google Scholar 

  • Schuckit MA, Smith TL, Kramer J, Danko G, Volpe FR. The prevalence and clinical course of sedative-hypnotic abuse and dependence in a large cohort. Am J Drug Alcohol Abuse. 2002;28(1):73–90.

    PubMed  Google Scholar 

  • Schuman-Olivier Z, Hoeppner BB, Weiss RD, Borodovsky J, Shaffer HJ, Albanese MJ. Benzodiazepine use during buprenorphine treatment for opioid dependence: clinical and safety outcomes. Drug Alcohol Depend. 2013;132(3):580–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety disorders. N Engl J Med. 1993;328(19):1398–405.

    CAS  PubMed  Google Scholar 

  • Sieghart W, Sperk G. Subunit composition, distribution and function of GABA-A receptor subtypes. Curr Top Med Chem. 2002;2(8):795–816.

    CAS  PubMed  Google Scholar 

  • Sigel E, Schaerer MT, Buhr A, Baur R. The benzodiazepine binding pocket of recombinant α1β2γ2 γ-aminobutyric acidA receptors: relative orientation of ligands and amino acid side chains. Mol Pharmacol. 1998;54(6):1097–105.

    CAS  PubMed  Google Scholar 

  • Sinclair LI, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A, Srivastava S, Nutt DJ, Davies SJC. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6):483–90.

    PubMed  Google Scholar 

  • Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry. 2015;172(5):487–8.

    PubMed  PubMed Central  Google Scholar 

  • Snellgrove BJ, Steinert T, Jaeger S. Pregabalin use among users of illicit drugs: a cross-sectional survey in Southern Germany. CNS Drugs. 2017;31(10):891–8.

    CAS  PubMed  Google Scholar 

  • Soumerai SB, Simoni-Wastila L, Singer C, Mah C, Gao X, Salzman C, Ross-Degnan D. Lack of relationship between long-term use of benzodiazepines and escalation to high dosages. Psychiatr Serv. 2003;54(7):1006–11.

    PubMed  Google Scholar 

  • 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. Pharmacol Biochem Behav. 2007;87(2):250–7.

    CAS  PubMed  Google Scholar 

  • Soyka M. Treatment of benzodiazepine dependence. N Engl J Med. 2017;376(12):1147–57.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Supasitthumrong T, Bolea-Alamanac BM, Asmer S, Woo VL, Abdool PS, Davies SJ. Gabapentin and pregabalin to treat aggressivity in dementia: a systematic review and illustrative case report. Br J Clin Pharmacol. 2019;85(4):690–703.

    PubMed  PubMed Central  Google Scholar 

  • Suzette ME, Joseph R, Roland RG. Tandospirone and alprazolam: comparison of behavioral effects and abuse liability in humans. J Pharmacol Exp Ther. 1994;271(2):683–94.

    Google Scholar 

  • Takeshima N, Ogawa Y, Hayasaka Y, Furukawa TA. Continuation and discontinuation of benzodiazepine prescriptions: a cohort study based on a large claims database in Japan. Psychiatry Res. 2016;237:201–7.

    PubMed  Google Scholar 

  • Troisi JR II, Critchfield T, Griffiths RJ. Buspirone and lorazepam abuse liability in humans: behavioral effects, subjective effects and choice. Behav Pharmacol. 1993;4(3):217–30.

    CAS  Google Scholar 

  • Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet. 1981;317(8219):520–2.

    Google Scholar 

  • Uusi-Oukari M, Korpi ER. Regulation of GABAA receptor subunit expression by pharmacological agents. Pharmacol Rev. 2010;62(1):97–135.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Vinkers CH, van Oorschot R, Nielsen EØ, Cook JM, Hansen HH, Groenink L, Olivier B, Mirza NR. GABAA receptor α subunits differentially contribute to diazepam tolerance after chronic treatment. PLoS One. 2012;7(8):e43054.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Voshaar RCO, Gorgels WJ, Mol AJ, Van Balkom AJ, Van De Lisdonk EH, Breteler MH, van den Hoogen HJM, Zitman FG. 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.

    PubMed  Google Scholar 

  • Votaw VR, Geyer R, Rieselbach MM, McHugh RK. The epidemiology of benzodiazepine misuse: a systematic review. Drug Alcohol Depend. 2019;200:95–114.

    PubMed  PubMed Central  Google Scholar 

  • Voyer P, Préville M, Cohen D, Berbiche D, Béland S-G. The prevalence of benzodiazepine dependence among community-dwelling older adult users in Quebec according to typical and atypical criteria. Can J Aging. 2010;29(2):205–13.

    PubMed  Google Scholar 

  • WHO. International Classification of Diseases for mortality and morbidity statistics, 11th revision (ICD-11). Geneva: WHO; 2018.

    Google Scholar 

  • Zacny JP, Paice JA, Coalson DW. Subjective, psychomotor, and physiological effects of pregabalin alone and in combination with oxycodone in healthy volunteers. Pharmacol Biochem Behav. 2012;100(3):560–5.

    CAS  PubMed  Google Scholar 

  • Zahradnik A, Otto C, Crackau B, Löhrmann I, Bischof G, John U, Rumpf HJ. Randomized controlled trial of a brief intervention for problematic prescription drug use in non-treatment-seeking patients. Addiction. 2009;104(1):109–17.

    PubMed  Google Scholar 

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  1. Centre for Addiction and Mental Health, Toronto, ON, Canada

    Victor M. Tang & Simon J. C. Davies

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Victor M. Tang & Simon J. C. Davies

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  1. Victor M. Tang
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  1. Dept Psychiatry , Psychosomatics & Psychotherapy, University of Würzburg, Medical School Clinical Neurochemistry, Würzburg, Germany

    Peter Riederer

  2. Inst für Psychologische Medizin, Haag, Bayern, Germany

    Gerd Laux

  3. Fujita Health University School Medicine, Toyoake, Aichi, Japan

    Toshiharu Nagatsu

  4. Center Translational Res Neurol Diseases, Dalian Med Uni Shanghai Inst Health Sc Center Translational Res Neurol Diseases, Dalian, China

    Weidong Le

  5. Würzburg, Bayern, Germany

    Christian Riederer

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  1. Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

    Stefan Kloiber

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Tang, V.M., Davies, S.J.C. (2021). Anxiolytics: Misuse, Dependence, and Withdrawal Syndromes. In: Riederer, P., Laux, G., Nagatsu, T., Le, W., Riederer, C. (eds) NeuroPsychopharmacotherapy. Springer, Cham. https://doi.org/10.1007/978-3-319-56015-1_405-1

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