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Pharmacological management of psychoactive substance withdrawal syndrome

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Abstract

Rationale

Medications are available to manage alcohol and drug withdrawal, but they are underutilized. Only a handful, such as methadone, buprenorphine, clonidine, or benzodiazepines (chlordiazepoxide, lorazepam, or diazepam), are prescribed.

Objectives

Our objective was to provide an adjusted, inclusive, critical review of the clinical benefits of medications studied for the management of psychoactive substance withdrawal syndrome.

Methods

We performed an electronic literature search for randomized controlled trials (RCTs) and systematic reviews of RCTs with or without meta-analysis by free-text searching for pharmacotherapy on drug and alcohol withdrawal in eight databases.

Results

Doxepin, citalopram, doxepin, and pregabalin manage dysphoria and anxiety during opioid withdrawal. Gabapentin and atenolol lessen alcohol cravings. Gabapentin improves the sleep difficulties associated with cannabis withdrawal. Melatonin reduces anxiety, irritability, depressed mood, and cravings for nicotine. Doxepin alleviates benzodiazepine withdrawal anxiety and depression. Riluzole reduces amphetamine craving and depression. Modafinil reduces the intensity of cocaine cravings. Controlled trials on caffeine withdrawal were lacking. Buspirone and gabapentin accounted for more than 70% of all the medications studied. No conclusions can be drawn on adverse events because of reporting inconsistencies in the studies reviewed.

Conclusions

Substitution therapy seems to be the foremost choice for the treatment of psychoactive substance withdrawal. However, other medications are available but poorly utilized. Practitioners can use the armory of other available medications to manage psychoactive substance withdrawal. Patients can broaden their medication choice. Voltage-gated ion channels are a promising niche to explore.

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References

  1. World Health Organization. Neuroscience of psychoactive substance use and dependence. World Health Organization; 2004.

    Google Scholar 

  2. Olmedo R, Hoffman RS. Withdrawal syndromes. Emerg Med Clin North Am. 2000;18(2):273–88.

    Article  CAS  PubMed  Google Scholar 

  3. Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12(6):305–20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cantwell B, McBride AJ. Self-detoxication by amphetamine dependent patients: a pilot study. Drug Alcohol Depend. 1998;49(2):157–63.

    Article  CAS  PubMed  Google Scholar 

  5. Feng Y, He X, Yang Y, et al. Current research on opioid receptor function. Curr Drug Targets. 2012;13(2):230–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Littleton J. Neurochemical mechanisms underlying alcohol withdrawal. Alcohol Health Res World. 1998;22(1):13–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Bayard M, Mcintyre J, Hill K, et al. Alcohol withdrawal syndrome. Am Fam Phys. 2004;69(6):1443–50.

    Google Scholar 

  8. Milhorn HT. Sedative-hypnotic dependence. In: Substance use disorders. Springer, Cham; 2018, p. 59–76)

  9. Church J, Shacklock JA, Baimbridge KG. Dextromethorphan and phencyclidine receptor ligands: differential effects on K+-and NMDA-evoked increases in cytosolic free Ca2+ concentration. Neurosci Lett. 1991;124(2):232–4.

    Article  CAS  PubMed  Google Scholar 

  10. Miller S. Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol. 2005;10(4):325–7.

    Article  CAS  PubMed  Google Scholar 

  11. Center for Substance Abuse Treatment. Detoxification and Substance Abuse Treatment. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2006. (Treatment Improvement Protocol (TIP) Series, No. 45.) 4 Physical Detoxification Services for Withdrawal from Specific Substances. https://www.ncbi.nlm.nih.gov/books/NBK64116/.

  12. Paolini M, De Biasi M. Mechanistic insights into nicotine withdrawal. Biochem Pharmacol. 2011;82(8):996–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic, and psychostimulant effects. Brain Res Brain Res Rev. 1992;17(2):139–70.

    Article  CAS  PubMed  Google Scholar 

  14. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology. 2004;176(1):1–29.

    Article  CAS  PubMed  Google Scholar 

  15. Schlienz NJ, Budney AJ, Lee DC, et al. Cannabis withdrawal: a review of neurobiological mechanisms and sex differences. Curr Addict Rep. 2017;4(2):75–81.

    Article  PubMed  PubMed Central  Google Scholar 

  16. D’Souza DC, Cortes-Briones JA, Ranganathan M, et al. Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1(1):60–7.

    PubMed  PubMed Central  Google Scholar 

  17. Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003;348(18):1786–95.

    Article  CAS  PubMed  Google Scholar 

  18. Dang D, Dearholt SL. Johns Hopkins Nursing evidence-based practice models and guidelines. 3rd ed. Sigma Theta Tau International; 2017.

    Google Scholar 

  19. Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71–6.

    Article  CAS  PubMed  Google Scholar 

  20. McDonough M, Kennedy N, Glasper A, et al. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend. 2004;75(1):3–9.

    Article  CAS  PubMed  Google Scholar 

  21. Giannini AJ, Loiselle RH, Graham BH, et al. Behavioral response to buspirone in cocaine and phencyclidine withdrawal. J Subst Abuse Treat. 1993;10(6):523–7.

    Article  CAS  PubMed  Google Scholar 

  22. Shoptaw SJ, Kao U, Heinzerling K, et al. treatment for amphetamine withdrawal. Cochrane Database Syst Rev. 2009;2:CD003021.

    Google Scholar 

  23. Ahmadi J, Sahraian A, Biuseh M. A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving. Trials. 2019;20(1):468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Farahzadi MH, Moazen-Zadeh E, Razaghi E, et al. Riluzole for treatment of men with methamphetamine dependence: a randomized, double-blind, placebo-controlled clinical trial. J Psychopharmacol. 2019;33(3):305–15.

    Article  CAS  PubMed  Google Scholar 

  25. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010;20(11):823–8.

    Article  CAS  PubMed  Google Scholar 

  26. Mousavi SG, Sharbafchi MR, Salehi M, et al. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med. 2015;18(1):28–33.

    PubMed  Google Scholar 

  27. Kampman KM, Dackis C, Pettinati HM, et al. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addict Behav. 2011;36(3):217–21.

    Article  PubMed  Google Scholar 

  28. Kampman KM, Pettinati HM, Lynch KG, et al. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend. 2013;133(1):94–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology. 2005;30(1):205–11.

    Article  CAS  PubMed  Google Scholar 

  30. Kampman KM, Lynch KG, Pettinati HM, et al. A double blind, placebo-controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend. 2015;155:105–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kampman KM, Volpicelli JR, Mulvaney F, et al. Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend. 2001;63(1):69–78.

    Article  CAS  PubMed  Google Scholar 

  32. Giannini AJ, Folts DJ, Feather JN, et al. Bromocriptine and amantadine in cocaine detoxification. Psychiatry Res. 1989;29(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  33. Eiler K, Schaefer MR, Salstrom D, et al. Double-blind comparison of bromocriptine and placebo in cocaine withdrawal. Am J Drug Alcohol Abuse. 1995;21(1):65–79.

    Article  CAS  PubMed  Google Scholar 

  34. Tennant FS Jr, Sagherian AA. Double-blind comparison of amantadine and bromocriptine for ambulatory withdrawal from cocaine dependence. Arch Intern Med. 1987;147(1):109–12.

    Article  PubMed  Google Scholar 

  35. LaRowe SD, Kalivas PW, Nicholas JS, et al. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict. 2013;22(5):443–52.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Amato L, Davoli M, Minozzi S, et al. Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database Syst Rev. 2013;2:CD003409.

    Google Scholar 

  37. Gowing L, Ali R, White JM, et al. buprenorphine for managing opioid withdrawal. Cochrane Database Syst Rev. 2017;2(2):CD002025.

    PubMed  Google Scholar 

  38. Tabassomi F, Zarghami M, Shiran MR, et al. Opium tincture versus methadone syrup in management of acute raw opium withdrawal: a randomized, double-blind, controlled trial. J Addict Dis. 2016;35(1):8–14.

    Article  PubMed  Google Scholar 

  39. Glue P, Cape G, Tunnicliff D, et al. ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients. Clin Pharmacol Drug Dev. 2016;5(6):460–8.

    Article  CAS  PubMed  Google Scholar 

  40. Zarghami M, Masoum B, Shiran MR. Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial. J Addict Dis. 2012;31(2):112–7.

    Article  PubMed  Google Scholar 

  41. Ziaaddini H, Ziaaddini A, Asghari N, et al. trial of tramadol plus gabapentin for opioid detoxification. Iran Red Crescent Med J. 2014;17(1):e18202.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Salehi M, Amanatkar M, Barekatain M. Comparison of the Efficacy of Methadone and Tramadol in Opioid-Assisted Detoxification. Iranian Journal of Medical Sciences. 2007;32(1):28–31.

    Google Scholar 

  43. Chawla JM, Pal H, Lal R, et al. Comparison of efficacy between buprenorphine and tramadol in the detoxification of opioid (heroin)-dependent subjects. J Opioid Manag. 2013;9(1):35–41.

    Article  PubMed  Google Scholar 

  44. Dunn KE, Tompkins DA, Bigelow GE, et al. Efficacy of tramadol extended release for opioid withdrawal: a randomized clinical trial. JAMA Psychiat. 2017;74(9):885–93.

    Article  Google Scholar 

  45. Lofwall MR, Babalonis S, Nuzzo PA, et al. efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial. Drug Alcohol Depend. 2013;133(1):188–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Umbricht A, Montoya ID, Hoover DR, et al. naltrexone shortened opioid detoxification with buprenorphine. Drug Alcohol Depend. 1999;56(3):181–90.

    Article  CAS  PubMed  Google Scholar 

  47. Mannelli P, Patkar AA, Peindl K, et al. Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial. Addict Biol. 2009;14(2):204–13.

    Article  CAS  PubMed  Google Scholar 

  48. Afshari R, Khadem-Rezaiyan M, Khatibi Moghadam H, et al. Very low dose naltrexone in opioid detoxification: a double-blind, randomized clinical trial of efficacy and safety. Toxicol Res. 2019;36(1):21–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Gowing L, Farrell M, Ali R, et al. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016;5:CD002024.

    Google Scholar 

  50. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, et al. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. J Clin Pharm Ther. 2000;25(5):347–53.

    Article  CAS  PubMed  Google Scholar 

  51. Assadi SM, Radgoodarzi R, Ahmadi-Abhari SA. Baclofen for maintenance treatment of opioid dependence: a randomized double-blind placebo-controlled clinical trial [ISRCTN32121581]. BMC Psychiatry. 2003;18(3):16.

    Article  Google Scholar 

  52. Drummond DC, Turkington D, Rahman MZ, et al. Chlordiazepoxide vs. methadone in opiate withdrawal: a preliminary double-blind trial. Drug Alcohol Depend. 1989;23(1):63–71.

    Article  CAS  PubMed  Google Scholar 

  53. Gallimberti L, Canton G, Gentile N, et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet. 1989;2(8666):787–9.

    Article  CAS  PubMed  Google Scholar 

  54. Gallimberti L, Cibin M, Pagnin P, et al. Gamma-hydroxybutyric acid for treatment of opiate withdrawal syndrome. Neuropsychopharmacology. 1993;9(1):77–81.

    Article  CAS  PubMed  Google Scholar 

  55. Mokhber N, Soltanifar A, Talebi M. Efficacy of topiramate as an adjunct medication in heroin withdrawal: a randomized control trial. J Pak Psychiatric Soc. 2008;5(1):22–5.

    Google Scholar 

  56. Rosen MI, Pearsall HR, Kosten TR. The effect of lamotrigine on naloxone-precipitated opiate withdrawal. Drug Alcohol Depend. 1998;52(2):173–6.

    Article  CAS  PubMed  Google Scholar 

  57. Bertschy G, Bryois C, Bondolfi G, et al. The association carbamazepine-mianserin in opiate withdrawal: a double-blind pilot study versus clonidine. Pharmacol Res. 1997;35(5):451–6.

    Article  CAS  PubMed  Google Scholar 

  58. Salehi M, Safavi P, Barktin M. The effect of sodium valporate on the treatment of opium withdrawal patients. Yafte. 2006;7(1):37–43.

    Google Scholar 

  59. Krupitsky EM, Ilyuk RD, Mikhailov AD, et al. Randomizirovannoe kontroliruemoe issledovanie effektivnosti pregabalina v terapii sindroma otmeny opiatov [A randomized single blind study of the efficacy of pregabalin in the treatment of opioid withdrawal syndrome]. Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(7):29–36.

    Article  CAS  PubMed  Google Scholar 

  60. Kheirabadi GR, Salehi M, Bahrami M, et al. Gabapentin, pregabalin, and placebo in reducing opioid withdrawal symptoms in opioid-dependent individuals: a randomized-controlled trial. Addict Disord Treat. 2018;17(2):55–64.

    Article  Google Scholar 

  61. Kheirabadi GR, Ranjkesh M, Maracy MR, et al. Effect of add-on gabapentin on opioid withdrawal symptoms in opium-dependent patients [published correction appears in Addiction. 2009 Oct;104(10):1776]. Addiction. 2008;103(9):1495–9.

    Article  PubMed  Google Scholar 

  62. Sanders NC, Mancino MJ, Gentry WB, et al. Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure. Exp Clin Psychopharmacol. 2013;21(4):294–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ansari MA, Memon Z, Ahmed SP, et al. Comparison of the efficacy and safety of chlorpromazine with verapamil for the treatment of acute opioid abstinence syndrome. Pak J Med Sci. 2009;25(4):641–5.

    Google Scholar 

  64. Fluyau D, Revadigar N, Pierre CG. Clinical benefits and risks of N-methyl-d-aspartate receptor antagonists to treat severe opioid use disorder: a systematic review. Drug Alcohol Depend. 2020;208:107845.

    Article  CAS  PubMed  Google Scholar 

  65. Hooten WM, Warner DO. Varenicline for opioid withdrawal in patients with chronic pain: a randomized, single-blinded, placebo-controlled pilot trial. Addict Behav. 2015;42:69–72.

    Article  PubMed  Google Scholar 

  66. Bisaga A, Sullivan MA, Glass A, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended-release naltrexone. Drug Alcohol Depend. 2015;154:38–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lofwall MR, Babalonis S, Nuzzo PA, et al. Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans. Drug Alcohol Depend. 2016;164:143–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Herman I, Shamir D, Bar-Hamburger R, et al. The effect of mianserin add-on, on the intensity of opioid withdrawal symptoms during detoxification program–a randomized, double blind, placebo controlled, prospective study. Addict Behav. 2005;30(6):1154–67.

    Article  CAS  PubMed  Google Scholar 

  69. Srisurapanont M, Jarusuraisin N. Amitriptyline vs. lorazepam in the treatment of opiate-withdrawal insomnia: a randomized double-blind study. Acta Psychiatr Scand. 1998;97(3):233–5.

    Article  CAS  PubMed  Google Scholar 

  70. Krupitsky EM, Burakov AM, Didenko TY, et al. Effects of citalopram treatment of protracted withdrawal (Syndrome of Anhedonia) in patients with heroin addiction. Addict Disord Treat. 2002;1(1):29–33.

    Article  Google Scholar 

  71. Täschner K. A controlled comparison of clonidine and doxepin in the treatment of the opiate withdrawal syndrome. Pharmacopsychiatry. 1986;19(03):91–5.

    Article  PubMed  Google Scholar 

  72. Lin S-K, Chen C-H, Pan C-H. Venlafaxine for acute heroin detoxification. J Clin Psychopharmacol. 2008;28(2):189–94.

    Article  CAS  PubMed  Google Scholar 

  73. Rose JS, Branchey M, Wallach L, et al. Effects of buspirone in withdrawal from opiates. Am J Addict. 2003;12(3):253–9.

    Article  PubMed  Google Scholar 

  74. Buydens-Branchey L, Branchey M, Reel-Brander C. Efficacy of buspirone in the treatment of opioid withdrawal. J Clin Psychopharmacol. 2005;25(3):230–6.

    Article  CAS  PubMed  Google Scholar 

  75. Chu LF, Sun J, Clemenson A, et al. Ondansetron does not reduce withdrawal in patients with physical dependence on chronic opioid therapy. J Addict Med. 2017;11(5):342–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Erlendson MJ, D’Arcy N, Encisco EM, et al. Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study. Am J Drug Alcohol Abuse. 2017;43(1):78–86.

    Article  PubMed  Google Scholar 

  77. Yang Z, Shao YC, Li SJ, et al. Medication of l-tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study. Acta Pharmacol Sin. 2008;29(7):781–8.

    Article  CAS  PubMed  Google Scholar 

  78. Maayan R, Touati-Werner D, Shamir D, et al. The effect of DHEA complementary treatment on heroin addicts participating in a rehabilitation program: a preliminary study. Eur Neuropsychopharmacol. 2008;18(6):406–13.

    Article  CAS  PubMed  Google Scholar 

  79. Morabbi MJ, Razaghi E, Moazen-Zadeh E, et al. Pexacerfont as a CRF1 antagonist for the treatment of withdrawal symptoms in men with heroin/methamphetamine dependence: a randomized, double-blind, placebo-controlled clinical trial. Int Clin Psychopharmacol. 2018;33(2):111–9.

    Article  PubMed  Google Scholar 

  80. Cooper ZD, Johnson KW, Pavlicova M, et al. The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers. Addict Biol. 2016;21(4):895–903.

    Article  CAS  PubMed  Google Scholar 

  81. Song H, Li J, Lu CL, et al. Tetrodotoxin alleviates acute heroin withdrawal syndrome: a multicentre, randomized, double-blind, placebo-controlled study. Clin Exp Pharmacol Physiol. 2011;38(8):510–4.

    Article  CAS  PubMed  Google Scholar 

  82. Liu S, Li L, Shen W, et al. Scopolamine detoxification technique for heroin dependence: a randomized trial. CNS Drugs. 2013;27(12):1093–102.

    Article  CAS  PubMed  Google Scholar 

  83. Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA. 1997;278(2):144–51.

    Article  CAS  PubMed  Google Scholar 

  84. Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010;3:CD005063.

    Google Scholar 

  85. Liu J, Wang LN. Baclofen for alcohol withdrawal. Cochrane Database Syst Rev. 2019;11:CD008502.

    Google Scholar 

  86. Mo Y, Thomas MC, Karras GE Jr. Barbiturates for the treatment of alcohol withdrawal syndrome: a systematic review of clinical trials. J Crit Care. 2016;32:101–7.

    Article  CAS  PubMed  Google Scholar 

  87. Hammond DA, Rowe JM, Wong A, et al. Patient outcomes associated with phenobarbital use with or without benzodiazepines for alcohol withdrawal syndrome: a systematic review. Hosp Pharm. 2017;52(9):607–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Minozzi S, Amato L, Vecchi S, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;3:CD005064.

    Google Scholar 

  89. Latifi S, Messer T. The efficacy of tiapride and carbamazepine combination therapy in reducing alcohol withdrawal symptoms: a systematic review and meta-analysis. Pharmacopsychiatry. 2019;52(5):209–16.

    Article  CAS  PubMed  Google Scholar 

  90. Björkqvist SE, Isohanni M, Mäkelä R, et al. Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal multicentre double-blind comparison with placebo. Acta Psychiatr Scand. 1976;53(5):333–42.

    Article  PubMed  Google Scholar 

  91. Sampliner R, Iber FL. Diphenylhydantoin control of alcohol withdrawal seizures. Results of a controlled study. JAMA. 1974;230(10):1430–2.

    Article  CAS  PubMed  Google Scholar 

  92. Ahmed S, Stanciu CN, Kotapati PV, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord. 2019;21(4):19r02465.

    Article  PubMed  Google Scholar 

  93. Sellers EM, Zilm DH, Degani NC. Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. J Stud Alcohol. 1977;38(11):2096–108.

    Article  CAS  PubMed  Google Scholar 

  94. Bailly D, Servant D, Blandin N, et al. Effects of beta-blocking drugs in alcohol withdrawal: a double-blind comparative study with propranolol and diazepam. Biomed Pharmacother. 1992;46(9):419–24.

    Article  CAS  PubMed  Google Scholar 

  95. Worner TM. Propranolol versus diazepam in the management of the alcohol withdrawal syndrome: double-blind controlled trial. Am J Drug Alcohol Abuse. 1994;20(1):115–24.

    Article  CAS  PubMed  Google Scholar 

  96. Kraus ML, Gottlieb LD, Horwitz RI, et al. Randomized clinical trial of atenolol in patients with alcohol withdrawal. N Engl J Med. 1985;313(15):905–9.

    Article  CAS  PubMed  Google Scholar 

  97. Gottlieb LD, Horwitz RI, Kraus ML, et al. Randomized controlled trial in alcohol relapse prevention: role of atenolol, alcohol craving, and treatment adherence. J Subst Abuse Treat. 1994;11(3):253–8.

    Article  CAS  PubMed  Google Scholar 

  98. Horwitz RI, Gottlieb LD, Kraus ML. The efficacy of atenolol in the outpatient management of the alcohol withdrawal syndrome. Results of a randomized clinical trial. Arch Intern Med. 1989;149(5):1089–93.

    Article  CAS  PubMed  Google Scholar 

  99. Wilkins AJ, Jenkins WJ, Steiner JA. Efficacy of clonidine in treatment of alcohol withdrawal state. Psychopharmacology. 1983;81(1):78–80.

    Article  CAS  PubMed  Google Scholar 

  100. Baumgartner GR, Rowen RC. Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome. Arch Intern Med. 1987;147(7):1223–6.

    Article  CAS  PubMed  Google Scholar 

  101. Robinson BJ, Robinson GM, Maling TJ, et al. Is clonidine useful in the treatment of alcohol withdrawal? Alcohol Clin Exp Res. 1989;13(1):95–8.

    Article  CAS  PubMed  Google Scholar 

  102. Cushman P Jr, Forbes R, Lerner W, et al. Alcohol withdrawal syndromes: clinical management with lofexidine. Alcohol Clin Exp Res. 1985;9(2):103–8.

    Article  PubMed  Google Scholar 

  103. Banger M, Benkert O, Röschke J, et al. Nimodipine in acute alcohol withdrawal state. J Psychiatr Res. 1992;26(2):117–23.

    Article  CAS  PubMed  Google Scholar 

  104. Koppi S, Eberhardt G, Haller R, et al. Calcium-channel-blocking agent in the treatment of acute alcohol withdrawal–caroverine versus meprobamate in a randomized double-blind study. Neuropsychobiology. 1987;17(1–2):49–52.

    Article  CAS  PubMed  Google Scholar 

  105. Borg V, Weinholdt T. Bromocriptine in the treatment of the alcohol-withdrawal syndrome. Acta Psychiatr Scand. 1982;65(2):101–11.

    Article  CAS  PubMed  Google Scholar 

  106. Burroughs AK, Morgan MY, Sherlock S. Double-blind controlled trial of bromocriptine, chlordiazepoxide and chlormethiazole for alcohol withdrawal symptoms. Alcohol Alcohol. 1985;20(3):263–71.

    CAS  PubMed  Google Scholar 

  107. Sellers EM, Cooper SD, Zilm DH, et al. Lithium treatment during alcoholic withdrawal. Clin Pharmacol Ther. 1976;20(2):199–206.

    Article  CAS  PubMed  Google Scholar 

  108. Wilson A, Vulcano B. A double-blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcohol Clin Exp Res. 1984;8(6):542–5.

    Article  CAS  PubMed  Google Scholar 

  109. Stephens DN, King SL, Lambert JJ, et al. GABAA receptor subtype involvement in addictive behaviour. Genes Brain Behav. 2017;16(1):149–84.

    Article  CAS  PubMed  Google Scholar 

  110. Baandrup L, Ebdrup BH, Rasmussen JØ, et al. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst Rev. 2018;3(3):CD011481.

    PubMed  Google Scholar 

  111. Beurmanjer H, Luykx JJ, De Wilde B, et al. Tapering with pharmaceutical GHB or benzodiazepines for detoxification in GHB-dependent patients: a matched-subject observational study of treatment-as-usual in Belgium and The Netherlands. CNS Drugs. 2020;34(6):651–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  113. Hair PI, McCormack PL, Curran MP. Eszopiclone: a review of its use in the treatment of insomnia. Drugs. 2008;68(10):1415–34.

    Article  CAS  PubMed  Google Scholar 

  114. MacFarlane J, Morin CM, Montplaisir J. Hypnotics in insomnia: the experience of zolpidem. Clin Ther. 2014;36(11):1676–701.

    Article  CAS  PubMed  Google Scholar 

  115. Finsterer J, Frank M. Zolpidem-triggered seizures, depression, and reduced locomotion. J Clin Neurosci. 2016;33:271–2.

    Article  PubMed  Google Scholar 

  116. Fontaine R, Beaudry P, Le Morvan P, et al. Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety. Int Clin Psychopharmacol. 1990;5(3):173–83.

    Article  CAS  PubMed  Google Scholar 

  117. Shiffman S, Johnston JA, Khayrallah M, et al. The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology. 2000;148(1):33–40.

    Article  CAS  PubMed  Google Scholar 

  118. Teneggi V, Tiffany ST, Squassante L, et al. Effect of sustained-release (SR) bupropion on craving and withdrawal in smokers deprived of cigarettes for 72 h. Psychopharmacology. 2005;183(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  119. Robinson MD, Pettice YL, Smith WA, et al. Buspirone effect on tobacco withdrawal symptoms: a randomized placebo-controlled trial. J Am Board Fam Pract. 1992;5(1):1–9.

    CAS  PubMed  Google Scholar 

  120. Hilleman DE, Mohiuddin SM, Del Core MG, et al. Effect of buspirone on withdrawal symptoms associated with smoking cessation. Arch Intern Med. 1992;152(2):350–2.

    Article  CAS  PubMed  Google Scholar 

  121. West R, Baker CL, Cappelleri JC, et al. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology. 2008;197(3):371–7.

    Article  CAS  PubMed  Google Scholar 

  122. Foulds J, Russ C, Yu CR, et al. Effect of varenicline on individual nicotine withdrawal symptoms: a combined analysis of eight randomized, placebo-controlled trials. Nicotine Tob Res. 2013;15(11):1849–57.

    Article  CAS  PubMed  Google Scholar 

  123. Dunn KE, Marcus TF, Kim C, et al. Zonisamide reduces withdrawal symptoms but does not enhance varenicline-induced smoking cessation. Nicotine Tob Res. 2016;18(5):1171–9.

    Article  PubMed  Google Scholar 

  124. Herman AI, Waters AJ, McKee SA, et al. Effects of pregabalin on smoking behavior, withdrawal symptoms, and cognitive performance in smokers. Psychopharmacology. 2012;220(3):611–7.

    Article  CAS  PubMed  Google Scholar 

  125. Sofuoglu M, Babb D, Hatsukami DK. Labetalol treatment enhances the attenuation of tobacco withdrawal symptoms by nicotine in abstinent smokers. Nicotine Tob Res. 2003;5(6):947–53.

    Article  CAS  PubMed  Google Scholar 

  126. David SP, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2013;6(6):CD003086.

    Google Scholar 

  127. Schmaal L, Berk L, Hulstijn KP, et al. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res. 2011;17(4):211–6.

    Article  PubMed  Google Scholar 

  128. Froeliger B, McConnell PA, Stankeviciute N, et al. The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: a double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. 2015;156:234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rohsenow DJ, Tidey JW, Miranda R, et al. Olanzapine reduces urge to smoke and nicotine withdrawal symptoms in community smokers. Exp Clin Psychopharmacol. 2008;16(3):215–22.

    Article  CAS  PubMed  Google Scholar 

  130. Zhdanova IV, Piotrovskaya VR. Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans. Pharmacol Biochem Behav. 2000;67(1):131–5.

    Article  CAS  PubMed  Google Scholar 

  131. Levin FR, Mariani JJ, Brooks DJ, et al. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011;116(1–3):142–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Trigo JM, Lagzdins D, Rehm J, et al. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug Alcohol Depend. 2016;161:298–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Allsop DJ, Copeland J, Lintzeris N, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiat. 2014;71(3):281–91.

    Article  CAS  Google Scholar 

  134. Haney M, Cooper ZD, Bedi G, et al. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology. 2013;38(8):1557–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nielsen S, Gowing L, Sabioni P, et al. Pharmacotherapies for cannabis dependence. Cochrane Database Syst Rev. 2019;1(1):CD008940.

    PubMed  Google Scholar 

  136. Mason BJ, Crean R, Goodell V, et al. A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal, and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology. 2012;37(7):1689–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gilbert DG, Rabinovich NE, McDaniel JT. Nicotine patch for cannabis withdrawal symptom relief: a randomized controlled trial. Psychopharmacology. 2020;237(5):1507–19.

    Article  CAS  PubMed  Google Scholar 

  138. Koob GF, Nestler EJ. The neurobiology of drug addiction. J Neuropsychiatry Clin Neurosci. 1997;9(3):482–97.

    Article  CAS  PubMed  Google Scholar 

  139. Brodie MJ, Besag F, Ettinger AB, et al. Epilepsy, antiepileptic drugs, and aggression: an evidence-based review. Pharmacol Rev. 2016;68(3):563–602.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA

    Dimy Fluyau & Sarah Clare Cook

  2. Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30310, USA

    Ashmeer Chima

  3. Northern Light Health, 43 Whiting Hill Rd, Brewer, ME, 04412, USA

    Vasanth Kattalai Kailasam

  4. Columbia University, 630 W 168th St, New York, NY, 10032, USA

    Neelambika Revadigar

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  1. Dimy Fluyau
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  2. Sarah Clare Cook
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  5. Neelambika Revadigar
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Correspondence to Dimy Fluyau.

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No sources of funding were used to conduct this study or prepare this manuscript.

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Dimy Fluyau, Sarah Clare Cook, Ashmeer Chima, Vasanth Kattalai Kailasam, Neelambika Revadigar have no conflicts of interest that are directly relevant to the content of this article.

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Dimy Fluyau conceptualized, determined the methodology, played the role of project administrator, provided resources, and wrote the original draft of the investigation. All authors validated, reviewed, and edited the final draft. Dimy Fluyau, Sarah Clare Cook, Ahmeer Chima, and Vasanth Kattalai Kailasam supervised the investigation.

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Fluyau, D., Cook, S.C., Chima, A. et al. Pharmacological management of psychoactive substance withdrawal syndrome. Drugs Ther Perspect 37, 519–535 (2021). https://doi.org/10.1007/s40267-021-00874-7

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