Benzodiazepine addiction

Reynaud M, Petit G, Potard D, et al Six deaths linked to concomitant use of buprenor-phine and benzodiazepines. Addiction 93 1383-1392, 1998 Richards JG, Martin JR Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands. Brain Res Bull 43 381-387, 1998... 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

B. Rapid reversal of benzodiazepine effect in patients with benzodiazepine addiction or high tolerance may result in an acute withdrawal state, including hyperexcitability, tachycardia, and seizures (rarely reported). 

In general, with the exception of the central role that benzodiazepines play in the treatment of alcohol withdrawal, the use of medications that have been approved for alcoholism rehabilitation remains very limited. A survey of nearly 1,400 addiction physicians showed that they prescribed disulfiram to only 9% of their alcoholic patients and that naltrexone was prescribed for only slightly higher proportion of patients (13%) (Market al. 2003). These tesults contrast with findings for antidepressants, which were prescribed to 44% of alcoholic patients. Although neatly all of these physicians had heatd of both disulfiram and naltrexone, their self-reported level of knowledge of these medications was much lowet than that of antidepressants. 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

Anxiety disorders are common in the population of opioid-addicted individuals however, treatment studies are lacking. It is uncertain whether the frequency of anxiety disorders contributes to high rates of illicit use of benzodiazepines, which is common in methadone maintenance programs (Ross and Darke 2000). Increased toxicity has been observed when benzodiazepines are co-administered with some opioids (Borron et al. 2002 Caplehorn and Drummer 2002). Although there is an interesting report of clonazepam maintenance treatment for methadone maintenance patients who abuse benzodiazepines, further studies are needed (Bleich et al. 2002). Unfortunately, buspirone, which has low abuse liability, was not effective in an anxiety treatment study in opioid-dependent subjects (McRae et al. 2004). Current clinical practice is to prescribe SSRIs or other antidepressants that have antianxiety actions for these patients. Carefully controlled benzodiazepine prescribing is advocated by some practitioners. 

Ross J, Darke S The nature of benzodiazepine dependence among heroin users in Sydney, Australia. Addiction 95 1785-1793, 2000 Rounsaville BJ, Kleber HD Untreated opiate addicts. Arch Gen Psychiatry 42 1072— 1077, 1985b... 

A dramatically different pattern is found in surveys of drug abuse treatment facilities. Substance abuse treatment centers have reported that more than 20% of patients use benzodiazepines weekly or more frequently, with 30%— 90% of opioid abusers reporting illicit use (Iguchi et al. 1993 Stitzer et al 1981). Methadone clinics reported that high proportions ofurine samples are positive for benzodiazepines (Darke et al. 2003 Dinwiddle et al. 1996 Ross and Darke 2000 Seivewright 2001 Strain et al. 1991 Williams et al. 1996). The reasons for the high rates of benzodiazepine use in opioid addicts include self-medication of insomnia, anxiety, and withdrawal symptoms, as well as attempts to boost the euphoric effects of opioids. 

In subjects with sedative-hypnotic dependence who underwent detoxification in an addictions treatment unit, a significant association was not found between abstinence rate and either gender or psychiatric status (Charney et al. 2000). Patients dependent on benzodiazepines reported decreased anxiety during follow-up, even though their use of these agents had decreased. 

Busto U, Simpkins], Sellers EM, et al Objective determination of benzodiazepine use and abuse in alcoholics. Br J Addict 78 429 35, 1983... 

Busto U, Sellers EM, Naranjo CA, et al Patterns of benzodiazepine abuse and dependence. Br J Addict 81 87—94, 1986b... 

Ciraulo DA, Nace EP Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Greenblatt DJ, et al Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men. J Clin Psychiatry 49 333—337, 1988a... 

Darke S, Ross J, Teesson M, et al Health service utilization and benzodiazepine use among heroin users findings from the Australian Tfearment Outcome Smdy (ATOS). Addiction 98 1129-1135, 2003... 

Greenblatt DJ, Shader RI Dependence, tolerance, and addiction to benzodiazepines clinical and pharmacokinetic considerations. Drug Merab Rev 8 13-28, 1978... 

Ibrahim RB, Wilson JG, Thorsby ME, et al Effect of buprenorphine on CYP3Aactivity in rat and human liver microsomes. Life Sci 66 1293—1298, 2000 Iguchi MY, Handelsman L, Bickel WK, et al Benzodiazepine and sedative use/abuse by methadone maintenance clients. Drug Alcohol Depend 32 257—266, 1993 Isbell H Manifestations and treatment of addiction to narcotic drugs and barbiturates. Med Clin North Am 34 423 38, 1950... 

Perera KM, Jenner FA Some characteristics distinguishing high and low dose users of benzodiazepines. Br J Addict 82 1329-1334, 1987 Perez MF, Salmiron R, Ramirez OA NMDA-NRl and -NR2B subunits mRNA expression in the hippocampus of rats tolerant to diazepam. Behav Brain Res 144 119-124, 2003... 

Petursson H, Lader MH Benzodiazepine dependence. BrJ Addict 76 133—143,1981a Petursson H, Lader MH Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed) 283 643—643, 1981b Pichard L, Gillet G, Bonfils C, et al Oxidative metabolism of zolpidem by human liver... 

Posternak MA, Mueller TI Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence. Am J Addict 10 48-68, 2001... 

Schweizer E, Patterson W, Rickels K, et al Double-blind, placebo-controlled study of a once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Am J Psychiatry 150 1210-1215, 1993 Seivewright N Benzodiazepine misuse by illicit drug misusers. Addiction 96 333—334, 2001... 

Vorma H, Naukkarinen H, Sarna S, et al Treatment of out-patients with complicated benzodiazepine dependence comparison of two approaches. Addiction 97 851-859, 2002... 

Williams H, Oyefeso A, Ghodse AH Benzodiazepine misuse and dependence among opiate addicts in treatment. It J Psychol Med 13 62-64, 1996 Wiseman SM, Spencer-Peet J Prescribing for alcoholics a survey of drugs taken prior to admission to an alcoholism unit. Practitioner 229 88—89, 1985 Wolf B, Grohmann R, Biber D, et al Benzodiazepine abuse and dependence in psychiatric inpatients. Pharmacopsychiatry 22 54—60, 1989 Wood MR, Kim JJ, Han W, et al Benzodiazepines as potent and selective bradykinin B1 antagonists. J Med Chem 46 1803—1806, 2003 Zawertailo LA, Busto UE, Kaplan HL, et al Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital. J Clin Psycho-pharmacol 23 269-280, 2003... 

Secobarbital exhibits the same pharmacologic properties as other members of the barbiturate class. Most nonmedical use is with short-acting barbiturates, such as secobarbital. Although there may be considerable tolerance to the sedative and intoxicating effects of the drug, the lethal dose is not much greater in addicted than in normal persons. Tolerance does not develop to the respiratory effect. The combination of alcohol and barbiturates may lead to fatalities because of their combined respiratory depressive effects. Similar outcomes may occur with the benzodiazepines. Severe withdrawal symptoms in epileptic patients may include grand mal seizures and delirium. 

Benzodiazepines are addictive and associated with high risk of adverse effects... 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

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