Anxiolytics withdrawal

Glassification of Substance-Related Disorders. The DSM-IV classification system (1) divides substance-related disorders into two categories (/) substance use disorders, ie, abuse and dependence and (2) substance-induced disorders, intoxication, withdrawal, delirium, persisting dementia, persisting amnestic disorder, psychotic disorder, mood disorder, anxiety disorder, sexual dysfunction, and sleep disorder. The different classes of substances addressed herein are alcohol, amphetamines, caffeine, caimabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics, polysubstance, and others. On the basis of their significant socioeconomic impact, alcohol, nicotine, cocaine, and opioids have been selected for discussion herein. 

Benzodiazepines and other anxiolytics. Although benzodiazepines are widely used in the treatment of acute alcohol withdrawal, most nonmedical personnel involved in the treatment of alcoholism are opposed to the use of medications that can induce any variety of dependence to treat the anxiety, depression, and sleep disturbances that can persist for months following withdrawal. Researchers have debated the pros and cons of the use of benzodiazepines for the management of anxiety or insomnia in alcoholic patients and other substance abuse patients during the postwithdrawal period (Ciraulo and Nace 2000 Posternak and Mueller 2001). 

The answer is d. (Hardman, p 564.) A long-acting benzodiazepine, such as diazepam, is effective in blocking the secobarbital withdrawal symptoms. The anxiolytic effects of bus pi rone take several days to develop, obviating its use for acute severe anxiety... 

Alternative pharmacological approaches Clonidine, an o2 adrenergic agonist, has been employed as adjunctive therapy to assist in smoking cessation. However, results have been mixed or the effects small (Gourlay et al. 1994 Hilleman et al. 1993 Franks et al. 1989). Buspirone (BuSpar) is a 5-HTlA partial agonist with anxiolytic effects. It has been tested as a treatment for smoking cessation because anxiety is a prominent feature of nicotine withdrawal (Farid and Abate 1998). To date, results have been mixed and more controlled research is needed. 

Valerian extracts show sedative and anxiolytic effects. Whereas passionflower and chamomile have relatively specific anxiolytic effects, valerian shows more general sedative effects, but all effects occur in a dose-dependent manner (Della Logia et al. 1981 Leuschner et al. 1993). The sedative effects of valerian extract are moderate when compared to diazepam and the neuroleptic chlorpromazine (Leuschner et al. 1993). However, valepotriates reverse the anxiogenic effects of diazepam withdrawal in rats in the elevated plus maze. This effect is dose dependent, effective at 12 mg/kg but not 6 mg/kg. Interestingly, the fragrant valerian compound bornyl acetate has sedative effects in mice, but only when inhaled (Buchbauer et al. 1992). 

Catania MA, Firenzuoli F, Crupi A, Mannucd C, Caputi AP, Calapai G (2003) Hypericum perforatum attenuates nicotine withdrawal signs in mice. Psychopharmacology 169 186-189 Cheeta S, Irvine EE, Kenny PJ, File SE (2001) The dorsal raphd nucleus is a crucial structure mediating nicotine s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology 155 78-85... 

Barbiturates. The hrst barbiturate, barbital, was introduced in 1903 and was followed a few years later by phenobarbital. The barbiturates effectively relieve anxiety, but they are never used as anxiolytics today due to toxicity and abuse concerns. However, several barbiturates, including phenobarbital (Luminal), secobarbital (Seconal), and pentobarbital (Nembutal), remain available and are occasionally used to treat epilepsy and rarely to manage acute alcohol withdrawal. 

Azapirones. Though several azapirones have been developed and tested in the laboratory setting, only one, bnspirone (Bnspar), is currently on the market. Buspirone is the first nonsedating, nonbenzodiazepine anxiolytic, other than the antidepressants described earlier. It has no dependence or addictive liability and is not lethal in overdose. Buspirone is also devoid of many of the problems of the benzodiazepines such as sedation, motor impairment, addiction, physical dependence, or withdrawal. Yet, doubts remain in the minds of many practitioners regarding the effectiveness of buspirone. This will be discussed in more detail later in this chapter. 

In general, the lowest effective dose of the drug should be used, particularly in elderly patients. Dose titration should be undertaken slowly. Similarly, on discontinuation of a drug, the dose should be reduced slowly, the rate of decrease being decided by the elimination half-life of the drug. Some psychotropic drugs produce a discontinuation syndrome that can usually be avoided by slow withdrawal. In particular, sedatives, anxiolytics and antidepressants can cause withdrawal effects. 

In switching drugs, the half-life of elimination that is being stopped should be considered if drug interactions are to be avoided. The time taken for the withdrawal of a drug depends on the duration of treatment sedatives, antiepileptics and anxiolytics may take several weeks to withdraw. 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

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. 

It does not cause cognitive impairment and has a low potential for abuse. It does not show withdrawal reactions and has no anticonvulsive, hypnotic, muscle relaxant and sedative effects. The anxiolytic effect gradually evolves over 1-3 weeks, it does not potentiate the sedative effects of alcohol and is indicated for the short-term management of generalized anxiety disorder. 

Redmond DE Jr (1981) Clonidine and the primate locus coeruleus evidence suggesting anxiolytic and anti-withdrawal effects. Prog Clin Biol Res 71 147-163 Reiman EM, Raichle ME, Robins E, Butler FK, Herscovitch P, Fox P, Perlmutter P (1986) The applications of positron emission tomography to the study of panic disorder. Am J Psychiatry 143 469-477... 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

Antidepressants differ from benzodiazepines in the onset and course of their actions (Fig. 2). Most cause an increase in anxiety on initiation of therapy, and anxiolytic effects occur later. In comparative studies, improvement matches that on benzodiazepines after 4 weeks (Rocca et al. 1997). Withdrawal effects, particularly rebound, are less problematic with antidepressants, although stopping treatment is associated with a significant rate of relapse, and a withdrawal syndrome has been described for most of the shorter-acting drugs. 

The longstanding use in some countries of hydroxyzine, a centrally-acting Hi-histamine receptor antagonist, is supported by positive findings in controlled trials in GAD (Ferreri and Hantouche 1998 Lader and Scotto 1998). Hydroxyzine promotes sleep and its anxiolytic effects have an early onset. Although it causes sedation, tolerance to this effect often occurs and effects on psychomotor performance are smaller than with benzodiazepines (de Brabander and Deberdt 1990). It is well-tolerated and withdrawal effects have not been reported. Although the evidence for its efficacy is not large, hydroxyzine provides an option for some patients with GAD for whom standard treatments are unsuitable. 

Buspirone is as effective as the benzodiazepines in the treatment of general anxiety. However, the full anxiolytic effect of buspirone takes several weeks to develop, whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. In addition, buspirone does not potentiate the central nervous system depression caused by sedative-hypnotic drugs or by alcohol, and it does not prevent the symptoms associated with benzodiazepine withdrawal. 

---