Withdrawal From Benzodiazepines

Although rare, benzodiazepine toxicity may occur from an overdose of the drug. Benzodiazepine toxicity causes sedation, respiratory depression, and coma. Flumazenil (Romazicon) is an antidote (antagonist) for benzodiazepine toxicity and acts to reverse die sedation, respiratory depression, and coma within 6 to 10 minutes after intravenous administration. The dosage is individualized based on the patient s response, widi most patients responding to doses of 0.6 to 1 mg. However, die drug s action is short, and additional doses may be needed. Adverse reactions of flumazenil include agitation, confusion, seizures, and in some cases, symptoms of benzodiazepine withdrawal. Adverse reactions of flumazenil related to the symptoms of benzodiazepine withdrawal are relieved by die administration of die benzodiazepine. 

The clinician must be cautious in interpreting some of these symptoms (especially anxiety) in patients withdrawing from benzodiazepines. Anxiety fearfulness, and dysphoria may represent symptoms that were treated by the benzodiazepine and unmasked on withdrawal. 

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... 

Psychopharmacology (Bed) 141 30-36, 1999 Mullins ME, Fitzmaurice SC Lack of efficacy of benzodiazepines in treating gamma hydroxybutyrate withdrawal. J Emerg Med 20 418 20, 2001 Mycyk MB, Wilemon C, Aks SE Two cases of withdrawal from 1,4-butanediol use. Ann Emerg Med 38 345-346, 2001... 

Substance-Induced Anxiety Disorder. Numerous medicines and drugs of abuse can produce panic attacks. Panic attacks can be triggered by central nervous system stimulants such as cocaine, methamphetamine, caffeine, over-the-counter herbal stimulants such as ephedra, or any of the medications commonly used to treat narcolepsy and ADHD, including psychostimulants and modafinil. Thyroid supplementation with thyroxine (Synthroid) or triiodothyronine (Cytomel) can rarely produce panic attacks. Abrupt withdrawal from central nervous system depressants such as alcohol, barbiturates, and benzodiazepines can cause panic attacks as well. This can be especially problematic with short-acting benzodiazepines such as alprazolam (Xanax), which is an effective treatment for panic disorder but which has been associated with between dose withdrawal symptoms. 

Historically, the treatment of alcohol use disorders with medication has focused on the management of withdrawal from the alcohol. In recent years, medication has also been used in an attempt to prevent relapse in alcohol-dependent patients. The treatment of alcohol withdrawal, known as detoxification, by definition uses replacement medications that, like alcohol, act on the GABA receptor. These medications (i.e., barbiturates and benzodiazepines) are cross-tolerant with alcohol and therefore are useful for detoxification. By contrast, a wide variety of theoretical approaches have been used to reduce the likelihood of relapse. This includes aversion therapy and anticraving therapies using reward substitutes and interference approaches. Finally, medications to treat comorbid psychiatric illness, in particular, depression, have also been used in attempts to reduce the likelihood of relapse. 

Withdrawal from long-term high-dose use of alcohol or sedative-hypnotic drugs can be life threatening if physical dependence is present. Benzodiazepines, such as chlordiazepoxide Librium) and diazepam Valium), are sometimes used to lessen the intensity of the withdrawal symptoms when alcohol or sedative-hypnotic drug use is discontinued. Benzodiazepines are also employed to help relieve the anxiety and other behavioral symptoms that may occur during rehabilitation. 

In view of the potential pitfalls in giving benzodiazepines to polydrug users, the subject will be examined carefully, starting with probably the only situation in which it is definitely advisable to prescribe, which is in short-term withdrawal from benzodiazepine misuse where there is demonstrable physical dependence and within a closely monitored arrangement... 

Antidepressants appear sometimes useful in aiding withdrawal attempts, rather as they can he in withdrawal from benzodiazepines or alcohol. There is some positive evidence for serotonin re-uptake inhibitors and nortriptyline, but the strongest is for bupropion, which in the UK at least is the only antidepressant licensed for use as a cessation aid. Success rates for this seem to be very similar to those with nicotine replacement, approximately doubling a smoker s chances (Hughes et al. 2007). The latest option is varenicline, which acts as a partial agonist on one of the nicotinic receptors. 

Petursson H Lader MH (1981). Withdrawal from long-term benzodiazepine treatment. British Medical Journal, 238, 643-5 Philips G, Gossop M Bradley M (1986). The influence of psychological factors on the opiate withdrawal syndrome. British Journal of Psychiatry, 149, 135-8 Philhps AN, Gazzard BG, Clumeck N, Losso MH Lundgren JD (2007). When should antiretroviral therapy for HIV be started British Medical Journal, 334, 76-8 Poikolainen K (2002). Antecedents of substance use in adolescence. Current Opinion in Psychiatry, 15, 241-5... 

Petursson H, Gudjonsson GH, Lader MH. Psychosomatic performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology 1983 81 345-349. 

Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use a report of four cases. Psychol Med 1984 14 937-940. 

Rickels K, Case WG, Schweizer E. Withdrawal from benzodiazepines. In Hindmarch I, Beaumont G, Brandon S, et al., eds. perspectives. West Sussex, U.K. John Wiley Sons, 1990 199-210. 

Petursson, H. (1982) Clinical and laboratory studies of withdrawal from long-term benzodiazepine treatment , PhD thesis, London Institute of Psychiatry. 

Petursson, H. and Lader, M.H. (1981) Withdrawal from long-term benzodiazepines treatment , British Medical Journal, 283 643-5. 

WITHDRAW Project (1986) Aspects of Withdrawal from Benzodiazepines— A guide for those who work with tranquilliser withdrawal, WITHDRAW Project, North Birmingham Health Authority. 

Benzodiazepines are commonly prescribed as anxiolytics and sleep medications. They represent a moderate risk for abuse, which has to be weighed against their beneficial effects. Benzodiazepines are abused by some persons for their euphoriant effects, but most often abuse occurs concomitant with other drugs, eg, to attenuate anxiety during withdrawal from opioids. 

Although benzodiazepine dependence is very common, cases that fulfill all the diagnostic criteria for addiction are rare. Withdrawal from benzodiazepines occurs within days of stopping the medication and varies as a function of the half-life of elimination. Symptoms include irritability, insomnia, phono- and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1-2 weeks. 

Actions at benzodiazepine receptors are thought to underlie virtually all the pharmacological actions of the benzodiazepines, those that are desirable as well as those that are undesirable. This includes the desirable therapeutic actions of benzodiazepines as anxiolytics and sedative-hypnotics, as well as anticonvulsants and muscle relaxants. It also includes their undesirable side effects as amnestic agents and as agents that cause adaptations at the benzodiazepine receptor with chronic administration, which are thought to underlie the production of dependence and withdrawal from these agents (see Chapter 13). 

Individuals who are addicted to benzodiazepines should not try to quit cold turkey on their own. Often, individuals addicted to a benzodiazepine have an addiction to another substance or drug, such as cocaine or alcohol. These multiple addictions are complicated. Recovery from these addictions should not be attempted alone. Withdrawal from abuse of benzodiazepines may cause life-threatening complications. 

Patients undergoing abrupt withdrawal from GBL are monitored in the intensive care unit and are typically hospitalized for about five days for supportive care and treatment with pentobarbital, a strong sedative sometimes used for anesthesia. Withdrawal symptoms are so severe that benzodiazepines, which are milder tranquilizers than pentobarbital and which are typically the first line of treatment... 

Withdrawal reactions are more problematical. Hypnotics, by and large, are benzodiazepine like in their pharmacology, receptor binding, etc. The main differences relate to duration of action and to putative selectivity of binding. The benzodiazepine withdrawal reaction has been described many times, and rating scales have been developed to measure the symptoms. Withdrawal reactions from hypnotics would be expected to display similar symptomatic patterns and to follow time-courses dictated by the pharmacokinetic properties of the drug. 

An evaluation has been made of the utility of zopiclone substitution in facilitating the withdrawal of flunitrazepam [31]. Twenty-four volunteers with insomnia and a history of long-term benzodiazepine hypnotic use were assessed with both subjective and objective measures during a 5-week substitution with zopiclone and subsequent withdrawal or continuation on flunitrazepam. Withdrawal from flunitrazepam was accompanied a worsening of sleep quality, both subjectively and objectively. No such deterioration was seen in the zopiclone-substituted groups. 

Several studies have evaluated the usefulness of zolpidem in facilitating withdrawal from long-term benzodiazepine use (e.g., [43, 44]). It appears that most patients on long-term hypnotics can be transferred to zolpidem and that the subsequent withdrawal from zolpidem is much easier. By and large, such strategies should only be resorted to if simple tapering of the benzodiazepine dosage has proven unsuccessful. 

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