Benzodiazepines withdrawal syndrome

A rebound sleep disturbance has been found after only 7—10 days of treatment with therapeutic doses of triazolam (Greenblatt et al. 1987). Others have described a withdrawal syndrome after substitution of a short-acting benzodiazepine for a long-acting benzodiazepine (Conell and Berhn 1983). Rebound insomnia may occur with zolpidem. 

Goodman WK, Charney DS, Price LH, et al Ineffectiveness of clonidine in the treatment of the benzodiazepine withdrawal syndrome report of three cases. Am J Psychiatry 143 900—903, 1986... 

Sellers EM Alcohol, barbiturate and benzodiazepine withdrawal syndromes clinical management. CMAJ 139 113—120, 1988... 

Side effects of benzodiazepines include sedation, dizziness, poor coordination, and, at higher doses, amnesia. Benzodiazepines also increase the effects of alcohol therefore, alcohol use should be avoided or markedly curtailed. Benzodiazepines can also exacerbate the breathing problems of patients with sleep apnea and other respiratory disorders such as emphysema. Like the barbiturates, long-term use of benzodiazepines can lead to physical dependence, and abrupt discontinuation can produce an unpleasant, or even dangerous, withdrawal syndrome. 

However, there are disadvantages to benzodiazepines. They prodnce sedation and can impair short-term memory and coordination (psychomotor fnnction such as driving). They can magnify the effects of alcohol and are snbject to abuse and withdrawal syndromes. Refer to Section 5.1 for a more extended discussion of benzodiazepines. 

Q68 Benzodiazepines with a short elimination half-life present a less severe withdrawal after drug discontinuation than drugs with a long elimination half-life. Symptoms of benzodiazepine withdrawal syndrome include anxiety, depression, insomnia and headache. 

The withdrawal syndrome from ethanol includes anxiety, insomnia, possibly convulsions and visual hallucinations (delirium tremens - the Dts). It is treated or better still prevented by a calm environment, adequate (but not excessive) hydration, and careful monitoring, with the added use of anticon-vulsive/sedative agents, mainly benzodiazepines to prevent or treat convulsions. The preventive effects of benzodiazepines on withdrawal morbidity has been clearly demonstrated. There do not seem to be major differences between benzodiazepines, such as chlordiazepoxide or diazepam or others. Because of the abuse potential in these highly susceptible patients, these should be rapidly weaned, and proper prevention of relapse instituted. Other drugs such as meprobamate and clomethiazole (Hemineurin) are commonly used in some countries. The effectiveness... 

A benzodiazepine withdrawal syndrome has been described in some patients discontinuing therapy (Table 2). Although potentially serious, it is generally mild and self-limiting (up to 6 weeks), but may accompany or provoke a recurrence of anxiety symptoms and cause great concern to the patient. As with any other treatment, the risks and benefits of benzodiazepine therapy should be carefully assessed and discussed with the patient. Monotherapy will not be first-line treatment for the majority of patients, but benzodiazepines offer a valuable option that should not be discounted. 

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. 

Dependence on benzodiazepines, as evidenced by a withdrawal syndrome, can develop to large doses of drugs. Mild dependence is produced at therapeutic doses. 

A second issue relating to long-term medication is the effect of withdrawing medication at the end of a period of treatment. Benzodiazepines are associated with discontinuation symptoms, and their repeated use may foster the development of true physiological dependence. In a study of discontinuation of treatment for panic disorder [Rickels et al. 1993) with either alprazolam [n = 27), imipramine [n = 11) or placebo [n = 10), a withdrawal syndrome was observed in almost all patients treated with alprazolam but in few pa-... 

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... 

Martinez-Cano H, Vela-Bueno A, de Iceta M, et al. Benzodiazepine withdrawal syndrome seizures. Pharmacopsychiatry 1995 28 257-262. 

Lader M, Morton S. Benzodiazepine withdrawal syndrome. Br J Psychiatry 1991 158 435-436. 

Higgitt A, Fonagy P, Toone B, et al. The prolonged benzodiazepine withdrawal syndrome anxiety or hysteria Acta Psych iatr Scand 1990 82 165-168. 

Tyrer P. The benzodiazepine post-withdrawal syndrome. Stress Med 1991 7 1-2. 

The experience of pregnancy itself is often anxiety provoking, and symptoms sufficient to warrant drug therapy are common in this group ( 16). Although this discussion primarily focuses on the benzodiazepines (BZDs), antidepressants and buspirone may also be used for women of childbearing age with certain anxiety-related disorders. Perhaps the best-documented adverse effect of the BZDs is a neonatal withdrawal syndrome, which has been reported to occur with several of the agents (e.g., diazepam, alprazolam, and triazolam). In addition, there is a weak positive relationship between diazepam exposure and oral clefts ( 17). 

How soon the withdrawal syndrome starts is partly dependent upon the half-life of the tranquilliser being taken, and whether other benzodiazepines are also being used (for example, hypnotics). If the half-life is shorter (that is, less than twelve hours), then a person may experience withdrawal between doses. However, if the tranquilliser is longer acting, then withdrawal can start within three to ten days of any reduction (Committee on the Review of Medicines... 

One way of estimating the likelihood and severity of the withdrawal syndrome (which should affect time taken to withdraw) is to use the Cumulative Benzodiazepine Exposure Index developed by Busto et al. (1986) which measures a person s total tranquilliser... 

MacKinnon, G.L. and Parker, W.A. (1982) Benzodiazepine withdrawal syndrome a literature review and evaluation , American Journal of Drug and Alcohol Abuse, 9 (1) 19-33. 

Longer-term difficulties associated with benzodiazepine use for insomnia come from observations that many patients develop tolerance for these agents, so that they stop working after a week or two. To avoid this, patients must take a sleeping pill only a few times within several days, or for only about 10 days in a row followed by several days or weeks with no drug treatment. Furthermore, if patients persist in taking benzodiazepines as sedative-hypnotics for several weeks to months, there can be a withdrawal syndrome once the medications are stopped, particularly if they are stopped suddenly. This is discussed in further detail in Chapter 13. 

Tolerance to the effects of marijuana clearly exist even though chronic users have described a reversed tolerance and claim that smaller doses of the drug are necessary to produce the desired effects. This effect is probably related to the manner of use and the expectations of the user. Chronic, high-dose cannabis users may experience an abstinence or withdrawal syndrome on abrupt discontinuation of use. Signs and symptoms include irritability, restlessness, nervousness, weight loss, insomnia, and rapid eye movement (REM) rebound. Onset of this syndrome is several hours after the last dose, and it lasts 4 to 5 d. Because withdrawal is not life-threatening, treatment involves little more than supportive therapy with short-term, low doses of benzodiazepines. 

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