Benzodiazepines withdrawal effects

Pecknold JC, McClure DJ, Fleury D, et al. Benzodiazepine withdrawal effects. Prog Neuropsychopharmacol Biol Psychiatry 1982 6 517-522. 

Mental Ayurvedic compound herbal preparation. controlled animal study showed efficacy in reversing acute benzodiazepine withdrawal effects. 

Saxon L, Hjemdahl P, Hiltunen AJ, et al Effects of flumazentl in the treatment of benzodiazepine withdrawal—a double-hlind pilot study. Psychopharmacology (Bed) 131 153-160, 1997... 

Clonazepam, a typical 1 4 benzodiazepine, is effective in absence seizures, myoclonic jerks and tonic-clonic seizures and given intravenously it attenuates status epilepticus. It is less sedative than phenobarbitone but tolerance develops and its withdrawal, as... 

The use of benzodiazepines should be avoided. There are other safer pharmacological alternatives. Benzodiazepine withdrawal may play a role in the occurrence of delirium in the elderly. Other withdrawal symptoms include tremor, agitation, insomnia and seizures (Turnheim 2003). Thus, when there is long-term use of benzodiazepines abrupt discontinuation might be difficult. Discontinuation should however not be withheld but done slowly and step-wise. If benzodiazepines are used in the elderly, short-acting benzodiazepines such as oxazepam are preferred, because they do not accumulate in the elderly to the same extent (Kompoliti and Goetz 1998). If short-acting benzodiazepines are used they should be prescribed with caution, at low doses, and for short periods. As with all pharmacotherapy the effects should be evaluated. Benzodiazepines are sometimes used as a behavioural control. One should always ask if this use is for the benefit of staff or the benefit of the patient. The presence of staff may be sufficient for behavioural control. 

Flumazenil s one problematic side effect is that it can trigger benzodiazepine withdrawal including increased pulse, increased blood pressure, shakiness, anxiety, and seizures. Because it is only used in the hospital, supportive medical care is, by definition, available if this occurs. 

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. 

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. 

Benzodiazepines have a low abuse potential when they are properly prescribed and their use is supervised (American Psychiatric Association 1990). However, physical dependence often occurs when benzodiazepines are taken at higher-than-usual doses or for prolonged periods. If benzodiazepines are discontinued precipitously, withdrawal effects (including hyperpyrexia, seizures, psychosis, and even death) may occur. Signs and symptoms of withdrawal may include tachycardia, increased blood pressure, muscle cramps, anxiety, insomnia, panic attacks, impairment of memory and concentration, perceptual disturbances, and delirium. In addition, withdrawal-related derealization, hallucinations, and other psychotic symptoms have been reported. These withdrawal symptoms may begin as early as the day after discontinuation of the benzodiazepine, and they may continue for weeks to months. Evidence indicates that withdrawal reactions associated with shorter-half-life benzodiazepines peak more rapidly and more intensely. 

Unlike benzodiazepines, buspirone is not associated with sedative or abuse problems, but some clinicians have observed that bus-pirone s anxiolytic properties do not appear to be as potent as those of benzodiazepines, particularly in patients who have previously received a benzodiazepine. Because buspirone is not sedating and has no psychomotor effects, it has a distinct advantage over benzodiazepines when optimal alertness and motor performance are necessary. Response to buspirone occurs in approximately 2-4 weeks. Buspirone does not show cross-tolerance with benzodiazepines and other sedative or hypnotic drugs such as alcohol, barbiturates, and chloral hydrate. Therefore, buspirone does not suppress benzodiazepine withdrawal symptoms. In anxious patients who are taking a benzodiazepine and who require a switch to buspirone, the benzodiazepine must be tapered gradually to avoid withdrawal symptoms, despite the fact that the patient is receiving buspirone. 

Rickels K, Schweizer E, Garcia Espana F, et al. Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy effects on withdrawal symptoms and taper outcome. Psychopharmacology (Bert) 1999 141 1-5. 

Partial agonists at benzodiazepine receptors As discussed for general anxiolytic agents in Chapter 8, the partial benzodiazepine agonists could be a theoretical advance over the marketed benzodiazepines. Partial agonists should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects. 

The manner and severity of withdrawal symptoms varies according to the type of drug and the extent of physical dependence.50 Withdrawal after short-term benzodiazepine use may be associated with problems such as sleep disturbances (i.e., so-called rebound insomnia).34 62 As discussed earlier, withdrawal effects seem to be milder with the newer nonbenzodiazepine agents (zolpidem and zaleplon).34,62 Newer agents, however, are not devoid of these problems and care should be taken with prolonged use, especially in people with psychiatric disorders or a history of substance abuse.26... 

In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1,4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7-180 days. By contrast, after 3 weeks of abercamil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercamil administered. 

Patients with mild symptoms of alcohol withdrawal do not generally require medication therapy. Benzodiazepines, like diazepam or alprazolam, are the treatment of choice for patients with severe alcohol withdrawal syndromes like delirium tremens. Barbiturates can also be used for this disorder, but are often less prescribed because they are not as safe as benzodiazepines. Both barbiturates and benzodiazepines are effective in treating the anxiety, tremor, insomnia, and hand tremors associated with delirium tremens. 

---