Alprazolam became the second most popular drug, increasing more than eightfold. In some cases, you can take your entire daily dosage before bedtime. The first benzodiazepine, chlordiazepoxide Librium , was synthesized in by Leo Sternbach while working at Hoffmann—La Roche on the development of tranquilizers. Journal List Aust Prescr v. The message that GABA transmits is an inhibitory one: This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Some will even take you off your benzodiazepine over a one week period with a Valium or Phenobarbital substitute.
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|Clonazepam 1 mg klonopin VS1||The increase symptoms sleep duration can withdrawal accounted for by an increase in the time spent comparison stage 2 of sleep, while the amount of time spent in slow-wave sleep deep and REM rapid eye movement is actually decreased clonazepam As a result of physiologic dependence, withdrawal symptoms emerge with rapid dose reduction or abrupt discontinuation benzodiazepines the drug. Handbook of psychiatric drug therapy. Many people experience muscle and joint pain during withdrawal. Essential reference tools, including a drug-interaction checker, medical calculators, and a pill identifier.|
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Courses were developed especially for physicians by business health experts and experienced physicians. Develop Your Own Curriculum. Choose courses based on your needs. Earn course certificates and optional CME. In such patients, alternatives to benzodiazepines may be preferable and may include antidepressants, anticonvulsants, buspirone, antihypertensive agents and the newer neuroleptic medications.
Caution must be used when prescribing benzodiazepines to patients with a current or remote history of substance abuse. There is little doubt of the therapeutic efficacy of benzodiazepines in reducing anxiety, inducing sleep and quelling panic symptoms. As noted in a report by the American Psychiatric Association APA on benzodiazepine dependence, toxicity and abuse, 1 the anxiolytic and hypnotic efficacy of benzodiazepines has been well established by numerous placebo-controlled studies.
Benzodiazepines are widely prescribed, with four of them—alprazolam Xanax , clonazepam Klonopin , diazepam Valium and lorazepam Ativan —listed among the top most commonly prescribed medications. Because many of the anxiety disorders wax and wane over time, patients with these disorders often prefer benzodiazepines because these agents can be taken intermittently, when patients feel the need to take them, and most patients can use benzodiazepines judiciously.
Neonatal seizures or febrile convulsions. Paraplegia secondary to spinal trauma. Akathisia associated with neuroleptic use. Anxiety associated with depression. Diagnostic studies, such as computed tomography, magnetic resonance imaging and endoscopy. Clinical uses of benzodiazepines. J Clin Psychopharmacol ;13 suppl 1: According to the APA report on benzodiazepines, 1 11 to 15 percent of the adult population has taken a benzodiazepine one or more times during the preceding year, but only 1 to 2 percent have taken benzodiazepines daily for 12 months or longer.
In psychiatric treatment settings and in substance-abuse populations, however, the prevalence of benzodiazepine use, abuse and dependence is substantially higher than that in the general population. Because benzodiazepines are controlled substances with abuse potential, special attention must be directed toward the patient's addiction history before these agents are prescribed.
An understanding of the toxicity and side effects of benzodiazepines, abuse patterns and alternative anxiolytic and hypnotic agents may help clinicians maximize treatment outcomes and reduce medicolegal liability risks. Benzodiazepine receptors are ubiquitous throughout the central nervous system. Activation of the benzodiazepine-GABA-chloride ionophor complex is responsible for producing the therapeutic anxiolytic effects of benzodiazepines and for mediating many of the side effects and, possibly, dependence and withdrawal from these drugs.
Similarly, other sites for drug and neurotransmitter binding are associated with the GABA receptor complex, which serves as a primary site of action of benzodiazepines, barbiturates and other sedative-hypnotics, such as alcohol. They do so by allosterically altering the receptor changing its conformation so that it has a greater binding affinity for GABA. Ethanol modifies the receptor by altering the membrane environment so that it has increased affinity for GABA and the other sedative-hypnotic drugs.
That benzodiazepines, barbiturates and ethanol all have related actions on a common receptor type, which explains their pharmacologic synergy and cross tolerance. Thus, benzodiazepines are used during alcohol detoxification. With long-term high-dose use of benzodiazepines or ethanol , there is an apparent decrease in the efficacy of GABA-A receptors, presumably a mechanism of tolerance.
With the introduction of chlordiazepoxide Librium in , and because of the relative safety of benzodiazepines, these agents rapidly replaced barbiturates as sedative-hypnotics. They cause significantly less respiratory depression than barbiturates and, consequently, are rarely lethal in an overdose. As a class of drugs, benzodiazepines share many clinical properties, although the different agents in this class may display different pharmacokinetic and pharmacodynamic properties Table 2.
Pharmacologic properties such as potency, half-life and lipophilicity, the duration of treatment and the rate of a dosage increase or decrease have a bearing on the occurrence of side effects. When used alone, benzodiazepines carry an extremely low risk of acute toxicity. However, benzodiazepines often are used with other types of medications, including other drugs with abuse potential, and these drugs can enhance the toxic effects of benzodiazepines.
The latter interact synergistically with other central nervous system depressants, including other hypnotics, sedating antidepressants, neuroleptics, anticonvulsants, antihistamines and alcohol. In addition, pharmacokinetic drug interactions may occur. For instance, selective serotonin reuptake inhibitors SSRIs may increase diazepam blood levels, 9 and nefazadone Serzone may increase alprazolam levels 10 through hepatic enzyme inhibition, leading to increased sedative-hypnotic effects or side effects.
Psychomotor slowing may be especially profound following initial administration of a benzodiazepine or with a sudden dosage increase. It also may be noted in patients, such as the elderly, who have decreased rates of metabolism or greater susceptibility to central nervous system depression. Benzodiazepines induce anterograde amnesia, which accounts for the beneficial effects of benzodiazepines such as midazolam Versed for presurgical medication.
These specific amnestic effects appear to be separate from sedation. Specific deficits in visuospatial ability and sustained attention have also been described in patients who have taken therapeutic doses of benzodiazepines regularly for longer than one year. Increased excitement, irritability, aggression, hostility and impulsivity may occur in some patients who take benzodiazepines. This paradoxical disinhibition may, in rare cases, result in attacks of rage or violence, or other indiscretionary or antisocial behaviors.
These reactions occur most commonly in children, in the elderly and in persons with developmental disabilities. An association has been noted between benzodiazepine use and depressive symptoms and, in some cases, the emergence of suicidal ideation. Some evidence indicates that higher benzodiazepine dosages are associated with an increased risk of depression and that reducing the dosage or discontinuing therapy may resolve the depressive symptoms.
This effect may be sought by drug addicts who become progressively more incapable of tolerating their emotions and life stressors. Benzodiazepines cross the placenta and are classified as class D teratogens. They may lead to the development of dependence and consequent withdrawal symptoms in the fetus. Tolerance to all of the actions of benzodiazepines can develop, although at variable rates and to different degrees.
Tolerance to the hypnotic effects tends to develop rapidly, which may be beneficial in daytime anxiolysis but makes long-term management of insomnia difficult. Dosage escalation often maintains the cycle of tolerance and dependence, and patients may have difficulty discontinuing drug therapy. Benzodiazepine therapy can give rise to physiologic and psychologic dependence based on the drug's dosage, duration of therapy and potency.
As a result of physiologic dependence, withdrawal symptoms emerge with rapid dose reduction or abrupt discontinuation of the drug. Psychologically, long-term use of benzodiazepines may lead to overreliance on the need for the agent, loss of self-confidence and varying degrees of drug-seeking behavior. Withdrawal effects from therapeutic dosages of benzodiazepines are mainly anxiety symptoms. The most serious acute withdrawal symptoms are seizures and delirium tremens, which most commonly occur with abrupt discontinuation.
The time frame for the emergence of acute withdrawal symptoms corresponds to the half-life of the particular agent being used. Some elements of withdrawal are believed to occur in a majority of patients who have taken therapeutic dosages of benzodiazepines for more than a few months, although the severity of withdrawal symptoms generally depends on the amount of the original dosage, the rate at which the dosage is tapered, the selection of patients and the definition of withdrawal symptoms.
A protracted abstinence syndrome has been observed by addictionologists who are familiar with benzodiazepine addiction. In addition, physical symptoms related to gastrointestinal, neurologic and musculoskeletal effects may occur. This abstinence phenomenon may develop despite long, slow, judicious tapering of the dosage and is hypothesized to result from chronic neuroadaptation. Among the elderly, the risk of drug interactions, psychomotor slowing, cognitive dysfunction and paradoxical disinhibition may be amplified.
Benzodiazepine use in the elderly is associated with an increased rate of falls that cause hip and femur fractures and an increased likelihood of motor vehicle crashes. Cognitive deterioration associated with normal aging processes and dementia can be worsened by benzodiazepine side effects. Cortical suppression mechanisms may be disturbed in the elderly, and disinhibited behaviors may increase with benzodiazepine use.
With less cognitive and social reserve in the elderly patient, the short- and long-term withdrawal symptoms and other benzodiazepine side effects may lead the patient to frequently visit or telephone the physician. In one study, 26 this impasse was broken by referring elderly patients to inpatient detoxification, which resulted in a dramatic decrease in annual physician visits. Benzodiazepines are rarely the preferred or sole drug of abuse.
An estimated 80 percent of benzodiazepine abuse is part of polydrug abuse, most commonly with opioids. Studies indicate that from 5 percent to as many as 90 percent of methadone users are also regular users of benzodiazepines. High-dose benzodiazepine abuse is especially prevalent in patients who are taking methadone. Studies indicate that 3 to 41 percent of alcoholic persons report that they abused benzodiazepines at some time, often to modulate intoxication or withdrawal effects.
As many as 80 percent of alcoholics under the age of 30 have been addicted to or use at least one other drug. Medical prescriptions constitute the primary source of supply for people who abuse benzodiazepines. Prescriptions may also have a street value, which encourages rerouting to illicit sources. Benzodiazepines have multiple uses for polydrug addicts: As potential drugs of abuse, short-acting benzodiazepines seem to be preferred among addicts because of the rapidity of their onset of action.
Clonazepam is a high-potency benzodiazepine with a long half-life. It is widely prescribed for a variety of psychiatric and neurologic conditions. On the other hand, oxazepam Serax , clorazepate Tranxene and chlordiazepoxide appear to have lower reinforcing effects than other benzodiazepines. The problems with benzodiazepine dependence, tolerance, withdrawal, rebound and abuse limit their use for long-term treatment of anxiety disorders in patients with alcohol or drug addiction.
A growing body of literature now supports the anxiolytic efficacy of numerous other agents Table 3. Antidepressants, anticonvulsants, buspirone Buspar , certain antihypertensive agents and newer neuroleptics all have been shown to be effective in subsets of patients with anxiety. Most addiction medicine specialists believe that benzodiazepines are relatively contraindicated in patients with current alcohol or drug abuse problems and in patients who are in recovery.
To choose an appropriate alternative to a benzodiazepine, physicians should be able to delineate which subtype of anxiety disorder exists in a particular patient. Patients should be encouraged to understand that the onset of action of antidepressants, buspirone and anticonvulsants is not as immediate as that of benzodiazepines. Therapy may require patience and, because of side effects, a low dosage may be required initially. Insomnia is a common sequela of numerous medical and psychiatric conditions, and is often associated with substance-use disorders, early abstinence or protracted withdrawal.
Management of insomnia includes attention to sleep hygiene techniques, such as maintaining a regular sleep-wake cycle, avoiding daytime naps, avoiding caffeine or heavy meals at night, and engaging in gentle exercise or utilizing other relaxation techniques. Nonbenzodiazepine pharmacotherapies for the management of insomnia include the sedating antidepressant trazodone Desyrel , tertiary tricyclic antidepressants such as amitriptyline Elavil and doxepin Sinequan , and newer antidepressant agents such as nefazodone and mirtazapine Remeron.
Zolpidem Ambien , an imidazopyridine, is a hypnotic agent with a chemical structure unrelated to benzodiazepines. Tolerance and withdrawal symptoms do not appear as readily with this agent as with benzodiazepines. However, zolpidem is classified as a schedule IV controlled substance like benzodiazepines , and synergistic effects with benzodiazepines and alcohol have been observed.