Benzodiazepines

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The benzodiazepines were recognized in animal experiments in the 1950s for their ability to produce "taming" without apparent sedation. Cats, which are extremely sensitive to even small electrical shocks, were obviously sedated when given enough alcohol or barbiturates to prevent anxious avoidance behavior of impending shocks. In contrast, when given benzodiazepines, the cats appeared normal in all of their behavior, except that they did not show the exaggerated anticipatory sensitivity to mild electrical shocks that they showed prior to treatment with benzodiazepines.

Chlordiazepoxide (Librium), the first benzodiazepine used in clinical practice, was introduced in 1961. More than 3,000 additional benzodiazepines have been synthesized, of which about 50 have been used clinically (Baldessarini, 2001). Several of the benzodiazepines, including alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), and clonazepam (Klonopin) are among not only the most widely prescribed medicines for anxiety but are also the most frequently prescribed medicines worldwide.

The identification of the benzodiazepine receptors in 1977 began the modern era of benzodiazepine research, establishing this class as the best understood of the psychiatric medicines. GABA receptors are membrane-bound proteins divided into three subtypes, GABA-A, GABA-B, and GABA-C receptors. The GABA-A receptors are composed of five subunits that together form the chloride channel, which primarily mediates neuronal excitability (seizures), rapid mood changes, and clinical anxiety, as well as sleep. GABA-B receptors mediate memory, mood, and analgesia. The role of the GABA-C receptors remains unclear. The effects of benzodiazepines are reversed by benzodiazepine antagonists, one of which—flumazenil—is used clinically to reverse rapidly the effects of benzodiazepine overdoses (Charney et al., 2001). The benzodiazepine receptors, part of the GABA system, are found in approximately 30% of CNS synapses and in all species above the level of the shark, demonstrating their fundamental biological importance.

There are pharmacological differences among the individual benzodiaze-pines that have clinical significance. The differences between the benzodiaze-pines resemble the differences between the individual medicines in two other major classes of psychotropic medicines: antipsychotics and antidepressants. Although there are many overlapping effects within each class, there are also important differences among the medicines in each class, so that the medicines within a class cannot be used interchangeably. These pharmacological differences among the benzodiazepines include the rapidity of onset (distributional half-life), persistence of active drug and/or metabolite in the body (elimination half-life), major metabolic breakdown pathways (conjugation vs. oxidation), and specific molecular structure (e.g., alprazolam has a unique triazolo ring that may account for some differences in its clinical effects) (Charney et al., 2001). Table 10.1 summarizes these differences for the most widely used benzodiaze-pines, along with clinically important pharmacological characteristics as they relate to the use and abuse of the benzodiazepines (Chouninard, Lefko-Singh, & Teboul, 1999). Benzodiazepines may produce some clinically relevant effects by mechanisms that do not involve GABA-mediated chloride conductance (Burt & Kamatchi, 1991). The benzodiazepines have only a slight effect on rapid eye movement (REM) sleep, but they do suppress deeper, stage 4 sleep. Although this effect is probably of no clinical significance in most settings, diazepam has been used to prevent "night terrors" that arise in stage 4 sleep.

Speed of Onset

The most important distinction among the benzodiazepines in the substance abuse context is the speed of onset, which determines abuse potential (Griffiths & Werts, 1997). Those benzodiazepines with a slow onset (because they are either slowly absorbed or they must be metabolized to produce an active substance) have a relatively lower abuse potential. Those that rapidly reach peak

TABLE 10.1. Pharmacological Characteristics of Benzodiazepines

Onset of action

Metabolized

Elimination

Maximum

after oral

Rate of

primarily by liver

Active

half-life

usual dose

Drug

Trade name

administration

metabolism

oxidation

metabolites

(hours)

(mg/day)

Used primarily to treat anxiety

Alprazolam

Xanax

Intermediate

Intermediate

Yes

Yes

12-15

4

Chlordiazepoxide

Librium

Intermediate

Long

Yes

Yes

5-30

100

hydrochloride

10-15

Clonazepam"

Klonopin

Fast

Long

Yes

No

26-30

2

Clorazepate" dipotassium

Tranxene

Fast

Long

Yes

Yes

36-200

60

Diazepam"''

Valium

Fast

Long

Yes

Yes

20-50

40

Halazepam

Paxipam

Intermediate

Long

Yes

Yes

50-100

160

Lorazepam

Ativan

Intermediate

Short

No

No

10-14

6

Oxazepam

Serax

Slow

Short

No

No

5-10

60

Prazepam

Centrax

Slow

Long

Yes

Yes

36-200

60

Used primarily to treat insomnia

Estazolam

ProSom

Fast

Short

Yes

No

10-24

2

Flurazepam

Dalmane

Intermediate

Long

Yes

Yes

40-100

30

hydrochloride

Quazepam

Doral

Fast

Long

Yes

Yes

20-120

30

Temazepam

Restoril

Intermediate

Short

No

Yes

8-12

30

Triazolam

Halcion

Intermediate

Short

Yes

No

2-5

0.25

a Approved to treat epilepsy. h Approved as muscle relaxant.

brain levels after oral administration are relatively more likely to produce euphoria, and are therefore more likely to be abused by alcoholics and drug addicts. Diazepam has a relatively rapid onset of action and is therefore among the most effective producers of euphoria. In contrast, the more slow-acting benzodiazepines, such as oxazepam (Serax) and prazepam (Centrax), appear to have lower abuse potentials.

Clorazepate and prazepam, with inactive parent compounds, are also less likely to be abused for their euphoric effects because of slower onset of action. Oxazepam and the other slower onset benzodiazepines, like phenobarbital compared to other barbiturates and codeine compared to other opiates, appear to have relatively low abuse potentials.

The relative rapidity of onset of diazepam does not mean that it is more likely than other benzodiazepines to lead to abuse by medical patients who have no addiction history. None of the benzodiazepines, including diazepam, are reinforcing for patients who do not have a history of addiction. On the other hand, the pharmacology of the benzodiazepines suggests that, for patients with a history of addiction to alcohol and other drugs, diazepam may be more likely to be abused than oxazepam, clorazepate, or prazepam (Griffiths & Weerts, 1997).

Some serious students of the pharmacology of benzodiazepines believe that abuse is no more likely for diazepam than for oxazepam (Woods, Katz, & Winger, 1988). Addicts' greater liking for diazepam in some studies, in this view, is the result of the dose: Raise the dose of oxazepam in the double-blind studies, and the liking scores of oxazepam are indistinguishable from those of diazepam. In contrast, other well-respected researchers are convinced that diaz-epam, lorazepam, and alprazolam have greater abuse potential—not solely because of dosage factors—because of their more rapid absorption and penetration of the blood-brain barrier due to greater lipid solubility (Griffiths & Sannerud, 1987).

Metabolic Pathways

The metabolic pathways of the various benzodiazepines are important clinically, because those benzodiazepines that are metabolized by oxidation in the liver may alter the effects of other drugs. This is illustrated by the "boosting" effect of some benzodiazepines when used by methadone-maintained patients. Although the pharmacology of this effect is not well understood, it appears that simultaneous use of a benzodiazepine (e.g., diazepam or alprazolam) that competes with methadone for oxidative pathways in the liver produces higher peak levels of methadone in the blood (and brain) shortly after methadone is administered. Thus, prior use of some benzodiazepines may enhance brain reward for an hour or so after oral methadone dosages.

Benzodiazepines that have conjugation as the major metabolic pathway are not dependent on liver functioning, so they are less likely to raise methadone plasma levels or to build up plasma levels of the active benzodiazepine in patients who have compromised liver functioning, including alcoholics and the elderly. The benzodiazepines metabolized by conjugation include lorazepam, oxazepam, and temazepam. Thus, because these are less "liked" by methadone-maintained patients and may be better choices for these patients and for patients with compromised liver functioning, a benzodiazepine is to be used.

Oxazepam is both a slow-onset and a conjugated benzodiazepine, making it perhaps the best choice for methadone-maintained patients who are treated with a benzodiazepine. On the other hand, oxazepam has a short elimination half-life, which means it must be taken three or four times a day for continuous therapeutic effects. Oxazepam is no less likely to produce physical dependence (including difficulties on discontinuation) than any other benzodiazepine. Oxazepam is a widely used benzodiazepine in Europe (but not in the United States, where it is commonly abused by drug addicts and alcoholics). Thus, whatever benefit oxazepam may possess for alcoholics and drug addicts compared to other benzodiazepines is relative and not absolute (DuPont, 1988).

Persistence

Persistence of a benzodiazepine (or an active metabolite) in the body is important clinically, because it governs the rapidity of onset of withdrawal symptoms after the last dose for people who have used benzodiazepines for prolonged periods. The benzodiazepines with shorter elimination half-lives are more likely to produce early and pronounced withdrawal symptoms on abrupt discontinuation, whereas those with longer elimination half-lives generally produce more delayed and somewhat attenuated withdrawal symptoms. In general, alprazo-lam, lorazepam, and oxazepam are more rapidly eliminated than are clorazepate, diazepam, flurazepam, and prazepam. Thus, the benzodiazepines with shorter elimination half-lives are more likely to produce acute withdrawal on abrupt cessation after prolonged use. Clonazepam has a longer elimination half-life than alprazolam or lorazepam, so it is less likely to produce interdose withdrawal symptoms and is more appealing as a withdrawal agent (for the same reason, methadone and phenobarbital are attractive as agents in opiate withdrawal and sedative-hypnotic withdrawal).

When discontinuing treatment with a benzodiazepine abruptly, the speed of onset and the severity of symptoms are greater for benzodiazepines with shorter elimination half-lives (e.g., alprazolam or lorazepam) than for those with a longer half-life (such as clonazepam). However, abrupt discontinuation is not an appropriate medical treatment for benzodiazepine discontinuation after prolonged, everyday use. When short-acting benzodiazepines are withdrawn gradually over several weeks or longer, they do not produce more symptoms of withdrawal than do longer acting benzodiazepines (Sellers et al., 1993).

Although a long half-life may be beneficial in reducing the speed of onset and severity of benzodiazepine withdrawal on abrupt discontinuation, it can be more problematic in other situations. An increase in motor vehicle crash involvement was found in elderly persons using long half-life benzodiazepines, whereas use of shorter half-life benzodiazepines showed no increase in the probability of crashes in elderly persons compared to same-age persons who did not use a benzodiazepine (Hemmelgarn, Suissa, Huang, Boivin, & Pinard, 1997; Wang, Bohn, Glynn, Mogun, & Avom, 2001).

Reinforcement

Three additional aspects of benzodiazepine pharmacology are relevant to the treatment of addicted patients: reinforcement, withdrawal, and tolerance. Reinforcement is the potential for these medicines to be abused or "liked" by alcoholics and drug addicts. In controlled studies, benzodiazepines are not reinforcing or "liked" by either normal or anxious subjects. For example, normal and anxious subjects, given a choice between placebos and benzodiazepines, more often choose the placebo in double-blind acute dose experiments, regardless of the specific benzodiazepine given. In contrast, subjects with a history of addiction in double-blind studies prefer benzodiazepines—especially at high doses—to placebos. Studies have demonstrated that people with a history of addiction show a greater preference for intermediate-acting barbiturates and stimulants, as well as narcotics, than for benzodiazepines. Thus, the benzo-diazepines are reinforcing for alcoholics and drug addicts (though not for anxious people or for people who do not have a history of addiction). The benzo-diazepines are relatively weak reinforcers compared to opiates, stimulants, and barbiturates among alcoholics and drug addicts.

This research confirms the common clinical observation that benzo-diazepines are rarely drugs of choice among addicted people for their euphoric effects (DuPont, 1984, 1988). Although it remains unclear why alcoholics and drug addicts react differently to the benzodiazepines than do normal or anxious subjects, this phenomenon exists with all abused drugs. It is not limited to the benzodiazepines. Normal subjects in double-blind studies do not generally "like" abused drugs, including stimulants, narcotics, and even alcohol. People who are not addicted to alcohol and other drugs do not like the feeling of being intoxicated. Whether addicted people learn to like the intoxicated feeling or whether they have some innate (perhaps genetically determined) difference that explains this characteristic response to alcohol and controlled substances remains an unanswered question of great importance to the prevention of addiction.

When it comes to the outpatient treatment of anxiety in patients with active addiction (e.g., current or recent abuse of alcohol or other drugs), the use of a controlled substance, including benzodiazepines, is generally contraindi-

cated. A number of alternative treatments for anxiety are available, including nonpharmacological treatments, antidepressants, and buspirone (Buspar), a nonsedating antianxiety medicine with no abuse potential. As a general principle, the use of psychotropic medicines, whether controlled (e.g., benzodiazepines) or noncontrolled substances (e.g., antidepressants or antipsychotics), is unlikely to produce a therapeutic benefit for the actively using addicted patient. Stable abstinence is required for these antianxiety medicines to produce therapeutic results.

For patients who have been stable in recovery (including recovering alcoholics) and need treatment for anxiety, it is advisable not to use benzo-diazepines, unless the physician can be sure that the patient uses the benzo-diazepine only as prescribed and in the absence of any nonmedical drug use, including alcohol use. For many recovering people, successful use of benzo-diazepines in the treatment of their anxiety disorders has not threatened their sobriety. We have seen many more patients in recovery who do not want to use any controlled substance and have done well with their anxiety problems, without using a benzodiazepine (Ciraulo et al., 1996; Sattar & Bhatia, 2003).

If a benzodiazepine is to be administered to a recovering person, it may be prudent to use one of the slow-onset medicines (e.g., oxazepam, clorazepate, or prazepam) and to include a family member, as well as the sponsor from a 12-step fellowship in the therapeutic alliance, to help ensure that there is no abuse of the benzodiazepine or any other drug, including alcohol.

Withdrawal

All of the medicines that influence the GABA system show cross-tolerance and similar withdrawal patterns. Because of cross-tolerance within this class of sedatives and hypnotics, an alcoholic or barbiturate addict can be withdrawn under medical supervision using a benzodiazepine. For the same reason, phenobarbital can be used to manage benzodiazepine withdrawal (Wesson, Smith, & Ling, 2003). Compared to other benzodiazepines, however, alprazolam withdrawal may be inadequately covered by substitution. Alprazolam detoxification should include an estimation of daily use and a slow withdrawal over a period of weeks. Clonazepam has been found to be helpful in this condition.

The sedatives/hypnotics withdrawal syndrome, including the potential for withdrawal seizures on abrupt discontinuation, is also a phenomenon of this class of medicines, which argues against abrupt discontinuation of any of these medicines after daily use for more than a few weeks. Cessation of use of the benzodiazepines, along with the other sedatives and hypnotics, can cause withdrawal seizures, because they are potent antiepilepsy drugs that raise the seizure threshold. Medicines that raise the seizure threshold, when abruptly discontinued, produce a rebound drop in the seizure threshold that may cause seizures, even in people who have not previously had an epileptic seizure.

Some recovering people believe that they are more likely to have withdrawal symptoms when they discontinue a benzodiazepine, even if it has been taken within medical guidelines. Research on the topic suggests that this is not the case, but this often contentious issue is best dealt with as an unresolved question in clinical practice.

Tolerance

Tolerance is rapid, and all but complete, to the sedative and to the euphoric effects of the benzodiazepines on repeated administration at a steady dose level for even a few days. This rapidly developing tolerance for both sedation and euphoria/reward is seen clinically when these medicines are used to treat anxiety. Patients often experience sedation or drowsiness when they take their first few benzodiazepine doses, but within a few days of steady dosing, the symptoms of sedation lessen and, for most patients, disappear.

By contrast, tolerance to the antianxiety and antipanic effects of benzo-diazepines is nonexistent. Medical patients who are not alcoholics or drug addicts, and who use a benzodiazepine to treat chronic anxiety, obtain substantial beneficial effects at standard, low doses. They do not escalate their benzo-diazepine doses beyond common therapeutic levels, even after they have taken benzodiazepines every day for many years.

This distinction between the rapid tolerance to the sedating and the euphoric effects and the absence of tolerance to the antianxiety effects of benzodiazepines is important for the clinician. Patients who use benzodiaze-pines to get high typically add other substances and escalate their benzodiaze-pine dose over time. This commonly observed pattern reflects the existence of tolerance to the euphoric effects of benzodiazepines among addicted people. In contrast, typical medical patients using benzodiazepines for their antianxiety effects take them at low and stable doses, without the addition of other drugs, including alcohol.

Some patients who use benzodiazepines daily, even after a long time, do escalate their dose beyond the usually prescribed level, add other drugs (especially alcohol), and/or have a poor clinical response to the benzodiazepine use (inadequate suppression of anxiety). Usually, but not always, these patients have a personal and a family history of addiction to alcohol and other drugs. These same patients sometimes have unusual difficulty in discontinuing their use of benzodiazepines. This group of problems with long-term benzodiazepine use is commonly seen in treatment programs for alcoholics and drug addicts, reinforcing the view in the addiction field that benzodiazepines are ineffective, problem-generating medications, especially after long-term use. Although this pattern of problems exists, it is, in our experience, uncommon in the typical medical or psychiatric practice dealing with anxious patients who do not have a history of addiction. Nevertheless, when it occurs, the best response is discon tinuation of benzodiazepine use. For some patients, this requires inpatient treatment.

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