The prevalence of anxiety disorders per se in the elderly is unknown, but has been estimated at about 3%.] However, anxiety as a complaint is one of the most common problems for which elderly patients seek psychiatric help. The elderly also are prone to a host of medical problems that may cause anxiety, some of which may be amenable to adjunctive treatment with benzodiazepines. In addition, these agents are widely prescribed for other indications in the geriatric population, including agitation, insomnia, and nocturnal myoclonus, to name a few.
It is generally believed that new onset of anxiety disorders in old age is relatively rare. However, older adults present with anxiety in a variety of contexts, such as an underlying depressive disorder. In addition, some elderly patients are unwilling or unable to describe an uncomfortable affect as such, and will instead complain of headache, musculoskeletal pain, or other somatic symptoms.2 Salzman has stated that in the elderly "anxiety symptoms are invariably mixed with symptoms of depression, physical disorders, and even cognitive dysfunction."3 As in younger individuals, ruling out organic pathology, such as hyperthyroidism, silent myocardial infarction, pulmonary embolus, congestive heart failure, or medication effect is the first order of business.
In addition to depression, other psychiatric disorders may present with prominent anxiety symptoms. Schizophrenia and delusional disorders are often accompanied by significant anxiety, although these diagnoses will usually be fairly apparent once psychotic symptoms are evident. Somewhat less obvious is the elderly person with a very early, mild dementing illness, who may show nervousness, perplexity, and psychomotor restlessness.
As a result of such factors, benzodiazepines are very frequently prescribed for elderly patients. Ray et al4 found that 3.7% to 5.8% of hospitalized Medicaidenrollcd elderly subjects were taking long half-life (i.e.. >24 hours) benzodiazepines, and 2.6% were taking short half-life (i.e., <24 hours) benzodiazepines. Another study of nursing home residents found that 20% of them were receiving a benzodiazepine; 30% of these residents were prescribed long-acting agents.5
There are several clinically relevant normal and pathological physiologic changes that accompany the aging process of which the clinician must be aware in order to use benzodiazepines effectively and safely in this population. As will be discussed, the long- versus short-acting distinction has important implications when considering the use of benzodiazepines in the elderly.
PHARMACOKINETIC AND PHARMACODYNAMIC ISSUES
Age-Related Pharmacokinetic Changes
In comparison to young adults, the pharmacokinetic characteristics of benzodiazepines are altered among elderly adults in two major ways. First, the volume of distribution for benzodiazepines is increased in elderly adults. The increase in the proportion of body fat that generally occurs with aging and the lipophilic nature of benzodiazepines contribute to this change. Second, the rate of hepatic oxidative metabolism declines with aging. This results in the prolongation of the elimination half-lives for benzodiazepines that are metabolized primarily by oxidative processes (Table 1). In contrast, hepatic conjugation appears relatively unchanged with aging. The half-lives of the hepatically conjugated benzodiazepines lorazepam, oxazepam, and temazepam are similar for young and elderly adults.6,9
The accumulation index is a function of both half-life and dosing interval and describes the relative extent of drug accumulation.1" Because of longer half-lives, the magnitude of benzodiazepine and benzodiazepine metabolite accumulation is increased in the elderly. For example, desmethyldiazepam is an active metabolite of halazepam, chlordiazepoxide, clorazepate, diazepam, and prazepam (Table 1). When any one of these drugs is given every 12 hours, the accumulation index for desmethyldiazepam is approximately 15. This means that the amount of desmethyldiazepam in the body at steady state increases 15-fold relative to the amount from a single dose. The extent to which drug accumulation contributes to adverse effects from benzodiazepines in the elderly is not totally defined,111'' but may result in prolonged adverse effects, particularly sedation and cognitive impairment.
Age-Related Changes in Pharmacodynamics
Elderly adults appear to be more sensitive than younger adults to the therapeutic and adverse effects of benzodiazepines. The responsiveness of elderly adults may result from increased intrinsic sensitivity, i.e., altered pharmacodynamics, in addition to changes in pharmacokinetic factors.14
Reidenberg15 measured plasma diazepam concentrations in a series of patients undergoing elective cardioversion. The dose of intravenous diazepam administered prior to cardioversion was titrated so that patients were unresponsive to verbal stimulation but responsive to painful stimulation. Both the plasma diazepam concentration and the diazepam dose necessary to produce this effect were found to be negatively correlated with patient age. Similar results have been reported with intravenous diazepam in a group of patients undergoing dental procedures or endoscopy."' In both studies, elderly patients required lower plasma diazepam concentrations than younger adults to achieve a given level of sedation.
Comparison of Benzodiazepines
Numerous medications have been reported or suspected to interact with benzodiazepines.1' Cimetidine, erythromycin, fluoxetine, isoniazid, and omeprazole appear to inhibit hepatic microsomal enzymes and, as a result, reduce hepatic clearance and increase plasma concentrations of some of the oxidatively metabolized benzodiazepines (Table 1). Sedative effects of benzodiazepines may be increased with acute ethanol ingestion and decreased with chronic ethanol use. Theophylline may antagonize the sedative effects of diazepam.
PROBLEMS ASSOCIATED WITH BENZODIAZEPINE USE IN THE ELDERLY
It is well established that benzodiazepines may have an adverse effect on memory and certain other cognitive functions. In the elderly, these drugs may induce amnesia, particularly anterograde, 1H as well as cause psychomotor slowing and delayed recall.19 In some cases, these adverse CNS effects include confusion, disorientation, agitation, and wandering behavior, which may resemble dementia.8
Many investigators also feel that benzodiazepines interfere with the memory consolidation process, and can thus impair long-term memory as well as recent memory. In one study of 308 patients with global cognitive impairment, the use of long-acting benzodiazepines was found to be the commonest cause of excess morbidity20 AU subjects taking long-acting benzodiazepines improved after being taken off the drugs, although most remained demented.
The literature is divided, however, about which benzodiazepines are most likely to cause cognitive dysfunction. Some feel that short-acting agents are most prone to cause this problem,2 whereas others relate the side effect as a function of affinity for the GABA receptor, i.e., potency.18 Perhaps most accurate is the statement that "all benzodiazepines probably can affect memory"21 There is some evidence that patients may develop partial tolerance to the cognitive side effects of benzodiazepines.19
In addition, elderly patients are subject to withdrawal delirium when benzodiazepines are abruptly decreased in dose or discontinued. Thus, such changes should be accomplished gradually.
Falls and Hip Fractures
In recent years a number of reports have suggested an increased risk of falls and hip fractures in the elderly who take benzodiazepines. One often-cited study found a 70% increase in the rate of hip fractures in users of long half-life benzodiazepines, but no increase in hip fractures with short-acting agents.1 However, another study of 174 women with hip fractures and 174 controls failed to find any such association with the use of longeracting versus shorter-acting benzodiazepines.22 If benzodiazepines do contribute to an increase in falls and fractures, this effect is likely to be related to sedation, ataxia, or psychomotor slowing.19
While the benzodiazepines have a relatively low risk of causing respiratory depression, especially in comparison with older sedative-hypnotic agents such as barbiturates, some clinicians remain reluctant to use benzodiazepines in patients with chronic obstructive pulmonary disease (COPD) and other lung disease because of fear of this complication. One author19 notes that benzodiazepines may actually worsen anxiety in COPD patients. However, Salzman21 states, "Judicious low doses of benzodiazepines will not adversely affect respiration, even in the elderly patient with COPD." Nevertheless, it would be prudent to use low doses of short-acting benzodiazepines for elderly patients with COPD if an anxiolytic is indicated.
On the other hand, there is genuine cause for concern when using benzodiazepines in patients with sleep apnea, as these drugs may worsen apnea19 and thus cause hypoxia or perhaps death in susceptible individuals.
There are two types of sleep apnea, obstructive and central23; in both types, sleep is accompanied by episodes of apnea lasting 10 seconds or longer, and the affected person may complain of fragmented sleep and daytime tiredness. In obstructive sleep apnea, respiratory efforts are met with resistance, thought to be from redundant tissue in the posterior pharynx. Bed partners may complain that the person with obstructive sleep apnea snores loudly and has frequent awakenings at night.
Conversely, in central sleep apnea, no respiratory effort is made during the apneic episode, presumably as a result of CNS pathology. Although central sleep apnea may be more susceptible to the respiratory depressant effects of sedativehypnotics, most psychopharmacologists recommend avoiding benzodiazepine use in patients with known or suspected sleep apnea of either type. Interestingly, however, there is a report of successful use of clonazepam for treatment of central sleep apnea associated with nocturnal myoclonus,24 which brings into question some of the conventional wisdom regarding benzodiazepine use in patients with sleep apnea.
Benzodiazepines may cause respiratory depression in the absence of an existing sleep apnea or respiratory disorder. Sullivan25 reported a case of an 83-yearold woman who received a single dose of 0.5 mg triazolam, and who subsequently became stuporous and hypoxic, requiring intubation and ventilatory support for 36 hours. The author speculates that a contributing factor was concurrent use of erythromycin, which impairs hepatic biotransformation and may have led to benzodiazepine toxicity on that basis.
Occasionally, patients receiving a benzodiazepine will become agitated, belligerent, enraged, and even assaultive. This effect is also referred to as "disinhibition," presuming interference with physiologic mechanisms that normally prevent such outbursts. A number of reports suggest that patients with preexisting brain damage (e.g., from dementia, strokes, or trauma) are more susceptible to this effect.2,3,8
As noted above, long-acting benzodiazepines are associated with a number of potentially serious side effects in elderly patients. Such short-acting agents as lorazepam, oxazepam, and alprazolam are better tolerated. As shown in Table 1, starting doses would be 0.5 mg lorazepam, 15 mg oxazepam, or 0.25 mg alprazolam one to three times daily. Because the elimination half-life of any hepatically metabolized drug is likely to be increased to some extent in an elderly patient, the time required to reach steady state is likewise increased. As a result, the clinician should avoid making rapid dosage increases but instead wait a week or more to be able to adequately assess the effect of a particular dose.
Key Points Regarding Benzodiazepine Use in the Elderly
The next question that arises is how long to maintain a patient on a benzodiazepine. The answer to this depends primarily on the indication for the drug. For acute problems (e.g., anxiety related to a specific stressor), short-term therapy is indicated. Under these conditions, a benzodiazepine might be used for a few weeks. Likewise, for anxiety related to a depressive disorder, an adjunctive benzodiazepine might be used for several weeks while the antidepressant takes effect, and then withdrawn.
Clearly, however, there are many patients with long-standing anxiety disorders who will require long-term treatment. Even in these cases, however, the clinician should regularly reevaluate the need for ongoing benzodiazepine therapy, and attempt to either reduce or eliminate the drug perhaps every six months. Significantly, patients with lifelong anxiety disorders often experience a decreased dosage requirement as they age. In any event, as with younger patients, older patients on benzodiazepines for more than a few weeks should be tapered off the drug slowly (e.g., by reducing daily dosage by 10' ? to 25 % every week) if this is necessary to prevent withdrawal symptoms. This is particularly important for patients on short-acting benzodiazepines.
For elderly patients with significant anxiety and mild depressive symptoms, there is evidence that alprazolam alone may treat both disorders. Alprazolam has been shown to prolong REM latency,8 an effect shared by antidepressants, which suggests an independent antidepressant effect of this drug. In a recently published study, Weissman et al26 found alprazolam was in fact an effective antidepressant in the geriatric population.
Agitation is a state of uncomfortable motor drivenness, often manifested by severe restlessness, pacing, swearing, shouting, and/or physical aggression. It may be caused by a wide range of disorders including delirium, dementia, schizophrenia, mania, and many others. Antipsychotics are the most commonly prescribed agents for agitation, but benzodiazepines are also used frequently.
As noted above, patients with underlying brain damage may be at increased risk of behavioral worsening when benzodiazepines are used to treat agitation, although the risk of paradoxical excitation is still fairly low. After first excluding acute organic causes of agitation (e.g., metabolic abnormalities, infection), use of a short-acting benzodiazepine may be considered. Other options for patients unresponsive to or intolerant of benzodiazepines include trazodone, buspirone, lithium, beta blockers, and carbamazepine.
The elderly are predisposed to a host of sleep problems. Some relate to misinterpretation of normal changes in sleep architecture with aging, others to the presence of chronic medical conditions. Thus, elderly patients often complain of insomnia and request a "sleeping pill." As with younger adults, the sleep complaint should be evaluated and remediable illnesses sought before prescribing a drug. Sleep apnea is a common problem in the elderly, and often leads to complaints of daytime somnolence and nocturnal insomnia. Other sleep-related disorders include nocturnal myoclonus and restless legs syndrome, which may respond to clonazepam.
When medication is indicated for insomnia, short-acting (e.g., triazolam) and intermediate-acting (e.g., temazepam) benzodiazepines are generally preferred. Due to recent studies that report adverse reactions to triazolam, including amnesia, anxiety, and rebound insomnia,27 Greenblatt et al7 suggest initiating triazolam at the lowest available dose in the elderly, 0.125 mg. There is little, if any, role for the use of long-acting benzodiazepines such as Flurazepam or quazepam in the elderly, in light of potential side effects attributable to their accumulation. Indeed, one of the authors (SPW) recently treated a 76-year-old gentleman with delirium, ataxia, and severe functional impairment caused by quazepam; within a week after its withdrawal, the patient became much more alert, conversant, and oriented, and his gait improved to the point that he was no longer wheelchai r-bound.
Another important point regarding benzodiazepines as hypnotics is the recommendation by most authorities to use these drugs for relatively brief periods, e.g., a few weeks while a stressor is resolving. For patients with long-standing insomnia, there are a variety of behavioral treatments that may be more appropriate than long-term use of benzodiazepines.28
Because of pharmacokinetic and pharmacodynamic changes with aging, the frequent presence of multiple medical problems, polypharmacy, and other issues, benzodiazepines must be used with special care in the elderly. If so used, benzodiazepines can be helpful, usually on a short-term basis, to improve quality of life.
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Comparison of Benzodiazepines
Key Points Regarding Benzodiazepine Use in the Elderly