Evidence-Based Practice in LTC

Cholinesterase Inhibitors

Appropriate uses in LTC

by Charles Crecelius, MD, PhD, CMD
Medical Director, Delmar Gardens, St. Louis, MO
Member, Caring's Editorial Board

Steven Levenson, MD, CMD
Multi-Facility Medical Director, Baltimore, MD
Chair, Caring's Editorial Board

Common Practice

Cholinesterase inhibitors (including donepezil, galantamine, and rivastigmine) are being prescribed more in nursing homes to treat individuals with dementia. They increase the activity of acetylcholine, an important chemical in the brain, by inhibiting the enzyme that breaks it down. Their appropriate use in individuals with dementia can be beneficial. But their role in treating the nursing home population remains unclear--largely because relevant data are scarce.

Dementia is a general term used to describe a diverse group of illnesses that include cognitive loss. Each cause of dementia has unique features and responds differently to medications. Because behavioral problems are common in individuals with dementia, cholinesterase inhibitors are increasingly used instead of--or in addition to--other medications with other potentially serious side effects.

When used appropriately, cholinesterase inhibitors can be beneficial. But cholinesterase inhibitors are often prescribed regardless of the type of underlying illness. Despite being indicated only for mild to moderate dementia, they may be prescribed regardless of the severity of dementia. They may be continued indefinitely despite functional or cognitive decline or without evidence of measurable functional or cognitive improvement.

Cholinesterase inhibitors may be prescribed without considering nonpharmacologic interventions or the role of the existing medication regimen in causing or exacerbating problematic behavior. Medications that potentially interact with cholinesterase inhibitors, such as anticholinergic agents, are often prescribed simultaneously. Relative contraindications to the use of cholinesterase inhibitors may be overlooked. Subsequent treatment failures can be attributed to poor prescribing.

The potential of cholinesterase inhibitors to cause significant adverse drug reactions or drug interactions may be overlooked. Example: They can cause increasing apathy, delirium, paranoia, nausea, anorexia, and weight loss. They may be continued indefinitely despite functional or cognitive decline or without evidence of measurable functional or cognitive improvement. All too often, residents are continued on them without regard to appropriateness. Sometimes residents continue taking cholinesterase inhibitors until they can no longer swallow. The failure to recognize their limitations and identify their adverse effects can cause resident decline and diminish quality of life.

Often, the effectiveness of cholinesterase inhibitors is not assessed or documented. Nurses and physicians may assume that their efficacy cannot be readily measured or may not know how to measure it appropriately. Helpful historical information about the prior use and effectiveness of these medications rarely accompanies new admissions to nursing homes.

The Evidence

Cholinesterase inhibitors have been available since 1993, with increasing use both in and outside of the nursing home. They have been extensively studied in the outpatient setting, and are well accepted as having a limited but statistically significant effect on cognition, global functioning, activities of daily living ability, behavior, and caregiver burden. Relatively little data exist regarding their effectiveness in the nursing home population.

It is crucial to accurately diagnose the underlying cause of dementia because cholinesterase inhibitors are only approved for individuals with Alzheimer's disease. Some preliminary data suggest possible value in treating individuals with Lewy body dementia and vascular dementia with cholinesterase inhibitors, but a recent FDA application for the latter indication was rejected pending further study. Cholinesterase inhibitors have proven ineffective in individuals with frontotemporal dementia and in Parkinson-related dementia.

In various trials, cholinesterase inhibitors have stabilized cognitive function and activities of daily living for an average of one year in community dwelling Alzheimer's disease patients with mild to moderate disease. Several studies (conducted primarily in relatively healthy individuals with little resemblance to the typical nursing home resident) have suggested that these medications may stabilize undesired behaviors and reduce caregiver time and burden--although these are not FDA-approved indications.

To date, there is only one study of treatment of nursing home residents, involving donepezil in a placebo-controlled, double-blinded trial. As measured by the Neuropsychiatric Inventory, only the score for agitation/aggression behavior was statistically affected by active treatment.

By the study's conclusion, mini-mental status exam score and Physical Self-Maintenance Scale score did not improve significantly. The cholinesterase inhibitor produced a small improvement in global function (based on the Clinical Dementia Rating--Sum of the Boxes).

Acetylcholine is a key chemical compound of the parasympathetic nervous system. It directly or indirectly affects many bodily organs, including the brain, gastrointestinal tract, heart, and bladder. Therefore, any medication--including cholinesterase inhibitors--that either inhibits or augments acetylcholine can potentially affect various body functions.

The only absolute contraindication to using cholinesterase inhibitors is hypersensitivity to the drug or derivatives. But they should be used cautiously in those with severe liver disease, peptic ulcer disease, asthma, chronic obstructive pulmonary disease, current alcoholism, or previous difficulty tolerating other cholinesterase inhibitors.

Adverse reactions to cholinesterase inhibitors may arise because of increased cholinergic activity on the gastrointestinal tract. The side effects may vary with the medication and dosage used. They must be identified and taken seriously, as they may or may not subside over time.

Nausea is the most common side effect of cholinesterase inhibitors, with an incidence ranging from 17% to 47%. Incidence of vomiting and diarrhea vary from 6% to 31%, and anorexia from 7% to 17%. Insomnia, which is often overlooked, is reported to range from zero to 14%, depending on the drug used. These problems can be significant, especially in frail elders with compromised nutritional status due to comorbid conditions.

Conclusions & Recommendations

Cholinesterase inhibitors have proved relatively effective in community living elders, with about one-fourth responding significantly and another half showing some stabilization. Clinical trials in nursing home residents are minimal and show only marginal results to date.

The use of cholinesterase inhibitors in individuals with advanced dementia is questionable. There is little evidence of significant effect on cognition, function, or behavior in nursing home residents with severe dementia. Current guidelines suggest that cholinesterase inhibitors be discontinued or not initiated at this stage. If they are used anyway, carefully monitor their efficacy and side effects.

Use cholinesterase inhibitors appropriately. Before starting them in a nursing home patient, identify the individual's baseline cognition, function, and behavior to permit subsequent comparison. Establish measurable objectives; for example, improvement by one level in activity of daily living, increased independence, or reduction in their frequency of verbal aggressive outbursts.

Before using cholinesterase inhibitors to address problematic behavior, carefully review possible underlying causes, such as adverse side effects of the patient's existing medication regimen. If an individual benefits from a cholinesterase inhibitor, cognition and function may return to baseline levels if the medication is stopped. If there is no objective evidence that a patient receiving an optimal dose of a cholinesterase inhibitor has measurably improved cognition, behavior, or function, then reconsider the use of the cholinesterase inhibitor.

Avoid using anticholinergic drugs (those that oppose the cholinergic nervous system) in individuals with dementia because they may adversely affect cognition. This is especially true when using cholinesterase inhibitors to attempt to improve cognition, function or behavior.

Example: Avoid anticholinergic medications to treat overactive bladder or gastrointestinal symptoms. It makes little sense to stimulate neurotransmitters with one medication while suppressing them with another.

Don't underestimate the potential for side effects related to cholinesterase inhibitors. Individuals with dementia often can't report symptoms reliably. Therefore, they depend on others to recognize a condition change and seek its underlying causes.

If significant symptoms occur that could be related to a cholinesterase inhibitor, consider tapering or stopping other medications in the regimen that may cause the symptoms or interact with or oppose the action of the cholinesterase inhibitor. If that is unsuccessful, then the cholinesterase inhibitor may be the problem. Adding other medications may only expose the individual to more serious side effects.

Example: If someone receiving a cholinesterase inhibitor falls repeatedly or develops insomnia, anorexia, or unplanned weight loss, then suspect the cholinesterase inhibitor as a possible cause or contributing factor. The cholinesterase inhibitor can always at least be stopped and restarted later, if appropriate. Often, unless the cholinesterase inhibitor is suspected and adjusted at least on a trial basis, the symptoms persist or worsen and may lead to additional complications.

Memantine, a medication recently approved to treat individuals with dementia in the United States, works differently than the cholinesterase inhibitors by inhibiting a specific brain receptor site.

Approved for use in individuals with moderate to severe dementia, it can be used alone or combined with a cholinesterase inhibitor. Because of the advanced dementia of many nursing home residents and the potential risks of multiple medications with central nervous system effects, careful study of the appropriate use of memantine is still needed, however.

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