A Review of Long-Term Treatment With the Alzheimer's Disease Drug Donepezil (ARICEPT) Ineffective

Almost 3.0 million prescriptions were dispensed for donepezil (ARICEPT) in U.S. pharmacies in 2003 amounting to retail sales of more than $486 million. At the level of an individual Alzheimer’s disease patient or family, the cost of a one-year supply of donepezil, at a dose of 10 milligrams per day, is $1,872 at a Washington, DC chain pharmacy. Sadly, it appears that this money is wasted according to a long-term study published in the June 26, 2004 issue of the journal The Lancet.

Donepezil belongs to the family of drugs known as acetylcholinesterase inhibitors that also includes rivastigmine (EXELON), galantamine (REMINYL), and tacrine (COGNEX). These drugs increase the level of acetylcholine, a brain transmitter, with the assumption that this might improve Alzheimer’s-associated dementia. We have listed all of these drugs as DO NOT USE drugs because of their lack of clinically important efficacy and in some cases because of safety concerns.

The Lancet study, also known as AD2000 (Alzheimer’s Disease 2000), was conducted in the United Kingdom (UK) and was funded by the British government’s National Health Service. This study was different from those that have been sponsored by the drug companies which manufacture Alzheimer’s disease drugs in that the research subjects were typical patients referred from local clinics and managed by local physicians.

AD2000 involved 283 patients assigned randomly to take donepezil, in a dosage of either 5 or 10 milligrams per day, and 283 patients given a placebo. The main aims of the study were to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioral and psychological symptoms, caregivers’ psychological wellbeing, or delay in institutionalization. The study lasted three years and is the first study of its type, a randomized placebo controlled trial (the scientific gold standard), that looked at donepezil’s effectiveness beyond one year.

The main outcomes of the study, called the primary endpoints, were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). The BADLS is designed to reveal the everyday ability of people who have memory difficulties from various causes. It asks important questions relating to function such as is the individual able to wash regularly and independently; eat appropriately using the correct utensils; and select appropriate clothing and dress without assistance.

No significant difference was seen among patients receiving donepezil and placebo in the rate of entry to institutional care. After one year, nine percent of the donepezil patients and 14 percent of patients given placebo were institutionalized. This was not a statistically significant difference. At the end of the three-year study, 42 percent of patients taking donepezil and 44 percent of those on placebo had been institutionalized.

The results for progression of disability using the BADLS found no statistically significant difference between donepezil and placebo at one year. There were 13 percent of donepezil users and 19 percent of those taking placebo classified as having their disability progress during this time period. At the end of the three-year study, 55 percent of patients taking donepezil and 53 percent of those on placebo were classified as having their disability progress.

Donepezil was found to be statistically better than placebo on a commonly used survey known as the mini-mental state examination (MUSE). The MUSE is a measure of cognitive status in adults. It can be used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual’s response to treatment. Donepezil was 0.8 points better on average than placebo on this 30 point survey.

There was no statistical difference between donepezil and the placebo in behavioral and psychological symptoms, carer psychopathology, cost of care, unpaid caregiver time, adverse effects or deaths.

The AD2000 authors concluded that:

Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer’s disease.

The editorial accompanying The Lancet study from the Department of Psychiatry and the Behavioral Sciences, Department of Neurology at the University of Southern California said:

Results are incompatible with many drug-company-sponsored observational studies and advertisements claiming remarkable effects for cholinesterase inhibitors. For example, claims that donepezil stabilizes cognitive decline, or delays nursing-home placement by 2-5 years now can be seen as implausible in the light of AD2000.

We first listed donepezil as a DO NOT USE drug in the 1999 edition of our book Worst Pills, Best Pills. The basis for this classification was from several sources including the highly respected Medical Letter on Drugs and Therapeutics and the English language French publication Prescrire International.

The Medical Letter editors in their June 6, 1997 review of donepezil said:

“There is no evidence that use of either donepezil or tacrine [a drug we also listed as DO NOT USE] leads to substantial functional improvement or prevents the progression of the disease.”

Prescrire International’s October 1998 review of donepezil found that:

“... the effects of donepezil are moderate and visible only on psychometric scales [surveys]; the possible clinical benefit is unknown. In the long term, donepezil only delays cognitive deterioration by a few months.”

Later research strengthened our original designation for this drug. A statistical summary of clinical trials known as a meta-analysis, conducted by the prestigious Cochrane Collaboration in 2003, found in selected patients with mild or moderate Alzheimer’s disease treated for periods of 12, 24 or 52 weeks that:

“... donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers [care givers] is unclear.”

In the measures that are most important to patients and their families, the results of AD2000 show that long-term treatment with donepezil has no effect on an Alzheimer’s disease patient’s chance of being institutionalized or the progression of their disability. Subjective survey’s show only small changes on numerical scales in patients on donepezil that do not appear to translate to a change that can be recognized by either the patient or a family member.

Donepezil has been deceptively oversold to physicians and patients, perpetuating the exploitation of patients with Alzheimer’s disease and their families.

What You Can Do

Donepezil should not be used because there is a lack of evidence that this drug provides any meaningful benefit to Alzheimer’s disease patients.