A study published in the April 2011 medical journal Archives of Neurology revealed no statistical differences in outcomes between mild Alzheimer’s disease patients treated with memantine (NAMENDA) and those given a placebo. Memantine is not approved by the Food and Drug Administration (FDA) to treat mild Alzheimer’s disease. This finding prompted Public Citizen to revisit the use of memantine and other Alzheimer’s disease drugs and to reiterate why we have listed them as “Do Not Use” drugs...
A study published in the April 2011 medical journal Archives of Neurology revealed no statistical differences in outcomes between mild Alzheimer’s disease patients treated with memantine (NAMENDA) and those given a placebo. Memantine is not approved by the Food and Drug Administration (FDA) to treat mild Alzheimer’s disease. This finding prompted Public Citizen to revisit the use of memantine and other Alzheimer’s disease drugs and to reiterate why we have listed them as “Do Not Use” drugs in Worst Pills, Best Pills News.
Two families of drugs are used for Alzheimer’s disease — the N-methyl-D-aspartate (NMDA) receptor blockers, of which memantine is the only FDA-approved member, and the cholinesterase inhibitors. The table lists the generic and brand names of all of the drugs in the two families (five drugs) currently approved by the FDA for treatment of Alzheimer’s disease in the U.S.
In 2003, the FDA approved memantine for moderate to severe Alzheimer’s dementia, which includes symptoms of memory loss, confusion and disorientation. The Archives of Neurology study reviewed the published medical evidence for the use of memantine for mild Alzheimer’s disease. The use of memantine to manage the mild form of the disease is not FDA approved, a practice therefore referred to as off-label use. However, more than 4 million prescriptions were dispensed for the drug in 2009, totaling more than $670 million, and it is likely that some of these prescriptions were for the unapproved off-label use for mild Alzheimer’s disease.
One theory justifying memantine’s use is that Alzheimer’s disease may be caused, in part, by overactivation of NMDA receptors by the brain transmitter glutamate, which may add to the destruction of nerve cells. Memantine is postulated to work by blocking the NMDA receptors from binding to glutamate, thereby preventing cell death.
The authors of the study found that there were no statistically significant differences between memantine and a placebo for any outcomes measured in the patients with mild Alzheimer’s disease. For those with moderate disease, there were small, statistically significant, but clearly not clinically important differences on two of the four rating scales used to assess the efficacy of drugs for Alzheimer’s disease, and no differences on the two remaining rating scales. The authors concluded, “Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD [Alzheimer’s disease], and there is meager evidence for its efficacy in moderate AD.”
Memantine was not a new drug when it was approved for sale in the U.S. in 2003. It had been marketed in Europe since the 1980s for the treatment of Parkinson’s disease, cerebral and peripheral spasticity, and organic brain syndrome.
The most recent revision of the FDA-approved Patient Package Insert for memantine states, “There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer’s disease.”
This family of Alzheimer’s drugs includes donepezil (ARICEPT), galantamine (RAZADYNE), rivastigmine (EXELON) and tacrine (COGNEX). These drugs inhibit an enzyme that increases the concentration of the chemical acetylcholine in the brain, a malfunction that is thought to play a role in Alzheimer’s disease.
In the October 2005 issue of Worst Pills, Best Pills News, we wrote about an August 5, 2005, British Medical Journal article that reviewed the evidence for donepezil, galantamine and rivastigmine for Alzheimer’s disease. The British Medical Journal authors concluded:
“Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer’s disease is questionable.”
The authors also found that “donepezil, rivastigmine, and galantamine caused a broad spectrum of adverse events — nausea, vomiting, diarrhoea, and weight loss were the most common.”
The following statements appear in the FDA-approved Patient Package Inserts for each of these drugs.
- “There is no evidence that donepezil alters the course of the underlying dementing process.”
- “There is no evidence that galantamine alters the course of the underlying dementing process.”
- “There is no evidence that rivastigmine alters the course of the underlying dementing process.”
A major clinical trial evaluating tacrine found a statistically significant reduction in the decline of cognitive function in patients taking the drug compared to those taking a placebo. However, an editorial accompanying this clinical trial stated that the differences between the placebo and tacrine groups, although statistically significant, were “clinically trivial.”
In a July/August 2003 review of the drug in Prescrire International, a respected, independent source of drug information, the authors found that “it is impossible to confirm that tacrine has any real clinical efficacy.” The Prescrire review described the results of a French study involving 5,000 patients. Nearly half the patients who received tacrine had elevations in liver enzymes, an early sign of potential liver toxicity.
The Patient Package Insert for tacrine carries the same statement as the other cholinesterase inhibitors:
“There is no evidence that tacrine alters the course of the underlying dementing process.”
What can we say about the effectiveness of these other Alzheimer’s disease drugs? Overall, they have no effect on the underlying disease process. The only notable effect appears to be small changes in the scores on some rating scales, changes so small that they are not likely seen by patients’ family members or doctors.
An Alzheimer’s disease expert and professor at the Johns Hopkins University School of Medicine was quoted in a New York Times front-page article on April 7, 2004. He placed the value of the current Alzheimer’s disease drugs in perspective, saying, “You can name 11 fruits in a minute instead of 10. Is that worth 120 bucks a month?”
What You Can Do
You or family members who may have Alzheimer’s disease should not use these drugs. At this time, there are no safe and effective treatments that substantially alter the progression of Alzheimer’s disease.
Consumers may report serious adverse events with any of these drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.
- Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
- Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
- Fax: (800) FDA-0178
- Phone: (800) FDA-1088
NMDA Receptor Blocker
* Do Not Use
** Tacrine is not approved in Europe and is rarely used in the U.S. because of its liver toxicity