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Study Raises Concerns About Medications Prescribed to Parkinson's Patients with Dementia



DR. ALLISON WILLIS: “Taking a medication that has strong anticholinergic properties is not recommended for older adults in general. But for someone with Parkinsons disease who has lost neurons, who is at great risk for cognitive impairment, they are a big no-no, especially when there are low or no anticholinergic alternatives.”

Researchers reported that many Parkinson's disease are being treated with acetylcholinesterase inhibitors for dementia as well as at least one high-potency anticholinergic medication, which may lead to opposing effects. And these prescribing practices were more common among black and Hispanic patients.

Parkinson's disease (PD) patients who take medication for dementia frequently are on other drugs with pharmacologically opposing effects, a risky combination that could end up making their cognition worse, according to a new study of Medicare patients.

The study in the October 1 online edition of JAMA Neurology found that 44.5 percent of PD patients taking an acetylcholinesterase inhibitor (ACHEI) for dementia were concurrently prescribed at least one high-potency anticholinergic medication — a practice that the study authors described as a “frank prescribing error” and a potential “never event.” Doctors “are giving patients a dementia drug that releases acetylcholine and simultaneously giving them a drug that potentially blocks acetylcholine receptors in the brain. The two drugs can cancel each other out,” said study coauthor Allison Willis, MD, assistant professor of neurology and of epidemiology at the University of Pennsylvania Perelman School of Medicine. “It could be like giving someone a drug to raise their blood pressure while also giving one to lower blood pressure.”

Dr. Willis said she and her colleagues chose the term “never event” to characterize the prescribing practice because it should not happen, especially with PD patients who may be particularly vulnerable to the possible adverse effects of anticholinergic drugs, including diminished cognitive function and falls.

“Taking a medication that has strong anticholinergic properties is not recommended for older adults in general. But for someone with Parkinson's disease who has lost neurons, who is at great risk for cognitive impairment, they are a big no-no, especially when there are low or no anticholinergic alternatives,” said Dr. Willis.


DR. CHARLES H. ADLER: “If a physician chooses to prescribe two competing drugs there needs to be a strong follow-up to check for benefits and unwanted side effects.”


Among PD patients, cognitive impairment is a major driver of loss of independence, nursing home placement, and health care costs, the study authors noted. One in four patients with PD has objective cognitive impairment at the time of diagnosis, and the prevalence of dementia reaches 80- to 90-percent by 12 years after PD diagnosis, they wrote.

But despite how common cognitive impairment is among PD patients, there is little research data in the US on which medications they are given and how prescribing patterns may vary depending on a patient's gender, race/ethnicity, or where they live, the study said. Identifying prescribing shortcomings and fixing them could improve the lives of PD patients, the authors said.

The study authors explained that ACHEIs “improve cognition by increasing cholinergic activity and include the most widely used dementia drug in the world, donepezil hydrochloride, as well as rivastigmine tartrate and galantamine hydrobromide.”

At the same time, drugs that block cholinergic transmission or have anticholinergic activity are widely prescribed by all clinical specialties for a variety of conditions, often unrelated to Parkinson's disease or dementia. Such drugs are among the most popular medications in the world, including oxybutynin chloride, paroxetine hydrochloride, and diphenhydramine hydrochloride.

“In the general adult population, anticholinergic medication use is associated with worse performance on cognitive testing, increased risk of dementia, falls, diminished health-related quality of life, and higher health service utilization,” the study authors wrote. “Patients with Parkinson disease may be even more vulnerable to the adverse effects of anticholinergic drugs because of the disease-related disruption of central cholinergic pathways.”

An accompanying editorial by Christopher Hess, MD, of the University of Florida, and colleagues questioned whether it was an overstatement to say that the dual prescribing of ACHEIs and anticholinergic drugs was an outright “prescribing error” or “never event,” noting that in some patients in some circumstances, using both classes of drugs may be justified. They said concerns about “potentially inappropriate medication prescribing” should not “replace patient-specific clinical judgement.”


The study, funded by the National Institutes of Health, used data from the 2014 Carrier, Beneficiary Summary, and Prescription Drug Event research identifiable files of the Centers for Medicare & Medicaid Services. The data included information on diagnoses, procedures, prescription claims, and patient demographics. The analysis included Medicare patients aged 65 or older with a PD diagnosis and 12 consecutive months of inpatient, outpatient, and prescription drug coverage from January 1, 2014 to December 31, 2014. Patients with other parkinsonian syndromes were excluded.

There were 268,407 Medicare patients with PD, with an average age of 78.9. Of those, 73,093 (27.2 percent) were given a prescription for at least one antidementia medication. The most commonly prescribed drugs were donepezil hydrochloride (63 percent), memantine hydrochloride (41.8 percent), and rivastigmine tartrate (26.4 percent).

Dementia drugs were more likely to be prescribed to blacks and Hispanics, compared to whites, and less likely to be prescribed to Native Americans. Women were less likely than men to be given a prescription.Of 64,017 PD patients receiving an ACHEI, 28,495 (44.5 percent) were also taking at least one anticholinergic drug considered to be “high potency,” according to the Anticholinergic Cognitive Burden Scale, which ranks anticholinergic drugs according to their effects on cognition.

The study found that Hispanics and women were most likely to be on both ACHEI and anticholinergic drugs. There were also geographic differences, shown on a map in the report.

“Statistically significant clusters of the prevalence of this prescribing error were observed across the United States, with clusters of high prevalence in the southern and midwestern states,” the researchers wrote. They said their findings “may serve as national and local targets for improving care quality and outcomes for persons with Parkinson disease.”

The study left many questions unanswered, including the specialty of the prescribing physician — a neurologist, other specialist, or a general practitioner — and whether the PD patients were getting competing medications from the same or different doctor for other medical conditions, such as an endocrinologist or cardiologist.


Chantale Branson, MD, assistant professor of neurology at Morehouse School of Medicine, said the new study highlights an important prescribing concern and raises questions about why there are disparities in prescribing patterns by sex, race/ethnicity, and geography. She said a shortage of neurologists in some areas of the country may be a factor, exposing patients to a more fractured approach to care.

Dr. Branson, who is also an adjunct assistant professor of neurology at Boston University School of Medicine, said the study points to the importance of doctors carefully reviewing with patients the medicines they are taking or have a prescription for. Electronic medical records that include pharmacy information can help flag potential problems, she said.

“Various physicians can be prescribing drugs that interfere with each other, and not know it,” Dr. Branson said. “Neurologists want their patients to see the doctors who take of them, but there needs to be communication [between them].”

Lisa Shulman, MD, FAAN, professor of neurology at the University of Maryland School of Medicine, objected to the study's use of “never event” and “prescribing error” to describe the concurrent use of ACHEIs and anticholinergic drugs, noting that in every prescribing decision “the benefits of a medication are weighed against the risk.”

“More often than not medicine is about individualized and patient-centered care, which is why clinical practice is an art,” Dr. Shulman said.

She described common scenarios, such as when the PD patient being treated for dementia is most troubled by parkinsonian tremors that are best controlled by an anticholinergic drug. Likewise, a patient with urinary urgency and incontinence may be well served by an anticholinergic agent despite the need for treatment of dementia, she said.

“The bottom line is the importance of listening to our patients,” Dr. Shulman said.

Dr. Shulman stressed that she is not discounting the concerns raised by the study, but she said more research is needed to identify the safest and most effective ways to treat PD patients with “combinations of problems.” She said there is not always an alternative drug to consider and certain drugs may be the best choice despite some risk, especially in older patients.

Charles H. Adler, MD, PhD, FAAN, professor of neurology at Mayo Clinic College of Medicine in Scottsdale, AZ, agreed. He said it is not uncommon for PD patients to take medications for hallucinations that are listed as having potential anticholinergic properties, even as they are being treated with an ACHEI for dementia. And numerous comorbidities, such as heart arrhythmias, depression, and seasonal allergies, may involve treating with medications that have some anticholinergic properties.

He said that instead of saying “never,” physicians should carefully review medications a patient is on, from each of their doctors, so that there is “complete knowledge” of possible downsides and risks.

“If a physician chooses to prescribe two competing drugs there needs to be a strong follow-up to check for benefits and unwanted side effects,” Dr. Adler said. For instance, has the patient's confusion or forgetfulness gotten worse since taking a new drug? These and other concerns must be considered, he said.


•. Mantri S, Fullard M, Gray SL, et al. Patterns of dementia treatment and frank prescribing in older adults with Parkinson disease JAMA Neurol 2018; Epub 2018 Oct 1.
    •. Hess CW, Okun MS, Ramirez-Zamora A. Editorial: Challenges in defining inappropriate medication use in Parkinson disease dementia JAMA Neurol 2018; Epub 2018 Oct. 1.