Rate of Benzodiazepine Use in Alzheimer's 'Alarming'

Pauline Anderson

November 10, 2015

Benzodiazepines, which are typically prescribed to treat anxiety, agitation, and sleep disturbances, are not recommended in patients with dementia, but a new study shows that more patients with Alzheimer's disease (AD) take these drugs than people without this disorder.

"This is especially alarming when you look at when these patients are starting to take benzodiazepines; they're starting to use them even before the diagnosis of Alzheimer's disease," said Sirpa Hartikainen, MD, professor, geriatric pharmacotherapy, University of Eastern Finland, Kuopio, told Medscape Medical News.

"It means that in a way, these people are being treated on the basis of symptoms such as behavioral disturbances, and not on the basis of the real disease." Cholinesterase inhibitors (ChEIs) are the first-line pharmacologic treatment for AD, he noted.

The study was published online October 17 in the Journal of Alzheimer's Disease.

Community-Dwelling Patients

The analysis used the Medication use and Alzheimer's disease (MEDALZ) cohort, which captured all Finnish residents diagnosed with AD between 2005 and 2011. It included 51,981 community-dwelling patients with AD as well as 4 controls for each patient, matched for age, sex, and region of residence, for a total cohort of 211,955.

Researchers collected registry data on drug use from 1995 to 2012. They categorized lorazepam, oxazepam, and temazepam as medium-acting benzodiazepines and alprazolam, chlordiazepoxide, diazepam, and nitrazepam as long-acting benzodiazepines. Zolpidem and zopiclone were considered as Z-drugs.

Midazolam, triazolam, and zaleplon were excluded from the analyses because these agents were not reimbursed during the study period. Clobazam was excluded because it's indicated only for the treatment of epilepsy.

The investigators defined the 5-year incidence of benzodiazepine use as having purchased at least one of the included drugs during this period. They calculated incidence rates (IRs) for each 6-month interval during the follow-up as a rate per 100 person-years. The comparison between IRs of patients with AD and controls was reported as IR ratios (IRRs).

To exclude prevalent benzodiazepine users from the analysis, investigators used a 1-year washout period for these drugs. The washout period began 3 years before and ended 2 years before the diagnosis of AD.

The analysis showed that 25.7% of patients with AD and 16.9% of controls initiated benzodiazepine use during follow-up (P < .0001). Benzodiazepine users were more likely to be women and have a higher Charlson comorbidity index (CCI), and rates of cardiovascular diseases, asthma/chronic obstructive pulmonary disease, hypothyroidism, and history of psychiatric disorders.

The IR of benzodiazepine use was higher in patients with AD starting from 12 months before the diagnosis of AD, and the difference remained significant until the end of the follow-up.

The difference between the IRs of benzodiazepine use was highest at 6 months after the diagnosis (11.2/100 person-years for patients with AD vs 4.1/100 person-years for controls; IRR: 2.6 [95% confidence interval, 2.48 - 2.76]).

Benzodiazepines used by patients with AD were mainly medium-acting drugs, which have a smaller risk for accumulation because of delayed elimination and associated excess daytime sedation.

Patients with AD were more likely to be treated with benzodiazepines along with other drugs. The incidence of polypharmacy, defined as concomitant use for at least 60 days (to distinguish it from drug switches), was twice as high in this population compared with controls.

This higher prevalence of benzodiazepine polypharmacy raises concerns because AD itself is a risk factor for falls and fractures, as are benzodiazepines, which can affect gait and balance. "These drugs increase the risk of falling and that might lead to a disaster because if you get a hip fracture, you might be at higher risk for mortality," said Dr Hartikainen.

For this reason, said the authors, these drugs as well as psychotropic polypharmacy should be avoided in this population.

Older people are more sensitive to the central nervous system effects of benzodiazepines, which may also cause daytime sleepiness and impair alertness.

"If you have memory problems, you should practice your cognitive skills, but when you're drowsy, you can't do this," said Dr Hartikainen.

Adding a benzodiazepine to the first-line ChEI treatment may hinder monitoring the effectiveness of ChEIs because benzodiazepines are associated with cognitive decline in patients with AD, according to the authors.

If ChEIs are not effective, benzodiazepines can be used in infrequent or short-term treatment of anxiety and agitation, they said. But they noted that benzodiazepines may actually worsen behavioral symptoms.

Although AD diagnostic practices in Finland are "quite good," it seems that there's still a delay in linking behavioral and psychological symptoms to AD, said Dr Hartikainen.

As well, she said, Finland has a "long history of using benzodiazepines more commonly than in other countries."

Dr Hartikainen is keen to raise awareness among researchers and clinicians, as well as among family members, about inappropriate use of benzodiazepines.

In the study, the IR of Z-drug use in patients with AD was higher from the diagnosis to 18 months after diagnosis compared with controls.

Limitations of the study were that the register-based data didn't include benzodiazepine use during hospital care or nursing home stays or contain indication for benzodiazepine use. As well, the study lacked information on severity of AD and behavioral and psychological symptoms of dementia.

Asked to comment on the study, David Knopman, MD, Mayo Clinic, Rochester, Minnesota, and vice chair, Alzheimer's Association Medical and Scientific Advisory Council, said he "certainly" agrees with the authors that benzodiazepines should generally not be used in people with dementia.

"In my experience, they worsen memory, increase risk for falls, and in chronic use they don't have much benefit on anxiety," said Dr Knopman. "They're not good at all for the treatment of agitation."

According to the Alzheimer's Association, nonpharmacologic approaches should be tried as a first-line alternative to pharmacologic therapy for the treatment of behavioral and psychotic symptoms. Such therapies could include validation therapy, which is based on accepting the perception of reality of the person with dementia, and redirection techniques that divert the attention of patients with AD away from stressful events that may trigger unacceptable behaviors.

The Association recommends training and education for both professional and family caregivers on these interventions, Dr Knopman said.

Dr Hartikainen has disclosed no relevant financial relationships.

J Alzheimers Dis. Published online October 17, 2015. Abstract

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