Benzodiazepines, 'z-drugs' increase death risk when taken with opioids

by Vanderbilt University Medical Center

Credit: CC0 Public Domain

A new study by Vanderbilt University Medical Center researchers of more the 400,000 Medicare patients taking medications for insomnia found that the risk of death is increased when either benzodiazepines or 'z-drugs' are taken with opioids.

18 july 2021--The study, published July 15 in PLOS Medicine and led by Wayne Ray, Ph.D., professor of Health Policy at VUMC, compared patients taking these drugs with opioids to comparable patients taking trazodone, another commonly prescribed sleep medication for older patients. The researchers found that those using benzodiazepines had a 221% increase in the risk of death from any cause and those taking non-benzodiazepine hypnotics, or 'z-drugs', had a 68% increased risk.

"Our findings indicate that the risks of benzodiazepine-opioid use go well beyond the recognized hazards of overdose. They also suggest that the z-drugs, thought to have better safety than the benzodiazepines, in fact are dangerous when prescribed in combination with opioid pain medications," Ray said.

Benzodiazepines, including brand names such as Restoril, Ativan, and Halcion and the 'z-drugs', a type of medication known more commonly under names like Ambien, Lunesta and Sonata, are among the most frequently prescribed medications for older adults.

Trazodone, a medication initially introduced for depression, is often prescribed in low doses for insomnia. Although researchers have speculated about the relative safety of these sleep medications, there is limited relative safety data.

Ray said the study findings could help to fill this data gap and thus lead to changes in both provider behavior and policy.

"Our findings add urgency to efforts to limit concurrent prescribing of benzodiazepines and opioids. They also suggest that targeted warnings are needed to advise older patients and their providers regarding the potential risks of taking z-drugs with opioids," Ray said.

The study was supported by a grant from the National Heart, Lung and Blood Institute.

More information: Wayne A. Ray et al, Mortality and concurrent use of opioids and hypnotics in older patients: A retrospective cohort study, PLOS Medicine (2021). DOI: 10.1371/journal.pmed.1003709

Provided by Vanderbilt University Medical Center 

 The danger of Z-drugs for dementia patients

by University of East Anglia

Credit: CC0 Public Domain

Strong sleeping pills known as 'Z-drugs' are linked with an increased risk of falls, fractures and stroke among people with dementia—according to research from the University of East Anglia.

27 nov 2020--Sleep disturbance is common among people with dementia and the impact for patients and their families is significant.

To date there are no proven effective treatments available, however people with dementia are often prescribed Z-drugs (zopiclone, zaleplon, and zolpidem).

But a new study published today reveals that stronger doses of these drugs are linked with an increased risk of adverse effects.

These adverse effects were found to be similar or greater than those for higher dose benzodiazepines or 'benzos' - which are also used to treat sleep disturbance, and are known to have several adverse effects.

The team say that patients already taking higher doses of Z-drugs should not stop taking their medication suddenly, however they should seek a review with their GP.

Prof Chris Fox, from UEA's Norwich Medical School, said: "As many as 90 percent of people with dementia suffer sleep disturbances and it has a big impact on their mental and physical health, as well as that of their carers.

"Z-drugs are commonly prescribed to help people sleep—however these medicines were never licensed for dementia and they have been associated with adverse events such as falls and fracture risks in older people.

"We wanted to find out how they affect people with dementia, who are frequently prescribed them to help with sleep disturbance."

The team analysed data from 27,090 patients in England diagnosed with dementia between January 2000 and March 2016. The average age of the patients was 83 and 62 percent were women.

They looked at the adverse events for 3,532 patients who had been prescribed Z-drugs and compared them to people suffering sleep disturbance who had not been prescribed sedatives, and patients who had been prescribed benzodiazepines.

They also looked to see whether Z-drug dosage played a part in adverse outcomes.

Prof Fox said: "We studied a range of adverse outcomes including fractures, falls, deep vein thrombosis, stroke and death—over two years. And we were particularly interested to see whether higher doses led to worse outcomes."

Higher dose Z-drugs and benzodiazepines were defined as prescriptions equivalent to >7.5mg zopiclone or >5mg diazepam daily.

"For patients prescribed Z-drugs, 17 percent were given higher doses. And we found that these patients on higher doses were more at risk of falls and fractures, particularly hip fractures, and stroke—compared with patients who were not taking any medication for sleep disturbance," said Prof Fox.

Those on lower doses however (<3.75mg zopiclone or equivalent) were not found to have an increased risk of adverse outcomes.

And there were no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs.

Prof Fox said: "This research shows us that higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered.

"Patients already taking higher dose Z-drugs should not stop taking their medication, but we recommend that they should make an appointment to see their GP for a review," he added.

Prof Clive Ballard, of the University of Exeter Medical School, who collaborated on the study, said: "Our findings serve an important caution regarding the harms of sleeping tablets in people with dementia.

"This research is a very timely and unfortunately necessary reminder that sedative medications are not a helpful way to manage social isolation during COVID-19.

"Our study also highlights the importance of research to develop non-drug approaches to help people with dementia to sleep—whether they are at home or in residential care."

Dr. Ian Maidment, Reader in Clinical Pharmacy at Aston University and lead pharmacist on the study stated: "Z-drugs are widely used to treat insomnia in people living with dementia, but are only recommended as a short-term treatment for the maximum of four weeks. Our work shows the importance of clinicians including GPs and pharmacists reviewing patients on long-term Z-drugs."

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More information: 'Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study' is published in the journal BMC Medicine on November 24, 2020.

Provided by University of East Anglia 

Popular sleep medicine puts older adults at risk for falls, cognitive impairment

A new study led by CU-Boulder Associate Professor Kenneth Wright, above, indicates a common sleep medication puts adults more at risk for nighttime falls and potential injuries. Credit: Photo by Patrick Campbell/University of Colorado

Adults who take one of the world's most commonly prescribed sleep medications are significantly more at risk for nighttime falls and potential injury, according to a new study by the University of Colorado at Boulder.

18 jan 2011--The study, which involved 25 healthy adults, showed 58 percent of the older adults and 27 percent of the young adults who took a hypnotic, sleep-inducing drug called zolpidem showed a significant loss of balance when awakened two hours after sleep. The findings are important because falls are the leading cause of injury in older adults, and 30 percent of adults 65 and older who fall require hospitalization each year, said CU-Boulder Associate Professor Kenneth Wright, lead study author.

To measure balance, the research team used a technique known as a "tandem walk" in which subjects place one foot in front of the other with a normal step length on a 16-foot-long, six-inch-wide beam on the floor. In 10 previous practice trials with no medication, none of the 25 participants stepped off the beam, indicating no loss of balance. All participants were provided with stabilizing assistance to prevent falls during the trials, he said.

"The balance impairments of older adults taking zolpidem were clinically significant and the cognitive impairments were more than twice as large compared to the same older adults taking placebos," said Wright, a faculty member in the integrative physiology department. "This suggests to us that sleep medication produces significant safety risks."

The new CU-Boulder study is the first to measure both the walking stability and cognition of subjects taking hypnotic sleep medicines or placebos. In addition to the balance problems caused by zolpidem, the study also showed that waking up after two hours of sleep after taking zolpidem enhances sleep inertia, or grogginess, a state that temporarily impairs working memory. The study participants were given computerized performance tests that involved adding randomly generated numbers.

A paper on the subject was published Jan. 13 in the Journal of the American Geriatric Society. Co-authors included CU-Boulder's Daniel Frey, Justus Ortega, Courtney Wiseman and Claire Farley. The study was funded primarily by the National Institutes of Health.

The effects of sleep inertia even without sleep medication has previously been shown to cause cognitive impairment, said Wright. But when the CU-Boulder study subjects took zolpidem rather than a placebo, the cognitive impairments essentially doubled.

One unexpected study finding was that young people taking placebos appear to be more cognitively impacted by sleep inertia than older adults taking placebos, he said.

A 2006 study led by Wright showed that study subjects who took no sleep medicine and were awakened after eight hours of sleep were more cognitively impaired, for a short period of time, than a totally sleep deprived person.

Several billion doses of zolpidem have been prescribed worldwide, said Wright, who also directs CU-Boulder's Sleep and Chronobiology Laboratory. Zolpidem is a generic drug that is marketed under a number of different brand names, including Ambien, Zolpimist, Edluar, Hypogen, Somidem and Ivedal.

The CU-Boulder team also measured balance and cognition in older adults who took no sleep medication and were kept awake for two hours past their normal bedtime. They found that 25 percent of these older adults failed the tandem walking balance test, which is consistent with what is seen in people who have insomnia. "Just having insomnia itself increases your risk of falls, even without sleep medication," he said.

The finding that zolpidem affected older adults more than younger adults in balance tests may be explained in part by the fact that both groups were given five milligram doses on study nights. While the normal dose for older adults is five milligrams, the standard dosage for younger adults being treated for insomnia is 10 milligrams. "This is an area that needs more study," he said.

The study results showing that both hypnotic sleep medications and sleep inertia cause significant impairment have important public health implications, said Wright. In older adults, falls have caused millions of nonfatal injuries annually and more than 300,000 fatalities worldwide. "Falls can be very debilitating, especially when older people break their hips and require hospitalization, causing their quality of life to go down," said Wright.

In addition, the cognitive impairments caused by both zolpidem and sleep inertia may impact decision-making, including responding to situations like fire alarms and medical emergencies as well as caring for sick children or driving to a clinic or hospital, said Wright.

"One of the goals of this study was to understand the risk of this sleep medication and of sleep inertia on human safety and cognition and to educate adults and health care workers about potential problems," said Wright. "We are not suggesting that sleep medications should not be used, because they have their place in terms of the treatment of insomnia."

One possible solution to reducing falls of older people due to zolpidem, other sleep medications or sleep inertia would be to install bedside commodes for those who frequently wake up in the night to void themselves, said Wright. Additional research is needed on this important public health and safety topic, he said.

Provided by University of Colorado at Boulder

Sleeping Pill Wakes Woman After 2 Years in Coma

Ambien 'mini-miracle' may give more insight into how the brain works, experts say
By Jeffrey PerkelHealthDay Reporter
TUESDAY, March 13 (HealthDay News) -- A dose of the prescription sleep aid Ambien had the opposite effect on one French woman, awakening her from a two-year coma.
The 48-year-old woman suffered from akinetic mutism -- a sort of persistent coma in which the patient is alert but can neither speak nor move. She had lain in this state after sustaining damage to the frontal lobe of her brain due to a lack of oxygen caused by an attempted suicide by hanging.
But one day she was given zolpidem (Ambien) to treat ongoing insomnia.
"Twenty minutes later, her family noticed surprising signs of enhanced arousal," the study authors wrote. "She became able to communicate to her family, to eat without (swallowing) troubles, and to move alone in her bed. These effects started 20 minutes after drug administration and lasted for two to three hours."
After treatment, the patient could walk for short periods, and to speak if prompted, though not spontaneously. "This phenomenon was so reproducible that caregivers used to give her up to three tablets each day without sleepiness as 'side effect,' " the researchers wrote.
Using positron emission tomography (PET) scans, the researchers found that the drug treatment caused the woman's frontal lobes to become "way more active," noted Dr. James Grisolia, a neurologist at Scripps Mercy Hospital in San Diego. He was not involved in the research, which was led by Dr. Christine Brefel-Courbon, of the University Hospital in Toulouse, France.
http://www.healthscout.com/news/1/602688/main.html