Benzodiazepines Plus Opioids, Common Combo in Alzheimer's

Batya Swift Yasgur, MA, LSW

November 29, 2018

One in five patients with Alzheimer's disease (AD) who take a benzodiazepine also take an opioid, results of a large study show.

In the Finnish Medication and Alzheimer's disease (MEDALZ) study, investigators found that one fifth of AD patients who were receiving a benzodiazepine were also taking an opioid. In addition, 50% of concomitant benzodiazepine/opioid users were taking these drugs for an inappropriately prolonged period — more than 3 months — irrespective of their AD status.

Furthermore, AD patients who were taking a benzodiazepine were prescribed stronger opioids than patients who did not have AD.

"Concomitant use of benzodiazepines and opioids was common in people with or without AD, but those with AD were prescribed strong opioids more frequently than comparison persons, and half of concomitant users continued the use of these drugs for more than 3 consecutive months," lead author Niina Karttunen, PhD (Pharm), University of Eastern Finland, Kuopio Research Center of Geriatric Care, told Medscape Medical News.

"Prolonged concomitant use was associated with risk factors such as osteoporosis and a history of hip fracture — these patients are vulnerable to falls and fractures, which are known risks for both drug groups," she said.

The study was published online October 29 in the International Journal of Geriatric Psychiatry.

Widespread, Problematic Use

Benzodiazepines and related drugs (BZDRs) are "widely used in older patients, especially for the treatment of rather common symptoms, such as anxiety and insomnia," the authors write.

However, their use is problematic because they are associated with sedation, dependence, falls, and fractures and are therefore approved only for short-term use (less than 2 - 4 weeks), the authors point out.

Concomitant use of BZDRs and opioid analgesics appears to be rising, further increasing the prevalence of adverse events. Both drug classes cause sedation and dizziness that predispose older people to falls and fractures.

Clinical guidelines advise against coprescribing drugs that act on the central nervous system, and therefore "the concomitant use of BZDRs and opioids in an older population, in which this combination is generally contraindicated, represents a public health issue that is associated with several risks," the authors state.

"Our study group had earlier studied benzodiazepine and opioid use separately, and after that, we were interested in concomitant use of these drugs [but] could not find any report concerning older people with AD, and that motivated us to conduct this study," Karttunen said.

To investigate the question, the researchers used data from the MEDALZ study, which includes all community-dwelling Finnish citizens newly diagnosed with AD during the period 2005-2011 (n = 70,718).

Each AD patient was matched with a comparison person on the basis of age, sex, and region of residence at the date of AD diagnosis.

Data regarding prescriptions and diagnoses were taken from several nationwide healthcare registers.

BZDRs included benzodiazepines and Z-hypnotics; opioids included weak opioids (codeine and tramadol), partial opioid agonists (buprenorphine), and strong opioids (morphine, hydromorphone, oxycodone, fentanyl, dextropropoxyphene, and pentazocine).

Long-term use of BZDRs was defined as continuous use of any BZDR for a period of 180 days or longer. Prolonged concomitant BZDR and opioid use was defined as overlapping use of a BZDR and an opioid for a period of 90 days or longer.

The researchers also gathered data on an array of medical and psychiatric comorbidities, as well as data on socioeconomic status; all were gleaned from national registers.

Surprisingly Common Practice

The current study included 69,353 individuals with AD and 69,353 persons without AD (mean age, 80.0 years; SD, 7.1 years; 65.1% women).

BZDRs were being used by 41% of individuals with AD, compared to 35.3% of those without AD (P < .001).

When the researchers analyzed only the BZDR users, they found that individuals without AD were more likely to be prescribed opioids than were those with AD (31.6% and 21.0%, respectively).

Prolonged concomitant use of BZDRs and opioids (≥90 days) was more common among BZDR users without AD than among those with AD (16.1% vs 10.4%, respectively).

Similar results were obtained if the duration of concomitant use was reduced to between 1 and 89 days (15.6% and 10.4%, respectively).

For people without AD, the median length of concomitant BZDR and opioid use was 224 days (interquartile rate [IQR], 124 - 519); for persons with AD, it was 202 days (IQR, 123 - 406) (P < .001).

The mortality rate was higher for those with AD than for those without AD (26.1% vs 20.7%, respectively), as was the rate of transfer into long-term institutional care (21.2% vs 7.2%, respectively). This shortened the length of follow-up time for those with AD to a median of 1095 days (IQR, 637 - 1698); for those without AD, it was 1370 days (IQR, 781 - 2010) (P <.001).

Patients who used BZDRs and opioids concomitantly, regardless of AD status, were more often older than 80 years, female, and of lower socioeconomic status.

Moreover, such patients had more comorbidities, including cardiovascular disease, diabetes, asthma or COPD, rheumatoid arthritis, osteoporosis, active cancer, depression or bipolar disease, a history of hip fracture, substance abuse, and long-term BZDR use.

In unadjusted as well as adjusted logistic regression models, AD was inversely associated with prolonged concomitant BZDR and opioid use, compared to BZDR use without prolonged concomitant opioid use.

Additionally, female sex, low socioeconomic status, and all comorbidities except schizophrenia were associated with concomitant use in all BZDR users.

The most commonly used drug combinations were a Z-drug with a weak opioid (31.7%) and a benzodiazepine with a weak opioid (29.9%), although people with AD were more frequently prescribed a benzodiazepine with a weak opioid rather than a Z-drug with a weak opioid (27.6% vs 24.8%, respectively).

Additionally, combinations that included buprenorphine or a strong opioid were more common among persons with AD than among those without AD.

Karttunen said she was surprised by the findings.

"I assumed that concomitant use of these drugs is rather common, but it was surprising that about half of all concomitant users were prolonged users who used these drugs for more than 3 consecutive months," she said.

She emphasized that prolonged concomitant use of these drugs "should be avoided, but if the use is necessary in some patients, it should be carefully monitored and terminated as soon as possible."

She added, "all medicines should be reviewed regularly, especially in older persons with impaired cognition."

Try Nonpharmacologic Treatments First

Commenting on the study for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association, who was not involved with the study, said it is "fairly common for people with dementia to end up either overmedicated or undermedicated."

He recommended that nonpharmacologic interventions be tried for agitated patients with dementia prior to initiating benzodiazepine therapy. Such interventions include modifying environmental triggers of the agitation or distracting the person.

The Alzheimer's Association provides a list of nonpharmacologic interventions.

It is important not to "allow the pendulum to swing too far in the other direction," Fargo warned.

Karttunen agreed, stating that nonpharmacologic approaches and antidementia drugs are recommended as first-line treatments of behavioral and psychological symptoms of dementia (ie, restlessness, anxiety, and sleep changes).

No source of funding for the study was provided. Dr Karttunen and Dr Fargo have disclosed no relevant financial relationships. Financial disclosures for other study authors are listed on the original article.

Int J Geriatr Psychiatry. Published online October 29, 2018. Abstract

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