Tag: Lunesta

07/2/19

Nightmares with Z-Drugs

© alphaspirit | stockfresh.com

The FDA announced it will require that a boxed warning be added to the prescribing information and the Medication Guides for certain prescription insomnia medications because of the dangers of complex sleep behaviors such as “sleepwalking, sleep driving and engaging in other activities while not fully awake.” Some deaths have been reported. “These behaviors appear to be more common with zopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist) than other prescription medicines used for sleep.” Additionally, the FDA will require a “Contraindication,” their strongest warning to avoid using these medications in patients who previously experienced an episode of complex sleep behavior while taking them. All three so-called z-drugs—zaleplon, zolpidem and zopicione—are currently Schedule IV controlled substances (as are benzodiazepines), ostensibly with a lower risk of abuse relative to substances in Schedule III.

Serious injuries and death from complex sleep behaviors have occurred in patients with and without a history of such behaviors, even at the lowest recommended doses, and the behaviors can occur after just one dose. These behaviors can occur after taking these medicines with or without alcohol or other central nervous system depressants that may be sedating such as tranquilizers, opioids, and anti-anxiety medicines.

The New York Times quoted Dr. Irene Rosen, a professor of clinical medicine at the University of Pennsylvania, and former president of the American Academy of Sleep Medicine as being surprised the warning is just coming out now. “This is something I’ve been telling my patients for the last 15 years, and in the sleep community this is well known. And I’d like to think we’ve done a good job putting the news out there, that these drugs have some risks.” These “z-drugs” are not on the hospital formulary at the University of Pennsylvania because of their association to sleepwalking, falls and other concerns. The overall risks are not well-known, as incidents are rare or rarely reported. The FDA said:

These cases included accidental overdoses, falls, burns, near drowning, exposure to extreme cold temperatures leading to loss of limb, carbon monoxide poisoning, drowning, hypothermia, motor vehicle collisions with the patient driving, and self-injuries such as gunshot wounds and apparent suicide attempts. Patients usually did not remember these events. The underlying mechanisms by which these insomnia medicines cause complex sleep behaviors are not completely understood.

About one in eight people with sleeping problems report using these drugs. Among individuals of retirement age, more than 33% report taking a sleeping aide. “Prescriptions for sleeping pills grew to more than 20 million in 2010 from 5.3 million in 1999, according to national estimates.” The FDA announced prior concerns with these insomnia medications in May of 2013 (approved lower recommended doses for zolpidem) and May of 2014 (risk of next-morning impairment with zopiclone; lowered recommended dose). “We are continuing to monitor the safety of insomnia medicines and will update the public as new information becomes available.”

A study published in JAMA Internal Medicine, “Assessment of Patterns of Potentially Unsafe Use of Zolpidem,” found that over ¾ of zolpidem (Ambien) users do not follow FDA recommendations to reduce the risks of side effects and drug dependency. The following three recommendations were given by the FDA when taking zolpidem. First, only use it short-term because long-term use leads to a loss of effectiveness. Second, use lower doses (5mg) for women and adults 65 and older due to higher blood concentrations, which can be 45% to 50% higher. Third, because of increased risk when combined with other central nervous system (CNS)-depressant drugs, limit their combined use.

Mad in America reported that the researchers found that 77.4% were not observing 2 or more of the recommendations. Women were almost twice as likely to use zolpidem and 64% of adults 65 and over were taking higher than recommended doses. Further, 68% used zolpidem for over 60 days and among those who used it for a sustained time period, 41% were also taking another CNS-depressant. “26% combined zolpidem with an opioid.”

These findings are especially concerning since zolpidem use results in more emergency department visits due to adverse effects than any other psychotropic drug. The findings also suggest women are at higher risk for adverse effects, given their higher rates of zolpidem use and that women’s bodies take longer to clear the drug from their system, resulting in 45% higher blood concentrations.

Z-drugs emerged in the late 1980s and early 1990s when zopicione (Imovane) and zolpidem (Ambien) were approved. In 1999 the FDA approved zaleplon (Sonata) and in 2005 it approved zopicione (Lunesta). In 2012 the FDA approved Intermezzo, a half-strength dose of zolpidem for middle-of-the-night insomnia. They are categorized as nonbenzodiazepines, acting as specific agonists of the GABAA receptors, while lacking the fused benzene and diazepine rings of benzodiazepines. Common adverse effects include drowsiness, amnesia, paresthesias (a burning or prickling sensation), abnormal vision, dizziness, headache, hangover effect, rebound insomnia and confusion.

A 2012 study published in BMJ Open, the BMJ’s Open Access Journal, found that any patient prescribed a hypnotic drug like zolpidem had elevated hazards of dying compared to those who were not prescribed hypnotics. Receiving a hypnotic prescription was associated with greater than a threefold increased of death, even when prescribed less than 18 pills per year. “Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using <18 hypnotic pills per year.” Commenting on the study, Dr. Peter Breggin said the authors drew no firm conclusions on how the medications caused increased mortality. He believed the impaired judgment caused by all sedating drugs played a role in the death rates. “Because of impaired judgment, these drugs often lead to unintentional overdose.” The BMJ study concluded:

Excess mortality is associated with hypnotic use. Hypnotic users had more prevalent disease of many sorts than non-users before hypnotics were ordered. However, the consistent results across varying levels of comorbidity and the persistent elevated hazards within strata of users and non-users matched for comorbid diagnoses strongly suggest that neither the level of individual health nor the presence of particular categories of comorbidity explains the bulk of the hazard associated with the use of hypnotic medications.

A 2013 study published in the Journal of Medical Toxicology, “The Clinical and Forensic Toxicology of Z-drugs,” found that z-drugs had few distinct advantages over benzodiazepines, “and in many ways they have similar adverse and toxic effects, especially zopiclone [Imovane].” Adverse drug effects and toxicity were more likely with polydrug use in therapeutics and when co-ingested with psychoactive substances in overdose. Their short half-lives “make them seldom found substances in forensic cases, both in drug-related deaths as well as in drug-facilitated crimes.” There have been several reported fatalities of zaleplon with other drugs, but none have been attributed solely to zaleplon. “This may represent lower zaleplon use or difficulties in measuring zaleplon levels due to its ultra-short half-life and rapid antemortem [before death] metabolism.”

A 2017 review of major adverse events with benzodiazepines and z-drugs in epidemiological research for Drugs in R&D found there was sufficient, converging evidence to establish a strong causal link between benzodiazepine/z-drug use and motor vehicle accidents, falls and fractures as a consequence of psycho-motor impairment. A strong causal link between benzodiazepine/z-drug use and dementia could not be concluded because of insufficient and conflicting evidence with both epidemiologic and experimental studies. “As doubt and controversy persists regarding many of these adverse harm associations, further research is required to reconcile the evidence base for the sake of optimizing medication safety in the population.”

Nevertheless, the FDA has been progressively moving towards the caution of black-boxed warnings for z-drugs and the “Contraindication” for a number of years. So be forewarned while you wait for science to sort out the contradictions with z-drugs. Your insomnia problem could potentially become a nightmare.

08/5/15

Pleasant Dreams with Z-Drugs

© Todsaporn Udompon | 123rf.com
© Todsaporn Udompon | 123rf.com

“Frigatebird” glanced at the pillows next to him on the couch and started laughing hysterically because they were alive. “They had arms and legs and were married.” He didn’t really believe this; he knew it was a hallucination, but could see the pillows talking to one another. When he looked at his friend, Andy had four noses drifting around his face, gently waving “like a sea anemone waves in the current.” Someone named “Hyper Jesus” said she didn’t expect to psychically alter the physical makeup of her ceiling, have a lengthy discussion with a plastic bag, or have her bed turn into a planet inhabited by ants who thought she was a god. “Needless to say, I was surprised when all of that happened.” These were the reported experiences of individuals who took Ambien, the popular sleep aide medication.

In Medication Madness, Peter Breggin wrote that although Ambien has a different chemical structure than benzodiazepines, it affects the same neurotransmitter system. And it produces similar effects, including abnormal behaviors and addiction. Read “Downward Spiral” for a description of Ambien-related addiction and abnormal behavior in a 24 year-old Australian man. “Frigatebird’s” complete story (“Powerful Imagination Enhancer”) and that of “Hyper Jesus” (“Lilith and the Shadow People”) can also be read on Erowid, a pro drug website.

Dr. Breggin commented that the Ambien CR label described how patients in brief three-week trials developed hallucinations, disorientation, anxiety, depression, mental and physical slowing, depersonalization, disinhibition, euphoric mood, and mood swings. He added there was a special concerns section that also indicated the possibility of memory problems, tolerance, dependence and withdrawal. All of the above are related in the three stories noted above.

Given these concerns, it shouldn’t be surprising that zolpidem, the generic form of Ambien, was found by the CDC to be the most frequently identified psychiatric drug as the reason for emergency room visits. Not surprisingly, zolpidem was the 19th most frequently prescribed medication in 2013, with 41.5 million prescriptions.

Twenty-five percent of these visits required hospital admission, according to Quarter Watch. It seems that the problems were the result of a pattern of unsafe use—using higher doses than recommended and using it for a longer period of time than recommended. According to Quarter Watch, “Zolpidem is recommended for short term use, based on pivotal efficacy trials of 21-37 days. We found 68% of zolpidem patients were sustained users, with 3 or more prescriptions/refills and a mean of 229 days supply.”

A 2013 DAWN report by SAMHSA said that in 2010, there were 64,174 ER visits involving zolpidem. Thirty percent of them (19,487) were attributed to adverse reactions—adverse health consequences resulting from taking zolpidem. An ER visit was not included if an illicit drug was involved. The number of adverse reactions from zolpidem rose nearly 220% from those reported in 2005. Patients 65 and over represented the largest percentage of zolpidem-related ER visits involving adverse reactions (32%), followed by patients aged 45 to 54 (22%) and those aged 55 to 64 (20%).

Forty percent of these adverse reactions were from the person only taking zolpidem; 50% involved other pharmaceuticals: 21% from narcotic pain relievers; 14% from benzdiazepines; 19% from antidepressants; and 8% from antipsychotics.  “In one tenth (1,970 visits, or 10 percent) of visits, alcohol was the only substance combined with zolpidem.” See Table 1 in the 2013 DAWN Report for further data on additional drug combinations.

A 2014 DAWN report by SAMHSA reported that one third of the 20,793 ER visits in 2010 involving zolpidem were for overmedication—when a patient exceeds the prescribed or recommended dose. These overmedication visits may have involved other medications, but excludes visits involving drug-related suicide attempts and the use of prescription medications not prescribed to the person. The number of ER visits involving overmedication of zolpidem rose 107% from 21,824 in 2005-2006 to 42,274 in 2009-2010.

Thirty seven percent of ER visits were for overmedication of only zolpidem; 57% involved other pharmaceuticals: 25% from narcotic pain relievers; 26% from benzodiazepines; 19% from antidepressants; and 14% from antipsychotics. “About 13 percent involved alcohol combined with zolpidem.”

Researchers previously found that use of zolpidem in combination with other pharmaceuticals or alcohol was associated with increased likelihood of being admitted or transferred to the ICU.Findings in this report show that almost half of zolpidem-related ED visits involving overmedication resulted in hospital admission or transfer. More than two thirds of ED visits that resulted in hospital admission or transfer involved other pharmaceuticals, mostly other CNS depressant medications. CNS depression is the result of decreased brain activity, which may be caused by taking one or several CNS depressant medications and/or alcohol in combination that may then have cumulative depressant effects on the brain.These depressant effects include a decreased breathing rate, decreased heart rate, and loss of consciousness, possibly leading to coma or death.

While the previously reported adverse reactions were more common among older age groups, overmedication ER visits were more evenly distributed across all age groups. While 31% of patients aged 45 to 54 had the largest proportion of zolpidem-related ER visits involving overmedication, only 11% of those patients were 65 and older and 14% of those were between 55 and 64.

Besides Ambien, some other non-benzodiazepine sleep aides approved by the FDA are: Lunesta (eszopicione) and Sonata (zalepion). All three have a risk of dependency. All three carry warnings of possible sleep-related activities, such as: sleep-walking, sleep-driving, making and eating food, talking on the phone, having sex. “The next morning, you may not remember that you did anything during the night.” And they have similar serious side effects: sleep-related activities, abnormal thoughts and behaviors (more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations worsening of depression, suicidal thoughts or actions), memory loss, and anxiety. The links for each of these three Z-drugs are to the FDA approved medications guides. And there are descriptions of individuals with psychoactive “experiences” with Lunesta and Sonata on Erowid as well.

Benzodiazepines and z-drugs are both Schedule IV controlled substances (they have the same addictive potential). Another similarity is that they are commonly used on a long-term basis instead of the recommended short-term basis. The long-term use of z-drugs and the resulting increased tolerance contribute to the problems discussed above with Ambien, adverse drug events and overmedication. Tolerance builds up with regular use, requiring more of the z-drug to get to sleep. I’ve known where a second medication was added; sometimes the off label use of antipsychotics. This brings in another whole set of potential side effects and adverse drug events.

A study published in the British Medical Journal on the effectiveness of so-called z-drugs (non-benzodiazepine hypnotics, like Ambien, Lunesta and Sonata) found that both the drug effect and the placebo response were “small and of questionable clinical importance.” But when the two were put together, there was a reasonably large clinical effect.

These data suggest that the placebo response is a major contributor to the effectiveness of Z drugs. The remaining effect needs to be balanced against the harms associated with these drugs. The substantial proportion of the drug response accounted for by the placebo response indicates the importance of non-specific factors in the treatment of insomnia. As the placebo effect is a psychological phenomenon, these data suggest that increased attention should be directed at psychological interventions for insomnia.

If individuals aren’t informed of the dangers of mixing z-drugs and other medications like opioids, antidepressants and benzodiazepines, they are an adverse drug event waiting to happen. Because of the physical tolerance that can develop, rebound insomnia is likely if the medications are tapered too quickly. It may even occur with a gradual taper in some people. And then to top it all off, the z-drug effect was small and of questionable clinical importance. But on the other hand—maybe your pillow will dance; or you’ll become a god to nonexistent ants crawling around on your bed. Pleasant Dreams!