Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults
Importance The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications.
Objective To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).
Design, Setting, and Participants The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC−participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015.
Main Outcomes and Measures Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC− participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression.
Results The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale–Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC− participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC− participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC−participants; P = .04) than the 350 AC− participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC− participants.
Conclusions and Relevance The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.
Source : JAMA (April 2016)
Anticholinergic drugs are used to treat a variety of conditions:
- Gastrointestinal disorders (e.g., gastritis, diarrhea, pylorospasm, diverticulitis, ulcerative colitis, nausea, and vomiting)
- Genitourinary disorders (e.g., cystitis, urethritis, and prostatitis)
- Respiratory disorders (e.g., asthma, chronic bronchitis, and chronic obstructive pulmonary disease [COPD])
- Sinus bradycardia due to a hypersensitive vagus nerve.
- Insomnia, although usually only on a short-term basis.
- Dizziness (including vertigo [a.k.a. 'the spins'] and motion sickness-related symptoms)
List of AC Drugs
- Amitriptyline (Elavil)
- Benztropine (Cogentin)
- Chlorpheniramine (Actifed, Allergy & Congestion Relief, Chlor-Trimeton,Codeprex, Efidac-24 Chlorpheniramine, etc.)
- Chlorpromazine (Thorazine)
- Clomipramine (Anafranil)
- Clozapine (Clozaril)
- Cyclobenzaprine (Amrix, Fexmid, Flexeril)
- Cyproheptadine (Periactin)
- Desipramine (Norpramin)
- Dicyclomine (Bentyl)
- Diphenhydramine (Advil PM, Aleve PM, Bayer PM, Benadryl, Excedrin PM, Nytol, Simply Sleep, Sominex, Tylenol PM, Unisom, etc.)
- Doxepin (Adapin, Silenor, Sinequan)
- Fesoterodine (Toviaz)
- Hydroxyzine (Atarax, Vistaril)
- Hyoscyamine (Anaspaz, Levbid, Levsin, Levsinex, NuLev)
- Imipramine (Tofranil)
- Meclizine (Antivert, Bonine)
- Nortriptyline (Pamelor)
- Olanzapine (Zyprexa)
- Orphenadrine (Norflex)
- Oxybutynin (Ditropan, Oxytrol)
- Paroxetine (Brisdelle, Paxil)
- Perphenazine (Trilafon)
- Prochlorperazine (Compazine)
- Promethazine (Phenergan)
- Protriptyline (Vivactil)
- Pseudoephedrine HCl/Triprolidine HCl (Aprodine)
- Scopolamine (Transderm Scop)
- Thioridazine (Mellaril)
- Tolterodine (Detrol)
- Trifluoperazine (Stelazine)
- Trimipramine (Surmontil)
- Alprazolam (Xanax)
- Amantadine (Symmetrel)
- Carisoprodol (Soma)
- Cetirizine (Zyrtec)
- Cimetidine (Tagamet)
- Clorazepate (Tranxene)
- Digoxin (Lanoxicaps, Lanoxin)
- Diphenoxylate (Lomotil)
- Fluphenazine (Prolixin)
- Furosemide (Lasix)
- Hydrochlorothiazide (Esidrix, Dyazide, HydroDIURIL, Maxzide & literally scores of other medications for high blood pressure)
- Loperamide (Imodium)
- Loratadine (Alavert, Claritin)
- Nifedipine (Adalat, Procardia)
- Ranitidine (Zantac)
- Thiothixene (Navane)
- Tizanidine (Zanaflex)
Eszopiclone Containing Sleep Aids: Drug Safety Communication - Can Cause Next-Day Impairment
Including Lunesta and generics
ISSUE: FDA has notified health professionals and their medical care organizations of a new warning that the insomnia drug Lunesta (eszopiclone) can cause next-day impairment of driving and other activities that require alertness. FDA recommends a decreased starting dose of Lunesta to 1 mg at bedtime. Women and men are equally susceptible to impairment from Lunesta, so the recommended starting dose of 1 mg is the same for both. FDA approved changes to the Lunesta prescribing information and the patient Medication Guide to include these new recommendations. The drug labels for generic eszopiclone products will also be updated to include these changes.
BACKGROUND: A study of Lunesta found that the previously recommended dose of 3 mg can cause impairment to driving skills, memory, and coordination that can last more than 11 hours after receiving an evening dose (see Data Summary). Despite these driving and other problems, patients were often unaware they were impaired. The new lower recommended starting dose of 1 mg at bedtime will result in less drug in the blood the next day.
RECOMMENDATION: Health care professionals should follow the new dosing recommendations when starting patients on Lunesta. Patients should continue taking their prescribed dose of Lunesta and contact their health care professionals to ask about the most appropriate dose for them. FDA is continuing to evaluate the risk of impaired mental alertness with the entire class of sleep aid drugs, including over-the-counter drugs available without a prescription, and will update the public as new information becomes available.
Source : FDA (May 2014)
Zolpidem Containing Products: - FDA Requires Lower Recommended Doses Including Ambien, Ambien CR, Edluar, and Zolpimist
FDA is notifying the public of new information about zolpidem, a widely prescribed insomnia drug. FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. This announcement focuses on zolpidem products approved for bedtime use, which are marketed as generics and under the brand names Ambien, Ambien CR, Edluar, and Zolpimist.FDA is also reminding the public that all drugs taken for insomnia can impair driving and activities that require alertness the morning after use. Drowsiness is already listed as a common side effect in the drug labels of all insomnia drugs, along with warnings that patients may still feel drowsy the day after taking these products. Patients who take insomnia drugs can experience impairment of mental alertness the morning after use, even if they feel fully awake.
For zolpidem products, data show the risk for next-morning impairment is highest for patients taking the extended-release forms of these drugs (Ambien CR and generics). Women appear to be more susceptible to this risk because they eliminate zolpidem from their bodies more slowly than men.
Because use of lower doses of zolpidem will result in lower blood levels in the morning, FDA is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose.
FDA is continuing to evaluate the risk of impaired mental alertness with other insomnia drugs, including over-the-counter (OTC) drugs available without a prescription.
BACKGROUND: Zolpidem is a sedative-hypnotic (sleep) medicine used in adults for the treatment of insomnia. It is marketed as generics and under the brand-names Ambien, Ambien CR, Edluar, Zolpimist, and Intermezzo.
RECOMMENDATION: FDA urges health care professionals to caution all patients (men and women) who use these products about the risks of next-morning impairment for activities that require complete mental alertness, including driving.
- The recommended dose of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release products (Ambien CR).
- For zolpidem and other insomnia drugs, prescribe the lowest dose that treats the patient’s symptoms.
- Inform patients that impairment from sleep drugs can be present despite feeling fully awake.
- The recommended doses of Intermezzo, a lower dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women than for men.
Source : FDA
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Die Early with Sleeping Pills
A new study shows prescription sleeping pills bring an increased risk of dying early—or getting cancer. So why is FDA rubber-stamping such dangerous drugs? Sleep deprivation is a serious issue. As many as 70 million Americans suffer from insomnia and other sleep disorders. Some 60 million prescriptions for sleeping pills—technically called hypnotic drugs—were filled in 2011 as compared to 47 million in 2006.
Stress, an over-full lifestyle, poor diet, and especially the use of artificial light in the evening after going to bed, can all prevent sleep. As we reported earlier this year, lack of sleep makes you more likely to get sick, raises your risk of type 2 diabetes, high blood pressure, and obesity, and makes you more prone to depression.
Some of the risks of sleeping pills are already well-documented: daytime drowsiness, headaches, nausea, dizziness, and addiction. But a new study published in the British Medical Journal says that people taking a prescription sleeping pill—even when taking fewer than eighteen pills per year—have nearly four times the mortality rate of those who don’t take the drugs. And patients who take higher doses of sleeping pills have a 35% increased cancer risk.
This study was prompted by earlier studies showing that hypnotic drugs are often deadly when mixed with alcohol or other drugs, are linked to an increased risk of car accidents and falls, may raise risk of suicide, and may damage chromosomes in cells which could lead to cancer.
What was significant about this study is that it was long-term, keeping track of 10,529 people who had at least one prescription for a sleeping pill between 2002 and 2007, compared with a control group. While the study doesn’t demonstrate causation, it did adjust for confounding factors such as age, smoking, weight, and other health conditions.
So why is FDA approving such dangerous sleeping pills? For one thing, the clinical trials required for FDA approval may be inadequate when it comes to hypnotic drugs. Many people take non-benzodiazepine sedative hypnotics for years, even though most are approved for only short-term use and their safety and effectiveness were not evaluated beyond several weeks in clinical trials. (One exception is Lunesta, which was tested for up to six months, and its list of known side effects is terrifying.)
Compare this to the FDA’s standard for supplements: the NDI draft guidance requires “25 years of widespread use” in order to meet the “history of safe use” standard, which must be met even for grandfathered supplements. (For more on grandfathered ingredients, see our article in this issue.) As the Life Extension Foundation points out, the safety testing required by FDA is wildly inappropriate for supplements, and is unnecessary for natural products with years of documented safe use. Yet despite their superb track record for safety, FDA and the media have cultivated an environment of fear around nutritional supplements—while maintaining a casual attitude toward dangerous (but approved) drugs.
Source : Alliance for Natural Health
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Sleeping Pill Death Toll May Top 500,000
By Charles Bankhead,
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania.
The use of hypnotic sleep aids was associated with a three- to five-fold higher mortality risk compared with the risk for nonusers, even when the prescription was for a small number of pills, investigators reported.
A prescription for 0.4 to 18 doses per year was associated with a mortality hazard ratio of 3.60 compared with patients who had no prescriptions for hypnotics.
The hazard jumped to 5.32 for patients prescribed more than 132 doses a year, investigators reported online in BMJ Open.
"Rough order-of-magnitude estimates ... suggest that in 2010, hypnotics may have been associated with 320,000 to 507,000 excess deaths in the U.S. alone," Daniel F. Kripke, MD, of the Scripps Clinic in La Jolla, Calif., and co-authors wrote. "From this nonrandomized study, we cannot be certain what portion of the mortality associated with hypnotics may have been attributable to these drugs, but the consistency of our estimates across a spectrum of health and disease suggests that the mortality effect of hypnotics was substantial."
Patients who used hypnotics most often also had an increased risk of cancer, with an overall cancer increase of 35% among those prescribed high doses.
More than 30 years ago, investigators in an American Cancer Society-supported study showed that both cigarette smoking and hypnotic use were associated with excess mortality (Arch Gen Psychiatry 1979; 36: 103-116). But the link to hypnotics was largely discounted because the study was not designed primarily to examine these drugs, Kripke and colleagues wrote.
Subsequently, at least two dozen studies examined the mortality risk associated with hypnotic use, and two-thirds of the studies demonstrated significant (P<0.05) associations. Lack of uniformity across the studies precluded a meta-analysis, but 22 of the reports showed a mortality hazard ratio that exceeded 1.0, the authors continued.
Previous studies had several notable limitations, including limited information on the specific types of drugs, confounding with tranquilizers, lack of monitoring of the quantities of drugs provided to patients, and limited data on newer short-acting hypnotics, such as zolpidem, zaleplon, and eszopiclone (Lunesta).
To address some of the limitations of previous work, Kripke and colleagues performed a matched-cohort study based on longitudinal data from a large U.S. health system.
A query of the database identified 10,531 adult patients who had at least one prescription for a hypnotic drug from Jan. 1, 2002 to Sept. 30, 2006. Using the same database, the authors matched the hypnotic-user group with 23,674 patients who did not have a prescription for a hypnotic during the period studied.
Three-fourths of patients prescribed a hypnotic had an explicitly stated sleep-related indication in their records.
Women (mean age 54) accounted for 63.9% of hypnotic users. Hypnotic users and the control group had been followed for about 2.5 years. The users had a mean morbidity score of 1.53. Zolpidem was the most commonly used hypnotic (4,338), followed by temazepam (2,076).
Overall, 6.1% of hypnotic users died during observation, compared with 1.2% of the nonusers. Hypnotic use was associated with a significantly increased mortality risk (P<0.001). The magnitude of the hazard ratio increased with the number of pills prescribed per year (P<0.001 for all comparisons versus nonusers):
- HR 3.60 for 0.4 to <18 pills
- HR 4.43 for 18 to 132 pills
- HR 5.32 for >132 pills
Patients with temazepam prescriptions totaling 1 mg/year to 240 mg/year had a mortality hazard of 3.71, increasing to 6.56 for >1,640 mg/year (P<0.001).
Overall, only patients whose hypnotic use fell into the top two categories (18 to 132 pills and >132 pills) had an increased cancer risk (HR 1.20, P=0.022; HR 1.35, P<0.001).
For individual drugs, only patients in the top category of zolpidem use had an increased cancer risk (HR 1.28, P=0.023), whereas the two top categories of temazepam use were associated with an increased mortality hazard (HR 1.44, P=0.024; HR 1.99, P<0.001).
The authors acknowledged limitations to this research, most notably that residual confounding could not be fully excluded "due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance."
They also pointed out that cohort studies may demonstrate an association but do not necessarily imply causality. However, "the preferable randomized controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations," they said.
"The meager benefits of hypnotics, as critically reviewed by groups without financial interest, would not justify substantial risks," the authors wrote. "A consensus is developing that cognitive behavioral therapy of chronic insomnia may be more successful than hypnotics.
"Against meager benefits, it is prudent to weigh the evidence of mortality risks from the current study and 24 previous reports, in order to reconsider whether even short-term use of hypnotics, as given qualified approval in National Institute for Clinical Excellence guidance, is sufficiently safe," they added.
Kripke disclosed that he has a long history of criticism of hypnotics on a personal website.
He also disclosed a family interest in an investment organization that has a small percentage of assets in stock of drug companies.
Primary source: BMJ Open
Kripke DF, et al "Hypnotics' association with mortality or cancer: A matched cohort study" BMJ Open 2012; 2: e000850.
Source : Medpage Today
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Common sleep drug can leave people groggy, clumsy
Popular sleep drugs such as Ambien can leave even the healthiest older people groggy and prone to stumbling, falling and confusion when they wake up, U.S. researchers reported on Thursday.
The drug, sold by Sanofi Aventis and other makers and known generically as zolpidem, appears to act broadly in the brain and has a numbing effect for at least half an hour after waking, the researchers reported in the Journal of the American Geriatric Society.
People should not avoid taking it but should be aware of the drug's effects, advised Kenneth Wright of the University of Colorado at Boulder and colleagues.
"If you have an individual who, even when they take their sleep medications, they wake up in the middle of the night to go to the bathroom, they need to be aware that they are at greater risk of falling," Wright said in a telephone interview.
If a couple is traveling together, he added, perhaps both should avoid taking such a drug at the same time while sleeping in unfamiliar quarters.
"What this also calls for is the development of new sleep medications that are effective but are safer," Wright said.
The drug is sold generically under the name zolpidem and brand names such as Zolpimist, Edluar, Hypogen, Somidem and Ivedal.
Wright's team tested 25 healthy adults by having them walk on a beam laid on the floor to test balance, and asking questions such as simple math problems to test thinking.
All had perfect balance and clear thinking when they were awakened after taking a placebo. But 58 percent of the volunteers over the age of 60 stumbled off the beam when awakened after taking zolpidem, Wright said.
"They are walking more slowly after they have taken zolpidem and they are more unstable," he said.
"You are much groggier, much more impaired -- more than twice as bad. You are slower and you can't think as clearly."
The effects were less pronounced in the adults under 60 but 27 percent of the younger volunteers were also affected by zolpidem, Wright's team found.
"These are temporary effects," he stressed. People are sometimes equally groggy after a sleepless night, so it would be important to continue taking the medications if prescribed.
The drug is extremely popular -- 7 billion doses of zolpidem have been prescribed worldwide, said Wright.
Other sleep medications also have undesirable side-effects.
Triazolam, marketed under brand names such as Halcion, Hypam, and Trilam, was banned in Britain in 1991 because it could cause psychosis and paranoia, although it remains legal in certain doses in the United States and elsewhere.
"One of the things about a lot of the sleep medications is they are acting on a nerve chemical in the brain called GABA," Wright said.
GABA affects sleep but also coordination and cognition, he said.
Safer sleep medications would target the regions specifically involved with sleep, Wright said. The problem is that researchers do not fully understand where all these are and precisely how they work.
Source : Reuters 13 Jan 2011
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