Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease
- CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne
- Published about 3 years ago
Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common.
Hip fractures in the older person lead to an increased risk of mortality, poorer quality of life and increased morbidity. Benzodiazepine (BNZ) use is associated with increased hip fracture rate, consequently Z-drugs are fast becoming the physician’s hypnotic prescription of choice yet data on their use is limited. We compared the risk of hip fracture associated with Z-drugs and BNZ medications, respectively, and examined if this risk varied with longer-term use.
BACKGROUND:: To investigate the efficacy and indications of zolpidem, a nonbenzodiazepine hypnotic, inducing arousal in vegetative state patients after brain injury. METHODS:: One hundred sixty-five patients were divided into 4 groups, according to area of brain damage and injury mechanism. All patients' brains were imaged by Tc-ECD single-photon emission computerized tomography (SPECT), before and 1 hour after treatment with 10 mg of zolpidem. Simultaneously, 3 quantitative indicators of brain function and damage were obtained using cerebral state monitor. Thirty-eight patients withdrew from the study after the first zolpidem dose. The remaining 127 patients received a daily dose of 10 mg of zolpidem for 1 week and were monitored again at the end of this week. RESULTS:: One hour after treatment with zolpidem, cerebral state index was increased and burst suppression reduced in both brain contrecoup contusion and space-occupying brain compression groups (P < 0.05). SPECT showed, 1 hour after medication, that cerebral perfusion was improved in both brain contrecoup contusion and space-occupying brain compression groups, but no changes were seen in primary and secondary brain stem injury groups. In the 127 patients' group, after 1 week of zolpidem treatment, all parameters obtained from cerebral state monitor were not statistically different compared with those after the initial medication (P > 0.05). CONCLUSIONS:: Zolpidem is an effective medicine to restore brain function in patients in vegetative state after brain injury, especially for those whose brain injuries are mainly in non-brain-stem areas. Improvement of brain function is sudden rather than gradual.
STUDY OBJECTIVES: To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. DESIGN: Multicenter randomized, double-blind, placebo-controlled, parallel-group. SETTING: Outpatient. PATIENTS: There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). INTERVENTIONS: After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. RESULTS: ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study. CONCLUSIONS: 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN. CLINICAL TRIAL INFORMATION: CLINICAL TRIALS REGISTRATION: NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2 CITATION: Roth T; Krystal A; Steinberg FJ; Singh NN; Moline M. Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study. SLEEP 2013;36(2):189-196.
Given its selective action on the ω1 subtype of the γ-aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic disorders.
Long-term sedative use is prevalent and associated with significant morbidity, including adverse events such as falls, cognitive impairment, and sedation. The development of dependence can pose significant challenges when discontinuation is attempted as withdrawal symptoms often develop. We conducted a scoping review to map and characterize the literature and determine opportunities for future research regarding deprescribing strategies for long-term benzodiazepine and Z-drug (zopiclone, zolpidem, and zaleplon) use in community-dwelling adults.
Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T(+)Itpr3(tf)/J (BTBR) mice, a model of idiopathic autism, have reduced spontaneous GABAergic neurotransmission. Treatment with low nonsedating/nonanxiolytic doses of benzodiazepines, which increase inhibitory neurotransmission through positive allosteric modulation of postsynaptic GABAA receptors, improved deficits in social interaction, repetitive behavior, and spatial learning. Moreover, negative allosteric modulation of GABAA receptors impaired social behavior in C57BL/6J and 129SvJ wild-type mice, suggesting that reduced inhibitory neurotransmission may contribute to social and cognitive deficits. The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit specific-the α2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α1-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and α2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.
zolpidem, zopiclone, eszopiclone and zaleplon, also known as ‘Z-drugs’, are commonly used as alternatives to benzodiazepines (BZDs) to treat insomnia. Z-drugs are often perceived as safer than BZDs. We conducted a systematic review and meta-analysis evaluating the association between Z-drugs and fracutres, falls and injuries.
Various adverse events resulting from, or associated with, benzodiazepine and/or Z-drug use have been extensively reported on and discussed in great detail within the biomedical literature. It is widely accepted that motor vehicle accidents and falls leading to fractures in older adults are major adverse events that have been shown to occur more frequently in users of sedative-hypnotic medication, especially of the benzodiazepine and related Z-drug variety. However, the last few years have seen increasing reports in the literature raising the issue of benzodiazepine and Z-drug exposure in the development of other serious medical issues including dementia, infections, respiratory disease exacerbation, pancreatitis, and cancer. This article provides an overview and interpretation on the current state of evidence regarding each of these associations and proposes what gaps in the evidence for drug-exposure-harm associations need to be addressed in the future for the purpose of evaluating causality of harm as it relates to these drugs.
Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about “sleep-related complex behaviors”, e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects.