Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010.
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SUBMITTER: Kaufmann CN
PROVIDER: S-EPMC4889508 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010.
Kaufmann Christopher N CN Spira Adam P AP Alexander G Caleb GC Rutkow Lainie L Mojtabai Ramin R
Pharmacoepidemiology and drug safety 20151229 6
<h4>Purpose</h4>Non-benzodiazepine receptor agonists (nBZRAs) were developed as an alternative to benzodiazepines (BZDs) to treat insomnia. Little is known about how the introduction of nBZRAs influenced trends in BZD prescribing. We examined BZD and nBZRA prescribing trends from 1993 to 2010.<h4>Methods</h4>We used the National Ambulatory Medical Care Survey to examine 516,118 patient visits between 1993 and 2010. We categorized visits as BZD, nBZRA, or BZD + nBZRA visits based on medications p ...[more]
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Project description:Study objectivesTo evaluate prevalence of sedative hypnotic medications and their potential indication among active duty service members (ADSM) and non-ADSM receiving care in the Military Health System (MHS).MethodsUsing a retrospective cohort study design, we extracted data on sedative hypnotic medications (benzodiazepine receptor agonists, benzodiazepines, sedating antidepressants, and melatonin receptor agonist) dispensed from January 2009 to December 2015. Prevalence was defined as ≥ 1 dispensing per patient per year whereas chronic episode was categorized as ≥ 90 days of continuous therapy. Chi square statistics, odds ratios, and 95% confidence intervals were calculated to assess meaningful differences between ADSM and non-ADSM.ResultsMean age at dispensing was 33.5 years in ADSM compared to 59.1 years in non-ADSM. Of all drugs dispensed, 79.2% (n = 2.4 million) were to male ADSM compared to 34.5% (11.5 million) to male non-ADSM. Zolpidem and trazodone were the two most frequently used medications, comprising more than 75% of all prescriptions. Age- and sex-adjusted prevalence peaked at 8.1% in 2013 for ADSM and at 4.9% in 2012 for non-ADSM and remained stable thereafter for both groups. Most episodes for ADSM (81.0%) and non-ADSM (65.0%) were acute or intermittent. ADSM were significantly more likely to have a sleep-related diagnosis associated with their episode than non-ADSM (odds ratio 2.35, 95% confidence interval 2.33-2.36), most frequently insomnia.ConclusionsADSM had a 2% to 3% higher adjusted prevalence of sedative hypnotic medications than non-ADSM. The use of sedative hypnotics in the young ADSM population highlights the need for military-appropriate sleep practices and novel interventions to mitigate sleep disturbances and chronic sleep disorders in this population.
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Project description:Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the ?-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile.The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043.AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration.AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.
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Project description:BackgroundSoft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives.Methodology/principal findingsFluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and ?-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size.Conclusions/significanceThe rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.
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