Outdoor Artificial Nighttime Light and Use of Hypnotic Medications in Older Adults: A Population-Based Cohort Study.

STUDY OBJECTIVES: Outdoor artificial nighttime light is increasingly recognized as a form of environmental pollution. Excessive nighttime light exposure, whether from indoor or outdoor sources, has been associated with a number of deleterious effects on human health. We performed a population-based cohort study in South Korea to assess the possible association between outdoor nocturnal lighting and insomnia in older adults, as measured by prescriptions for hypnotic drugs. METHODS: This study used data from the 2002-2013 National Health Insurance Service-National Sample Cohort (NHIS-NSC), and a total of 52,027 adults who were age 60 years or older were included in the study. Light data were based on satellite mapping of artificial light. The usage data of two hypnotic drugs, zolpidem (N05CF02) and triazolam (N05CD05), were extracted from the NHIS-NSC records. RESULTS: Of the 52,027 patients in this cohort, 11,738 (22%) had prescriptions for hypnotic drugs. Increasing outdoor artificial nighttime light exposure (stratified by quartile) was associated with an increased prevalence of hypnotic prescriptions and daily dose intake. Compared with individuals in the lowest quartile 1, the regression coefficients for prescription days and daily defined doses of all hypnotic drugs and certain hypotonic drugs were significantly higher among those living in areas with higher outdoor artificial nighttime light (quartiles 2 through 4). CONCLUSIONS: Outdoor artificial nighttime light exposure was significantly associated with prescription of hypnotic drugs in older adults. These findings are consistent with the hypothesis that outdoor artificial nighttime light may cause sleep disturbances.

Proposed Guideline Revisions for Dental Sedation and General Anesthesia: Why Target the Safest Level of Sedation?

Recently proposed revisions to the American Dental Association's Guidelines for the Use of Sedation and General Anesthesia by Dentists, aimed at improving safety in dental offices, differentiate between levels of sedation based on drug-induced changes in physiologic and behavioral states. However, the author of this op-ed is concerned the proposed revisions may have far-reaching and unintended consequences.

An improved human anxiety process biomarker: characterization of frequency band, personality and pharmacology.

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4-12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis.

Pharmacokinetic evaluation of eszopiclone: clinical and therapeutic implications.

INTRODUCTION: Eszopiclone is the active S-enantiomer of R,S-zopiclone, and is a cyclopyrrolone hypnotic acting via the GABA-benzodiazepine receptor system. Nearly 6 million prescriptions for eszopiclone are written yearly in the United States. AREAS COVERED: This paper addresses the pharmacokinetic properties of eszopiclone and the extent to which the longer half-life of eszopiclone compared to other commonly used hypnotics (immediate-release zolpidem, modified-release zolpidem, triazolam, zaleplon) may translate into either improved efficacy in enhancing sleep maintenance, or increased probability of residual sedative or performance-impairing effects. EXPERT OPINION: Eszopiclone is metabolized mainly by Cytochrome P450-3A (CYP3A) isoforms. The mean half-life in healthy nonelderly individuals (6.1 h) is prolonged in the elderly, in patients with hepatic insufficiency, and by coadministration of CYP3A inhibitors. In clinical trials, eszopiclone consistently improves sleep maintenance relative to placebo, based on measures of shortened wake time after sleep onset, and prolonged total sleep time. However eszopiclone may also produce residual sedation and impairment of driving performance in the initial morning waking hours. A bitter or metallic taste is a common though non-serious adverse effect of eszopiclone. Overall, eszopiclone provides a therapeutic option for patients with sleep maintenance problems, though with accompanying potential for residual morning sedation, as well as a relatively high dollar cost of treatment.

The efficacy and safety of muscle relaxants in inflammatory arthritis: a Cochrane systematic review.

OBJECTIVE: To determine the efficacy and safety of muscle relaxants in pain management in patients with inflammatory arthritis (IA). METHODS: We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any muscle relaxant (administered via any route) to another analgesic intervention or placebo. We also searched the 2008-2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief ≥ 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. RESULTS: Six trials (126 participants) were included in this review. All trials were deemed to have a high risk of bias. Five crossover trials evaluated benzodiazepine; 4 assessed diazepam (n = 71), and one assessed triazolam (n = 15). The sixth trial, a parallel-group study, evaluated zopiclone (non-benzodiazepine, n = 40). No trial was longer than 2 weeks and 3 single-dose trials assessed outcomes at 24 hours only. Overall, the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo (at 24 hours, 1 week, or 2 weeks) or in addition to nonsteroidal antiiflammatory drugs (at 24 hours) on pain intensity, function, or quality of life. Data from 2 trials of longer than 24-hour duration (diazepam and zopiclone, n = 74) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo [number needed to harm (NNTH) 3, 95% CI 2 to 7]. These were predominantly central nervous system side effects including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). CONCLUSION: Based upon the currently available evidence in patients with IA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or 1 week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over 2 weeks. However, even short-term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

Muscle relaxants for pain management in rheumatoid arthritis.

BACKGROUND: Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. OBJECTIVES: The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). SEARCH METHODS: We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. SELECTION CRITERIA: We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. DATA COLLECTION AND ANALYSIS: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. MAIN RESULTS: Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11).  AUTHORS' CONCLUSIONS: Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

Sedação consciente com triazolam em odontologia / Conscious sedation with triazolam in dentistry

O Triazolam, quando administrado por via oral, possui um rápido início de ação, duração dos efeitos relativamente curta e boa margem de segurança clínica. Desde que utilizado na dose adequada, torna-se um dos benzodiazepínicos de escolha para a sedação consciente em odontologia. O objetivo deste trabalho foi apresentar dados relacionados aos parâmetros farmacocinéticos, reações adversas, preucauções e contra-indicações e posologia do Triazolam, dando suporte ao seu uso na clínica odontológica.

Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans.

Drugs that act as allosteric activators at the benzodiazepine site of the gamma-aminobutyric acid (GABA(A)) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA(A) allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep-dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG-measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non-selective or alpha1-preferring benzodiazepine site allosteric activators can interfere with sleep-dependent memory consolidation.

Effects of ramelteon and triazolam in a mouse genetic model of early morning awakenings.

The onset of the daily wheel running bout precedes dark onset by several hours in the early runner genetic variant of mice. Here, we test the hypothesis that timed daily administration of a melatonin agonist, ramelteon, or a benzodiazepine, triazolam, normalizes the timing of daily wheel-running rhythms in early runner mice. The daily profiles of wheel-running activity of early runner mice were monitored continuously in a 12:12 light/dark cycle. Wheel running was assessed before, during and after timed daily oral administration of saline vehicle (n=12), ramelteon (10 mg/kg, n=12), or triazolam (1 mg/kg, n=12). The timing of wheel-running rhythms relative to the light/dark cycle was used as a measure of the timing of wake onset. Under baseline conditions, early runner mice entrained to a light/dark cycle at an advanced phase, approximately 3 h before dark onset, on average. Triazolam, but not ramelteon, suppressed wheel-running acutely when administered just prior to the time at which wheel-running onset had occurred under baseline conditions. On a washout day under a light/dark cycle subsequent to one week of once daily administration, the onset of wheel-running was delayed relative to baseline in both ramelteon-treated mice and triazolam-treated mice. In constant dark subsequent to a second week of once daily administration, the onset of wheel-running activity was not affected by either compound. Thus, ramelteon and triazolam caused a shift in the timing of wheel-running rhythms in an LD cycle but did so without long-term effects on the functioning of the circadian clock.

Effectiveness and safety of hypnotic drugs in the treatment of insomnia in over 70-year old people.

Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed.

Beating jet lag.

Jet lag is often cited as a cause of poor sporting performance. We report on the case of a rugby league player who flew 20,000 km and 12 time zones, then repeated the feat a few days later, prior to playing with distinction in an important final match in an international series.

Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects.

CONTEXT: Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for insomnia treatment. Most approved insomnia medications have potential for abuse and cause motor and cognitive impairment. OBJECTIVE: To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug. DESIGN: In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days. All participants received each treatment on different days. Most outcome measures were assessed at 0.5 hours before drug administration and repeatedly up to 24 hours after drug administration. SETTING: Residential research facility. PARTICIPANTS: Fourteen adults with histories of sedative abuse. MAIN OUTCOME MEASURES: Subject-rated measures included items relevant to potential for abuse (eg, drug liking, street value, and pharmacological classification), as well as assessments of a broad range of stimulant and sedative subjective effects. Observer-rated measures included assessments of sedation and impairment. Motor and cognitive performance measures included psychomotor and memory tasks and a standing balance task. RESULTS: Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo. Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability. CONCLUSION: Ramelteon demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications.

Discriminative-stimulus effects of triazolam in women and men.

Benzodiazepines are among the most commonly prescribed therapeutics. Women seem to be more likely than men to be prescribed a benzodiazepine and to use benzodiazepines for nonmedical reasons; they also appear to be at higher risk for benzodiazepine dependence. The aim of the present investigation was to assess the acute behavioral effects of a benzodiazepine in women and men. To accomplish this, 13 volunteers (6 women, 7 men) first learned to discriminate 0.375-mg triazolam, a triazolobenzodiazepine hypnotic. After acquiring the discrimination, (i.e., >80% correct responding on 4 consecutive sessions) a range of doses of triazolam (0, 0.0625, 0.125, 0.25, and 0.375 mg) were tested in each participant. Triazolam dose dependently increased drug-appropriate responding and subject ratings of sedation and impaired performance (i.e., significant effect of dose). The women and men did not differ significantly on any measure. The results of the present experiment suggest that women and men are not differentially sensitive to the behavioral effects of triazolam.

The use of anxiolytic medications to supplement local anesthesia in the anxious patient.

Local anesthetic failures in dental patients can have many causes, including anatomical variations, technique, and anxiety/fear. By understanding the mechanisms responsible for failed local anesthesia, patients can be treated more comfortably. The interaction of anxiety and fear is discussed. Oral sedation dentistry is highlighted as a way to reduce anxiety/fear and the patient's perception of pain. Profound anesthesia can be accomplished more easily in relaxed patients with diminished or eliminated anxiety/fear.

Rehabilitation of a fearful dental patient with oral sedation: utilizing the incremental oral administration technique.

The treatment of fearful or anxious patients presents a myriad of problems for the dentist. In-office sedation using oral (enteral) medications is an effective means of increasing patient tolerance of invasive dental procedures. The incremental oral administration technique is a protocol that can be utilized to treat fearful or anxious patients. A case is presented in which this technique was used as an adjunct to the rehabilitation of a debilitated mouth.

Zaleplon (Sonata) oral sedation for outpatient third molar extraction surgery.

Zalpelon was compared with triazolam for oral sedation in a third molar surgery model using a double-blind crossover design. Factors such as anxiolysis, amnesia, and quality of sedation were assessed. Of the 14 participants who completed the study, zaleplon sedation was found to be similar to triazolam sedation in all regards except that recovery from zaleplon was more rapid.