Actigraphy assessment of sleep quality among patients with acute myeloid leukaemia during induction chemotherapy.

OBJECTIVES: Patients receiving induction chemotherapy for acute myeloid leukaemia (AML) anecdotally describe poor sleep, but sleep disturbances have not been well-characterised in this population. We aimed to test the feasibility of measuring sleep quality in AML inpatients using a wearable actigraphy device. METHODS: Using the Actigraph GT3X 'watch', we assessed the total sleep time, sleep onset latency, wake after sleep onset, number of awakenings after sleep onset and sleep efficiency for inpatients with AML receiving induction chemotherapy. We assessed patient self-reported sleep quality using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Of the 12 patients enrolled, 11 completed all actigraphy and PSQI assessments, demonstrating feasibility. Patients wore the Actigraph device for a mean (SD) of 15.92 (8.3) days, and actigraphy measures suggested poor sleep. Patients had a median average awakening length of 6.92 min, a median number of awakenings after sleep onset of 4 and a median sleep onset latency of 10.8 min. Actual median sleep efficiency (0.91) was high, suggesting that patients' poor sleep was not due to insomnia but perhaps due to interruptions, such as administration of medications, lab draws and vital sign measurements. CONCLUSIONS: Collection of sleep quality data among inpatients with AML via a wearable actigraphy device is feasible. AML inpatients appear to have poor sleep quality and quantity, suggesting that sleep issues represent an area of unmet supportive care needs in AML. Further research in this areas is needed to inform the development of interventions to improve sleep duration and quality in hospitalised patients with AML.

[Sleep disorders and impaired sleep as adverse drug reactions of psychotropic drugs: an evaluation of data of summaries of product characteristics]. / Schlafstörungen und Beeinträchtigungen des Schlafs als Nebenwirkungen von Psychopharmaka: eine Bewertung der Daten aus Fachinformationen.

OBJECTIVE: Psychopharmacotherapy is essential in the treatment of many mental disorders. Adverse drug reactions (ADR) have impact on compliance and tolerability. Sleep disorders or impaired sleep may occur as ADRs of psychopharmacotherapy. Sleep disorders are associated with an increased risk for physical and mental illness and may impair cognition, impulse control, emotion regulation and mood. Objective of the following study was the systematic presentation of type and risk of sleep disorders/impairments of sleep of frequently prescribed psychotropic drugs. METHODS: Psychotropic agents that are most frequently prescribed in Germany were identified by using the Arzneiverordnungs-Report 2016. Summaries of product characteristics (SmPC) of corresponding original products were analyzed regarding presence and frequency of sleep disorders/impairments of sleep according to the International Classification of Sleep Disorders 3 (ICSD-3). RESULTS: N = 64 SmPCs were analyzed. In most of the analyzed SmPCs, at least one sleep disorder (50/64; 78 %) was listed. At least one SmPC with a corresponding ADR was found in the categories insomnia (52 %), parasomnias (33 %), and sleep-related movement disorders (20 %); sleep-related breathing disorders (6 %) and central disorders of hypersomnolence (5 %) were rarely listed; circadian rhythm sleep-wake disorder was not found. The SmPCs of the four most frequently prescribed agents (citalopram > venlafaxine > mirtazapine > sertraline) listed insomnia as an ADR. Nearly all analysed hypnotics (except chloral hydrate) were associated with nightmares. CONCLUSION(S): Most of the psychotropic agents frequently prescribed in Germany may induce sleep disorders/impairments of sleep. The four most frequently prescribed agents were antidepressants and all of the corresponding SmPCs listed insomnia as a possible ADR. Sleep disorders should be taken seriously as possible ADRs of psychopharmacotherapy.

Assessment of tolerance to the effects of methamphetamine on daytime and nighttime activity evaluated with actigraphy in rhesus monkeys.

RATIONALE: Methamphetamine is one of the most largely consumed illicit drugs, and its use is associated with abuse liability and several adverse health effects, such as sleep impairment. Importantly, sleep quality can influence addiction treatment outcomes. Evidence suggests that tolerance can develop to the sleep-disrupting effects of stimulant drugs. OBJECTIVE: The aim of the present study was to investigate the development of tolerance to the actigraphy-based sleep-disrupting and stimulant effects of methamphetamine self-administration in rhesus monkeys. METHODS: Methamphetamine (0.03 mg/kg/inf, i.v.) self-administration was carried out following three different protocols: 14 consecutive days of self-administration, 5 days/week for 3 weeks, with a 2-day interval between 5-day blocks of self-administration, and 3 days/week for 3 weeks, with a 4-day interval between 3-day blocks of self-administration. Daytime activity and activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline parameters) and throughout each protocol. RESULTS: Methamphetamine self-administration markedly disrupted sleep-like measures and increased daytime activity. Tolerance developed to those effects with repeated methamphetamine intake exceeding five consecutive days. Inclusion of washout periods (2 or 4 days) between blocks of methamphetamine self-administration attenuated the development of tolerance, with longer breaks from methamphetamine intake being more effective in maintaining the sleep-disrupting and stimulant effects of methamphetamine. CONCLUSIONS: Tolerance can develop to the stimulant and sleep-disrupting effects of methamphetamine self-administration. Interruption of drug intake extends the effects of methamphetamine on sleep-like measures and daytime activity.

A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales.

BACKGROUND: People with severe asthma experience significant respiratory symptoms and suffer adverse effects of oral corticosteroids (OCS), including disturbed mood and physical symptoms. OCS impacts on health-related quality of life (HRQoL) have not been quantified. Asthma HRQoL scales are valid as outcome measures for patients requiring OCS only if they assess the deficits imposed by OCS. AIMS: The aim of this study was to compare the burden of disease and treatment in patients with severe asthma with items in eight asthma-specific HRQoL scales. METHODS: Twenty-three patients with severe asthma recruited from a severe asthma clinic were interviewed about the impact of their respiratory symptoms and the burden of their treatment. The domains from a thematic analysis of these interviews were compared with the items of eight asthma-specific HRQoL scales. RESULTS: In addition to the burden caused by symptoms, ten domains of OCS impact on HRQoL were identified: depression, irritability, sleep, hunger, weight, skin, gastric, pain, disease anxiety, and medication anxiety. Some patients experienced substantial HRQoL deficits attributed to OCS. Although all HRQoL scales include some OCS-relevant items, all eight scales fail to adequately assess the several types of burden experienced by some patients while on OCS. CONCLUSION: The burden of OCS in severe asthma is neglected in policy and practice because it is not assessed in outcome studies. Existing asthma HRQoL scales provide an overly positive estimation of HRQoL in patients with frequent exposure to OCS and underestimate the benefit of interventions that reduce OCS exposure. Changes to existing measurement procedures are needed.

Pharmacoeconomic impact of adverse events of long-term opioid treatment for the management of persistent pain.

Opioids are the most powerful analgesic drugs currently available and consequently form an essential part of the treatment options for malignant and non-malignant chronic pain. However, the benefits of these medications can be offset by gastrointestinal adverse events such as nausea, vomiting and constipation, as well as adverse events affecting the CNS. These occur relatively frequently in patients receiving long-term opioids for pain relief and are a cause of additional patient suffering and reduced work and social functioning, measured as reductions in quality-of-life outcomes. Consequently, adverse events are often the cause of treatment non-compliance or discontinuation (non-persistence). A literature search was conducted using BIOSIS Previews, EMBASE, Cochrane Collaboration and MEDLINE databases to identify references with specific relevance to the measurement of health outcomes related to adverse events of long-term opioid treatment of chronic pain. The results of this search highlighted that clinical interventions required to manage adverse events associated with opioids, and to provide alternative methods of pain control, both incur direct costs. These are largely driven by the cost of medical consults and drug supplies. Indirect costs are generated from work absences and reduced social functioning. Estimated preference ratings, providing an insight into the trade-off between effective pain control and adverse events, have shown that utility decrements associated with an increase in adverse-event severity were similar in size to those caused by a shift from well controlled to poorly controlled pain. Given the rising prevalence of chronic pain conditions (affecting one in five adult Europeans), the direct and indirect costs incurred from the management of adverse events with long-term opioids are likely to be multiplied, contributing to the socioeconomic burden of chronic pain. For this reason, the adverse-event profile of opioid-based analgesics should be improved to achieve more efficient long-term pain control.

Early adverse events and attrition in selective serotonin reuptake inhibitor treatment: a suicide assessment methodology study report.

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of adverse effects or the frequency, intensity, or burden of adverse effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n = 265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific adverse effects were evaluated with the Systematic Assessment for Treatment Emergent Events--Systematic Inquiry, and at week 2, the Frequency, Intensity, and Burden of Side Effects Rating globally assessed adverse effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 adverse effect, either treatment-emergent or with worsening intensity, was independently associated with attrition. Global ratings of adverse effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific adverse effects at week 2 were related to patient attrition during SSRI treatment. Other factors seem to contribute to patient decisions about continuing with treatment.

Psychiatric aspects of pediatric cancer.

The diagnosis and treatment of children and adolescents with cancer has a tremendous and lasting effect on the patients, their families, and other individuals in their social network. It carries a host of psychological and behavioral ramifications, from questions of mortality to changes in levels of functioning in multiple domains. In this review the authors address the psychosocial and treatment-related issues that arise in children with cancer, with attention to the adjustment to cancer at different developmental stages, mood and anxiety issues, treatment-related psychiatric sequelae, and the challenges faced by childhood cancer survivors.

Repeated dosing with oral cocaine in humans: assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.

Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies.

We sought to develop an enrichment crossover study design that would allow us to efficiently evaluate and compare promising candidate neuropathic pain drugs. We evaluated the efficacy of gabapentin or tramadol vs. active placebo (diphenhydramine) in subjects with biopsy-proven painful idiopathic small fiber neuropathy (SFN) who were self-reported gabapentin responders. Eligible subjects entered two single blind run-in phases. In the first phase (Period A), subjects were treated with single blinded gabapentin at their prestudy dose followed by a second run-in phase (Period B) in which they were treated with diphenhydramine active placebo. Subjects with >or=3 pain and a >or=30% increase in pain intensity in Period B compared to Period A were then randomized to a double-blind three period cross over trial of gabapentin at pre study dosage, tramadol 50mg QID and diphenhydramine 50mgqhs. Of the 59 subjects enrolled, 41 subjects were excluded: Twenty-three had an insufficient rise in pain intensity in Period B; eight had skin biopsies that did not confirm SFN. Eighteen subjects were randomized into the double-blind, crossover phase. There was a significant treatment effect of gabapentin vs. diphenhydramine (p=0.001) and tramadol vs. diphenhydramine (p=0.018) by the before-bed daily pain score averaged over the final 7 days of each treatment period. We conclude that gabapentin and tramadol were effective in the treatment of painful SFN and that this experimental enrichment paradigm is attractive to screen potential neuropathic pain compounds for efficacy in proof-of-concept studies.

Hypnosedative-induced complex behaviours : incidence, mechanisms and management.

A number of news items and case reports describing complex behaviours (e.g. sleep driving, sleep cooking, sleep eating, sleep conversations, sleep sex) associated with the use of hypnosedative medications have recently received considerable attention. Regulatory agencies examining these reports have subsequently issued warnings regarding the potential of hypnosedative agents to produce complex behaviours. Despite these warnings, little is known about the likelihood, presentation, treatment or prevention of hypnosedative-induced complex behaviours. The purpose of this review is to evaluate the published evidence regarding the clinical presentation, incidence, mechanism and management of sleep-related behaviours induced by nonbenzodiazepine receptor agonists (NBRAs).Review of the literature identified ten published case reports of NBRA-induced complex behaviours involving 17 unique patients. Fifteen of the 17 patients described in the case reports had taken zolpidem, one had taken zaleplon and one had taken zopiclone. The complex behaviours most commonly reported were sleep eating, sleepwalking with object manipulation, sleep conversations, sleep driving, sleep sex and sleep shopping. Elevated serum concentrations resulting from increased medication dose or drug-drug interactions appeared to play a role in some but not all cases. Sex, age, previous medication exposure and concomitant disease states were not consistently found to be related to the risk of experiencing a medication-induced complex behaviour.From a pharmacological standpoint, enhancement of GABA activity at GABAA receptors (particularly alpha1-GABAA receptors) is a possible mechanism for hypnosedative complex behaviours and amnesia. Evidence suggests that complex behaviour risk may increase with both dose and binding affinity at alpha1-GABAA receptors. The amnesia that accompanies complex behaviours is possibly due to inhibition of consolidation of short- to long-term memory, suggesting that the risk may extend to non-GABAergic hypnosedatives. While amnesia and GABA-related receptor actions are the most frequently discussed mechanisms for complex behaviours in the literature, they do not fully explain such behaviours, suggesting that other mechanisms and factors probably play a role.A number of potential strategies are available to manage or prevent hypnosedative-induced complex behaviours. These include lowering the dose of, or stopping, the offending hypnosedative, switching to a different hypnosedative, treating patients with other classes of medications, using nonpharmacological treatment strategies for patients with sleep disorders, examining drug regimens for potential drug interactions that may predispose patients to experiencing complex behaviours, administering hypnosedative medications appropriately and selecting patients more carefully for treatment in terms of their likelihood of experiencing medication adverse effects.

Medication and dietary compliance beliefs in heart failure.

Patients with heart failure are required to comply with a medication regimen and dietary sodium restrictions. The objectives of this study were to determine the most frequently perceived benefits of and barriers to compliance with medication and dietary sodium restrictions and evaluate the relevancy of these scale items for testing in tailored intervention studies. Data were collected as part of two studies that evaluated the psychometric properties of two questionnaires. The most frequently identified benefit of medication compliance was decreasing the chance of being hospitalized, and the most commonly reported barrier was disruption of sleep. Patients were knowledgeable about the benefits of compliance with dietary sodium restrictions, and the poor taste of food on the low sodium diet was the most common barrier. Heart failure patients perceive benefits of and barriers to compliance with therapeutic regimens that are likely to be amenable to tailored interventions designed to enhance compliance.

Comprehensive care of the epilepsy patient--control, comorbidity, and cost.

Traditionally, control of seizures in patients with epilepsy is viewed as the most important clinical outcome. Yet, current antiepileptic drugs (AEDs) do not always achieve this. Around 30-40% of patients remain uncontrolled despite pharmacological intervention. Poor tolerability of AEDs is a large part of the problem and contributes as much to the overall effectiveness of therapy as efficacy. Comorbid conditions are present in many patients, and appropriate management of these can further improve seizure control and quality of life. Patients with epilepsy often experience--among other disorders--neuropsychological effects, migraines, and psychological problems (especially anxiety and depression). Sleep disturbances are also common and have been shown to contribute to the intractability of seizures in some patients. Many anticonvulsant treatments have the potential to improve--or in some cases worsen--these concurrent conditions, and these properties should therefore be considered in the total care of the patient. Finally, the costs of uncontrolled epilepsy are measured not only in terms of direct healthcare-related costs, but also in terms of lost productivity and opportunity. The indirect costs of epilepsy are substantial and account for 70-85% of total disease-related costs. Patients with uncontrolled seizures contribute disproportionately to healthcare costs, reinforcing the need for the development of newer AEDs with improved profiles of efficacy and tolerability, but with minimal adverse effects on behavior, cognition, and sleep.

Aeroallergens, allergic rhinitis, and sedating antihistamines: risk factors for traumatic occupational injury and economic impact.

BACKGROUND: The U.S. workplace injury burden is significant. Our objective was to assess the particular impact of aeroallergen, allergic rhinitis, and antihistamine exposures and side effects on the risk of traumatic work-related injuries, and the associated economic impact. METHODS: This is an observational case-control study with 1,223 acute traumatic injury cases that are compared to 1,202 chronic back injury controls. Structured telephone interviews were conducted in 1998 and 1999 on Workers' Compensation applicants injured in 1997. Antihistamine use and pollen levels were measured 2 weeks prior to the injury date. RESULTS: Sedating antihistamine exposures elevated acute injury risk (main effect OR: 2.93). A significant increase in traumatic injury risk was observed for combined sedating antihistamine and high pollen exposures among subjects with physician and self-diagnosed allergic rhinitis (OR: 2.41). Direct medical costs associated with this increased risk were estimated at $143 million in 2001. CONCLUSIONS: Workers with physician-diagnosed allergic rhinitis have as high a reliance on sedating antihistamines as do self-diagnosed and self-medicating nasal allergy sufferers. High pollen exposures along with sedating antihistamine use may confer significant additional injury risks among allergic rhinitis sufferers. Medical management "best practices" of diagnosed allergic rhinitis should include avoidance of sedating antihistamines to minimize acute, traumatic injury risks.

Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz.

OBJECTIVES: The Sensio study objectives were to assess the outcome of neuropsychiatric adverse reactions (NPAR) that develop after initiation of efavirenz (EFV) therapy, to ascertain the late NPAR after a 3-month treatment period, to evaluate the impact of NPAR on patients' quality of life (QoL) in a real-life population. METHODS: During a 6-month period, consecutive HIV-infected adult outpatients receiving an ongoing EFV therapy for at least 3 months were asked to fill in a specifically designed self-administered questionnaire addressing sleep disturbances, behavioural changes, mood disturbances, anxiety, cognitive disorders, hallucinations, dizziness and the general impact on patients' QoL. RESULTS: A total of 174 questionnaires were analyzed. The main late emergent NPAR were sleep disorders: abnormal dreams 24.7%, nocturnal waking 19.6%, trouble falling asleep 17.8%; cognitive disorders: memory disorders 23.0%, impaired concentration 18.9%; anxiety 15.5%; mood disorders: sadness 19.3%, suicidal ideations 9.2%. Global neuropsychic discomfort was moderate to severe in 23% of patients after a 3-month treatment period. CONCLUSION: NPAR occur mainly during the first month of EFV therapy but often persist thereafter. A significant percentage of patients reported suicidal ideations at the time of the study. Our results suggest the need for routine screening for NPAR among patients receiving EFV therapy and better management.

A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression.

The authors assessed the severity of nortriptyline's side-effects in older patients with recurrent major depression during placebo-controlled, double-blind maintenance therapy. Data were from 37 patients completing 2-3 years of maintenance therapy; 29 were on nortriptyline and eight were on placebo. The authors detected a time-by-treatment interaction for dry mouth (greater in nortriptyline-treated patients), but no increased association of nortriptyline with constipation, weight change or orthostatic symptoms. Heart rate was consistently higher in nortriptyline-maintained patients as compared with placebo. The total 'side-effect' score on the Asberg Rating Scale, as well as complaints of physical tiredness, daytime sleepiness and nocturnal sleep disturbance, were related primarily to residual depression rather than treatment with nortriptyline.

Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: The increasing costs of managing asthma are due in part to the introduction of new medications, such as leukotriene receptor antagonists. These antagonists interfere with the action of leukotrienes, which are implicated in bronchoconstriction and the formation of airway edema in patients with asthma. Leukotriene receptor antagonists must be shown to be clinically and economically effective for their clinical use to be justified. OBJECTIVE: To assess the clinical and economic effectiveness of zafirlukast, a leukotriene receptor antagonist, in patients with mild-to-moderate asthma who might benefit from regular anti-inflammatory therapy. DESIGN: Randomized, double-blind, multicenter, placebo-controlled trial. SETTING: 28 outpatient clinics. PATIENTS: 146 patients with mild-to-moderate asthma who were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, had an FEV1 at least 55% of the predicted value with no upper limit, had demonstrated bronchial hyperresponsiveness, and were symptomatic during the 7-day run-in period. All patients were seen every 2 to 3 weeks for 13 weeks. INTERVENTION: 103 patients received zafirlukast (20 mg twice daily), and 43 patients received placebo (twice daily). All patients received inhaled beta-agonists as needed. MEASUREMENTS: Data were obtained from medical examinations, patient questionnaires, and daily diaries. The clinical effectiveness outcomes were days per month without asthma symptoms, limitation of activity, use of beta-agonists, sleep disturbance, and episodes of asthma (the latter was a composite measure made up of the first four outcomes plus the occurrence of adverse events). The economic effectiveness outcomes were frequency and type of unscheduled health care contacts, use of beta-agonist inhalers, consumption of nonasthma medications, and days of absence from work or school. RESULTS: The zafirlukast group had 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without use of beta-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). They also had 55% (95% CI, 19% to 74%) fewer health care contacts (18.5 compared with 40.7 per 100 per month; P = 0.007) and 55% (CI, 3% to 79%) fewer days of absence from work or school (15.6 compared with 35.0 per 100 per month; P = 0.04). They used 17% fewer canisters of inhaled beta-agonists (P = 0.17) and 19% less nonasthma medication (P < 0.2). CONCLUSIONS: A daily regimen of zafirlukast added to as-needed inhaled beta-agonists is more effective than beta-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma.