Opioid analgesic effects on subjective well-being in the operating theatre.

Exposure to opioid analgesics due to surgery increases the risk of new persistent opioid use. A mechanistic hypothesis for opioids' abuse liability rests on the belief that, in addition to pain relief, acute opioid treatment improves well-being (e.g. via euphoria) and relieves anxiety. However, opioids do not consistently improve mood in laboratory studies of healthy non-opioid users. This observational study determined how two commonly used opioid analgesics affected patients' subjective well-being in standard clinical practice. Day surgery patients rated how good and how anxious they felt before and after an open-label infusion of remifentanil (n = 159) or oxycodone (n = 110) in the operating theatre before general anaesthesia. One minute after drug injection, patients reported feeling intoxicated (> 6/10 points). Anxiety was reduced after opioids, but this anxiolytic effect was modest (remifentanil Cohen's d = 0.21; oxycodone d = 0.31). There was moderate to strong evidence against a concurrent improvement in well-being (Bayes factors > 6). After remifentanil, ratings of 'feeling good' were significantly reduced from pre-drug ratings (d = 0.28). After oxycodone, one in three participants felt better than pre-drug. Exploratory ordered logistic regressions revealed a link between previous opioid exposure and opioid effects on well-being, as only 14 of the 80 opioid-naïve patients reported feeling better after opioid injection. The odds of improved well-being ratings after opioids were higher in patients with previous opioid exposure and highest in patients with > 2 weeks previous opioid use (adjusted OR = 4.4). These data suggest that opioid-induced improvement of well-being is infrequent in opioid-naïve patients. We speculate that peri-operative exposure could increase risk of persistent use by rendering subsequent positive opioid effects on well-being more likely.

Understanding and restoring dopaminergic function in fibromyalgia patients using a mindfulness-based psychological intervention: a [18F]-DOPA PET study. Study protocol for the FIBRODOPA study-a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) is a very prevalent and debilitating chronic pain disorder that is difficult to treat. Mindfulness-based techniques are regarded as a very promising approach for the treatment of chronic pain and in particular FM. The Mindfulness-Oriented Recovery Enhancement (MORE) intervention, a mindfulness-based group intervention, has shown beneficial effects in opioid-treated chronic pain patients, including reduced pain severity, functional interference, and opioid dosing, by restoring neurophysiological and behavioral responses to reward. The first evidence for a hypodopaminergic state and impaired reward processing in FM has been reported. However, little is known about its impact on dopamine (DA) function and in particular with regard to DA responses to monetary reward in FM. The aim of the present study protocol is to evaluate if MORE is able to restore the DA function in FM patients, in particular with regard to the DA responses to reward, and to reduce pain and mood complaints in FM. METHODS: The present study is a multi-center interventional RCT with 3 time points: before the intervention, after completion of the intervention, and 3 months after completion of the intervention. Sixty-four FM patients will be randomly assigned to either the MORE intervention (N = 32) or a non-intervention control group (N = 32). Additionally, a comparison group of healthy women (N = 20) for PET measures will be enrolled and another group of healthy women (N = 15) will do the ambulatory assessments only. The MORE intervention consists of eight 2-h-long group sessions administered weekly over a period of 8 weeks. Before and after the intervention, FM participants will undergo [18F] DOPA positron emission tomography (PET) and functional MR imaging while performing a reward task. The primary outcome will be endogeneous DA changes measured with [18F] DOPA PET at baseline, after the intervention (after 8 weeks for the non-intervention control group), and at 3 months' follow-up. Secondary outcomes will be (1) clinical pain measures and FM symptoms using standardized clinical scales; (2) functional brain changes; (3) measures of negative and positive affect, stress, and reward experience in daily life using the ambulatory assessment method (AA); and (4) biological measures of stress including cortisol and alpha-amylase. DISCUSSION: If the findings of this study confirm the effectiveness of MORE in restoring DA function, reducing pain, and improving mood symptoms, MORE can be judged to be a promising means to improve the quality of life in FM patients. The findings of this trial may inform health care providers about the potential use of the MORE intervention as a possible non-pharmacological intervention for FM. TRIAL REGISTRATION: ClinicalTrials.gov NCT04451564 . Registered on 3 July 2020. The trial was prospectively registered.

The face of postural tachycardia syndrome - insights from a large cross-sectional online community-based survey.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There are minimal data detailing the demographics, clinical features and clinical course of this condition. This online, community-based survey highlights patients' experience with POTS. It consists of the largest sample of POTS patients reported to date. OBJECTIVES: To describe the demographics, past medical history, medications, treatments and diagnostic journey for patients living with POTS. METHODS: Postural tachycardia syndrome patients completed an online, community-based, cross-sectional survey. Participants were excluded if they had not received a diagnosis of POTS from a physician. The questions focused on the patient experience and journey, rather than physiological responses. RESULTS: The final analysis included 4835 participants. POTS predominantly affects white (93%) females (94%) of childbearing age, with approximately half developing symptoms in adolescence (mode 14 years). POTS is a chronic multisystem disorder involving a broad array of symptoms, with many patients diagnosed with comorbidities in addition to POTS. POTS patients often experience lengthy delays [median (interquartile range) 24 (6-72) months] and misdiagnosis, but the diagnostic delay is improving. POTS patients can present with a myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%). CONCLUSIONS: These data provide important insights into the background, clinical features and diagnostic journey of patients suffering from POTS. These data should serve as an essential step for moving forward with future studies aimed at early and accurate diagnoses of these patients leading to appropriate treatments for their symptoms.

Restructuring Reward Mechanisms in Nicotine Addiction: A Pilot fMRI Study of Mindfulness-Oriented Recovery Enhancement for Cigarette Smokers.

The primary goal of this pilot feasibility study was to examine the effects of Mindfulness-Oriented Recovery Enhancement (MORE), a behavioral treatment grounded in dual-process models derived from cognitive science, on frontostriatal reward processes among cigarette smokers. Healthy adult (N = 13; mean (SD) age 49 ± 12.2) smokers provided informed consent to participate in a 10-week study testing MORE versus a comparison group (CG). All participants underwent two fMRI scans: pre-tx and after 8-weeks of MORE. Emotion regulation (ER), smoking cue reactivity (CR), and resting-state functional connectivity (rsFC) were assessed at each fMRI visit; smoking and mood were assessed throughout. As compared to the CG, MORE significantly reduced smoking (d = 2.06) and increased positive affect (d = 2.02). MORE participants evidenced decreased CR-BOLD response in ventral striatum (VS; d = 1.57) and ventral prefrontal cortex (vPFC; d = 1.7) and increased positive ER-BOLD in VS (dVS = 2.13) and vPFC (dvmPFC = 2.66). Importantly, ER was correlated with smoking reduction (r's = .68 to .91) and increased positive affect (r's = .52 to .61). These findings provide preliminary evidence that MORE may facilitate the restructuring of reward processes and play a role in treating the pathophysiology of nicotine addiction.

Treating child and adolescent anxiety effectively: Overview of systematic reviews.

We conducted an overview of systematic reviews about child and adolescent anxiety treatment options (psychosocial; medication; combination; web/computer-based treatment) to support evidence informed decision-making. Three questions were addressed: (i) Is the treatment more effective than passive controls? (ii) Is there evidence that the treatment is superior to or non-inferior to (i.e., as good as) active controls? (iii) What is the quality of evidence for the treatment? Pre-specified inclusion criteria identified high quality systematic reviews (2000-2015) reporting treatment effects on anxiety diagnosis and symptom severity. Evidence quality (EQ) was rated using Oxford evidence levels [EQ1 (highest); EQ5 (lowest)]. Twenty-two of 39 eligible reviews were high quality (AMSTAR score≥3/5). CBT (individual or group, with or without parents) was more effective than passive controls (EQ1). CBT effects compared to active controls were mixed (EQ1). SSRI/SNRI were more effective than placebo (EQ1) but comparative effectiveness remains uncertain. EQ for combination therapy could not be determined. RCTs of web/computer-based interventions showed mixed results (EQ1). CBM/ABM was not more efficacious than active controls (EQ1). No other interventions could be rated. High quality RCTs support treatment with CBT and medication. Findings for combination and web/computer-based treatment are encouraging but further RCTs are required. Head-to-head comparisons of active treatment options are needed.

A Pilot Study of Citalopram Treatment in Preventing Relapse of Depressive Episode after Acute Treatment.

PURPOSE: To examine the benefit of continuation treatment with citalopram in adolescents 13 to 18 years of age with major depression using a multi-site randomized placebo controlled discontinuation design. METHODS: Subjects with depression who responded to open label treatment with citalopram in 12-week acute phase were randomized to continued treatment with citalopram or placebo for 24 weeks. RESULTS: Twenty five subjects were randomized to either continued treatment with citalopram (n = 12) versus placebo (n = 13). Seventy-five percent of subjects on citalopram (75%) remained well as compared to placebo (62%). Time to relapse was compared between groups using the log rank test and was not found to be significantly different (χ(2)(1) = 0.35, P = 0.55). A Cox proportional hazards model including drug assignment (hazard ratio (HR = 0.51, 95% CI 0.11 to 2.36, P = 0.39), gender (HR = 0.58, 95% CI 0.14 to 2.37, P = 0.44), or HAM-score at entry to continuation phase (HR = 1.33, 95% CI 0.90 to 1.95, P = 0.95) was not significant. CONCLUSION: Although we did not find statistically significant differences between citalopram and placebo, the findings suggest a possible benefit of continued treatment with citalopram over placebo. A larger clinical trial with adequate power is required to confirm or disconfirm these findings.

OBJECTIF: Examiner l'avantage d'un traitement de stabilisation par citalopram chez des adolescents de 13 à 18 ans souffrant de dépression majeure au moyen d'un essai d'arrêt randomisé, multicentrique et contrôlé contre placebo. MÉTHODES: Les sujets souffrant de dépression qui ont répondu au traitement avec étiquetage en clair par citalopram durant une phase aiguë de 12 semaines ont été randomisés dans le traitement de stabilisation par citalopram ou placebo durant 24 semaines. RÉSULTATS: Vingt-cinq sujets ont été randomisés dans un traitement de stabilisation soit par citalopram (n = 12), soit contre placebo (n = 13). Soixante-quinze pour cent des sujets traités par citalopram (75%) sont demeurés sans rechute comparativement à ceux du placebo (62%). Le délai avant la rechute a été comparé entre les groupes à l'aide du test de Mantel-Haenzel et n'était pas significativement différent (χ2(1) = 0,35; P = 0,55). Un modèle de risques proportionnels de Cox incluant l'assignation des médicaments (rapport des risques (RR = 0,51; IC à 95% 0,11 à 2,36; P = 0,39), le sexe (RR = 0,58; IC à 95% 0,14 à 2,37; P = 0,44), ou le score à l'échelle HAM au départ jusqu'à la phase de stabilisation (RR = 1,33; IC à 95% 0,90 à 1,95; P = 0,95) n'était pas significatif. CONCLUSION: Bien que nous n'ayons pas observé de différences statistiquement significatives entre le citalopram et le placebo, les résultats suggèrent un avantage possible du traitement de stabilisation par citalopram plutôt que placebo. Il faut un essai clinique plus vaste de puissance adéquate pour confirmer ou infirmer ces résultats.

PREVENTING CHILD AND ADOLESCENT ANXIETY DISORDERS: OVERVIEW OF SYSTEMATIC REVIEWS.

Overviews of systematic reviews (OSRs) provide rapid access to high quality, consolidated research evidence about prevention intervention options, supporting evidence-informed decision-making, and the identification of fruitful areas of new research. This OSR addressed three questions about prevention strategies for child and adolescent anxiety: (1) Does the intervention prevent anxiety diagnosis and/or reduce anxiety symptoms compared to passive controls? (2) Is the intervention equal to or more effective than active controls? (3) What is the evidence quality (EQ) for the intervention? Prespecified inclusion criteria identified systematic reviews and meta-analyses (2000-2014) with an AMSTAR quality score ≥ 3/5. EQ was rated using Oxford evidence levels EQ1 (highest) to EQ5 (lowest). Three reviews met inclusion criteria. One narrative systematic review concluded school-based interventions reduce anxiety symptoms. One meta-analysis pooled 65 randomized controlled trials (RCTs; any intervention) and reported a small, statistically significant reduction in anxiety symptoms and diagnosis incidence. Neither review provided pooled effect size estimates for specific intervention options defined by type (i.e., universal/selective/indicated), intervention content, or comparison group (i.e., passive/active control), thus precluding EQ ratings. One meta-analysis pooled trials of vigorous exercise and reported small, nonstatistically significant reductions in anxiety symptoms for comparisons against passive and active controls (EQ1). Better use of primary studies in meta-analyses, including program-specific pooled effect size estimates and network meta-analysis is needed to guide evidence-informed anxiety prevention program choices. RCTs of innovative community/primary care based interventions and web-based strategies can fill knowledge gaps.

Origins of the classical gene concept, 1900-1950: genetics, mechanistic, philosophy, and the capitalization of agriculture.

In the period of "classical genetics" (roughly 1915-950), the common view of the gene was mechanistic--hat is, genes were seen as individual, atomistic units, as material components of the chromosomes. Although it was recognized early on that genes could interact and influence each other's expression, they were still regarded as individually functioning units, much like the chemists' atoms or molecules. Although geneticists in particular knew the story was more complex, the atomistic gene remained the central view for a variety of reasons. It fit the growing philosophy of mechanistic materialism in the life sciences, as biologists tried to make their field more quantitative,rigorous, and predictive, like physics and chemistry. Conceptually and pedagogically, it provided a simple way to depict genes (as beads on a string) that fit with the exciting new work on chromosomal mapping. The atomistic gene also fit well with the increasing drive to move capital into agriculture, both for potential patenting purposes and for ease of experimental manipulation and prediction. It is the latter point that the present essay explores most thoroughly. The rise of agriculture as an industrialized process provided a context and material support that fueled much of the rapid growth of genetics in the first half of the 20th century.

"Culling the herd": eugenics and the conservation movement in the United States, 1900-1940.

While from a late twentieth- and early twenty-first century perspective, the ideologies of eugenics (controlled reproduction to eliminate the genetically unfit and promote the reproduction of the genetically fit) and environmental conservation and preservation, may seem incompatible, they were promoted simultaneously by a number of figures in the progressive era in the decades between 1900 and 1950. Common to the two movements were the desire to preserve the "best" in both the germ plasm of the human population and natural environments (including not only natural resources, but also undisturbed nature preserves such as state and national parks and forests). In both cases advocates sought to use the latest advances in science to bolster and promote their plans, which in good progressive style, involved governmental planning and social control. This article explores the interaction of eugenic and conservationist ideologies in the careers of Sacramento banker and developer Charles M. Goethe and his friend and mentor, wealthy New York lawyer Madison Grant. In particular, the article suggests how metaphors of nature supported active work in both arenas.

Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children.

BACKGROUND: The annual cut-off date of birth for entry to school in British Columbia, Canada, is Dec. 31. Thus, children born in December are typically the youngest in their grade. We sought to determine the influence of relative age within a grade on the diagnosis and pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD) in children. METHODS: We conducted a cohort study involving 937 943 children in British Columbia who were 6-12 years of age at any time between Dec. 1, 1997, and Nov. 30, 2008. We calculated the absolute and relative risk of receiving a diagnosis of ADHD and of receiving a prescription for a medication used to treat ADHD (i.e., methylphenidate, dextroamphetamine, mixed amphetamine salts or atomoxetine) for children born in December compared with children born in January. RESULTS: Boys who were born in December were 30% more likely (relative risk [RR] 1.30, 95% confidence interval [CI] 1.23-1.37) to receive a diagnosis of ADHD than boys born in January. Girls born in December were 70% more likely (RR 1.70, 95% CI 1.53-1.88) to receive a diagnosis of ADHD than girls born in January. Similarly, boys were 41% more likely (RR 1.41, 95% CI 1.33-1.50) and girls 77% more likely (RR 1.77, 95% CI 1.57-2.00) to be given a prescription for a medication to treat ADHD if they were born in December than if they were born in January. INTERPRETATION: The results of our analyses show a relative-age effect in the diagnosis and treatment of ADHD in children aged 6-12 years in British Columbia. These findings raise concerns about the potential harms of overdiagnosis and overprescribing. These harms include adverse effects on sleep, appetite and growth, in addition to increased risk of cardiovascular events.

Eugenics and modern biology: critiques of eugenics, 1910-1945.

Eugenics in most western countries in the first four decades of the 20th century was based on the idea that genes control most human phenotypic traits, everything from physical features such as polydactyly and eye colour to physiological conditions such as the A-B-O blood groups to mental and personality traits such as "feeblemindedness," alcoholism and pauperism. In assessing the development of the eugenics movement-its rise and decline between 1900 and 1950-it is important to recognise that its naïve assumptions and often flawed methodologies were openly criticised at the time by scientists and nonscientists alike. This paper will present a brief overview of the critiques launched against eugenicists' claims, particularly criticisms of the American school led by Charles B. Davenport. Davenport's approach to eugenics will be contrasted to his British counterpart, Karl Pearson, founder and first editor of the Annals of Eugenics. It was not the case that nearly everyone in the early 20th century accepted eugenic conclusions as the latest, cutting-edge science. There are lessons from this historical approach for dealing with similar naïve claims about genetics today.

Evaluation of a preventive intervention for child anxiety in two randomized attention-control school trials.

The present research examined the effectiveness of a cognitive-behavioral therapy (CBT) based intervention program, FRIENDS, for children from grades 4 to 6, using random assignment at the school-level and an attention-control design in two longitudinal studies. The first study targeted children with anxiety symptoms (N=191, mean age=10.1) as screened with self, parent, and teacher-reports; the second study took a universal approach with full classrooms of children participating (N=253, mean age=9.8). The results showed no intervention effect in both studies, with children's anxiety symptoms decreasing over time regardless of whether they were in the story-reading (attention control) or FRIENDS condition. The findings also indicated that girls reported a higher level of anxiety than boys and children in higher grades reported lower anxiety relative to younger children in both studies. In addition, similar patterns were found using a subgroup of children with high-anxiety symptoms from both studies.

A cross-sectional study contrasting olfactory function in autonomic disorders.

OBJECTIVE: To compare odor identification function in patients with peripheral or central autonomic neurodegeneration and in patients with intact autonomic neurons but undetectable norepinephrine. METHODS: Olfactory function was evaluated with the University of Pennsylvania Smell Identification Test (UPSIT) in 12 patients with pure autonomic failure, 10 patients with multiple system atrophy, and 4 patients with dopamine ß-hydroxylase deficiency. Blood pressure and catecholamine data were also compared. RESULTS: Odor identification was significantly impaired in patients with pure autonomic failure relative to patients with multiple system atrophy or dopamine ß-hydroxylase deficiency. Out of 40 odors, the patients correctly identified mean (95% confidence interval) 19.2 (14.1 to 24.2), 34.4 (32.2 to 36.6), and 31.7 (29.4 to 34.1) (p < 0.001). The difference between patients with pure autonomic failure and those with multiple system atrophy or dopamine ß-hydroxylase deficiency persisted after adjustment for age (p = 0.001). Patients with pure autonomic failure also had a greater orthostatic fall in blood pressure and lower plasma norepinephrine levels than patients with multiple system atrophy. CONCLUSIONS: Olfactory function was relatively intact in patients with dopamine ß-hydroxylase deficiency, who have intact noradrenergic neurons but lack norepinephrine. Odor identification was impaired in pure autonomic failure but not in multiple system atrophy, suggesting that 1) peripheral noradrenergic innervation is important for olfactory identification but norepinephrine is not essential and 2) UPSIT may be useful in the differential diagnosis between these disorders.

Do Hospital and Community SSRI Usage Patterns in Children and Adolescents Match the Evidence?

OBJECTIVES: 1) To review SSRI prescribing patterns for children and adolescents in our hospital and provincial prescription database and 2) To evaluate whether prescribing practices are consistent with expectations, based on published evidence and practice recommendations. METHODS: A PubMed online search was conducted to obtain all randomized controlled trials assessing efficacy of SSRI use in children and adolescents. The inpatient hospital pharmacy database at BC Children's Hospital (BCCH) and the BC Pharmacare database were used to identify all unique patients (under 19 years of age) seen in the inpatient department of psychiatry at BCCH or as outpatients in the province of BC receiving SSRI prescriptions between 2005-2009. RESULTS: Fluoxetine, citalopram, escitalopram and sertraline have evidence supporting their efficacy in the treatment of depressive disorders. Fluoxetine, fluvoxamine, sertraline, paroxetine and venlafaxine have evidence for use in the treatment of anxiety disorders. Between 2005-2009, BCCH inpatient data revealed that fluoxetine is the most frequently prescribed SSRI, followed by citalopram, sertraline, fluvoxamine, venlafaxine, paroxetine and escitalopram. In the community outpatients, fluoxetine was most frequently prescribed SSRI followed by citalopram, venlafaxine, sertraline, paroxetine, fluvoxamine and escitalopram. CONCLUSIONS: Prescribing patterns for SSRIs at BC Children's Hospital are consistent with the available evidence in the pediatric population. Furthermore, with the exception of citalopram, provincial outpatient and inpatient prescriptions appear to follow published national guidelines. Hospital SSRI usage more closely reflects the available literature than outpatient community usage does.