Combination pharmacotherapy for the treatment of fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects. OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache. AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.

Economies of scale: body mass index and costs of cardiac surgery in Ontario, Canada.

An obesity paradox has been described, whereby obese patients have better health outcomes than normal weight patients in certain clinical situations, including cardiac surgery. However, the relationship between body mass index (BMI) and resource utilization and costs in patients undergoing coronary artery bypass graft (CABG) surgery is largely unknown. We examined resource utilization and cost data for 53,224 patients undergoing CABG in Ontario, Canada over a 10-year period between 2002 and 2011. Data for costs during hospital admission and for a 1-year follow-up period were derived from the Institute for Clinical Evaluative Sciences, and analyzed according to pre-defined BMI categories using analysis of variance and multivariate models. BMI independently influenced healthcare costs. Underweight patients had the highest per patient costs ($50,124 ± $36,495), with the next highest costs incurred by morbidly obese ($43,770 ± $31,747) and normal weight patients ($42,564 ± $30,630). Obese and overweight patients had the lowest per patient costs ($40,760 ± $30,664 and $39,960 ± $25,422, respectively). Conversely, at the population level, overweight and obese patients were responsible for the highest total yearly population costs to the healthcare system ($92 million and $50 million, respectively, compared to $4.2 million for underweight patients). This is most likely due to the high proportion of CABG patients falling into the overweight and obese BMI groups. In the future, preoperative risk stratification and preparation based on BMI may assist in reducing surgical costs, and may inform health policy measures aimed at the management of weight extremes in the population.

A novel software program for detection of potential air emboli during cardiac surgery.

BACKGROUND: Risks associated with air emboli introduced during cardiac surgery have been highlighted by reports of postoperative neuropsychological dysfunction, myocardial dysfunction, and mortality. Presently, there are no standard effective methods for quantifying potential emboli in the bloodstream during cardiac surgery. Our objective was to develop software that can automatically detect and quantify air bubbles within the ascending aorta and/or cardiac chambers during cardiac surgery in real time. FINDINGS: We created a software algorithm ("Detection of Emboli using Transesophageal Echocardiography for Counting, Total volume, and Size estimation", or DETECTS™) to identify and measure potential emboli present during cardiac surgery using two-dimensional ultrasound. An in vitro experiment was used to validate the accuracy of DETECTS™ at identifying and measuring air emboli. An experimental rig was built to correlate the ultrasound images to high definition camera images of air bubbles created in water by an automatic bubbler system. There was a correlation between true bubble size and the size reported by DETECTS™ in our in vitro experiment (r = 0.76). We also tested DETECTS™ using TEE images obtained during cardiac surgery, and provide visualization of the software interface. CONCLUSIONS: While monitoring the heart during cardiac surgery using existing ultrasound technology and DETECTS™, the operative team can obtain real-time data on the number and volume of potential air emboli. This system will potentially allow de-airing techniques to be evaluated and improved upon. This could lead to reduced air in the cardiac chambers after cardiopulmonary bypass, possibly reducing the risk of neurological dysfunction following cardiac surgery.

Novel male exposure reduces uterine e-cadherin, increases uterine luminal area, and diminishes progesterone levels while disrupting blastocyst implantation in inseminated mice.

Exposure to novel male mice disrupts blastocyst implantation in inseminated female mice, and evidence increasingly implicates the female's absorption of male urinary estrogens. We observed implantation sites in male-exposed and isolated control female mice during gestation days (GD) 2-8, observing a significant reduction in male-exposed females compared to controls, particularly on GD 6 and 8. We also measured transitions in uterine luminal area and e-cadherin expression, as these processes are modulated by estrogens. Luminal area was greater in male-exposed females than in controls during the post-implantation period (GD 5-7). E-cadherin levels were suppressed by male exposure, particularly during GD 4-6 Serum progesterone levels were also reduced in male-exposed females. The effects of male exposure on uterine closure and e-cadherin levels are consistent with established effects of estrogens, and suggest a possible mechanism that could contribute to implantation failure. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

Estrogen-progesterone balance in the context of blastocyst implantation failure induced by predator stress.

Diverse stressors can disrupt blastocyst implantation in inseminated female mammals. Stress-induced implantation failure can be mimicked by minute doses of exogenous estradiol, and some evidence indicates that it may be mitigated by exogenous progesterone. In Experiment 1, we showed that acute exposure to a rat across a wire-mesh grid caused elevation of corticosterone and progesterone. In Experiment 2, we showed that exposure of inseminated mice to rats across a grid during gestation days 1-5 was associated with avoidance of proximity to the grid and a significantly reduced number of implantation sites on gestation day 6. Rat-exposure also resulted in elevated progesterone levels in females that maintained their pregnancies, and elevated estradiol levels in females that lost their pregnancies. In Experiment 3, we investigated whether exogenous progesterone, estradiol, or a combination of both could influence implantation failure induced by rat-exposure stress. Treatment with 100 ng estradiol per day on gestation days 1-5 induced a complete absence of implantation sites on gestation day 6, regardless of the presence or absence of the stressor. Administration of 500 µg progesterone per day was insufficient to prevent the stress-induced pregnancy loss. However, 500 µg progesterone plus 10 ng estradiol per day did prevent implantation failure in rat-exposed females. These findings are consistent with the hypothesis that estradiol elevations contribute to stress-induced pregnancy loss, but show paradoxically that low doses of estradiol can act together with progesterone to mitigate stress-induced pregnancy loss.

Perturbation of male sexual behavior in mice (Mus musculus) within a discrete range of perinatal bisphenol-A doses in the context of a high- or low-phytoestrogen diet.

Differentiation of masculine and feminine behavior in mammals depends on perinatal sex steroids. As bisphenol-A (BPA) can be estrogenic and anti-androgenic, we examined impacts of perinatal exposure upon adult sexual behavior and morphology of male mice. In Experiment 1, dams were fed either a high- or low-phytoestrogen diet and received daily oral doses of 0, 0.175, 1.75, or 17.5µg BPA from gestation day 10 through post-partum day 9. Male offspring from the high-phytoestrogen plus 17.5µg BPA condition showed reduced mass of vesicular-coagulating but not other male glands, and showed increased latency to insemination when paired with females. In Experiment 2, these procedures were replicated but with all animals fed the high-phytoestrogen diet and perinatal BPA doses of 0, 17.5, 175, or 1750µg/day. Adult masses of testes and male-accessory glands and levels of urinary steroids were not significantly affected. When males each encountered a sexually receptive female, there were fewer intromissions among those given 17.5 or 175µg and fewer ejaculations among those given 17.5µg, but the 1750µg dose had no effect. Perinatal BPA dosages thus influenced male sexual behavior non-monotonically, with impairment evident in a discrete dose range among males on a high-phytoestrogen diet.

Oestradiol treatment restores the capacity of castrated males to induce both the Vandenbergh and the Bruce effects in mice (Mus musculus).

Androgen-dependent urinary constituents from males hasten reproductive maturation (the Vandenbergh effect) and disrupt peri-implantation pregnancy (the Bruce effect) in nearby females. Each of these effects can be mimicked in socially isolated females by direct administration of exogenous oestrogens. The current experiments were designed to determine the role of males' urinary 17ß-oestradiol (E(2)) in their capacities to induce these effects. A preliminary experiment showed that both males on a phyto-oestrogen-rich soy-based diet and those on a phyto-oestrogen-free diet could induce both effects. For subsequent experiments, males were castrated and treated with either oil vehicle or E(2). Enzyme immunoassay was conducted on non-invasively collected urine samples from these males. Concentrations of urinary testosterone were subnormal in both conditions, but urinary E(2) was restored to the normal range for intact males in castrates given E(2). Urinary creatinine was also quantified as a measure of hydration and was significantly reduced in males treated with E(2). Castration diminished the capacity of males to promote growth of the immature uterus and also their capacity to disrupt blastocyst implantation in inseminated females. Injections of E(2) to castrated males restored both capacities. These data converge with other studies indicating that E(2) is the main constituent of male urine responsible for induction of both the Vandenbergh and the Bruce effects.