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Expert Opinion on Pharmacotherapy Oct 2021: Cluster headache (CH) is probably the most severe idiopathic pain condition, yet its current medical management remains poor.: Only repurpose medicines are currently...
: Cluster headache (CH) is probably the most severe idiopathic pain condition, yet its current medical management remains poor.: Only repurpose medicines are currently in use for the prevention of CH, partially because the pathophysiology of the condition is still elusive. In this article we performed a systematic review to evaluate the evidence for efficacy of the currently available or emerging treatments for CH.: We found several ongoing randomized clinical trials testing prophylactic treatments for CH and only few for the standard ones. Recent data from randomized trials with monoclonal antibodies targeting the calcitonin gene related peptide pathway (anti-CGRP mAbs) are controversial, although its role in the pathogenesis of the condition is well documented. This inconsistency may depict inadequacies in clinical trial designing. Anti-CGRP mAbs and antagonists of pituitary adenylate cyclase-activating polypeptide (PACAP) along with neuromodulation techniques, are curing the necessary valuable evidence that could illuminate the therapeutical future for cluster headache. Orexin pathway is another attractive target for CH treatment. To improve the evidence for efficacy, we further propose that the design of the clinical trials for CH needs to be radically reviewed to allow more patients to participate.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Calcitonin Gene-Related Peptide; Cluster Headache; Humans; Migraine Disorders
PubMed: 33989098
DOI: 10.1080/14656566.2021.1924148 -
Journal of Experimental Pharmacology 2021Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the... (Review)
Review
Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I-III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.
PubMed: 33889031
DOI: 10.2147/JEP.S261403 -
Sleep Medicine May 2021Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in... (Meta-Analysis)
Meta-Analysis Review
Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in narcolepsy patients are widely investigated in the literature, the results are controversial. We performed a systematic search of literature to identify metabolic profiling studies in narcolepsy patients. A total of 48 studies were included in the meta-analysis. Narcolepsy patients exhibited higher prevalence of obesity (log OR = 0.93 [0.73-1.13], P < 0.001), diabetes mellitus (log OR = 0.64 [0.34, 0.94], P < 0.001), hypertension (log OR = 0.33 [0.11, 0.55], P < 0.001), and dyslipidemia (log OR = 1.19 [0.60, 1.77], P < 0.001) compared with non-narcoleptic controls. Narcolepsy was associated with higher BMI (SMD = 0.50 [0.32-0.68], P < 0.001), waist circumference (MD = 8.61 [2.03-15.19], P = 0.01), and plasma insulin (SMD = 0.61 [0.14-1.09], P = 0.01). Levels of fasting blood glucose (SMD = -0.25 [-0.61,0.10], P = 0.15), BMR-RMR (SMD = -0.17 [-0.52-0.18], P = 0.34), systolic blood pressure (SMD = 0.29 [-0.39-0.97], P = 0.40), diastolic blood pressure (SMD = 0.39 [-0.62, 1.40], P = 0.45), CSF melanin-concentrating hormone (MD = 5.56 [-30.79-41.91], P = 0.76), serum growth hormone (SMD = 7.84 [-7.90-23.57], P = 0.33), as well as plasma and CSF leptin (SMD = 0.10 [-1.32-1.51], P = 0.89 and MD = 0.01 [-0.02-0.04], P = 0.56, respectively) did not significantly differ between narcolepsy patients and controls. These findings necessitate early screening of metabolic alterations and cardiovascular risk factors in narcolepsy patients to reduce the morbidity and mortality rates.
Topics: Humans; Leptin; Metabolome; Narcolepsy; Obesity; Orexins; Sleep Wake Disorders
PubMed: 33740593
DOI: 10.1016/j.sleep.2021.02.040 -
The Cochrane Database of Systematic... Nov 2020Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant carer distress, increased healthcare costs, and institutionalisation. Although non-drug interventions are recommended as the first-line approach to managing these problems, drug treatment is often sought and used. However, there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this clinically vulnerable population.
OBJECTIVES
To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia.
SEARCH METHODS
We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 19 February 2020, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, and sundowning.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data on study design, risk of bias, and results. We used the mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) as the measures of treatment effect, and where possible, synthesised results using a fixed-effect model. Key outcomes to be included in our summary tables were chosen with the help of a panel of carers. We used GRADE methods to rate the certainty of the evidence.
MAIN RESULTS
We found nine eligible RCTs investigating: melatonin (5 studies, n = 222, five studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), the sedative antidepressant trazodone (1 study, n = 30), the melatonin-receptor agonist ramelteon (1 study, n = 74, no peer-reviewed publication), and the orexin antagonists suvorexant and lemborexant (2 studies, n = 323). Participants in the trazodone study and most participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study and the orexin antagonist studies had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. Primary sleep outcomes were measured using actigraphy or polysomnography. In one study, melatonin treatment was combined with light therapy. Only four studies systematically assessed adverse effects. Overall, we considered the studies to be at low or unclear risk of bias. We found low-certainty evidence that melatonin doses up to 10 mg may have little or no effect on any major sleep outcome over eight to 10 weeks in people with AD and sleep disturbances. We could synthesise data for two of our primary sleep outcomes: total nocturnal sleep time (TNST) (MD 10.68 minutes, 95% CI -16.22 to 37.59; 2 studies, n = 184), and the ratio of day-time to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; 2 studies; n = 184). From single studies, we found no evidence of an effect of melatonin on sleep efficiency, time awake after sleep onset, number of night-time awakenings, or mean duration of sleep bouts. There were no serious adverse effects of melatonin reported. We found low-certainty evidence that trazodone 50 mg for two weeks may improve TNST (MD 42.46 minutes, 95% CI 0.9 to 84.0; 1 study, n = 30), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; 1 study, n = 30) in people with moderate-to-severe AD. The effect on time awake after sleep onset was uncertain due to very serious imprecision (MD -20.41 minutes, 95% CI -60.4 to 19.6; 1 study, n = 30). There may be little or no effect on number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8; 1 study, n = 30) or time asleep in the day (MD 5.12 minutes, 95% CI -28.2 to 38.4). There were no serious adverse effects of trazodone reported. The small (n = 74), phase 2 trial investigating ramelteon 8 mg was reported only in summary form on the sponsor's website. We considered the certainty of the evidence to be low. There was no evidence of any important effect of ramelteon on any nocturnal sleep outcomes. There were no serious adverse effects. We found moderate-certainty evidence that an orexin antagonist taken for four weeks by people with mild-to-moderate AD probably increases TNST (MD 28.2 minutes, 95% CI 11.1 to 45.3; 1 study, n = 274) and decreases time awake after sleep onset (MD -15.7 minutes, 95% CI -28.1 to -3.3: 1 study, n = 274) but has little or no effect on number of awakenings (MD 0.0, 95% CI -0.5 to 0.5; 1 study, n = 274). It may be associated with a small increase in sleep efficiency (MD 4.26%, 95% CI 1.26 to 7.26; 2 studies, n = 312), has no clear effect on sleep latency (MD -12.1 minutes, 95% CI -25.9 to 1.7; 1 study, n = 274), and may have little or no effect on the mean duration of sleep bouts (MD -2.42 minutes, 95% CI -5.53 to 0.7; 1 study, n = 38). Adverse events were probably no more common among participants taking orexin antagonists than those taking placebo (RR 1.29, 95% CI 0.83 to 1.99; 2 studies, n = 323).
AUTHORS' CONCLUSIONS
We discovered a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. In particular, we found no RCTs of many widely prescribed drugs, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks for these common treatments. We found no evidence for beneficial effects of melatonin (up to 10 mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists and no evidence of harmful effects in these small trials, although larger trials in a broader range of participants are needed to allow more definitive conclusions to be reached. Systematic assessment of adverse effects in future trials is essential.
Topics: Alzheimer Disease; Azepines; Caregiver Burden; Cognition; Humans; Indenes; Melatonin; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep; Sleep Wake Disorders; Time Factors; Trazodone; Triazoles
PubMed: 33189083
DOI: 10.1002/14651858.CD009178.pub4 -
Obesity Reviews : An Official Journal... Nov 2020In the current study, a systematic review and meta-analysis were conducted to summarize and assess whether short sleep duration is associated with appetite-regulating... (Meta-Analysis)
Meta-Analysis Review
In the current study, a systematic review and meta-analysis were conducted to summarize and assess whether short sleep duration is associated with appetite-regulating hormones and adipokine levels. Reference databases were searched for studies related to sleep and appetite-regulating hormones and adipokines. Qualitative and quantitative syntheses were conducted to evaluate the relationship between sleep duration and the level of appetite-regulating hormones and adipokines, including leptin, ghrelin, adiponectin, resistin, and orexin. Twenty-one of 3536 studies, covering a total of 2250 participants, met the inclusion criteria. Leptin, ghrelin, and adiponectin were included in the meta-analysis. Ghrelin levels were higher in the short sleep group (standard mean difference [SMD] = 0.14, 95% CI [0.03, 0.25], p = 0.01). Significant differences between the short sleep group and recommended sleep group were also noted in leptin level experimental subgroup studies (SMD = 0.19, 95% CI [0.03, 0.35], p = 0.02) and ghrelin level cross-sectional subgroup studies (SMD = 0.14, 95% CI [0.02, 0.27], p = 0.03). A rise in leptin and ghrelin levels were also observed in sleep deprivation groups (SMD = 0.24, 95% CI [0.10, 0.39], p = 0.001 and SMD = 0.18, 95% CI [0.04, 0.33], p = 0.01, respectively). In conclusion, short sleep duration is associated with an increased ghrelin level, while sleep deprivation had a significant effect on the levels of both leptin and ghrelin.
Topics: Adipokines; Appetite; Cross-Sectional Studies; Humans; Sleep; Time Factors
PubMed: 32537891
DOI: 10.1111/obr.13051 -
Sleep Medicine Reviews Oct 2020Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically...
Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically evaluated. Thus, we performed a systematic review to assess how these compounds effect sleep architecture in healthy and clinical human samples. Relevant articles were identified via searches of PubMed, Embase, the Cochrane central register of controlled trials, and clinicaltrials. gov. From 1147 retrieved records, 18 satisfied inclusion criteria and formed the basis of this review. Of these, fifteen studies administered dual orexin receptor antagonists (DORA) in a healthy control (five studies) or clinical sample (ten studies). By contrast, three studies administered selective orexin receptor-2 antagonists (2-SORA) in either a healthy control (one study) or clinical sample (two studies). Results reveal DORAs increase total sleep time primarily by promoting REM sleep, without affecting, or even decreasing, non-REM sleep, especially in clinical samples. Therefore, the clinical utility of DORAs may depend on the specific sample being treated. For 2-SORAs, limited evidence available precludes firm conclusions about their influence on human sleep architecture and, thus, further investigation of 2-SORAs is required to define their effects and make comparisons on this basis with DORAs.
Topics: Azepines; Healthy Volunteers; Humans; Orexin Receptor Antagonists; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep, REM; Triazoles
PubMed: 32505969
DOI: 10.1016/j.smrv.2020.101332 -
Journal of Critical Care Oct 2020To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.
PURPOSE
To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.
MATERIALS AND METHODS
Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies.
RESULTS
In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo.
CONCLUSION
Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.
Topics: Aged; Aged, 80 and over; Azepines; Critical Care; Critical Illness; Delirium; Drug Therapy, Combination; Female; Humans; Indenes; Length of Stay; Male; Middle Aged; Orexin Receptor Antagonists; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Retrospective Studies; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 32480359
DOI: 10.1016/j.jcrc.2020.05.006 -
Sleep Medicine Reviews Aug 2020The hypocretin system consists of two peptides hypocretin-1 and hypocretin-2 (HCRT1 and HCRT2). Hypocretin-containing neurons are located in the posterior and lateral...
The hypocretin system consists of two peptides hypocretin-1 and hypocretin-2 (HCRT1 and HCRT2). Hypocretin-containing neurons are located in the posterior and lateral hypothalamus, and have widespread projections throughout the brain and spinal cord. In addition to its presence in the cerebrospinal fluid (CSF), peripheral HCRT1 has been detected in plasma. Robust experimental evidence demonstrates functions of hypothalamic-originated HCRT1 in regulation of multiple biological systems related to sleep-wake states, energy homeostasis and endocrine function. In contrast, HCRT1 studies with human participants are limited by the necessarily invasive assessment of CSF HCRT1 to patients with underlying morbidity. Regulation by HCRT1 of energy homeostasis and reproduction in animals suggests similar regulation in humans and prompts these two systematic reviews. These reviews translate prior experimental findings from animal studies to humans and examine associations between HCRT1 and: 1) metabolic risk factors; 2) reproductive function in men, women and children. A total of 21 studies and six studies met the inclusion criteria for the two searches, respectively. Research question, study design, study population, assessments of HCRT1, reproductive, cardiometabolic data and main findings were extracted. Associations between HCRT1, metabolic and reproductive function are inconsistent. Limitations of studies and future research directions are outlined.
Topics: Animals; Cardiometabolic Risk Factors; Homeostasis; Humans; Hypothalamus; Neurons; Orexins; Plasma; Reproductive Health; Sleep
PubMed: 32259696
DOI: 10.1016/j.smrv.2020.101307 -
Clinical Neuropharmacology 2019Pharmacotherapy, psychotherapy, and complementary therapy have been used for primary insomnia. However, the efficacy and placebo response are not exactly clear because...
BACKGROUND
Pharmacotherapy, psychotherapy, and complementary therapy have been used for primary insomnia. However, the efficacy and placebo response are not exactly clear because of limited clinical data. We therefore conducted a systematic review to examine the efficacy and placebo response of multimodal treatments.
METHODS
We performed a comprehensive literature search for randomized placebo-controlled clinical trials evaluating the efficacy of multimodal treatments addressing primary insomnia. To pool effect size estimates (Hedges' g) of active and placebo conditions across studies for outcome measures, a meta-analysis was done according to the Cochrane guideline.
RESULTS
The results of network meta-analysis for sleep efficiency showed that orexin receptor antagonists had the maximum effect size of 1.35 (95% confidence interval [CI], 0.88-1.82), followed by γ-aminobutyric acid agonists of 1.28 (95% CI, 0.85-1.71), cognitive behavioral therapy for insomnia of 1.07 (95% CI, 0.10-2.05), acupuncture of 0.64 (95% CI, -0.17 to 2.36), and repetitive transcranial magnetic stimulation of 0.61 (95% CI, -0.52 to 1.75), respectively. However, the placebo response was also significant and robust to improve insomnia symptoms, and 65.9% (95% CI, 49.3%-82.5%) of the effect size of multimodal treatments was actually produced by placebo conditions.
CONCLUSIONS
The pharmacotherapy seems the most effective in improving sleep efficiency. However, the optimal therapeutic regimen is still uncertain. In addition, the placebo response is significant and robust in treatments of primary insomnia.
Topics: Combined Modality Therapy; Humans; Network Meta-Analysis; Placebo Effect; Sleep Initiation and Maintenance Disorders
PubMed: 31725474
DOI: 10.1097/WNF.0000000000000369 -
Sleep Mar 2020The placebo response to orexin receptor antagonists in primary insomnia is little-known. Our aim was, therefore, to conduct a systematic review of placebo-controlled... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The placebo response to orexin receptor antagonists in primary insomnia is little-known. Our aim was, therefore, to conduct a systematic review of placebo-controlled randomized clinical trials to characterize placebo response.
METHODS
We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of orexin receptor antagonists addressing primary insomnia. To pool effect size estimates (Cohen's d) of placebo and orexin receptor antagonists across trials for outcome measures, a meta-analysis was done according to the Cochrane guideline.
RESULTS
The placebo response was significant and robust to improve the symptoms of insomnia in terms of objective and subjective measures, and the effects (0.70 ± 0.51) in subjective measures were smaller than that (1.10 ± 1.14) in objective measures (p = 0.027). The biphasic feature of placebo response showed an initial short-term increase of placebo effect and subsequent changeless long-term effect.
CONCLUSION
The biphasic feature of placebo response is clinically useful, and neuroimaging is essential to clarify the long-term mechanism in the future.
Topics: Double-Blind Method; Humans; Orexin Receptor Antagonists; Placebo Effect; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders
PubMed: 31593985
DOI: 10.1093/sleep/zsz238