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British Journal of Clinical Pharmacology Apr 2016The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into... (Meta-Analysis)
Meta-Analysis Review
AIMS
The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design and reference category.
METHOD
A systematic review of studies published between 1966 and November 2015 was conducted using embase and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models.
RESULTS
Twenty-three studies were included. Compared with non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n = 15 studies), major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n = 18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n = 8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n = 4 studies) and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n = 4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed.
CONCLUSIONS
Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.
Topics: Abnormalities, Drug-Induced; Female; Heart Defects, Congenital; Humans; Maternal Exposure; Paroxetine; Pregnancy; Pregnancy Trimester, First; Risk Assessment; Selective Serotonin Reuptake Inhibitors
PubMed: 26613360
DOI: 10.1111/bcp.12849 -
Sexual Health Apr 2016Eutectic Mixture of Local Anaesthetics (EMLA) is recommended for use off-label as a treatment for premature ejaculation (PE). Other topical anaesthetics are available,... (Meta-Analysis)
Meta-Analysis Review
Eutectic Mixture of Local Anaesthetics (EMLA) is recommended for use off-label as a treatment for premature ejaculation (PE). Other topical anaesthetics are available, some of which have been evaluated against oral treatments. The purpose of this systematic review was to evaluate the evidence from randomised controlled trials (RCTs) for topical anaesthetics in the management of PE. Bibliographic databases including MEDLINE were searched to August 2014. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. IELT and other outcomes were pooled across RCTs in a meta-analysis. Between-trial heterogeneity was assessed. Nine RCTs were included. Seven were of unclear methodological quality. Pooled evidence (two RCTs, 43 participants) suggests that EMLA is significantly more effective than placebo at increasing IELT (P<0.00001). Individual RCT evidence also suggests that Topical Eutectic-like Mixture for Premature Ejaculation (TEMPE) spray and lidocaine gel are both significantly more effective than placebo (P=0.003; P<0.00001); and lidocaine gel is significantly more effective than sildenafil or paroxetine (P=0.01; P=0.0001). TEMPE spray is associated with significantly more adverse events than placebo (P=0.003). More systemic adverse events are reported with tramadol, sildenafil and paroxetine than with lidocaine gel. Diverse methods of assessing sexual satisfaction and ejaculatory control with topical anaesthetics are reported and evidence is conflicting. Topical anaesthetics appear more effective than placebo, paroxetine and sildenafil at increasing IELT in men with PE. However, the methodological quality of the existing RCT evidence base is uncertain.
Topics: Anesthetics, Local; Humans; Male; Premature Ejaculation; Randomized Controlled Trials as Topic
PubMed: 26599522
DOI: 10.1071/SH15042 -
The American Journal of Psychiatry Feb 2016Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.
METHOD
The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.
RESULTS
Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54).
CONCLUSIONS
Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.
Topics: Citalopram; Depressive Disorder, Major; Dose-Response Relationship, Drug; Fluoxetine; Fluvoxamine; Humans; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 26552940
DOI: 10.1176/appi.ajp.2015.15030331 -
The International Journal of... Jul 2015Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The objective of the current systematic review and meta-analysis was to assess the pooled efficacy of antidepressants on various domains of cognition in MDD.
METHODS
Trials published prior to April 15, 2015, were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsychINFO, Clinicaltrials.gov, and relevant review articles. Data from randomized clinical trials assessing the cognitive effects of antidepressants were pooled to determine standard mean differences (SMD) using a random-effects model.
RESULTS
Nine placebo-controlled randomized trials (2 550 participants) evaluating the cognitive effects of vortioxetine (n = 728), duloxetine (n = 714), paroxetine (n = 23), citalopram (n = 84), phenelzine (n = 28), nortryptiline (n = 32), and sertraline (n = 49) were identified. Antidepressants had a positive effect on psychomotor speed (SMD 0.16; 95% confidence interval [CI] 0.05-0.27; I(2) = 46%) and delayed recall (SMD 0.24; 95% CI 0.15-0.34; I(2) = 0%). The effect on cognitive control and executive function did not reach statistical significance. Of note, after removal of vortioxetine from the analysis, statistical significance was lost for psychomotor speed. Eight head-to-head randomized trials comparing the effects of selective serotonin reuptake inhibitors (SSRIs; n = 371), selective serotonin and norepinephrine reuptake inhibitors (SNRIs; n = 25), tricyclic antidepressants (TCAs; n = 138), and norepinephrine and dopamine reuptake inhibitors (NDRIs; n = 46) were identified. No statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs. Significant limitations were the heterogeneity of results, limited number of studies, and small sample sizes.
CONCLUSIONS
Available evidence suggests that antidepressants have a significant positive effect on psychomotor speed and delayed recall.
Topics: Antidepressive Agents; Cognition; Cognition Disorders; Depressive Disorder, Major; Humans; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26209859
DOI: 10.1093/ijnp/pyv082 -
The Cochrane Database of Systematic... Jun 2015Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms.
OBJECTIVES
The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles.
SELECTION CRITERIA
We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline.
DATA COLLECTION AND ANALYSIS
Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion.
MAIN RESULTS
The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together.All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17.SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement.SSRIs were superior to placebo in the reduction of depression: SMD -0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05.
AUTHORS' CONCLUSIONS
There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate.
Topics: Amitriptyline; Citalopram; Fibromyalgia; Fluoxetine; Humans; Melatonin; Musculoskeletal Pain; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Syndrome
PubMed: 26046493
DOI: 10.1002/14651858.CD011735 -
The Cochrane Database of Systematic... May 2015This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the management of cancer-related fatigue'.In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients' fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Fatigue frequently occurs in patients with advanced disease (e.g. cancer-related fatigue) and modalities used to treat cancer can often contribute. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The pathophysiology is not fully understood and evidence-based treatment approaches are needed.
OBJECTIVES
To evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases.
SEARCH METHODS
For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. We searched the references of identified articles and contacted authors to obtain unreported data. To validate the search strategy we selected sentinel references.
SELECTION CRITERIA
We considered randomised controlled trials (RCTs) concerning adult palliative care with a focus on pharmacological treatment of fatigue compared to placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We did not include studies on fatigue related to antineoplastic treatment (e.g. chemotherapy, radiotherapy, surgical intervention). We also included secondary outcomes that were assessed in fatigue-related studies (e.g. exhaustion, tiredness).
DATA COLLECTION AND ANALYSIS
Two review authors (MM and MC) independently assessed trial quality and extracted data. We screened the search results and included studies if they met the selection criteria. If we identified two or more studies that investigated a specific drug with the same dose in a population with the same disease and using the same assessment instrument or scale, we conducted meta-analysis. In addition, we compared the type of drug investigated in specific populations, as well as the frequent adverse effects of fatigue treatment, by creating overview tables.
MAIN RESULTS
For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact.
AUTHORS' CONCLUSIONS
Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.
Topics: Adult; Amantadine; Benzhydryl Compounds; Carnitine; Central Nervous System Stimulants; Chronic Disease; Fatigue; Humans; Kidney Failure, Chronic; Methylphenidate; Modafinil; Multiple Sclerosis; Neoplasms; Palliative Care; Pemoline; Randomized Controlled Trials as Topic
PubMed: 26026155
DOI: 10.1002/14651858.CD006788.pub3 -
Journal of Molecular Psychiatry 2015Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver...
Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver injury. The authors therefore address the need to comprehensively evaluate the potential risk posed by agomelatine of inducing liver injury by reviewing data from published and unpublished clinical trials in both the pre- and postmarketing settings, as well as data from non-interventional studies, pharmacovigilance database reviews and one case report. Recommendations for clinicians are also provided. In this review, agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provides evidence for the existence of a positive relationship between agomelatine dose and liver injury. Furthermore, rates of liver injury were found to be lower in non-interventional studies. Findings from pharmacovigilance database reviews and one case report also highlight the risk of agomelatine-induced liver injury. As agomelatine does pose a risk of liver injury, clinicians must carefully monitor liver function throughout treatment. However, agomelatine's unique mechanism of action and favourable safety profile render it a valuable treatment option. A quantitative analysis of agomelatine-induced liver injury is lacking in the literature and would be welcomed.
PubMed: 25932327
DOI: 10.1186/s40303-015-0011-7 -
The Cochrane Database of Systematic... May 2015This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache.
OBJECTIVES
To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults.
SEARCH METHODS
For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials.
SELECTION CRITERIA
We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period.
MAIN RESULTS
The original review included six studies on tension-type headache. We now include eight studies with a total of 412 participants with chronic forms of tension-type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow-up ranged between two and four months.Six studies explored the effect of SSRIs or SNRIs on tension-type headache frequency, the primary endpoint. At eight weeks of follow-up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) -0.96, 95% confidence interval (CI) -3.95 to 2.03; I(2)= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI -2.05 to 3.57; I(2)= 44%).When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD -1.87, 95% CI -2.09 to -1.65; I(2)= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I(2)= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity.SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I(2)= 25% and OR 1.55, 95% CI 0.71 to 3.38; I(2)= 0%).We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non-drug therapies (e.g. psycho-behavioural treatments, manual therapy, acupuncture).
AUTHORS' CONCLUSIONS
Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine (a SNRI) as preventive drugs for tension-type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension-type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow-up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension-type headache is not supported by evidence.
Topics: Adrenergic Uptake Inhibitors; Adult; Citalopram; Cyclohexanols; Fluoxetine; Fluvoxamine; Humans; Norepinephrine; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Tension-Type Headache; Venlafaxine Hydrochloride
PubMed: 25931277
DOI: 10.1002/14651858.CD011681 -
Health Technology Assessment... Mar 2015Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE... (Review)
Review
BACKGROUND
Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130-4). Treatments include behavioural and pharmacological interventions.
OBJECTIVE
To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE.
DATA SOURCES
The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched.
METHODS
Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs).
RESULTS
A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics - eutectic mixture of local anaesthetics (EMLA(®), AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) - citalopram (Cipramil(®), Lundbeck), escitalopram (Cipralex(®), Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy(®), Menarini), 30 mg or 60 mg; serotonin-noradrenaline reuptake inhibitors - duloxetine (Cymbalta(®), Eli Lilly & Co Ltd); tricyclic antidepressants - inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors - vardenafil (Levitra(®), Bayer), tadalafil (Cialis(®), Eli Lilly & Co Ltd); opioid analgesics - tramadol (Zydol SR(®), Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies - improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers - terazosin (Hytrin(®), AMCO) not significantly different to antidepressants in ejaculation control; acupuncture - improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine - improvements over treatment as usual; delay device - improvements in IELT when added to stop-start technique; yoga - improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions.
LIMITATIONS
Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report.
CONCLUSIONS
Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42013005289.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Adult; Anesthetics, Local; Behavior Therapy; Humans; Male; Phosphodiesterase 5 Inhibitors; Premature Ejaculation; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 25768099
DOI: 10.3310/hta19210 -
British Journal of Clinical Pharmacology Aug 2015The aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults. (Meta-Analysis)
Meta-Analysis
AIM
The aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults.
METHODS
A literature search using CINAHL, Cochrane Library, Embase and PubMed databases was conducted for randomized controlled trials, prospective and retrospective cohort and case-control studies examining the use of DACEs in subjects ≥65 years with outcomes on falls, cognitive impairment and all-cause mortality. Retrieved articles were published on or before June 2013. Anticholinergic exposure was investigated using drug class, DACE scoring systems (anticholinergic cognitive burden scale, ACB; anticholinergic drug scale, ADS; anticholinergic risk scale, ARS; anticholinergic component of the drug burden index, DBIAC ) or assessment of individual DACEs. Meta-analyses were performed to pool the results from individual studies.
RESULTS
Eighteen studies fulfilled the inclusion criteria (total 124 286 participants). Exposure to DACEs as a class was associated with increased odds of cognitive impairment (OR 1.45, 95% CI 1.16, 1.73). Olanzapine and trazodone were associated with increased odds and risk of falls (OR 2.16, 95% CI 1.05, 4.44; RR 1.79, 95% CI 1.60, 1.97, respectively), but amitriptyline, paroxetine and risperidone were not (RR 1.73, 95% CI 0.81, 2.65; RR 1.80, 95% CI 0.81, 2.79; RR 1.39, 95% CI 0.59, 3.26, respectively). A unit increase in the ACB scale was associated with a doubling in odds of all-cause mortality (OR 2.06, 95% CI 1.82, 2.33) but there were no associations with the DBIAC (OR 0.88, 95% CI 0.55, 1.42) or the ARS (OR 3.56, 95% CI 0.29, 43.27).
CONCLUSIONS
Certain individual DACEs or increased overall DACE exposure may increase the risks of cognitive impairment, falls and all-cause mortality in older adults.
Topics: Accidental Falls; Aged; Aged, 80 and over; Bias; Cholinergic Antagonists; Cognition Disorders; Female; Humans; Male
PubMed: 25735839
DOI: 10.1111/bcp.12617