Phosphodiesterase Type 5 Inhibitors for Premature Ejaculation: A Systematic Review and Meta-analysis.

CONTEXT: Phosphodiesterase type 5 inhibitors (PDE5-Is) are prescribed off-label for the treatment of premature ejaculation (PE). OBJECTIVE: To systematically review the evidence from randomised controlled trials (RCTs) for PDE5-Is in the management of PE. EVIDENCE ACQUISITION: Medline and other databases were searched through September 2015. Quality of RCTs was assessed. Intravaginal ejaculatory latency time (IELT) data were pooled in a meta-analysis. Heterogeneity was assessed. EVIDENCE SYNTHESIS: Fifteen RCTs were included. The majority were of unclear methodological quality. Pooled IELT evidence suggests that PDE5-Is are significantly more effective than placebo (231 participants, p<0.00001), that there is no difference between PDE5-Is and selective serotonin reuptake inhibitors (SSRIs; 405 participants, p=0.50), and that PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone (521 participants, p=0.001); however, high levels of statistical heterogeneity are evident (I2 ≥ 40%). Single-RCT evidence suggests that sildenafil is significantly more effective than the squeeze technique, but both lidocaine gel and tramadol are significantly more effective than sildenafil. Sildenafil combined with behavioural therapy is significantly more effective than behavioural therapy alone. Sexual satisfaction and ejaculatory control appear to be better with PDE5-Is compared with placebo and with PDE5-Is combined with an SSRI compared with an SSRI alone. Adverse events are reported with both PDE5-Is and other agents. CONCLUSIONS: PDE5-Is are significantly more effective than placebo and PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone at increasing IELT and improving other effectiveness outcomes; however, heterogeneity is evident across RCTs. The methodological quality of the majority of RCTs is unclear. PATIENT SUMMARY: We reviewed phosphodiesterase type 5 inhibitors (PDE5-Is) for treating premature ejaculation. We found evidence to suggest that PDE5-Is are effective compared with placebo and that PDE5-Is combined with an SSRI are more effective than an SSRI alone. Adverse events are reported with PDE5-Is and other agents; however, the quality of the evidence is uncertain. TRIAL REGISTRATION: PROSPERO registration number CRD42013005289.

Complementary and Alternative Medicine for Management of Premature Ejaculation: A Systematic Review.

INTRODUCTION: Premature ejaculation (PE) is defined as ejaculation within 1 minute (lifelong PE) or 3 minutes (acquired PE), inability to delay ejaculation, and negative personal consequences. Management includes behavioral and pharmacologic approaches. AIM: To systematically review effectiveness, safety, and robustness of evidence for complementary and alternative medicine in managing PE. METHODS: Nine databases including Medline were searched through September 2015. Randomized controlled trials evaluating complementary and alternative medicine for PE were included. MAIN OUTCOME MEASURES: Studies were included if they reported on intravaginal ejaculatory latency time (IELT) and/or another validated PE measurement. Adverse effects were summarized. RESULTS: Ten randomized controlled trials were included. Two assessed acupuncture, five assessed Chinese herbal medicine, one assessed Ayurvedic herbal medicine, and two assessed topical "severance secret" cream. Risk of bias was unclear in all studies because of unclear allocation concealment or blinding, and only five studies reported stopwatch-measured IELT. Acupuncture slightly increased IELT over placebo in one study (mean difference [MD] = 0.55 minute, P = .001). In another study, Ayurvedic herbal medicine slightly increased IELT over placebo (MD = 0.80 minute, P = .001). Topical severance secret cream increased IELT over placebo in two studies (MD = 8.60 minutes, P < .001), although inclusion criteria were broad (IELT < 3 minutes). Three studies comparing Chinese herbal medicine with selective serotonin reuptake inhibitors (SSRIs) favored SSRIs (MD = 1.01 minutes, P = .02). However, combination treatment with Chinese medicine plus SSRIs improved IELT over SSRIs alone (two studies; MD = 1.92 minutes, P < .00001) and over Chinese medicine alone (two studies; MD = 2.52 minutes, P < .00001). Adverse effects were not consistently assessed but where reported were generally mild. CONCLUSION: There is preliminary evidence for the effectiveness of acupuncture, Chinese herbal medicine, Ayurvedic herbal medicine, and topical severance secret cream in improving IELT and other outcomes. However, results are based on clinically heterogeneous studies of unclear quality. There are sparse data on adverse effects or potential for drug interactions. Further well-conducted randomized controlled trials would be valuable.

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES: The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS: Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003386. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Topical anaesthetics for premature ejaculation: a systematic review and meta-analysis.

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.

Behavioral Therapies for Management of Premature Ejaculation: A Systematic Review.

INTRODUCTION: Premature ejaculation (PE) is defined by short ejaculatory latency and inability to delay ejaculation causing distress. Management may involve behavioral and/or pharmacological approaches. AIM: To systematically review the randomized controlled trial (RCT) evidence for behavioral therapies in the management of PE. METHODS: Nine databases including MEDLINE were searched up to August 2014. Included RCTs compared behavioral therapy against waitlist control or another therapy, or behavioral plus drug therapy against drug treatment alone. [Correction added on 10 September 2015, after first online publication: Search period has been amended from August 2013 to August 2014.]. MAIN OUTCOME MEASURE: Intravaginal ejaculatory latency time (IELT), sexual satisfaction, ejaculatory control, and anxiety and adverse effects. RESULTS: Ten RCTs (521 participants) were included. Overall risk of bias was unclear. All studies assessed physical techniques, including squeeze and stop-start, sensate focus, stimulation device, and pelvic floor rehabilitation. Only one RCT included a psychotherapeutic approach (combined with stop-start and drug treatment). Four trials compared behavioral therapies against waitlist control, of which two (involving squeeze, stop-start, and sensate focus) reported IELT differences of 7-9 minutes, whereas two (web-based sensate focus, stimulation device) reported no difference in ejaculatory latency posttreatment. For other outcomes (sexual satisfaction, desire, and self-confidence), some waitlist comparisons significantly favored behavioral therapy, whereas others were not significant. Three trials favored combined behavioral and drug treatment over drug treatment alone, with small but significant differences in IELT (0.5-1 minute) and significantly better results on other outcomes (sexual satisfaction, ejaculatory control, and anxiety). Direct comparisons of behavioral therapy vs. drug treatment gave mixed results, mostly either favoring drug treatment or showing no significant difference. No adverse effects were reported, though safety data were limited. CONCLUSIONS: There is limited evidence that physical behavioral techniques for PE improve IELT and other outcomes over waitlist and that behavioral therapies combined with drug treatments give better outcomes than drug treatments alone. Further RCTs are required to assess psychotherapeutic approaches to PE.

Interventions to treat premature ejaculation: a systematic review short report.

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.

Tramadol for premature ejaculation: a systematic review and meta-analysis.

BACKGROUND: Tramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation (PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE is yet not supported by a high level of evidence. The purpose of this study was to systematically review the evidence from randomised controlled trials (RCT) for tramadol in the management of PE. METHODS: We searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-group differences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trial heterogeneity was assessed. RESULTS: A total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were of unclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, a high level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol is significantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is not assessed in the current evidence base. CONCLUSIONS: Tramadol appears effective in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence. The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration does not permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, including addiction potential, for men with PE have not been evaluated in the current evidence base. TRIAL REGISTRATION: The review is registered on PROSPERO 2013: CRD42013005289 .

Measuring quality of life in children with speech and language difficulties: a systematic review of existing approaches.

BACKGROUND: Children's and adolescent's speech and language difficulties (SaLD) can affect various domains of quality of life (QoL), and speech and language therapy interventions are critical to improving QoL. Systematically measuring QoL outcomes in this population is highly complex due to factors such as heterogeneity in impairments and differing targets during intervention. However, measurements of QoL are increasingly required by healthcare commissioners and policy-makers to inform resource allocation. AIMS: To review the use of QoL measures in research involving children (age ≤ 18 years) with SaLD. METHODS & PROCEDURES: A systematic review was undertaken. A systematic search across various databases was performed. Information on the methodological details of each relevant study, along with descriptions of the QoL measures employed, were extracted into standardized data extraction forms. Findings were discussed in a narrative synthesis. OUTCOMES & RESULTS: Twenty-one relevant studies were identified that deal with a range of subpopulations of children with SaLD. For the most part, generic QoL measures were used, although there was little convergence on the type of QoL measures employed throughout the literature. Five studies utilized preference-based QoL measures, including the 16D/17D, HUI3, EQ-5D and QWB-SA. Of these measures, the HUI3 demonstrated the most promising discriminant validity, although the preference weights for this measure were generated with adults. CONCLUSIONS & IMPLICATIONS: QoL among children with SaLD is not yet being captured in a systematic way. The HUI3 measure appears to show some promise for generating relevant preference-based QoL estimates, although further testing of the measure is required.