Number Needed To Treat To Benefit Research Articles

Influenza vaccines for preventing acute otitis media in infants and children.

Acute otitis media (AOM) is one of the most common infectious diseases in children. It has been reported that 64% of infants have an episode of AOM by the age of six months and 86% by one year. Although most cases of AOM are due to bacterial infection, it is commonly triggered by a viral infection. In most children it is self limiting, but it does carry a risk of complications. Since antibiotic treatment increases the risk of antibiotic resistance, influenza vaccines might be an effective way of reducing this risk by preventing the development of AOM. To assess the effectiveness of influenza vaccine in reducing the occurrence of acute otitis media (AOM) in infants and children. We searched CENTRAL (2014, Issue 6), MEDLINE (1946 to July week 1, 2014), EMBASE (2010 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014), Web of Science (1955 to July 2014) and reference lists of articles to July 2014. Randomised controlled trials (RCTs) comparing influenza vaccine with placebo or no treatment in infants and children aged younger than six years old. We included children of either sex and of any ethnicity, with or without a history of recurrent AOM. Two review authors independently screened studies, assessed trial quality and extracted data. We performed statistical analyses using the random-effects and fixed-effect models and expressed the results as risk ratio (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, with 95% confidence intervals (CI). We included 10 trials (six trials in high-income countries and four multicentre trials in high-, middle- and low-income countries) involving 16,707 children aged six months to six years. Eight trials recruited participants from a healthcare setting. Nine trials (and all five trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment and nine trials reported adequate blinding of participants and personnel. Attrition was low for all trials included in the analysis.The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (five trials, 4736 participants: RR 0.80, 95% CI 0.67 to 0.96; RD -0.04, 95% CI -0.07 to -0.02; NNTB 25, 95% CI 15 to 50).The subgroup analyses (i.e. number of courses, settings, seasons or types of vaccine administered) showed no differences.There was a reduction in the use of antibiotics in vaccinated children (two trials, 1223 participants: RR 0.70, 95% CI 0.59 to 0.83; RD -0.15, 95% CI -0.30 to -0.00).There was no significant difference in the utilisation of health care for the one trial that provided sufficient information to be included. The use of influenza vaccine resulted in a significant increase in fever (six trials, 10,199 participants: RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI -0.00 to 0.05) and rhinorrhoea (six trials, 10,563 children: RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16) but no difference in pharyngitis. No major adverse events were reported.Compared to the protocol, the review included a subgroup analysis of AOM episodes by season, and changed the types of influenza vaccine from a secondary outcome to a subgroup analysis. Influenza vaccine results in a small reduction in AOM. The observed reduction with the use of antibiotics needs to be considered in the light of current recommended practices aimed at avoiding antibiotic overuse. Safety data from these trials are limited. The benefits may not justify the use of influenza vaccine without taking into account the vaccine efficacy in reducing influenza and safety data. The quality of the evidence was high to moderate. Additional research is needed.

Psychological therapies (remotely delivered) for the management of chronic and recurrent pain in children and adolescents.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of psychological therapies delivered remotely compared to waiting-list, treatment-as-usual, or active control for the management of chronic pain in children and adolescents.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants.

In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for closure of a PDA in preterm or low-birth-weight infants. We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials. We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤ 34 weeks postmenstrual age (PMA)). We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I(2) = 0 % for RR and 23% for RD).There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for 'duration for need of supplemental oxygen' (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160). Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, long-term follow-up to at least 18 to 24 months postnatal age must be incorporated in any studies of paracetamol in the newborn population. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.

Single dose oral ibuprofen plus codeine for acute postoperative pain in adults.

This is an update of the original Cochrane review published in Issue 3, 2013. There is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific effects are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations and when tested in the same and different trials. Some combinations of ibuprofen and codeine are available without prescription (but usually only from a pharmacy) where the dose of codeine is lower, and with a prescription when the dose of codeine is higher.Use of combination analgesics that contain codeine has been a source of some concern because of misuse from over-the-counter preparations. To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus codeine for acute moderate-to-severe postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and the reference lists of articles. The date of the most recent search was 1 December 2014. Randomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus codeine for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus codeine, placebo, or the same dose of ibuprofen alone with at least 50% pain relief over six hours, using validated equations. We calculated the risk ratio (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. Analyses were planned for different doses of ibuprofen and codeine, but especially for codeine where we set criteria for low (< 10 mg), medium (10 to 20 mg), and high (> 20 mg) doses. Since the last version of this review no new studies were found. Information was available from six studies with 1342 participants, using a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 mg to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% confidence interval 1.8 to 2.6) (high quality evidence). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (1.01 to 1.6) (moderate quality evidence). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies (moderate quality evidence). The combination of ibuprofen 400 mg plus codeine 25.6 mg to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone, and that similar numbers of people experience adverse events with the combination as with placebo.

Inositol in preterm infants at risk for or having respiratory distress syndrome.

Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life. To assess the effectiveness and safety of supplementary inositol in preterm infants with or without respiratory distress syndrome (RDS) in reducing adverse neonatal outcomes. The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, CINAHL, Clinicaltrials.gov and Controlled-trials.com were searched in September 2014. The reference lists of identified randomised controlled trials (RCTs), personal files and Web of Science were searched. All RCTs of inositol supplementation of preterm infants compared with a control group that received a placebo or no intervention were included. Outcomes of interest were neonatal death, infant death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and sepsis. Data on neonatal outcomes were abstracted independently by the three review authors and any discrepancy was resolved through consensus. Outcomes were reported as relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) or to harm (NNTH). Four published RCTs and one ongoing RCT were identified. Study quality varied and interim analyses had occurred in all trials of repeat doses of inositol that provided data for the outcomes of interest in this review. In these trials neonatal death was found to be significantly reduced (3 trials, 355 neonates; typical RR 0.53, 95% CI 0.31 to 0.91; typical RD -0.09, 95% CI -0.17 to -0.03; NNTB 11, 95% CI 6 to 33). Infant deaths were reduced (3 trials, 355 infants; typical RR 0.55, 95% CI 0.40 to 0.77; typical RD -0.18, 95% CI -0.27 to -0.08; NNTB 6, 95% CI 4 to 13). ROP stage ≥ 3 was significantly reduced (2 trials, 262 infants; typical RR 0.09, 95% CI 0.01 to 0.67; typical RD -0.08, 95% CI -0.13 to -0.03; NNTB 13, 95% CI 8 to 33) and IVH grade > II was significantly decreased (3 trials, 355 infants; typical RR 0.53, 95% CI 0.31 to 0.90; typical RD -0.09, 95% CI -0.16 to -0.02; NNTB 11, 95% CI 6 to 50). Neither sepsis nor NEC differed significantly between groups. One study (74 infants) that administered a single dose of inositol (60 or 120 mg/kg) found no significant differences in adverse outcomes using RR, but an increased RD for BPD at 36 weeks postmenstrual age (RD 0.23, 95% CI 0.03 to 0.43; NNTH 4, 95% CI 2 to 33). This result should be interpreted with caution as only one dose of inositol was given and only the RD, but not the RR, was significant. One ongoing large study of repeat doses of inositol in preterm infants was identified. Inositol supplementation results in statistically significant and clinically important reductions in important short-term adverse neonatal outcomes. A large size multi-centre randomised controlled trial is currently ongoing and the trial will likely confirm or refute the findings from this systematic review.

Caffeine as an analgesic adjuvant for acute pain in adults.

This is an updated version of the original Cochrane review published in Issue 3, 2012. Caffeine has been added to common analgesics such as paracetamol, ibuprofen, and aspirin, in the belief that it enhances analgesic efficacy. Evidence to support this belief is limited and often based on invalid comparisons. To assess the relative efficacy of a single dose of an analgesic plus caffeine against the same dose of the analgesic alone, without restriction on the analgesic used or the pain condition studied. We also assessed serious adverse events. We searched CENTRAL, MEDLINE, and EMBASE from inception to 28 August 2014, the Oxford Pain Relief Database, and also carried out Internet searches and contacted pharmaceutical companies known to have carried out trials that have not been published. We included randomised, double-blind studies that compared a single dose of analgesic plus caffeine with the same dose of the analgesic alone in the treatment of acute pain. Two review authors independently assessed the eligibility and quality of studies, and extracted data. Any disagreements or uncertainties were settled by discussion with a third review author. We sought any validated measure of analgesic efficacy, but particularly the number of participants experiencing at least 50% of the maximum possible pain relief over four to six hours, participants reporting a global evaluation of treatment of very good or excellent, or headache relief after two hours. We pooled comparable data to look for a statistically significant difference, and calculated numbers needed to treat to benefit (NNT) with caffeine. We also looked for any numerical superiority associated with the addition of caffeine, and information about any serious adverse events. We identified no new studies with available results for this update. The earlier review included 20 studies (7238 participants) in valid comparisons, but because we used different outcomes for some headache studies, the number of participants in the analyses of the effects of caffeine is now 4262 when previously it was 5243. The studies were generally of good methodological quality, using standard designs and mostly standard scales of pain measurement, although many of those treating postoperative pain were small.Most studies used paracetamol or ibuprofen, with 100 mg to 130 mg caffeine, and the most common pain conditions studied were postoperative dental pain, postpartum pain, and headache. There was a small but statistically significant benefit with caffeine used at doses of 100 mg or more, which was not dependent on the pain condition or type of analgesic. About 5% to 10% more participants achieve a good level of pain relief (at least 50% of the maximum over four to six hours) with the addition of caffeine, giving a NNT of about 14 (high quality evidence).Most comparisons individually demonstrated numerical superiority with caffeine, but not statistical superiority. One serious adverse event was reported with caffeine, but was considered unrelated to any study medication.We know of the existence of around 25 additional studies with almost 12,500 participants for which data for analysis were not obtainable. The additional analgesic effect of caffeine remained statistically significant but clinically less important even if all the known missing data had no effect; the bulk of the unobtainable data are reported to have similar results as this review. The addition of caffeine (≥ 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief.

Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane review first published in 2010. To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) in children with PFAPA. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2013. Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. Two authors independently assessed trial quality and extracted data. We used the standard methodological procedures expected by The Cochrane Collaboration. Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias.One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months.Combining the trial results suggests that patients with PFAPA experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution).There was a large overall reduction in the average number of episodes over the total length of follow-up in these studies (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years. The severity, as indicated by the length of PFAPA symptoms during these episodes, was also reduced. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group. The proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92).Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Other outcomes such as quality of life, number of days with pain after surgery and absence from school were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

Glutamine supplementation for critically ill adults.

Glutamine supplementation for critically ill adults.

Colchicine for acute gout.

Colchicine for acute gout.

Tiotropium versus placebo for chronic obstructive pulmonary disease.

Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease (COPD). In the past few years there have been several systematic reviews of the efficacy of tiotropium, however, several new trials have compared tiotropium treatment with placebo, including those of a soft mist inhaler, making an update necessary. To evaluate data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints. We searched the Cochrane Airways Group's Specialised Register of Trials (CAGR) and ClinicalTrials.gov up to February 2012. We included parallel group RCTs of three months or longer comparing treatment with tiotropium against placebo for patients with COPD. Two review authors independently assessed studies for inclusion and then extracted data on study quality and the outcome results. We contacted study authors and trial sponsors for additional information, and collected information on adverse effects from all trials. We analysed the data using Cochrane Review Manager 5, RevMan 5.2. This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung function at the end of the study compared with those on placebo (trough forced expiratory volume in one second (FEV1) MD 118.92 mL; 95% CI 113.07 to 124.77). This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.

Calcium channel blockers for inhibiting preterm labour and birth.

Calcium channel blockers for inhibiting preterm labour and birth.

Single dose oral etoricoxib for acute postoperative pain in adults.

This is an updated version of the original Cochrane review first published in Issue 2, 2009, and updated in Issue 4, 2012.Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor licensed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain in some jurisdictions. This class of drugs is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). To assess the efficacy and adverse effects of single dose etoricoxib for acute postoperative pain using methods that permit accurate comparison with other analgesics evaluated in the same way, using criteria of efficacy recommended by in-depth studies at the individual patient level. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, www.clinicaltrials.gov, and reference lists of articles. The date of the most recent search was 31 January 2014. Randomised, double-blind, placebo-controlled clinical trials of single dose, oral etoricoxib for acute postoperative pain in adults. Two review authors independently considered studies for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed etoricoxib or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. We identified no new studies for this updated review, which includes six studies with 1214 participants in comparisons of etoricoxib with placebo. All six studies reported on the 120 mg dose (798 participants in a comparison with placebo). Sixty-six per cent of participants with etoricoxib 120 mg and 12% with placebo reported at least 50% pain relief (NNT 1.8 (1.7 to 2.0); high-quality evidence). For dental studies only, the NNT was 1.6 (1.5 to 1.8). A single dose of 90 mg produced similar results in one large trial. Other doses (60, 180, and 240 mg) were each studied in only one treatment arm.Significantly fewer participants used rescue medication over 24 hours when taking etoricoxib 120 mg than placebo (NNT to prevent remedication 2.2 (1.9 to 2.8)), and the median time to use of rescue medication was 20 hours for etoricoxib and two hours for placebo. Adverse events were reported at a similar rate to placebo (moderate-quality evidence), with no serious events. Single-dose oral etoricoxib produces high levels of good quality pain relief after surgery, and adverse events did not differ from placebo in these studies. The 120 mg dose is as effective as, or better than, other commonly used analgesics.

Psychological therapies for the management of chronic and recurrent pain in children and adolescents.

Psychological therapies for the management of chronic and recurrent pain in children and adolescents.

Gabapentin for chronic neuropathic pain and fibromyalgia in adults.

This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia. To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia. We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014. Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults. Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional painsyndrome type 1 (CRPS-1), and fibromyalgia. Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently-introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions. There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy.

Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of early initiation of EPO or darepoetin (initiated before eight days after birth) in reducing red blood cell (RBC) transfusions in preterm and/orlow birth weight infants. The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of identified trials and reviews, Pediatric Academic Societies Annual meetings 2000 to 2013 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp) were searched in July 2013. Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weightinfants. The methods of the Neonatal Cochrane Review Group were used. The updated review includes 27 studies enrolling 2209 infants. One study enrolling infants at a mean age of > eight days and one duplicate publication were excluded. One new study using darepoetin was identified.Early EPO reduced the risk of the 'use of one or more RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.73 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I(2) = 54% for both; number needed to treat to benefit (NNTB) 7, 95% CI 6 to 10; 16 studies, 1661 infants).The total volume of RBCs transfused per infant was reduced (typical mean difference (MD) 7 mL/kg, 95% CI -12 to - 2; I(2) = 63%; 7 studies, 581 infants). The number of RBC transfusions per infant was minimally reduced (typical MD -0.27, 95% CI -0.42 to -0.12; I(2) = 64%; 13 studies, 951 infants). The number of donors to whom the infants were exposed was significantly reduced (MD-0.54, 95% CI -0.89 to -0.20; I(2) = 0%; 3 studies, 254 infants).There was a non-significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.37, 95% CI 0.87 to 2.17; I(2) = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I(2) = 29%; 7 studies, 801 infants). A post hoc analysis including all studies that reported on ROP stage ≥ 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I(2) = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I(2) = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity). In an Italian study in which the authors compared the use of early intravenous EPO with subcutaneous EPO the overall incidence of stage ≥ 3 was 15%, similar to the incidence of 17% in the study by Romagnoli and co-workers.The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months varied. Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure after study entry. The small reductions are likely to be of limited clinical importance. Donor exposure is probably not avoided since all but one study included infants who had received RBC transfusions prior to trial entry. In this update there was no significant increase in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age. In a post hoc analysis including all studies that reported on ROP stage ≥ 3 regardless of age at initiation of treatment there was an increased risk of ROP. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months vary in the studies published to date. Ongoing research should deal with the issue of ROP and evaluate current clinical practice that will limit donor exposure. Due to the limited benefits and the possibly increased risk of ROP, administration of EPO is not recommended. Darbepoetin requires further study. The possible neuroprotective role of EPO in neonates will be reviewed in separate Cochrane reviews.

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2013. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2013 (Abstracts2View™) and clinical trials registries (www.clinicaltrials.gov; www.controlled-trials.com; and who.int/ictrp/en). For this update we moved one study from the early EPO review to this late EPO review. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We include 30 studies (31 comparisons) randomising 1591 preterm infants. Literature searches in 2013 did not identify any new study for inclusion. For this update we moved one study enrolling 230 infants from the early EPO review to this late EPO review.Most included trials were of small sample size. The meta-analysis showed a significant effect of the use of one or more RBC transfusions (20 studies (n = 1142); typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 68%; RD I² = 60%). We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants]. There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was minimal heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). There were no significant differences in other clinical outcomes. There was no reduction in necrotizing enterocolitis in spite of a reduction in the use of RBC transfusions. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (ml/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Neuraminidase inhibitors for preventing and treating influenza in adults and children.

© 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Background: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. Objectives: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. Main results: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). Authors' conclusions: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials...

Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Objectives To describe the potential benefits and harms of zanamivir.Design Systematic review of clinical study reports of randomised placebo controlled trials and regulatory informationData sources Clinical study reports, trial registries,...

Post-exposure passive immunisation for preventing measles.

Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no minimum effective dose has been determined. To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation) for preventing measles when administered to exposed susceptible people before the onset of symptoms. We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE (1974 to August 2013). We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded studies of other sources of immunoglobulins. Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for missing information. We described the results of studies not included in meta-analyses. We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44).Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin.No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified.Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness.The included studies were not specifically designed to detect adverse events.Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.