High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: This overview was originally published in 2017, and is being updated in 2022.  Chronic pain is typically described as pain on most days for at least three months. Chronic non-cancer pain (CNCP) is any chronic pain that is not due to a malignancy. Chronic non-cancer pain in adults is a common and complex clinical issue, for which opioids are prescribed by some physicians for pain management. There are concerns that the use of high doses of opioids for CNCP lacks evidence of effectiveness, and may increase the risk of adverse events. OBJECTIVES: To describe the evidence from Cochrane Reviews and overviews regarding the efficacy and safety of high-dose opioids (defined as 200 mg morphine equivalent or more per day) for CNCP. METHODS: We identified Cochrane Reviews and overviews by searching the Cochrane Database of Systematic Reviews in The Cochrane Library. The date of the last search was 21 July 2022. Two overview authors independently assessed the search results. We planned to analyse data on any opioid agent used at a high dose for two weeks or more for the treatment of CNCP in adults. MAIN RESULTS: We did not identify any reviews or overviews that met the inclusion criteria. The excluded reviews largely reflected low doses or titrated doses, where all doses were analysed as a single group; we were unable to extract any data for high-dose use only. AUTHORS' CONCLUSIONS: There is a critical lack of high-quality evidence, in the form of Cochrane Reviews, about how well high-dose opioids work for the management of CNCP in adults, and regarding the presence and severity of adverse events.  No evidence-based argument can be made on the use of high-dose opioids, i.e. 200 mg morphine equivalent or more daily, in clinical practice. Considering that high-dose opioids have been, and are still being used in clinical practice to treat CNCP, knowing about the efficacy and safety of these higher doses is imperative.

Pharmacological Interventions for Primary Psychodermatologic Disorders: An Evidence Mapping and Appraisal of Randomized Controlled Trials.

BACKGROUND: The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs). METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment. RESULTS: Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania (n = 12), pathologic skin picking (n = 5), nail biting (n = 2), delusional parasitosis (n = 1), and dermatitis from compulsive hand washing (n = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking. CONCLUSION: Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.

Characteristics and Prognostic Factors for Return to Work in Public Safety Personnel with Work-Related Posttraumatic Stress Injury Undergoing Rehabilitation.

PURPOSE: Public safety personnel (PSP) are at risk of developing posttraumatic stress injury (PTSI) due to exposure to traumatic experiences and accidents. Rehabilitation programs are available, but their success varies. We studied: (1) characteristics of PSP undergoing PTSI rehabilitation in comparison to non-PSP workers; and (2) predictive value of various factors for return to work. Methods A population-based cohort study was conducted using data on injured workers undergoing PTSI rehabilitation. Of the 488 workers included, 131 were PSP. Outcome measures were: (1) return to pre-accident work at rehabilitation discharge; (2) days receiving wage replacement benefits in the year following rehabilitation. Results PSP were mainly employed (90.8%), male (59.5%), paramedics/ambulance workers (58.0%); a minority (43.5%) returned to pre-accident work after rehabilitation. Compared to non-PSP workers, PSP were more likely to initially be diagnosed with psychological injuries (94.7% versus 59.4%, p < 0.001) rather than musculoskeletal injuries. Return to pre-accident work was predicted by shorter injury duration, having a primary mental health diagnosis, working at time of admission, and not having symptoms requiring treatment in a complex rehabilitation program. PSPs were slower to experience full recovery in the year after rehabilitation. Factors predicting fewer benefit days included not having a secondary psychological injury, being employed, and working at time of admission. Conclusions Most PSP did not return to work in full after PTSI rehabilitation. Outcomes are likely to improve by starting treatment earlier and maintaining connections with the workplace.

Association between supportive interventions and healthcare utilization and outcomes in patients on long-term prescribed opioid therapy presenting to acute healthcare settings: a systematic review and meta-analysis.

BACKGROUND: Long-term prescription of opioids by healthcare professionals has been linked to poor individual patient outcomes and high resource utilization. Supportive strategies in this population regarding acute healthcare settings may have substantial impact. METHODS: We performed a systematic review and meta-analysis of primary studies. The studies were included according to the following criteria: 1) age 18 and older; 2) long-term prescribed opioid therapy; 3) acute healthcare setting presentation from a complication of opioid therapy; 4) evaluating a supportive strategy; 5) comparing the effectiveness of different interventions; 6) addressing patient or healthcare related outcomes. We performed a qualitative analysis of supportive strategies identified. We pooled patient and system related outcome data for each supportive strategy. RESULTS: A total of 5664 studies were screened and 19 studies were included. A total of 9 broad categories of supportive strategies were identified. Meta-analysis was performed for the "supports for patients in pain" supportive strategy on two system-related outcomes using a ratio of means. The number of emergency department (ED) visits were significantly reduced for cohort studies (n = 6, 0.36, 95% CI [0.20-0.62], I2 = 87%) and randomized controlled trials (RCTs) (n = 3, 0.71, 95% CI [0.61-0.82], I2 = 0%). The number of opioid prescriptions at ED discharge was significantly reduced for RCTs (n = 3, 0.34, 95% CI [0.14-0.82], I2 = 78%). CONCLUSION: For patients presenting to acute healthcare settings with complications related to long-term opioid therapy, the intervention with the most robust data is "supports for patients in pain".

Random drug and alcohol testing for preventing injury in workers.

BACKGROUND: Drug- and alcohol-related impairment in the workplace has been linked to an increased risk of injury for workers. Randomly testing populations of workers for these substances has become a practice in many jurisdictions, with the intention of reducing the risk of workplace incidents and accidents. Despite the proliferation of random drug and alcohol testing (RDAT), there is currently a lack of consensus about whether it is effective at preventing workplace injury, or improving other non-injury accident outcomes in the work place. OBJECTIVES: To assess the effectiveness of workplace RDAT to prevent injuries and improve non-injury accident outcomes (unplanned events that result in damage or loss of property) in workers compared with no workplace RDAT. SEARCH METHODS: We conducted a systematic literature search to identify eligible published and unpublished studies. The date of the last search was 1 November 2020. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, two other databases, Google Scholar, and three trials registers. We also screened the reference lists of relevant publications known to us. SELECTION CRITERIA: Study designs that were eligible for inclusion in our review included randomised controlled trials (RCTs), cluster-randomised trials (CRTs), interrupted time-series (ITS) studies, and controlled before-after (CBA) studies. Studies needed to evaluate the effectiveness of RDAT in preventing workplace injury or improving other non-injury workplace outcomes. We also considered unpublished data from clinical trial registries. We included employees working in all safety-sensitive occupations, except for commercial drivers, who are the subject of another Cochrane Review. DATA COLLECTION AND ANALYSIS: Independently, two review authors used a data collection form to extract relevant characteristics from the included study. They then analysed a line graph included in the study of the prevalence rate of alcohol violations per year. Independently, the review authors completed a GRADE assessment, as a means of rating the quality of the evidence. MAIN RESULTS: Although our searching originally identified 4198 unique hits, only one study was eligible for inclusion in this review. This was an ITS study that measured the effect of random alcohol testing (RAT) on the test positivity rate of employees of major airlines in the USA from 1995 to 2002. The study included data from 511,745 random alcohol tests, and reported no information about testing for other substances. The rate of positive results was the only outcome of interest reported by the study. The average rate of positive results found by RAT increased from 0.07% to 0.11% when the minimum percentage of workers who underwent RAT annually was reduced from 25% to 10%. Our analyses found this change to be a statistically significant increase (estimated change in level, where the level reflects the average percentage points of positive tests = 0.040, 95% confidence interval 0.005 to 0.075; P = 0.031). Our GRADE assessment, for the observed effect of lower minimum testing percentages associating with a higher rate of positive test results, found the quality of the evidence to be 'very low' across the five GRADE domains. The one included study did not address the following outcomes of interest: fatal injuries; non-fatal injuries; non-injury accidents; absenteeism; and adverse effects associated with RDAT. AUTHORS' CONCLUSIONS: In the aviation industry in the USA, the only setting for which the eligible study reported data, there was a statistically significant increase in the rate of positive RAT results following a reduction in the percentage of workers tested, which we deem to be clinically relevant. This result suggests an inverse relationship between the proportion of positive test results and the rate of testing, which is consistent with a deterrent effect for testing. No data were reported on adverse effects related to RDAT. We could not draw definitive conclusions regarding the effectiveness of RDAT for employees in safety-sensitive occupations (not including commercial driving), or with safety-sensitive job functions. We identified only one eligible study that reflected one industry in one country, was of non-randomised design, and tested only for alcohol, not for drugs or other substances. Our GRADE assessment resulted in a 'very low' rating for the quality of the evidence on the only outcome reported. The paucity of eligible research was a major limitation in our review, and additional studies evaluating the effect of RDAT on safety outcomes are needed.

Making Glove Decision Less of a White Knuckling Experience: A Systematic Review and Inventory of Glove Accelerator Contents.

BACKGROUND: Accelerators in medical gloves are a common cause of allergic contact dermatitis among healthcare workers. OBJECTIVE: A systematic review of medical and nursing literature, patch testing reports, and chemical analyses of gloves was conducted to assess accelerator contents reported in the literature and to identify accelerator-free gloves. METHODS: A systematic literature search was performed in OVID Medline and OVID EMBASE. Hand-searching of reference lists of articles in the field and author input generated the remainder of articles assessed. RESULTS: We present an inventory of accelerator contents of gloves and accelerator-free glove options as reported in the literature as a clinical reference tool to assist allergen-free glove selection for individuals suffering from allergic contact dermatitis due to rubber accelerators. LIMITATIONS: Pertinent limitations of our review include lack of predefined study exclusion criteria and screening of the studies identified in the search by 1 review author only. CONCLUSION: The glove inventory we provide summarizes the available literature regarding medical and surgical glove accelerator content, describing gloves both by brand and manufacturer as well as by accelerators.

Decline of COPD exacerbations in clinical trials over two decades - a systematic review and meta-regression.

BACKGROUND: An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. METHODS: We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). RESULTS: Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB <  0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV1) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the "placebo" group, also yielded consistent results. CONCLUSIONS: In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed. REGISTRATION: PROSPERO 2018 CRD4218118823.

Pregabalin for neuropathic pain in adults.

BACKGROUND: This review updates part of an earlier Cochrane Review titled "Pregabalin for acute and chronic pain in adults", and considers only neuropathic pain (pain from damage to nervous tissue). Antiepileptic drugs have long been used in pain management. Pregabalin is an antiepileptic drug used in management of chronic pain conditions. OBJECTIVES: To assess the analgesic efficacy and adverse effects of pregabalin for chronic neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from January 2009 to April 2018, online clinical trials registries, and reference lists. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing pregabalin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and biases. Primary outcomes were: at least 30% pain intensity reduction over baseline; much or very much improved on the Patient Global Impression of Change (PGIC) Scale (moderate benefit); at least 50% pain intensity reduction; or very much improved on PGIC (substantial benefit). We calculated risk ratio (RR) and number needed to treat for an additional beneficial (NNTB) or harmful outcome (NNTH). We assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 45 studies lasting 2 to 16 weeks, with 11,906 participants - 68% from 31 new studies. Oral pregabalin doses of 150 mg, 300 mg, and 600 mg daily were compared with placebo. Postherpetic neuralgia, painful diabetic neuropathy, and mixed neuropathic pain predominated (85% of participants). High risk of bias was due mainly to small study size (nine studies), but many studies had unclear risk of bias, mainly due to incomplete outcome data, size, and allocation concealment.Postherpetic neuralgia: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (50% vs 25%; RR 2.1 (95% confidence interval (CI) 1.6 to 2.6); NNTB 3.9 (3.0 to 5.6); 3 studies, 589 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (32% vs 13%; RR 2.5 (95% CI 1.9 to 3.4); NNTB 5.3 (3.9 to 8.1); 4 studies, 713 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (62% vs 24%; RR 2.5 (95% CI 2.0 to 3.2); NNTB 2.7 (2.2 to 3.7); 3 studies, 537 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (41% vs 15%; RR 2.7 (95% CI 2.0 to 3.5); NNTB 3.9 (3.1 to 5.5); 4 studies, 732 participants, moderate-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 16% versus 5.5%, 600 mg 25% versus 5.8%; dizziness 300 mg 29% versus 8.1%, 600 mg 35% versus 8.8%.Painful diabetic neuropathy: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (47% vs 42%; RR 1.1 (95% CI 1.01 to 1.2); NNTB 22 (12 to 200); 8 studies, 2320 participants, moderate-quality evidence), more had at least 50% pain intensity reduction (31% vs 24%; RR 1.3 (95% CI 1.2 to 1.5); NNTB 22 (12 to 200); 11 studies, 2931 participants, moderate-quality evidence), and more had PGIC much or very much improved (51% vs 30%; RR 1.8 (95% CI 1.5 to 2.0); NNTB 4.9 (3.8 to 6.9); 5 studies, 1050 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (63% vs 52%; RR 1.2 (95% CI 1.04 to 1.4); NNTB 9.6 (5.5 to 41); 2 studies, 611 participants, low-quality evidence), and more had at least 50% pain intensity reduction (41% vs 28%; RR 1.4 (95% CI 1.2 to 1.7); NNTB 7.8 (5.4 to 14); 5 studies, 1015 participants, low-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 11% versus 3.1%, 600 mg 15% versus 4.5%; dizziness 300 mg 13% versus 3.8%, 600 mg 22% versus 4.4%.Mixed or unclassified post-traumatic neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (48% vs 36%; RR 1.2 (1.1 to 1.4); NNTB 8.2 (5.7 to 15); 4 studies, 1367 participants, low-quality evidence), and more had at least 50% pain intensity reduction (34% vs 20%; RR 1.5 (1.2 to 1.9); NNTB 7.2 (5.4 to 11); 4 studies, 1367 participants, moderate-quality evidence). Somnolence (12% vs 3.9%) and dizziness (23% vs 6.2%) were more common with pregabalin.Central neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (44% vs 28%; RR 1.6 (1.3 to 2.0); NNTB 5.9 (4.1 to 11); 3 studies, 562 participants, low-quality evidence) and at least 50% pain intensity reduction (26% vs 15%; RR 1.7 (1.2 to 2.3); NNTB 9.8 (6.0 to 28); 3 studies, 562 participants, low-quality evidence). Somnolence (32% vs 11%) and dizziness (23% vs 8.6%) were more common with pregabalin.Other neuropathic pain conditions: Studies show no evidence of benefit for 600 mg pregabalin in HIV neuropathy (2 studies, 674 participants, moderate-quality evidence) and limited evidence of benefit in neuropathic back pain or sciatica, neuropathic cancer pain, or polyneuropathy.Serious adverse events, all conditions: Serious adverse events were no more common with placebo than with pregabalin 300 mg (3.1% vs 2.6%; RR 1.2 (95% CI 0.8 to 1.7); 17 studies, 4112 participants, high-quality evidence) or pregabalin 600 mg (3.4% vs 3.4%; RR 1.1 (95% CI 0.8 to 1.5); 16 studies, 3995 participants, high-quality evidence). AUTHORS' CONCLUSIONS: Evidence shows efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified post-traumatic neuropathic pain, and absence of efficacy in HIV neuropathy; evidence of efficacy in central neuropathic pain is inadequate. Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment. There were no substantial changes since the 2009 review.

Perioperative intravenous ketamine for acute postoperative pain in adults.

BACKGROUND: Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting. OBJECTIVES: To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We sought randomised, double-blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non-steroidal anti-inflammatory drug (NSAID), with a basic analgesic alone. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S-ketamine and one only R-ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non-stratified analysis.Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate-quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate-quality evidence; 37 studies, 2449 participants).Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high-quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high-quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate-quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low-quality evidence; 23 studies, 1353 participants).Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small-study effects were present, or twice if numbers were small and small-study effects likely but testing not possible.Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate-quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI -11.9 to -2.2), compared with placebo (very low-quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small-study effects or because the number of participants was below 400.CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high-quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high-quality evidence; 95 studies, 5965 participants). AUTHORS' CONCLUSIONS: Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance.

Birth risks according to maternal height and weight - an analysis of the German Perinatal Survey.

Objective To investigate the variability in the prevalences of selected birth risks in women of different heights and weights. Methods Data from the German Perinatal Survey of 1998-2000 were analyzed: 503,468 cases contributed to our analysis of the prevalences of selected birth risks specified according to maternal weight groups, 502,562 cases contributed to our analysis according to maternal height groups and 43,928 cases contributed to our analysis of birth risks in women with a body mass index (BMI) of 21-23 kg/m2 but different heights and weights. Data analysis was performed using SPSS version 22. Results Some birth risks varied substantially by maternal height in women with a "normal" BMI of 21-23 kg/m2: the prevalence of post-term birth increased from 8.7% in women with a height of 150 cm to 13.5% in 185 cm tall women, the prevalence of preterm birth decreased from 5.9% (150 cm tall women) to 3.1% (185 cm tall women), a pathologic cardiotocography (CTG) or poor fetal heart sounds on auscultation occurred in 19.4% of the 150 cm tall women but only in 9.2% of 185 cm tall women and cephalopelvic disproportion decreased from 12.3% (150 cm tall women) to 1.2% (185 cm tall women). Analyses of women in different body height and weight groups (without restriction of BMI) likewise showed differences in the prevalences of some birth risks. Conclusion Birth risks may vary by height and weight in women with the same, "normal" BMI. BMI should not be the only way by which the impact of maternal height and weight is assessed with regard to perinatal outcomes such as birth risks.

Somatic development at birth as influenced by maternal characteristics - an analysis of the German Perinatal Survey.

We investigated the effects of maternal age, body weight, body height, weight gain during pregnancy, smoking during pregnancy, previous live births and being a single mother on somatic development at birth. We analysed data from the German Perinatal Survey for the years 1998-2000 from eight German federal states. We had available data on 508,926 singleton pregnancies and neonates in total; for 508,893 of which we could classify the neonates as small, appropriate or large for gestational age (SGA, AGA or LGA) based on the 10th and 90th birth weight percentiles. Multivariable regression analyses found statistically significant effects of a clinically relevant magnitude for smoking during pregnancy [odds ratio (OR) 2.9 for SGA births for women smoking >10 cigarettes per day], maternal height (OR 1.4 for SGA births for women <162 cm; OR 1.4 for LGA births for women >172 cm), maternal weight (OR 1.5 for SGA births for women <59 kg; OR 1.9 for LGA births for women >69 kg), weight gain during pregnancy (OR 1.9 for SGA births for women with a weight gain <8 kg; OR 2.0 for LGA births for women with a weight gain >18 kg) and previous live births (OR 2.1 for LGA births for women with one or more previous live births). Maternal age and being a single mother also had significant effects but their magnitude was small. Our analysis confirms the clinically relevant effects of smoking, maternal anthropometric measures and weight gain during pregnancy on neonatal somatic development.

High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is typically described as pain on most days for at least three months. Chronic non-cancer pain (CNCP) is any chronic pain that is not due to a malignancy. Chronic non-cancer pain in adults is a common and complex clinical issue where opioids are routinely used for pain management. There are concerns that the use of high doses of opioids for chronic non-cancer pain lacks evidence of effectiveness and may increase the risk of adverse events. OBJECTIVES: To describe the evidence from Cochrane Reviews and Overviews regarding the efficacy and safety of high-dose opioids (here defined as 200 mg morphine equivalent or more per day) for chronic non-cancer pain. METHODS: We identified Cochrane Reviews and Overviews through a search of the Cochrane Database of Systematic Reviews (The Cochrane Library). The date of the last search was 18 April 2017. Two review authors independently assessed the search results. We planned to analyse data on any opioid agent used at high dose for two weeks or more for the treatment of chronic non-cancer pain in adults. MAIN RESULTS: We did not identify any reviews or overviews meeting the inclusion criteria. The excluded reviews largely reflected low doses or titrated doses where all doses were analysed as a single group; no data for high dose only could be extracted. AUTHORS' CONCLUSIONS: There is a critical lack of high-quality evidence regarding how well high-dose opioids work for the management of chronic non-cancer pain in adults, and regarding the presence and severity of adverse events. No evidence-based argument can be made on the use of high-dose opioids, i.e. 200 mg morphine equivalent or more daily, in clinical practice. Trials typically used doses below our cut-off; we need to know the efficacy and harm of higher doses, which are often used in clinical practice.

Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'. OBJECTIVES: To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults. METHODS: We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework. MAIN RESULTS: We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity. AUTHORS' CONCLUSIONS: A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.

Vitamin D levels and deficiency with different occupations: a systematic review.

BACKGROUND: Vitamin D deficiency is prevalent worldwide, but some groups are at greater risk. We aim to evaluate vitamin D levels in different occupations and identify groups vulnerable to vitamin D deficiency. METHODS: An electronic search conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and CINAHL Plus with Full Text generated 2505 hits; 71 peer-reviewed articles fulfilled the inclusion criteria. Occupations investigated included outdoor and indoor workers, shiftworkers, lead/smelter workers, coalminers, and healthcare professionals. We calculated the pooled average metabolite level as mean ± SD; deficiency/insufficiency status was described as % of the total number of subjects in a given category. RESULTS: Compared to outdoor workers, indoor workers had lower 25-hydroxyvitamin D (25-(OH)D) levels (40.6 ± 13.3 vs. 66.7 ± 16.7 nmol/L; p < 0.0001). Mean 25-(OH)D levels (in nmol/L) in shiftworkers, lead/smelter workers and coalminers were 33.8 ± 10.0, 77.8 ± 5.4 and 56.6 ± 28.4, respectively. Vitamin D deficiency (25-(OH)D < 50 nmol/L), was high in shiftworkers (80%) and indoor workers (78%) compared to outdoor workers (48%). Among healthcare professionals, medical residents and healthcare students had the lowest levels of mean 25-(OH)D, 44.0 ± 8.3 nmol/L and 45.2 ± 5.5 nmol/L, respectively. The mean 25-(OH)D level of practising physicians, 55.0 ± 5.8 nmol/L, was significantly different from both medical residents (p < 0.0001) and healthcare students (p < 0.0001). Nurses and other healthcare employees had 25-(OH)D levels of 63.4 ± 4.2 nmol/L and 63.0 ± 11.0 nmol/L, respectively, which differed significantly compared to practising physicians (p = 0.01), medical residents (p < 0.0001) and healthcare students (p < 0.0001). Rates of vitamin D deficiency among healthcare professionals were: healthcare students 72%, medical residents 65%, practising physicians 46%, other healthcare employees 44%, and nurses 43%. Combined rates of vitamin D deficiency or insufficiency (25-(OH)D < 75 nmol/L) were very high in all investigated groups. Potential confounders such as gender and body composition were not consistently reported in the primary studies and were therefore not analyzed. Furthermore, the descriptions of occupational characteristics may be incomplete. These are limitations of our systematic review. CONCLUSIONS: Our review demonstrates that shiftworkers, healthcare workers and indoor workers are at high risk to develop vitamin D deficiency, which may reflect key lifestyle differences (e.g. sunlight exposure). This may help target health promotion and preventive efforts.

Effects of food on pharmacokinetics of immediate release oral formulations of aspirin, dipyrone, paracetamol and NSAIDs - a systematic review.

AIMS: It is common to advise that analgesics, and especially non-steroidal anti-inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states. METHODS: A systematic review of comparisons of oral analgesics in fed and fasting states published to October 2014 reporting kinetic parameters of bioavailability, time to maximum plasma concentration (tmax ), and its extent (Cmax ) was conducted. Delayed-release formulations were not included. RESULTS: Bioavailability was not different between fasted and fed states. Food typically delayed absorption for all drugs where the fasting tmax was less than 4 h. For the common analgesics (aspirin, diclofenac, ibuprofen, paracetamol) fed tmax was 1.30 to 2.80 times longer than fasted tmax . Cmax was typically reduced, with greater reduction seen with more rapid absorption (fed Cmax only 44-85% of the fasted Cmax for aspirin, diclofenac, ibuprofen and paracetamol). CONCLUSION: There is evidence that high, early plasma concentrations produces better early pain relief, better overall pain relief, longer lasting pain relief and lower rates of remedication. Taking analgesics with food may make them less effective, resulting in greater population exposure. It may be time to rethink research priorities and advice to professionals, patients and the public.

The effect of adding a background infusion to patient-controlled epidural labor analgesia on labor, maternal, and neonatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Patient-controlled epidural analgesia (PCEA) has gained popularity, but it is still unclear whether adding a background infusion confers any benefit. METHODS: A systematic literature search in PubMed, Embase, CINAHL, LILACS, CENTRAL, Clinicaltrials.gov, and ISI WOS was performed to identify randomized controlled double-blind trials that compare PCEA-only with PCEA combined with a continuous infusion (PCEA + CI) in parturients. The data were subjected to meta-analyses using the random-effects model. Our primary outcome was the incidence of instrumental vaginal delivery. Secondary outcomes were incidences of spontaneous vaginal and cesarean deliveries, duration of labor, analgesic outcomes, maternal outcomes (visual analog scale scores for pain, maternal satisfaction, nausea, pruritus, hypotension), and neonatal outcomes (Apgar score, umbilical artery pH). RESULTS: We identified 7 trials with a low risk of bias, reporting on 891 parturients, for inclusion in our systematic review. The risk of instrumental vaginal delivery was increased in the PCEA + CI group, risk ratio (RR) 1.66 (95% confidence interval 1.08-2.56, P = 0.02; I = 0%); the RR for cesarean delivery was 0.83 (95% confidence interval 0.61-1.13, I = 0%). The second stage of labor was prolonged (weighted mean difference 12.3 minutes, 95% confidence interval 5.1-19.5 minutes, P = 0.0008; I = 0%) in the PCEA + CI group. Fewer patients in the PCEA + CI group required physician-administered boluses (RR 0.35 [95% confidence interval 0.25-0.47, P < 0.00001; I = 0%]). No differences regarding maternal adverse events (nausea, pruritus, hypotension) or neonatal outcomes (Apgar scores <7, umbilical artery pH) were observed. CONCLUSIONS: On the basis of current evidence, no conclusion can be drawn regarding the risks or benefits of adding a continuous background infusion to PCEA compared with PCEA-only epidural labor analgesia. Further high-quality studies involving a sufficient number of patients are required.

Vitamin D for the treatment of chronic painful conditions in adults.

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 1, 2010) on 'Vitamin D for the treatment of chronic painful conditions in adults'.Vitamin D is produced in the skin after exposure to sunlight and can be obtained through food. Vitamin D deficiency has been linked with a range of conditions, including chronic pain. Observational and circumstantial evidence suggests that there may be a role for vitamin D deficiency in the aetiology of chronic painful conditions. OBJECTIVES: To assess the efficacy and safety of vitamin D supplementation in chronic painful conditions when tested against placebo or against active comparators. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to February 2015. This was supplemented by searching the reference lists of retrieved articles, reviews in the field, and online trial registries. SELECTION CRITERIA: We included studies if they were randomised double-blind trials of vitamin D supplementation compared with placebo or with active comparators for the treatment of chronic painful conditions in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies for inclusion, assessed methodological quality, and extracted data. We did not undertake pooled analysis due to the heterogeneity of the data. Primary outcomes of interest were pain responder outcomes, and secondary outcomes were treatment group average pain outcomes and adverse events. MAIN RESULTS: We included six new studies (517 participants) in this review update, bringing the total of included studies to 10 (811 participants). The studies were heterogeneous with regard to study quality, the chronic painful conditions that were investigated, the dose of vitamin D given, co-interventions, and the outcome measures reported. Only two studies reported responder pain outcomes; the other studies reported treatment group average outcomes only. Overall, there was no consistent pattern that vitamin D treatment was associated with greater efficacy than placebo in any chronic painful condition (low quality evidence). Adverse events and withdrawals were comparatively infrequent, with no consistent difference between vitamin D and placebo (good quality evidence). AUTHORS' CONCLUSIONS: The evidence addressing the use of vitamin D for chronic pain now contains more than twice as many studies and participants than were included in the original version of this review. Based on this evidence, a large beneficial effect of vitamin D across different chronic painful conditions is unlikely. Whether vitamin D can have beneficial effects in specific chronic painful conditions needs further investigation.

Codeine, alone and with paracetamol (acetaminophen), for cancer pain.

BACKGROUND: Pain is very common in patients with cancer. Opioid analgesics, including codeine, play a significant role in major guidelines on the management of cancer pain, particularly for mild to moderate pain. Codeine is widely available and inexpensive, which may make it a good choice, especially in low-resource settings. Its use is controversial, in part because codeine is not effective in a minority of patients who cannot convert it to its active metabolite (morphine), and also because of concerns about potential abuse, and safety in children. OBJECTIVES: To determine the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 2), MEDLINE and EMBASE from inception to 5 March 2014, supplemented by searches of clinical trial registries and screening of the reference lists of the identified studies and reviews in the field. SELECTION CRITERIA: We sought randomised, double-blind, controlled trials using single or multiple doses of codeine, with or without paracetamol, for the treatment of cancer pain. Trials could have either parallel or cross-over design, with at least 10 participants per treatment group. Studies in children or adults reporting on any type, grade, and stage of cancer were eligible. We accepted any formulation, dosage regimen, and route of administration of codeine, and both placebo and active controls. DATA COLLECTION AND ANALYSIS: Two review authors independently read the titles and abstracts of all studies identified by the searches and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, two authors read the full manuscripts and assessed them for inclusion. We resolved discrepancies between review authors by discussion. Included studies were described qualitatively, since no meta-analysis was possible because of the small amount of data identified, and clinical and methodological between-study heterogeneity. MAIN RESULTS: We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately.Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg.There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators.Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. AUTHORS' CONCLUSIONS: We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.