Malgorzata M Bala

Epidemiology of chronic non-cancer pain in Europe: narrative review of prevalence, pain treatments and pain impact.

Abstract Background: Estimates on the epidemiology of chronic non-cancer pain vary widely throughout Europe. It is unclear whether this variation reflects true population differences or methodological factors. Such epidemiological information supports European decision makers in allocating healthcare resources. Objective: Pan-Europe epidemiological data about chronic non-cancer pain was obtained using systematic review principles in searching and summarising results. Methods: Multiple databases (MEDLINE, EMBASE, Cochrane Library, CRD Databases, and GIN) were systematically searched for primary studies containing epidemiological data on chronic non-cancer pain in Europe excluding studies that solely concerned migraines, headaches and pain associated with specific disease conditions. The studies were prioritised according to quality, recency and validity. Main outcomes: Eighteen research questions concerning aspects of chronic pain included: prevalence; incidence; pain treatments, control and compliance; treatment satisfaction; and quality of life and economic impacts. Results: The search yielded 16 619 references and 45 were relevant to Europe. Studies for each question were selected that provided the most recent, representative and valid data. There was a clear lack of studies concerning chronic non-cancer pain in Europe as a whole. The 1-month prevalence of moderate-to-severe non-cancer chronic pain was 19%. Chronic pain significantly impacted on patient-perceived health status, affected everyday activities including economic pursuits and personal relationships, and was significantly associated with depressive symptoms. The majority relied on drugs for pain control and NSAIDs were the most frequent drug choice. Despite pain medications, a large proportion had inadequate pain control. Conclusion: To the authors’ knowledge this is the most comprehensive literature review on epidemiological data in this field. It is clear that chronic pain has a dramatic impact on European society. Since chronic non-cancer pain is treated differently from cancer-related pain, the lack of data in this area clearly underlines the need for decision makers in healthcare to gather further epidemiological data.

Credibility of claims of subgroup effects in randomised controlled trials: systematic review

Objective To investigate the credibility of authors’ claims of subgroup effects using a representative sample of recently published randomised controlled trials. Design Systematic review. Data source Core clinical journals, as defined by the National Library of Medicine, in Medline. Study selection Randomised controlled trials published in 2007. Using prespecified criteria, teams of trained reviewers independently judged whether authors claimed subgroup effects and the strength of their claims. Reviewers assessed each of these claims against 10 predefined criteria, developed through a search of existing criteria and a consensus process. Results Of 207 randomised controlled trials reporting subgroup analyses, 64 (31%) made claims for the primary outcome. Of those, 20 were strong claims and 28 claims of a likely effect. Authors included subgroup variables measured at baseline in 60 (94%) trials, used subgroup variable as a stratification factor at randomisation in 13 (20%), clearly prespecified their hypotheses in 26 (41%), correctly prespecified direction in 4 (6%), tested a small number of hypotheses in 28 (44%), carried out a test of interaction that proved statistically significant in 6 (9%), documented replication of a subgroup effect with previous related studies in 21 (33%), identified consistency of a subgroup effect across related outcomes in 19 (30%), and provided a compelling indirect evidence for the effect in 14 (22%). In the 19 trials making more than one claim, only one (5%) checked the independence of the interaction. Of the 64 claims, 54 (84%) met four or fewer of the 10 criteria. For strong claims, more than 50% failed each of the individual criteria, and only three (15%) met more than five criteria. Conclusion Authors often claim subgroup effects in their trial report. However, the credibility of subgroup effects, even when claims are strong, is usually low. Users of the information should treat claims that fail to meet most criteria with scepticism. Trial researchers should report the conduct of subgroup analyses and provide sufficient evidence when claiming a subgroup effect or suggesting a possible effect.

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies

Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies.

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. Design Systematic review and meta-analysis of randomised and observational studies. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts. Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure. Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach. Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v 33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use. Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.

Systematic review of the (cost-)effectiveness of spinal cord stimulation for people with failed back surgery syndrome

ObjectivesWe conducted a systematic review to assess the (cost)effectiveness of spinal cord stimulation (SCS) in relieving certain kinds of pain for people with chronic pain owing to failed back surgery syndrome (FBSS). MethodsWe considered randomized trials, controlled observational studies of adult patients with chronic pain owing to FBSS, and case series with at least 50 patients permanently implanted, at least 60% FBSS patients and at least 1-year follow-up. SCS was additional to usual care and compared with usual care. The primary outcome was reduction of pain. Medline, Embase, Lilacs, Cinahl, and Cochrane Library databases were searched from inception until September 2006. An update search was carried out in January 2008. ResultsFor the effectiveness analysis, 1 fully published randomized controlled trial, one randomized controlled trial with 6 month results (both of moderate quality), 1 retrospective cohort study, and 13 case series (all of low quality) were included. The mean period of follow-up was between 6 months and 8.8 years. These studies show that SCS is effective in the treatment of FBSS in terms of pain reduction. The effect was consistent in all analyzed studies. Improvements were also reported for other outcomes, such as quality of life and functional status. All the studies reported some complications, most of which were technical problems. In terms of cost-effectiveness, 3 studies met the inclusion criteria and offered the same conclusion that SCS is both more effective and less costly in the long-term, but there is an initial high cost associated with device implantation and maintenance.

The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review

Objective To investigate the impact of industry funding on reporting of subgroup analyses in randomised controlled trials. Design Systematic review. Data sources Medline. Study selection Randomised controlled trials published in 118 core clinical journals (defined by the National Library of Medicine) in 2007. 1140 study reports in a 1:1 ratio by high (five general medicine journals with largest number of total citations in 2007) versus lower impact journals, were randomly sampled. Two reviewers, independently and in duplicate, used standardised, piloted forms to screen study reports for eligibility and to extract data. They also used explicit criteria to determine whether a randomised controlled trial reported subgroup analyses. Logistic regression was used to examine the association of prespecified study characteristics with reporting versus not reporting of subgroup analyses. Results 469 randomised controlled trials were included, of which 207 (44%) reported subgroup analyses. High impact journals (adjusted odds ratio 2.64, 95% confidence interval 1.62 to 4.33), non-surgical (versus surgical) trials (2.10, 1.26 to 3.50), and larger sample size (3.38, 1.64 to 6.99) were associated with more frequent reporting of subgroup analyses. The strength of association between trial funding and reporting of subgroups differed in trials with and without statistically significant primary outcomes (interaction P=0.02). In trials without statistically significant results for the primary outcome, industry funded trials were more likely to report subgroup analyses (2.29, 1.30 to 4.72) than non-industry funded trials. This was not true for trials with a statistically significant primary outcome (0.79, 0.46 to 1.36). Industry funded trials were associated with less frequent prespecification of subgroup hypotheses (31.3% v 38.0%, adjusted odds ratio 0.49, 0.26 to 0.94), and less use of the interaction test for analyses of subgroup effects (41.4% v 49.1%, 0.52, 0.28 to 0.97) than non-industry funded trials. Conclusion Industry funded randomised controlled trials, in the absence of statistically significant primary outcomes, are more likely to report subgroup analyses than non-industry funded trials. Industry funded trials less frequently prespecify subgroup hypotheses and less frequently test for interaction than non-industry funded trials. Subgroup analyses from industry funded trials with negative results for the primary outcome should be viewed with caution.

Effects of megestrol acetate in patients with cancer anorexia-cachexia syndrome--a systematic review and meta-analysis.

INTRODUCTION Anorexia-cachexia syndrome (ACS) often occurs in patients with advanced cancer. OBJECTIVES To review the effect of megestrol acetate (MA) in patients with ACS. PATIENTS AND METHODS To identify eligible studies, systematic review by Lopez et al. (2004) was used, electronic databases (MEDLINE, EMBASE and CENTRAL) were searched and reference lists of included studies were reviewed. The studies were included in the review if they were randomized, enrolled patients with non-hormone-sensitive cancer and ACS and assessed the effects of MA compared with placebo, other drugs or different doses of MA. RESULTS The study population is characterized by high mortality and progressive weight loss irrespective of the treatment. Compared to placebo, the effect of MA on survival is similar, but MA increases appetite (number needed to treat [NNT]: 3) and leads to weight gain (NNT: 8) in more patients. The data on other aspects of the quality of life are limited. The comparison of MA and glucocorticosteroids showed no statistical difference in their effect on appetite and weight. CONCLUSIONS Compared to placebo, MA reduces the symptoms of ACS, with no effect on survival. The beneficial effect of MA on the overall quality of life has not been confirmed. In identified studies the effect of MA and glucocorticosteroids on anorexia and cachexia is similar. The estimation of the treatment utility in ACS depends on the weight attributed to discomfort caused by symptoms, adverse effects of the drugs and the treatment cost. Because of the low quality of the included studies a new randomized controlled trial is needed for valid assessment of the effects of MA.

Transcatheter versus surgical aortic valve replacement in patients with severe aortic stenosis at low and intermediate risk: systematic review and meta-analysis

Objective To examine the effect of transcatheter aortic valve implantation (TAVI) versus surgical replacement of an aortic valve (SAVR) in patients with severe aortic stenosis at low and intermediate risk of perioperative death. Design Systematic review and meta-analysis Data sources Medline, Embase, and Cochrane CENTRAL. Study selection Randomized trials of TAVI compared with SAVR in patients with a mean perioperative risk of death <8%. Review methods Two reviewers independently extracted data and assessed risk of bias for outcomes important to patients that were selected a priori by a parallel guideline committee, including patient advisors. We used the GRADE system was used to quantify absolute effects and quality of evidence. Results 4 trials with 3179 patients and a median follow-up of two years were included. Compared with SAVR, transfemoral TAVI was associated with reduced mortality (risk difference per 1000 patients: −30, 95% confidence interval −49 to −8, moderate certainty), stroke (−20, −37 to 1, moderate certainty), life threatening bleeding (−252, −293 to −190, high certainty), atrial fibrillation (−178, −150 to −203, moderate certainty), and acute kidney injury (−53, −39 to −62, high certainty) but increased short term aortic valve reintervention (7, 1 to 21, moderate certainty), permanent pacemaker insertion (134, 16 to 382, moderate certainty), and moderate or severe symptoms of heart failure (18, 5 to 34, moderate certainty). Compared with SAVR, transapical TAVI was associated higher mortality (57, −16 to 153, moderate certainty, P=0.015 for interaction between transfemoral versus transapical TAVI) and stroke (45, −2 to 125, moderate certainty, interaction P=0.012). No study reported long term follow-up, which is particularly important for structural valve deterioration. Conclusions Many patients, particularly those who have a shorter life expectancy or place a lower value on the risk of long term valve degeneration, are likely to perceive net benefit with transfemoral TAVI versus SAVR. SAVR, however, performs better than transapical TAVI, which is of interest to patients who are not candidates for transfemoral TAVI. Systematic review registration PROSPERO CRD42016042879

Epidemiology of Chronic Pain in Denmark and Sweden

Introduction. Estimates on the epidemiology of chronic pain vary widely throughout Europe. It is unclear whether this variation reflects true differences between populations or methodological factors. Information on the epidemiology of chronic pain can support decision makers in allocating adequate health care resources. Methods. In order to obtain epidemiological data on chronic pain in Denmark and Sweden, we conducted a literature review of epidemiological data primarily on chronic noncancer pain, prioritising studies of highest quality, recency, and validity by conducting a systematic search for relevant studies. Following quality assessment, data were summarised and assigned to the research questions. Results. The prevalence of moderate to severe noncancer pain was estimated at 16% in Denmark and 18% in Sweden. Chronic pain impacts negatively on perceived health status, quality of life and is associated with increased cost. Despite using pain medications, a large proportion of chronic pain sufferers have inadequate pain control. There was a lack of high-quality and low-bias studies with clear inclusion criteria. Conclusions. In both Denmark and Sweden, chronic pain is a common health problem which is potentially undertreated and warrants attention of health care workers, policy makers and researchers. Future research should utilise clear reporting guidelines to assist decision and policy makers, in this important area.

5% lidocaine-medicated plaster vs other relevant interventions and placebo for post-herpetic neuralgia (PHN): a systematic review.

Wolff RF, Bala MM, Westwood M, Kessels AG, Kleijnen J. 5% lidocaine‐medicated plaster vs other relevant interventions and placebo for post‐herpetic neuralgia (PHN): a systematic review.
Acta Neurol Scand: 2011: 123: 295–309.
© 2010 John Wiley & Sons A/S.