Michael Andreae

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data

UNLABELLED Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. PERSPECTIVE This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment.

Swallowed Fluticasone Propionate Is an Effective Long-Term Maintenance Therapy for Children With Eosinophilic Esophagitis

OBJECTIVES:Although effective in the treatment of eosinophilic esophagitis (EoE) in children, limited data exist on long-term safety and efficacy of swallowed topical corticosteroids. We investigated whether long-term use of swallowed fluticasone in children with EoE leads to sustained reduction in esophageal eosinophils, and endoscopic and clinical improvement.METHODS:In an open-label, prospective, single-center study, we offered pediatric patients with active EoE fluticasone 2 puffs to swallow twice a day (strengths in μg/puff: 2–4 years: 44, 5–11 years: 110, ≥12 years: 220). Clinical, endoscopic, and histological assessments were performed at baseline and shortly after therapy. If histological remission was seen, fluticasone was continued with clinical follow-ups every 4 months and endoscopic and histological follow-ups yearly. Clinical scores were derived from eight symptoms (abdominal pain, nausea, vomiting, regurgitation, chest pain, dysphagia, food impaction, and early satiety). Endoscopic scores were derived from six features (rings, exudates, furrows, edema, stricture, and shearing). Scores were expressed as ratio (features present/total). In addition to peak eosinophils/high power field (HPF) (primary outcome), histological features (eosinophilic microabscesses, degranulation, superficial layering, basal zone hyperplasia, dilated intercellular spaces, and lamina propria fibrosis) were assessed. Median clinical and endoscopic scores and individual histologic features were compared over 4 time intervals: <4 months, 4–12 months, 13–24 months, and >24 months. Growth and adverse effects were monitored.RESULTS:We enrolled 54 patients, 80% male, median age 6.5 years (range 2–17 years), 85% atopic (57% asthma, 68% allergic rhinitis, and 31% atopic dermatitis), and 74% with food allergy. Mean follow-up was 20.4 months, the longest being 68 months (5.7 years). Esophageal eosinophil counts significantly decreased (median peak eosinophils/HPF at baseline 72, <4 months: 0.5, 4–12 months: 1.75, 13–24 months: 10, and >24 months: 12, all P<0.01). All histological features significantly decreased from baseline to all follow-up time points (all P<0.01). Lamina propria fibrosis significantly decreased (% patients with fibrosis at baseline 92, <4 months: 41, 4–12 months: 50, 13–24 months: 45, and >24 months: 39, all P<0.01). Endoscopic features improved (score at baseline 0.37, <4 months: 0.17, 4–12 months: 0.17, 13–24 months: 0, and >24 months: 0.1, all P<0.01, except at >24 months: P<0.05). Symptoms improved (score at baseline 0.22, <4 months: 0, 4–12 months: 0.11, 13–24 months: 0.11, and >24 months: 0.11, all P<0.05 except at >24 months: P=0.05). In a mixed linear regression model that accounts for correlation of repeated observations in the patient in a per-patient analysis, we found that treatment with swallowed fluticasone led to a statistically significant and sustained decrease in peak esophageal eosinophil counts. Asymptomatic esophageal candidiasis was seen in three children but resolved with anti-fungal therapy. Height and weight z-scores followed expected growth curves.CONCLUSIONS:We demonstrate that swallowed fluticasone is effective as a long-term maintenance therapy for children with EoE, without growth impediment or serious side effects.

An Ethical Exploration of Barriers to Research on Controlled Drugs

We examine the ethical, social, and regulatory barriers that may hinder research on therapeutic potential of certain controversial controlled substances like marijuana, heroin, or ketamine. Hazards for individuals and society and potential adverse effects on communities may be good reasons for limiting access and justify careful monitoring of these substances. Overly strict regulations, fear of legal consequences, stigma associated with abuse and populations using illicit drugs, and lack of funding may, however, limit research on their considerable therapeutic potential. We review the surprisingly sparse literature and address the particular ethical concerns pertinent to research with illicit and addictive substances, such as undue inducement, informed consent, therapeutic misconception, and risk to participants, researchers, and institutions. We consider the perspectives of key research stakeholders and explore whether they may be infected with bias. We conclude by proposing an empirical research agenda to provide an evidentiary basis for ethical reasoning.

A longitudinal linear model of patient characteristics to predict failure to attend an inner-city chronic pain clinic

UNLABELLED Patients often fail to attend appointments in chronic pain clinics for unknown reasons. We hypothesized that certain patient characteristics predict failure to attend scheduled appointments, pointing to systematic barriers to accessing chronic pain services for certain underserved populations. We collected retrospective data from a longitudinal observational cohort of patients at an academic pain clinic in Newark, New Jersey. To examine the effect of demographic factors on appointment status, we fit a marginal logistic regression using generalized estimating equations with exchangeable correlation. A total of 1,394 patients with 3,488 total encounters between January 1, 2006, and December 31, 2009, were included. Spanish spoken as a primary language (alternatively Hispanic or other race) and living between 5 and 10 miles from the clinic were associated with reduced odds of arriving for an appointment; making an appointment for a particular complaint such as cancer pain or back pain, an interventional pain procedure scheduled in connection with the appointment, unemployed status, and continuity of care (as measured by office visit number) were associated with increased odds of arriving. Spanish spoken as a primary language and distance to the pain clinic predicted failure to attend a scheduled appointment in our cohort. If these constitute systematic barriers to access, they may be amenable to targeted interventions. PERSPECTIVE We identified certain patient characteristics, specifically Spanish spoken as a primary language and geographic distance from the clinic, that predict failure to attend an inner-city chronic pain clinic. These identified barriers to accessing chronic pain services may be modifiable by simple cost-effective interventions.

Micronutrients in HIV: A Bayesian Meta-Analysis

Background Approximately 28.5 million people living with HIV are eligible for treatment (CD4<500), but currently have no access to antiretroviral therapy. Reduced serum level of micronutrients is common in HIV disease. Micronutrient supplementation (MNS) may mitigate disease progression and mortality. Objectives We synthesized evidence on the effect of micronutrient supplementation on mortality and rate of disease progression in HIV disease. Methods We searched MEDLINE, EMBASE, the Cochrane Central, AMED and CINAHL databases through December 2014, without language restriction, for studies of greater than 3 micronutrients versus any or no comparator. We built a hierarchical Bayesian random effects model to synthesize results. Inferences are based on the posterior distribution of the population effects; posterior distributions were approximated by Markov chain Monte Carlo in OpenBugs. Principal Findings From 2166 initial references, we selected 49 studies for full review and identified eight reporting on disease progression and/or mortality. Bayesian synthesis of data from 2,249 adults in three studies estimated the relative risk of disease progression in subjects on MNS vs. control as 0.62 (95% credible interval, 0.37, 0.96). Median number needed to treat is 8.4 (4.8, 29.9) and the Bayes Factor 53.4. Based on data reporting on 4,095 adults reporting mortality in 7 randomized controlled studies, the RR was 0.84 (0.38, 1.85), NNT is 25 (4.3, ∞). Conclusions MNS significantly and substantially slows disease progression in HIV+ adults not on ARV, and possibly reduces mortality. Micronutrient supplements are effective in reducing progression with a posterior probability of 97.9%. Considering MNS low cost and lack of adverse effects, MNS should be standard of care for HIV+ adults not yet on ARV.

Long-term Functional Outcomes after Regional Anesthesia: A Summary of the Published Evidence and a Recent Cochrane Review.

population-based average effects or biomarkers as evidence of meaningful improvement in care are unconvincing in this day and age. Outcomes suitable as arguments for the sustained value of regional anesthesia should instead be patient centered. Patient preferences, shared decision-making, and individualized tailored care are the hallmarks of this new paradigm in outcomes research, differentiating it from previous concepts of comparative effectiveness research. Much needs to be done to define and investigate patient-centered outcomes in anesthesiology and pain medicine, especially long-term outcomes. Pay for performance is another emerging concept, forcing us to emphasize our unique contribution to the quality of patient outcomes. What is the added value that anesthesiologists providing patients regional anesthesia contribute in the long run in the perioperative surgical home, where these anesthesiology subspecialists serve as the shepherds guiding the individualized perioperative recovery process? Outcomes suitable as arguments for the sustained value of regional anesthesia should be patient centered. Pain, Function, and Cognition as Cornerstones of Meaningful Long-term Recovery In this chapter, we examine the clinical evidence suggesting that regional anesthesia has meaningful benefits for our patients and society beyond the immediate perioperative period. Although there are several other outcomes of interest, such as morbidity and mortality or cancer recurrence, we focus on three long-term outcomes after elective surgery based on their particular importance: (1) Persistent pain (2) Joint function (3) Cognitive outcomes We also selected these outcomes because their impact and significance are easy to convey to any interlocutor—surgical colleague, lay person, hospital administrator, or politician— regardless of their previous training or experience. FOCUS 1: REGIONAL ANESTHESIA FOR THE PREVENTION OF PERSISTENT PAIN AFTER SURGERY

Probiotics in Human Immunodeficiency Virus Infection: A Systematic Review and Evidence Synthesis of Benefits and Risks.

The risk of sepsis is low. The best probiotic to optimize outcomes has not yet been identified. Potential benefit for CD4 count, recurrence or management of bacterial vaginosis and diarrhea. Uncertain effect on translocation, BV treatment.

Probiotics in HIV Infection: A Systematic Review and Evidence Synthesis of Benefits and Risks

The risk of sepsis is low. The best probiotic to optimize outcomes has not yet been identified. Potential benefit for CD4 count, recurrence or management of bacterial vaginosis and diarrhea. Uncertain effect on translocation, BV treatment.

Correction: Micronutrients in HIV: A Bayesian Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0120113.].

Editor's choice: Probiotics in Human Immunodeficiency Virus Infection: A Systematic Review and Evidence Synthesis of Benefits and Risks

The risk of sepsis is low. The best probiotic to optimize outcomes has not yet been identified. Potential benefit for CD4 count, recurrence or management of bacterial vaginosis and diarrhea. Uncertain effect on translocation, BV treatment.