A meta-analysis of gabapentin and multimodal analgesics

Multimodal analgesia has been proposed as a useful strategy to reduce postoperative pain while decreasing opioid consumption and thus opioid adverse events. Gabapentin is one such agent although previous results have been heterogeneous. This thesis aimed to review randomised controlled trials of gabapentin for reducing pain, opioid adverse effects and the haemodynamic response to intubation while attempted to predict clinical effectiveness from these trials using meta-regression. Extending this principle, we evaluated other multimodal analgesic agents to identify whether heterogeneity could be explained by various clinical and methodological covariates. Our gabapentin review included 133 randomised controlled trials and demonstrated its efficacy in reducing pain scores, opioid consumption and opioid adverse events such as nausea, vomiting and pruritus. However, gabapentin increased the risk of sedation. Gabapentin was effective at reducing the haemodynamic response to intubation in 29 randomised controlled trials although trials failed to report on clinically relevant outcomes. Gabapentin exhibited no pre-emptive analgesic effect in 4 randomised controlled trials. There was evidence of considerable statistical heterogeneity on meta-analysis of gabapentin for pain scores and 24-hour morphine consumption. Meta-regression analysis showed however that baseline risk predicted the majority of the heterogeneity between studies. Extending this approach to other multimodal analgesics from 344 randomised controlled trials; we demonstrated this was true for analgesic agents in general. In addition to baseline risk, methodological limitations, especially inadequate allocation concealment, explained some of the residual heterogeneity. There was evidence of funnel plot asymmetry for most analgesic agents, suggesting publication bias. However, this may be a product of trials with higher baseline risk having larger standard errors, rather than true publication bias. Indeed, when we simulated meta-analyses with no publication bias, with both effect size and standard deviations dependent on baseline risk, funnel plot asymmetry was still evident (p<0.001). Therefore, conventional funnel plots may be an unsuitable method of detecting publication bias where baseline risk predicts between-study heterogeneity. We present an alternative method using meta-regression residuals that corrects funnel plot asymmetry in the presence of no publication bias. Finally, due to concerns that methodological limitations exaggerated effect estimates, we used trial sequential analysis to determine whether sufficient low risk of bias evidence exists to reject type I and type II errors in the analyses of analgesic adjuncts. We demonstrated there is currently insufficient evidence from low risk of bias trials to be confident of the efficacy of the majority of analgesic adjuncts

A meta-analysis of gabapentin and multimodal analgesics

Multimodal analgesia has been proposed as a useful strategy to reduce postoperative pain while decreasing opioid consumption and thus opioid adverse events. Gabapentin is one such agent although previous results have been heterogeneous. This thesis aimed to review randomised controlled trials of gabapentin for reducing pain, opioid adverse effects and the haemodynamic response to intubation while attempted to predict clinical effectiveness from these trials using meta-regression. Extending this principle, we evaluated other multimodal analgesic agents to identify whether heterogeneity could be explained by various clinical and methodological covariates. Our gabapentin review included 133 randomised controlled trials and demonstrated its efficacy in reducing pain scores, opioid consumption and opioid adverse events such as nausea, vomiting and pruritus. However, gabapentin increased the risk of sedation. Gabapentin was effective at reducing the haemodynamic response to intubation in 29 randomised controlled trials although trials failed to report on clinically relevant outcomes. Gabapentin exhibited no pre-emptive analgesic effect in 4 randomised controlled trials. There was evidence of considerable statistical heterogeneity on meta-analysis of gabapentin for pain scores and 24-hour morphine consumption. Meta-regression analysis showed however that baseline risk predicted the majority of the heterogeneity between studies. Extending this approach to other multimodal analgesics from 344 randomised controlled trials; we demonstrated this was true for analgesic agents in general. In addition to baseline risk, methodological limitations, especially inadequate allocation concealment, explained some of the residual heterogeneity. There was evidence of funnel plot asymmetry for most analgesic agents, suggesting publication bias. However, this may be a product of trials with higher baseline risk having larger standard errors, rather than true publication bias. Indeed, when we simulated meta-analyses with no publication bias, with both effect size and standard deviations dependent on baseline risk, funnel plot asymmetry was still evident (p<0.001). Therefore, conventional funnel plots may be an unsuitable method of detecting publication bias where baseline risk predicts between-study heterogeneity. We present an alternative method using meta-regression residuals that corrects funnel plot asymmetry in the presence of no publication bias. Finally, due to concerns that methodological limitations exaggerated effect estimates, we used trial sequential analysis to determine whether sufficient low risk of bias evidence exists to reject type I and type II errors in the analyses of analgesic adjuncts. We demonstrated there is currently insufficient evidence from low risk of bias trials to be confident of the efficacy of the majority of analgesic adjuncts

An Investigation of the Concentration Dependence and Response to Analyte Mixtures of Carbon Black/Insulating Organic Polymer Composite Vapor Detectors

The responses relative to an air background of carbon black/polymer composite vapor detectors have been determined as a function of the concentration of a homologous series of alcohols (n-C_nH_(2n+1)OH, 1 ≤ n ≤ 8), a homologous series of alkanes (n-C_nH_(2n+2), 5 ≤ n ≤ 10 and n = 12, 14), and a set of diverse solvent vapors. In all cases, the steady-state relative differential resistance responses, ΔR/R_b, of the carbon black/polymer composite vapor detectors were well-described by a linear relationship with respect to the analyte partial pressure, at least over the tested concentration range (P/P° = 0.005−0.03, where P° is the vapor pressure of the analyte). When two vapors in air were simultaneously presented to the detectors, the ΔR/R_b response, relative to an air background, was the sum of the ΔR/R_b values obtained when each analyte was exposed separately to the carbon black/polymer composite detectors under study. Similarly, when an analyte was exposed to the detectors on top of a background level of another analyte, the ΔR/R_b values of the array of detectors were very close to those obtained when the test analyte was exposed to the detectors only in the presence of background air. The initial training requirements from the array response output data of such detectors are minimized because the ΔR/R_b response pattern produced by the analyte of concern can be associated uniquely with that odor, under the conditions explored in this work

Trends in odor intensity for human and electronic noses: Relative roles of odorant vapor pressure vs. molecularly specific odorant binding

Response data were collected for a carbon black-polymer composite electronic nose array during exposure to homologous series of alkanes and alcohols. The mean response intensity of the electronic nose detectors and the response intensity of the most strongly driven set of electronic nose detectors were essentially constant for members of a chemically homologous odorant series when the concentration of each odorant in the gas phase was maintained at a constant fraction of the odorant’s vapor pressure. A similar trend is observed in human odor detection threshold values for these same homologous series of odorants. Because the thermodynamic activity of an odorant at equilibrium in a sorbent phase is equal to the partial pressure of the odorant in the gas phase divided by the vapor pressure of the odorant and because the activity coefficients are similar within these homologous series of odorants for sorption of the vapors into specific polymer films, the data imply that the trends in detector response can be understood based on the thermodynamic tendency to establish a relatively constant concentration of sorbed odorant into each of the polymeric films of the electronic nose at a constant fraction of the odorant’s vapor pressure. Similarly, the data are consistent with the hypothesis that the odor detection thresholds observed in human psychophysical experiments for the odorants studied herein are driven predominantly by the similarity in odorant concentrations sorbed into the olfactory epithelium at a constant fraction of the odorant’s vapor pressure

Progress in the development of an electronic nose using arrays of chemically sensitive carbon black-polymer resistors

Response data were collected for a carbon black-polymer composite electronic nose array during exposure to homologous series of alkanes and alcohols. At a fixed partial pressure of odorant in the vapor phase, the mean response intensity of the electronic nose signals varied significantly for members of each series of odorants. However, the mean response intensity of the electronic nose detectors, and the response intensity of the most strongly-driven set of electronic nose detectors, was essentially constant for members of a chemically homologous odorant series when the concentration of each odorant in the gas phase was maintained at a constant fraction of the odorant's vapor pressure. Because the thermodynamic activity of an odorant at equilibrium in a sorbent phase is equal to the partial pressure of the odorant in the gas phase divided by the vapor pressure of the odorant, and because the activity coefficients are similar within these homologous series of odorants for sorption of the vapors into specific polymer films, the data imply that the trends in detector response can be understood based on the thermodynamic tendency to establish a relatively constant concentration of sorbed odorant into each of the polymeric films of the electronic nose at a constant fraction of the odorant's vapor pressure. This phenomenon provides a natural mechanism for enhanced sensitivity to low vapor pressure compounds, like TNT, in the presence of high vapor pressure analytes, such as diesel fuel. In a related study to evaluate the target recognition properties of the electronic nose, a statistical metric based on the magnitudes and standard deviations along Euclidean projections of clustered array response data, was utilized to facilitate an evaluation of the performance of detector arrays in various vapor classification tasks. This approach allowed quantification of the ability of a fourteen-element array of carbon black-insulating polymer composite chemiresistors to distinguish between members of a set of nineteen solvent vapors, some of which vary widely in chemical properties (e.g. methanol and benzene) and others of which are very similar (e.g. n-pentane and n-heptane). The data also facilitated evaluation of questions such as array performance as a function of the number of detectors in the system

A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain

We searched MEDLINE, Embase, CINAHL, AMED and CENTRAL databases until December 2014 and included 133 randomised controlled trials of peri-operative gabapentin vs placebo. Gabapentin reduced mean (95% CI) 24-h morphine-equivalent consumption by 8.44 (7.26–9.62) mg, p < 0.001, whereas more specific reductions in morphine equivalents were predicted (R2 = 90%, p < 0.001) by the meta-regression equation: 3.73 + (−0.378 × control morphine consumption (mg)) + (−0.0023 × gabapentin dose (mg)) + (−1.917 × anaesthetic type), where ‘anaesthetic type’ is ‘1’ for general anaesthesia and ‘0’ for spinal anaesthesia. The type of surgery was not independently associated with gabapentin effect. Gabapentin reduced postoperative pain scores on a 10-point scale at 1 h, 2 h, 6 h, 12 h and 24 h by a mean (95% CI) of: 1.68 (1.35–2.01); 1.21 (0.88–1.55); 1.28 (0.98–1.57); 1.12 (0.91–1.33); and 0.71 (0.56–0.87), respectively, p < 0.001 for all. The risk ratios (95% CI) for postoperative nausea, vomiting, pruritus and sedation with gabapentin were: 0.78 (0.69–0.87), 0.67 (0.59–0.76), 0.64 (0.51–0.80) and 1.18 (1.09–1.28), respectively, p < 0.001 for all. Gabapentin reduced pre-operative anxiety and increased patient satisfaction on a 10-point scale by a mean (95% CI) of 1.52 (0.78–2.26) points and 0.89 (0.22–1.57) points, p < 0.001 and p = 0.01, respectively. All the effects of gabapentin may have been overestimated by statistically significant small study effects

A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection

BackgroundResection of colorectal cancer (CRC) initiates inflammation, mediated at least partly by NFĸB (nuclear factor kappa-light-chain-enhancer of activated B-cells), leading to muscle catabolism and reduced physical performance. Eicosapentaenoic acid (EPA) has been shown to modulate NFĸB, but evidence for its benefit around the time of surgery is limited.ObjectiveTo assess the effect of EPA supplementation on muscle inflammation and physical function around the time of major surgery.DesignIn a double-blind randomized control trial, 61 patients (age: 68.3 ± 0.95 y; 42 male) scheduled for CRC resection, received 3 g per day of EPA (n = 32) or placebo (n = 29) for 5-days before and 21-days after operation. Lean muscle mass (LMM) (via dual energy X-ray absorptiometry (DXA)), anaerobic threshold (AT) (via cardiopulmonary exercise testing (CPET)) and hand-grip strength (HG) were assessed before and 4-weeks after surgery, with muscle biopsies (m. vastus lateralis) obtained for the assessment of NF-ĸB protein expression.ResultsThere were no differences in muscle NFĸB between EPA and placebo groups (mean difference (MD) −0.002; 95% confidence interval (CI) −0.19 to 0.19); p = 0.98). There was no difference in LMM (MD 704.77 g; 95% CI -1045.6 g–2455.13 g; p = 0.42) or AT (MD 1.11 mls/kg/min; 95% CI -0.52 mls/kg/min to 2.74 mls/kg/min; p = 0.18) between the groups. Similarly, there was no difference between the groups in HG at follow up (MD 0.1; 95% CI -1.88 to 2.08; p = 0.81). Results were similar when missing data was imputed.ConclusionEPA supplementation confers no benefit in terms of inflammatory status, as judged by NFĸB, or preservation of LMM, aerobic capacity or physical function following major colorectal surgery

Baseline morphine consumption may explain between-study heterogeneity in meta-analyses of adjuvant analgesics and improve precision and accuracy of effect estimates

BACKGROUND: Statistical heterogeneity can increase the uncertainty of results and reduce the quality of evidence derived from systematic reviews. At present, it is uncertain what the major factors are that account for heterogeneity in meta-analyses of analgesic adjuncts. Therefore, the aim of this review was to identify whether various covariates could explain statistical heterogeneity and use this to improve accuracy when reporting the efficacy of analgesics. METHODS: We searched for reviews using MEDLINE, EMBASE, CINAHL, AMED, and the Cochrane Database of Systematic Reviews. First, we identified the existence of considerable statistical heterogeneity (I2 > 75%). Second, we conducted meta-regression analysis for the outcome of 24-hour morphine consumption using baseline risk (control group morphine consumption) and other clinical and methodological covariates. Finally, we constructed a league table of adjuvant analgesics using a novel method of reporting effect estimates assuming a fixed consumption of 50 mg postoperative morphine. RESULTS: We included 344 randomized controlled trials with 28,130 participants. Ninety-one percent of analyses showed considerable statistical heterogeneity. Baseline risk was a significant cause of between-study heterogeneity for acetaminophen, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, tramadol, ketamine, [alpha]2-agonists, gabapentin, pregabalin, lidocaine, magnesium, and dexamethasone (R2 = 21%-100%; P 10 mg). We could not exclude a moderate clinically significant effect with ketamine. Dexamethasone demonstrated a small clinical benefit (>5 mg). CONCLUSIONS: We empirically identified baseline morphine consumption as the major source of heterogeneity in meta-analyses of adjuvant analgesics across all surgical interventions. Controlling for baseline morphine consumption, clinicians can use audit data to estimate the morphine-reducing effect of adding any adjuvant for their local population, regardless which surgery they undergo. Moreover, we have utilized these findings to present a novel method of reporting and an amended method of graphically displaying effect estimates, which both reduces confounding from variable baseline risk in included trials and is able to adjust for other clinical and methodological confounding variables. We recommend use of these methods in clinical practice and future reviews of analgesics for postoperative pain

An Investigation of the Concentration Dependence and Response to Analyte Mixtures of Carbon Black/Insulating Organic Polymer Composite Vapor Detectors

The responses relative to an air background of carbon black/polymer composite vapor detectors have been determined as a function of the concentration of a homologous series of alcohols (n-C_nH_(2n+1)OH, 1 ≤ n ≤ 8), a homologous series of alkanes (n-C_nH_(2n+2), 5 ≤ n ≤ 10 and n = 12, 14), and a set of diverse solvent vapors. In all cases, the steady-state relative differential resistance responses, ΔR/R_b, of the carbon black/polymer composite vapor detectors were well-described by a linear relationship with respect to the analyte partial pressure, at least over the tested concentration range (P/P° = 0.005−0.03, where P° is the vapor pressure of the analyte). When two vapors in air were simultaneously presented to the detectors, the ΔR/R_b response, relative to an air background, was the sum of the ΔR/R_b values obtained when each analyte was exposed separately to the carbon black/polymer composite detectors under study. Similarly, when an analyte was exposed to the detectors on top of a background level of another analyte, the ΔR/R_b values of the array of detectors were very close to those obtained when the test analyte was exposed to the detectors only in the presence of background air. The initial training requirements from the array response output data of such detectors are minimized because the ΔR/R_b response pattern produced by the analyte of concern can be associated uniquely with that odor, under the conditions explored in this work

Surgical interventions for the treatment of sacrococcygeal pilonidal sinus disease in children: a systematic review and meta-analysis

BackgroundPilonidal sinus disease (PNS) is not uncommon in children. Controversy remains over the best treatment and there is limited evidence. This systematic review and meta-analysis aims to establish which techniques have the best outcomes in children.MethodsMEDLINE, EMBASE and CENTRAL databases were searched. Studies reporting treatment outcomes for PNS in children were included.ResultsOpen healing has pooled risk of recurrence of 26% (95%CI 15–38%), risk of wound complication of 21% (9–36%) and wound healing ranged from 38–92 days. Midline primary closure has pooled risk of recurrence of 12% (8–18%), risk of wound complication of 30% (19–46%) and wound healing ranged from 8 to 32 days. Off-midline primary closure has pooled risk of recurrence of 6% (1–15%), risk of wound complication of 14% (6–25%) and wound healing was 27 days. VAC therapy has pooled risk of recurrence of 20% (0–65%) and wound healing ranged from 38 to 92 days. Minimally invasive techniques has pooled risk of recurrence of 7% (1–16%) and wound healing ranged from 21-30 days. Marsupialisation has pooled risk of recurrence of 6% (0–22%), and wound healing ranged from 6 to 41 days.ConclusionEvidence for management of PNS in children is poor. Off-midline primary closure, minimally invasive techniques, and marsupialisation have the best outcomes