Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven. OBJECTIVES: To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). SEARCH STRATEGY: We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. SELECTION CRITERIA: We selected trials including pregnant women between 24 and 36(6/7)  weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. DATA COLLECTION AND ANALYSIS: The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. MAIN RESULTS: Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01). CONCLUSION: Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. TWEETABLE ABSTRACT: Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.

Preeclampsia and risk of developing subsequent diabetes.

OBJECTIVE: Determine whether preeclampsia is associated with developing diabetes. METHODS: Subsequent diabetes was ascertained using ICD-9 codes, pharmacy and glucose data in a retrospective cohort study of 2,032 women with preeclampsia and 29,431 without preeclampsia. RESULTS: During a median follow-up of 8.2 years, 342 women developed diabetes. Preeclampsia was associated with a higher risk of diabetes adjusting for age, primigravidity, and gestational diabetes (hazard ratio, HR 1.82, 95%CI 1.26, 2.62) and in women without gestational diabetes (n = 30,109; HR 1.86, 95%CI 1.22, 2.84). CONCLUSION: Women with preeclampsia have greater risk of developing diabetes, even in the absence of gestational diabetes.

Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice.

Glyburide's pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady-state PK of glyburide, as well as insulin sensitivity, beta-cell responsivity, and overall disposition indices after a mixed-meal tolerance test (MMTT) in women with GDM (n = 40), nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 26), and healthy pregnant women (n = 40, MMTT only). At equivalent doses, glyburide plasma concentrations were approximately 50% lower in pregnant women than in nonpregnant subjects. The average umbilical cord/maternal plasma glyburide concentration ratio at the time of delivery was 0.7 +/- 0.4. Insulin sensitivity was approximately fivefold lower in women with GDM as compared with healthy pregnant women. Despite comparable beta-cell responsivity indices, the average beta-cell function corrected for insulin resistance was more than 3.5-fold lower in women with glyburide-treated GDM than in healthy pregnant women. Women with GDM in whom glyburide treatment has failed may benefit from alternative medication or dosage escalation; however, fetal safety should be kept in mind.

Clonidine pharmacokinetics in pregnancy.

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

An examination of beta-cell function measures and their potential use for estimating beta-cell mass.

A characteristic and dominant feature of type 2 diabetes is a reduction in beta-cell function that is associated with a decrease in beta-cell volume. A decline in the first-phase insulin response following intravenous glucose administration can be demonstrated as the fasting glucose concentration increases. This response is completely absent before the glucose threshold that defines diabetes has been reached and at a time when beta-cells are clearly still present, implying that a functional beta-cell lesion has to exist independent of beta-cell loss. Surgical or chemical reductions of up to 65% of beta-cell volume demonstrate that functional adaptation of the normal beta-cell prevents a rise in fasting glucose or reduction in first-phase insulin response. However, the ability of glucose to potentiate the beta-cell's response to non-glucose secretagogues is reduced and is more closely associated with the reduction in beta-cell volume. The future, in terms of prevention and treatment of type 2 diabetes, lies in the ability to prevent and revert both beta-cell loss and dysfunction. However, until beta-cell volume can be quantified reliably and non-invasively, we will need to rely on the ability of glucose to potentiate insulin release as the best surrogate estimate of the number of beta-cells.

Mu-opioid antagonists for opioid-induced bowel dysfunction.

BACKGROUND: Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life. OBJECTIVES: To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD. SEARCH STRATEGY: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers. SELECTION CRITERIA: Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events. MAIN RESULTS: Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate. AUTHORS' CONCLUSIONS: Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.

Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study.

The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P-glycoprotein (P-gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1-2 weeks at 28-32 weeks gestation, and the same order was repeated at 6-10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography-mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/F(unbound) (593 +/- 237 l/min vs. 345 +/- 103 l/min; P = 0.007), digoxin CL(Renal, unbound) (272 +/- 45 ml/min vs. 183 +/- 37 ml/min; P < 0.002) and digoxin CL(secretion,) (unbound) (109 +/- 34 ml/min vs. 58 +/- 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P-gp activities during pregnancy.

Within-subject variability of measures of beta cell function derived from a 2 h OGTT: implications for research studies.

AIMS/HYPOTHESIS: Knowledge of the within-subject variability of a parameter is required to properly design and calculate sample sizes for longitudinal studies. We sought to determine the day-to-day variability of measures of beta cell function derived from an OGTT. METHODS: Thirty-seven adults (13 with normal glucose tolerance, ten with impaired glucose tolerance, 14 with type 2 diabetes) underwent a standard 2 h 75 g OGTT on two separate days (median time between tests, 7 days; range, 5-14). From these data, the reproducibility of several indices of beta cell function were determined: insulinogenic index (DeltaI(0-30)/DeltaG(0-30)), early C-peptide response (DeltaCP(0-30)/DeltaG(0-30)), incremental AUC insulin to glucose response (incAUC(ins)/incAUC(glu)), integrated insulin secretion response from 0 to 120 min (IS/Glu(0-120)) and indices of beta cell function derived from a mathematical model. RESULTS: Within-subject variability for DeltaI(0-30)/DeltaG(0-30) (CV 57.1%) was higher than DeltaCP(0-30)/DeltaG(0-30) (CV 34.7%). Measures integrated over the full 120 min of the OGTT, incAUC(ins)/incAUC(glu) (CV 24.9%) and IS/Glu(0-120) (CV 17.4%), demonstrated less variability. The mathematical model-derived measures of beta cell glucose sensitivity (CV 20.3%) and potentiation (CV 33.0%) showed moderate variability. The impact of the different measures' variability on sample size (30% change from baseline) is demonstrated by calculated sample sizes of 89 for DeltaI(0-30)/DeltaG(0-30), 37 for DeltaCP(0-30)/DeltaG(0-30), 21 for incAUC(ins)/incAUC(glu) and 11 for IS/Glu(0-120). CONCLUSIONS/INTERPRETATION: Some OGTT-derived indices of beta cell function, in particular the insulinogenic index, demonstrate high within-subject variability. Integrated measures that utilise multiple time points and measures that use C-peptide show less variability and may lead to a reduced sample size requirement.

Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies.

Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women received amoxicillin during gestation (18-22 weeks (T2) and 30-34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single-dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration-time profiles following different dosage strategies. Amoxicillin CL(renal) (T2: 24.8+/-6.7 l/h, P<0.001; T3: 24.0+/-3.9 l/h, P<0.001; and PP: 15.3+/-2.6 l/h) and renal CL(secretion) (T2: 280+/-105 ml/min, P<0.002; T3: 259+/-54 ml/min, P<0.001; and PP: 167+/-47 ml/min) were higher during pregnancy than postpartum. Simulations suggest that amoxicillin concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and postpartum. Increases in amoxicillin CL(renal) and renal CL(secretion) reflect increases in filtration and secretory transport or diminished reabsorption in the kidneys. Amoxicillin may not be an appropriate antibiotic for post-anthrax exposure prophylaxis.

Intra-abdominal fat accumulation predicts the development of the metabolic syndrome in non-diabetic Japanese-Americans.

AIMS/HYPOTHESIS: Intra-abdominal fat (IAF) is an important risk factor for CHD and type 2 diabetes, and in cross-sectional studies is associated with the metabolic syndrome (MetS). Our aim was to determine whether IAF accumulation predicts the future development of MetS in non-diabetic Japanese-Americans. SUBJECTS AND METHODS: We conducted a prospective study of 457 Japanese-American men and women (mean+/-SD: age 51.5 +/- 12.0 years, BMI 23.9 +/- 3.1 kg/m(2)) without diabetes or MetS at baseline. Of these, 408 completed a 5-year follow-up and 366 completed a 10-year follow-up. BMI, waist circumference, IAF and subcutaneous fat (SCF) areas by computed tomography, blood pressure, fasting plasma glucose, insulin, triacylglycerol and HDL-cholesterol were measured at baseline and at 5- and 10-year follow-up. MetS was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Incidence of MetS was 15.3% at 5 years and 17.8% at 10 years. A change of 1 SD in IAF area was associated with a 2.1-fold increase in the odds of MetS at 10 years (odds ratio = 2.08, 95% CI 1.41-3.07) after adjusting for age, sex, baseline IAF and the presence of each individual MetS criteria at baseline. This association was independent of changes in fasting insulin and SCF areas. CONCLUSIONS/INTERPRETATION: We conclude that IAF accumulation over time independently predicts the development of MetS and thus may play an important role in the development of MetS in Japanese-Americans.

Plasma pancreatic polypeptide levels are associated with differences in body fat distribution in human subjects.

AIMS/HYPOTHESIS: Pancreatic polypeptide (PP) is produced by the F-cells of the pancreas, and its plasma concentration has been used as a marker of parasympathetic activity. Recent work in rodents suggests that there is both sympathetic and parasympathetic innervation of white adipose tissue and that parasympathetic activity is anabolic resulting in lipid accumulation. We have examined whether in humans increased PP levels are associated with increased intra-abdominal fat (IAF), and thereby insulin resistance. MATERIALS AND METHODS: We measured PP levels in 177 non-diabetic subjects (75 male/102 female; age 32-75 years) 3 min after an i.v. glucose bolus during a frequently sampled intravenous glucose tolerance test. IAF and s.c. fat (SCF) areas were measured by CT scan. The insulin sensitivity index (S (I)) was quantified using Bergman's minimal model. RESULTS: PP levels were higher in men than in women (96.2 +/- 72.2 vs 76.1 +/- 55.0 pg/ml, mean +/- SD, p = 0.037), as was IAF area (124.7 +/- 67.4 vs 83.0 +/- 57.7 cm(2), p < 0.001). While PP levels were significantly associated with IAF (r = 0.16, p = 0.031), WHR (r = 0.30, p < 0.001) and age (r = 0.37, p < 0.01), they were not associated with SCF (r = 0.02, p = 0.829). The association between PP and IAF was not independent of age and/or sex. S(I) was negatively associated with PP levels (r = -0.17, p = 0.026) and IAF area (r = -0.65, p < 0.001). The association between S(I) and PP disappeared after adjusting for IAF area, indicating that S(I) was not a major determinant of PP levels. CONCLUSIONS/INTERPRETATION: In humans, age and sex may modulate the association between plasma PP level and IAF area, suggesting that they may be determinants of parasympathetic activity and thus IAF accumulation.

Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain.

BACKGROUND: Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne found a strong patient preference for PCA over conventional analgesia but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, Walder's review in 2001 did not find a significant differences in pain intensity and pain relief between PCA and conventionally treated groups. OBJECTIVES: To evaluate the efficacy of PCA versus conventional analgesia (such as a nurse administering an analgesic upon a patient's request) for postoperative pain control. SEARCH STRATEGY: Randomized controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2004, Issue 3), MEDLINE (1966 to 2004), and EMBASE (1994 to 2004). Additional reports were identified from the reference lists of retrieved papers. SELECTION CRITERIA: RCTs of PCA versus conventional analgesia that employed pain intensity as a primary or secondary outcome were selected. These trials included RCTs that compared PCA without a continuous background infusion versus conventional parenteral analgesic regimens. Studies that explicitly stated they involved patients with chronic pain were excluded. DATA COLLECTION AND ANALYSIS: Trials were scored using the Oxford Quality Scale. Meta-analyses were performed of outcomes that included analgesic efficacy assessed by a Visual Analog Scale (VAS), analgesic consumption, patient satisfaction, length of stay and adverse effects. A sufficient number of the retrieved trials reported these parameters to permit meta-analyses. MAIN RESULTS: Fifty-five studies with 2023 patients receiving PCA and 1838 patients assigned to a control group met inclusion criteria. PCA provided better pain control and greater patient satisfaction than conventional parenteral 'as-needed' analgesia. Patients using PCA consumed higher amounts of opioids than the controls and had a higher incidence of pruritus (itching) but had a similar incidence of other adverse effects. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS: This review provides evidence that PCA is an efficacious alternative to conventional systemic analgesia for postoperative pain control.

Opioids for neuropathic pain.

BACKGROUND: The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term risk-benefit ratio of this treatment. OBJECTIVES: To assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (2nd Quarter 2005), MEDLINE (1966 to June 2005), and EMBASE (1980 to 2005 Week 27) for articles in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA: Trials were included in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology, pain was assessed using validated instruments, and adverse events were reported. Studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects. MAIN RESULTS: Twenty-three trials met the inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = eight to 70 days; n = 9). The short-term trials had contradictory results. In contrast all nine intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis of seven intermediate-term studies showed mean post-treatment visual analog scale scores of pain intensity after opioids to be 13 points lower on a scale from zero to 100 than after placebo (95% confidence interval -16 to -9; P < 0.00001). The most common adverse events were nausea (33% opioid versus 9% control: number needed to treat to harm (NNH) 4.2) and constipation (33% opioid versus 10% control: NNH 4.2), followed by drowsiness (29% opioid versus 12% control: NNH 6.2), dizziness (21% opioid versus 6% control: NNH 7.1), and vomiting (15% opioid versus 3% control: NNH 8.3). Where reported, 23 (11%) of 212 participants withdrew because of adverse events during opioid therapy versus nine (4%) of 202 receiving placebo. AUTHORS' CONCLUSIONS: Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain, whereas intermediate-term studies demonstrate significant efficacy of opioids over placebo, which is likely to be clinically important. Reported adverse events of opioids are common but not life threatening. Further randomized controlled trials are needed to establish long-term efficacy, safety (including addiction potential), and effects on quality of life.

Music for pain relief.

BACKGROUND: The efficacy of music for the treatment of pain has not been established. OBJECTIVES: To evaluate the effect of music on acute, chronic or cancer pain intensity, pain relief, and analgesic requirements. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, PsycINFO, LILACS and the references in retrieved manuscripts. There was no language restriction. SELECTION CRITERIA: We included randomized controlled trials that evaluated the effect of music on any type of pain in children or adults. We excluded trials that reported results of concurrent non-pharmacological therapies. DATA COLLECTION AND ANALYSIS: Data was extracted by two independent review authors. We calculated the mean difference in pain intensity levels, percentage of patients with at least 50% pain relief, and opioid requirements. We converted opioid consumption to morphine equivalents. To explore heterogeneity, studies that evaluated adults, children, acute, chronic, malignant, labor, procedural, or experimental pain were evaluated separately, as well as those studies in which patients chose the type of music. MAIN RESULTS: Fifty-one studies involving 1867 subjects exposed to music and 1796 controls met inclusion criteria. In the 31 studies evaluating mean pain intensity there was a considerable variation in the effect of music, indicating statistical heterogeneity ( I(2) = 85.3%). After grouping the studies according to the pain model, this heterogeneity remained, with the exception of the studies that evaluated acute postoperative pain. In this last group, patients exposed to music had pain intensity that was 0.5 units lower on a zero to ten scale than unexposed subjects (95% CI: -0.9 to -0.2). Studies that permitted patients to select the music did not reveal a benefit from music; the decline in pain intensity was 0.2 units, 95% CI (-0.7 to 0.2). Four studies reported the proportion of subjects with at least 50% pain relief; subjects exposed to music had a 70% higher likelihood of having pain relief than unexposed subjects (95% CI: 1.21 to 2.37). NNT = 5 (95% CI: 4 to 13). Three studies evaluated opioid requirements two hours after surgery: subjects exposed to music required 1.0 mg (18.4%) less morphine (95% CI: -2.0 to -0.2) than unexposed subjects. Five studies assessed requirements 24 hours after surgery: the music group required 5.7 mg (15.4%) less morphine than the unexposed group (95% CI: -8.8 to -2.6). Five studies evaluated requirements during painful procedures: the difference in requirements showed a trend towards favoring the music group (-0.7 mg, 95% CI: -1.8 to 0.4). AUTHORS' CONCLUSIONS: Listening to music reduces pain intensity levels and opioid requirements, but the magnitude of these benefits is small and, therefore, its clinical importance unclear.

Systemic administration of local anesthetic agents to relieve neuropathic pain.

BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy. OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions. SEARCH STRATEGY: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews. SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause. DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively. MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.

Local anesthetic sympathetic blockade for complex regional pain syndrome.

BACKGROUND: Local anesthetic blockade of the sympathetic chain is widely used to treat reflex sympathetic dystrophy (RSD) and causalgia. These two pain syndromes are now conceptualized as variants of a single entity: complex regional pain syndrome (CRPS). A recent meta-analysis of the topic has been published. However, this study only evaluated studies in English language and therefore it could have overlooked some randomized controlled trials. OBJECTIVES: This systematic review had three objectives: to determine the likelihood of pain alleviation after sympathetic blockade with local anesthetics in the patient with CRPS; to assess how long any benefit persists; and to evaluate the incidence of adverse effects of the procedure. SEARCH STRATEGY: We searched the Cochrane Pain, Palliative and Supportive Care Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS, and conference abstracts of the World Congresses of the International Association for the Study of Pain. Bibliographies from retrieved articles were also searched for additional studies. SELECTION CRITERIA: We considered for inclusion randomized controlled trials that evaluated the effect of sympathetic blockade with local anesthetics in children or in adult patients to treat RSD, causalgia, or CRPS. DATA COLLECTION AND ANALYSIS: The outcomes of interest were the number of patients who obtained at least 50% of pain relief shortly after sympathetic blockade (30 minutes to 2 hours) and 48 hours or later. We also assessed the presence of adverse effects in each treatment arm. A random effects model was used to combine the studies. MAIN RESULTS: Two small randomized double blind cross over studies that evaluated 23 subjects were found. The combined effect of the two trials produced a relative risk (RR) to achieve at least 50% of pain relief 30 minutes to 2 hours after the sympathetic blockade of 1.17 (95% CI 0.80-1.72). It was not possible to determine the effect of sympathetic blockade on long-term pain relief because the authors of the two studies evaluated different outcomes. AUTHORS' CONCLUSIONS: This systematic review revealed the scarcity of published evidence to support the use of local anesthetic sympathetic blockade as the 'gold standard' treatment for CRPS. The two randomized studies that met inclusion criteria had very small sample sizes, therefore, no conclusion concerning the effectiveness of this procedure could be drawn. There is a need to conduct randomized controlled trials to address the value of sympathetic blockade with local anesthetic for the treatment of CRPS.

Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans.

AIMS/HYPOTHESIS: The aim of this study was to further elucidate the relationship between resistin and insulin sensitivity, body fat distribution and the metabolic syndrome in humans. METHODS: We measured plasma resistin levels in 177 non-diabetic subjects (75 male, 102 female; age 32-75 years). BMI, waist circumference, blood pressure, lipids, glucose, plasminogen-activator inhibitor 1 (PAI-1), adiponectin and leptin levels were also measured. The insulin sensitivity index (S(I)) was quantified using Bergman's minimal model. Intra-abdominal fat (IAF) and subcutaneous fat (SQF) areas were quantified by CT scan. Presence of metabolic syndrome criteria was determined using the National Cholesterol Education Program Adult Treatment Panel III guidelines. RESULTS: When subjects were divided into categories based on BMI (< or > or =27.5 kg/m(2)) and S(I) (< or > or = 7 x 10(-5) min(-1) [pmol/l](-1)), resistin levels did not differ between the lean, insulin-sensitive (n=53, 5.36+/-0.3 ng/ml), lean, insulin-resistant (n=67, 5.70+/-0.4 ng/ml) and obese, insulin-resistant groups (n=48, 5.94+/-0.4 ng/ml; ANOVA p=0.65). Resistin correlated with age (r=-0.22, p<0.01), BMI (r=0.16, p=0.03) and SQF (r=0.19, p=0.01) but not with S(I) (p=0.31) or IAF (p=0.52). Resistin did not correlate with the number of metabolic syndrome criteria or any of the individual metabolic syndrome criteria. In contrast, adiponectin, PAI-1 and leptin each correlated with IAF, SQF and S(I). Additionally, the number of metabolic syndrome criteria correlated with adiponectin (r=-0.32, p<0.001), leptin (r=0.31, p<0.001) and PAI-1 (r=0.26, p=0.001). CONCLUSIONS/INTERPRETATION: In contrast to other adipokines, resistin is only weakly associated with body fat and is unlikely to be a major mediator of insulin resistance or the metabolic syndrome in humans.

Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation.

AIMS/HYPOTHESIS: Increased dietary fat intake is associated with obesity and insulin resistance, but studies have shown that the subsequent increase in insulin release is not appropriate for this obesity-induced insulin resistance. We therefore sought to determine whether the impaired beta cell adaptation is due to inadequate expansion of the beta cell population or to a lack of an adaptive increase in insulin release. METHODS: Male mice were fed diets containing increasing amounts of fat (15, 30 or 45% of energy intake) for 1 year, after which islet morphology and secretory function were assessed. RESULTS: Increased dietary fat intake was associated with a progressive increase in body weight (p<0.001). Fractional beta cell area (total beta cell area/section area) was increased with increasing dietary fat (1.36+/-0.39, 2.46+/-0.40 and 4.93+/-1.05%, p<0.001), due to beta cell hyperplasia, and was positively and highly correlated with body weight (r2=0.68, p<0.005). In contrast, insulin release following i.p. glucose did not increase with increasing dietary fat (118+/-32, 108+/-47 and 488+/-200 pmol/l per mmol/l, p=0.07) and did not correlate with body weight (r2=0.11). When this response was examined relative to fractional beta cell area (insulin release/fractional beta cell area), it did not increase but rather tended to decrease with increasing dietary fat (157+/-55, 43+/-13 and 97+/-53 [pmol/l per mmol/l]/%, p=0.06) and did not correlate with body weight (r2=0.02). CONCLUSIONS/INTERPRETATION: Long-term fat feeding is associated with an increase in the beta cell population but an inadequate functional adaptation. Thus, a functional rather than a morphological abnormality appears to underlie dietary-fat-induced beta cell dysfunction.

NSAIDS or paracetamol, alone or combined with opioids, for cancer pain.

BACKGROUND: NSAIDs are widely applied to treat cancer pain and are frequently combined with opioids in combination preparations for this purpose. However, it is unclear which agent is most clinically efficacious for relieving cancer-related pain, or even what may be the additional benefit of combining an NSAID with an opioid in this setting. OBJECTIVES: To assess the effects of NSAIDs, alone or combined with opioids, for the treatment of cancer pain. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Issue 2, 2002), MEDLINE (January 1966 to March 2003), EMBASE (January 1980 to December 2001), LILACS (January 1984 to December 2001) and reference list of articles. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials that compared NSAID versus placebo; NSAID versus NSAID; NSAID versus NSAID plus opioid; opioid versus opioid plus NSAID; or NSAID versus opioid. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse event information was collected from trials. Where there was disagreement between reviewers, the opinion of an additional reviewer was sought to resolve the issue. MAIN RESULTS: Forty-two trials involving 3084 patients were included. Clinical heterogeneity of study methods and outcomes precluded meta-analyses and only supported a qualitative systematic review. Seven of eight papers that compared NSAID with placebo demonstrated superior efficacy of NSAID with no difference in side effects. Thirteen papers compared one NSAID with another; four reported increased efficacy of one NSAID over another. Four different studies found that one NSAID had fewer side effects than one or more others. Twenty-three studies compared NSAIDs and opioids in combination or alone with NSAID/opioid combinations. Thirteen out of 14 studies found no difference, or low clinical difference, when combining an NSAID plus an opioid versus either drug alone. Comparisons between various NSAID/opioid combinations were inconclusive. Nine studies assessed the association between dose and efficacy and safety. Four papers demonstrated increased efficacy with increased dose, but no dose-dependent increase in side effects within the dose ranges studied. Study duration ranged from single dose studies performed over six hours to crossover studies lasting six weeks; however the majority of studies were of less than seven days duration. AUTHORS' CONCLUSIONS: Based upon limited data, NSAIDs appear to be more effective than placebo for cancer pain; clear evidence to support superior safety or efficacy of one NSAID over another is lacking; and trials of combinations of an NSAID with an opioid have disclosed either no difference (4 out of 14 papers), a statistically insignificant trend towards superiority (1 out of 14 papers), or at most a slight but statistically significant advantage (9 out of 14 papers), compared with either single entity. The short duration of studies undermines generalization of their findings on efficacy and safety of NSAIDs for cancer pain.

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.

AIMS/HYPOTHESIS: Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. METHODS: We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S(I)) in 182 subjects (76 M/106F). RESULTS: Adiponectin concentrations were higher in women than in men (7.4+/-2.9 vs 5.4+/-2.3 micro g/ml, p<0.0001) as were leptin concentrations (19.1+/-13.7 vs 6.9+/-5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S(I): 6.8+/-3.9 vs 5.9+/-4.4 x 10(-5) min(-1)/(pmol/l), p<0.01) and had more subcutaneous (240+/-133 vs 187+/-90 cm(2), p<0.01), but less intra-abdominal fat (82+/-57 vs 124+/-68 cm(2), p<0.0001). By simple regression, adiponectin was positively correlated with age ( r=0.227, p<0.01) and S(I) ( r=0.375, p<0.0001), and negatively correlated with BMI ( r=-0.333, p<0.0001), subcutaneous ( r=-0.168, p<0.05) and intra-abdominal fat ( r=-0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides ( r=-0.281, p<0.001) and positively correlated with HDL cholesterol ( r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy ( r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age ( p<0.0001), sex ( p<0.005) and intra-abdominal fat ( p<0.01). S(I) was related to intra-abdominal fat ( p<0.0001) and adiponectin ( p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. CONCLUSION/INTERPRETATION: These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile.