The use of sublingual fentanyl for breakthrough pain by using doses proportional to opioid basal regimen.

Abstract OBJECTIVE: The aim of this study was to prospectively assess the efficacy and safety of sublingual fentanyl (SLF) in doses proportional to opioid doses used for background analgesia for the treatment of BTP of cancer patients. METHODS: A sample of patients admitted to an acute palliative care unit, presenting breakthrough pain (BTP) episodes and receiving stable doses of opioids for background pain was selected to assess the efficacy and safety of SLF used in doses proportional to the basal opioid regimen used for the management of BTP. For each patient, data from four consecutive episodes were collected. For each episode, nurses collected changes in pain intensity and adverse effects when pain got severe (T0), and 5, 10, and 15 minutes after SLF was given (T15). RESULTS: Seventy patients were recruited for the study. The mean age was 61.7 (\ub111.5). Forty-one patients were males. A total of 173 episodes of BTP were recorded (mean 2.5 episodes/patient). In 19 events, documentation regarding changes in pain intensity was incomplete. Of the 154 evaluable episodes, 143 were successfully treated (92%). Mean doses of SLF were 637 \ub5g (SD 786), and 51 patients (72.8%) received SLF doses 65800 \ub5g. When compared to younger adult patients, older patients received significantly lower doses of SLF (p < 0.0005) [DOSAGE ERROR CORRECTED], similarly to their lower basal opioid regimen. Pain intensity significantly decreased at T5, 10 and T15 (p < 0.0005). The number of patients with a pain reduction of more than 33% at T5, T10, and T15 were 11, 79, and 137, respectively, and the number of patients with a reduction in pain intensity of more than 50% were 1, 21, 114 at the same intervals, respectively. No differences in changes in pain intensity for gender (p < 0.9) or age (p < 0.85) were observed. No significant changes in the number of patients reporting adverse effects of mild-moderate intensity were reported after SLF administration in comparison with baseline, and no adverse effects severe enough in intensity to require medical intervention were observed. Limitations of this study are represented by the uncontrolled design. CONCLUSION: This study suggests that SLF given in doses proportional to the basal opioid regimen for the management of BTP is safe and effective in clinical practice

Changes of QTc interval after opioid switching to oral methadone.

Abstract A consecutive sample of patients who were switched from strong opioids to methadone in a period of 1 year was surveyed. QTc was assessed before switching (T0) and after achieving adequate analgesia and an acceptable level of adverse effects (Ts). Twenty-eight of 33 patients were switched to methadone successfully. The mean initial methadone doses at T0 were 67.1 mg/day (SD \ub180.2, range 12-390). The mean QTc interval at T0 was 400 ms (SD \ub130, range 330-450). The mean QTc interval at Ts (median 5 days) was 430 ms (SD \ub126, range 390-500). The difference (7.7 %) was significant (p\u2009<\u20090.0005). Only two patients had a QTc of 500 ms. No serious arrhythmia was observed. At the linear regression analysis, there was no significant association between mean opioid doses expressed as oral morphine equivalents and QTc at T0 (p\u2009=\u20090.428), nor between mean methadone doses and QTc at Ts (p\u2009=\u20090.315). No age differences were found with previous opioid doses (p\u2009=\u20090.917), methadone doses (p\u2009=\u20090.613), QTc at T0 (p\u2009=\u20090.173), QTc at Ts (p\u2009=\u20090.297), and final opioid-methadone conversion ratio (p\u2009=\u20090.064). While methadone used for opioids switching seems to be an optimal choice to improve the opioid response in patients poorly responsive to the previous opioid, the possible QTc prolongation should be of concern despite not producing clinical consequences in this group of patients. A larger number of patients should be assessed to quantify the risk of serious arrhythmia

Opioid use and effectiveness of its prescription at discharge in an acute pain relief and palliative care unit

The aim of this study was to present how opioids are used in an acute pain relief and palliative care unit (APRPCU), where many patients with difficult pain conditions are admitted from GPs, home palliative care programs, oncology departments, other hospitals or emergency units, and other regional places. From a consecutive sample of cancer patients admitted to an APRPCU for a period of 6 months, patients who had been administered opioids were included in this survey. Basic information was collected as well as opioid therapy prescribed at admission and, subsequently, during admission and at time of discharge. Patients were discharged once stabilization of pain and symptoms were obtained and the treatment was considered to be optimized. One week after being discharged, patients or relatives were contacted by phone to gather information about the availability of opioids at dosages prescribed at time of discharge. One hundred eighty six of 231 patients were specifically admitted for uncontrolled pain, with a mean pain intensity of 6.8 (SD 2.5). The mean dose of oral morphine equivalents in patients receiving opioids before admission was 45 mg/day (range 10–500 mg). One hundred seventy five patients (75.7 %) were prescribed around the clock opioids at admission. About one third of patients changed treatment (opioid or route). Forty two of 175 (24 %), 27/58 (46.5 %), 10/22 (45.4 %), and 2/4 (50 %) patients were receiving more than 200 mg of oral morphine equivalents, as maximum dose of the first, second, third, and fourth opioid prescriptions, respectively. The pattern of opioids changed, with the highest doses administered with subsequent line options. The mean final dose of opioids, expressed as oral morphine equivalents, for all patients was 318 mg/day (SD 798), that is more than six times the doses of pre-admission opioid doses. One hundred eighty six patients (80.5 %) were prescribed a breakthrough cancer pain (BTcP) medication at admission. Sixty five patients changed their BTcP prescription, and further 27 patients changed again. Finally, eight patients were prescribed a fourth BTcP medication. Of 46 patients available for interview, the majority of them (n=39, 84 %) did not have problems with their GPs, who facilitated prescription and availability of opioids at the dosages prescribed at discharge. For patients with severe distress, APRPCUs may guarantee a high-level support to optimize pain and symptom intensities providing intensive approach and resolving highly distressing situations in a short time by optimizing the use of opioids

Volumetric Differences in Mapped Hippocampal Regions Correlate with Increase of High Alpha Rhythm in Alzheimer's Disease

Objective. The increase of high alpha relative to low alpha power has been recently demonstrated as a reliable EEG marker of hippocampal atrophy conversion of patients with mild cognitive impairment (MCI) in Alzheimer's disease (AD). In the present study we test the reliability of this EEG index in subjects with AD. Methods. Correlation between EEG markers and volumetric differences in mapped hippocampal regions was estimated in AD patients. Results. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of mapped hippocampal regions in Alzheimer's disease. Conclusions. The findings confirm the possible diagnostic role of EEG markers

Cancer pain management in an oncological ward in a comprehensive cancer center with an established palliative care unit.

Abstract BACKGROUND: This survey was performed to draw information on pain prevalence, intensity, and management from a sample of patients who were admitted to an oncologic center where a palliative care unit (PCU) has been established for 13 years. METHODS: Cross-sectional survey in an oncological department performed 1 day per month for six consecutive months. RESULTS: Of the 385 patients, 69.1, 19.2, 8.6, and 3.1 % had no pain, mild, moderate, and severe pain, respectively. Inpatients and patients with a low Karnofsky score showed higher levels of pain intensity (p < 0.0005). One hundred twenty-eight patients with pain or receiving analgesics were analyzed for pain management index (PMI). Only a minority of patients had negative PMI score, which was statistically associated with inpatient admission (p = 0.011). Fifty of these 128 patients had breakthrough pain (BTP), and all of them were receiving some medication for BTP. CONCLUSION: It is likely that the presence of PCU team providing consultation, advices, and cultural pressure, other than offering admissions for difficult cases had a positive impact on the use of analgesics, as compared with previous similar surveys performed in oncological setting, where a PCU was unavailable. This information confirms the need of the presence of a PCU in a high volume oncological department

Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.Acknowledgements: This work was supported by grants from the International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT-2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.); GENMED Labex and JPND PERADES grant; and JPND EADB grant (German Federal Ministry of Education and Research, BMBF: 01ED1619A)

Automated hippocampal segmentation in 3D MRI using random undersampling with boosting algorithm

The automated identification of brain structure in Magnetic Resonance Imaging is very important both in neuroscience research and as a possible clinical diagnostic tool. In this study, a novel strategy for fully automated hippocampal segmentation in MRI is presented. It is based on a supervised algorithm, called RUSBoost, which combines data random undersampling with a boosting algorithm. RUSBoost is an algorithm specifically designed for imbalanced classification, suitable for large data sets because it uses random undersampling of the majority class. The RUSBoost performances were compared with those of ADABoost, Random Forest and the publicly available brain segmentation package, FreeSurfer. This study was conducted on a data set of 50 T1-weighted structural brain images. The RUSBoost-based segmentation tool achieved the best results with a Dice’s index of (Formula presented.) (Formula presented.) for the left (right) brain hemisphere. An independent data set of 50 T1-weighted structural brain scans was used for an independent validation of the fully trained strategies. Again the RUSBoost segmentations compared favorably with manual segmentations with the highest performances among the four tools. Moreover, the Pearson correlation coefficient between hippocampal volumes computed by manual and RUSBoost segmentations was 0.83 (0.82) for left (right) side, statistically significant, and higher than those computed by Adaboost, Random Forest and FreeSurfer. The proposed method may be suitable for accurate, robust and statistically significant segmentations of hippocampi

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.