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- Standardizing morphine use for ventilated preterm neonates with a nursing-driven comfort protocol. [JOURNAL ARTICLE]
- J Perinatol 2014 Jul 24.
Objective:To test whether implementing a nursing-driven comfort protocol standardizes morphine use in one neonatal intensive care unit (NICU) and to examine how non-standard morphine (N-SM) relates to days of ventilation, days of total parenteral nutrition (TPN) and length of stay (LOS).Study Design:This was a retrospective/prospective observational study using pharmacy records, medical records, and an outcomes database. Comfort protocol implementation began February 2011 and was applied to preterm, ventilated neonates <1500 grams. Pre- and post-implementation proportions of N-SM days were compared using the binomial test. A percent 'P'-chart spanning 30 quarters was constructed with statistical-process control analysis. Multivariable linear regression adjusting for acuity assessed the relationship between N-SM use and days of ventilation, TPN and LOS.Result:Hundred and thirty-four patients met inclusion criteria, 116 prior to and 18 after implementation. The proportion of patients given N-SM for one or more days decreased from 59 to 35% after protocol implementation (P=0.017). A 9-month period of decreased N-SM days was observed after protocol implementation. Controlling for acuity, each additional day of N-SM use was associated with 0.47 more days of ventilation (95% confidence interval (CI): 0.26-0.69, P<0.001) and 0.52 more days of TPN (95% CI: 0.35-0.68, P<0.001). Exposure to N-SM was associated with 17 additional days of hospitalization (P=0.009, 95% CI: 4.5-30).Conclusion:Implementing a nursing-driven comfort protocol significantly reduced N-SM use. N-SM in the NICU is negatively associated with key clinical outcomes. Testing similar protocols in other settings is warranted.Journal of Perinatology advance online publication, 24 July 2014; doi:10.1038/jp.2014.131.
- Analysis of candidate genes for morphine preference quantitative trait locus Mop2. [JOURNAL ARTICLE]
- Neuroscience 2014 Jul 21.
Compared to DBA/2J (D2), C57BL/6J (B6) inbred mice exhibit strong morphine preference when tested using a two-bottle choice drinking paradigm. A morphine preference quantitative trait locus (QTL), Mop2, was originally mapped to proximal chromosome 10 using a B6xD2 F2 intercross population, confirmed with reciprocal congenic strains and fine mapped with recombinant congenic strains. These efforts identified a ∼10 Mbp interval, underlying Mop2, containing 35 genes. To further reduce the interval, mice from the D2.B6-Mop2-P1 congenic strain were backcrossed to parental D2 mice and two new recombinant strains of interest were generated: D2.B6-Mop2-P1.pD.dB and D2.B6-Mop2-P1.pD.dD. Results obtained from testing these strains in the two-bottle choice drinking paradigm suggest that the gene(s) responsible for the Mop2 QTL is one or more of 22 remaining within the newly defined interval (∼7.6 Mbp) which includes Oprm1 and several other genes related to opioid pharmacology. Real-time qRT-PCR analysis of Oprm1 and opioid-related genes Rgs17, Ppp1r14c, Vip, and Iyd revealed both between-strain and within-strain expression differences in comparisons of saline- and morphine-treated B6 and D2 mice. Analysis of Rgs17 protein levels also revealed both between-strain and within-strain differences in comparisons of saline- and morphine-treated B6 and D2 mice. Results suggest that the Mop2 QTL represents the combined influence of multiple genetic variants on morphine preference in these two strains. Relative contributions of each variant remain to be determined.
- Nonmyeloablative HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Phenotype. [JOURNAL ARTICLE]
- JAMA 2014 Jul 2; 312(1):48-56.
Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant.To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia.From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from human leukocyte antigen-matched siblings.The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing.Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95% CI, 1.83-4.63) the year before, 0.63 (95% CI, 0.26-1.01) the first year after, 0.19 (95% CI, 0-0.45) the second year after, and 0.11 (95% CI, 0.04-0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95% CI, 220-1058) of intravenous morphine-equivalent dose the week of their transplants and 140 mg (95% CI, 56-225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects.Among 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants. Further accrual and follow-up are required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.clinicaltrials.gov Identifier: NCT00061568.
- eIF2α Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):10010-21.
Maladaptive memories elicited by exposure to environmental stimuli associated with drugs of abuse are often responsible for relapse among addicts. Interference with the reconsolidation of drug memory can inhibit drug seeking. Previous studies have indicated that the dephosphorylation of the eukaryotic initiation factor 2 α-subunit (eIF2α) plays an important role in synaptic plasticity and long-term memory consolidation, but its role in the reconsolidation of drug memory remains unknown. The amygdala is required for the reconsolidation of a destabilized drug memory after retrieval of drug-paired stimuli. Here, we used conditioned place preference (CPP) and self-administration procedures to determine whether amygdala eIF2α dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2α phosphorylation (Ser51) and activating transcription factor 4 (ATF4) were decreased after reexposure to a previously morphine- or cocaine-paired context (i.e., a memory retrieval procedure) in the basolateral amygdala (BLA) but not in the central amygdala. Intra-BLA infusions of Sal003, a selective inhibitor of eIF2α dephosphorylation, immediately after memory retrieval disrupted the reconsolidation of morphine- or cocaine-induced CPP, leading to a long-lasting suppression of drug-paired stimulus-induced craving. Advanced knockdown of ATF4 expression in the BLA by lentivirus-mediated short-hairpin RNA blocked the disruption of the reconsolidation of morphine-induced CPP induced by Sal003 treatment. Furthermore, inhibition of eIF2α dephosphorylation in the BLA immediately after light/tone stimulus retrieval decreased subsequent cue-induced heroin-seeking behavior in the self-administration procedure. These results demonstrate that eIF2α dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.
- Randall Selitto pressure algometry for assessment of bone-related pain in rats. [JOURNAL ARTICLE]
- Eur J Pain 2014 Jul 23.
Deep pain is neglected compared with cutaneous sources. Pressure algometry has been validated in the clinic for assessment of bone-related pain in humans. In animal models of bone-related pain, we have validated the Randall Selitto behavioural test for assessment of acute and pathological bone pain and compared the outcome with more traditional pain-related behaviour measures.Randall Selitto pressure algometry was performed over the anteromedial part of the tibia in naïve rats, sham-operated rats, and rats inoculated with MRMT-1 carcinoma cells in the left tibia, and the effect of morphine was investigated. Randall Selitto measures of cancer-induced bone pain were supplemented by von Frey testing, weight-bearing and limb use test. Contribution of cutaneous nociception to Randall Selitto measures were examined by local anaesthesia.Randall Selitto pressure algometry over the tibia resulted in reproducible withdrawal thresholds, which were dose-dependently increased by morphine. Cutaneous nociception did not contribute to Randall Selitto measures. In cancer-bearing animals, compared with sham, significant differences in pain-related behaviours were demonstrated by the Randall Selitto test on day 17 and 21 post-surgery. A difference was also demonstrated by von Frey testing, weight-bearing and limb use tests.Our results indicate that pressure applied by the Randall Selitto algometer on a region, where the bone is close to the skin, may offer a way to measure bone-related pain in animal models and could provide a supplement to the traditional behavioural tests and a means to study deep pain.
- [Assessment of pain relief in patients receiving different variants of multimodal analgesia after major gynecological surgery]. [English Abstract, Journal Article]
- Anesteziol Reanimatol 2014 Mar-Apr; (2):32-7.
The major gynecology surgery generally results in severe postoperative pain. Currently multimodal analgesia concept is widely used for the aim of postoperative pain relief optimization. According to this theory it is worth using the medication with different mechanism in order to increase analgesia qualify, decrease analgesic consumption and avoid adverse reaction. Unfortunately the surveys recently conducted have been pointed out the postoperative analgesia quality is still insufficient despite of using the concept mentioned above. One way to solve the problem is appearing in daily practice nefopam--centrally acting non-opioid analgesic that inhibits reuptake of serotonin, norepinephrine, and dopamine and also mitigates glutamatergic neurotransmission. In this trial we tried to assess the postoperative daily used analgesia quality and potency of preemptive multimodal analgesia model consisted of nefopam, ketoprofen, paracetamol and morphine.
- Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. [Journal Article]
- Pain Physician 2014 Jul-Aug; 17(4):329-43.
Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain.To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain.Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303).Primary, secondary, and tertiary care settings in 16 countries.Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100 - 250 mg bid) or morphine sulfate CR (40 - 100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: 1) completed the maintenance period, 2) a mean pain intensity < 5 during maintenance, and 3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration.Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively.Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration.Results obtained during maintenance indicate that tapentadol PR (100 - 250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40 - 100 mg bid), but is associated with better gastrointestinal tolerability.
- Effect of Thoracic Epidural Analgesia on Pro-inflammatory Cytokines in Patients Subjected to Protective Lung Ventilation During Ivor Lewis Esophagectomy. [Journal Article]
- Pain Physician 2014 Jul-Aug; 17(4):305-15.
Thoracic epidural analgesia (TEA) has a well-known effect on neurohormonal response. Attenuation of stress response by post-operative epidural analgesia has shown beneficial effects such as lower pain scores and less immunological alterations.Investigation of the combined effects of TEA and protective lung ventilation on pro-inflammatory cytokines and patients' outcome after Ivor Lewis esophagectomy.A randomized controlled study.Academic medical center.Thirty patients of the American Society of Anesthesiologists (ASA) I and II were randomly allocated into 2 groups: G1 (n = 15) patients received general anesthesia and were mechanically ventilated with 9 mL/kg during 2 lung ventilations, reduced to 5 mL/kg and 5cm H2O positive end expiratory pressure (PEEP) during one lung ventilation (OLV) or GII) (n = 15) patients received TEA and the same general anesthesia and mechanical ventilation used in G1. Assessment parameters included hemodynamics, pain severity, total analgesic consumption, and measurement of interleukins (IL) (IL-6 and IL-8) at baseline time after anesthetic induction (TBaseline,); at the end of the abdominal stage of the operation (TAbdo,); 15 minutes after initiation and at the end of OLV (TOLV 15) and (TOLV End) respectively; one and 20 hours after the end of the surgical procedure (TPostop1 and TPostop20), respectively, and patient's outcome also recorded.There was a significant reduction in mean arterial blood pressure (MAP) and pulse rate in GII during the intraoperative period, at Tabdo, TOLV15, and TOLV End (P < 0.05). The mean of systolic blood pressure (SBP) values were significantly lower in GII over all 3 post-operative days (P = 0.001), and the mean diastolic blood pressure (DBP) showed a significant reduction in GII for 16 hours post-operatively (P = 0.001). The mean of heart rate values showed a significant reduction in GII over all 3 post-operative days in comparison to GI (P = 0.001). The mean resting and dynamic VAS scores were significantly reduced in GII at all time periods studied in comparison to G1 (P = 0.001). The daily PCA morphine consumption was markedly decreased in GII compared to GI in the first 3 days post-operatively (P = 0.001). There were significant reductions in blood level of IL-6 and IL-8 in GII compared to G1 over the entire study period (P < 0.05). There were no significant differences in post-operative adverse effects between the 2 groups (P > 0.05). The duration of stay in PACU was significantly decreased in GII (10 ± 2 days) compared to GI (15 ± 3 days) (P = 0.001).This study is limited by its sample size.Our study concluded that TEA reduced the systemic pro-inflammatory response and provided optimal post-operative pain relief. Although there were no significant differences in adverse events, there was a trend towards improved outcome. Further clinical studies with larger numbers of patients are required.
- Empirical comparison of four baseline covariate adjustment methods in analysis of continuous outcomes in randomized controlled trials. [Journal Article]
- Clin Epidemiol 2014.:227-35.
Although seemingly straightforward, the statistical comparison of a continuous variable in a randomized controlled trial that has both a pre- and posttreatment score presents an interesting challenge for trialists. We present here empirical application of four statistical methods (posttreatment scores with analysis of variance, analysis of covariance, change in scores, and percent change in scores), using data from a randomized controlled trial of postoperative pain in patients following total joint arthroplasty (the Morphine COnsumption in Joint Replacement Patients, With and Without GaBapentin Treatment, a RandomIzed ControlLEd Study [MOBILE] trials).Analysis of covariance (ANCOVA) was used to adjust for baseline measures and to provide an unbiased estimate of the mean group difference of the 1-year postoperative knee flexion scores in knee arthroplasty patients. Robustness tests were done by comparing ANCOVA with three comparative methods: the posttreatment scores, change in scores, and percentage change from baseline.All four methods showed similar direction of effect; however, ANCOVA (-3.9; 95% confidence interval [CI]: -9.5, 1.6; P=0.15) and the posttreatment score (-4.3; 95% CI: -9.8, 1.2; P=0.12) method provided the highest precision of estimate compared with the change score (-3.0; 95% CI: -9.9, 3.8; P=0.38) and percent change (-0.019; 95% CI: -0.087, 0.050; P=0.58).ANCOVA, through both simulation and empirical studies, provides the best statistical estimation for analyzing continuous outcomes requiring covariate adjustment. Our empirical findings support the use of ANCOVA as an optimal method in both design and analysis of trials with a continuous primary outcome.
- Pharmacokinetic interactions between ethanol and heroin: A study on post-mortem cases. [JOURNAL ARTICLE]
- Forensic Sci Int 2014 Jul 6.:127-134.
Ethanol and heroin are both depressant drugs on the central nervous system, and combined use is known to be dangerous due to pharmacodynamic interactions, leading to an even higher risk of respiratory depression and death. In addition, previous studies have suggested a pharmacokinetic interaction between ethanol and the metabolism of heroin. The aim of the present study was to investigate if there was a pharmacokinetic interaction between heroin and ethanol, by comparing concentrations of heroin metabolites in cases with and without ethanol, as detected in blood samples collected from a large material of forensic autopsy cases.The material consisted of 1583 forensic autopsy cases, all containing 6-monoacetylmorphine (6-MAM), as evidence of heroin intake, in either blood or urine samples, from the time period between the 1st of January 2000 and the 31st of December 2012. Due to the high risk of post-mortem ethanol formation in cases revealing blood ethanol concentrations between 0.1 and 0.3‰, these cases were excluded from the study, along with cases where the analysis for ethanol was missing. After this exclusion of cases, the material (n=1474) was divided into two groups; one group where ethanol was not detected in blood (n=1160), and another group where ethanol was detected in blood at or above the concentration of 0.4‰ (n=314). Furthermore, the material was also divided into two other subgroups; one group where 6-MAM was detected in blood samples, indicating a very recent intake of heroin, and another group where 6-MAM was detected in the urine, but not in blood, indicating a less recent heroin intake.The concentration ratios of morphine/6-MAM, morphine-3-glucuronide (M3G)/morphine, and morphine-6-glucuronide (M6G)/morphine in blood samples, were all significantly lower in the ethanol positive cases compared with that of the ethanol negative cases. For the subgroup of cases revealing a very recent intake of heroin (n=645), only the morphine/6-MAM ratio was significantly lower in the ethanol positive cases than in the ethanol negative cases. For the subgroup of cases with a less recent heroin intake (n=817), lower M3G/morphine and M6G/morphine ratios were found among the ethanol positive cases.The results indicate that ethanol inhibits two steps in the heroin metabolism; the hydrolysis of 6-MAM to morphine, and the glucuronidation of morphine to M3G and M6G. This pharmacokinetic interaction could further complicate the outcome after combined use of heroin and ethanol, in addition to the already well-known pharmacodynamic interactions.