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- Randomized double-blind placebo-controlled trial of celecoxib for oral mucositis in patients receiving radiation therapy for head and neck cancer. [JOURNAL ARTICLE]
- Oral Oncol 2014 Aug 20.
Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck cancer (H&NC). OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to treatment interruptions. Based on the role of inflammatory pathways in OM pathogenesis, we investigated effect of cyclooxygenase-2 (COX-2) inhibition on severity and morbidity of OM.In this double-blind placebo-controlled trial, 40 H&NC patients were randomized to daily use of 200mg celecoxib or placebo, for the duration of RT. Clinical OM, normalcy of diet, pain scores, and analgesic use were assessed 2-3 times/week by blinded investigators during the 6-7week RT period, using validated scales.Twenty subjects were randomized to each arm, which were similar with respect to tumor location, radiation dose, and concomitant chemotherapy. In both arms, mucositis and pain scores increased over course of RT. Intention-to-treat analyses demonstrated no significant difference in mean Oral Mucositis Assessment Scale (OMAS) scores at 5000cGy (primary endpoint). There was also no difference between the two arms in mean OMAS scores over the period of RT, mean worst pain scores, mean normalcy of diet scores, or mean daily opioid medication use in IV morphine equivalents. There were no adverse events attributed to celecoxib use.Daily use of a selective COX-2 inhibitor, during period of RT for H&NC, did not reduce the severity of clinical OM, pain, dietary compromise or use of opioid analgesics. These findings also have implications for celecoxib use in H&NC treatment regimens (NCT00698204).
- Audit improves Emergency Department triage, assessment, multi-modal analgesia and nerve block use in the management of pain in older people with neck of femur fracture. [JOURNAL ARTICLE]
- Australas Emerg Nurs J 2014 Aug 20.
The use of NBs as a mode of analgesia for #NOF in the ED is not common practice despite the reported clinical benefits of quicker onset of pain relief, decreased use of additional analgesia and decreased amounts of analgesia required when more than one mode of analgesia is prescribed.This study aims to test the hypothesis that the implementation of educational and awareness strategies increases knowledge, and implementation of the evidence based use of nerve blocks NB's, as a mode of analgesia for elderly patients with a fractured neck of femur (#NOF) in the Emergency Department (ED).A retrospective clinical audit of medical records using explicit chart review pre and post implementation.Implementation of educational and awareness strategies on pain management to clinical staff in the ED resulted in a significant increase in the administration of NBs, use of multimodal analgesia, and a reduction in average milligrams of morphine administrated to elderly patients with #NOF.The number of older people with #NOF presenting to the ED in Australia is increasing and historically, pain management in this group of patients could be improved. This study demonstrated that an audit, intervention and re-audit design that focused on the implementation of educational and promotional strategies informed by evidence on current and best practice standards were successful in improving delivery of analgesia to elderly patients with #NOF in the ED.
- A microbial biomanufacturing platform for natural and semisynthetic opioids. [JOURNAL ARTICLE]
- Nat Chem Biol 2014 Aug 24.
Opiates and related molecules are medically essential, but their production via field cultivation of opium poppy Papaver somniferum leads to supply inefficiencies and insecurity. As an alternative production strategy, we developed baker's yeast Saccharomyces cerevisiae as a microbial host for the transformation of opiates. Yeast strains engineered to express heterologous genes from P. somniferum and bacterium Pseudomonas putida M10 convert thebaine to codeine, morphine, hydromorphone, hydrocodone and oxycodone. We discovered a new biosynthetic branch to neopine and neomorphine, which diverted pathway flux from morphine and other target products. We optimized strain titer and specificity by titrating gene copy number, enhancing cosubstrate supply, applying a spatial engineering strategy and performing high-density fermentation, which resulted in total opioid titers up to 131 mg/l. This work is an important step toward total biosynthesis of valuable benzylisoquinoline alkaloid drug molecules and demonstrates the potential for developing a sustainable and secure yeast biomanufacturing platform for opioids.
- Hair analysis in order to evaluate drug abuse in driver's license regranting procedures. [JOURNAL ARTICLE]
- Forensic Sci Int 2014 Aug 4.:16-19.
In Italy, driving under the influence of drugs determines the suspension of the offender's driver's license. To regain the license the person must be drug free during an observation period. People whose license has been revoked or suspended can obtain, or re-obtain their driver's license subject to the judgment of a medical commission. The exclusion of illicit drug use is determined by means of toxicological analysis, mainly on urine or hair matrices. We reported the results of several years of experience of the forensic toxicology laboratory of the University of Macerata in the use of hair analysis for the assessment of past exposure to drugs in people suspected of driving under the influence of drugs. From 2004 to 2013, 8612 hair samples, were analyzed for opiates, cocaine and delta-9-tetrahydrocannabinol (Δ(9)-THC) using gas chromatography/mass spectrometry (GC/MS) method. We used a cutoff (SoHT or national guidelines) to determine the positive data, regardless of the hair sample concentrations. 1213 samples resulted positive, 71.7% were positive for cocaine and metabolites, 19.8% for morphine and metabolites, 8.5% for Δ(9)-THC. We also studied the timeframe of the abuse, as well as gender and age distribution of positive subjects. Moreover, we analyzed the possible deterrent effect of the hair analysis on driving under the influence of psychoactive substances.
- Prenatal Buprenorphine Versus Methadone Exposure and Neonatal Outcomes: Systematic Review and Meta-Analysis. [JOURNAL ARTICLE]
- Am J Epidemiol 2014 Aug 22.
Increasing rates of maternal opioid use during pregnancy and neonatal withdrawal, termed neonatal abstinence syndrome (NAS), are public health concerns. Prenatal buprenorphine maintenance treatment (BMT) versus methadone maintenance treatment (MMT) may improve neonatal outcomes, but associations vary. To summarize evidence, we used a random-effects meta-analysis model and estimated summary measures of BMT versus MMT on several outcomes. Sensitivity analyses evaluated confounding, publication bias, and heterogeneity. Subjects were 515 neonates whose mothers received BMT and 855 neonates whose mothers received MMT and who were born from 1996 to 2012 and who were included in 12 studies. The unadjusted NAS treatment risk was lower (risk ratio = 0.90, 95% confidence interval (CI): 0.81, 0.98) and mean length of hospital stay shorter (-7.23 days, 95% CI: -10.64, -3.83) in BMT-exposed versus MMT-exposed neonates. In treated neonates, NAS treatment duration was shorter (-8.46 days, 95% CI: -14.48, -2.44) and morphine dose lower (-3.60 mg, 95% CI: -7.26, 0.07) in those exposed to BMT. BMT-exposed neonates had higher mean gestational age and greater weight, length, and head circumference at birth. Fewer women treated with BMT used illicit opioids near delivery (risk ratio = 0.44, 95% CI: 0.28, 0.70). Simulations suggested that confounding by indication could account for some of the observed differences. Prenatal BMT versus MMT may improve neonatal outcomes, but bias may contribute to this protective association. Further evidence is needed to guide treatment choices.
- Inhibition of intracellular signaling pathways NF-κB and MEK1/2 attenuates neuropathic pain development and enhances morphine analgesia. [Journal Article]
- Pharmacol Rep 2014 Oct; 66(5):845-51.
Neuropathic pain is clinically challenging because it is resistant to alleviation by morphine. The nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways may be involved in the development of neuropathic pain. The aim of our study was to examine the influence of a chronic, intrathecal administration of parthenolide (PTL, inhibitor of NF-κB) and U0126 (inhibitor of MEK1/2) on nociception and morphine effectiveness in a rat model of neuropathy.The chronic constriction injury of the sciatic nerve in Wistar rats was performed. PTL and U0126 were injected chronic intrathecally and morphine was injected once at day 7. To evaluate allodynia and hyperalgesia, the von Frey and cold plate tests were used, respectively. The experiments were carried out according to IASP rules. Using qRT-PCR we analyzed mRNAs of μ-(mor), δ-(dor) and κ-(kor)-opioid receptors in the lumbar spinal cord after drugs administration.The administration of PTL and U0126 decreased allodynia and hyperalgesia and significantly potentiated morphine effect. The mor, dor and kor mRNAs were down-regulated 7 days after injury in the ipsilateral spinal cord. The PTL and U0126 significantly up-regulated the mRNA levels of all opioid receptors. The levels of mor and dor mRNAs were much higher compared to those in naïve, but only the kor levels returned to control values.These results indicate that the inhibition of the NF-κB pathway has better analgesic effects. Both inhibitors similarly potentiate morphine analgesia, which parallels the up-regulation of both mor and dor mRNAs expression spinal levels of the model of neuropathy.
- Randomized Clinical Trial of Continuous Femoral Nerve Block Combined with Sciatic Nerve Block Versus Epidural Analgesia for Unilateral Total Knee Arthroplasty. [JOURNAL ARTICLE]
- J Arthroplasty 2014 Jul 31.
Pain control following total knee arthroplasty (TKA) is crucial to hasten rehabilitation and decrease morbidity. We evaluated whether there is a difference between epidural infusion and continuous femoral nerve block with respect to postoperative pain control and rehabilitation course. Fifty patients completed the study. There was no statistically significant difference in the pain scores (P=0.33), morphine consumption (P=0.09) mean blood pressure or heart rate (P=0.957, and P=0.716) between groups. The postoperative daily mobilization (P=0.80), knee joint range of motion (P=0.83), and straight leg test (P=0.99) were also similar between both groups. Patients were highly satisfied with their pain management in both groups without statistically significant difference (P=0.98).
- Cytochrome P450 epoxygenase dependence of opioid analgesia: fluconazole does not interact with remifentanil-mediated analgesia in human subjects. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2014 Aug 22.
CYP inhibitors may reduce opioid analgesia by inhibiting CYP activity dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function and side effects in 21 healthy volunteers, prior and during steady-state concentrations of remifentanil at effect site (CNS) of 1.5 ng/ml and 3 ng/ml, administration of 400 mg/d fluconazole for 8 days in a double-blind, placebo-controlled manner, failed to attenuate opioid effects. Although CYP inhibitors like fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because opioid differences, like e.g. ligand-selective biased signaling at opioid receptors, leave the possibility that brain CYP dependent opioid signaling might be limited to morphine but not remifentanil.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 22 August 2014; doi:10.1038/clpt.2014.169.
- Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton. [Journal Article]
- ACS Med Chem Lett 2014 Aug 14; 5(8):868-72.
We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m-hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (-)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the κ opioid receptor (KOR). Subcutaneously administered (-)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist.
- Comparison of intravenous lidocaine versus morphine in alleviating pain in patients with critical limb ischaemia. [JOURNAL ARTICLE]
- Emerg Med J 2014 Aug 21.
Numerous drugs have been proposed to alleviate ischaemic limb pain, but none have been successful in relieving ischaemic pain thoroughly and rapidly.To compare the effectiveness of intravenous lidocaine and intravenous morphine in decreasing pain in patients with critical limb ischaemia.A randomised double-blind controlled trial was performed in 63 patients with critical limb ischaemia recruited from the emergency department between October 2012 and December 2013; 23 patients were excluded and the remainder were randomly divided into two groups of 20 patients. Patients in the lidocaine group received lidocaine infusion (2 mg/kg) while patients in the morphine group received morphine (0.1 mg/kg). Patients' visual analogue pain scores (VAS), from 0 to 10, were reported before and 15 and 30 min after the infusion.Before the infusion the mean±SD VAS score was 7.50±1.93 in the lidocaine group and 7.65±1.92 in the morphine group. At 15 min the mean±SD VAS score in the lidocaine group was lower than in the morphine group (5.75±1.77 vs 7.00±1.83; mean difference 1.25, 95% CI 0.095 to 2.405) and, at 30 min, the mean±SD VAS score in the lidocaine group was again lower (4.25±1.48 vs 6.50±1.73; mean difference 2.25, 95% CI 1.218 to 3.282).Lidocaine may be helpful in decreasing ischaemic pain in patients with critical limb ischaemia.http://www.irct.irIRCT201210148872N2.