Opioid-Induced Constipation Survey in Patients with Chronic Noncancer Pain.

Chronic pain patients relying on chronic opioid therapy are often challenged with opioid-induced constipation (OIC), a difficult condition to treat that has a significant psychosocial impact on those who are affected (Bruner et al., J Pain Res, 8, 2015, 289). Unlike other side effects of opioids, OIC does not resolve over time during chronic opioid use, and treatments used for functional constipation often fail to provide adequate symptom relief (Nelson and Camilleri, Therap Adv Gastroenterol, 8, 2015, 206). Estimates of the prevalence of OIC vary. It has been reported that 15% to 90% of opioid users are affected by OIC (Gaertner et al., J Clin Gastroenterol, 49, 2015, 9; Wan et al., Am Health Drug Benefits, 8, 2015, 93; Coyne et al., Clinicoecon Outcomes Res, 6, 2014, 269). In addition, a recent rise in opioid prescriptions by nonpain specialists has contributed to the increase in opioid-related side effects, such as OIC (Nelson and Camilleri, Therap Adv Gastroenterol, 8, 2015, 206; Tuteja et al., Neurogastroenterol Motil, 22, 2010, 424). We conducted a survey on OIC through PainPathways magazine in fall of 2014 and in spring of 2015. Survey results showed the prevalence of depression and the modification of opioid dosage were higher than previously thought. Additionally, we found that discussions with healthcare workers regarding OIC do not take place regularly. Our results re-emphasize the need for a consensus on OIC-specific diagnostic criteria, evidence-based treatment strategies, outcome metrics, and education about OIC for both prescribers and patients to improve clinical outcome as well as patient satisfaction.

Clinical Outcomes of 1 kHz Subperception Spinal Cord Stimulation in Implanted Patients With Failed Paresthesia-Based Stimulation: Results of a Prospective Randomized Controlled Trial.

BACKGROUND: Pain relief via spinal cord stimulation (SCS) has historically revolved around producing paresthesia to replace pain, with success measured by the extent of paresthesia-pain overlap. In a recent murine study, by Shechter et al., showed the superior efficacy of high frequency SCS (1 kHz and 10 kHz) at inhibiting the effects of mechanical hypersensitivity compared to sham or 50 Hz stimulation. In the same study, authors report there were no differences in efficacy between 1 kHz and 10 kHz delivered at subperception stimulation strength (80% of motor threshold). Therefore, we designed a randomized, 2 × 2 crossover study of low frequency supra-perception SCS vs. subperception SCS at 1 kHz frequency in order to test whether subperception stimulation at 1 kHz was sufficient to provide effective pain relief in human subjects. METHODS: Twenty-two subjects with SCS, and inadequate pain relief based on numeric pain rating scale (NPRS) scores (>5) were enrolled, and observed for total of seven weeks (three weeks of treatment, one week wash off, and another three weeks of treatment). Subjects were asked to rate their pain on NPRS as a primary efficacy variable, and complete the Oswestry Disability Index (ODI) and Patient's Global Impression of Change (PGIC) as secondary outcome measures. RESULTS: Out of 22 subjects that completed the study, 21 subjects (95%) reported improvements in average, best, and worst pain NPRS scores. All NPRS scores were significantly lower with subperception stimulation compared to paresthesia-based stimulation (p < 0.01, p < 0.05, and p < 0.05, respectively). As with NPRS scores, the treatment effect of subperception stimulation was significantly greater than that of paresthesia based stimulation on ODI scores (p = 3.9737 × 10-5 ) and PGIC scores (p = 3.0396 × 10-5 ).

The Effect of a Novel form of Extended-Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open-Label Pilot Study.

INTRODUCTION: We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). METHODS: Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). RESULTS: A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. LIMITATIONS: Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. CONCLUSIONS: Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep.

Involvement of SIRT1 in hypoxic down-regulation of c-Myc and ß-catenin and hypoxic preconditioning effect of polyphenols.

SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis. In this study, we investigated the role of SIRT1 signaling in the hypoxic down-regulations of c-Myc and ß-catenin and hypoxic preconditioning effect of the red wine polyphenols such as piceatannol, myricetin, quercetin and resveratrol. We found that the expression of SIRT1 was significantly increased in hypoxia-exposed or hypoxic preconditioned HepG2 cells, which was closely associated with the up-regulation of HIF-1α and down-regulation of c-Myc and ß-catenin expression via deacetylation of these proteins. In addition, blockade of SIRT1 activation using siRNA or amurensin G, a new potent SIRT1 inhibitor, abolished hypoxia-induced HIF-1α expression but increased c-Myc and ß-catenin expression. SIRT1 was also found to stabilize HIF-1α protein and destabilize c-Myc, ß-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1α and down-regulated c-Myc, PHD2 and ß-catenin expressions via SIRT1 activation, in a manner that mimics hypoxic preconditioning. This study provides new insights of the molecular mechanisms of hypoxic preconditioning and suggests that polyphenolic SIRT1 activators could be used to mimic hypoxic/ischemic preconditioning.

Evaluation of a rapid immunodiagnostic test kit for rabies virus.

A rapid immunodiagnostic test kit for rabies virus detection was evaluated using 51 clinical samples and 4 isolates of rabies virus. The quick detection of rabies virus under field conditions may be helpful in determining if post-exposure prophylaxis is needed, thereby avoiding unnecessary treatments, as well as undue economic burden. There are several widely used diagnostic methods for rabies, including fluorescent antibody tests, reverse transcription polymerase chain reaction, and electron microscopy; however, these methods include time-consuming, intricate, and costly procedures. The rapid immunodiagnostic test was able to detect rabies virus in clinical samples, including brain tissue and saliva, in addition to 10(3.2) 50% lethal dose (LD(50))/mL cell-adapted rabies virus. The assay was not cross-reactive with non-rabies virus microbes. When the performance of the rapid immunodiagnostic test was compared to a fluorescent antibody test, the rapid immunodiagnostic test had a sensitivity of 91.7% and specificity of 100% (95.8% CI).

An observational feasibility study to assess the safety and effectiveness of intranasal fentanyl for radiofrequency ablations of the lumbar facet joints.

PURPOSE: The purpose of the present observational, feasibility study is to assess the preliminary safety and effectiveness of intranasal fentanyl for lumbar facet radiofrequency ablation procedures. PATIENTS AND METHODS: This cohort observational study included 23 adult patients. Systolic and diastolic blood pressures, heart rate, oxygen saturation percent, Pasero Opioid-Induced Sedation Scale score, and the Defense and Veterans Pain Rating Scale pain score were assessed prior to the procedure and intranasal fentanyl (100 µg) administration and every 15 minutes after administration, up to 60 minutes post administration. Follow-up of patient satisfaction with pain control and treatment was assessed 24 hours after discharge. The primary outcome was safety as evidenced by adverse events. Secondary outcomes included the above-mentioned vital signs and pain ratings. RESULTS: No adverse events occurred in the present study and all participants maintained an acceptable level of awareness throughout the assessment period. One-way repeated measures analyses of covariance tests with Bonferroni-adjusted means indicated that oxygen saturation, blood pressure, and heart rate changed from baseline, whereas pain scores were lower at post-administration levels compared with baseline. Finally, the majority of participants reported being satisfied with pain control and treatment. CONCLUSION: Preliminary evidence indicates that intranasal fentanyl is safe and effective for lumbar facet radiofrequency ablation procedures. Future rigorous randomized control trials are needed to confirm the present results and to examine the effects of intranasal fentanyl on intraoperative and postoperative opioid use.

Ku70 acetylation and modulation of c-Myc/ATF4/CHOP signaling axis by SIRT1 inhibition lead to sensitization of HepG2 cells to TRAIL through induction of DR5 and down-regulation of c-FLIP.

In this study, we investigated the role of c-Myc/ATF4/CHOP signaling pathway in sensitization of human hepatoma HepG2 cells to TRAIL. Knockdown of SIRT1 or treatment with SIRT1 inhibitor caused the up-regulation of DR5 and down-regulation of c-FLIP through modulation of c-Myc/ATF4/CHOP pathway, and subsequently enhanced the cytotoxic and apoptotic effects of TRAIL on HepG2 cells. Interestingly, SIRT1 interacted directly with c-FLIP(L) and Ku70, and treatment with SIRT1 inhibitor enhanced acetylation of Ku70 and subsequently decreased its binding to c-FLIP. And this was followed by degradation of c-FLIP. Moreover, Ku70(-/-) MEF and Ku70-knockdown HepG2 cells showed the increased levels of c-Myc, ATF4, CHOP, and DR5 and decreased level of c-FLIP. These results were followed by increased sensitivity of Ku70(-/-) MEF cells and Ku70-knockdown HepG2 cells to TRAIL compared with their control cells. These findings reveal for the first time that SIRT1 inhibition increases Ku70 acetylation, and the acetylated Ku70 with a decreased function mediates the induction of DR5 and the down-regulation of c-FLIP by up-regulating c-Myc/ATF4/CHOP pathway, and consequently promotes the TRAIL-induced apoptosis of HepG2 cells. This study provides important mechanistic insight of the synergism exhibited by SIRT1 inhibition and TRAIL.