Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.

BACKGROUND: Ritonavir inhibition of cytochrome P450 3A4 decreases the elimination clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome P450 3A4 inhibition. METHODS: Fentanyl absorption from the epidural space was modeled using tanks-in-series delay elements. Systemic fentanyl disposition was described using a three-compartment pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the model to reported plasma fentanyl concentrations measured after epidural administration. The validity of the model was assessed by comparing predicted plasma concentrations after epidural administration to published data. The effect of ritonavir was modeled as a 67% decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and control models. Simulated data were analyzed to determine if plasma fentanyl concentrations producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. RESULTS: Simulated plasma fentanyl concentrations in the ritonavir group were higher than those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, respectively, and did not reach concentrations associated with 50% decrease in minute ventilation. CONCLUSION: Our model predicts that even with maximal clinical dosing regimens of epidural fentanyl over 24 h, ritonavir-induced cytochrome P450 3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.

Teaching neuraxial anesthesia techniques for obstetric care in a Ghanaian referral hospital: achievements and obstacles.

Anesthesia providers in low-income countries may infrequently provide regional anesthesia techniques for obstetrics due to insufficient training and supplies, limited manpower, and a lack of perceived need. In 2007, Kybele, Inc. began a 5-year collaboration in Ghana to improve obstetric anesthesia services. A program was designed to teach spinal anesthesia for cesarean delivery and spinal labor analgesia at Ridge Regional Hospital, Accra, the second largest obstetric unit in Ghana. The use of spinal anesthesia for cesarean delivery increased significantly from 6% in 2006 to 89% in 2009. By 2012, >90% of cesarean deliveries were conducted with spinal anesthesia, despite a doubling of the number performed. A trial of spinal labor analgesia was assessed in a small cohort of parturients with minimal complications; however, protocol deviations were observed. Although subsequent efforts to provide spinal analgesia in the labor ward were hampered by anesthesia provider shortages, spinal anesthesia for cesarean delivery proved to be practical and sustainable.

Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions.

Central pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson's disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development.

Experiences of Internalized and Enacted Stigma among Women with Obstetric Fistula in Tanzania

Background: Obstetric fistula is the development of a necrosis between the bladder and the vagina and/or the bladder and the rectum as a result of prolonged obstructed labor, resulting in urinary or fecal incontinence. In Tanzania surgical repair for obstetric fistula is provided freely by the government but it is estimated that there are over 25,000 women living with an untreated fistula. These women experience high degrees of psycho-social stresses exacerbated by the stigma surrounding their condition. There is a dire need to explore stigma within this population in order to better understand its impact, as stigma affects both treatment seeking behavior as well as long term recovery of those who access surgical repair.

Study Aims: This study aims to understand the experiences of stigma among women with obstetric fistulas by examining both internalized and enacted stigma, and by identifying pertinent correlates of internalized stigma.

Methods: This mixed-methods study utilized both quantitative and qualitative data collected in two related studies at a single hospital in Moshi, Tanzania. All study participants were women receiving surgical repair for an obstetric fistula. In the quantitative portion, cross-sectional survey data were collected from 52 patients. The primary outcome was fistula-related stigma, measured using an adaptation of the HASI-P stigma scale, which included constructs of both internalized and enacted stigma. In the qualitative portion, 45 patients participated in a semi-structured in-depth interview, which explored topics such as stressors caused by the fistula, coping mechanisms, and available support. The transcripts were analyzed using analytic memos and an iterative process of thematic coding using the framework of content analysis.

Results: Expressions of internalized stigma were common in the sample, with a median score of 2.1 on a scale of 0 – 3. Internalized was significantly correlated with negative religious coping, social participation, impact of incontinence and enacted stigma. Qualitative analysis was consistent and demonstrated widespread themes of shame and embarrassment. Experiences of enacted stigma were not as common (median score of 0), although some items, like those pertaining to mockery and blame, were endorsed by up to 25% of the study sample. Themes of anticipated stigma (isolation and non-disclosure due to the possibility of stigmatization) were also evident in the qualitative sample and may explain the low enacted stigma scores observed.

Conclusion: In this sample of women receiving surgical repair for an obstetric fistula, stigma was evident, with internalized stigma resulting in psychological impacts for patients. Experiences of both anticipated and enacted stigma were also observed. There is a need to explore interventions that would decrease stigma while also increasing support for these women, as stigma may be a barrier towards accessing surgical repair and reintegration following surgery.

Keywords: Tanzania, obstetric fistula, stigma, maternal health

Auriculotherapy for pain management: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Side-effects of standard pain medications can limit their use. Therefore, nonpharmacologic pain relief techniques such as auriculotherapy may play an important role in pain management. Our aim was to conduct a systematic review and meta-analysis of studies evaluating auriculotherapy for pain management. DESIGN: MEDLINE,(®) ISI Web of Science, CINAHL, AMED, and Cochrane Library were searched through December 2008. Randomized trials comparing auriculotherapy to sham, placebo, or standard-of-care control were included that measured outcomes of pain or medication use and were published in English. Two (2) reviewers independently assessed trial eligibility, quality, and abstracted data to a standardized form. Standardized mean differences (SMD) were calculated for studies using a pain score or analgesic requirement as a primary outcome. RESULTS: Seventeen (17) studies met inclusion criteria (8 perioperative, 4 acute, and 5 chronic pain). Auriculotherapy was superior to controls for studies evaluating pain intensity (SMD, 1.56 [95% confidence interval (CI): 0.85, 2.26]; 8 studies). For perioperative pain, auriculotherapy reduced analgesic use (SMD, 0.54 [95% CI: 0.30, 0.77]; 5 studies). For acute pain and chronic pain, auriculotherapy reduced pain intensity (SMD for acute pain, 1.35 [95% CI: 0.08, 2.64], 2 studies; SMD for chronic pain, 1.84 [95% CI: 0.60, 3.07], 5 studies). Removal of poor quality studies did not alter the conclusions. Significant heterogeneity existed among studies of acute and chronic pain, but not perioperative pain. CONCLUSIONS: Auriculotherapy may be effective for the treatment of a variety of types of pain, especially postoperative pain. However, a more accurate estimate of the effect will require further large, well-designed trials.

Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.

Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.

Prevalence and predictors of giving birth in health facilities in Bugesera District, Rwanda.

BACKGROUND: The proportion of births attended by skilled health personnel is one of two indicators used to measure progress towards Millennium Development Goal 5, which aims for a 75% reduction in global maternal mortality ratios by 2015. Rwanda has one of the highest maternal mortality ratios in the world, estimated between 249-584 maternal deaths per 100,000 live births. The objectives of this study were to quantify secular trends in health facility delivery and to identify factors that affect the uptake of intrapartum healthcare services among women living in rural villages in Bugesera District, Eastern Province, Rwanda. METHODS: Using census data and probability proportional to size cluster sampling methodology, 30 villages were selected for community-based, cross-sectional surveys of women aged 18-50 who had given birth in the previous three years. Complete obstetric histories and detailed demographic data were elicited from respondents using iPad technology. Geospatial coordinates were used to calculate the path distances between each village and its designated health center and district hospital. Bivariate and multivariate logistic regressions were used to identify factors associated with delivery in health facilities. RESULTS: Analysis of 3106 lifetime deliveries from 859 respondents shows a sharp increase in the percentage of health facility deliveries in recent years. Delivering a penultimate baby at a health facility (OR = 4.681 [3.204 - 6.839]), possessing health insurance (OR = 3.812 [1.795 - 8.097]), managing household finances (OR = 1.897 [1.046 - 3.439]), attending more antenatal care visits (OR = 1.567 [1.163 - 2.112]), delivering more recently (OR = 1.438 [1.120 - 1.847] annually), and living closer to a health center (OR = 0.909 [0.846 - 0.976] per km) were independently associated with facility delivery. CONCLUSIONS: The strongest correlates of facility-based delivery in Bugesera District include previous delivery at a health facility, possession of health insurance, greater financial autonomy, more recent interactions with the health system, and proximity to a health center. Recent structural interventions in Rwanda, including the rapid scale-up of community-financed health insurance, likely contributed to the dramatic improvement in the health facility delivery rate observed in our study.

Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.

PDLA a potential new potent topical analgesic: a case report.

Polymer D-lactic acid (PDLA) is a hydrogel that has been shown to sequester L-lactate (lactate). This reaction is rapid, spontaneous, and non-enzymatic. Lactate has been shown to have many functions within the nervous system including its use as a secondary fuel to sustain neural activity and as a neuromodulator. In the central nervous system, lactate is produced in glial cells and shuttled to neurons to be used mostly as a fuel. Lactate dehydrogenase (LDH)1 is the predominant LDH isoform within neurons and unlike LDH5, it preferentially converts lactate to pyruvate which can be used to produce adenosine triphosphate (ATP). Considering that lactate is intimately involved in the sustenance of neural activity, PDLA was applied to an open wound and its effects were examined. The results showed that the application of PDLA induced topical analgesia. This may be the first report to demonstrate that sequestering lactate, a source of energy required to sustain the firing of action potentials in neurons, may produce analgesia.

Low Molecular Weight Opioid Peptide Esters Could be Developed as a New Class of Analgesics.

Low molecular weight opioid peptide esters (OPE) could become a class of analgesics with different side effect profiles than current opiates. OPE may have sufficient plasma stability to cross the blood brain barrier (BBB), undergo ester hydrolysis and produce analgesia. OPE of dipeptides, tyr-pro and tyr-gly conjugated to ethanol have a structure similar to the anesthestic agent, etomidate. Based upon the analgesic activity of dipeptide opioids, Lipinski's criteria, and permeability of select GABA esters to cross the BBB, opioid peptides (OP) conjugated to ethanol, cholesterol or 3-glucose are lead recommendations. Preliminary animal data suggests that tyr-pro-ethyl ester crosses the BBB and unexpectedly produces hyperalgesia. Currently, there are no approved OP analgesics available for clinical use. Clinical trials of good manufacturing practice OP administered to patients suffering from chronic pain with indwelling intrathecal pumps could resolve the issue that OP may be superior to opiates and may redirect research.