Abstract An attenuated strain (263) of the tick-borne encephalitis virus, isolated from field ticks, was either serially subcultured, 5 times in mice, or at 40 °C in PS cells, producing 2 independent ...strains, 263-m5 and 263-TR with identical genomes; both strains exhibited increased plaque size, neuroinvasiveness and temperature-resistance. Sequencing revealed two unique amino acid substitutions, one mapping close to the catalytic site of the viral protease. These observations imply that virus adaptation from ticks to mammals occurs by selection of pre-existing virulent variants from the quasispecies population rather than by the emergence of new random mutations. The significance of these observations is discussed.
Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. ...A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD.
Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation.
Background
The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown.
Objective
Our objective was to assess exposure to morphine as an etiologic factor ...for acute chest syndrome in sickle cell disease.
Methods
A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5–17 years) with sickle cell crisis were randomized to receive oral sustained‐release morphine, 1.9 mg · kg−1 · 12 h−1, or a continuous intravenous infusion of morphine at 0.04 mg · kg−1 · h−1 by use of a double‐blind, placebo‐controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine‐6‐glucuronide were also studied.
Results
At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2‐fold higher morphine area under the concentration‐time curve at steady state (AUCss) and a 3‐fold higher morphine‐6‐glucuronide AUCss with oral morphine than with a continuous intravenous infusion of morphine (P < .001 and P < .006, respectively). New onset of acute chest syndrome was 3‐fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P < .001).
Conclusions
The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine‐6‐glucuronide after oral administration of slow‐release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as‐yet‐unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration‐time curve should be further studied in children with sickle cell disease.
Clinical Pharmacology & Therapeutics (2004) 75, 140–146; doi: 10.1016/j.clpt.2003.10.007
To further characterize the pharmacokinetics of Xtampza
ER.
This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects ...received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin
(intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations.
Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR.
This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606.
Abstract
There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This ...has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.
The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to ...determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability.
This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation.
A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P < 0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P < 0.001). Light touch and pinprick were detectable by most subjects.
The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application.
Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical ...efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design.
56 children aged 5–17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg
−1 h
−1, plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2–3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator.
50 children completed the study (28 boys, 22 girls; mean age 11.2 years SD 3.5; mean oral morphine dose 2.99 mg/kg daily 0.75; mean intravenous morphine dose, 0.81 mg/kg daily 0.30). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 1.5
vs 6.4 1.4, p=0.8; Oucher, 31.5 25.4
vs 39.2 21.7, p=0.3; Faces, 2.2 1.4
vs 2.4 1.3, p=0.6; clinical rating, 1.7 0.7
vs 1.9 0.5, p=0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p=0.0591). Pain scores from all scales correlated significantly (
r=0.5865–0.8980, p=0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 0.8
vs 0.9 0.7 doses daily, p=0.2). Frequency and severity of adverse events did not differ significantly.
Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children.
Objectives: This post hoc analysis of data from a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal Phase III study evaluated the safety, tolerability, and ...analgesic efficacy of Oxycodone DETERx extended-release (ER), abuse-deterrent capsules (XtampzaR ER) in subjects with chronic low back pain who were successfully transitioned from immediate-release (IR) oxycodone. Methods: Continuous outcomes were analyzed using a mixed-model repeated-measures approach; binomial outcomes were analyzed using chi-squared; and time-to-event outcomes using Kaplan-Meier analyses. Results: A total of 110 subjects previously prescribed IR oxycodone entered the Open-label Titration Phase. Forty-four subjects were randomized to Oxycodone DETERx (n=22) or placebo (n=22) in the 12-week Double-blind Maintenance Phase. Efficacy results in this subgroup showed a statistically significant difference between Oxycodone DETERx and placebo in average pain intensity scores from Randomization Baseline to Week 12 (least squares mean + or - standard error, -1.88 0.70; P=0.0078). Additional efficacy results indicated that Oxycodone DETERx vs placebo was associated with a statistically significant benefit in durability of effect from Week 2 through Week 12 (P<0.01), numbers of subjects with a greater than or equal to30% (n % 10 45.5% vs 0 0%; P=0.0004) and greater than or equal to50% (10 45.5% vs 0 0%; P=0.0004) improvement in pain intensity, longer time-to-exit (P=0.0014), a greater number of subjects who completed the study (14 63.6% vs 4 18.2%), and less rescue medication use (acetaminophen; mean SD, 163.5 337.8 mg) vs 216.2 377.3 mg). Adverse event profiles were consistent with opioid class effects and results from the original study; Oxycodone DETERx was well tolerated in subjects previously treated with short-acting oxycodone. Conclusions: Oxycodone DETERx resulted in clinically meaningful and statistically significant efficacy in subjects with chronic low back pain who were previously prescribed IR oxycodone and were successfully switched to ER Oxycodone DETERx. Keywords: oxycodone, DETERx, Xtampza ER, chronic low back pain, extended-release, immediate-release, opioid
The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, ...intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.
This retrospective chart review presents the patient characteristics and utilization of the home-based palliative care program at The Hospital for Sick Children in Toronto. A total of 126 children ...dying from a broad spectrum of diseases was admitted during the period 1986-1994, referred from neurosurgery, genetic/metabolic, neurology, neonatology, nephrology, cardiology, general pediatrics, general surgery, and pulmonology. At the time of review, 15 patients remained alive and 18 had been discharged from the program. Mean age at the time of referral was 4.8 +/- 0.51 years and mean age at death was 5.3 +/- 0.55 years. The mean number of days in hospital was 26.5 +/- 14.6 while days spent at home averaged 98.4 +/- 15.2; thus 80% of the children's remaining time was spent at home. The average number of parent-team contacts was 3.5 +/- 0.9 by pager and 24.0 +/- 2.9 by telephone. Of the 93 patients who died in the program, 53% died at home, 18% died in community hospitals, and 29% died in a tertiary care facility. Analgesic medications were administered to 54% of the patients; 56% of these then required opioid analgesia for pain and symptom management. Home-based palliative care appeared to be an effective program for many children with a variety of terminal illnesses after adequate supports for the child and family had been established.
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