Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

OBJECTIVE: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. METHODS: This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). RESULTS: The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (-0.41, 2.94), preladenant 10 mg = 0.40 (-1.29, 2.11), and rasagiline 1 mg = 0.30 (-1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%). CONCLUSIONS: No evidence supporting the efficacy of preladenant as monotherapy was observed in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT01155479. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Predicting response to pregabalin from pretreatment pain quality: clinical applications of the pain quality assessment scale.

OBJECTIVE: The aim of this study is to assess the Pain Quality Assessment Scale (PQAS) in predicting pregabalin in peripheral neuropathic pain (NP). STUDY DESIGN: Post hoc analysis of a double-blind, placebo-controlled, enriched enrollment, randomized withdrawal trial evaluating pregabalin in 99 patients with NP who completed the PQAS, which comprises 20 questions regarding individual pain domains and qualities that are scored into three scales: paroxysmal, deep, and surface. METHODS: Patients rated the average pain intensity and pain quality using the PQAS at baseline; average pain intensity was assessed again after 40 days of treatment with pregabalin. Associations between pretreatment PQAS scores and treatment response were estimated using Pearson's r. Logistic regression was used to identify pretitration PQAS scores contributing unique variance to predicting treatment response. RESULTS: Fifty participants provided baseline PQAS scores and received pregabalin for the entire length of the study. Nine of 23 PQAS baseline scales and items were significantly associated with treatment response to pregabalin: the paroxysmal and deep scales, and the items assessing the following pain domains and qualities: intensity, electric, tingling, cramping, radiating, throbbing, and deep (P values range, 0.002-0.045; rs range, 0.28-0.43). The PQAS items assessing sharp, hot, and unpleasant pain items demonstrated nonsignificant trends (P < 0.10) to be associated with treatment response. In the logistic regression analysis, pretitration PQAS scores had 77% sensitivity and 83% specificity to correctly identify pregabalin responders. Significantly correlated PQAS items had a sensitivity of 85% and specificity of 76%. CONCLUSION: Pretitration PQAS scores reliably predicted pregabalin responders in patients with NP.

Long-term open-label safety study of rizatriptan acute treatment in pediatric migraineurs.

OBJECTIVE: To evaluate the safety/tolerability of rizatriptan in the long-term acute treatment of migraine in pediatric patients. BACKGROUND: Acute migraine treatment options for children are limited. A recent single-attack trial demonstrated that rizatriptan is effective in eliminating migraine headache pain in this population. We evaluated the long-term safety and efficacy of rizatriptan when used for intermittent acute treatment. METHODS: Open-label study in pediatric migraineurs ages 12-17 years. Patients weighing <40 kg received rizatriptan (orally disintegrating tablet) 5 mg, and those weighing ≥40 kg received 10 mg. Patients could treat up to 8 mild/moderate/severe migraine attacks per month for up to 12 months. One dose of study medication was allowed in a 24-hour period. RESULTS: A total of 674 patients were enrolled, and 606 patients were treated with study medication (N = 583 for 10 mg, N = 23 for 5 mg). The mean duration in the study was 292 days, and the mean number of doses of study medication taken was 20. Over the course of the study within 14 days post-any-dose, 66.0% (400) of the 606 treated patients had any adverse event, 2.3% (14) discontinued due to an adverse event, 2.6% (16) had a serious adverse event, and 23.4% (142) had a triptan-related adverse event. Of the 16 patients with serious adverse events within 14 days post-any-dose, the adverse events in 3 were considered drug-related; all 3 patient's adverse events were classified as serious only because they were associated with an overdose (use of >1 dose of study medication in a 24-hour period). The mean percentage of patient's attacks with pain freedom at 2-hours post-dose was 46.3%; this was relatively consistent over time (Months 1-3 = 43.7%, Months 4-6 = 51.9%, Months 7-9 = 49.9%, Months 10-12 = 49.5%). CONCLUSION: Rizatriptan was generally safe and well tolerated in the long-term acute treatment of migraine in pediatric patients aged 12-17 years and demonstrated a consistent treatment effect over time.

Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design.

BACKGROUND: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for ≥ 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds. RESULTS: A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds. CONCLUSION: Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001234.

The pain quality response profile of pregabalin in the treatment of neuropathic pain.

OBJECTIVE: To identify and describe the response profile of pregabalin on the qualities of pain associated with peripheral neuropathy. METHODS: A post hoc analysis to examine the effects of pregabalin on pain quality in patients with moderate-to-severe peripheral neuropathic pain was performed using data from an enriched enrollment randomized withdrawal proof-of-concept study. Patients rated the quality of their pain experience using the Pain Quality Assessment Scale (PQAS) at baseline, after a 12-day titration period, after a 9-day maintenance period, and after a 19-day randomized withdrawal period. Pretitration to posttitration and prewithdrawal to postwithdrawal changes in PQAS paroxysmal, surface, and deep pain scale scores were examined. RESULTS: PQAS data were available for 99 of the 104 participants who entered all phases of the study. There were significant (P<0.006, Bonferroni adjusted for multiple tests) improvements pretitration to posttitration in all 3 PQAS subscales, with a greater effect on paroxysmal and deep pain than on surface pain. During the withdrawal phase, pregabalin was significantly (P<0.006) more effective than placebo for improvements in paroxysmal and surface pain only, although the pregabalin group continued to show numerical improvement in deep pain relative to placebo. DISCUSSION: Pregabalin had a greater effect on PQAS-assessed paroxysmal pain than on surface or deep pain in patients with peripheral neuropathy. The findings corroborate previous research demonstrating differential effects of analgesic drugs across pain qualities, further emphasizing the need to assess individual pain qualities in addition to overall pain intensity.

The value of HAZWOPER medical surveillance.

Medical surveillance is mandated for workers with potential exposure to hazardous materials. However, little guidance is provided regarding the components of a medical surveillance testing program for these individuals. This article describes the medical surveillance program for a group of 72 employees who respond to hazardous material releases throughout the United States. Conditions related to chemical exposures were not identified in this group. However, several non-occupational health conditions were identified, including a relatively high prevalence of one or more signs of metabolic syndrome. Medical surveillance may provide valuable information regarding an individual's underlying health status and non-occupational health conditions to be addressed at an early stage.

Randomized controlled study of telcagepant plus ibuprofen or acetaminophen in migraine.

OBJECTIVE: To evaluate the efficacy and tolerability of telcagepant when co-administered with ibuprofen or acetaminophen for the acute treatment of migraine. BACKGROUND: Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. METHODS: Randomized, double-blind, placebo-controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N =170), or placebo (N = 171). The primary efficacy endpoint was 2-hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. RESULTS: The percentages of patients with 2-hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥ 4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. CONCLUSIONS: The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).

Can Reactive Airways Dysfunction Syndrome (RADS) be iatrogenic?

Reactive airways dysfunction syndrome (RADS) is an asthma-like illness that develops after a single high-level exposure to a pulmonary irritant. Two different cases are reviewed, in which the exposure circumstances were not sufficient to result in adverse health effects yet resulted in persistent respiratory symptoms and a clinical diagnosis of RADS. Potential explanations for an erroneous diagnosis of RADS included an incomplete exposure assessment, medication adverse effects that can contribute to respiratory symptoms, and alternative explanations for respiratory symptoms or test findings. In particular, the empirical use of bronchodilator medications without a clear indication appeared to contribute to continued respiratory symptoms. Without a clear understanding of the patient's exposure, a RADS diagnosis should be carefully considered. The possibility of an iatrogenic sequence of events in which medication adverse effects facilitate respiratory symptoms and a mistaken RADS diagnosis should be considered, particularly in patients who have a poorly defined exposure history.

Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.

BACKGROUND: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. METHODS: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. RESULTS: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. CONCLUSIONS: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain.

The objective of this study was to evaluate how enrichment for responders increases assay sensitivity in an enriched enrollment randomized withdrawal (EERW) proof-of-concept (POC) study in neuropathic pain. Adults with moderate to severe peripheral neuropathic pain entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided pain control (pregabalin 50-200mg t.i.d.), and then a 9-day maintenance period. Subjects were stratified as primary responders (⩾30%), secondary responders (⩾10% to <30%), or nonresponders (<10%) based on decrease in pain intensity and were randomized to placebo or pregabalin during the randomized withdrawal period. The primary endpoint was mean of average 24-h pain intensity during the last 3days of treatment period relative to the 3days before randomization. Time-to-efficacy-failure was the key secondary endpoint. Other features included not requiring discontinuation of current analgesic therapies and blinding investigators to study design elements that could contribute to non-treatment-related responses. Effect size (ES) (mean treatment difference/SD) was used to measure assay sensitivity. Pregabalin-treated subjects (n=52) had significantly less pain than those receiving placebo (n=51) (P⩽.003). Effect size of the primary endpoint was 0.72 for primary responders and decreased if secondary and nonresponders were included in the analysis. The highest ES (1.68) was demonstrated for the endpoint time-to-efficacy-failure seen in primary responders with painful diabetic neuropathy. The EERW trial design using time-to-efficacy-failure may provide a sensitive and efficient method to conduct POC studies of novel therapies in patients with neuropathic pain. Enriching a study population with patients who have achieved a 30% decrease in pain with an investigational therapy, and using time-to-efficacy-failure during the randomized withdrawal phase as the primary endpoint, can be used for a proof-of-concept study to optimize assay sensitivity and efficiently determine the analgesic potential of a new treatment for neuropathic pain.

Comparison of the efficacy and tolerability of preservative-free and preservative-containing formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure in a randomized clinical trial.

BACKGROUND: The aim of this study was to compare the efficacy and tolerability of preservative-free (PF) and preservative-containing (PC) formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure (IOP). METHODS: A parallel, randomized, double-masked study was conducted. After a 3-week run-in on timolol, patients with ocular hypertension, as confirmed by an IOP ≥22 mmHg, were randomized 1:1 to receive PF or PC dorzolamide/timolol twice daily for 12 weeks. IOP was measured at hour 0 (drug trough) and hour 2 (drug peak) at baseline (last day of 3-week timolol run-in), and weeks 2, 6 and 12. RESULTS: A total of 261 patients were randomized. Mean baseline IOPs were 23.7 mmHg for both treatments at hour 0 and 21.2 mmHg for PF dorzolamide/timolol and 21.4 mmHg for PC dorzolamide/timolol at hour 2. At all study time points (trough and peak at weeks 2, 6, and 12), the difference between treatments in mean change from baseline IOP was <0.5 mmHg. The 95% confidence intervals for the estimated treatment difference (PF minus PC) in mean change from baseline IOP at week 12 was -0.86 to 0.23 mmHg for trough (primary endpoint) and -0.39 to 0.67 mmHg for peak (secondary endpoint). The most common adverse events were ocular burning/stinging, reported by 16.0% and 21.5% of patients receiving PF and PC dorzolamide/timolol respectively, and taste perversion, reported by 3.1% and 5.4% of patients receiving PF and PC dorzolamide/timolol respectively. CONCLUSIONS: In patients with elevated IOP, PF and PC dorzolamide/timolol were equivalent in efficacy for change in trough and peak IOP, and had generally similar tolerability.

Physical therapists' perceptions of ease of care in patients receiving 2 forms of analgesia after total hip arthroplasty.

BACKGROUND: Pain management modalities that facilitate patient mobility may contribute to recovery after total hip replacement (THR) surgery. OBJECTIVE: The aim of this study was to evaluate the impact of morphine intravenous (IV) patient-controlled analgesia (PCA) and the fentanyl iontophoretic transdermal system (fentanyl ITS) on physical therapists' ability to complete care tasks for patients after THR. DESIGN: The data were from an open-label, randomized, multicenter, active-control phase IIIb clinical trial. METHODS: The settings were 52 US-based teaching and community hospitals. The patients were >or=18 years of age (mean [SEM]: 62.8 [0.6] years in the fentanyl ITS group and 62.9 [0.6] years in the morphine IV PCA group); had an American Society of Anesthesiologists physical status of I, II, or III; and were scheduled to undergo primary unilateral THR surgery. The patients were randomized to receive analgesia for up to 72 hours via the fentanyl ITS (40 microg of fentanyl over 10 minutes for up to 6 doses per hour for 24 hours or 80 doses per system, whichever occurred first) or morphine IV PCA (1-mg bolus doses [with a 5-minute lockout interval between doses] for up to 10 doses per hour for 24 hours). All patients received the usual treatment administered by physical therapists. After each therapy session, physical therapists completed a validated Physical Therapist Ease-of-Care Questionnaire, which included time efficiency and convenience subscales (lower scores indicated more positive responses) and a satisfaction subscale (a higher score indicated a more positive response). Therapists whose average scores were or=4 on both items of the satisfaction subscale were considered responders. RESULTS: Higher percentages of physical therapists were responders for the fentanyl ITS than for morphine IV PCA on the subscales that assessed time efficiency (84.9% and 59.1%, respectively), convenience (86.6% and 71.2%, respectively), and satisfaction (54.3% and 30.5%, respectively). Higher percentages of physical therapists favored the fentanyl ITS than favored morphine IV PCA. Limitations The trial was limited by its open-label design, and physical therapists were more familiar with IV PCA than with the fentanyl ITS. CONCLUSIONS: The findings demonstrate benefits to physical therapists of using the fentanyl ITS over morphine IV PCA in terms of time efficiency, convenience, and satisfaction.

Development and validation of a new instrument to evaluate the ease of use of patient-controlled analgesic modalities for postoperative patients.

OBJECTIVE: To describe the development and psychometric evaluation of a questionnaire assessing the ease of use that patients associate with patient-controlled analgesia (PCA) modalities. METHODS: Qualitative interviews were conducted with patients who had experience with intravenous (IV) PCA for postoperative pain management to generate items relevant to the ease of using PCA modalities. The content validity of the resulting questionnaire was examined through follow-up patient interviews, and an expert panel reviewed the questionnaire. Cognitive debriefing interviews were conducted with patients to determine the clarity and content of the instructions, items, and response scales, and the ease of completing the instrument. Psychometric evaluation was performed with patients who had undergone surgery and received IV PCA for postoperative pain management. Item and scale quality and the internal consistency reliability of the questionnaire were assessed. Construct validity was evaluated by examining the relationship between subscales of the questionnaire with patient-reported outcome measures. Known-groups validity was determined by assessing the instrument's ability to differentiate between patients with versus without an IV PCA problem. A potential limitation of this study was the exclusive sampling of patients who had experience with IV PCA. RESULTS: The Patient Ease-of-Care (EOC) Questionnaire included 23 items in the following subscales: Confidence with Device, Comfort with Device, Movement, Dosing Confidence, Pain Control, Knowledge/Understanding, and Satisfaction. Coefficient alpha reliability estimates were ≥ 0.66 for Overall EOC (includes all subscales except Satisfaction) and all EOC subscales. Construct validity was supported by the moderate relationship between the Pain Control subscale and measures of pain severity and pain interference; additional evidence of construct validity was provided by correlations of the Confidence with Device subscale, the Satisfaction subscale, and Overall EOC with measures of pain severity, pain interference, and satisfaction. Significant mean score differences were reported between participants with and without IV PCA problems for Overall EOC and for the Comfort with Device, Confidence with Device, Movement, Pain Control, and Satisfaction subscales indicating known-groups validity. CONCLUSIONS: Results provide evidence for the reliability and validity of the Patient EOC Questionnaire as a measure of the ease of use that patients associate with PCA systems and may be useful for evaluating emerging PCA modalities.

Patients' assessment of the convenience of fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous patient-controlled analgesia (IV PCA) in the management of postoperative pain after major surgery.

The patient-controlled fentanyl HCl iontophoretic transdermal system (ITS) is a compact, self-contained, needle-free system that has been approved for acute postoperative pain management in hospitalized adults. The objective of the present analysis was to evaluate patients' assessment of fentanyl ITS and morphine intravenous patient-controlled analgesia (IV PCA) convenience on 7 different subscales, using a validated patient ease of care (EOC) questionnaire in 2 prospective, open-label, randomized, phase IIIb clinical trials. Patients received fentanyl ITS or morphine IV PCA (N = 1,305) for up to 72 h after total hip replacement surgery (THR study) or abdominal or pelvic surgery (APS study). For the majority of items on the patient EOC questionnaire, trends suggest that greater percentages of patients reported the most positive response for fentanyl ITS than they did for morphine IV PCA in both studies; differences were particularly noteworthy for items on the Movement subscale. In the THR study, more patients in the fentanyl ITS group were responders compared with those in the morphine IV PCA group for the subscales Confidence with Device, Pain Control, Knowledge/Understanding, and Satisfaction. In the APS study, responder rates for these subscales did not differ between treatment groups. These findings indicate that patients assessed the EOC associated with fentanyl ITS higher compared with morphine IV PCA for the management of acute postoperative pain and suggest that fentanyl ITS has the potential to improve acute postoperative pain care for patients and nurses.

Characterization of a fatal methyl bromide exposure by analysis of the water cooler.

BACKGROUND: A suspected inhalation exposure to methyl bromide (MeBr) in the packaging and shipping area of a chemical manufacturer resulted in a worker fatality and several symptomatic cases. However, air testing was negative for MeBr resulting in uncertainty regarding the potential chemical exposure. Methods of quickly confirming the exposure and magnitude were sought. METHODS: Head space air and water samples were obtained from the breakroom water cooler in the facility and tested for MeBr. RESULTS: Increased levels of MeBr were identified in the air and water samples from the cooler and used to calculate the MeBr concentration of air entering the cooler. The MeBr air concentration within the breakroom was estimated as 1,200-2,100 ppm depending on assumptions regarding the amount of water dispensed from the cooler both before and during the incident. CONCLUSIONS: Estimated MeBr air concentrations in the breakroom were consistent with those known to be associated with reported health effects among the involved workers. The water cooler analysis represented a unique method of retrospectively verifying and quantifying exposure to MeBr.

Using the patient global assessment of the method of pain control to assess new analgesic modalities in clinical trials.

OBJECTIVE: To assess the validity of the patient global assessment (PGA) of the method of pain control, a single-item patient-reported outcome measure of a method of pain control for patients experiencing postoperative pain. RESEARCH DESIGN AND METHODS: Content validity of the PGA of the method of pain control was assessed using cognitive debriefing interviews. Construct validity was evaluated using data from six clinical trials that compared the efficacy of the fentanyl HCl iontophoretic transdermal system (fentanyl ITS) with morphine intravenous patient-controlled analgesia or placebo fentanyl ITS for acute postoperative pain management. MAIN OUTCOME MEASURES: To assess the construct validity of the PGA rating scale, four hypotheses were developed that related positive PGA ratings ('good' or 'excellent') to (1) lower pain intensity scores, (2) higher satisfaction ratings, (3) a greater propensity to select the assigned pain control method in the future, and (4) favorable ratings of ease of use/convenience on the Patient Ease-of-Care Questionnaire. Descriptive statistics were used to evaluate the association of pain intensity and Overall Ease-of-Care scores with PGA ratings. An exact linear-by-linear association test was conducted to evaluate the association of satisfaction ratings and propensity to select the pain control method in the future with PGA ratings. RESULTS: Results of cognitive debriefing interviews indicated that the PGA incorporates patient perceptions of several aspects of treatment with an analgesic modality, including level of pain, ease of use, and control of administration. PGA ratings were associated in the expected direction with other patient-reported outcomes used in several clinical studies. CONCLUSIONS: Findings suggest that both the content and construct validity of the PGA of the method of pain control in clinical trial settings are supported. However, this conclusion is potentially limited by the use of a narrow range of therapeutic interventions and, in some cases, small sample sizes in the clinical trials used to assess construct validity. The PGA of the method of pain control is an informative and useful measure for assessing pain control provided by different drug delivery systems for patients experiencing postoperative pain.

Interpretation of the "positive" methacholine challenge.

BACKGROUND: A methacholine challenge may be used in confirming the diagnosis of asthma, occupational asthma, or reactive airways dysfunction syndrome (RADS) through identification of bronchial hyperreactivity (BHR). While sensitivity of the test in diagnosing clinically significant asthma is excellent, specificity of the test is poor. Since there are many conditions which have been associated with BHR, a positive test must be interpreted cautiously. METHODS: This paper reviews potential causes of a positive methacholine challenge other than asthma or RADS which have been reported in the medical literature. RESULTS: Factors which may be associated with a positive methacholine test include test methodology, normal variation of BHR in the general population, and numerous medical conditions. CONCLUSIONS: In cases of inhalation exposure evaluations, alternative explanations must be considered when determining whether a causal association exists between the exposure and a positive methacholine test result.

Efficacy and safety of the fentanyl iontophoretic transdermal system (ITS) and intravenous patient-controlled analgesia (IV PCA) with morphine for pain management following abdominal or pelvic surgery.

OBJECTIVE: The fentanyl HCl iontophoretic transdermal system (ITS) has effectively managed pain following several types of surgery. This study evaluated the efficacy, safety, and ease of care associated with fentanyl ITS and morphine intravenous patient-controlled analgesia (IV PCA) for pain management following abdominal or pelvic surgery. DESIGN: This open-label, multicenter, randomized, active-controlled, parallel-group, phase IIIb study enrolled 506 postoperative patients at 39 U.S. sites. Patients received fentanyl ITS (40 microg fentanyl/dose) or morphine IV PCA (1 mg morphine/dose). The primary efficacy measure was demonstrating equivalence on the patient global assessment (PGA) of the method of pain control in the first 24 hours of treatment between the groups. RESULTS: Percentages of patients in the fentanyl ITS and morphine IV PCA groups reporting PGA ratings of "good" or "excellent" in the first 24 hours were statistically equivalent (84.9% vs 84.3%, respectively; difference = 0.7%, 95% CI: -5.6% to 7.0%). Equivalence was also demonstrated based on mean last pain intensity scores in the first 24 hours (3.0 vs 2.9, respectively; difference = 0.1, 95% CI: -0.28 to 0.43). Overall discontinuation rates were not significantly different between groups (16.7% vs 11.8%, respectively; P = 0.128). Patients and nurses reported better ease-of-care ratings for fentanyl ITS than for morphine IV PCA. Commonly occurring adverse events were similar between groups. CONCLUSIONS: Fentanyl ITS and morphine IV PCA were comparable methods of pain control following abdominal or pelvic surgery; however, fentanyl ITS was rated better than morphine IV PCA for ease of care by patients and nurses.