Phase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema.

BACKGROUND: Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE) / empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (scuPA), which is relatively resistant to PA inhibitor-1 (PAI-1), would be well-tolerated. METHODS: This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS: LTI-01 was well tolerated with no bleeding, treatment-emergent adverse events or surgical referrals (n=14 subjects). uPA antigen increased in PFs at 3 hours after LTI-01 (p<0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1-resistant bioactive complexes, increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis, nor increments in plasma D-dimer. Decreased pleural opacities occurred in all but one subject. Both subjects receiving 800,000 IU required two doses to relieve pleural sepsis, with two other subjects similarly responding at lower doses. CONCLUSION: LTI-01 IPFT was well-tolerated at these doses with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.

Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.

RATIONALE: Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. OBJECTIVES: An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. METHODS: Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. MEASUREMENTS AND MAIN RESULTS: This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022. CONCLUSIONS: In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.

Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.

BACKGROUND: Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. METHODS: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects. RESULTS: Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28. CONCLUSIONS: The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 2: impact on function, mood, and quality of life.

BACKGROUND: Prior studies of breakthrough pain (BTP) largely focus on patients with advanced cancer or those receiving inpatient care. Very few studies have evaluated BTP in populations with chronic noncancer pain. Data that illuminate the impact of BTP may not generalize to other, less selected patient populations. AIM: The aim of this study was to evaluate the impact of BTP in opioid-treated ambulatory patients with chronic cancer pain or noncancer pain treated in community practices. METHODS: Eligible patients--those with any diagnosis who reported chronic pain for at least 3 months, who were receiving long-term opioid therapy, and who met criteria for controlled baseline pain--were recruited for a cross-sectional observational study by primary care physicians or community-based oncologists at 17 sites in the United States. The patients responded to a structured interview for breakthrough pain and also completed the Brief Pain Inventory-Modified Short Form (BPI-SF) and the Brief Battery for Health Improvement 2 (BBHI 2). RESULTS: Of 355 patients screened, 191 were eligible and 177 (93 percent) provided data for analysis. Twenty-six of the 78 with cancer pain (33 percent) and 48 of the 99 with noncancer pain (48 percent) had BTP. Compared with those without BTP, both patients with cancer (p = 0.004) and patients without cancer (p = 0.019) with BTP had increased pain interference in function, as measured by the BPI-SF, and patients without cancer were more impaired than patients with cancer. On the BBHI 2, BTP was associated with increased somatic complaints (p = 0.036 cancer and p = 0.024 noncancer) and pain complaints (p = 0.037 cancer and p = 0.037 noncancer); among patients without cancer, BTP was also associated with increased difficulties with functioning (p = 0.023), depression (p = 0.039), and decreased quality of life (p = 0.003). CONCLUSIONS: These data extend published observations about the association between BTP and adverse effects on mood and function to populations undergoing routine treatment in the community setting and provide evidence that these associations are greater in those with noncancer pain. They suggest the need for additional studies to clarify causality and determine whether undertreatment of BTP is a factor contributing to adverse pain-related outcomes.

Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 1: prevalence and characteristics.

BACKGROUND: Most breakthrough pain (BTP) studies assess patients with advanced cancer or those receiving inpatient care. Studies in noncancer populations are limited to surveys of pain clinics and patients with other advanced diseases. To better understand BTP, data are needed from less selected populations. AIM: The aim of this study was to evaluate BTP in opioid-treated ambulatory patients with chronic cancer or noncancer pain treated in community practices. METHODS: Primary care physicians or community-based oncologists recruited a convenience sample for a cross-sectional study of BTP at 17 sites in the United States. Physicians could not be pain specialists. Patients were eligible if they had any type of pain for > or = 3 months and were receiving an opioid drug on a regular basis that controlled the pain. The patients responded to a structured interview comprising items that assessed the baseline pain and items that assessed BTP, if present. RESULTS: In total, 355 patients were screened, 191 were eligible and 177 (93 percent) provided data for analysis. Seventy-eight patients had cancer pain and 99 had noncancer pain. Patients with cancer were older (mean +/- SD age 61.3 +/- 11.2 years vs 51.4 +/- 13.6 years, p < 0.001), and patients without cancer had more neuropathic pain (21 vs 12 percent, p < 0.05) and a longer pain duration (median 3.5 vs 1 years, p < 0.001). BTP occurred in 33 percent with cancer and 48 percent with noncancer pain (p = 0.042). BTP did not vary by diagnosis, but neuropathic pain was more common in those with BTP (27 vs 10 percent, p < 0.001). In patients with and without cancer, the median daily number of episodes was 1, the median time to maximum pain was 1-2 minutes, and the median duration was 45-60 minutes. There were fewer BTP precipitants in the patients with cancer (46 vs 80 percent of pains, p < 0.05), and they had less predictable pain (p < 0.05). CONCLUSIONS: The prevalence of BTP among community-dwelling patients is lower than that found in prior studies of more selected populations. BTP is more prevalent among patients with noncancer pain than patients with cancer pain, and although there are many similarities, some differences may be relevant to treatment strategies.

Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) patients have a variable response profile to the P2Y(12) receptor antagonist clopidogrel. P2Y(12) receptor signalling promotes platelet procoagulant activity. The aim of this study was to determine if T2DM patients with suboptimal clopidogrel response have greater platelet procoagulant activity compared with optimal responders and evaluate if this can be modulated by enhancing P2Y(12) receptor inhibition. MATERIALS AND METHODS: A total of 50 T2DM patients in a steady state phase of clopidogrel therapy were studied. Suboptimal responders were randomly assigned to standard (75 mg) or high (150 mg) clopidogrel maintenance therapy for one-month. Afterwards, all patients resumed standard therapy. Platelet procoagulant activity assessed by thrombin-induced platelet-fibrin clot formation using thrombelastography (TEG) was determined at baseline, one-month post-randomization, and one-month after resuming standard therapy. RESULTS: In the overall study population, the reaction time (R), a measure of time to initial thrombin induced platelet-fibrin clot formation, and the time to maximum rate of thrombin generation (TMRTG) values were 6.3+/-1.7 and 7.6+/-1.9 minutes, respectively. Suboptimal clopidogrel responders (n=30) had acceleration of R (p=0.002) and TMRTG (p=0.002) compared to optimal responders (n=20). Suboptimal clopidogrel responders treated with a 150 mg dose showed prolongation of R (p=0.0001) and TMRTG (p<0.0001), which returned to baseline values after resuming standard dosage. No differences were observed among patients randomized to 75 mg. CONCLUSIONS: T2DM patients with suboptimal clopidogrel response have enhanced platelet procoagulant activity compared to patients with optimal response, which can be down-regulated by more potent platelet P2Y(12) inhibition using high clopidogrel maintenance dosing.

A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study.

AIMS: Patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with non-diabetics following P2Y(12) receptor blockade. Whether inhibition of P2Y(12) signalling can be enhanced by adjunctive treatment with cilostazol in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of cilostazol in T2DM patients on standard aspirin and clopidogrel treatment. METHODS AND RESULTS: This was a prospective, double-blind, double-dummy, placebo-controlled, randomized, cross-over platelet function study. T2DM patients on dual antiplatelet therapy were assigned to receive cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. Platelet function was performed at three time points: at baseline, 14 days after randomization, and 14 days after treatment cross-over. The P2Y(12) reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. In addition to this flow cytometric evaluation, light transmittance aggregometry and VerifyNow testing were performed. A total of 25 T2DM patients were randomized; five patients discontinued treatment due to side effects. The P2Y(12) reactivity index was significantly lower following cilostazol treatment compared with placebo (36.3 +/- 20 vs. 59.9 +/- 16%; P = 0.0002). All other P2Y(12)-specific functional assessments showed enhanced inhibition of this signalling pathway following treatment with cilostazol. CONCLUSION: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y(12) signalling.

Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment.

Updated guidelines on percutaneous coronary intervention recommend increasing the dose of clopidogrel to 150 mg in high-risk patients if <50% platelet inhibition is demonstrated. However, to date, the functional impact of this recommendation has been poorly explored. The aim of this study was to assess the functional implications associated with the use of clopidogrel 150 mg/day in patients with inadequate platelet inhibition while receiving standard 75 mg/day maintenance treatment. Patients with diabetes mellitus have a higher prevalence of inadequate clopidogrel-induced antiplatelet effects and stent thrombosis compared with those without diabetes and were selected for this analysis. Platelet inhibition was assessed using the VerifyNow P2Y12 assay in patients with type 2 diabetes receiving dual-antiplatelet therapy. Patients (n = 17) with <50% platelet inhibition were treated with clopidogrel 150 mg/day for 1 month. Adenosine diphosphate-induced aggregation and the P2Y12 reactivity ratio were also assessed. Platelet function profiles were compared with that of a control group (n = 17) with >or=50% inhibition. Platelet inhibition increased from 27.1 +/- 12% to 40.6 +/- 18% in patients treated with clopidogrel 150 mg/day (p = 0.009; primary end point). All other functional measures also showed enhanced clopidogrel-induced antiplatelet effects. The degree of platelet inhibition achieved after treatment with clopidogrel 150 mg/day varied broadly, and only 35% of patients yielded a degree of platelet inhibition >or=50%. Increasing the dose in patients with inadequate response to clopidogrel did not reach the same degree of antiplatelet effects as those achieved in patients with adequate response while receiving 75 mg/day. In conclusion, the use of a 150 mg maintenance dose of clopidogrel in patients with type 2 diabetes with <50% platelet inhibition is associated with enhanced antiplatelet effects. However, the antiplatelet effects achieved are nonuniform, and a considerable number of patients persist with inadequate platelet inhibition.

Quantitative magnetic resonance perfusion imaging detects anatomic and physiologic coronary artery disease as measured by coronary angiography and fractional flow reserve.

OBJECTIVES: To evaluate the ability of quantitative perfusion cardiac magnetic resonance (CMR) to assess the hemodynamic significance of coronary artery disease (CAD) compared with well-established anatomic and physiologic techniques. BACKGROUND: Fractional flow reserve (FFR) is considered by many investigators to be a reliable stenosis-specific method to determine hemodynamically significant CAD. Quantitative perfusion CMR is a promising noninvasive approach to detect CAD but has yet to be validated against FFR. METHODS: This is a prospective study in patients with suspected CAD who underwent coronary angiography, FFR, and CMR assessments. The quantitative myocardial perfusion reserve (MPR) was calculated in 720 myocardial sectors (8 sectors/slice). The MPR was calculated from the ratio between stress and rest myocardial flow based on signal intensity time curves using deconvolution analysis. Stress was simulated with adenosine for both FFR and MPR. The MPR assessments were compared to FFR (n = 44 coronary segments) and quantitative coronary angiography (n = 108 segments) in the corresponding coronary territories. RESULTS: The MPR was 1.54 +/- 0.36 in segments with FFR < or =0.75 (n = 14) and 2.11 +/- 0.68 in those with FFR >0.75 (n = 30; p = 0.0054). An MPR cutoff of 2.04 was 92.9% (95% CI 77.9 to 100.0) sensitive and 56.7% (95% CI 32.8 to 80.6) specific in predicting a coronary segment with FFR < or =0.75. The MPR was 1.54 +/- 0.49 in coronary segments with > or =50% diameter stenosis (DS) (n = 47) and 2.13 +/- 0.80 in segments with <50% DS (n = 61; p < 0.001). An MPR cutoff of 2.04 was 85.1% (95% CI 71.1 to 99.2) sensitive and 49.2% (95% CI 33.6 to 64.8) specific in predicting CAD with > or =50% DS. CONCLUSIONS: Quantitative perfusion CMR is a safe noninvasive test that represents a stenosis-specific alternative to determine the hemodynamic significance of CAD.

Evaluation of cardiac magnetic resonance imaging parameters to detect anatomically and hemodynamically significant coronary artery disease.

BACKGROUND: Cardiac magnetic resonance (cMR) perfusion imaging is a promising technique to assess coronary artery disease (CAD). Our objective was to evaluate accuracy of various cMR imaging parameters to detect significant CAD as compared with angiography or fractional flow reserve (FFR). METHODS: We prospectively enrolled 37 patients who underwent coronary angiography, FFR, and cMR perfusion imaging. Semiquantitative assessments, namely maximum up-slope and peak-intensity indexes, were derived from time-intensity ratios between rest and stress. Myocardial perfusion reserve (MPR), calculated using Fermi deconvolution technique, was the quantitative cMR imaging parameter. Qualitative assessments were visually performed by independent analysts. Accuracy of quantitative, semiquantitative, and qualitative cMR imaging data was compared with quantitative coronary angiography in 108 segments and FFR in 44 segments. RESULTS: Sensitivity and specificity for hemodynamically significant CAD (FFR < or = 0.75) were 92.9% and 56.7%, respectively, for MPR (cutoff, 2.06). Area under the curve to detect FFR < or = 0.75 was 0.78 for MPR (P < .01), 0.63 for up-slope (P = NS), and 0.66 (P = NS) for peak intensity. Sensitivity and specificity for anatomically significant CAD (> 50% diameter stenosis [DS]) were 87.2% and 49.2%, respectively, for MPR (cutoff, 2.06). Area under the curve was 0.75 for MPR, 0.69 for up-slope, and 0.65 for peak intensity to detect > 50% DS (all P < .05). Visual assessment yielded sensitivity of 78.6% and specificity of 65.5% to predict FFR < or = 0.75 and sensitivity of 74.5% and specificity of 67.2% to predict > 50% DS. CONCLUSIONS: Myocardial perfusion reserve appears to be the most accurate index to detect anatomical and hemodynamically significant CAD. Standardization of such quantitative methods, with minimal operator dependency, would be useful for clinical and research applications.

Prevalence and characteristics of breakthrough pain in patients receiving opioids for chronic back pain in pain specialty clinics.

OBJECTIVE: We sought to assess the prevalence and characteristics of breakthrough pain (BTP) in patients with chronic back pain. DESIGN: Researchers utilized a telephone survey using a pain assessment algorithm. This report represents a subset of patients from a larger survey of 228 patients with chronic pain unrelated to cancer. PARTICIPANTS: This study employed 117 subjects taking opioids for a primary diagnosis of back pain and receiving care at geographically dispersed pain treatment centers. Subjects had pain lasting at least six months and had "controlled" baseline pain. RESULTS: Eighty-seven subjects (74 percent) experienced 93 types of BTP. The median number of BTP episodes per day was two; median time to maximum intensity was 10 minutes, and median duration was 55 minutes. Onset could not be predicted for 46 percent of pains. Eighty-three percent of subjects used shorter-acting opioids for BTP. Other medications used for pain included NSAIDs, antidepressants, anticonvulsants, skeletal muscle relaxants, intrathecal local anesthetics, and transdermal local anesthetics. CONCLUSIONS: These patients with opioid-treated chronic back pain commonly experienced BTP, which often had a rapid onset and a relatively short duration and was difficult to predict. Opioids were the mainstay of pharmacologic therapy, but nonopioid analgesics and adjuvant analgesics were commonly used.

Cardiac transplantation in patients with anti-phospholipid antibodies.

Patients with severe heart failure are known to have an increased incidence of thromboembolic events and frequently have a visible thrombus in the left ventricle. Thromboemboli in heart failure patients are usually attributed to the underlying heart failure, and alternative etiologies for thrombus formation are rarely sought. However, anti-phospholipid antibodies and other inherited or acquired clotting abnormalities may contribute to hypercoagulability in heart failure patients and can lead to a persistent high risk for clotting, even after heart transplantation has corrected the underlying heart failure. We report outcomes with heart transplantation in 3 young patients with anti-phospholipid antibodies and a history of pre-heart transplantation thromboembolic events, and demonstrate the importance of post-heart transplantation anti-coagulation in these patients.

Impact of breakthrough pain on quality of life in patients with chronic, noncancer pain: patient perceptions and effect of treatment with oral transmucosal fentanyl citrate (OTFC, ACTIQ).

OBJECTIVE: To characterize breakthrough pain (BTP), its qualitative impact on quality of life (QoL), and the effects of BTP treatment on QoL. DESIGN: Multicenter patient-reported survey. SETTING: Five pain treatment centers. PATIENTS: Fifty-six adults with chronic noncancer pain using oral transmucosal fentanyl citrate (OTFC, ACTIQ). RESULTS: Forty-three patients qualified for in-depth analysis. BTP had a mean intensity of 9.0 (range 5-10) on an 11-point numerical scale (0 = no pain to 10 = worst possible pain), had a mean duration of 83 minutes, and had an adverse effect on multiple QoL domains. The largest negative QoL impacts were on "general activity level" and "ability to work." OTFC had a positive impact on both controlling BTP and improving QoL. CONCLUSIONS: BTP appears to be a clinically important condition in this population and is associated with an adverse impact on QoL. Understanding those QoL domains most affected by BTP and those potentially improved with treatment should help in developing quantitative QoL assessment tools and other outcome measures for BTP management studies.

Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.

BACKGROUND: After treatment with clopidogrel, patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with patients who are not diabetic. Whether platelet inhibition can be enhanced by increasing clopidogrel maintenance dosage in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of a high maintenance dose in T2DM patients with suboptimal clopidogrel-induced antiplatelet effects. METHODS AND RESULTS: T2DM patients on chronic dual antiplatelet therapy were screened to identify suboptimal clopidogrel responders. The latter were randomized to 30-day treatment with a standard (75 mg; n=20) or high (150 mg; n=20) daily maintenance dose. Platelet function was assessed at 3 time points: baseline, 30 days after randomization, and 30 days after resuming standard dosing. Platelet function parameters included adenosine diphosphate-induced (20 and 5 micromol/L) maximal and late platelet aggregation, inhibition of platelet aggregation, platelet disaggregation, and P2Y12 reactivity index. A total of 64 T2DM patients were screened to identify 40 suboptimal responders. After randomization, maximal adenosine diphosphate-induced (20 micromol/L) platelet aggregation was significantly reduced in the 150-mg group compared with the 75-mg group (P=0.002; primary end point). However, suboptimal clopidogrel response was still present in 60% of patients on the 150-mg regimen. All other platelet function parameters showed enhanced clopidogrel-induced antiplatelet effects with 150 mg, which returned to baseline values after resumption of standard dosing. CONCLUSIONS: A 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with 75 mg in high-risk T2DM patients. However, enhanced ex vivo platelet reactivity continues to persist, the clinical implications of which are unknown and need to be evaluated in large-scale clinical trials.

Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain.

UNLABELLED: Breakthrough pain is well-characterized in cancer patients but not in patients with chronic noncancer pain. We recruited 228 patients with diverse types of chronic noncancer pain from 9 pain programs and administered a telephone questionnaire with a breakthrough pain assessment algorithm originally designed for cancer patients. All patients had controlled baseline pain, and 168 (74%) experienced severe to excruciating breakthrough pain. Among those with breakthrough pain, the most common syndrome was low back pain (52%), and the underlying pathophysiology was variably characterized as somatic (38%), neuropathic (18%), visceral (4%), or mixed (40%). A total of 189 different types of breakthrough pain were reported. The median number of episodes per day was 2 (range, <1 to 12). Median time to maximum intensity was 10 minutes (range, 0 to 180 minutes). Median duration of the breakthrough pain was 60 minutes (range, 1 to 720 minutes). Patients identified a precipitant for 69% of pains, and 92% of these were activity-related. Onset could never be predicted for 45% of pains and only sometimes predicted for 31% of pains. Breakthrough pain is highly prevalent and varied in this population. Further studies are warranted to clarify whether the clinical impact and therapeutic challenges posed by this phenomenon are comparable to the cancer population. PERSPECTIVE: This article presents results from a survey that demonstrates that breakthrough pain is highly prevalent and varied in opioid-treated patients with chronic noncancer pain. These findings will assist clinicians in assessing and managing this type of pain.

Breakthrough pain in opioid-treated patients with neuropathic pain.

OBJECTIVE: This report aims to describe the prevalence and characteristics of breakthrough pain in patients with neuropathic pain. METHODS: The study represents data from a subset of patients from a larger survey of 228 patients with chronic noncancer pain. Patients were identified from nine pain programs and were administered a telephone questionnaire. The study population comprised 45 chronic noncancer pain patients with primary neuropathic pain diagnoses who were being treated with opioids. RESULTS: Pain had been present for a median of six years. Medications used for pain in addition to opioids included nonsteroidal anti-inflammatory agents (29 percent), antidepressants (60 percent), and anticonvulsants (53 percent). Thirty-five of the patients (78 percent) described a total of 42 distinct types of breakthrough pain. The median number of episodes per day was two; the median time to maximum intensity was 10 minutes, and the median duration of pain was 60 minutes. Patients could identify a precipitant for 62 percent of the pains, and 88 percent of the precipitants were activity related. The onset of breakthrough pain could not be predicted for 48 percent of the pains and could only sometimes bepredicted for 29 percent of the pains. CONCLUSION: Breakthrough pain is common in opioid-treated patients with chronic neuropathic pain. Such pain often has a rapid onset and a relatively short duration, and it is frequently difficult to predict, similar to breakthrough pain in cancer patients.

Left ventricular dysfunction after pericardiectomy for constrictive pericarditis.

A 56-year-old man was admitted to our hospital with a diagnosis of suspected constrictive pericarditis. After the diagnosis was confirmed by cardiac catheterization, an elective pericardiectomy was performed without complication. Four days after surgery dyspnea developed in the patient, and he was found to have an acute decrease in left ventricular ejection fraction (LVEF) by echocardiography. The patient's symptoms and the LVEF improved over time and returned to normal 4 weeks after surgery. Transient hemodynamic dysfunction of the left ventricle has previously been reported after pericardiectomy or pericardiocentesis; however, we know of no reports in the literature that confirm an acute reduction in LVEF by echocardiography after pericardiectomy for constrictive pericarditis.