BACKGROUND & AIMS: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients. METHODS: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves. RESULTS: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to - 0.83; PAC-QOL cutoff values ranged from - 0.93 to - 0.82. CONCLUSIONS:Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful.

Background: Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs). Methods: Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed. Results: The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p < 0.0001) and non-PLR (54.3%; p = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar. Conclusion: This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups. [ ClinicalTrials.gov identifier: NCT01965158 and NCT01993940]

OBJECTIVE:Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies.METHODS:COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo-controlled, parallel-group studies of 12 weeks' duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks' duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for ≥3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored.RESULTS:The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire.DISCUSSION:Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL.CLINICALTRIALSGOV REGISTRATION:NCT01965158, NCT01993940, NCT01965652.

Purpose: Naldemedine, an oral, peripherally acting p.-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), is renally excreted. This subgroup analysis integrated data from 3 Phase 3 trials (COMPOSE-1, COMPOSE-2, COMPOSE-3) to evaluate the safety and efficacy of naldemedine in patients with renal impairment (RI). Patients and Methods: Patients age 18-80 years with chronic non-cancer pain (CNCP) and OIC received oral naldemedine 0.2 mg or placebo once daily. RI subgroups consisted of patients with normal function (baseline glomerular filtration rate >= 90 mL/min/1.73 m(2)), mild (>= 60 to <90 mL/min/1.73 m(2)), and moderate (>= 30 to <60 mL/min/1.73 m(2)) RI. Safety assessments based on <= 12 weeks of treatment from all 3 studies included incidence of treatment-emergent adverse events (TEAEs). Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2 only, defined as >= 3 spontaneous bowel movements (SBMs)/week and a >= 1-SBM/week increase from baseline for >= 9 of 12 weeks and >= 3 of the last 4 weeks. Results: In total, 2328 patients were included in this analysis. The incidence of TEAEs was similar in the naldemedine and placebo groups (overall, 47.1% vs 45.6%; normal, 44.6% vs 43.6%; mild RI, 49.0% vs 44.7%; moderate RI, 46.6% vs 55.9%). GI-related TEAEs occurred more frequently in the naldemedine group versus placebo (overall, 21.8% vs 13.8%; normal, 21.6% vs 12.5%; mild RI, 22.6% vs 14.7%; moderate RI, 18.0% vs 14.2%). A significantly greater proportion of patients in the naldemedine 0.2 mg group were responders versus the placebo group (overall, 50.1% vs 34.1%, P<0.0001; normal, 52.0% vs 39.3%; mild RI, 48.3% vs 30.3%; moderate RI, 52.5% vs 31.7%). Conclusion: This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients with CNCP and mild or moderate RI. Safety and efficacy results were consistent with the overall population.

Opioid-induced constipation (OIC), the most common side effect of opioid treatment, is under-recognized and undertreated in older patients. Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), is approved in Japan, the United States, and the European Union for treatment of OIC in adult patients. This integrated analysis of three phase 3 trials (COMPOSE-1, COMPOSE-2, and COMPOSE-3) evaluated the safety and efficacy of naldemedine for up to 12 weeks in a subgroup of patients aged ≥ 65 years. Patients aged 18–80 years with chronic non-cancer pain for ≥ 3 months (treated with opioids for ≥ 3 months in COMPOSE-1 and COMPOSE-2) and OIC received oral naldemedine 0.2 mg or placebo once daily. Safety assessments included overall incidence of treatment-emergent adverse events (TEAEs), TEAEs in the gastrointestinal disorders System Organ Class, and TEAEs of opioid withdrawal or possible opioid withdrawal. Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2, defined as having ≥ 3 spontaneous bowel movements/week and a ≥ 1-spontaneous bowel movement/week increase from baseline for ≥ 9 of 12 weeks and ≥ 3 of the last 4 weeks. A total of 14.8% (344/2328) of patients were aged ≥ 65 years in all studies. The incidence of TEAEs in naldemedine-treated patients aged ≥ 65 years (45.9%) was comparable to that in patients aged ≥ 65 years receiving placebo (51.6%) and in the overall naldemedine group (47.1%). The incidence of gastrointestinal disorders System Organ Class TEAEs in naldemedine-treated patients aged ≥ 65 years (20.2%) was also comparable to that in patients aged ≥ 65 years receiving placebo (16.1%) and in the overall naldemedine group (21.8%). The incidence of TEAEs of opioid withdrawal with naldemedine was 1.1% in patients aged ≥ 65 years and 1.0% overall, and the incidence of TEAEs of possible opioid withdrawal was 1.1% in patients aged ≥ 65 years and 1.7% overall. The proportion of responders was higher in naldemedine-treated patients versus placebo, both overall (50.1% vs 34.1%; p < 0.0001) and in those aged ≥ 65 years (51.8% vs 37.6%). This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients aged ≥ 65 years with chronic non-cancer pain. Safety and efficacy results were consistent with the overall patient population. NCT01965158, NCT01993940, NCT01965652.

Opioid-induced constipation (OIC) is a common side effect of chronic opioid therapy. Previously, naldemedine, a peripherally acting μ-opioid receptor antagonist demonstrated efficacy in the treatment of OIC. In this exploratory analysis, the onset of action of naldemedine was evaluated in 2 identically designed phase 3, randomized, placebo-controlled trials. Proportion of patients experiencing a spontaneous bowel movement (SBM) within 24 hours of treatment initiation, time from initial dose to first SBM and weekly SBM frequency were assessed. Naldemedine was associated with significant increases in the proportion of patients experiencing an SBM at 4, 8, 12, and 24 hours after the initial dose compared with placebo (all P < 0.0001). Within 24 hours in both studies, statistically significantly (P < 0.0001) more patients treated with naldemedine compared with placebo experienced an SBM (61.2% vs 28.3% and 56.5% vs 33.6%, respectively). Median times to first SBM were significantly shorter in the naldemedine group vs placebo (COMPOSE-1, 16.1 vs 46.7 hours; COMPOSE-2, 18.3 vs 45.9 hours; P < 0.0001). Naldemedine was also associated with significant increases in weekly SBM frequency vs placebo within 1 week (P < 0.001). Most common treatment-emergent adverse events were gastrointestinal-related (abdominal pain, diarrhea, and nausea). Treatment-emergent adverse events were reported most frequently on day 1, followed by a decrease from days 2 to 7. Naldemedine had a timely onset of effect, and gastrointestinal adverse events largely resolved within the first week. These findings should assist clinicians counseling patients with chronic noncancer pain on expectations when initiating naldemedine for OIC.

Abstract Objective To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP). Design Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181). Setting Multicenter, long-term clinical research study. Methods NKTR-181 administered at doses of 100–600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF). Results The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events. Conclusions The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP.

Introduction: Opioid-induced constipation (OIC), a common side effect of opioid utilization in treating chronic non-cancer pain, is caused by the action of opioids on peripheral μ-opioid receptors in the enteric nervous system. Naldemedine (NAL), a peripherally acting μˆ-opioid receptor antagonist (PAMORA), demonstrated consistent efficacy and safety in the treatment of OIC from two phase 3, randomised, placebo-controlled, double-blind clinical trials [NCT01965158 (COMPOSE-1) and NCT01993940 (COMPOSE-2)]. In both studies there were significant improvements in the frequency of Spontaneous Bowel Movements (SBMs) and in the OIC symptoms of incomplete evacuation and straining. The effect of NAL in treating the symptoms of OIC in laxative inadequate responders (LIR) has not been reported. Methods: A post-hoc analysis from the pooled two phase 3, randomized, placebo-controlled, doubleblind clinical trials (COMPOSE-1; COMPOSE-2) was performed in the LIR and Non-LIR subgroup. LIR was defined as subjects who were on laxative therapy prior to entering the study and those who stopped its use within 30 days prior to screening, and who signed the informed consent which required the subject to have self-reported OIC (ie, incomplete bowel movement, hard stools, straining, or false alarms). Non-LIR was defined as those subjects who did not receive laxatives or only received rescue laxatives at or after screening. NAL effect on SBM frequency, complete SBMs (CSBM), and SBMs without straining was evaluated. Treatment-emergent adverse events (TEAEs) were defined as those that were reported after randomization and were assessed as well. Results: There was statistically significant increase in SBM frequency (Fig 1), CSBMs (Fig 2), and SBM without straining for both LIR and non-LIR groups as compared to placebo. TEAEs were comparable between the NAL and PBO in both LIR and non-LIR groups. The most common TEAEs were gastrointestinal-related.431_A Figure 1. Change in the Frequency of SBMs per Week from Baseline to Each Week by LIR/Non-LIR Subgroups: LS Mean ± SE431_B Figure 2. Change in the Frequency of CSBMs per Week from Baseline to Each Week by LIR/Non-LIR Subgroups: LS Mean ± SEConclusion: These data demonstrate that NAL improved the key symptoms of OIC: frequency, incomplete evacuation, and straining, in those subjects who have been previously treated with a laxative. These results suggest that NAL is a useful treatment option in the management of OIC in subjects with chronic non-cancer pain.

Background Opioid-induced constipation is a frequent side-effect of opioid treatment, and standard interventions have limited or inconsistent efficacy. This study assessed the efficacy and safety of naldemedine, a peripherally acting mu-opioid receptor antagonist, for the treatment of opioid-induced constipation in patients with chronic non-cancer pain.Methods We report two double-blind, randomised, placebo-controlled trials in adults with chronic non-cancer pain and opioid-induced constipation. The first (COMPOSE-1) was done in 68 outpatient sites in seven countries and the second (COMPOSE-2) at 69 outpatient sites in six countries; both studies were done in Europe and the USA. Eligible patients were aged 18-80 years, did not use laxatives, and had a stable opioid regimen for treatment of chronic non-cancer pain with a total daily dose averaging at least 30 mg (morphine equivalent) for at least 1 month before screening. Patients were randomly assigned (1: 1) to receive either oral naldemedine 0.2 mg or matching placebo once a day for 12 weeks. Randomisation was stratified by average total daily opioid dose (30-100 mg and >100 mg equivalents of oral morphine sulphate). The primary endpoint was proportion of responders. A responder had at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks. Efficacy endpoints were analysed by intention to treat and the safety population included all patients who received at least one dose of study drug. These trials have both been completed and are registered with ClinicalTrials.gov, numbers NCT01965158 and NCT01993940.Findings In COMPOSE-1, 547 patients were recruited between Aug 29, 2013, and Jan 22, 2015, and were randomly assigned to receive naldemedine (n=274) or placebo (n=273). Patients for COMPOSE-2 were recruited between Nov 4, 2013, and June 9, 2015; 553 patients were randomly assigned to receive naldemedine (n=277) or placebo (n=276). Five patients were enrolled at more than one site, so were excluded from the intention-to-treat population (COMPOSE-1: one per group; COMPOSE-2: one in the naldemedine group, two from the placebo group), with intention-to-treat group sizes of 273 in the naldemedine group and 272 in the placebo group in COMPOSE-1, and 276 in the naldemedine group and 274 in the placebo group in COMPOSE-2. The proportion of responders in both trials was significantly higher with naldemedine than with placebo in COMPOSE-1 (130 responders [47.6%] of 273 in the naldemedine group vs 94 responders [34.6%] of 272 in the placebo group, difference 13.0% [95% CI 4.8-21.3]; p=0.002) and in COMPOSE-2 (145 [52.5%] of 276 vs 92 [33.6%] of 274, difference 18.9% [10.8-27.0]; p<0.0001). Incidence of adverse events with naldemedine was similar to placebo (COMPOSE-1: 132 [49%] of 271 in the naldemedine group vs 123 [45%] of 272 in the placebo group; COMPOSE-2: 136 [50%] of 271 vs 132 [48%] of 274). Treatment-related adverse events were noted in 59 (22%) of 271 patients in the naldemedine group and 45 (17%) of 272 in the placebo group in COMOPOSE-1, and in 54 (20%) of 271 patients in the naldemedine group and 31 (11%) of 274 in the placebo group of COMPOSE-2; the between-group differences were largely due to gastrointestinal disorders, which were more common with naldemedine than placebo (COMPOSE-1: 40 [15%] patients in the naldemedine group vs 18 [7%] in the placebo group; COMPOSE-2: 42 [16%] vs 20 [7%]).Interpretation Naldemedine treatment led to a significantly higher responder rate than did placebo and was generally well tolerated. These results support that naldemedine could be a new option for the treatment of opioid-induced constipation in patients with chronic non-cancer pain.Funding Shionogi & Co, Ltd.

Introduction: Opioid-induced constipation (OIC) is a well-known side effect of opioid therapy. Naldemedine (NAL) is a peripherally-acting μ-opioid receptor antagonist approved for the treatment of OIC in patients with chronic non-cancer pain. Methods: Two randomized, double-blind placebo (PBO) controlled 12-week studies (NCT01965158 and NCT01993940), assessed the effect over time of NAL 0.2 mg once daily vs PBO in the frequency of spontaneous bowel movements (SBMs), complete SBMs (CSBMs, defined as SBMs with a perception of complete evacuation), SBMs without straining, and SBMs with a Bristol Stool Scale (BSS) Score of 3 or 4 in adult (age 18-80 years) subjects with chronic non-cancer pain and OIC. Subjects were required to not be on laxatives at screening or to agree to discontinue laxatives upon signing informed consent. The mean changes in the frequency per week from baseline to each week was compared between NAL and PBO, with a mixed-effects model repeated measures which opioid dose strata and study as a covariate and treatment group, time, time-by-treatment group interaction as fixed effects. Safety was assessed based on the incidence of adverse events (AEs). Results: In the two studies pooled, 1095 subjects were randomized 1:1 to NAL (N=549) or PBO (N=546) for 12 weeks. In all four endpoints, NAL was associated with a significantly (P≤0.0001) greater improvement from baseline at each week relative to PBO, starting at Week 1 and up to Week 12 (Figure). The overall incidence of AEs was generally similar between groups. Treatment with NAL was associated with a greater incidence of gastrointestinal AEs (abdominal pain, diarrhea, nausea) compared with PBO (Table).Figure: Change from Baseline* to Each Week (LS Mean ± SE) in Assessed Endpoints.Table: Table. Overall Summary of Treatment Emergent Adverse Events (Safety Population)Conclusion: Treatment with NAL over 12 weeks compared with placebo improved the frequency of bowel movements as well as the signs and symptoms of OIC frequently reported with bowel movements including perception of incomplete evacuation, need for straining, and hard stools,. NAL was generally well tolerated.

Introduction: Opioid-induced constipation (OIC) is a common side effect of opioid analgesics, caused by the agonistic effects of opioids on opioid receptors in the enteric nervous system which lead to decreased gastrointestinal motility and decreased intestinal fluid secretion. Naldemedine (NAL), a peripherally-acting μ-opioid receptor antagonist, is being developed for the treatment of OIC. In two randomized phase 3 trials, NAL has demonstrated a consistent efficacy and safety profile in patients with chronic non-cancer pain1. The aim of this analysis is to assess the onset of action of NAL in the two phase 3 trials. Methods: Two identically designed, phase 3, double-blind, randomized, placebo-controlled 12-week studies (COMPOSE 1 and 2) were conducted. In both studies, subjects 18 to 80 years old, with chronic non-cancer pain and OIC, taking opioids for ≥3 months and on a stable regimen for ≥1 month, not on laxatives, and meeting all other eligibility criteria were randomized (1:1) to NAL 0.2 mg taken orally QD or placebo. The objective of the current analyses was to compare the proportions of subjects with spontaneous bowel movement (SBM) and subjects with complete SBM (CSBM) within 4 hours and within 24 hours after the initial dose of study drug between the NAL and placebo groups. The safety and tolerability of NAL were also assessed (ClinicalTrials.gov identifier NCT01965158 and NCT01993940). Results: In COMPOSE 1 study, 547 subjects were randomized (NAL 274; placebo 273) and in COMPOSE 2 study, 553 subjects were randomized (NAL 277; placebo 276). In both studies, significantly greater proportions of subjects had SBM, both within 4 hours and within 24 hours after the first dose of study drug, in the NAL groups relative to the placebo groups (Table 1). Similar results were observed for proportions of subjects with CSBM after the first dose of study drug. Treatment emergent adverse events that occurred in ≥ 5% of subjects were diarrhea and abdominal pain.Table 1: Proportion of Subjects with Spontaneous Bowel Movement within a Specified Time Period after the First Dose of Study Drug - Intent-to-Treat PopulationConclusion: Treatment of OIC with naldemedine in subjects with chronic non-cancer pain led to a higher proportion of subjects having SBM or CSBM after the first dose relative to placebo, and was generally well tolerated.

Background & Aims: The recent description of the genetic features that characterize pancreatic cystic neoplasms has opened new opportunities to improve the diagnosis of pancreatic cysts by analyzing molecular markers in cyst fluid.We previously reported, in an analysis of 130 cyst fluid samples, that a panel of molecular markers could be used to accurately diagnose the four main pancreatic cystic neoplasms.The aim of this study was to evaluate the performance of this molecular marker panel on a large cohort of cystic lesions, including benign and rare cyst types, with the goal of improving the clinical classification and management of pancreatic cysts.Methods: In this international, multicenter study, cyst fluid samples from approximately 600 patients with surgically resected pancreatic cystic neoplasms will be assessed.In this abstract, we present the preliminary analysis on the first 323 samples.Cyst fluid was analyzed to identify low-abundance somatic mutations in genes known to be mutated in intraductal papillary mucinous neoplasms (IPMN), serous cystadenomas (SCA), mucinous cystic neoplasms (MCN), and solid-pseudopapillary neoplasms (SPN): BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL.These analyses were performed with highly accurate massively parallel sequencing-based technologies.Results: We analyzed 142 IPMN, 70 MCN, 35 SCA, and 5 SPN.We also evaluated 39 pancreatic ductal adenocarcinomas (PDACs) with cystic degeneration, and 32 with other cystic lesions, including cystic neuroendocrine neoplasms, pseudocysts, and other non-neoplastic pancreatic cysts.The results of the analysis are shown in Table 1.IPMNs were characterized by a high prevalence of KRAS, GNAS and RNF43 mutations, with 107 of 142 IPMNs (75%) having a mutation in either KRAS or GNAS.GNAS mutations were not found in any other cyst type, with the exception of six PDAC cases, suggesting that these carcinomas may have originated from IPMNs.VHL mutations were only found in SCA.No additional mutations were found in this cyst type.SPNs harbored CTNNB1 mutations, but no other mutations.Other non-neoplastic cyst types rarely harbored mutations in any

OBJECTIVE:A single-agent, extended-release formulation of hydrocodone (HC) has been developed for treatment of chronic moderate-to-severe pain. This study was designed to examine the safety and efficacy of HC extended release in opioid-experienced adults with moderate-to-severe chronic low back pain (CLBP).METHODS:This multicenter, enriched enrollment, randomized withdrawal study comprised an open-label conversion/titration phase (≤6 weeks) followed by placebo-controlled, double-blind treatment (12 weeks). During the conversion/titration phase, subjects (N = 510) converted from their current opioid and were titrated to a stabilized dose of HC extended release (20-100 mg every 12 hours). During treatment, subjects (N = 151 per group) received HC extended release or placebo; rescue medication was permitted. The primary efficacy end point was mean change in average pain intensity from baseline to day 85. Response rates (30% pain improvement) and satisfaction (Subject Global Assessment of Medication) were assessed.RESULTS:Demographic and baseline characteristics were similar between groups. Mean ± SD change in average pain intensity score from baseline to day 85 was significantly lower in the HC extended-release treatment group vs placebo (0.48 ± 1.56 vs 0.96 ± 1.55; P = 0.008). Significantly more responders were in the treatment group (68% vs 31%; P < 0.001). Mean Subject Global Assessment of Medication scores increased significantly (0.8 ± 1.3 vs 0.0 ± 1.4; P < 0.0001), indicating greater satisfaction with HC extended release. The adverse event profile was consistent with other opioids.CONCLUSIONS:Extended-release HC is well tolerated and effective, without acetaminophen-associated risks of liver toxicity, for treatment of CLBP.

BACKGROUND:Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain. METHODS:Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study. RESULTS:A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients. CONCLUSION:Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.

OBJECTIVE To compare the efficacy and safety of controlled-release oxycodone given every 12 hours with immediate-release oxycodone given four times daily in patients with persistent back pain. DESIGN Randomized, double-blind, active-controlled, two-period crossover trial. PATIENTS Fifty-seven adult outpatients with stable, chronic, moderate-to-severe low back pain despite analgesic therapy were enrolled; 47 were randomized; 11 discontinued for side effects, most commonly nausea and vomiting. INTERVENTIONS Controlled-release oxycodone tablets given every 12 hours; immediate-release oxycodone tablets given four times daily; dose titration with controlled-release or immediate-release for up to 10 days; double-blind treatment for 4-7 days each. OUTCOME MEASURES Patients' pain scores (0 = none, 1 = slight, 2 = moderate, 3 = severe). RESULTS Pain intensity decreased from moderate to severe at baseline to slight at the end of titration with both oxycodone formulations. The daily oxycodone dose was 40 mg or less in 68% of patients. During double-blind treatment, mean pain intensity was maintained at 1.2 (0.1 SE) with controlled-release and at 1.1 (0.1 SE) with immediate-release oxycodone. The most common adverse events were constipation, nausea, pruritus, somnolence, and dizziness. CONCLUSIONS Controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety, and it provides convenient, twice-daily, around-the-clock treatment for selected patients with persistent back pain that is inadequately controlled by nonopioids or as-needed opioid therapy.