Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain

Lynn R Webster1, John F Peppin2, Frederick T Murphy3,4, Jeffrey K Tobias5, Geertrui F Vanhove51Lifetree Clinical Research and Pain Clinic, Lifetree Medical Inc, Salt Lake City, UT, USA; 2Clinical Research Division, The Pain Treatment Center of the Bluegrass, Lexington, KY, USA; 3Altoona Center for Clinical Research, Duncansville, PA, USA; 4University of Pennsylvania, School of Medicine, Philadelphia, PA, USA; 5NeurogesX Inc, San Mateo, CA, USABackground: The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain.Methods: This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4® [Ferndale Laboratories Inc, Ferndale, MI], Topicaine® Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL]) for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included “pain now” Numeric Pain Rating Scale (NPRS) scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs), clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for “average pain for the past 24 hours” from baseline to weeks 2 through 12.Results: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate, and could be adequately managed by local cooling or short-acting oral opioid analgesics. Although slightly more patients used medication for treatment-related discomfort following pretreatment with Topicaine compared with L.M.X.4 or Betacaine, there were no statistical differences between the topical anesthetics. Neuropathic pain reduction from baseline to weeks 2 through 12 was approximately 30% and was similar among the topical anesthetics; the proportion of responders ranged from 45% to 50%.Conclusion: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated; no significant differences in the parameters measured were noted between the pretreatment groups.Keywords: neuropathic pain, capsaicin patch, tolerability, topical anesthetic

Peripherally acting mu-opioid antagonist for the treatment of opioid-induced constipation: Systematic review and meta-analysis

Background and Aim Opioid-induced constipation (OIC) is a frequent adverse event (AE) that impairs patients' quality of life (QOL). Peripherally acting mu-opioid receptor antagonists (PAMORAs) have been recognized as a treatment option for OIC, but the effect consistent across the studies has not been evaluated. Methods We conducted a quantitative meta-analysis to explore the efficacy of PAMORA for OIC (registered with PROSPERO: CRD42018085298). We systematically searched randomized controlled trials (RCTs) in Medline, Embase, and Central databases. Change from baseline in spontaneous bowel movements, pooled proportion of responders, QOL, and AEs were calculated and compared with results in placebo cases. Results We included 31 RCTs with 7849 patients. A meta-analysis revealed that patients under PAMORA therapy had considerably improved spontaneous bowel movement from baseline compared with those given placebo (20 RCTs; mean difference, 1.43; 95% confidence interval [CI], 1.18-1.68; n = 5622) and more responded (21 RCTs; risk ratio [RR], 1.81; 95% CI, 1.55-2.12; n = 4821). Moreover, QOL of patients receiving PAMORA was significantly better (8 RCTs; mean difference, -0.22; 95% CI, -0.28 to -0.17; n = 2884). AEs were increased significantly in the PAMORA group (26 RCTs; RR, 1.10; 95% CI, 1.06-1.15; n = 7715), especially in gastrointestinal disorders, whereas serious AEs were not significant (17 RCTs; RR, 1.04; 95% CI, 0.85-1.28; n = 5890). Conclusion Peripherally acting mu-opioid receptor antagonist has been shown to be effective and durable for patients with OIC and is the only drug with confirmed evidence in meta-analysis. The possibility of publication bias was the limitation of this study.ArticleJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY.34(5):818-829(2019)journal articl

Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide

<p>Abstract</p> <p>Background</p> <p>Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO₂), a measure of respiratory-depression, were evaluated and these data are reported here.</p> <p>Methods</p> <p>Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO₂was measured by noninvasive capnography.</p> <p>Results</p> <p>Significant differences in EtCO₂least-squares means across all treatments for maximal effect (E_max) and area under the effect curve (AUE_0-2, AUE_0-8, AUE_0-24) were detected (all p ≤ 0.0011). EtCO₂E_maxvalues for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TE_max) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h).</p> <p>Conclusions</p> <p>Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO₂when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.</p

Discerning suicide in drug intoxication deaths: Paucity and primacy of suicide notes and psychiatric history

Objective A paucity of corroborative psychological and psychiatric evidence may be inhibiting detection of drug intoxication suicides in the United States. We evaluated the relative importance of suicide notes and psychiatric history in the classification of suicide by drug intoxication versus firearm (gunshot wound) plus hanging/suffocation—the other two major, but overtly violent methods. Methods This observational multilevel (individual/county), multivariable study employed a generalized linear mixed model (GLMM) to analyze pooled suicides and undetermined intent deaths, as possible suicides, among the population aged 15 years and older in the 17 states participating in the National Violent Death Reporting System throughout 2011–2013. The outcome measure was relative odds of suicide versus undetermined classification, adjusted for demographics, precipitating circumstances, and investigation characteristics. Results A suicide note, prior suicide attempt, or affective disorder was documented in less than one-third of suicides and one-quarter of undetermined deaths. The prevalence gaps were larger among drug intoxication cases than gunshot/hanging cases. The latter were more likely than intoxication cases to be classified as suicide versus undetermined manner of death (adjusted odds ratio [OR], 41.14; 95% CI, 34.43–49.15), as were cases documenting a suicide note (OR, 33.90; 95% CI, 26.11–44.05), prior suicide attempt (OR, 2.42; 95% CI, 2.11–2.77), or depression (OR, 1.61; 95% CI, 1.38 to 1.88), or bipolar disorder (OR, 1.41; 95% CI, 1.10–1.81). Stratification by mechanism/cause intensified the association between a note and suicide classification for intoxication cases (OR, 45.43; 95% CI, 31.06–66.58). Prior suicide attempt (OR, 2.64; 95% CI, 2.19–3.18) and depression (OR, 1.48; 95% CI, 1.17–1.87) were associated with suicide classification in intoxication but not gunshot/hanging cases. Conclusions Without psychological/psychiatric evidence contributing to manner of death classification, suicide by drug intoxication in the US is likely profoundly under-reported. Findings harbor adverse implications for surveillance, etiologic understanding, and prevention of suicides and drug deaths

Effect of duration of postherpetic neuralgia on efficacy analyses in a multicenter, randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia

<p>Abstract</p> <p>Background</p> <p>Postherpetic neuralgia (PHN) is a painful and difficult to treat complication of acute herpes zoster. Current treatment options provide only partial relief and are often limited by poor tolerability. We evaluated the safety and efficacy of a single 60-minute application of NGX-4010, an 8% capsaicin patch, in patients with PHN.</p> <p>Methods</p> <p>This multicenter, double-blind, controlled study randomized 155 patients 2:1 to receive either NGX-4010 or a 0.04% capsaicin control patch. Patients were at least 18 years old with PHN for at least 3 months, and an average Numeric Pain Rating Scale (NPRS) score of 3 to 9. The primary efficacy endpoint was the percentage change in NPRS score from baseline to weeks 2-8.</p> <p>Results</p> <p>The mean percent reduction in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 was greater in the NGX-4010 group (36.5%) compared with control (29.9%) although the difference was not significant (p = 0.296). PGIC analysis demonstrated that more NGX-4010 recipients considered themselves improved (much, or very much) compared with control at weeks 8 and 12, but the differences did not reach statistical significance. Post hoc analyses of patients with PHN for at least 6 months showed significantly greater reductions in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 in NGX-4010 patients compared to controls (37.6% versus 23.4%; p = 0.0291). PGIC analysis in this subgroup demonstrated that significantly more NGX-4010 recipients considered themselves much or very much improved compared with control at week 12 (40% versus 20%; p = 0.0403;).</p> <p>Conclusions</p> <p>Although treatment appeared to be safe and well tolerated, a single 60-minute application of NGX-4010 failed to show efficacy in this study which included patients with PHN for less than 6 months. Large reductions in pain observed among control patients with pain for less than 6 months may have been due to spontaneous resolution of PHN, may have confounded the results of the prespecified analyses, and should be taken into account when designing PHN studies.</p> <p>Trial Registration</p> <p>NCT00068081</p

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model