Tapentadol extended release for the management of chronic neck pain

BACKGROUND: The role of opioids in the management of chronic neck pain is still poorly investigated. No data are available on tapentadol extended release (ER). In this article, we present 54 patients with moderate-to-severe chronic neck pain treated with tapentadol ER. PATIENTS AND METHODS: Patients received tapentadol ER 100 mg/day; dosage was then adjusted according to clinical needs. The following parameters were recorded: pain; Douleur Neuropathique 4 score; Neck Disability Index score; range of motion; pain-associated sleep interference; quality of life (Short Form [36] Health Survey); Patient Global Impression of Change (PGIC); Clinician GIC; opioid-related adverse effects; and need for other analgesics. RESULTS: A total of 44 of 54 patients completed the 12-week observation. Tapentadol ER daily doses increased from 100 mg/day to a mean (standard deviation) dosage of 204.5 (102.8) mg/day at the final evaluation. Mean pain intensity at movement significantly decreased from baseline (8.1 [1.1]) to all time points (P<0.01). At baseline, 70% of patients presented a positive neuropathic component. This percentage dropped to 23% after 12 weeks. Tapentadol improved Neck Disability Index scores from 55.6 (18.6) at baseline to 19.7 (20.9) at the final evaluation (P<0.01). Tapentadol significantly improved neck range of motion in all three planes of motion, particularly in lateral flexion. Quality of life significantly improved in all Short Form (36) Health Survey subscales (P<0.01) and in both physical and mental status (P<0.01). Based on PGIC results, approximately 90% of patients rated their overall condition as much/very much improved. Tapentadol was well tolerated: no patients discontinued due to side effects. The use of other analgesics was reduced during the observed period. CONCLUSION: Our results suggest that tapentadol ER, started at 100 mg/day, is effective and well tolerated in patients with moderate-to-severe chronic neck pain, including opioid-naïve subjects. Patients can expect a decrease in pain, an improvement in neck function, and a decrease in neuropathic symptoms

A look inside the association codeine-paracetamol: clinical pharmacology supports analgesic efficacy

Acute and chronic pain often requires a multimodal approach. Combination therapy reduces the number of individual daily administrations and improves patient's compliance with the prescribed analgesic treatment. Despite the association codeine/paracetamol is one of the most widely used central analgesic, the exact mechanism of action, particularly of paracetamol, is still object of pharmacological research. Recent findings showed that paracetamol may act through cerebral cyclo-oxygenase, descending opioidergic inhibitory pathways, serotonin pathway, and the endocannabinoid system; while codeine activity seems to related not only to its conversion to morphine, as previously known, but also by itself and through its metabolites, such as norcodeine (NORC) and codeine-6-glucuronide (C-6-G). The addition of codeine to paracetamol significantly improves the analgesic action and reduces the number needed to treat (NNT) from 5 to 2.3-3.1. Recent warnings about the risk of its metabolism related to CYP450 and its genetic variability in general population should be mainly considered when the association is used in paediatric patients undergoing tonsillectomy and/or adenoidectomy procedures for obstructive sleep apnoea syndrome (OSAS). In adults, the association codeine/paracetamol has been shown to be effective and safe in different settings: acute pain, trauma patients, and chronic nociceptive pain

Order Dynamics in the Italian Treasury Security Wholesale Secondary Market

MTS markets are an example of quote driven electronic order book markets for Government securities. Proposals are firm, immediately executable and aggregated in a limit order book. In this paper we analyse the evolution of the interaction between the order book and order flow by exploring the determinants of the flows of limit and market orders over three years. We are able to test several hypotheses coming from theoretical models. This is, to our knowledge, one of the first empirical test of these hypotheses based on Government bond data. We find that market and limit orders show positive autocorrelation and clustering as in Biais et al. (1995). No activity is clustered as well. This diagonal effect could also explain the positive impact of book depth near the quote on the flows of new limit orders. On the contrary, depth beyond the second best price seems to play no role in book dynamics. Furthermore, increasing competition, measured as an increase in the number of operators, has a negative effect on orders. In addition, we find mild support to the theoretical prediction of a positive effect of book depth on order aggressiveness. Best spread, instead, behaves consistently with theoretical models: a larger best spread encourages new limit orders inside-thequote.limit order, market order, order flow, liquidity, Government bonds

A pedagogical introduction to the replica method for fragile glasses

In this note I present a simplified version of the recent computation (Mezard and Parisi 1998, 1999) of the properties of glasses in the low temperature phase in the framework of the replica theory, using an extension of the tools used in liquid theory. I will only consider here the case of the internal energy at T=0, which can be studied in a simple way without introducing replicas.Comment: 7 pages, 1 figure Talk given at Andalo, March 1999; minor errors have been correcte

Theoretical models and numerical methods for the study of sub-cellular phenomena

Nella presente tesi si discute sia la transizione di denaturazione del DNA che la dinamica enzimatica di Michaelis-Menten, introducendo entrambi gli argomenti partendo dalla loro importanza dal punto di vista di una migliore comprensione dei fenomeni intra-cellulari. Vengono quindi presentati i risultati originali ottenuti. Si è effettuata un'analisi approfondita di dati numerici su un modello disordinato di Poland-Scheraga per la transizione di denaturazione del DNA in cui l'effetto di auto-evitamento è tenuto correttamente in considerazione, nella quale: i) sono state introdotte delle appropriate pseudo-temperature critiche dipendenti dalla sequenza, il che ha permesso intanto di ottenere una stima rifinita dell'esponente che caratterizza il comportamento al punto critico disordinato, in accordo con una transizione di fase di ordine maggiore del secondo; ii) sulla base di questa analisi si è inoltre potuto caratterizzare il lento approccio all'equilibrio termodinamico osservato introducendo un'appropriata lunghezza di crossover, definita come la lunghezza delle sequenze al di sopra della quale l'effetto del disordine diviene evidente (sia dal comportamento delle varie osservabili mediate sulle sequenze, sia da quello in particolare del parametro d'ordine e della suscettività in circa la metà delle singole sequenze); iii) infine, si è descritto in dettaglio uno scenario fenomenologico nell'ambito del quale la lunghezza di crossover viene messa in relazione con i parametri del modello, e quindi, attraverso il calcolo combinatoriale della probabilità di ottenere una regione rara di lunghezza L in una sequenza di lunghezza N, si possono ottenere delle predizioni sul comportamento di taglia finita per diversi valori dei parametri. Nel caso della dinamica enzimatica di Michaelis Menten, si è portato a termine un dettagliato studio analitico, partendo dall'approssimazione standard di stato quasi-stazionario, che chiarisce le similitudini e le differenze tra l'approccio alternativo che si è introdotto, basato su tecniche di gruppo di rinormalizzazione, ed il metodo perturbativo che si è soliti applicare a sistemi ad effetto strato come quello considerato: i) in particolare, si è arrivati al secondo ordine nello sviluppo nel parametro appropriato, ottenendo corrispondentemente per la prima volta le soluzioni interne a quest'ordine, che non erano note in letteratura; ii) sulla base dell'analisi del comportamento delle approssimazioni uniformi così ottenute, alcune delle cui caratteristiche appaiono iterabili, si è potuto predire anche una parte del contributo a quest'ordine delle soluzioni esterne, quindi delle approssimazioni uniformi che riproducono il comportamento numerico delle soluzioni meglio di quelle note in una larga parte della finestra di tempo in cui svolge il fenomeno, anche in un caso studiato particolarmente sfavorevole sia dal punto di vista dei valori delle costanti cinetiche che di quello del parametro di espansione, tendendo inoltre correttamente a zero asintoticamente; iii) il metodo introdotto risulta quindi efficace, e le verifiche che sono state fatte dovrebbero permettere la sua futura applicazione intanto alla dinamica enzimatica di Michaelis Menten nell'ambito dell'approssimazione totale di stato quasi-stazionario

Measuring and Analyzing the Liquidity of the Italian Treasury Security Wholesale Secondary Market

Although its importance, only recently the issue of liquidity in Treasury markets has received greater attention. We survey the literature about market liquidity and liquidity measures, and we put forward new measures. The aim is to provide a description of the liquidity of the Italian wholesale secondary market, which we describe thoroughly. We apply a large set of measures on a unique dataset, which gives us a complete view of the market. Even though the market provides an amount of liquidity that fits the market needs, the quality of the order book is low, and despite the presence of a large number of market makers, the degree of competition among them is not very high. Moreover, no clear and general relationship emerges between trading and order book measures. Indeed, even though trading activity is higher for on-the-run securities with respect to the off-the-run securities, there is not a sharp difference in terms of liquidity of the order book between them. In this case market regulation plays an important role. Finally, we investigate how long it takes for a new issue to become the benchmark for its segment. Our evidence shows that some modifications of the issuance policy in order to have a larger outstanding since the first auction could help securities in gaining earlier their benchmark status, especially in case of 10-year BTPs.Liquidity, liquidity measures, Government securities, market microstructure, benchmark status.

From acute to chronic pain: tapentadol in the progressive stages of this disease entity

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain

Numerical study of DNA denaturation with self-avoidance: pseudo-critical temperatures and finite size behaviour

We perform an extensive numerical study of the disordered Poland-Scheraga (PS) model for DNA denaturation in which self-avoidance is completely taken into account. In complement to our previous work, we focus here on the finite size scaling in terms of pseudo-critical temperatures. We find notably that the mean value and the fluctuations of the pseudo-$T_c$ scale with the same exponent, the correlation length exponent $\nu_r$ (for which we provide the refined evaluation $\nu_r=2.9 \pm 0.4$). This result (coherent with the typical picture that describes random ferromagnets, when disorder is relevant) is at variance with numerical results reported in the literature for the PS model with self-avoidance, leading to an alternative scenario with a pseudo first order transition. We moreover introduce a crossover chain length $N^*$, which we evaluate, appropriate for characterizing the approach to the asymptotic regime in this model. Essentially, below $N^*$, the behaviour of the model in our study could also agree with such alternative scenario. Based on an approximate prediction of the dependence of $N^*$ on the parameters of the model, we show that following the choice of such parameters it could be not possible to reach the asymptotic regime in practice. In such context it becomes then possible to reconcile the apparently contradictory numerical studies.Comment: 31 pages with 20 ps figures. Revised version with major improvements in the presentation of the results and some references added. This is the manuscript version that has been accepted for publicatio

The unsolved case of “bone-impairing analgesics”. The endocrine effects of opioids on bone metabolism

The current literature describes the possible risks for bone fracture in chronic analgesics users. There are three main hypotheses that could explain the increased risk of fracture associated with central analgesics, such as opioids: 1) the increased risk of falls caused by central nervous system effects, including sedation and dizziness; 2) reduced bone mass density caused by the direct opioid effect on osteoblasts; and 3) chronic opioid-induced hypogonadism. The impact of opioids varies by sex and among the type of opioid used (less, for example, for tapentadol and buprenorphine). Opioid-associated androgen deficiency is correlated with an increased risk of osteoporosis; thus, despite that standards have not been established for monitoring and treating opioid-induced hypogonadism or hypoadrenalism, all patients chronically taking opioids (particularly at doses ≥100 mg morphine daily) should be monitored for the early detection of hormonal impairment and low bone mass density

Financing obstacles and growth: an analysis for euro area non-financial corporations

This paper investigates whether financial obstacles, and, more generally, financial pressure faced by firms, significantly affect firm growth. For this purpose, we use an unbalanced panel of about 1,000,000 observations for around 155,000 non-financial corporations in five euro area countries. In addition to the balance sheet information in this panel, we also rely on firm-level survey data. In this way we are able to work out a direct measure of the firms’ probability of facing financing obstacles. Our results indicate that, though based on few variables, this measure appears to be relevant in explaining firm growth in four out of the five countries considered. Other firm-level variables related to the financial pressure faced by firms, such as cash flow (debt burden) are found to exert a positive (negative) impact on firm growth, while the results for leverage are less clear-cut. JEL Classification: C23, E22, G32, L11, L25Financing Constraints, Firm Growth, panel data