Dialyzability of Oxycodone and Its Metabolites in Chronic Noncancer Pain Patients with End-Stage Renal Disease.

OBJECTIVES: Opioids are the preferred analgesic drugs to treat severe chronic pain conditions among dialysis patients; however, knowledge about their dialyzability features is limited. Oxycodone is increasingly used for the treatment of chronic pain conditions as oral controlled release (CR) tablets; however, evidence about this drug and its metabolites' dialyzability is lacking. METHODS: We assessed, during 4-hour dialysis sessions, the effect of standard hemodialysis (HD) and online hemodiafiltration (HDF) methods on the plasma concentration of oxycodone and its metabolites in n = 20 chronic pain patients with end-stage renal disease who were stably treated with oral CR oxycodone. Chromatographic techniques were used to evaluate the studied compounds' plasma concentrations at three different time points during dialysis. RESULTS: Mean plasma concentrations of oxycodone and noroxycodone in the sample showed an overall reduction trend over time, but it was less enhanced for noroxycodone. Mean reduction in oxycodone and noroxycodone arterial concentrations was significant and higher with HDF (54% and 27%, respectively) than with HD (22% and 17%, respectively). Analysis of the regression of these compounds' clearance on their increasing arterial concentration showed a more stable and linear clearance prediction with HDF (roughly 85 mL/min); with HD, for increasing arterial concentration, clearance of oxycodone decreased while noroxycodone clearance increased. DISCUSSION: While no oxymorphone or noroxymorphone metabolites were detected, limited dialyzability of oxycodone and noroxycodone was documented along with insignificant postdialysis pain increment. This evidence will contribute toward considerations as to the safety of the use of oxycodone in dialysis patients in the future.

Medical Evidence Influence on Inpatients and Nurses Pain Ratings Agreement.

Biased pain evaluation due to automated heuristics driven by symptom uncertainty may undermine pain treatment; medical evidence moderators are thought to play a role in such circumstances. We explored, in this cross-sectional survey, the effect of such moderators (e.g., nurse awareness of patients' pain experience and treatment) on the agreement between n = 862 inpatients' self-reported pain and n = 115 nurses' pain ratings using a numerical rating scale. We assessed the mean of absolute difference, agreement (κ-statistics), and correlation (Spearman rank) of inpatients and nurses' pain ratings and analyzed congruence categories' (CCs: underestimation, congruence, and overestimation) proportions and dependence upon pain categories for each medical evidence moderator (χ (2) analysis). Pain ratings agreement and correlation were limited; the CCs proportions were further modulated by the studied moderators. Medical evidence promoted in nurses overestimation of low and underestimation of high inpatients' self-reported pain. Knowledge of the negative influence of automated heuristics driven by symptoms uncertainty and medical-evidence moderators on pain evaluation may render pain assessment more accurate.

Development, validation and psychometric properties of a diagnostic/prognostic tool for breakthrough pain in mixed chronic-pain patients.

BACKGROUND/OBJECTIVE: Breakthrough pain (BTP) shows variable prevalence in different clinical contexts of cancer and non-cancer patients. BTP diagnostic tools with demonstrated reliability, validation and prognostic capability are lacking. We report the development, psychometric and validation properties of a diagnostic/prognostic tool, the IQ-BTP, for BTP recognition, its likelihood and clinical features among chronic-pain (CP) patients. PATIENTS: n=120 consecutive mixed cancer/non-cancer CP in/outpatients. Development, psychometric analyses and formal validation included: Face/Content validity (by 'experts' opinion and assessing the relationship between the IQ-BTP classes and criteria derived from BTP operational-case-definition); Construct validity, by Principle Component Analysis (PCA); and the strength of Spearman correlation between IQ-BTP classes and the Brief Pain Inventory (BPI) items; Reliability, by Cronbach's alpha statistics. Associations with clinical/demographic moderators were assessed applying χ(2) analysis. RESULTS: Potential-BTP was found in 36.7% of patients (38.4% of non-cancer and 32.4% of cancer patients). Among these the likelihood for BTP diagnosis was 'high' in 25%, 'intermediate' in 41% and, 'low' 34% of patients. Analyses showed significant differences between IQ-BTP classes and between the latter BPI pain-item scores. Correlation between IQ-BTP classes and BPI items was moderate. PCA and scree test identified 3 components accounting for 62.3% of the variance. Cronbach's alpha was 0.71. CONCLUSIONS: The IQ-BTP showed satisfactory psychometric and validation properties. With adequate feasibility it enabled the allocating of cancer/non-cancer CP patients in three prognostic classes. Results are sufficient to warrant a subsequent impact study of the IQ-BTP as prognostic model and screening tool for BTP in both CP populations.

Lasting Prolonged-Release Tapentadol for Moderate/Severe Non-Cancer Musculoskeletal Chronic Pain.

INTRODUCTION: Despite opioids' recognized role in the treatment of moderate/severe musculoskeletal chronic pain, their long-term benefits need investigation. We explored the lasting analgesic efficacy, tolerability, influence on life quality, and chronicity stage of the novel prolonged release (PR) opioid, tapentadol, in 30 outpatients. METHODS: We evaluated patients' pain intensity and relief (Numerical Rating Scale; NRS), adverse effects, sleep quality, treatment satisfaction, health status (12-questions Health-Survey; SF-12), chronicity stage (Italian Mainz Pain-Staging System; I-MPSS) at 10, 30, 60, and 90 days after tapentadol prescription. RESULTS: At follow-ups, the investigated outcomes showed an overall statistically significant (Wilcoxon signed-rank test) improvement and remained stable over time, as did the health status and chronicity stage. Adverse effects were limited, transitory, and tolerable. CONCLUSIONS: Twelve weeks of PR tapentadol in outpatients with moderate/severe chronic musculoskeletal pain showed satisfactory analgesic efficacy and tolerability, and had a positive influence on life quality and chronicity stage. The results are robust enough to warrant a subsequent study with a larger sample and a longer observation period.

Pre-Operative, High-IL-6 Blood Level is a Risk Factor of Post-Operative Delirium Onset in Old Patients.

BACKGROUND: Post-operative delirium (POD) is a common complication in elderly patients undergoing surgery, but the underpinning causes are not clear. We hypothesized that inflammaging, the subclinical low and chronic grade inflammation characteristic of old people, can contribute to POD onset. Accordingly, we investigated the association of pre-operative and circulating cytokines in elderly patients (>65 years), admitted for elective and emergency surgery. METHODS: This is a secondary analysis of a sub-cohort of patients belonging to a previous large case-control study, where 351 patients were clinically and cognitively thoroughly characterized, together with the assessment of POD (47 patients) by confusion assessment method and delirium rating scale. Seventy-four pre-operative plasma samples were selected from a larger bio-bank and they included 37 subjects with POD and 37 without POD. Inflammaging related cytokines, i.e., IL-1ß, IL-2, IL-6, IL-8, IL-10, and TNF-α, were assayed by ELISA in pre-operative blood samples; univariate and multivariable analyses have been applied to identify cytokines independently associated to POD. Associations of cytokine levels with functional status, cognitive decline, intra-hospital mortality, and comorbidity were also analyzed independently of POD onset. RESULTS: High IL-6 and low-IL-2 levels were significantly associated with POD. After adjustment for potential confounders in multivariate analysis, high level of pre-operative IL-6 was confirmed to be significantly associated with risk of POD onset. High level of IL-6 was also associated with several baseline features (including poor functional status, cognitive impairment, emergency admission, and higher comorbidity burden) and intra-hospital mortality. CONCLUSION: Pre-operative, high-plasma level of IL-6 (≥9 pg/mL) was significantly associated with POD onset. We propose IL-6 as an additional risk factor of POD onset together with the previously identified factors. Discovery of all risk factors contributing to POD onset will permit to improve hospitalized patient management and the decrease of healthcare cost.

Psychometric properties and validation of the Italian version of the Mainz pain staging system as a tool for pain-patients referral selection.

RATIONALE, AIMS AND OBJECTIVES: Indications are lacking on which patient to refer to pain facilities. Pain-chronicity stage and outcome prognosis may be used for such aims. The Mainz pain-staging system (MPSS) classifies pain patients in three chronicity stages that respectively require more extensive management. We explored the psychometric and validation properties of its Italian version towards its application as screening/referral tool. METHODS: I-MPSS was administered to n=120 mixed non-cancer-pain outpatients. Psychometric analyses and formal validation included: content validity, by assessing the hypothesis of an existing relationship between the I-MPSS classes and criteria derived from an operational case definition of chronic pain; construct validity, by principle component analysis (PCA); the autonomous construct of the I-MPSS was assessed by the strength of the Spearman correlation between its classes and the brief pain inventory (BPI) items; and reliability, by applying Cronbach's alpha statistics. Associations between psychosocial moderators and the I-MPSS were assessed applying χ(2) analyses. RESULTS: Quantitative and qualitative analyses showed significant differences between I-MPSS classes for health care and drug utilization; BPI item scores significantly differed between the classes; Spearman correlation between I-MPSS classes and BPI items was mostly moderate or mild. PCA and scree test identified four components accounting for 63.7% of the variance. Cronbach's alpha was 0.842. CONCLUSIONS: The I-MPSS showed satisfactory psychometric and validation properties. With adequate feasibility, it enabled the screening of mixed non-cancer-pain outpatients in three chronicity/prognostic stages. Results are sufficient to warrant its use for a subsequent impact study as a prognostic model and screening tool for referring pain patients.

Opioid titration with sustained-release oxycodone and immediate-release morphine for moderate/severe cancer pain: a pilot assessment of the CoDem protocol.

OBJECTIVES: Opioid titration is the first challenging stage for rapid control of moderate/severe cancer pain. Evidence shows that sustained-release formulations may be used for opioid titration. We set a pilot assessment of the efficacy and tolerability of our in-house protocol (continuous and on demand opioids [CoDem]) of the association of sustained-release oxycodone and immediate-release morphine as rescue dose for opioid titration/rotation in opioid-naïve (NAOP, n = 13), tolerant to weak (WOP, n = 20), or strong opioids (STOP, n = 44) in-patients with moderate/severe cancer pain. METHODS: Observational and retrospective analysis of cancer in-patients treated for ≥7 days with the CoDem protocol. OUTCOME MEASURES: Pain intensity (patients self-reported pain with numerical rating scale [NRS] under static [NRSs] and dynamic [NRSd] conditions), amount of drug consumption, opioid adverse effects, and patient satisfaction. EFFICACY ENDPOINTS: In more than 50 percent of the patients and in <72 hours, steady NRSs and NRSd score reduction of at least two points, NRSs ≤ 3 and NRSd ≤4; and mean daily morphine consumption < mean of one rescue dose and t1:t6 ratio of mean oxycodone daily dose < 1:2. RESULTS: Endpoints were reached within 24 hours both within the sample and subgroups. Only NAOP patients reached NRSd ≤ 4 endpoint within 48 hours. Against moderate and transient adverse effects, most patients (84.4 percent) found pain treatment to be good or excellent. CONCLUSIONS: The CoDem protocol was shown to be effective and reasonably tolerated for titration for moderate/severe cancer pain relief in both opioid-naïve or opioid-tolerant cancer in-patients. This pilot assessment warrants prospective and comparative studies with larger samples for more generalized results.

Peri-operative risk management in patients with Alzheimer's disease.

The aim of this review is to identify an evidence-based perioperative management for patients affected by Alzheimer's disease (AD) that are scheduled to undergo surgery. This will minimize the negative effects of anesthesia and postoperative sedation and correct those perioperative variables possibly responsible for a decline in cognitive status and a worsening of AD. We here gather evidence on the importance of correct preoperative assessment regarding cognitive and functional status and the presence of preoperative delirium. The potential role of anesthesia, surgery, and postoperative analgosedation as risk factors for development of delirium are herein outlined. Finally, pain assessment instruments, as well as principles of management strategies for postoperative delirium in subjects with AD, are suggested.

Postoperative cognitive dysfunction: toward the Alzheimer's disease pathomechanism hypothesis.

Alzheimer's disease (AD), a chronic and progressive deterioration of memory and other cognitive domains, is the most common form of dementia. Because of related health and social impact, there is growing interest in assessing potential relationship between anesthesia and the onset and progression of chronic neurodegenerative disorders, including AD. Currently, preclinical and clinical research is addressed to identify underlying pathomechanisms, patient risk factors, and the use of the least provocative drugs and techniques, to minimize the incidence of chronic neurodegenerative disorders. Preclinical studies are providing an increasing body of evidences on some of the mechanisms that link anesthetics to neuronal programmed cell death (apoptosis) and accumulation of misfolded proteins in the aging brain. Therefore, risk factors and pathomechanisms of chronic neurodegenerative disorders, including AD, and persistent postoperative-postanesthesia cognitive dysfunction may overlap.

Cholinergic central system, Alzheimer's disease, and anesthetics liaison: a vicious circle?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation and aggregation of amyloid-ß peptide and loss of forebrain cholinergic neurons, resulting in progressive loss of memory and irreversible impairment of higher cognitive functions. Several studies have accounted for the close relationship between AD and the central cholinergic system, suggesting that a dysfunction of acetylcholine containing neurons in the brain contributes significantly to the cognitive deficit of individuals with AD. The aim of the present review is to survey current literature on this topic in order to provide a clear understanding of the role of the cholinergic system in the development and neurodegenerative process of AD. The implications for anesthesia are also discussed. This knowledge could be valuable to improve anesthesia performance and patient safety.

Categories of congruence between inpatient self-reported pain and nurses evaluation.

OBJECTIVE: To enhance the awareness that biased pain estimation may undermine its treatment, we sought to determine the congruence categories (CCs) between inpatient self-reported pain (PSRP) and nurse pain-evaluation (NEP) and to look for associations between CCs and inpatient and situational moderators. DESIGN: A point cross-sectional survey. SUBJECTS: The inpatient population [(n=869), > or = 6 years old and hospitalised for at least 24h] and n=115 nurses of the University of Bologna's teaching hospital, Italy. MEASURES: Using numerical rating scale, inpatients self-reported their pain while nurses indirectly rated these patients' pain using information acquired during their professional activity prior to the study and by reviewing patients' medical charts. OUTCOME MEASURES: Congruence moderator data were: gender, age, marital status, clinical area and length of hospital stay. The study was set to assess: PSRP-NEP mean of absolute difference (MAD), agreement and correlation; and to analyse the CCs dependence upon the PSRP and the congruence moderator variables. RESULTS: PSRP-NEP agreement and correlation were mild and moderate, respectively, while their MAD=2.0 (95% CI 1.8-2.2). Congruence was found in 50% of the cases. Under-estimation (21%) was directly proportional to the PSRP severity, while congruence and over-estimation (29%) were inversely proportional to it. The 'PSRP effect' on the CCs detected was further modulated by the moderators studied. CONCLUSIONS: PSRP-NEP congruence was limited while CCs were associated with PSRP, inpatient and situational moderators. Further prospective studies are needed to verify generalization and whether the studied moderators operate through patient stereotyping mechanisms. Awareness of the influence of such mechanisms on pain evaluation may ameliorate pain assessment.

The analgesic efficacy of continuous elastomeric pump ropivacaine wound instillation after appendectomy.

STUDY OBJECTIVE: To evaluate the analgesic efficacy and safety of ropivacaine 0.2% when administered continuously via elastomeric pump after appendectomy. DESIGN: Prospective, randomized, double-blinded study. SETTING: Surgical ward of a university hospital. PATIENTS: 96 ASA physical status I and II patients of at least 14 years of age, undergoing appendectomy through a McBurney incision. INTERVENTIONS: Patients were randomly assigned into two groups: 500 mg of ropivacaine in 48 hours (10 mL of 0.2% ropivacaine 20 mg, starter dose plus 5 mL/h continuous wound infusion via elastomeric pump device; n = 48) in the experimental group and 250 mL of normal saline, as placebo, in the control group. MEASUREMENTS: Postappendectomy pain, measured either with a simple verbal scale or with a visual analog scale, parenteral analgesic consumption, and global satisfaction were all measured. MAIN RESULTS: A reduction in postoperative pain was observed in the ropivacaine group. Degree of pain, with a simple verbal scale measurement of severe and unbearable, was significantly lower in the ropivacaine group than in the normal saline group from time 0 to 24 hours at rest and from time 0 to 36 hours on coughing. A significant lower pain intensity (visual analog scale) was found in the ropivacaine group both at rest and on coughing, beginning at three hours and continuing to 36 hours postoperatively. The mean number of rescue analgesic doses was significantly lower in the ropivacaine group. There were no statistically significant differences in the frequency of adverse events between the two groups. CONCLUSIONS: Wound instillation with ropivacaine 0.2% is a useful, practical, and safe method for management of postoperative pain after appendectomy.

Pain prevalence and predictors among inpatients in a major Italian teaching hospital. A baseline survey towards a pain free hospital.

Pain prevalence among inpatients is an important indicator of quality care; it may reach over 80% in various clinical settings. A cross-sectional survey was conducted in a teaching hospital to depict benchmark data regarding pain prevalence and predictors among the entire inpatient population. Overall 892 patients, 6 years old and hospitalized for at least 24 h in 57 hospital wards were interviewed using an internationally applied questionnaire. Patients self-reported their pain intensity at the time of the interview (T(0)) and worst pain perceived during the previous 24 h (T(-1)), using a numerical rating scale (NRS) and indicated current pain duration. Specific pain predictor data (hospital stay, gender, age and marital status) were obtained from patient medical charts. Pain prevalence at T(0) was 38% and 52% at T(-1). Pain was moderate to severe (NRS4) in approximately 25% of the patients at T(0) and in 40% at T(-1). High pain prevalence was found (at T(0) and T(-1), respectively) in Radiotherapy (63%;77%), Obstetrics (68%;54%), and Surgery (59%;45%) wards. Gender was a prominent determinant as pain was significantly associated with females. Pain prevalence was high among young adults or divorced/separated individuals and low among pediatric patients ( approximately 20%). Protracted hospitalization and prolonged pain duration were associated with major pain severity. Results yield Quality Assurance interventions to ameliorate pain undertreatment. Predictor analysis suggests that attention should be paid to pain management in young adults, socially vulnerable patients and those with protracted hospitalization and pain.

Postoperative Delirium after elective and emergency surgery: analysis and checking of risk factors. A study protocol.

BACKGROUND: Delirum is common in hospitalized elderly patients and may be associated with increased morbidity, length of stay and patient care costs. Delirium (acute confusional state) is defined as an acute disorder of attention and cognition. In elderly patients, delirium is often an early indicator of patho-physiological disturbances. Despite landmark studies dating back to the 1940s, the pathogenesis of Delirium remains poorly understood. Early investigators noted that Delirium was characterized by global cortical dysfunction that was associated predominantly with specific electroencephalographic changes. It's important to understand the risk factors and incidence of Delirium. Some of the risk factors are already identified in literature and can be summarized in the word "VINDICATE" which stands for: Vascular, Infections, Nutrition, Drugs, Injury, Cardiac, Autoimmune, Tumors, Endocrine. Aims of this study are: to re-evaluate the above mentioned clinical risk factors, adding some others selected from literature, and to test, as risk factors, a pattern of some genes associated to cognitive dysfunction and inflammation possibly related to postoperative Delirium. DESIGN: All patients admitted to our Emergency Unit who are meet our inclusion/exclusion criteria will be recruited. The arising of postoperative Delirium will select incidentally two groups (Delirium/non Delirium) and the forward analysis of correlate risk factors will be performed. As in a typical observational case/control study we will consider all the exposure factors to which our population are submitted towards the outcome (presence of Delirium). Our exposures are the following: ASA, Pain (SVS; VAS), Blood gas analysis (pH; Hb; pO2; pCO2), Residence pharmacological therapy (BDZ; hypnotics; narcotic drugs; alcohol; nitrous derivates), Body temperature, Arterial pressure, Heart frequency, Breath frequency, Na, K, Creatinin, Glicemia, Albumin, Hct, White blood cells, Glasgow Coma Scale (GCS), Cognitive state (SPMSQ), Functional state (ADL and IADL), Psychological Distress (HADS), Cumulative Illness Rating Scale (CIRS), Hypotension (classified in: light; moderate and severe and duration), Blood loss (classified in: < 2 lt and > 2 lt), Blood transfusions (< 2 lt and > 2 lt), Quantity of red cells and plasma transfusions, Visual VAS / SVS (timing: I-II-III post-operative day), Red cells and Plasma transfusions, Blood count evaluation and Saturation (O2%), Postoperative analgesia (Emilia-Romagna protocol), Presence of malignant tumoral disease, APACHE Score II. Moreover the presence of some relevant genetic polymorphisms will be studied in different genes such as IL-6, IL-10, TNF-alpha, and IL-1 cluster.

Hypotension as an isolated factor may not be sufficient to provoke hearing impairment.

OBJECTIVE: We investigated the possible role of hypotension and related autonomic phenomena in the pathogenic mechanism of sudden sensorineural hearing loss. METHODS: Forty-nine patients belonging to the ASA I-II classes of anaesthesiological risk and submitted to a non-otological surgical procedure were examined. Each operation was performed under general anaesthesia by controlled hypotension technique. Hearing function of the patients was evaluated before and after surgery by means of a pure tone audiometry recorded by the same clinician with the same instrument. RESULTS: No cases of bilateral hearing worsening were recorded after surgery. CONCLUSIONS: An induced and controlled steady hypotension under general anaesthesia did not affect the hearing function of any of the patients. It may be supposed, therefore, that an adverse effect on the cochlear oxygenation is more likely to be caused by the sympathetic changes induced by a consistent decrease of blood pressure rather than to hypotension itself.