A Prospective Study with Patients and Families on the Usefulness of Accurate Prognosis for Palliative Care Patients.

Prediction of life expectancy in terminally ill patients is an important end-of-life care issue for patients, families and mental health workers during the last days of life. This study was conducted to examine the importance/usefulness for patients/families to have an accurate prognosis and its impact on planning their activities prior to death. All patients admitted during a period of one year were included. Patients' and families' viewpoints on the usefulness of an accurate prognosis was documented at admission. There were 285 patients in the cohort. The median time to death was 8 days. Most families (83%) rated the importance of an accurate prognosis as moderately (13%) to very much useful (70%). A total of 42% of patients were able to complete e the questionnaire. Among these, 58% found it moderately to very much useful. For families, having an accurate prognosis influenced the planning of visits (69%), communication/closure (42%) and spiritual needs/funeral arrangements (31%). Patients identified planning of visits (10%), communication/closure (12%), and goals/accomplishments (9%) as very important. Discussing the prognosis and its impact is very helpful for the mental health professionals to have open and honest conversations with patients/families to identify, prioritize and adapt treatment to achieve goals prior to death.

Uncovering the Minor Contribution of Land-Cover Change in Upland Forests to the Net Carbon Footprint of a Boreal Hydroelectric Reservoir.

Hydropower in boreal conditions is generally considered the energy source emitting the least greenhouse gas per kilowatt-hour during its life cycle. The purpose of this study was to assess the relative contribution of the land-use change on the modification of the carbon sinks and sources following the flooding of upland forested territories to create the Eastmain-1 hydroelectric reservoir in Quebec's boreal forest using Carbon Budget Model of the Canadian Forest Sector. Results suggest a carbon sink loss after 100 yr of 300,000 ± 100,000 Mg CO equivalents (COe). A wildfire sensitivity analysis revealed that the ecosystem would have acted as a carbon sink as long as <75% of the territory had burned over the 100-yr-long period. Our long-term net carbon flux estimate resulted in emissions of 4 ± 2 g COe kWh as a contribution to the carbon footprint calculation, one-eighth what was obtained in a recent study that used less precise and less sensitive estimates. Consequently, this study significantly reduces the reported net carbon footprint of this reservoir and reveals how negligible the relative contribution of the land-use change in upland forests to the total net carbon footprint of a hydroelectric reservoir in the boreal zone can be.

[Effectiveness of psychotherapy compared to pharmacotherapy for the treatment of anxiety and depressive disorders in adults: A literature review]. / Efficacité de la psychothérapie comparativement à la pharmacothérapie dans le traitement des troubles anxieux et dépressifs chez l'adulte : une revue de la littérature.

Introduction In Quebec, mental disorders affect one in five people in their lifetime. Anxiety and depressive disorders are the main common or moderate mental health disorders. They affect both the individuals with the disorder and the people around them and have substantial economic impact. Psychotropic drugs are the treatment option most often proposed to patients presenting with moderate mental health disorders. Psychotherapy is nevertheless a treatment that should be given consideration.Physical and financial access to psychotherapy remains limited because only one third of professionals qualified to offer it practise in the public sector, and the coverage and reimbursement policy for this service is very restricted. In order to improve such coverage, the Ministère de la Santé et des Services sociaux (MSSS) mandated the Institut national d'excellence en santé et en services sociaux (INESSS) to assess the evidence on the effectiveness of psychotherapy compared with those of pharmacotherapy for the treatment of adults with anxiety and depressive disorders.Methods An update of a review of recent and good quality literature was conducted through a review of systematic reviews dealing with psychotherapy compared to pharmacotherapy in the treatment of anxiety and depression in adults. The period covered included 2009 to 2013. The literature search strategy, modelled on that of the reference review, was applied to Medline, Cochrane Library, CINAHL, Web of Science and health technology assessment agencies. Exploration of the grey literature focused on information available on the websites of various health assessment organizations.Results The level of scientific evidence overall was judged to be of moderate to high quality. In general, the data showed no significant difference between psychotherapy and pharmacotherapy in terms of symptoms reduction in patients with moderate anxiety or depressive disorders, indicating comparable effectiveness of these two modes of treatment. However, the benefits of psychotherapy lasted longer after the end of treatment than those of medication. Psychotherapy therefore offers better protection against relapse. Furthermore, the combination of psychotherapy and pharmacotherapy is more effective than psychotherapy alone in severe or chronic cases.Conclusion Psychotherapy appears to be as effective as pharmacotherapy in the treatment of adult patients with moderate anxiety and/or depressive disorders. Moreover, the beneficial effects of psychotherapy last longer after the end of treatment with a lower likelihood of relapse.

Correction factors for large-scale greenhouse gas assessment from pulp and paper mill sludge landfill sites.

Assessments of greenhouse gas (GHG) emissions in managed areas are facing various challenges. A non-flow-through, non-steady-state (NFT-NSS) chamber coupled to a frame permanently inserted into the landfilled substrates is a standard method for quantifying GHG emissions in managed areas, such as pulp and paper mill sludge (PPMS) landfill sites. Frequent measurements are needed to minimize uncertainties on GHG emission factors at the landfill site scale. However, maintaining a frame inserted into the substrates for a long time period is often impossible due to landfilling management operations. Therefore, GHG measurements using NFT-NSS chambers placed directly on substrates' surface could be an interesting option. Our objectives were to determine the relationships between CO2, CH4, and N2O fluxes measured with (F + ) and without (F-) a frame inserted in the substrates' surface and to develop correction factors for fluxes measured without a frame. Measurements were made at different PPMS landfill sites in the province of Québec, Canada. Stronger GHG flux relationships were observed at the provincial (across sites) than the specific site scale: the variance in GHG fluxes from F- chambers explained up to 80 % of variance in fluxes from F + chambers. The measured CO2, CH4, and N2O fluxes in F- chambers were on average 53, 78, and 63 % lower, respectively, than those estimated by the models at provincial scale. The correction factors developed with this approach could greatly extend the number of sites where in situ GHG measurements can be done and would help refining GHG inventories at the provincial and national levels.

Can We Make More Accurate Prognoses During Last Days of Life?

Background: Life expectancy prediction is important for end-of-life planning. Established methods (Palliative Performance Scale [PPS], Palliative Prognostic Index [PPI]) have been validated for intermediate- to long-term prognoses, but last-weeks-of-life prognosis has not been well studied. Patients admitted to a palliative care facility often have a life expectancy of less than three weeks. Reliable last-weeks-of-life prognostic tools are needed. Objective: To improve short-term survival prediction in terminally ill patients. Method: This prospective study included all patients admitted to a palliative care facility in Montreal, Canada, over one year. PPS and PPI were assessed until patients' death. Seven prognostic clinical signs of impending death (Short-Term Prognosis Signs [SPS]) were documented daily. Results: The analyses included 273 patients (76% cancer). The median survival time for a PPS ≤20% was 2.5 days, while for a PPS ≥50% it was 44.5 days, for a PPI >8 the median survival was 3.5 days and for a PPI ≤4 it was 38.5 days. Receiver operating characteristic curves showed a high accuracy in predicting survival. Median survival after the first occurrence of any SPS was below one week. Conclusions: This study demonstrated that the PPS and PPI perform well between one week and three months extending their usefulness to shorter term survival prediction. SPS items provided survival information during the last week of life. Using SPS along with PPS and PPI during the last weeks of life could enable a more precise short-term survival prediction across various end-of-life diagnoses. The translation of this research into clinical practice could lead to a better adapted treatment, the identification of a most appropriate care setting for patients, and improved communication of prognosis with patients and families.

Evaluation of the Use of Anticoagulotherapy in Cancer Patients in Palliative Care Residence.

Background: Several patients admitted to palliative care residences are on anticoagulotherapy (AC). Given the risks of venous thromboembolism (VTE) and bleeding, the decision to continue or stop AC on admission remains clinically challenging. Objectives: To determine the prevalence of AC use and incidence of suspected VTE and bleeding events in palliative care patients. Methods: Retrospective cohort study including all deceased patients at a Canadian palliative care residence over two years. Results: Among the 453 patients' charts reviewed (369 with cancer), 183 (40%) were on AC at admission or <30 days earlier. Only 64 (35%) continued AC, with 78% discontinuing it during their stay. Demographic parameters were similar in the AC and non-AC groups. The incidence of suspected VTE was lower in patients pursuing AC post-admission than in those who stopped: (4.6% vs. 6.7%) and, conversely, the incidence of bleeding was higher in patients on AC: (10.8% vs. 7.6%), though these differences were not statistically significant. The risk of death in cancer patients within 72 hours of suspected VTE or bleeding event was 80% and 30%, respectively. Patients on AC had a 33% reduced risk of VTE but a 44% increased risk of bleeding. Conclusion: This study provides information on the AC use in palliative care patients. In term of survivorship, it suggests a possible advantage to continue AC to prevent a symptomatic or distressing death. Given the low incidence of events, larger powered studies will be necessary to further characterize the risks/benefits of pursuing AC in patients in palliative care residences.

Edmonton Classification System for Cancer Pain: Comparison of Pain Classification Features and Pain Intensity across Diverse Palliative Care Settings in Canada.

Background: The goal of the Edmonton Classification System for Cancer Pain (ECS-CP) is to create an international classification system for cancer pain. Previous studies reinforce the need for standardized training to ensure consistency across assessors. There is no universally accepted classification for neuropathic pain. Objectives: Our primary objective was to describe the prevalence of ECS-CP features in a diverse sample of advanced cancer patients, using assessors with standardized training. The secondary objectives were to: (1) determine the prevalence of neuropathic pain using the Neuropathic Pain Special Interest Group (NeuPSIG) criteria and (2) examine the relationship between specific predictors: ECS-CP features, age, Palliative Performance Scale, Morphine Equivalent Daily Dose (MEDD), setting, and pain intensity; and neuropathic pain. Methods: A total of 1050 adult patients with advanced cancer were recruited from 11 Canadian sites. A clinician completed the ECS-CP and NeuPSIG criteria, and collected additional information including demographics and pain intensity (now). All assessors received standardized training. Results: Of 1050 evaluable patients, 910 (87%) had cancer pain: nociceptive (n = 626; 68.8%); neuropathic (n = 227; 24.9%); incident (n = 329; 36.2%); psychological distress (n = 209; 23%); addictive behavior (n = 51; 5.6%); and normal cognition (n = 639; 70.2%). The frequencies of ECS-CP features and pain intensity scores varied across sites and settings, with more acute settings having higher frequencies of complex pain features. The overall frequency of neuropathic pain was 24.9%, ranging from 11% (hospices) to 34.2% (palliative outpatient clinic) across settings. Multivariate logistic regression analysis revealed that age <60 years, MEDD ≥19 mg, pain intensity ≥7/10, and incident pain were significant independent predictors of neuropathic pain (p < 0.05). Conclusion: The ECS-CP was able to detect salient pain features across settings. Furthermore, the frequencies of neuropathic pain utilizing the NeuPSIG criteria fits within the lower-end of literature estimates (13%-40%). Further research is warranted to validate the NeuPSIG criteria in cancer pain.

Development of a Multi-Criteria Decision Analysis Rating Tool to Prioritize Real-World Evidence Questions for the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration.

The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration developed an MCDA rating tool to assess and prioritize potential post-market real-world evidence (RWE) questions/uncertainties emerging from public drug funding decisions in Canada. In collaboration with a group of multidisciplinary stakeholders from across Canada, the rating tool was developed following a three-step process: (1) selection of criteria to assess the importance and feasibility of an RWE question; (2) development of rating scales, application of weights and calculating aggregate scores; and (3) validation testing. An initial MCDA rating tool was developed, composed of seven criteria, divided into two groups. Group A criteria assess the importance of an RWE question by examining the (1) drug's perceived clinical benefit, (2) magnitude of uncertainty identified, and (3) relevance of the uncertainty to decision-makers. Group B criteria assess the feasibility of conducting an RWE analysis including the (1) feasibility of identifying a comparator, (2) ability to identify cases, (3) availability of comprehensive data, and (4) availability of necessary expertise and methodology. Future directions include partnering with the Canadian Agency for Drugs and Technology in Health's Provincial Advisory Group for further tool refinement and to gain insight into incorporating the tool into drug funding deliberations.

Women with pain due to osteoarthritis: the efficacy and safety of a once-daily formulation of tramadol.

OBJECTIVE: This analysis assesses the efficacy and safety of treatment with a once-daily oral formulation of tramadol for up to 12 weeks compared with placebo in women with moderate-to-severe pain due to osteoarthritis of the knee. DESIGN: Two parallel, placebo-controlled phase III clinical trials were analyzed; patients were randomized to a fixed dosage of Tramadol Contramid once a day (OAD) 100, 200, and 300 mg daily, or placebo. OUTCOME MEASURES: The primary efficacy end points were the percentage difference from baseline of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) subscale scores for pain and physical function, and the patient global rating of pain relief after 12 weeks of maintenance therapy. RESULTS: The analysis included 405 women receiving tramadol and 280 receiving placebo. At week 12, 179 of 204 women (87.7%) receiving tramadol rated their overall pain relief as effective or very effective compared with 134 of 177 (75.7%) receiving placebo. A time-weighted analysis revealed statistically significant improvements over placebo for all the WOMAC subscale scores across all three dosages. The percentage improvements from baseline of the WOMAC pain scores were significantly better than placebo for the 100-mg (58.8 +/- 37.1%, P = 0.018) and 300-mg (58.9 +/- 38.8%, P = 0.023) treatment arms; however, the 200-mg dosage was not significant (53.0 +/- 38.5%, P = 0.175). The WOMAC physical function scores showed significant improvement for the 100 (56.9 +/- 36.4%, P = 0.009), 200 (54.0 +/- 33.8%, P = 0.034), and 300 mg (53.4 +/- 41.4%, P = 0.043) daily dosages. CONCLUSION: For moderate-to-severe pain due to osteoarthritis of the knee, women experience significant analgesia and improvement of physical function over time with treatment with Tramadol Contramid OAD.

A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis.

One thousand twenty-eight (1,028) patients with pain due to osteoarthritis (OA) of the knee were enrolled in this multicenter, randomized, double-blind, parallel study designed to assess the analgesic efficacy and safety of Tramadol Contramid OAD compared to placebo. An open-label phase was followed by a double-blind phase, in which a total of 646 patients were randomized to double-blind treatment with placebo or Tramadol Contramid OAD. Patients were titrated to their optimal dose (200mg or 300 mg), which was maintained for 12 weeks. An absolute mean reduction of 3.0+/-2.1 on a Pain Intensity Numerical Rating Scale (PI-NRS) was noted in the Tramadol Contramid OAD treatment group. The difference between active and placebo groups regarding this absolute mean reduction was statistically significant (P<0.001) throughout the study. The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of >or=1 and >or=2 points on the PI-NRS score by the end of the study (P=0.035). A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change (P=0.0002). Both the 200mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD. The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity. These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA.

Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects.

BACKGROUND: Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. OBJECTIVE: Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets. METHODS: We conducted a PK study in 15 elderly (aged ≥75 years) subjects with mild renal insufficiency and 20 young (18-40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration-time curve (AUC), terminal elimination rate (k el), total body clearance, volume of distribution (V area/ F), and renal clearance (Clr0-48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times). RESULTS: NCA demonstrated comparable maximum plasma concentration (C max) and AUC between age groups for tramadol enantiomers, but significant differences in V area/ F (mean 34% higher) and k el (mean 28% lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0-inf (mean 35% higher), Clr0-48 (mean 29% lower), and k el (mean 33% lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50% longer mean elimination half-life in the elderly. No differences in absorption processes were observed. CONCLUSIONS: Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects.

Efficacy and Safety Assessment of a Novel Once-Daily Tablet Formulation of Tramadol : A Randomised, Controlled Study versus Twice-Daily Tramadol in Patients with Osteoarthritis of the Knee.

OBJECTIVE: To compare the 24-hour sustained efficacy and safety of a new tramadol once-daily formulation (tramadol OAD) using Contramid((R)) controlled-release technology with a marketed twice-daily formulation (tramadol BID). PATIENTS, DESIGN AND SETTING: 431 patients with osteoarthritis of the knee were enrolled in this randomised, double-blind, multicentre, parallel study. After titration to optimum dose (range 100-400mg), patients received medication for 12 weeks. MAIN OUTCOME MEASURES AND RESULTS: Efficacy evaluations included: Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores (pain, stiffness, physical function and global), daily efficacy ratings (post-dose: tramadol OAD 24 hours; tramadol BID 12 hours), pain ratings over 24 hours, and patient and investigator overall ratings. Non-inferiority was demonstrated for the primary endpoint, mean percentage change in WOMAC pain score from baseline to week 12 (tramadol OAD 58%; tramadol BID 59%) [95% CI -7.67, 3.82]. The median optimum dose received was 200mg (both treatments). In 73% of patients, pain was mild to absent at the end of the dosing interval for both treatments (tramadol OAD 24 hours; tramadol BID 12 hours). Pain ratings over 24 hours were similar between groups, indicating 24-hour sustained efficacy for tramadol OAD. More tramadol BID patients reported dizziness/vertigo (37% vs 26%), vomiting (14% vs 8%) and headache (18% vs 13%) while tramadol OAD patients reported more somnolence (30% vs 21%). CONCLUSIONS: This study demonstrated that this novel tramadol OAD formulation provides sustained analgesic efficacy over the entire 24-hour dosing interval and a clinically favourable safety profile, both of which will provide a clear clinical benefit.

Extended-release tramadol/paracetamol in moderate-to-severe pain: a randomized, placebo-controlled study in patients with acute low back pain.

OBJECTIVE: Combinations of oral analgesics may offer several potential benefits compared with an individual agent. The objective of this study was to investigate the efficacy and safety of an extended-release, twice-daily fixed combination of 75 mg tramadol/650 mg paracetamol (DDS-06C) in the treatment of moderate-to-severe pain, using acute low back pain as a model. RESEARCH DESIGN AND METHODS: In this phase III study, 277 patients with moderate-to-severe acute low back pain were randomized to 1-2 tablets of DDS-06C or placebo every 10-12 h for 2.5 days during the double-blind phase. Following the double-blind phase, patients had the option to continue for a 2.5-day open-label phase. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT00643383) MAIN OUTCOME MEASURES: The primary end point was the sum of pain intensity differences (SPID) over the 50-h double-blind phase (SPID50). Secondary end points included total pain relief score over the 50-h double-blind phase (TOTPAR50), patient's global impression of medication, and SPID over the first 4 h. RESULTS: A statistically significant (p = 0.038) greater decrease in pain intensity was observed in the DDS-06C group (median SPID50: -6.0) versus placebo (median SPID50: -4.0). Greater pain relief was also observed in patients randomized to DDS-06C: the median TOTPAR50 was 13.0 for the DDS-06C group and 11.0 for placebo (p = 0.026). DDS-06C demonstrated statistically significant superior efficacy compared with placebo for the majority of the other secondary end points. Overall, 38% of patients treated with DDS-06C experienced at least one adverse event; the intensity was mild-to-moderate in 81% of cases. The most commonly reported adverse events (>5% of patients receiving DDS-06C) were nausea, dizziness, vomiting, and somnolence. CONCLUSIONS: Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C was superior to placebo on measures of pain intensity and relief, and was well-tolerated.

Extended-release Trazodone in Major Depressive Disorder: A Randomized, Double-blind, Placebo-controlled Study.

OBJECTIVE: To investigate the efficacy, safety, and clinical benefit of a once-daily formulation of trazodone (Trazodone Contramid((c)) OAD) in the treatment of major depressive disorder. DESIGN/PARTICIPANTS: In this double-blind study, 412 patients with major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were randomized 1:1 to receive either Trazodone Contramid OAD (150 to 375mg) or placebo. Treatment was titrated over two weeks to each individual optimal dose. Patients then continued six weeks of treatment; further dose adjustments were allowed based on efficacy and tolerability. MEASUREMENTS: The primary end point was change in the 17-item Hamilton Depression Rating Scale total score from baseline to last study visit. Secondary end points included Hamilton Depression Rating Scale responders/remitters, change in Montgomery-Asberg Depression Rating Scale, Clinician and Patient Global Improvement Scales, and quality of sleep. RESULTS: From the end of titration to the end of the six-week treatment period, the mean maximum daily dose of the intent-to-treat population was 310mg for the active group and 355mg for the placebo group. There was a statistically significant difference between trazodone and placebo on the mean HAMD-17 score (-11.4 vs. -9.3, P=0.012). A significant difference was present as early as Week 1 and was maintained at all subsequent study visits. Many secondary end points supported these findings, including improvements in quality of sleep. The most frequent adverse events were the same for both the treatment and placebo groups: headache and somnolence. There were no serious adverse events that were considered related to treatment. There were no clinically significant electrocardiogram or laboratory abnormalities. CONCLUSIONS: The trazodone Contramid formulation was more effective than placebo in major depressive disorder and was well tolerated.

Onset of analgesic effect and plasma levels of controlled-release tramadol (Tramadol Contramid once-a-day) 200-mg tablets in patients with acute low back pain.

BACKGROUND AND AIMS: Tramadol hydrochloride, a centrally acting, synthetic analgesic, has been available in Europe since 1977 in a variety of formulations and in the United States since 1995. Its clinical efficacy was established in a variety of painful conditions (cance rpain, neuropathic pain, and osteoarthritis). Nonetheless, little published data exist regarding the relationship between analgesic onset and minimum therapeutic plasma levels. Tramadol Contramid once-a-day (OAD) demonstrates a pharmacokinetic profile with a sharp initial absorption slope similar to the pharmacokinetic profile of the immediate-release tramadol, suggesting that both the immediate-release and the once-daily (Contramid) formulation may produce a similar onset of analgesia. METHODS: This multicentre, open-label, single-dose study examined the pharmacokinetics/pharmacodynamics of Tramadol Contramid OAD in patients with acute low back pain. Patients who signed informed consent were screened and washed-out of prior analgesics. Patients received one dose of Tramadol Contramid OAD 200 mg. The patients indicated the time of onset of pain relief (stopwatch method). Ratings of pain intensity and pain relief and pharmacokinetic samples were taken prior to dosing, at the onset of pain relief and 3 and 6 hours postdose. No rescue medication was permitted until the end of the study (6-hour postdose). Adverse events were monitored throughout the study. RESULTS: Forty of the 47 patients enrolled completed the study. Onset of perceptible pain relief was achieved within 1 hour for the majority of patients and at plasma levels, suggesting a therapeutic threshold between 50 and 100 ng/mL. Two patients did not experience any pain relief CONCLUSIONS: The results of this exploratory study suggest that similar to immediate-release tramadol, onset of analgesia for this controlled-release formulation of tramadol (Tramadol Contramid OAD) occurs within 1 hour at a mean therapeutic threshold concentration of 56 +/- 38 ng/mL.

Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths.

A three-way crossover study in 27 human volunteers was conducted to characterize the pharmacokinetics and to assess the dose proportionality of 100 mg, 200 mg and 300 mg strengths of a novel once-a-day tramadol controlled-release tablet (Tramadol Contramid OAD) following single-dose administration. Serial blood samples were collected at predefined timepoints over a 48 h period and racemic tramadol and O-desmethyltramadol concentrations in plasma were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using noncompartmental methods. Following dose normalization and logarithmic transformation of concentration-dependent parameters, the results were compared using analysis of variance (ANOVA). The residual variability thereby obtained was used to construct 90% classical confidence intervals. The two one-sided tests procedure was used for all pairwise comparisons. Dose proportionality was concluded since the 90% CI for the ratio of geometric means was included in the acceptance range of 0.80-1.25 for all comparisons.

Efficacy and safety of 12 weeks of osteoarthritic pain therapy with once-daily tramadol (Tramadol Contramid OAD).

This placebo-controlled study examined the analgesic efficacy, safety, and clinical benefit of Tramadol Contramid OAD, a once-daily formulation with both immediate- and extended-release components. Five hundred and fifty-two patients with moderate to severe pain due to osteoarthritis (OA) of the knee were randomized into this multicenter, double-blind, parallel arm study. After randomization to Tramadol Contramid OAD 100, 200, or 300 mg, or to placebo, patients' dose was titrated to the fixed randomized dose and maintained for 12 weeks. Efficacy was evaluated with the Patients' Global Rating of Pain Relief (median ratings at maintenance visits), and the Western Ontario and McMaster University (WOMAC) Pain and Physical Function subscales (percent difference, baseline to end of study) as coprimary endpoints. A responder analysis was conducted (percentage of patients who achieved a 30 percent improvement on their baseline WOMAC pain score). The difference from placebo on the median Patient Global Rating of Pain Relief at the four maintenance visits was statistically significant (200 and 300 mg: p < or = 0.001). Treatment was rated effective or very effective by 75 percent and 80 percent of patients randomized to Tramadol Contramid OAD 200 mg and 300 mg, respectively. There was a 46 percent (300-mg dose; p = 0.016) and 43 percent (200-mg dose; p = 0.05) improvement on the WOMAC pain score (baseline to the end of the study) with Tramadol Contramid OAD compared with 32percent for placebo. The responder analysis demonstrated a statistically significant difference in the percentage of patients who achieved a 30 percent improvement in their baseline WOMAC pain score for both Tramadol Contramid OAD 200 mg (65 percent; p = 0.0095) and 300 mg (65 percent; p = 0.0104) compared with placebo (50 percent). The type and incidence of adverse events were typical of tramadol (nausea, dizziness/vertigo, vomiting, somnolence, and constipation) and the intensity was mild to moderate in 87percent of patients who experienced them regardless of dose. This study shows the efficacy and safety of Tramadol Contramid OAD 200 mg and 300 mg in patients with moderate or severe pain of the knee due to OA.