Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study.

BACKGROUND: A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome. METHODS: Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints. RESULTS: Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores. CONCLUSION: This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.

Safety and efficacy of once-daily hydromorphone extended-release versus twice-daily oxycodone hydrochloride controlled-release in chinese patients with cancer pain: a phase 3, randomized, double-blind, multicenter study.

UNLABELLED: Noninferiority of the efficacy of once-daily hydromorphone hydrochloride extended-release (hydromorphone ER) compared with twice-daily oxycodone hydrochloride controlled-release (oxycodone CR) was investigated in this randomized, double-blind study in Chinese patients with moderate to severe cancer pain requiring strong oral opioid analgesics. Randomization (1:1) to hydromorphone ER (8-32 mg) or oxycodone CR (10-40 mg) was followed by dose titration (up to 8 days) and dose maintenance (28 days, weekly visits). Primary endpoint was change from baseline to end of study in "worst pain in the past 24 hours" of Brief Pain Inventory (Short Form) score on last observation carried forward (per protocol set). A total of 137 of 260 randomized patients completed maintenance phase (hydromorphone ER: n = 70; oxycodone CR: n = 67); per protocol set: 81 patients. Mean age was 53.1 years (range: 18-70 years; males: 65.3%); most common Eastern Cooperative Oncology Group performance status = 2. Least square mean difference between 2 treatment groups for primary endpoint using analysis of covariance (baseline score, covariate) was -.1 (95% confidence interval: -1.3, 1.1), with upper bound of 95% confidence interval <1.5 (predefined noninferiority margin). Most common reason for deaths was disease progression (hydromorphone ER: 6.3%; oxycodone CR: 12.7%). Treatment-emergent adverse events were comparable between treatment groups. Hydromorphone ER was noninferior to oxycodone CR in alleviating cancer pain and was well tolerated. PERSPECTIVE: This article demonstrates clinical noninferiority of the efficacy of once-daily hydromorphone ER compared with twice-daily oxycodone CR in alleviating cancer pain in Chinese patients, with comparable safety profiles between the 2 treatment groups. Thus, a treatment option with the potential for a reduced dosing frequency exists for health care providers and patients.

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease.

BACKGROUND: Currently available treatments for Alzheimer's disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD. METHODS: In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the 'last observation carried forward' approach, in an analysis of covariance model. RESULTS: In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (-2.14 [4.34]) compared with the galantamine group (-1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (-10.81 [18.27]) versus the galantamine group (-8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group. CONCLUSION: Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients. IDENTIFICATION: This study is registered at ClinicalTrials.gov (NCT00679627).

Dose proportionality and pharmacokinetics of extended-release (OROS®) hydromorphone: a phase 1, open-label, randomized, crossover study in healthy Taiwanese subjects.

OBJECTIVES: Osmotic-controlled release oral delivery system (OROS®) hydromorphone - an extended-release preparation - is recommended long-term therapy for chronic pain patients. Dose proportionality of OROS hydromorphone has been shown in healthy Caucasian volunteers; however, no studies have been conducted in Asian populations. To determine whether ethnic differences affect the drug's pharmacokinetic (PK) profile, we evaluated the dose proportionality of OROS hydromorphone in healthy Taiwanese adults. METHODS: This 12-week, open-label, 4-way crossover, phase 1 study randomly assigned subjects to 1 of 4 treatment sequences - single oral dose OROS hydromorphone: 8 mg, 16 mg, 32 mg, or 64 mg - along with 50 mg naltrexone. Dose proportionality was assessed using a linear mixed-effects model to estimate the slope of the regression line and its 90% CI for Cmax, AUC0-48h, and AUClast. Descriptive statistics measured plasma hydromorphone concentrations, PK parameters, laboratory analytes, and vital signs. RESULTS: 23 subjects completed the study; a single-dose of OROS hydromorphone increased plasma concentration steadily for 6 hours and sustained it at or near maximum levels for ~ 24 hours. After dose normalization to a 16 mg dose, all studied doses demonstrated dose proportionality for Cmax, AUClast, and AUC0-48h,as the slopes of the regression lines for Cmax, AUClast, and AUC0-48h were close to zero, and the 90% CIs within pre-specified limits. Adverse events were as expected for hydromorphone administered with concomitant naltrexone. CONCLUSIONS: Single doses of 8 mg, 16 mg, 32 mg, and 64 mg of OROS hydromorphone were found to be dose proportional for Cmax, AUClast, and AUC0-48h and were generally safe and well-tolerated in healthy Taiwanese adults.

Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS(®) hydromorphone ER) in patients with chronic pain.

OBJECTIVE: To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications. METHODS: This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3-14 days and stabilized between 8-48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration-time curve from 0-24 hours (AUC(0-24)), maximum plasma concentration (C(max)), trough plasma concentration (C(min)), average plasma concentration (C(avg)), and degree of fluctuation (100 × [(C(max) - C(min)) ÷ C(avg)]) were calculated based on data from 14 patients. RESULTS: Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC(0-24), 41.1 ng · h/mL; C(max), 2.6 ng/mL; C(min), 1.1 ng/mL; C(avg), 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2-21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred. CONCLUSION: These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.

Integrating mental health into primary care an integrative collaborative primary care model--the Jamaican experience.

Many low-income countries face enormous constraints which limit the development of mental health services. The World Health Organization (WHO) made ten recommendations to facilitate the development of mental health services; among these is the integration of mental health into primary care. Jamaica developed an integrated collaborative system of mental health care through the adoption of a primary care model which is central to the delivery of mental health care. This model emphasized the integration of mental health into primary care and, in expanding the role of the mental health team, made it more collaborative. Mental health services were mainstreamed into primary care and several strategies facilitated this process. These included the training of staff in primary care, the availability of psychotropic medication in primary care facilities and the provision of mental health beds at the community level. Furthermore, focus was placed on human development and the involvement of consumers in the policy development and service delivery. This has resulted in a reduction in the population of the mental health hospital and expansion in the community mental health services.

Integrating mental health into primary care: an integrative collaborative primary care model - the Jamaican experience / Integrar la salud mental en la atención primaria: un modelo de integracional de la atención primaria - la experiencia jamaicana

Many low-income countries face enormous constraints which limit the development of mental health services. The World Health Organization (WHO) made ten recommendations to facilitate the development of mental health services; among these is the integration of mental health into primary care. Jamaica developed an integrated collaborative system of mental health care through the adoption of a primary care model which is central to the delivery of mental health care. This model emphasized the integration of mental health into primary care and, in expanding the role of the mental health team, made it more collaborative. Mental health services were mainstreamed into primary care and several strategies facilitated this process. These included the training of staff in primary care, the availability of psychotropic medication in primary care facilities and the provision of mental health beds at the community level. Furthermore, focus was placed on human development and the involvement of consumers in the policy development and service delivery. This has resulted in a reduction in the population of the mental health hospital and expansion in the community mental health services.

Muchos países de bajo ingreso enfrentan enormes restricciones que limitan el desarrollo de los servicios de salud mental. La Organización Mundial de la Salud (OMS) hizo diez recomendaciones para facilitar el desarrollo de los servicios para la salud mental. Entre estas recomendaciones, se encuentra la integración de la salud mental a la atención primaria. Jamaica desarrolló un sistema integracional colaborativo de atención a la salud mental a través de la adopción de un modelo de atención primaria de crucial importancia para el ofrecimiento del cuidado de salud mental. Este modelo puso el énfasis en la integración de salud mental en la atención primaria, y la expansión del papel del equipo de la salud mental, haciéndolo más colaborativo. Los servicios de salud mental fueron introducidos de manera regular en la atención primaria, y se trazaron varias estrategias a fin de facilitar este proceso. Éstas incluyeron el entrenamiento de personal en atención primaria, la disponibilidad de medicamentos psicotrópicos en los centros de atención primaria, y suministro de camas para la atención a la salud mental a nivel comunitario. Además, se puso énfasis en el desarrollo humano y la involucración de los consumidores en el desarrollo de políticas y el ofrecimiento de servicios. Esto ha traído consigo una reducción en la población hospitalaria atendida por salud mental, en tanto que por otra parte, ha producido una expansión en los servicios de salud mental en la comunidad.

Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system.

OBJECTIVES: Fentanyl is a potent synthetic opioid used for the management of chronic pain. A newer transdermal matrix system was developed and compared with a reservoir system used in the United States. SETTING: An open-label, single-center, randomized, two-period crossover study was conducted to evaluate the bioequivalence of the transdermal matrix system to the transdermal reservoir system. Seventy-four subjects completed treatment with both the reservoir system (100 microg/h) and the matrix system (100 microg/h), each applied for 72 hours. After application of the first system, subjects completed a 9-day washout and then crossed over to receive the other system for another 72 hours. MAIN OUTCOME MEASURE: Blood samples for the determination of serum fentanyl concentrations were taken in each treatment period for up to 120 hours following application. RESULTS: The ratios of geometric means for maximum fentanyl concentration (Cmax) and area under the concentration-time curve (AUClast, and AUCinfinity) were 106 percent, 110 percent, and 110 percent, respectively. The 90% confidence intervals for the ratios of the geometric means were contained within the bioequivalence criteria of 80-125 percent. The matrix system adhered well to skin. Systemic and topical safety profiles were comparable between treatments. CONCLUSIONS: The transdermal fentanyl matrix system adhered well, was well tolerated, and produced systemic exposures of fentanyl that were bioequivalent to the reservoir system.