[Guided discontinuation of antidepressants: approach and first results of a Dutch multidisciplinary outpatient clinic]. / Werkwijze en eerste resultaten van multidisciplinaire afbouwpoli anti-depressiva.

BACKGROUND: Discontinuation of antidepressant medication can be difficult due to withdrawal symptoms and relapse risk. Scientific evidence on the questions of who, when, and how to stop antidepressants is limited. In Amsterdam a multidisciplinary outpatient clinic was started to provide advice and guidance. AIM: To substantiate the design of the clinic. Central questions relate to knowing which patients are referred, the background of their request, and their experiences with the outpatient clinic. METHOD: The first 51 patients of the clinic were described on the basis of file research, in addition a survey was conducted into patient experiences. RESULTS: Half of the patients (55%) actually started discontinuation, 39% were advised not to do so (yet). Patients at the clinic had used antidepressants for an average of 10 years, and 76% had previously attempted to stop. 21% had now successfully stopped and 25% were satisfied with a lower dose. One patient relapsed during tapering. CONCLUSION: So far, patients with long-term antidepressant use and multiple quit attempts have been referred. Our experiences are aimed at helping individual patients but can also result in more knowledge about who can stop at what moment, and how this should be done.

Access to treatment with controlled medicines rationale and recommendations for neutral, precise, and respectful language.

The European Pain Federation EFIC, the International Association for Hospice and Palliative Care, International Doctors for Healthier Drug Policies, the Swiss Romandy College for Addiction Medicine, the Swiss Society of Addiction Medicine, and the World Federation for the Treatment of Opioid Dependence called on medical journals to ensure that authors always use terminology that is neutral, precise, and respectful in relation to the use of psychoactive substances. It has been shown that language can propagate stigma, and that stigma can prevent people from seeking help and influence the effectiveness of social and public-health policies. The focus of using appropriate terminology should extend to all patients who need controlled medicines, avoiding negative wording. A narrow focus on a few terms and medical communication only should be avoided. The appropriateness of terms is not absolute and indeed varies between cultures and regions and over time. For this reason, it is important that communities establish their own consensus of what is 'neutral', 'precise', and 'respectful'. We identified twenty-three problematic terms (most of them we suggest avoiding) and their possible alternatives. The use of appropriate language improves scientific quality of articles and increases chances that patients will receive the best treatment and that government policies on psychoactive substance policies will be rational.

The Global Opioid Policy Initiative (GOPI) project to evaluate the availability and accessibility of opioids for the management of cancer pain in Africa, Asia, Latin America and the Caribbean, and the Middle East: introduction and methodology.

Opioid analgesics are critical to the effective relief of cancer pain. Effective treatment is predicated on sound assessments, individually tailored analgesic therapy, and the availability and accessibility of the required medications. In some countries, pain relief is hampered by the lack of availability or barriers to the accessibility of opioid analgesics. As the follow-up to a successful project to evaluate the availability and accessibility of opioids and regulatory barriers in Europe, the European Society for Medical Oncology (ESMO) and the European Association for Palliative Care (EAPC) undertook to expand their research to those parts of the world where data were lacking regarding these aspects of care, in particular Africa, Asia, the Middle East, Latin America and the Caribbean, and the states of India. This project has been undertaken in collaboration with the Union for International Cancer Control (UICC), the Pain and Policy Studies Group (PPSG) of the University of Wisconsin, and the World Health Organization (WHO), together with a consortium of 17 international oncology and palliative care societies. This article describes the study methodology.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in India: a report from the Global Opioid Policy Initiative (GOPI).

India is the world's largest democracy with control of opioids divided between the national and state governments. While the global consumption of opioids has increased, the consumption has not increased at the same rate. This is the first comprehensive study of opioid availability and accessibility for cancer patients in India. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 24 of the states that make up India and the Administrative area around Delhi. About 1061 million of the nation's 1189 million people (89%) are covered by this survey. Without exception, opioid availability continues to be low throughout all of India. Even when opioids are on formulary, they are often unavailable. Access is significantly impaired by widespread over-regulation that continues to be pervasive across the nation.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in the Middle East: a report from the Global Opioid Policy Initiative (GOPI).

The Middle East is a heterogeneous region with substantial variability in social development, wealth and palliative care development. The region has few democracies, strong but diverse religious affiliations, and many of the region's counties are involved in political upheavals or regional conflicts. While the global consumption of opioids has increased throughout the last 30 years, there has been little increase in opioid consumption in the Middle East. This is the first comprehensive study of opioid availability and accessibility of opioids in the Middle East. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 16 of 24 countries. The data are relevant to 329 million of the region's 403 million people (82%). The survey found that with the exception of Israel, opioid availability continues to be low throughout most of the Middle East. Formulary deficiencies are severe in several countries in particular Afghanistan, Iraq, Lebanon, Libya, Palestine and Tunisia. Even when opioids are on formulary, they are often unavailable, particularly in these same countries. Access is also significantly impaired by widespread over-regulation that is pervasive across the region.

Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Africa: a report from the Global Opioid Policy Initiative (GOPI).

With nearly 1.1 billion inhabitants living in more than 50 countries, Africa is the world's poorest and most socioeconomically underdeveloped continent. Despite some advances for individual states, many African countries have very low opioid consumption and, overall, the continent has the lowest consumption per capita of any in the world. This article presents the findings of the first systematic study of the availability and accessibility of opioids for the management of cancer pain across the continent. Data are reported on the availability and accessibility of opioids for the management of cancer pain in 25 of 52 countries, with 744 million of the region's 1127 million people (66%) covered by the survey. Many countries had severely restricted formularies of opioids and only 15 of 25 had morphine available in oral IR, CR and injectable formulations. Even when opioids are on formulary they are often unavailable, and access is significantly impaired by widespread over-regulation that is pervasive across the region.

[The mechanism of action of cannabis and cannabinoids]. / Het werkingsmechanisme van cannabis en cannabinoïden.

The effect ofcannabis can be explained on the basis of the function of the cannabinoid receptor system, which consists of CB receptors (CB1, CB2), endoligands to activate these receptors and an enzyme--fatty acid amidohydrolase--to metabolize the endoligands. The endoligands of the cannabinoid receptor system are arachidonic acid-like substances, and are called endocannabinoids. Indications exist that the body also contains arachidonic acid-like substances that inhibit fatty acid amido hydrolase. Various cannabinoids have diverse effects on the receptors, functioning as agonists, antagonists or partial antagonists, as well as affecting the vanilloid receptor. Many known effects ofcannabis can be explained on the basis of this mechanism of action as can the use ofcannabis in various conditions including multiple sclerosis, Parkinson's disease, glaucoma, nausea, vomiting and rheumatoid arthritis.

A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia.

Relapses after initial successful treatment in acute myeloid leukemia are thought to originate from the outgrowth of leukemic stem cells. Their flow cytometrically assessed frequency is of importance for relapse prediction and is therefore assumed to be implemented in future risk group profiling. Since current detection methods are complex, time- and bone marrow consuming (multiple-tubes approach), it would be advantageous to have a broadly applicable approach that enables to quantify leukemia stem cells both at diagnosis and follow-up. We compared 15 markers in 131 patients concerning their prevalence, usefulness and stability in CD34(+)CD38(-) leukemic stem cell detection in healthy controls, acute myeloid leukemia diagnosis and follow-up samples. Ultimately, we designed a single 8-color detection tube including common markers CD45, CD34 and CD38, and specific markers CD45RA, CD123, CD33, CD44 and a marker cocktail (CLL-1/TIM-3/CD7/CD11b/CD22/CD56) in one fluorescence channel. Validation analyses in 31 patients showed that the single tube approach was as good as the multiple-tube approach. Our approach requires the least possible amounts of bone marrow, and is suitable for multi-institutional studies. Moreover, it enables detection of leukemic stem cells both at time of diagnosis and follow-up, thereby including initially low-frequency populations emerging under therapy pressure.

Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia.

As relapses are common in acute myeloid leukemia (AML), early relapse prediction is of high importance. Although conventional minimal residual disease (MRD) measurement is carried out in bone marrow (BM), peripheral blood (PB) would be an advantageous alternative source. This study aims to investigate the specificity of leukemia-associated immunophenotypes used for MRD detection in blood samples. Consistency of PB MRD as compared with BM MRD was determined in flow cytometric data of 205 paired BM and PB samples of 114 AML patients. A significant correlation was found between PB and BM MRD (r=0.67, P<0.001), while median PB MRD percentage was factor 4-5 lower compared with BM MRD. Primitive blast (CD34+/CD117+/CD133+) frequency was significantly lower in PB (median factor 23.7), indicating that PB MRD detection is more specific than BM. Cumulative incidence of relapse 1 year after induction therapy was 29% for PB MRD-negative and 89% for PB MRD-positive patients (P<0.001). Three-year OS was 52% for MRD-negative and 15% for MRD-positive patients (P=0.034). Similar differences were found after consolidation therapy. As PB MRD appeared to be an independent predictor for response duration, the highly specific PB MRD assay may have a prominent role in future MRD assessment in AML.

Modernizing methodology for the WHO assessment of substances for the international drug control conventions.

BACKGROUND: The WHO Executive Board revised the guidance that governs the procedures for the WHO review of psychoactive substances for international drug control in 2010. To meet the standards defined in these guidelines, the current evaluation methodology at WHO must be an evidence-based assessment. METHODS: We describe the history of substance evaluation from 1912 to the present and the development of the evaluation methods over time including a description of the current assessment system, using reports from WHO and its predecessor, the League of Nations. Furthermore, we describe the current review system. RESULTS: We found that some substances under international control were never reviewed; other substances were reviewed decades ago. CONCLUSIONS: We argue that assessments do not have unlimited validity, and therefore, substances need to be re-assessed periodically, as already recommended by the Expert Committee on Drug Dependence in 1982. We propose that the evaluation time be shortened; that the influence of the route of administration and/or dosage form of the preparation is considered in the evaluation; and we recommend studying national and regional assessment systems and adopting their best practices. With this article, we make a case for the inclusion of systematic review and other methods of comprehensive analysis of substance evaluation to arrive at a process of equal rigour and quality as already applied by WHO for the development of treatment guidelines.

Minimal residual disease detection defined as the malignant fraction of the total primitive stem cell compartment offers additional prognostic information in acute myeloid leukaemia.

INTRODUCTION: Immunophenotypic detection of minimal residual disease (MRD) in bone marrow (BM) of acute myeloid leukaemia (AML) patients is of high prognostic relevance. Standard MRD percentage is assessed as a percentage of total white blood cells (WBCs) and is therefore highly dependent on WBC count. Peripheral blood (PB) contains more than five times lower MRD percentages. Therefore, PB in BM aspirates cause dilution of the MRD cells, possibly leading to false-negative results for BM MRD. The latter is avoided when relating the fraction of malignant primitive cells, identified by aberrant marker expression [aberrant primitive cells (aPC)], to the total population of primitive cells. Such a fraction may in addition reflect an important biological parameter. METHODS: As this approach is thus independent of WBC count and the total size of the primitive compartment, we investigated the role of aPC fractions on overall and relapse-free survival (RFS) in 98 patients with AML under the age of 60. RESULTS: We show that this approach identifies MRD-negative (as defined by % of WBC) but aPC-positive (as defined by % of primitive cells) patients with poor outcome after both first and second induction cycle of chemotherapy. CONCLUSION: As a result, in cases with a primitive marker present, RFS is best predicted when combining standard MRD percentage with aPC fractions.