Małgorzata Krajnik

Understanding pruritus in systemic disease.

Many pruritic conditions do not originate in the skin, but are the result of systemic abnormality. Among the diseases that can cause pruritus are renal insufficiency, cholestasis, Hodgkins lymphoma, polycythemia vera, solid tumors, and many others. Other pruritic conditions appear to be iatrogenic; opioid-induced pruritus may be the most important in palliative medicine. Successful treatment of the underlying condition usually relieves itch. But, with time, many diseases progress and treatment of the cause will be impossible. Topical treatments may be of limited value. Strategies involving systemic treatments include use of antidepressants, oral opioid antagonists, or cholestyramine. There is no one cure for all pruritic symptoms. Better understanding of mechanisms of pruritus may help develop better treatments.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the study of pain and the Polish Neurological Society - part one.

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.

The presence of mu-, delta-, and kappa-opioid receptors in human heart tissue.

Abstract Functional evidence suggests that the stimulation of peripheral and central opioid receptors (ORs) is able to modulate heart function. Moreover, selective stimulation of either cardiac or central ORs evokes preconditioning and, therefore, protects the heart against ischemic injury. However, anatomic evidence for OR subtypes in the human heart is scarce. Human heart tissue obtained during autopsy after sudden death was examined immunohistochemically for mu- (MOR), kappa- (KOR), and delta- (DOR) OR subtypes. MOR and DOR immunoreactivity was found mainly in myocardial cells, as well as on sparse individual nerve fibers. KOR immunoreactivity was identified predominantly in myocardial cells and on intrinsic cardiac adrenergic (ICA) cell-like structures. Double immunofluorescence confocal microscopy revealed that DOR colocalized with the neuronal marker PGP9.5, as well as with the sensory neuron marker calcitonin gene-related peptide (CGRP). CGRP-immunoreactive (IR) fibers were detected either in nerve bundles or as sparse individual fibers containing varicose-like structures. Our findings offer the first hint of an anatomic basis for the existence of OR subtypes in the human heart by demonstrating their presence in CGRP-IR sensory nerve fibers, small cells with an eccentric nucleus resembling ICA cells, and myocardial cells. Taken together, this suggests the role of opioids in both the neural transmission and regulation of myocardial cell function.

Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients

Evidence is accumulating regarding the local opioid regulation of physiologic respiratory functions. However, anatomical evidence for a local opioid network of the respiratory system is scarce. In this study, tissue samples from 12 lung cancer patients undergoing lobectomy or pneumonectomy were examined immunohistochemically for the expression of the opioid network components met-enkephalin, the respective precursor proenkephalin, the key processing enzymes prohormone convertases 1 and 2, carboxypeptidase E, and the delta opioid receptor in different areas of human lung. Colocalization of proenkephalin with met-enkephalin, prohormone convertase 1, prohormone convertase 2, and carboxypeptidase E was demonstrated by double-immunofluorescence confocal microscopy in alveolar macrophages, submucosal glands, cancerous cells, and pulmonary neuroendocrine cells of bronchial epithelium. Corresponding delta opioid receptor was identified on cells of all these functionally relevant anatomical structures and on substance P-immunoreactive sensory nerve fibers arborizing within bronchial epithelium. Our findings provide evidence of a local opioid network, that is, the exact anatomical localization of proenkephalin, its functionally active peptide met-enkephalin, and the key processing enzymes as well as corresponding delta opioid receptor, linked to functionally important structures of the respiratory system. These findings encourage future studies to examine the functional role of local opioid peptides within the respiratory system.

Morphine Inhalation by Cancer Patients: A Comparison of Different Nebulization Techniques Using Pharmacokinetic, Spirometric, and Gasometric Parameters

Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System-Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2-5microm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5-2microm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6+/-2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8+/-8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20-40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs.

Local pulmonary opioid network in patients with lung cancer: a putative modulator of respiratory function

Recently, there has been growing interest in the opioid regulation of physiological respiratory function. However, evidence for a local opioid network that includes endogenous opioid peptides and their receptors is scarce. Tissue samples from patients with lung cancer were examined by immunohistochemistry to identify the components of the opioid network: beta-endorphin (END); its precursor, proopiomelanocortin (POMC); the key processing enzymes prohormone convertase 1 and 2; carboxypeptidase E; and ENDs corresponding opioid receptor, the mu-opioid receptor (MOR). Additionally, we tested pulmonary function parameters in a patient with advanced lung cancer after inhalation of nebulized morphine. Confocal immunofluorescence microscopy revealed that the opioid precursor POMC colocalizes with its active peptide END, key processing enzymes and MOR in alveolar macrophages, submucosal glands, cancerous cells, and pulmonary neuroendocrine cells within the bronchial epithelium. In addition, MOR was identified on sensory nerve endings within the bronchial epithelium. Furthermore, nebulized morphine improved pulmonary function parameters in advanced lung cancer. These findings provide evidence of a local opioid network in functionally important anatomical structures of the respiratory system; this network consists of all the machinery required for POMC processing into active peptides, such as END, and contains the receptors for END. Our findings indicate a need for further clinical trials to elucidate the modulatory function of peripheral endogenous opioids in the human lung.

The need to research refractory breathlessness.

The joint American Thoracic Society (ATS)/European Respiratory Society (ERS) statement “An official American Thoracic Society/European Respiratory Society statement: research questions in COPD” by Celli et al. [1] is a timely summary of the current evidence and the questions that arise directly from where that evidence reaches its limits. Such documents are crucial in framing research strategies for researchers and research funders. High-quality research is needed to improve quality of life for people with chronic refractory breathlessness in COPD http://ow.ly/Q2GDY

Funding models in palliative care: Lessons from international experience

Background: Funding models influence provision and development of palliative care services. As palliative care integrates into mainstream health care provision, opportunities to develop funding mechanisms arise. However, little has been reported on what funding models exist or how we can learn from them. Aim: To assess national models and methods for financing and reimbursing palliative care. Design: Initial literature scoping yielded limited evidence on the subject as national policy documents are difficult to identify, access and interpret. We undertook expert consultations to appraise national models of palliative care financing in England, Germany, Hungary, Republic of Ireland, New Zealand, The Netherlands, Norway, Poland, Spain, Sweden, Switzerland, the United States and Wales. These represent different levels of service development and a variety of funding mechanisms. Results: Funding mechanisms reflect country-specific context and local variations in care provision. Patterns emerging include the following: Provider payment is rarely linked to population need and often perpetuates existing inequitable patterns in service provision. Funding is frequently characterised as a mixed system of charitable, public and private payers. The basis on which providers are paid for services rarely reflects individual care input or patient needs. Conclusion: Funding mechanisms need to be well understood and used with caution to ensure best practice and minimise perverse incentives. Before we can conduct cross-national comparisons of costs and impact of palliative care, we need to understand the funding and policy context for palliative care in each country of interest.

Opioid receptor bronchial tree: current science.

Purpose of reviewSystemic opioids have the evidence to support their use in refractory dyspnea; however, the mechanisms of how they exert their effects are not fully understood. The relevance of peripheral mechanisms, in part, is still questioned, especially as a meta-analysis demonstrated no benefit from nebulized opioids. This might be related to the lack of standardization of the inhalation methods. There is a need to clarify whether peripheral opioid receptors may serve as the target for inhaled treatment and what are the potential peripheral mechanisms of opioids. Recent findingsOpioidergic systems are present in structures important for the regulation of bronchial and pulmonary vascular responses, as well as breathlessness perception in the human respiratory system. Opioid receptors located in the pulmonary neuroendocrine cells (PNECs) and sensory C-fibers within the bronchial epithelium are easily accessible for inhaled treatment. Morphine administrated by a pneumodosimetric method shows a different pharmacokinetic profile to those described for systemic routes, suggesting local metabolism in lung. SummaryResearch suggests that peripheral opioid receptors in lungs may be utilized as a target for therapeutic interventions. According to this hypothesis, to achieve breathlessness relief, opioids should be administered in close proximity to their receptors in the PNECs and sensory C-fibers of the bronchial epithelium.

End-of-life matters in chronic heart failure patients.

Purpose of reviewUntil recently, concepts of care for people with heart failure had rarely included preparation for unavoidable imminent death or caring for the dying.The purpose of this review is to provide an update on current end-of-life issues specific to heart failure patients. Recent findingsMortality in the heart failure population remains high, especially shortly after the first acute heart failure hospitalization. Patients with systolic heart failure die more frequently from progressive heart failure or sudden cardiac death; patients with diastolic heart failure for noncardiovascular reasons and sudden cardiac death. The mode of haemodynamic decline leading to heart failure death can be characterised by low cardiac output (with or without secondary end-organ dysfunction), congestion, or a combination of both. A new model of end-of-life trajectories has been proposed which takes into account influence of comorbidities on the prognosis of heart failure. Advance care planning for patients with implanted cardiac devices has been shown to be unsatisfactory. A recent strategy for managing implantable cardioverter defibrillators in patients approaching death is presented. SummaryThere is an emerging need to define specific challenges for end-of-life care for approaching death in heart failure patients. More research and education are needed to improve care for dying heart failure patients, including those with implanted cardiac devices.