Zbigniew Zylicz

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.

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.

Pruritus in the Course of Malignancy

Most patients who suffer from pruritus in the course of malignant diseases wish they had pain rather than itch. This recalcitrant symptom, although rare in most malignant diseases, is difficult to treat. The reason for this is that we know hardly anything about its etiology and treatment. Most therapeutic methods have been derived from empirical and serendipitous observations, rather than targeted research. In solid tumors (cancers) the incidence of severe itch is less than 1%.1 One of the authors (ZZ) interested in paraneoplastic itch has seen 32 cases in 15 years, treating more than 4,500 patients with advanced diseases during this time. In hematological malignancies, which are relatively rare in themselves, pruritus is much more common. In polycythemia vera up to 50%2 and in some rare cutaneous lymphomas as much as 100%3 of patients suffer from itch. On the other hand, chronic pruritus of unknown origin is thought to be associated with malignancies. Among 95 patients with this condition, a neoplasm was found in eight cases: seven hematological malignancies (three myeloma, two Hodgkin’s disease, and two myeloproliferative syndromes) and one solid cancer (pulmonary adenocarcinoma).4 This is in accordance with another study in which a thorough follow-up of 125 patients over 6 years with pruritus of unknown origin revealed no increased risk of cancer but a higher risk of lymphoma ( p < 0.01).5

Serotonin Reuptake Inhibitors and Other Antidepressants in the Treatment of Chronic Pruritus

The idea that antidepressants may be useful in the treatment of chronic pruritus appeared sometime in the 1990s. Although Zylicz et al. published a report in 1998 involving a series of patients suffering from various types of pruritus who responded to paroxetine,1 Browning et al.2 reported in 2003 on a group of 32 patients with primary biliary cirrhosis, also suffering from pruritus and having been observed for a mean of 7.5 years. In six out of seven patients who had been given sertaline initially for the treatment of depressive symptoms pruritus unexpectedly improved considerably, and in three of those subjects it completely disappeared.