Less Well-Known Consequences of the Long-Term Use of Opioid Analgesics: A Comprehensive Literature Review.

BACKGROUND: The adverse effects of short-term opioid analgesics are well known and acknowledged; however, the spectrum of the sequelae of long-term use seems less clear. Some effects may remain undetected but still have the potential to cause harm and reduce patients' quality of life. OBJECTIVE: To review the literature on the adverse effects of long-term opioid therapy. METHODS: We performed a quasi-systematic search, analyzing articles published in the MEDLINE database between January 2000 and March 2021 that identified adverse effects of opioids used for chronic pain treatment. RESULTS: Growing evidence indicates that there are multiple serious adverse effects of opioid treatment. Long-term opioid use may have significant effects on the endocrine, immune, cardiovascular, respiratory, gastrointestinal, and neural systems. Studies show that long-term opioid treatment increases the risk of fractures, infections, cardiovascular complications, sleep-disordered breathing, bowel dysfunction, overdose, and mortality. Opioids may potentially affect cancer development. Most consequences of the long-term use of opioids have been identified in studies of patients with non-malignant pain. CONCLUSION: Studies indicate that long-term use of opioids increases the risk of drug-related events in a significant number of patients. Clinicians should be aware of these complications associated with prescribing opioids, discuss them with patients, prevent complications, if possible, and diagnose them early and manage adequately. More human studies are needed to assess the risk, including trials with individual opioids, because they have different adverse effect profiles.

Paraneoplastic itch: an expert position statement from the Special Interest Group (SIG) of the International Forum on the Study of Itch (IFSI).

In clinical practice, the term "paraneoplastic itch" is used to describe itch in patients with cancer. Patients with hematological or solid tumor malignancies can be affected. In general, paraneoplastic itch is considered a rare disorder. However, paraneoplastic itch in hematological malignancies such as polycythemia vera and lymphoma are relatively frequent while other forms of paraneoplastic itch are in fact extremely rare. The true frequency of this symptom is unclear, epidemiological data in this field are limited. Itch in malignant disease may additionally impair patients' quality of life. A population-based cohort study showed that chronic itch without concomitant skin changes is a risk factor for having undiagnosed hematologic and bile duct malignancies. Paraneoplastic itch is rather resistant to treatment. In 2012, an interdisciplinary interest group of physicians and researchers was founded, aiming to generate a clear definition of paraneoplastic itch. In this paper we briefly review the current knowledge and aim to define what can be summarized under the term "paraneoplastic itch".

Dynorphin expression, processing and receptors in the alveolar macrophages, cancer cells and bronchial epithelium of lung cancer patients.

Functional evidence suggests that opioid peptides such as dynorphin are involved in the regulation of airway macrophage functions and of human cancer growth. However, anatomical evidence for components of a putative dynorphin network within lung cancer patients is scarce. Tissue from lung cancer patients was examined immunohistochemically for all components of a local dynorphin (DYN) network. Double immunofluorescence microscopy analysis revealed colocalization of the opioid precursor PDYN with its end-product DYN, and key processing enzymes prohormone convertases 1 and 2 and carboxypeptidase E, as well as the kappa-opioid receptor (KOR) within alveolar macrophages and cancerous cells in varying degrees among patients. Moreover, chromograninA-immunoreactive pulmonary neuroendocrine cells expressing DYN were close to substance P- and KOR-immunoreactive sensory nerves. Our findings give a first hint of a neuroanatomical basis for a peripheral DYN network, conceivably regulating pulmonary, immune and cell-proliferative functions within the human lung, most likely in a paracrine/autocrine fashion.

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 END's 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.

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.

Air humidity may influence the aerosol distribution of normal saline administered by closed or vented nebulizers operated continuously or dosimetrically.

In clinical practice the majority of inhaled agents require deposition in the most distant regions of the bronchial tree. Contrary to this, it is likely that morphine delivery in breathlessness and chronic cough should be directed to the tracheobronchial area. The aim of the present study was to assess how an environmental condition such as air humidity might influence the particle distribution of normal saline administered by closed or vented nebulizers operated continuously or dosimetrically. Aerosol generated as a saline solution was assessed for BCTSS (Bronchial Control Treatment System-Sidestream) and BCTS-MC (Bronchial Control Treatment System-Micro Cirrus), together with two pneumatic delivery systems: Pneumatic Inhalation-Sidestream (PI-S) and Pneumatic Inhalation-Micro Cirrus (PI-MC). To clarify the influence of humidity on the aerosol we introduced a fifth method, BCTS-S/C, which included a vented nebulizer operated continuously. The impact of different air humidity on the size of particles was examined. Only in the case of the vented methods (BCTS-S and BCTSS/C) of nebulization did air humidifying lead to a significant enlargement of particle size. Moreover, the mean particle size at 90% was almost twice as large with the use of BCTS-S than with BCTS-S/C. Our experiment demonstrated that ambient humidity has a greater effect on particle size with vented rather than nonvented nebulizers and the effect might be potentiated by the pulsative method of nebulization.

Severe pruritus of cholestasis in disseminated cancer: developing a rational treatment strategy. A case report.

Severe pruritus is a frequent complication of cholestasis. Both serotonin and opioids play an important role in the development of this symptom. Guidelines to provide rational management of pruritus of cholestasis do not exist. We describe a patient with complex and malignant course of pruritus. She responded to several measures proposed (among other naltrexone), but rapidly became tolerant to them. Buprenorphine with an ultra low dose of naloxone was able to control her symptoms without development of tolerance until her death.

What has dry cough in common with pruritus? Treatment of dry cough with paroxetine.

Distressing persistent dry cough is commonly the consequence of sensitization of the cough reflex. A slight and transient peripheral nociceptive impulse, such as bronchitis, may be perpetuated for weeks because of sensitization of the cough reflex. Cough usually can be inhibited by opioids, but some types of cough can be out of opioid control or even be induced by opioids. We describe here a series of 5 patients with dry cough that did not respond to codeine. Because two of these patients also suffered with pruritus, paroxetine was tried. In all patients, cough ceased within hours to days. The only observed adverse effect was sleepiness in the first days of therapy. Paroxetine should be investigated as antitussive in cases of opioid-resistant cough. The putative mechanism of action of paroxetine on pruritus and rough is discussed.

Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial.

Severe pruritus may be an idiopathic phenomenon or associated with advanced systemic disease. It is one of the most distressing and difficult to treat symptoms. Uncontrolled studies have suggested that, in patients experiencing severe pruritus, paroxetine appeared to have a rapid anti-pruritic effect. This study was a prospective double-blind, randomized within patient comparison of paroxetine and placebo. The intensity of pruritus was measured subjectively with a numerical analogue scale. The primary endpoint of the trial was the mean pruritus score, measured for seven days after randomization and after cross-over. The secondary endpoint was individual global response to the treatment. Response was defined as at least 50% reduction of intensity of pruritus in the last three days of the treatment period vs. baseline. Adverse effects and patient satisfaction and preferences were also recorded. Twenty-six patients were included in the study; 17 of them had solid tumors, 4 had hematological malignancies and 5 had various nonmalignant or idiopathic conditions. Eight patients had drug-induced pruritus (none opioid-induced), 7 patients had paraneoplastic pruritus and 3 had cholestatic pruritus. After a run-in period, patients were randomly assigned to treatment with 20 mg paroxetine or placebo. The crossover took place after 7 days. Two patients discontinued treatment because of adverse effects of paroxetine. Twenty-four patients treated with paroxetine had lower pruritus intensity scores over the 7 treatment periods (mean+/-SE=5.2+/-0.32) as compared to placebo (mean+/-SE=6.0+/-0.32). Mean difference between placebo and paroxetine was 0.78 (95% CI=0.37-1.19). Nine of twenty-four patients (37.5%) fulfilled criteria of response. The onset of anti-pruritic action was observed usually after 2-3 days, irrespective of the order of treatment. The outcome of this study indicates that paroxetine is effective in the treatment of severe pruritus of non-dermatological origin.