morphinans and Chronic-Disease

Chronic pruritus is frequently refractory to currently available treatments. Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus in both animals and humans. The antipruritic effect of kappa-opioid receptors agonists can currently be assumed to be related to their binding to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. To date, several case reports and 2 controlled trials have demonstrated a beneficial effect of systemic kappa-opioid receptor agonists in the treatment of uraemic pruritus, prurigo nodularis, paraneoplastic and cholestatic pruritus. Nalfurafine hydrochloride (Remitch(®)), a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan. The aim of this review is to provide an overview of the promising role of kappa- opioid receptors and their agonist in the pathophysiology and treatment of pruritus.

Topics: Animals; Antipruritics; Butorphanol; Chronic Disease; Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds; Treatment Outcome

Thirty patients with cancer pain completed a double-blind crossover study comparing controlled-release (CR) and immediate-release (IR) oxycodone. In open-label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double-blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (+/- SD) pain intensity (0 = none to 10 = severe) decreased from a baseline of 6.0 +/- 2.2 to 2.7 +/- 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double-blind treatment: 2.7 +/- 1.9 with CR oxycodone and 2.8 +/- 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double-blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biological Availability; Chronic Disease; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Pain Measurement; Therapeutic Equivalency; Vomiting

Sixty hospitalized subjects with chronic moderate to severe pain as a result of advanced cancer were enrolled in a randomized, parallel, double-blind trial comparing single doses and multiple doses of intramuscular dezocine (10 mg) with butorphanol (2 mg) and placebo. During the initial 6-hour efficacy evaluation, analgesia was measured using verbal and visual scriptors and vital signs, and acute toxicity information was recorded. Subjects with initial pain relief entered the 7-day multidose portion of the trial, and efficacy and toxicity data were recorded daily. After the initial dose the peak analgesia of the active agents was similar, but the duration of analgesia was longer with dezocine. After multiple doses, dezocine was superior to butorphanol in terms of length of treatment. Dezocine had less toxicity than had butorphanol after both single and repeated doses, further suggesting that dezocine may be beneficial in managing chronic cancer pain. The described study design is unique in that it compares the analgesic efficacy and toxicity of several analgesics with placebo after both single and multiple doses in the same subject. This method may prove to be an alternative pain model to evaluate chronic cancer pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds, Heterocyclic; Butorphanol; Chronic Disease; Clinical Trials as Topic; Cycloparaffins; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Neoplasms; Pain; Random Allocation; Tetrahydronaphthalenes

Topics: Adult; Antiparkinson Agents; Basal Ganglia Diseases; Biperiden; Chronic Disease; Clinical Trials as Topic; Cyclohexylamines; Evaluation Studies as Topic; Handwriting; Humans; Male; Middle Aged; Morphinans; Movement Disorders; Parkinson Disease; Psychiatric Status Rating Scales; Schizophrenia; Sulfonic Acids; Time Factors; Tranquilizing Agents

BACKGROUND In the present study, we aimed to investigate the effects of sinomenine (SIN) on chronic intermittent hypoxia (CIH)- induced lung injury in rats, and to explore the underlying mechanisms. MATERIAL AND METHODS To perform the investigation, a CIH rat model was established. ELISA assay was applied to detect the level of inflammatory cytokines. Oxidative stress bio-markers (MDA, SOD, and CAT) were determined in lung tissues. In addition, the expression level of NADPH oxidase 2 (Nox2) was analyzed by Western blotting and qRT-PCR, respectively. RESULTS The results showed that compared with other groups, more obvious pulmonary pathological changes were observed in the CIH group. The level of inflammatory cytokines in the CIH group was markedly higher than that in the control and Con-S groups. Compared with the control and Con-S groups, oxidative stress was notably increased in the CIH group. Expression of Nox2 was also increased in the CIH group. The effects caused by CIH in rats were attenuated by SIN treatment. CONCLUSIONS SIN can reverse chronic intermittent hypoxia-induced lung injury through inhibiting inflammation and oxidative stress.

Topics: Animals; Chronic Disease; Cytokines; Down-Regulation; Hypoxia; Inflammation; Inflammation Mediators; Lung; Lung Injury; Male; Mice; Morphinans; NADPH Oxidases; NF-E2-Related Factor 2; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction

Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients.. A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 μg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment.. Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses.. Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.

Topics: Adult; Aged; Aged, 80 and over; Antipruritics; Chronic Disease; Female; Humans; Liver Diseases; Male; Middle Aged; Morphinans; Patient Reported Outcome Measures; Pruritus; Quality of Life; Spiro Compounds; Surveys and Questionnaires; Treatment Outcome

Uremic pruritus in patients on hemodialysis is associated with depression, lower quality of life, and mortality. We studied the prevalence, awareness, and treatment of pruritus to assess how well this important condition is currently managed internationally.. Data from 35,452 patients on hemodialysis in up to 17 countries from the Dialysis Outcomes and Practice Patterns Study were analyzed to describe pruritus prevalence from 1996 to 2015. Data from 6256 patients and 268 medical directors in 17 countries in 2012-2015 were analyzed to describe predictors, effects, medical directors' awareness, and treatment of pruritus.. Patients very much or extremely bothered by itching declined from 28% in 1996 to 18% in 2015. In 2012-2015, among patients nearly always or always bothered by itching, pruritus had a major effect on work and social life; 18% used no treatment for pruritus, and 17% did not report itching to health care staff. In total, 69% of medical directors underestimated the prevalence of pruritus in their unit. Managing high serum phosphorus and low Kt/V was ranked as the most important intervention, but no relationship was found between these factors and pruritus; 57% of medical directors used oral antihistamines for first-line chronic treatment of pruritus. Gabapentin was used by 45% as first-, second-, or third-line treatment. Nalfurafine was only used in Japan.. The prevalence of pruritus in people on hemodialysis is decreasing but remains underestimated. Large numbers of patients on hemodialysis with severe pruritus do not receive treatment. There is wide variation in the use of unlicensed medications for the treatment of pruritus. These data provide a benchmark for initiatives to improve the management of uremic pruritus.. This article contains multimedia at https://vimeo.com/49458473This article contains multimedia at vimeo.com/49455976.

Topics: Aged; Aged, 80 and over; Amines; Antipruritics; Chronic Disease; Cyclohexanecarboxylic Acids; Female; Gabapentin; gamma-Aminobutyric Acid; Health Knowledge, Attitudes, Practice; Histamine Antagonists; Humans; Hyperphosphatemia; Internationality; Male; Middle Aged; Morphinans; Nephrology; Practice Patterns, Physicians'; Prevalence; Pruritus; Renal Dialysis; Risk Factors; Spiro Compounds; Surveys and Questionnaires; Uremia

Opioids are the preferred analgesic drugs to treat severe chronic pain conditions among dialysis patients; however, knowledge about their dialyzability features is limited. Oxycodone is increasingly used for the treatment of chronic pain conditions as oral controlled release (CR) tablets; however, evidence about this drug and its metabolites' dialyzability is lacking.. We assessed, during 4-hour dialysis sessions, the effect of standard hemodialysis (HD) and online hemodiafiltration (HDF) methods on the plasma concentration of oxycodone and its metabolites in n = 20 chronic pain patients with end-stage renal disease who were stably treated with oral CR oxycodone. Chromatographic techniques were used to evaluate the studied compounds' plasma concentrations at three different time points during dialysis.. Mean plasma concentrations of oxycodone and noroxycodone in the sample showed an overall reduction trend over time, but it was less enhanced for noroxycodone. Mean reduction in oxycodone and noroxycodone arterial concentrations was significant and higher with HDF (54% and 27%, respectively) than with HD (22% and 17%, respectively). Analysis of the regression of these compounds' clearance on their increasing arterial concentration showed a more stable and linear clearance prediction with HDF (roughly 85 mL/min); with HD, for increasing arterial concentration, clearance of oxycodone decreased while noroxycodone clearance increased.. While no oxymorphone or noroxymorphone metabolites were detected, limited dialyzability of oxycodone and noroxycodone was documented along with insignificant postdialysis pain increment. This evidence will contribute toward considerations as to the safety of the use of oxycodone in dialysis patients in the future.

Topics: Adult; Analgesics, Opioid; Chronic Disease; Chronic Pain; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Renal Dialysis

Chronic inflammation mediated by microglial cells is the fundamental process contributing to the death of dopamine (DA)-producing neurons in the brain. Production of inflammatory products by these microglial cells characterizes the slow destructive process in Parkinson's disease (PD). The activation of microglial cells and the generation of pro-inflammatory cytokines that characterize PD are mediated by several different signaling pathways, with the activation of the respiratory burst by microglial cells being a critical event in the ultimate toxicity of DA-neurons. The work on our lab is concerned with understanding the mechanisms of activation, response, and therapeutic targets of microglial cells, with the aim to provide more effective treatments for PD and other inflammatory diseases of the CNS.

Topics: Brain; Chronic Disease; Cytokines; Dopamine; Humans; Inflammation; Microglia; Morphinans; Parkinson Disease

Chronic cough is defined as that which is persisting at least for trhee weeks without an evident cause. It is very common on the otorhinological practice to receive patients with chronic cough in order to rule out that their chronic cough is not produced because of an alteration in the high respiratory system. We show a clinical case with chronic cough and we make reference to the physical exploration, diagnostical method, and possibilities of medical and surgical treatment.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Ulcer Agents; Antitussive Agents; Chronic Disease; Cough; Esophageal pH Monitoring; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Lansoprazole; Middle Aged; Morphinans; Radiography, Thoracic; Rhinitis, Vasomotor; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Turbinates

Chronic rejection (CR) with graft vasculopathy is recognized as a major cause of graft loss over time. Sinomenine (SN) has anti-inflammatory, antirheumatic, and immunomodulatory effects. Previously, we demonstrated antimacrophage and anti-T cell effects of SN in acute rejection. In the current study, we investigated the effect of SN in a rat cardiac allograft model of CR.. After a brief course of cyclosporine A (CsA), Lewis recipients of F344 hearts were treated with SN alone, CsA alone, or a combination of both drugs. Grafts were analyzed morphometrically and by immunohistochemistry. Expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and endothelin 1 was assessed by reverse transcription-polymerase chain reaction. Antidonor IgM formation was investigated by FACS.. Cardiac grafts from SN-treated rats showed less pronounced vasculopathy in comparison with untreated rats or CsA-treated recipients. After treatment with a combination of both drugs, rats had significantly less graft vasculopathy than rats receiving either drug alone. Treatment with CsA alone led to a decrease in bFGF expression, whereas SN alone did not affect gene expression. SN in combination with CsA, however, markedly reduced expression of bFGF, vascular endothelial growth factor, and endothelin 1. SN alone did not inhibit antidonor antibody formation.. These studies demonstrate for the first time the therapeutic value of SN in a model of chronic cardiac allograft rejection. SN in combination with low-dose T cell-targeted immunosuppression is effective in controlling tissue remodeling in the context of CR and is associated with inhibition of intragraft expression of mediators involved in angiogenesis, vascular tone, and tissue remodeling.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Chronic Disease; Cyclosporine; Cytokines; Drug Therapy, Combination; Graft Rejection; Growth Substances; Heart; Heart Transplantation; Immunosuppressive Agents; Male; Morphinans; Myocardium; Rats; Rats, Inbred F344; Transplantation, Homologous; Ventricular Remodeling

Co-localization of opioid and melanocortin receptor expression, especially at the spinal cord level in the dorsal horn and in the gray matter surrounding the central canal led to the suggestion that melanocortins might play a role in nociceptive processes. In the present studies, we aimed to determine the effects of melanocortins, administered intrathecally, on allodynia, and to ascertain whether there is an interaction between opioid and melanocortin systems at the spinal cord level. Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Tactile allodynia was assessed using von Frey filaments, while thermal hyperlagesia was evaluated in cold water allodynia test. In the present experiments, melanocortin receptor antagonist, SHU9119 was much more potent than mu-opioid receptor agonist, morphine after their intrathecal (i.th.) administration in neuropathic rats. SHU9119 alleviated allodynia in a comparable manner to DAMGO, a selective and potent mu-opioid receptor agonist. Administration of melanocortin receptor agonist, melanotan-II (MTII) increased the sensitivity to tactile and cold stimulation. Moreover, we demonstrated that the selective blockade of mu-opioid receptor by cyprodime (CP) enhanced antiallodynic effect of SHU9119 as well as pronociceptive action of MTII, whereas the combined administration of mu receptor agonist (DAMGO) and SHU9119 significantly reduced the analgesic effect of those ligands. DAMGO also reversed the proallodynic effect of melanocortin receptor agonist, MTII. In conclusion, it seems that the endogenous opioidergic system acts as a functional antagonist of melanocortinergic system, and mu-opioid receptor activity appears to be involved in the modulation of melanocortin system function.

Topics: alpha-MSH; Analgesics, Opioid; Animals; Chronic Disease; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Spinal; Male; Melanocyte-Stimulating Hormones; Morphinans; Morphine; Nociceptors; Oligopeptides; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Opioid, mu; Sciatica; Spinal Cord

During a 2-year period, 150 patients were treated with epidural opioids for more than 7 days; 89 received morphine and 61 buprenorphine. In 16 cases, medication was changed from morphine to buprenorphine, and in 6 from buprenorphine to morphine. In 19 patients in each group, the disease process was benign. The median daily dose of morphine was 17 mg given by an average of 2.9 injections; the corresponding figures in the buprenorphine group were 1.3 mg and 2.6 injections. The mean duration of treatment was 49 days (7-397) in the morphine group and 53 days (7-262) in the buprenorphine group. Satisfactory pain relief was achieved in 40 (45%) patients who received morphine and 41 (67%) patients given buprenorphine. Altering medication from morphine to buprenorphine improved analgesia in 32% of patients, while the reverse improved pain relief in a further 46% of the patients. Side effects were reported in 46% of patients given morphine and 20% given buprenorphine. Seventy-one patients were treated on an outpatient basis. In these cases, buprenorphine was administered for 89% of the total duration of treatment and morphine chloride for 52%.

Topics: Buprenorphine; Chronic Disease; Epidural Space; Humans; Injections; Morphinans; Morphine; Pain; Retrospective Studies

Buprenorphine was administered as sublingual tablets to 70 patients suffering from chronic pain of malignant or non-malignant origin. Daily doses ranging from 0.4 mg to 3.2 mg were administered and good analgesia was reported by the majority of patients. The most common unwanted effects were drowsiness/sleepiness, nausea and/or vomiting and sweating which appeared to be dose related but the incidence of dizziness was not related to daily dose. The incidence of all these unwanted effects except drowsiness/sleepiness decreased after the first week's treatment. No buprenorphine related changes in vital signs or laboratory values were observed and no signs of tolerance or physical dependence were seen in the short term period after discontinuation of treatment. A significant positive correlation between buprenorphine plasma concentration and daily dose was observed but there was no correlation between plasma levels and pain relief.

Topics: Administration, Oral; Adult; Aged; Buprenorphine; Chronic Disease; Evaluation Studies as Topic; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Pain

This case-report of a 78-year old patient, suffering from extreme pain caused by metastatic formation and pathological bone fractures, shows, that the epidural injection of buprenorphine is a good alternative compared to other means of pain-treatment. During almost four days heart rate, blood pressure and breathing frequency, as well as the general reactions of the patient, were observed. Few side effects and little discomfort make the method advisable for patients in poor general condition.

Topics: Aged; Anesthesia, Epidural; Breast Neoplasms; Buprenorphine; Chronic Disease; Epidural Space; Female; Femoral Neck Fractures; Humans; Injections; Morphinans; Neoplasm Metastasis; Pain

Topics: Animals; Biopsy; Cell Membrane; Cell Nucleus; Chronic Disease; Cytoplasmic Granules; Humans; Male; Mast Cells; Microscopy, Electron; Morphinans; p-Methoxy-N-methylphenethylamine; Rats; Skin; Stimulation, Chemical; Urticaria; Urticaria Pigmentosa

Topics: Acute Disease; Aged; Aging; Bronchitis; Chronic Disease; Cough; Drug Combinations; Humans; Laryngitis; Morphinans; Pentylenetetrazole; Pharyngitis; Respiratory Insufficiency