Effect of chronic lithium administration on endothelium-dependent relaxation of rat mesenteric bed: Role of nitric oxide

The mechanism of action of lithium, an effective treatment for bipolar disease, is still unknown. In this study, the mesenteric vascular beds of control rats and rats that were chronically treated with lithium were prepared by the McGregor method, and the mesenteric vascular bed vasorelaxation responses were examined. NADPH-diaphorase histochemistry was used to determine the activity of NOS (nitric oxide synthase) in mesenteric vascular beds. We demonstrated that ACh-induced vasorelaxation increased in the mesenteric vascular bed of rats treated with lithium. Acute No-nitro-L-arginine methyl ester (L-NAME) administration in the medium blocked ACh-induced vasorelaxation in the control group more effectively than in lithium-treated rats, while the vasorelaxant response to sodium nitroprusside, a NO donor, was not different between lithium-treated and control groups. Acute aminoguanidine administration blocked ACh-induced vasorelaxation of lithium-treated rats, but had no effect in the control rats. Furthermore, NOS activity, determined by NADPH-diaphorase staining, was significantly greater in the mesenteric vascular beds from chronic lithium-treated rats than in those from control rats. These data suggest that the enhanced ACh-induced endothelium-derived vasorelaxation in rat mesenteric bed from chronic lithium-treated rats might be associated with increased NOS activity, likely via iNOS. Simultaneous acute L-NAME and indomethacin administration suggests the possible upregulation of EDHF (endothelium-derived hyperpolarizing factor) in lithium-treated rats. © 2007 NRC

Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis

Background Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 - 250 mg. The aim of this review was to evaluate the safety of oral naltrexone by examining the risk of serious adverse events (SAEs) in randomised controlled trials (RCTs) of naltrexone compared to placebo. Methods A systematic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, other databases and clinical trials registries was undertaken up to March 2018. Parallel placebo-controlled RCTs longer than 4 weeks published after 1/1/2001, of oral naltrexone at any dose were selected. Any condition and age group were included, excluding only studies for opioid or ex-opioid users, due to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook throughout. Numerical data was independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane Risk of Bias Tool. Meta-analyses were performed using Stata 15 and R, using random and fixed effects models throughout. Results Eighty-nine RCTs with 11194 participants were found, studying alcohol use disorders, various psychiatric disorders, impulse control disorders, other addictions, obesity, Crohn’s disease, fibromyalgia and cancers. Twenty-six studies (4,960 participants) recorded SAEs occurring by arm of study. There was no evidence of increased risk of SAEs for naltrexone compared to placebo, relative risk (RR) 0.84 (95% CI: 0.66 to 1.06). Sensitivity analyses pooling risk differences supported this conclusion (RD = -0.01 (-0.02, 0.00)) and subgroup analyses showed that results were consistent across different doses and disease groups. The quality of evidence for this outcome was judged high using the GRADE criteria. Conclusions Naltrexone does not appear to increase the risk of SAEs over placebo. These findings confirm the safety of naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications

Pharmacological options for the management of refractory cancer pain—what is the evidence?

Refractory cancer pain that does not respond to standard opioid and/or co-analgesic therapy occurs in 10–20 % of patients. Risk factors include young age, neuropathic pain type, incident pain, psychological distress, previous opioid use, high tolerance, a history of addiction and impaired cognition. The management of patients with refractory pain remains a challenge. Treatment options include opioid manipulation (parenteral delivery, rotation, combination, methadone and buprenorphine), non-opioids and co-analgesics (paracetamol, non-steroidal anti-inflammatory agents, antidepressants and anticonvulsants), NMDA receptor antagonists, cannabinoids, lignocaine and corticosteroids. The evidence of benefit for any of these agents is weak, and each additional agent increases the risk of adverse events. Evidence-based guidelines cannot, therefore, be developed at present. New approaches are recommended including targeted opioid therapy, multimodal analgesia, a goal-oriented approach to pain management and increasing use of the multidisciplinary team and support services

Interventional options for the management of refractory cancer pain--what is the evidence?

PURPOSE: Pain is the most common symptom in cancer patients. Standard pain treatment according to the WHO three-step analgesic ladder provides effective pain management in approximately 70-90% of cancer patients. Refractory pain is defined as not responding to "standard" treatments. Interventional analgesic techniques can be used in an attempt to control refractory pain in patients in whom conventional analgesic strategies fail to provide effective pain relief or are intolerable due to severe adverse effects. This systematic review aims to provide the latest evidence on interventional refractory pain management in cancer patients. METHODS: Systematic literature search in Cochrane, EMBASE and PubMed including reviews and randomised controlled trials (RCTs) and non-randomised controlled trials in the absence of reviews. RESULTS: Neuraxial analgesia may play a role in refractory cancer pain management. Paravertebral blocks decrease the incidence of persistent post-surgical pain after breast cancer. Coeliac plexus blocks improve pain scores in refractory pancreatic cancer pain for up to 4 weeks after the intervention with fewer burdensome side effects as compared to opioids. Cordotomy has mainly been studied in mesothelioma, and the case series suggest possible benefit for pain at the expense of a relatively high risk of side effects. CONCLUSIONS: Overall, very few RCTs have been conducted on interventional pain techniques. In reality, it is very difficult to undertake large controlled trials for a number of reasons. Therefore, today's best evidence for practice may be from large case series of comparable patients with careful response and toxicity evaluation and follow-up

Morphine and breast tumor metastasis: the role of matrix-degrading enzymes

Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co-cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment

Effect of lysine antifibrinolytics and cyclooxygenase inhibitors on the proteolytic profile of breast cancer cells interacting with macrophages or endothelial cells

Extracellular matrix (ECM) proteases play a key role in the regulation of tumour invasion, growth, and transendothelial migration. The expression of ECM proteases and their endogenous inhibitors by cancer cells is regulated by stromal cells. We investigated the effect of commonly used perioperative medications on this regulation