Innovations In Clinical Neuroscience

Pain Management August 2016

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Hot Topics in Pain Management [August 2016] 10 fentanyl, were all administrated at f ixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of o pioids and required higher doses for pain management were determined and compared. Results. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Conclusion. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer. BACKGROUND As suggested in National Comprehensive Cancer Network (NCCN) guidelines, pain management contributes to broad quality-of-life improvement (www.nccn.org) [1, 2]. As pain killer for moderate to severe pain, opioids, like morphine, oxycodone and fentanyl approved by FDA, are widely used for pain management of cancer patients, particularly those with advanced diseases [3, 4]. Because of potential drug abuse, tolerance development, addiction and other side effects of opioids, opioid administration is under tight regulation to limit the usage and to avoid possible abuse. Opioids are normally administrated at relative low dose initially, and the dose is increased only if the pain is unchanged or increased during next pain level assessment. Therefore, the analgesia effects of opioids are important during pain management of cancer patients. Identifying the f actors that affect opioid analgesia and understating the underlying mechanisms may provide a better protocol to treat cancer pain with opioids and improve patients' q uality-of-life. In previous studies, cholesterol has already been identified as one of many factors that can affect functions of opioids [5, 6]. As a major mediator for morphine analgesia [7, 8], μ-opioid receptor (OPRM1 or MOR) locates in cholesterol-rich lipid raft micro- domain on cell membrane as some other G protein-coupled receptors (GPCRs) [9, 10, 11]. Cellular cholesterol regulates signal transduction of OPRM1 not only by supporting the entity of lipid raft micro-domain which subsequently maintains a specific membrane location for the interaction between OPRM1 and other signaling molecules, like G proteins and adenylyl cyclases, but also by stabilizing OPRM1 homodimerization and G protein coupling [5, 9]. Extracting cellular cholesterol or inhibiting cholesterol synthesis impairs the downstream signaling of OPRM1, like adenylyl cyclase inhibition, in HEK cell models and primary culture of rat neurons [6, 9, 12]. Actually, similar to the widely accepted understanding on GPCR and lipid raft [13, 14], the connection between cholesterol and opioid signaling has also be reported and confirmed by other laboratories. For example, reducing cholesterol level by methyl-β-cyclodextrin, a commonly used disruptor of lipid raft, impairs the signaling of δ-opioid receptor in neuronal cells [15], and cholesterol content is critical for δ- opioid receptor binding [16]. The contributions of cholesterol to OPRM1 signaling have also been described in rat caudate putamen [17], Chinese Hamster Ovary cells [18], and Human Embryonic Kidney Cells [19]. In addition, cholesterol level is important for opioid functions in vivo. By manipulating the lipid and cholesterol content in diet or a dministrating cholesterol lowering drug, simvastatin, the cholesterol levels in serum and brain of mice could be regulated successfully and significantly. Mice with high serum c holesterol levels require less morphine or fentanyl to achieve the similar analgesia effects than those with low serum cholesterol levels [6], suggesting analgesia abilities of opioids have a good correlation with cholesterol levels in mice. In addition, hypercholesterolaemic rabbits have significant increase in their responses to κ-opioid receptor agonist, which also suggests a correlation between high cholesterol level and enhanced opioid function in vivo [20]. Our previous studies also performed investigation on human subjects. When analyzing fentanyl usages for anesthesia before and during surgery, significant correlation was also identified between fentanyl usages and cholesterol levels in both male and female patients [6]. Thus, it is reasonable to hypothesize that patients with low cholesterol levels require higher doses of opioids for pain management. In previous studies with human patients, fentanyl was used for surgical anesthesia and the correlation might not be applicable when opioids were used as pain killer [6]. Thus in current studies, an extensive study was carried out to identify potential correlation between cholesterol levels and opioid usages during cancer pain management. Clinical records of patients met certain criteria were selected out from about 9,000 patients with lung cancer. RESULTS Clinical records of 282 patients are collected. The current studies were focused on patients with lung cancer, because lung cancer is the cancer with highest disease incidence and lethality rate in China [21, 22]. Improving pain management for these patients has significant social benefits.

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