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relative low dose of initial opioid a dministration, cholesterol levels should not be affected significantly. To further exclude this possibility, we selected and further analyzed the records of patients whose cholesterol l evels were measured again during the first month after opioid administration. The reason why we limited such investigation within the first month was to prevent the influences from cancer progression. In female patients, there were 16 patients had additional cholesterol measurement/s within the first month. For each of these 16 patients, all the measured cholesterol levels were normalized with the initial cholesterol level, and the largest difference in percentage was used for collective analysis. No significant change was identified on cholesterol levels were not significantly affected during first month after opioid administration (97 ± 9.1%, n = 16, P = 0.1528, Additional file 1: Table S1). Similar phenomenon was also observed with 32 male patients (97 ± 12%, n = 32, P = 0.7267, Additional file 1: Table S1). Thus opioid administration did not affect cholesterol level at least within our current paradigm. DISCUSSION As analyzed above, patients with low cholesterol have higher possibilities to require higher doses of opioids for pain management. Hence, we would like to suggest that pain level should be assessed more frequently or higher initial dose should be administrated for patients with low serum cholesterol levels in order to provide better pain management. Providing the patients with sufficient analgesic in a shorter time will reduce their suffering and improve their quality-of-life. In addition, we also suggested that the cholesterol levels of patients should be considered when determining the initial dose of opioid administration to reduce the overall usage of opioids. For example, lower/higher initial dose of opioid should be administrated for patients with high/low serum cholesterol l evels. During cancer progression, increasing doses of opioids are required for proper pain management not only because of the pain resulted from cancer enlargement and m etastasis, but also because of the development of opioid tolerance. The side effects of opioid like sedation and respiratory depression prevent us to treat tolerance by simply and un-limitedly increasing opioid doses [28, 29]. Therefore, reducing the overall usage of opioids slows the development of tolerance down, increases the available time for opioids to control cancer pain and subsequent improves quality-of-life. The mechanisms underlying the correlation between cholesterol level and opioid analgesia has been reported previously and mention in Introduction [5, 6]. Briefly, since opioids require proper signaling transduction of opioid receptor to function as analgesic, modulating opioid receptor is sufficient to affect the functions of opioids [30, 31]. In addition, cholesterol not only promotes the interaction between opioid receptor and downstream signaling factors as a main component of lipid raft micro-domain but also directly stabilize receptor homodimerization [5, 9]. Thus reducing cholesterol level impairs opioid function both in cells, in animal models [6, 9, 20], and there is a negative correlation between cholesterol level and opioid usage in current patients. Although the such correlation is weaker in vivo than in vitro, possibly because of the tighter regulation of cholesterol level in brain [32], it provides additional information for clinical application of opioids and agonists of other GPCRs. Since both the translocation of GPCRs into and out of lipid raft after agonist treatment have been reported [13, 33], it is reasonable to suggest the contributions of cholesterol to signaling transduction of other GPCRs, like Gonadotropin-releasing hormone receptors [34, 35], adrenergic receptor [36], cannabinoid receptor [37] and so on. Considering more than 40% marketed drugs t arget GPCRs [38, 39], it is possible to identify additional correlation between cholesterol level and drug function, which will be critical for related disease treatment and may f acilitate related research. In current database, only 282 patients were selected from about 9,000 lung cancer patients for the following reason. Firstly, surgery, radiation treatment, chemotherapy, or additional treatments for cancer- related syndrome may affect pain level within a short time frame and introduce additional difficulties and un-accuracy to the determination of "final dose" of opioids. Thus we excluded these patients from further analyzed. Secondly, since some patients were initially treated in other hospitals, it was difficult to collect their full opioid administration information in current studies. Finally, the patients should suffer from at least moderate pain (level 5 as in NCCN guideline) and require pain management. These reasons were also why the 282 selected patients were all diagnosed as Phase III or Phase IV lung cancer during their first visit as cancer patient. Since current patients were all diagnosed as Phase III or Phase IV lung cancer during their first visit as cancer patient, we could not determine the time interval between the emergence of cancer and first diagnosis, and subsequently had no access to the correlation between the duration of disease and the opioids. However, we suspected that there was an indirect connection between cancer progression and opioid efficacy via cholesterol levels. Weight loss during the late phase of cancer may also lead to the decrease in cholesterol level. Thus, during the cancer progression, the cholesterol level of patients decrease and subsequently requires higher dose of opioid. However, such correlation will not influences our conclusion, since current patients are in similar stage of cancer progression. In current database, the patients were initially administrated with a 14 Hot Topics in Pain Management [August 2016]