The Changes Of Plasma Concentration Of Beta-endorphin And Morphine In Cancer Patients With Breakthrough Pain

Background: Cancer pain can be caused by cancer, cancer-related lesions and cancer treatment, and most of them belonged to chronic pain. Cancer pain was one of the cardinal symptoms for cancer patients, especially patients with advanced cancer. With the progress of the cancer, the incidence of cancer-related pain grew up to 50%-70% [1,2]. 70%-90% of the cancer patients'pain can be controlled by using existing medical knowledge and treatment methods according the guideline proposed by WHO or other organizations. Breakthrough pain was often faced by many cancer patients. The prevalence of breakthrough pain ranges from 24% to 95% in previous studies, invariably dependented on disease type, stage of disease, patients, and therapeutic factors. Portenoy and Hagen[4] provided the first standardized definition of breakthrough pain in 1990, They defined breakthrough pain as a transient increase in pain to greater than moderate intensity, which occurred on cancer pain patients with a baseline pain of moderate intensity. Three types of breakthrough pain exist: incident pain, spontaneous pain and end-of-dose pain. Incident pain estimated prevalence of 50%–60% can be precipitated by predictable volitional factors such as movement or unpredictable non-volitional factors including bladder spasm. Spontaneous pain estimated prevalence of 20%–60% occurs in the absence of a specific trigger and can be unpredictable and occur at random. End-of-dose pain, consistently occurs just 1-2 hours before the next scheduled dose of opioids analges[3]. Clinical treatment of breakthrough pain was very difficult, especially incident pain and spontaneous pain. For the predictable breakthrough pain, it is mainly applied for analgesic drugs 30-45 minutes in advance to prevent the breakthrough pain occurrence. For the end-of-dose pain, we need to increase 25% -50% of the total dose in daily, if the patient can not tolerate the increased dose, we also can shorten the administrate time. For the spontaneous pain, there has no reliable measures to prevention and treatment. As early as 200 years ago, morphine has been a pain medication used in clinical treatment of cancer pain, and it was the mainstone drug for the treatment of cancer pain nowadays. Morphine is the"gold standard"in the treatment of cancer pain. Beta-endorphin, a neuropeptide consisting of 31 amino acids, is a derivative of proopiomelanocortin (POMC)[5]. The secretion of Beta-endorphin was regulated by the hypothalamus - pituitary - adrenal axis, and pain stimulation can promote the secretion ofβ-endorphin[6]. Plasmaβ-endorphin levels have been reported to correlate inversely with pain levels in cancer pain, that was plasmaβ-endorphin levels increase with improved pain control[7,8]. Did the plasma concentration of morphine andβ-endorphin changes in the occurrence of breathrough pain? And is there any correlation between these changes with the pain? We conducted a clinical study to explored these relationships. We used liquid chromatography - mass spectrometry (LC-MS/MS) , and combin- ed with high separating property of chromatographic separation and strength resolution performance of mass spectrometry, to improve the test sensitivity. LC-MS/MS has become the core technique to study the pharmacokinetics and metabolism. Radioimmunoassay (RIA) was used to measure plasmaβ-endorphin, as it is suitable to assay macromolecule of peptides and widespread in clinic and scientific research.Objective: To observe the changes of plasma concentration of beta-endorphin and morphine in cancer patients with breakthrough pain, and to explore the relationships between breakthrough pain and the plasma concentration of morphine orβ-endorphin, in order to provide information for further treatment of breakthrough pain.Methods: Thirty patients were enrolled in this study from the department of pain medicine and rehabilitation in the fourth Hospital of Hebei Medical University, date from February to October in 2010. All patients went through morphine titration, controlled cancer pain utilizing Morphine Sulfate Sustained-release Tablets but still remaining breakthrough pain. 17 males and 13 females, mean age (58±12). When the patient'pain is relatively stable at 9-10 am, the VAS score and 4ml blood sample was taken from the ulnar vein as control data. When the breakthrough pain happened, the VAS score and blood sample was taken again. The blood samples were quickly divided into 2 parts, one injected to the centrifuge tube containing 7.5% EDTA disodium and aprotinin, the other one injected to the tube containing heparin. Then we separated plasma after centrifuge 10min at 4℃. Plasma samples were stored frozen at–80℃. Radioimmunoassay(RIA) was used to measure plasmaβ-endorphin, and LC-MS/MS was used to measure plasma morphine. SPSS 13.0 was emploied in the data analyses.Result:1 The mean plasma concentration ofβ-endorphin was (310.31±46.46) pg/ml during the stable pain and increased to (353.10±69.04)pg/ml during the breakthrough pain. The differences between the stable stage and breakthrough pain got a statistically significant (P<0.05).2 The mean Plasma concentration of morphine was (30.41±12.64)ng/ml at the stable pain condition and decreased to (29.33±11.83)ng/ml during the breakthrough pain. The plasma concentration of morphine during the stable pain was higher than that during breakthrough pain, but the difference hadn't statistically significant (P>0.05).Conclusion: The occurrence of breakthrough pain was not due to the fluctuation of morphine in the patients in this study; the occurrence of breakthrough pain was not due toβ-endorphin secretion decreased ether. conversely the breakthrough pain stimulated the secretion ofβ-endorphin to help control the pain.