Original Article Impact of Epidural Analgesia on Quality of Life and Pain in Advanced Cancer Patients ---
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From the *Department of Anesthesiology, Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, P.R. China; †Department of Anesthesiology, Yantai Yuhuangding Hospital Laishan Branch, Yantai, P.R. China; ‡Department of Otorhinolaryngology, Yantaishan Hospital Affiliated to Medical College of Taishan, Yantai, P.R. China. Address correspondence to YongGang Xie, Department of Anesthesiology, Yuhuangding Hospital Affiliated to Medical College of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, P. R. China. E-mail: [email protected] Received July 21, 2014; Revised August 7, 2014; Accepted August 7, 2014. Qun-hui He and Qing-Ling Liu are co-first authors, and they contributed equally to this work. 1524-9042/$36.00 Ó 2015 by the American Society for Pain Management Nursing http://dx.doi.org/10.1016/ j.pmn.2014.08.003
Qun-Hui He, MM,* Qing-Ling Liu, MM,† Zhen Li, MM,‡ Ke-Zhong Li, MD,* and Yong-Gang Xie, MD*
ABSTRACT:
Patients with advanced cancer often experience chronic postoperative pain and poor quality of life. The objective of this study was to determine if epidural self-controlled analgesia reduced the incidence of chronic pain and improved the quality of life when compared with intravenous self-controlled analgesia. A total of 50 patients diagnosed with advanced cancer who received analgesia treatment were randomly divided into two groups, epidural self-controlled analgesia group (EA group, n ¼ 26) and intravenous self-controlled analgesia group (IA group, n ¼ 24). Visual analog scale (VAS) and Karnofsky score were used to assess the pain and the quality of life, respectively. A multifunction monitor was used to continuously record the physical signs of patients after treatment. The physical signs, such as heart failure, respiration, pulse, blood pressure, and oxygen saturation, in the two groups were better after analgesia treatment. Meanwhile, the respiration and oxygen saturation in the EA group were significantly improved compared with that of the IA group (p < .05). The VAS in the EA group was significantly lower than that in the IA group (p < .05), and the Karnofsky score in the EA group was significantly higher than that in the IA group (p < .05). Moreover, patients treated with EA felt more satisfied and experienced fewer complications than those with IA (p < .05). The epidural self-controlled analgesia may greatly improve the quality of life and relieve the pain in patients with advanced cancer. Ó 2015 by the American Society for Pain Management Nursing The most recurrent and debilitating symptom of metastatic cancer is pain, and this can manifest in the early stages of the disease (Cleeland et al., 1994; Di Maio et al., 2004). About half of cancer patients will suffer from pain, which can increase to three quarters of patients when advanced cancer is included, and 24%-30% will experience moderate or intense pain during oncologic treatment (Breivik et al., 2009; van den Beuken–van Everdingen et al., 2007). Pain Management Nursing, Vol 16, No 3 (June), 2015: pp 307-313
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Many of them have suffered from pain for months before it is controlled. Despite a general consensus among health care professionals that 90% of cancer patients can obtain sufficient pain relief with analgesics, many patients do not have adequate pain relief as a result of inadequate treatment (Larue, Colleau, Brasseur, & Cleeland, 1995; Yun et al., 2004). In fact, 17%-70% of cancer patients experience several levels of pain (Anderson et al., 2000; Beck & Falkson, 2001; Enting, Oldenmenger, Van Gool, van der Rijt, & Sillevis Smitt, 2007; Strohbuecker, Mayer, Evers, & Sabatowski, 2005). Consequently, this may negatively affect a patient’s quality of life, such as sleep, daily life, entertainment, work ability, and social activities (Cleeland et al., 1994; Di Maio et al., 2004; Strohbuecker et al., 2005). Treatment of cancer pain is challenging. The World Health Organization (WHO) elaborated on guidelines for the treatment of cancer pain in 1986 (revised in 1996), which indicated an inexpensive method to treat pain using a limited number of drugs in a stepwise approach (Felleiter, Gustorff, Lierz, Hornykewycz, & Kress, 2005). The WHO analgesic ladder supports medication choice according to pain intensity, in such a way that strong analgesics are introduced in the third step, replacing weak opioids. The use of the analgesic ladder in an inverse way has the advantage of using the same principles of the original ladder to treat crises of pain more efficiently and then step down to the ladder (Azevedo Sao Leao Ferreira, Kimura, & Jacobsen Teixeira, 2006; Zeppetella, 2011). There are two common techniques for postoperative pain control after cancer therapy: patient-controlled intravenous analgesia (PCIA) and continuous patient-controlled epidural analgesia (PCEA) (Werawatganon & Charuluxanun, 2005). The patient-controlled analgesia (PCA) paradigm is based on the pharmacologic concept of minimum effect analgesic concentration (MEAC), which means using the smallest serum opioid concentration sufficient to alleviate pain. Minimal analgesia occurs when the MEAC is reached, and after this point, further increments of opioid concentrations produce analgesic effects, creating a sigmoidal dose–response curve (Nolan & Wilson, 1995). Even though PCA pumps are successfully integrated into the treatment of postoperative pain (Sardin, Lecour, Terrier, & Grouille, 2012), there is limited evidence of safety and efficacy of PCA devices in oncologic patients (Dev, Del Fabbro, & Bruera, 2011). On the other hand, PCEA remained the preferred and well-recognized analgesic technique in patients undergoing major surgery because it provides good
pain control (Rigg et al., 2002). It is more effective than nitrous oxide, opioids, Transcutaneous Electrical Nerve Stimulation (TENS), and other common modalities of analgesia. When a catheter is placed into the epidural space, a continuous infusion can be maintained for several days, if needed. Epidural analgesia successfully has been used for postoperative analgesia, the treatment of back pain, chronic pain, and palliation of symptoms in terminal care (Ezhevskaia & Prusakova, 2012; Malvasi et al., 2009; Richter et al., 2002; Schulte et al., 2008). Evidence that use of epidural analgesia also enhances the recovery process would lead to wider adoption of this method and better quality of care for surgical patients (Fotiadis, Badvie, Weston, & Allen-Mersh, 2004; Yeh et al., 2005). However, to the best of our knowledge, the efficacy of PCEA in advanced cancer patients has not yet been investigated. We hypothesized that PCEA is better than PCA with respect to postoperative pain control for advanced cancer. To test this hypothesis, we performed the present study as a randomized clinical trial, because the aim was to demonstrate superiority of one analgesic regime and to show that PCA is worse than PCEA. Our study has used PCEA as analgesic therapy for patients with advanced cancer with satisfactory clinical effects.
MATERIALS AND METHODS Study Population After obtaining the approval of the Institutional Review Board of Qingdao Municipal Hospital of Shandong Province, participants were recruited from the Anesthesiology Preoperative Evaluation Clinic and provided written informed consent. This investigation was conducted at a single tertiary medical center in Qingdao from October 2009 to October 2013. A total of 50 adult patients diagnosed with an advanced malignant tumor in our hospital were included. The exclusion criteria were as follows: presence of spinal deformity or spinal disease; any contraindication to epidural or intrathecal injection; allergy to local anesthetics; inability to understand the pain scale; and any type of chronic pain or current opioid use. After written informed consent was obtained, patients were instructed on how to use the device for PCA and how to report pain via the visual analogue scale (VAS) the day before surgery. By using a table of random sampling numbers, patients were randomly allocated into either patientcontrolled intravenous analgesia (IA) group (receiving PCIA, n ¼ 24) or patient-controlled epidural analgesia
Epidural Analgesia Therapy for Cancer Patients
(EA) group (receiving PCEA, n ¼ 26) on the day of the surgery. Perioperative Pain Management In the EA group, an epidural catheter was placed before the induction of general anesthesia. Under standard monitoring, the epidural catheter was inserted into the epidural space by epidural puncture in the side entering. An epidural catheter containing steel wire was indwelled for 4-7 centimeters and established subcutaneous tunnel to the cephalad side for 5 centimeters, to fix the epidural catheter. Then the bacterial filter and injection pump were properly connected with the epidural catheter for PCEA. The placement of the epidural catheter was ruled out by confirming that no blood or cerebrospinal fluid was aspirated. Also, 5 mL of 2% lidocaine was administered. If there was no rapid onset of neuroaxial block, suggesting intrathecal delivery of the local anesthetic, the placement of the epidural catheter was completed. Before the induction of anesthesia, 100 mL of physiologic saline compound analgesic liquid mixture of 1 mg of morphine, 2.5 mg of droperidol, 5 mg of dexamethasone, and 80000 U of gentamicin was connected to the epidural catheter. The basal infusion of the pump was set at 4 mL/hr with a 0.5 mL bolus doses allowed every 15 minutes. The retention time of the piping system was regulated: If there was no special need, a lifelong tube was used; if there was epidural cavity infection or epidural catheter into subarachnoid space, the catheter was immediately removed and the patients received symptomatic treatment and close observation (Wiese et al., 2010). In the IA group, patients were given intravenous self-controlled analgesia. We chose to puncture the superficial vein of coarse straightly, and 22-puncture needle were placed into it, connected the mechanical analgesia pump with 1 mg of morphine, 5 mg of dexamethasone, and physiologic saline compound analgesic liquid (total volume of 100 ml). The basal infusion of the pump was set at 4 mL/hr with a 0.5 mL bolus doses allowed every 15 minutes. After beginning treatment, all patients remained in the hospital for 3-5 days to assess for drug complications. If complications occurred, patients could be treated on an inpatient or outpatient basis according to their wishes, and there were special persons to record and follow up with patients to monitor the parameters of disease conditions. Pain Score and Consumption of Analgesics Anesthesia was performed according to the same standard protocol in both groups. The patient was mechanically ventilated to maintain end-tidal carbon dioxide at
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35 5 mm Hg during the surgery. Anesthesia was maintained with 0.6-1.2 minimum alveolar end-tidal concentration of desflurane in an air–oxygen mixture (fraction of inspired oxygen ¼ 0.5) and 0.05-0.2 mg/ kg/min remifentanil infusion. The concentration of end-tidal desflurane and the infusion rate of remifentanil were adjusted according to clinical parameters (blood pressure or heart rate within 20% of the baseline). The parameters of heart failure (HR), respiration (R), pulse (P), blood pressure (BP), and oxygen saturation (SpO2) were monitored and recorded throughout the surgery by a multifunction monitor for 2 hours or 12 hours once a time during the first 48 hours. For prevention of postoperative nausea and vomiting, 0.3 mg of ramosetron was administered intravenously, at peritoneal closure. We used the VAS to evaluate anesthesia effect. The definitions were painless (score ¼ 0), best (score 5). Patients with scores of 4-10 before the experiment were recruited into the study, to record their scores 15 minutes and 2 hours after beginning the experiment and then subsequently on the first, seventh, thirteenth, and sixteenth days. We took samples from the injection pump to culture bacteria on the first and seventh days, and then every month during the experiment. We compared the satisfaction rates of analgesia methods; recorded the adverse effects, including nausea, vomiting, gastrointestinal disorders, constipation, and urinary retention; and then evaluated patients for 48 hours after surgery, according to WHO standards. The Karnofsky score was used to evaluate quality of life. The gain or loss of >10 on Karnofsky scale score after the experiment, compared with before the experiment, was defined as higher or lower, 1 kilogram after the experiment, compared with before, was defined as higher or lower, >1 kilogram as stable.
Statistical Analysis Where appropriate, results were shown as mean (SD) or median (interquartile range [IQR]). Comparisons of VAS scores and recovery profiles between the two groups were conducted using unpaired Student’s t tests. Differences between the two groups regarding the grade of discomfort during the procedure and duration of hospital stay were analyzed by the MannWhitney rank-sum test and the incidences of adverse effects, postoperative complications, and postoperative outcomes were compared using c2 test or Fisher’s exact test. All statistical analyses were performed using SPSS Version 12.0 software (SPSS Inc., Chicago, IL).
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TABLE 1. Demographic Data of Patients with Advanced Cancer Patient Characteristic
No. (%)
Gender Male
17 (65.4%) (EA group) 17 (70.8%) (IA group) 9 (34.6%) (EA group) 7 (29.2%) (IA group)
Female Age (yr) Mean SD
men and 7 women. All patients in the two groups were confirmed by pathologic, cytologic, and imaging diagnosis as having an advanced malignant tumor, were judged able to cooperate to complete the questionnaire, and gave informed consent. There were 15 cases of liver cancer, 12 cases of lung cancer, 6 cases of colorectal cancer, 5 cases of ovarian cancer, 3 cases of breast cancer, 5 cases of gastric cancer, 1 case of gallbladder cancer, and 3 cases of pancreatic cancer in the recruited samples. Patient characteristics are reported in Table 1.
63.9 4.5 (EA group) 62.9 5.6 (IA group)
Cancer Diagnosis Liver cancer Lung cancer Colorectal cancer Ovarian cancer Breast cancer Gastric cancer Gallbladder cancer Pancreatic cancer
15 (30%) 12 (24%) 6 (12%) 5 (10%) 3 (6%) 5 (10%) 1 (2%) 3 (6%)
EA ¼ epidural self-controlled analgesia; IA ¼ intravenous self-controlled analgesia group; SD ¼ standard deviation.
All p values are two tailed, and values 5), there were 23 cases (88.5%) of best, 2 cases (7.7%) of better, 1 case (3.8%) of worst in the EA group. However, there were 11 cases (45.8%) of best, 6 cases (25.0%) of better, and 7 cases (29.2%) of worst in the IA group. After comparison, we could see that the analgesic effects of EA were much better than IA (p < .05).
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Quality of Life Karnofsky score was used to assess quality of life. As we defined, better or worse (gain or loss of Karnofsky score >10) or stable (gain or loss of Karnofsky score .05). These suggested that EA could significantly relieve complications compared with IA. Retention of urine can be treated by catheterization. Two patients at 2 months were infected by Candida albicans, but not infected in the spinal canal; 1 patient chose to remove the epidural catheter and terminate treatment, and the other did not remove the epidural catheter and continued treatment with physiologic saline. No other complications occurred in these two patients; overall, the complication rate in the control group was significantly higher than in the EA group (p < .01; Table 3).
TABLE 3. Profiles of Anesthetics-related Adverse Effects between the Two Groups
Nausea and vomiting Gastrointestinal disorders Constipation Urinary retention
IA Group (n ¼ 24)
EA Group (n ¼ 26)
p Value
18 (75.0%) 13 (54.2%) 17 (70.8%) 3 (12.5%)
4 (15.4%) 5 (1.2%) 3 (11.5%) 5 (19.2%)
.011 .042 .023 .507
EA ¼ epidural self-controlled analgesia; IA ¼ intravenous self-controlled analgesia group. Date shown as number of patients (proportion, %).
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DISCUSSION About 50% of patients with cancer experience different degrees of pain, and approximately 75% of patients with advanced cancer suffer pain, of whom 40%-50% experience moderate to severe pain; another 25%-30% have more severe pain (Pennington, Caminiti, Schein, Hewitt, & Nelson, 2009). Cancer pain is an important factor affecting quality of life of patients with cancer, and effective analgesic therapy may be particularly important for patients with advanced cancer (Balch, Nephew, Huang, & Bapat, 2007). PCEA was developed based on the epidural anesthesia and is a common method of treating refractory cancer pain and is convenient and fast acting. The excitability of the sympathetic nerve in patients with cancer increases, perhaps because of pain and anxiety, with HR, R, and BP increasing and which in the study were all elevated before treatment compared with after (Colvin & Fallon, 2008). A good analgesic effect can greatly help to improve emotions and quality of life. We adopted blocking treatment according to the ganglion section of the pain to get better analgesic effect, which can be verified in the study. The analgesic effect is rapid, exact, produces few side effects, can significantly reduce the side effects of opioids in the experimental group by choosing an epidural puncture point according to the spinal pain point, and is consistent with the reported literature (Reyes-Gibby, Morrow, Buzdar, & Shete, 2009). Thus, the sum blockage of somatic nerves on somatic nerves and the morphine analgesic provides good effects to epidural analgesic. Meanwhile, patients can give self-controlled medicine, which can avoid various levels of pain caused by various painkillers in the subarachnoid space. Composite analgesic liquid not only has an analgesic effect on
many links, but also on the central analgesic, sedative, and nerve nutrition, antiemetic, antianxiety by dural into cerebrospinal fluid, and the application of analgesic liquid prevents spinal cord degeneration and increases the role of appetite (Cata, Weng, & Dougherty, 2008). The analgesic effect of epidural analgesia compared with intravenous self-controlled administration of the drug is more prominent with the prolonging time of analgesia in the study, and the vital signs of patients in the control group after administration of drug also have improved, but the HR and R increased along with the time extension compared with before treatment and the early period of treatment in the control group and SpO2 decreased; vital signs in the experimental group were more stable, and improvement of quality of life was significantly better (Cattaneo, 2010). However, the specific mechanism needs further study. The results indicate that the intermittent administration makes it easy to reach the blood concentration peak. Frequently suffering blood concentration peak would increase resistance, addiction and side effects to patients. Patients in this study were given, by continuous epidural administration, self-controlled analgesia, which can effectively maintain a stable blood drug level and achieve satisfactory analgesic effect, with no reduction in analgesic efficacy and no increased resistance, addiction, or serious complications of long-term application. Therefore, epidural cavity analgesia can be part of the long-term treatment of cancer pain. Acknowledgments The authors acknowledge the participating hospitals in Shandong Province.
REFERENCES Anderson, K. O., Mendoza, T. R., Valero, V., Richman, S. P., Russell, C., Hurley, J., DeLeon, C., Washington, P., Palos, G., Payne, R., & Cleeland, C. S. (2000). Minority cancer patients and their providers: Pain management attitudes and practice. Cancer, 88, 1929–1938. Azevedo Sao Leao Ferreira, K., Kimura, M., & Jacobsen Teixeira, M. (2006). The WHO analgesic ladder for cancer pain control, twenty years of use. How much pain relief does one get from using it? Support Care Cancer, 14, 1086–1093. Balch, C., Nephew, K. P., Huang, T. H., & Bapat, S. A. (2007). Epigenetic ‘‘bivalently marked’’ process of cancer stem cell-driven tumorigenesis. Bioessays, 29, 842–845. Beck, S. L., & Falkson, G. (2001). Prevalence and management of cancer pain in South Africa. Pain, 94, 75–84. Breivik, H., Cherny, N., Collett, B., de Conno, F., Filbet, M., Foubert, A. J., Cohen, R., & Dow, L. (2009). Cancer-related pain: A pan-European survey of prevalence, treatment, and patient attitudes. Annals of Oncology, 20, 1420–1433.
Cata, J. P., Weng, H. R., & Dougherty, P. M. (2008). The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Research, 1229, 100–110. Cattaneo, A. (2010). Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Current Opinion in Molecular Therapeutics, 12, 94–106. Cleeland, C. S., Gonin, R., Hatfield, A. K., Edmonson, J. H., Blum, R. H., Stewart, J. A., & Pandya, K. J. (1994). Pain and its treatment in outpatients with metastatic cancer. New England Journal of Medicine, 330, 592–596. Colvin, L., & Fallon, M. (2008). Challenges in cancer pain management—bone pain. European Journal of Cancer, 44, 1083–1090. Dev, R., Del Fabbro, E., & Bruera, E. (2011). Patientcontrolled analgesia in patients with advanced cancer. Should patients be in control? Journal of Pain and Symptom Management, 42, 296–300.
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Di Maio, M., Gridelli, C., Gallo, C., Manzione, L., Brancaccio, L., Barbera, S., Robbiati, S. F., Ianniello, G. P., Ferrau, F., Piazza, E., Frontini, L., Rosetti, F., Carrozza, F., Bearz, A., Spatafora, M., Adamo, V., Isa, L., Iaffaioli, R. V., Di Salvo, E., & Perrone, F. (2004). Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer. British Journal of Cancer, 90, 2288–2296. Enting, R. H., Oldenmenger, W. H., Van Gool, A. R., van der Rijt, C. C., & Sillevis Smitt, P. A. (2007). The effects of analgesic prescription and patient adherence on pain in a dutch outpatient cancer population. Journal of Pain and Symptom Manage, 34, 523–531. Ezhevskaia, A. A., & Prusakova, ZhB. (2012). [Epidural analgesia in surgical treatment of scoliosis]. Anesteziology Reanimatology 27–30. Felleiter, P., Gustorff, B., Lierz, P., Hornykewycz, S., & Kress, H. G. (2005). Use of the World Health Organization guidelines on cancer pain relief before referral to a specialized pain service. Schmerz, 19, 265. Fotiadis, R. J., Badvie, S., Weston, M. D., & AllenMersh, T. G. (2004). Epidural analgesia in gastrointestinal surgery. British Journal of Surgery, 91, 828–841. Larue, F., Colleau, S. M., Brasseur, L., & Cleeland, C. S. (1995). Multicentre study of cancer pain and its treatment in France. British Medical Journal, 310, 1034–1037. Malvasi, A., Tinelli, A., Brizzi, A., Greco, F., Celleno, D., & Tinelli, R. (2009). Long-term epidural analgesia treatment in pre-eclamptic women: A preliminary trial. Journal of Obstetrics and Gynaecology, 29, 114–118. Nolan, M. F., & Wilson, M. C. (1995). Patient-controlled analgesia: A method for the controlled self-administration of opioid pain medications. Physical Therapy, 75, 374–379. Pennington, P., Caminiti, S., Schein, J. R., Hewitt, D. J., & Nelson, W. W. (2009). Patients’ assessment of the convenience of fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous patient-controlled analgesia (IV PCA) in the management of postoperative pain after major surgery. Pain Management Nursing, 10, 124–133. Reyes-Gibby, C. C., Morrow, P. K., Buzdar, A., & Shete, S. (2009). Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel. Journal of Pain, 10, 1146–1150. Richter, A., Cederholm, I., Jonasson, L., Mucchiano, C., Uchto, M., & Janerot-Sjoberg, B. (2002). Effect of thoracic epidural analgesia on refractory angina pectoris: Long-term home self-treatment. Journal of Cardiothoracic and Vascular Anesthesia, 16, 679–684.
313
Rigg, J. R., Jamrozik, K., Myles, P. S., Silbert, B. S., Peyton, P. J., Parsons, R. W., & Collins, K. S. (2002). Epidural anaesthesia and analgesia and outcome of major surgery: A randomised trial. Lancet, 359, 1276–1282. Sardin, B., Lecour, N., Terrier, G., & Grouille, D. (2012). [About safety parameters for patient-controlled analgesia (PCA) devices]. Annales Francaises d Anesthesie et de Reanimation, 31, 813–817. Schulte, E., Hoffmann, B., Hohne, C., Hofmann, M., Olenberger, W., & Fritz, G. A. (2008). Intraoperative epidural analgesia does not reduce time of postoperative analgesic treatment compared to intravenous analgesia. European Journal of Anaesthesiology, 25, 763–765. Strohbuecker, B., Mayer, H., Evers, G. C., & Sabatowski, R. (2005). Pain prevalence in hospitalized patients in a German university teaching hospital. Journal of Pain Symptom and Management, 29, 498–506. van den Beuken–van Everdingen, M. H., de Rijke, J. M., Kessels, A. G., Schouten, H. C., van Kleef, M., & Patijn, J. (2007). High prevalence of pain in patients with cancer in a large population-based study in The Netherlands. Pain, 132, 312–320. Werawatganon, T., & Charuluxanun, S. (2005). Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database of Systematic Reviews(1), CD004088. Wiese, C. H., Loffler, E. K., Vormelker, J., Meyer, N., Taghavi, M., Strumpf, M., Kazmaier, S., Roessler, M., Zausig, Y. A., Popov, A. F., Lassen, C. L., Graf, B. M., & Hanekop, G. G. (2010). [Cancer pain therapy in palliative care patients: Knowledge of prehospital emergency physicians in training. Prospective questionnaire-based investigation]. Schmerz, 24, 508–516. Yeh, C. C., Jao, S. W., Huh, B. K., Wong, C. S., Yang, C. P., White, W. D., & Wu, C. T. (2005). Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative pain and bowel function in patients undergoing colonic surgery. Anesthesia and Analgesia, 100, 1384–1389, table of contents. Yun, Y. H., Mendoza, T. R., Heo, D. S., Yoo, T., Heo, B. Y., Park, H. A., Shin, H. C., Wang, X. S., & Cleeland, C. S. (2004). Development of a cancer pain assessment tool in Korea: A validation study of a Korean version of the brief pain inventory. Oncology, 66, 439–444. Zeppetella, G. (2011). The WHO analgesic ladder: 25 years on. British Journal of Nursing, 20. S4, S6.
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From the *Department of Anesthesiology, Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, P.R. China; †Department of Anesthesiology, Yantai Yuhuangding Hospital Laishan Branch, Yantai, P.R. China; ‡Department of Otorhinolaryngology, Yantaishan Hospital Affiliated to Medical College of Taishan, Yantai, P.R. China. Address correspondence to YongGang Xie, Department of Anesthesiology, Yuhuangding Hospital Affiliated to Medical College of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, P. R. China. E-mail: [email protected] Received July 21, 2014; Revised August 7, 2014; Accepted August 7, 2014. Qun-hui He and Qing-Ling Liu are co-first authors, and they contributed equally to this work. 1524-9042/$36.00 Ó 2015 by the American Society for Pain Management Nursing http://dx.doi.org/10.1016/ j.pmn.2014.08.003
Qun-Hui He, MM,* Qing-Ling Liu, MM,† Zhen Li, MM,‡ Ke-Zhong Li, MD,* and Yong-Gang Xie, MD*
ABSTRACT:
Patients with advanced cancer often experience chronic postoperative pain and poor quality of life. The objective of this study was to determine if epidural self-controlled analgesia reduced the incidence of chronic pain and improved the quality of life when compared with intravenous self-controlled analgesia. A total of 50 patients diagnosed with advanced cancer who received analgesia treatment were randomly divided into two groups, epidural self-controlled analgesia group (EA group, n ¼ 26) and intravenous self-controlled analgesia group (IA group, n ¼ 24). Visual analog scale (VAS) and Karnofsky score were used to assess the pain and the quality of life, respectively. A multifunction monitor was used to continuously record the physical signs of patients after treatment. The physical signs, such as heart failure, respiration, pulse, blood pressure, and oxygen saturation, in the two groups were better after analgesia treatment. Meanwhile, the respiration and oxygen saturation in the EA group were significantly improved compared with that of the IA group (p < .05). The VAS in the EA group was significantly lower than that in the IA group (p < .05), and the Karnofsky score in the EA group was significantly higher than that in the IA group (p < .05). Moreover, patients treated with EA felt more satisfied and experienced fewer complications than those with IA (p < .05). The epidural self-controlled analgesia may greatly improve the quality of life and relieve the pain in patients with advanced cancer. Ó 2015 by the American Society for Pain Management Nursing The most recurrent and debilitating symptom of metastatic cancer is pain, and this can manifest in the early stages of the disease (Cleeland et al., 1994; Di Maio et al., 2004). About half of cancer patients will suffer from pain, which can increase to three quarters of patients when advanced cancer is included, and 24%-30% will experience moderate or intense pain during oncologic treatment (Breivik et al., 2009; van den Beuken–van Everdingen et al., 2007). Pain Management Nursing, Vol 16, No 3 (June), 2015: pp 307-313
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Many of them have suffered from pain for months before it is controlled. Despite a general consensus among health care professionals that 90% of cancer patients can obtain sufficient pain relief with analgesics, many patients do not have adequate pain relief as a result of inadequate treatment (Larue, Colleau, Brasseur, & Cleeland, 1995; Yun et al., 2004). In fact, 17%-70% of cancer patients experience several levels of pain (Anderson et al., 2000; Beck & Falkson, 2001; Enting, Oldenmenger, Van Gool, van der Rijt, & Sillevis Smitt, 2007; Strohbuecker, Mayer, Evers, & Sabatowski, 2005). Consequently, this may negatively affect a patient’s quality of life, such as sleep, daily life, entertainment, work ability, and social activities (Cleeland et al., 1994; Di Maio et al., 2004; Strohbuecker et al., 2005). Treatment of cancer pain is challenging. The World Health Organization (WHO) elaborated on guidelines for the treatment of cancer pain in 1986 (revised in 1996), which indicated an inexpensive method to treat pain using a limited number of drugs in a stepwise approach (Felleiter, Gustorff, Lierz, Hornykewycz, & Kress, 2005). The WHO analgesic ladder supports medication choice according to pain intensity, in such a way that strong analgesics are introduced in the third step, replacing weak opioids. The use of the analgesic ladder in an inverse way has the advantage of using the same principles of the original ladder to treat crises of pain more efficiently and then step down to the ladder (Azevedo Sao Leao Ferreira, Kimura, & Jacobsen Teixeira, 2006; Zeppetella, 2011). There are two common techniques for postoperative pain control after cancer therapy: patient-controlled intravenous analgesia (PCIA) and continuous patient-controlled epidural analgesia (PCEA) (Werawatganon & Charuluxanun, 2005). The patient-controlled analgesia (PCA) paradigm is based on the pharmacologic concept of minimum effect analgesic concentration (MEAC), which means using the smallest serum opioid concentration sufficient to alleviate pain. Minimal analgesia occurs when the MEAC is reached, and after this point, further increments of opioid concentrations produce analgesic effects, creating a sigmoidal dose–response curve (Nolan & Wilson, 1995). Even though PCA pumps are successfully integrated into the treatment of postoperative pain (Sardin, Lecour, Terrier, & Grouille, 2012), there is limited evidence of safety and efficacy of PCA devices in oncologic patients (Dev, Del Fabbro, & Bruera, 2011). On the other hand, PCEA remained the preferred and well-recognized analgesic technique in patients undergoing major surgery because it provides good
pain control (Rigg et al., 2002). It is more effective than nitrous oxide, opioids, Transcutaneous Electrical Nerve Stimulation (TENS), and other common modalities of analgesia. When a catheter is placed into the epidural space, a continuous infusion can be maintained for several days, if needed. Epidural analgesia successfully has been used for postoperative analgesia, the treatment of back pain, chronic pain, and palliation of symptoms in terminal care (Ezhevskaia & Prusakova, 2012; Malvasi et al., 2009; Richter et al., 2002; Schulte et al., 2008). Evidence that use of epidural analgesia also enhances the recovery process would lead to wider adoption of this method and better quality of care for surgical patients (Fotiadis, Badvie, Weston, & Allen-Mersh, 2004; Yeh et al., 2005). However, to the best of our knowledge, the efficacy of PCEA in advanced cancer patients has not yet been investigated. We hypothesized that PCEA is better than PCA with respect to postoperative pain control for advanced cancer. To test this hypothesis, we performed the present study as a randomized clinical trial, because the aim was to demonstrate superiority of one analgesic regime and to show that PCA is worse than PCEA. Our study has used PCEA as analgesic therapy for patients with advanced cancer with satisfactory clinical effects.
MATERIALS AND METHODS Study Population After obtaining the approval of the Institutional Review Board of Qingdao Municipal Hospital of Shandong Province, participants were recruited from the Anesthesiology Preoperative Evaluation Clinic and provided written informed consent. This investigation was conducted at a single tertiary medical center in Qingdao from October 2009 to October 2013. A total of 50 adult patients diagnosed with an advanced malignant tumor in our hospital were included. The exclusion criteria were as follows: presence of spinal deformity or spinal disease; any contraindication to epidural or intrathecal injection; allergy to local anesthetics; inability to understand the pain scale; and any type of chronic pain or current opioid use. After written informed consent was obtained, patients were instructed on how to use the device for PCA and how to report pain via the visual analogue scale (VAS) the day before surgery. By using a table of random sampling numbers, patients were randomly allocated into either patientcontrolled intravenous analgesia (IA) group (receiving PCIA, n ¼ 24) or patient-controlled epidural analgesia
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(EA) group (receiving PCEA, n ¼ 26) on the day of the surgery. Perioperative Pain Management In the EA group, an epidural catheter was placed before the induction of general anesthesia. Under standard monitoring, the epidural catheter was inserted into the epidural space by epidural puncture in the side entering. An epidural catheter containing steel wire was indwelled for 4-7 centimeters and established subcutaneous tunnel to the cephalad side for 5 centimeters, to fix the epidural catheter. Then the bacterial filter and injection pump were properly connected with the epidural catheter for PCEA. The placement of the epidural catheter was ruled out by confirming that no blood or cerebrospinal fluid was aspirated. Also, 5 mL of 2% lidocaine was administered. If there was no rapid onset of neuroaxial block, suggesting intrathecal delivery of the local anesthetic, the placement of the epidural catheter was completed. Before the induction of anesthesia, 100 mL of physiologic saline compound analgesic liquid mixture of 1 mg of morphine, 2.5 mg of droperidol, 5 mg of dexamethasone, and 80000 U of gentamicin was connected to the epidural catheter. The basal infusion of the pump was set at 4 mL/hr with a 0.5 mL bolus doses allowed every 15 minutes. The retention time of the piping system was regulated: If there was no special need, a lifelong tube was used; if there was epidural cavity infection or epidural catheter into subarachnoid space, the catheter was immediately removed and the patients received symptomatic treatment and close observation (Wiese et al., 2010). In the IA group, patients were given intravenous self-controlled analgesia. We chose to puncture the superficial vein of coarse straightly, and 22-puncture needle were placed into it, connected the mechanical analgesia pump with 1 mg of morphine, 5 mg of dexamethasone, and physiologic saline compound analgesic liquid (total volume of 100 ml). The basal infusion of the pump was set at 4 mL/hr with a 0.5 mL bolus doses allowed every 15 minutes. After beginning treatment, all patients remained in the hospital for 3-5 days to assess for drug complications. If complications occurred, patients could be treated on an inpatient or outpatient basis according to their wishes, and there were special persons to record and follow up with patients to monitor the parameters of disease conditions. Pain Score and Consumption of Analgesics Anesthesia was performed according to the same standard protocol in both groups. The patient was mechanically ventilated to maintain end-tidal carbon dioxide at
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35 5 mm Hg during the surgery. Anesthesia was maintained with 0.6-1.2 minimum alveolar end-tidal concentration of desflurane in an air–oxygen mixture (fraction of inspired oxygen ¼ 0.5) and 0.05-0.2 mg/ kg/min remifentanil infusion. The concentration of end-tidal desflurane and the infusion rate of remifentanil were adjusted according to clinical parameters (blood pressure or heart rate within 20% of the baseline). The parameters of heart failure (HR), respiration (R), pulse (P), blood pressure (BP), and oxygen saturation (SpO2) were monitored and recorded throughout the surgery by a multifunction monitor for 2 hours or 12 hours once a time during the first 48 hours. For prevention of postoperative nausea and vomiting, 0.3 mg of ramosetron was administered intravenously, at peritoneal closure. We used the VAS to evaluate anesthesia effect. The definitions were painless (score ¼ 0), best (score 5). Patients with scores of 4-10 before the experiment were recruited into the study, to record their scores 15 minutes and 2 hours after beginning the experiment and then subsequently on the first, seventh, thirteenth, and sixteenth days. We took samples from the injection pump to culture bacteria on the first and seventh days, and then every month during the experiment. We compared the satisfaction rates of analgesia methods; recorded the adverse effects, including nausea, vomiting, gastrointestinal disorders, constipation, and urinary retention; and then evaluated patients for 48 hours after surgery, according to WHO standards. The Karnofsky score was used to evaluate quality of life. The gain or loss of >10 on Karnofsky scale score after the experiment, compared with before the experiment, was defined as higher or lower, 1 kilogram after the experiment, compared with before, was defined as higher or lower, >1 kilogram as stable.
Statistical Analysis Where appropriate, results were shown as mean (SD) or median (interquartile range [IQR]). Comparisons of VAS scores and recovery profiles between the two groups were conducted using unpaired Student’s t tests. Differences between the two groups regarding the grade of discomfort during the procedure and duration of hospital stay were analyzed by the MannWhitney rank-sum test and the incidences of adverse effects, postoperative complications, and postoperative outcomes were compared using c2 test or Fisher’s exact test. All statistical analyses were performed using SPSS Version 12.0 software (SPSS Inc., Chicago, IL).
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TABLE 1. Demographic Data of Patients with Advanced Cancer Patient Characteristic
No. (%)
Gender Male
17 (65.4%) (EA group) 17 (70.8%) (IA group) 9 (34.6%) (EA group) 7 (29.2%) (IA group)
Female Age (yr) Mean SD
men and 7 women. All patients in the two groups were confirmed by pathologic, cytologic, and imaging diagnosis as having an advanced malignant tumor, were judged able to cooperate to complete the questionnaire, and gave informed consent. There were 15 cases of liver cancer, 12 cases of lung cancer, 6 cases of colorectal cancer, 5 cases of ovarian cancer, 3 cases of breast cancer, 5 cases of gastric cancer, 1 case of gallbladder cancer, and 3 cases of pancreatic cancer in the recruited samples. Patient characteristics are reported in Table 1.
63.9 4.5 (EA group) 62.9 5.6 (IA group)
Cancer Diagnosis Liver cancer Lung cancer Colorectal cancer Ovarian cancer Breast cancer Gastric cancer Gallbladder cancer Pancreatic cancer
15 (30%) 12 (24%) 6 (12%) 5 (10%) 3 (6%) 5 (10%) 1 (2%) 3 (6%)
EA ¼ epidural self-controlled analgesia; IA ¼ intravenous self-controlled analgesia group; SD ¼ standard deviation.
All p values are two tailed, and values 5), there were 23 cases (88.5%) of best, 2 cases (7.7%) of better, 1 case (3.8%) of worst in the EA group. However, there were 11 cases (45.8%) of best, 6 cases (25.0%) of better, and 7 cases (29.2%) of worst in the IA group. After comparison, we could see that the analgesic effects of EA were much better than IA (p < .05).
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Quality of Life Karnofsky score was used to assess quality of life. As we defined, better or worse (gain or loss of Karnofsky score >10) or stable (gain or loss of Karnofsky score .05). These suggested that EA could significantly relieve complications compared with IA. Retention of urine can be treated by catheterization. Two patients at 2 months were infected by Candida albicans, but not infected in the spinal canal; 1 patient chose to remove the epidural catheter and terminate treatment, and the other did not remove the epidural catheter and continued treatment with physiologic saline. No other complications occurred in these two patients; overall, the complication rate in the control group was significantly higher than in the EA group (p < .01; Table 3).
TABLE 3. Profiles of Anesthetics-related Adverse Effects between the Two Groups
Nausea and vomiting Gastrointestinal disorders Constipation Urinary retention
IA Group (n ¼ 24)
EA Group (n ¼ 26)
p Value
18 (75.0%) 13 (54.2%) 17 (70.8%) 3 (12.5%)
4 (15.4%) 5 (1.2%) 3 (11.5%) 5 (19.2%)
.011 .042 .023 .507
EA ¼ epidural self-controlled analgesia; IA ¼ intravenous self-controlled analgesia group. Date shown as number of patients (proportion, %).
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DISCUSSION About 50% of patients with cancer experience different degrees of pain, and approximately 75% of patients with advanced cancer suffer pain, of whom 40%-50% experience moderate to severe pain; another 25%-30% have more severe pain (Pennington, Caminiti, Schein, Hewitt, & Nelson, 2009). Cancer pain is an important factor affecting quality of life of patients with cancer, and effective analgesic therapy may be particularly important for patients with advanced cancer (Balch, Nephew, Huang, & Bapat, 2007). PCEA was developed based on the epidural anesthesia and is a common method of treating refractory cancer pain and is convenient and fast acting. The excitability of the sympathetic nerve in patients with cancer increases, perhaps because of pain and anxiety, with HR, R, and BP increasing and which in the study were all elevated before treatment compared with after (Colvin & Fallon, 2008). A good analgesic effect can greatly help to improve emotions and quality of life. We adopted blocking treatment according to the ganglion section of the pain to get better analgesic effect, which can be verified in the study. The analgesic effect is rapid, exact, produces few side effects, can significantly reduce the side effects of opioids in the experimental group by choosing an epidural puncture point according to the spinal pain point, and is consistent with the reported literature (Reyes-Gibby, Morrow, Buzdar, & Shete, 2009). Thus, the sum blockage of somatic nerves on somatic nerves and the morphine analgesic provides good effects to epidural analgesic. Meanwhile, patients can give self-controlled medicine, which can avoid various levels of pain caused by various painkillers in the subarachnoid space. Composite analgesic liquid not only has an analgesic effect on
many links, but also on the central analgesic, sedative, and nerve nutrition, antiemetic, antianxiety by dural into cerebrospinal fluid, and the application of analgesic liquid prevents spinal cord degeneration and increases the role of appetite (Cata, Weng, & Dougherty, 2008). The analgesic effect of epidural analgesia compared with intravenous self-controlled administration of the drug is more prominent with the prolonging time of analgesia in the study, and the vital signs of patients in the control group after administration of drug also have improved, but the HR and R increased along with the time extension compared with before treatment and the early period of treatment in the control group and SpO2 decreased; vital signs in the experimental group were more stable, and improvement of quality of life was significantly better (Cattaneo, 2010). However, the specific mechanism needs further study. The results indicate that the intermittent administration makes it easy to reach the blood concentration peak. Frequently suffering blood concentration peak would increase resistance, addiction and side effects to patients. Patients in this study were given, by continuous epidural administration, self-controlled analgesia, which can effectively maintain a stable blood drug level and achieve satisfactory analgesic effect, with no reduction in analgesic efficacy and no increased resistance, addiction, or serious complications of long-term application. Therefore, epidural cavity analgesia can be part of the long-term treatment of cancer pain. Acknowledgments The authors acknowledge the participating hospitals in Shandong Province.
REFERENCES Anderson, K. O., Mendoza, T. R., Valero, V., Richman, S. P., Russell, C., Hurley, J., DeLeon, C., Washington, P., Palos, G., Payne, R., & Cleeland, C. S. (2000). Minority cancer patients and their providers: Pain management attitudes and practice. Cancer, 88, 1929–1938. Azevedo Sao Leao Ferreira, K., Kimura, M., & Jacobsen Teixeira, M. (2006). The WHO analgesic ladder for cancer pain control, twenty years of use. How much pain relief does one get from using it? Support Care Cancer, 14, 1086–1093. Balch, C., Nephew, K. P., Huang, T. H., & Bapat, S. A. (2007). Epigenetic ‘‘bivalently marked’’ process of cancer stem cell-driven tumorigenesis. Bioessays, 29, 842–845. Beck, S. L., & Falkson, G. (2001). Prevalence and management of cancer pain in South Africa. Pain, 94, 75–84. Breivik, H., Cherny, N., Collett, B., de Conno, F., Filbet, M., Foubert, A. J., Cohen, R., & Dow, L. (2009). Cancer-related pain: A pan-European survey of prevalence, treatment, and patient attitudes. Annals of Oncology, 20, 1420–1433.
Cata, J. P., Weng, H. R., & Dougherty, P. M. (2008). The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Research, 1229, 100–110. Cattaneo, A. (2010). Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Current Opinion in Molecular Therapeutics, 12, 94–106. Cleeland, C. S., Gonin, R., Hatfield, A. K., Edmonson, J. H., Blum, R. H., Stewart, J. A., & Pandya, K. J. (1994). Pain and its treatment in outpatients with metastatic cancer. New England Journal of Medicine, 330, 592–596. Colvin, L., & Fallon, M. (2008). Challenges in cancer pain management—bone pain. European Journal of Cancer, 44, 1083–1090. Dev, R., Del Fabbro, E., & Bruera, E. (2011). Patientcontrolled analgesia in patients with advanced cancer. Should patients be in control? Journal of Pain and Symptom Management, 42, 296–300.
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Di Maio, M., Gridelli, C., Gallo, C., Manzione, L., Brancaccio, L., Barbera, S., Robbiati, S. F., Ianniello, G. P., Ferrau, F., Piazza, E., Frontini, L., Rosetti, F., Carrozza, F., Bearz, A., Spatafora, M., Adamo, V., Isa, L., Iaffaioli, R. V., Di Salvo, E., & Perrone, F. (2004). Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer. British Journal of Cancer, 90, 2288–2296. Enting, R. H., Oldenmenger, W. H., Van Gool, A. R., van der Rijt, C. C., & Sillevis Smitt, P. A. (2007). The effects of analgesic prescription and patient adherence on pain in a dutch outpatient cancer population. Journal of Pain and Symptom Manage, 34, 523–531. Ezhevskaia, A. A., & Prusakova, ZhB. (2012). [Epidural analgesia in surgical treatment of scoliosis]. Anesteziology Reanimatology 27–30. Felleiter, P., Gustorff, B., Lierz, P., Hornykewycz, S., & Kress, H. G. (2005). Use of the World Health Organization guidelines on cancer pain relief before referral to a specialized pain service. Schmerz, 19, 265. Fotiadis, R. J., Badvie, S., Weston, M. D., & AllenMersh, T. G. (2004). Epidural analgesia in gastrointestinal surgery. British Journal of Surgery, 91, 828–841. Larue, F., Colleau, S. M., Brasseur, L., & Cleeland, C. S. (1995). Multicentre study of cancer pain and its treatment in France. British Medical Journal, 310, 1034–1037. Malvasi, A., Tinelli, A., Brizzi, A., Greco, F., Celleno, D., & Tinelli, R. (2009). Long-term epidural analgesia treatment in pre-eclamptic women: A preliminary trial. Journal of Obstetrics and Gynaecology, 29, 114–118. Nolan, M. F., & Wilson, M. C. (1995). Patient-controlled analgesia: A method for the controlled self-administration of opioid pain medications. Physical Therapy, 75, 374–379. Pennington, P., Caminiti, S., Schein, J. R., Hewitt, D. J., & Nelson, W. W. (2009). Patients’ assessment of the convenience of fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous patient-controlled analgesia (IV PCA) in the management of postoperative pain after major surgery. Pain Management Nursing, 10, 124–133. Reyes-Gibby, C. C., Morrow, P. K., Buzdar, A., & Shete, S. (2009). Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel. Journal of Pain, 10, 1146–1150. Richter, A., Cederholm, I., Jonasson, L., Mucchiano, C., Uchto, M., & Janerot-Sjoberg, B. (2002). Effect of thoracic epidural analgesia on refractory angina pectoris: Long-term home self-treatment. Journal of Cardiothoracic and Vascular Anesthesia, 16, 679–684.
313
Rigg, J. R., Jamrozik, K., Myles, P. S., Silbert, B. S., Peyton, P. J., Parsons, R. W., & Collins, K. S. (2002). Epidural anaesthesia and analgesia and outcome of major surgery: A randomised trial. Lancet, 359, 1276–1282. Sardin, B., Lecour, N., Terrier, G., & Grouille, D. (2012). [About safety parameters for patient-controlled analgesia (PCA) devices]. Annales Francaises d Anesthesie et de Reanimation, 31, 813–817. Schulte, E., Hoffmann, B., Hohne, C., Hofmann, M., Olenberger, W., & Fritz, G. A. (2008). Intraoperative epidural analgesia does not reduce time of postoperative analgesic treatment compared to intravenous analgesia. European Journal of Anaesthesiology, 25, 763–765. Strohbuecker, B., Mayer, H., Evers, G. C., & Sabatowski, R. (2005). Pain prevalence in hospitalized patients in a German university teaching hospital. Journal of Pain Symptom and Management, 29, 498–506. van den Beuken–van Everdingen, M. H., de Rijke, J. M., Kessels, A. G., Schouten, H. C., van Kleef, M., & Patijn, J. (2007). High prevalence of pain in patients with cancer in a large population-based study in The Netherlands. Pain, 132, 312–320. Werawatganon, T., & Charuluxanun, S. (2005). Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database of Systematic Reviews(1), CD004088. Wiese, C. H., Loffler, E. K., Vormelker, J., Meyer, N., Taghavi, M., Strumpf, M., Kazmaier, S., Roessler, M., Zausig, Y. A., Popov, A. F., Lassen, C. L., Graf, B. M., & Hanekop, G. G. (2010). [Cancer pain therapy in palliative care patients: Knowledge of prehospital emergency physicians in training. Prospective questionnaire-based investigation]. Schmerz, 24, 508–516. Yeh, C. C., Jao, S. W., Huh, B. K., Wong, C. S., Yang, C. P., White, W. D., & Wu, C. T. (2005). Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative pain and bowel function in patients undergoing colonic surgery. Anesthesia and Analgesia, 100, 1384–1389, table of contents. Yun, Y. H., Mendoza, T. R., Heo, D. S., Yoo, T., Heo, B. Y., Park, H. A., Shin, H. C., Wang, X. S., & Cleeland, C. S. (2004). Development of a cancer pain assessment tool in Korea: A validation study of a Korean version of the brief pain inventory. Oncology, 66, 439–444. Zeppetella, G. (2011). The WHO analgesic ladder: 25 years on. British Journal of Nursing, 20. S4, S6.
