Treatment Of Cancer Pain With External Traditional Chinese Medicine (Zhitong Ⅰ): Clinical And Experimental Research

BackgroudPain is one of the most common symptoms associated with cancer, and i s one of the symptoms patients fear most, which greatly affects their qua lity of life. Pain occurs in approximately 50-80% of cancer patients, and in 60-90% of advanced cancer patients. About 30% of sever cancer pain wa s not relieved. Recently, the analgesic guideline based on three-tiered "cancer pain ladder" developed by World Health Organization (WHO) and th e guideline developed by National Comprehensive Cancer Network (NCCN) wer e widely accepted with excellent analgesic effect. However, the side effe ct and dependence of opiod and other co-analgesic medicine limited its us e and therapy effects. Recently, traditional Chinese medicine (TCM) in ca ncer pain therapy were studied, including oral use, external use, and pun cture, and obtained significant analgesic effects. The external TCM was a n effective co-analgesic therapy to other treatments with few side effect s, and could improve overall quality of life, because of its percutaneous absorption and direct local effect.ObjectiveThe aim of this study was to observe the effects of external analgesi c Zhitong-I, as a co-analgesic therapy to the three-tiered "cancer pain 1 adder" in cancer pain, as well as its side effects, influence to quality of life (QOL) and analgesic mechanism in animal experiments and clinical trials.Methods1 Animal Experiments: 1.1 Acute toxicity testing:(1) 10 Kunming mice were treated with Zhitong-I every 2 hours for 6 times. The animal behavior and the skin status (edema, exudation and rash) were recorded and compared everyday for 1 week.(2) 10 Wistar rats'tails were soaked in the Zhitong-I liquid for 3 hours. The animal behavior and the skin status (edema, exudation and rash) were recorded and compared everyday for 72 hours.1.2 Acute pain testing:(1) 20 mice were used to induce acetic-acid pain models, and then divide d into 2 groups randomly. The models were smeared with Zhitong-I or alco hol at the abdomen respectively every 20 minutes for 6 times.30 minutes later, the number of writhing and writhing mice within 20 minutes in ea ch group was recorded.(2) 20 mice were used to induce hot-plate pain models, and then divided into 2 groups randomly. The models were smeared with Zhitong-I or alcoho 1 at the abdomen and feet respectively every 10 minutes for 3 times.15 minutes later, the pain threshold was measured for 8 times every 30 minu tes.1.3 Chronic pain testing:20 Wistar rats were divided into 2 groups ran domly, and were smeared with Zhitong-I or alcohol at the back legs and f eet for 6 times every 20 minutes.0.1 ml of 5% formaldehyde was injected at the right back plantar 30 minutes later. Thickness and perimeter of the plantar were measured 60 minutes after injection. The activity and c ontent of Substance P (SP) andβ-endorphin in the L4-5 spinal cord and hypothalamus were also observed and compared.2 Clinical TrialPatients eligible for the study were randomized into treatment group and control group. Patients in control group were treated according to the three-tiered "cancer pain ladder" guideline, while patients in trea tment group with mild pain were treated with external Zhitong-I, and tho se with moderate or severe pain were treated according to the three-tie red "cancer pain ladder" guideline and external Zhitong-I. The visual a nalogue scale (VAS), weighted VAS, quality of life and physical status w ere documented and compared. Results1 Animal Experiments:1.1 Acute toxicity testing:all the mice and rats activity were normal, a nd no death, fatigue, hair loss, anorexia, or local edema, exudation or r ash were observed.1.2 Acute pain testing:(1) Acetic-Acid Pain Model:The number of writhing were 9.23 vs.20.98 pe r 20 minutes in the experimental and control group, respectively. The ana lgesic rate was 55.98%(P<0.05).(2) Hot-Plated Pain Model:In the two groups, the pain threshold value wa s similar at 15,45 minutes. After 75 minutes, the pain threshold value w as significantly elevated in the experimental group, and the threshold pe ak appeared at 135 minutes, which was elevated by 61.3%, and lasted for 1 95 minutes (P<0.05). There was no difference in the pain threshold in the control group (P>0.05).1.3 Chronic pain testing:Plantar swelling were 3.84 VS.7.10 in the exp erimental group and control group, respectively (P<0.05). theβ-endorphi n activity in the spinal and hypothalamus was strongly positive in the ex perimental group, while it was weekly positive in the control group. Theβ-endorphin content was also significantly higher in the experimental gr oup (P<0.05). Otherwise, the SP activity was weekly positive in the expe rimental group, while it was strongly positive in the control group. The SP content in spinal was also significantly lower in the experimental gro up (P<0.05). However, the difference in SP content in hypothalamus was no t significant (P>0.05).2 Clinical Trial100 patients eligible entered this study during the period of January 2006 and December 2009, with 51 patients in treatment group and 49 patien ts in control group. All the patients accepted at least 1 cycle of the an algesic treatment. The clinical characteristics, including demographic ch aracteristics, VAS score, type of pain, primary tumor and metastasis, and TCM syndrome differentiation type, were statistically similar between th e two groups.(1) Analgesic Effects:①The VAS score in treatment group and control gr oup after 1,3,7 days of analgesic treatments were 5.83±1.97vs.5.7±2. 0.4.37±1.94 vs.4.53±1.89,3.53±1.79 vs.4.06±1.64, and 2.53±1.39 vs. 3.25±1.39, respectively. The VAS score was lower in the treatment group compared with that of the control group, although without significant di fference (P>0.05).②However, according to the weighted VAS score, the r ate of NR, MR, PR and CR between treatment and control group after 3,7 d ays of analgesic therapy were 4:24:19:4 vs.8:25:12:4,1:10:33:7 vs.4:17: 23:5, and the overall response rate (ORR) were 92.2% vs.83.7%,98% vs. 91.8%(P<0.05).③The ORR in patients with moderate pain in treatment and control group after 3,7 days of analgesic therapy were 88.9% vs.7 1.4%,100% vs.85.7%, respectively (P<0.05). No significant difference was seen in those with mild or sever pain (P>0.05).(2) Quality of Life:①The QOL score in treatment group after 3,7 days of analgesic treatments were significantly higher than those in control group, which were 43.29±4.54 vs.39.78±4.70,43.89±4.60 vs.41.47±4.35 (P< 0.05).②The KPS score in treatment and control group after 3,7 da ys of analgesic treatments were 72.65±10.67 vs.71.02±11.23 (P>0.05),7 9.12±10.23 vs.71.63±12.47 (P<0.05)(3) Side Effects:The side effects were similar in two groups after 3,7 days of treatments, including Nausea, vomiting, constipation, pruritus an d thirsty, etc.1 elderly male patients suffered acute urinary retention after treated with transmucosal fentanyl in the treatment group, and was cured after symptomatic therapy. The side effects rate was a little lower in treatment group than that in control group, without significant diffe rence (P>0.05). There were no side effects associated with external trad itional Chinese medicine.Gonclusion1. External Zhitong-I was safe and effective. The analgesic rate was 55.98 %. The analgesic effect began at 75 minutes, arrived the peak at 135 minu tes, and lasted for 195 minutes。2. External Zhitong-Ⅰcould relieve planter swelling and tenderness in pai n model induced by formaldehyde. Theβ-endorphin in CNS was significant ly higher and the SP was lower in the experimental group, which suggests that the analgesic mechanism of Zhitong-I may associated with exciting ce ntralβ-endorphin acceptors, elevatingβ-endorphin content and decreasi ng SP content.3. External Zhitong-I was an effective co-analgesic therapy to the three-t iered "cancer pain ladder" in cancer pain, which could control pain much earlier. External Zhitong-I could effectively control mild pain. And the analgesic effect was significantly better in moderate pain with external Zhitong-I and three-tiered "cancer pain ladder" than that with three-ti ered "cancer pain ladder" only.4.External Zhitong-I with three-tiered "cancer pain ladder" could improv e QOL and physical status, and could improve QOL earlier, without few sid e effects.