by Yang Xiaosong, Mao Chao, Jing Fengbiao, Zhu Guangrong,
Yang Jie, Liu Guihua, Fang Zhimei, Li Yunfei, and Cao Xiaobin,
　
435 heroin addicts were treated for 10days to evaluate the therapeutic effectiveness of abstinence capsule on heroin withdrawal symptoms and its main adverse actions. Lofexidine was applied in a control group of 48 addicts. The single blind method and some determination methods used internationally were employed to evaluate the therapeutic effectiveness and adverse actions of the drugs. The results showed that the abstinence capsule has better therapeutic effectiveness，with less adverse actions?wider safety range, longer time of action and less cost than lofexidine?br /> 　　
　　Breaking addiction is a key step in the treatment of heroin dependence and important for complete recovery of addicts. Although succedanea such as methadone have good therapeutic effects on drug addiction, their Performance range is limited because of their serious symptoms after narcotic withdrawal. Thus it is very necessary to develop effective non－anesthetic drugs for abstinence．The abstinence capsule，developed jointly by our Center and the Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine, has certain therapeutic effects in treatment Of the narcotic withdrawal symptoms．Application of lofexidine as a non－anesthetic drug for abstinence in China has been approved，so lofeximne was selected as a control drug to evaluate the therapeutic effectiveness and safety of the abstinence capsule

Criteria for Selection
　　1. Subjects:
　　The subjects were heroin addicts who had been diagnosed to suffer from
　　psychonosema（dependence to opiate）caused by mental－active substances of CCMD-2 and DSM-III-R.
　　2. Criteria for recruitment:
　　Voluntary narcotists for de-addiction who had taken heroin in different ways for over 3 months，and symptoms of heroin withdrawal would appear in 8?2 hours after its withdrawal；the patients who had taken
　　heroin in past 24 hours；the urine for morphine was positive；the ages varied from 16 to 45 years；abnormal functions of the heart ,liver, and kidney and psychonosema were not found? 　　Methods for Administration and Observation

l．Methods for grouping and administration?　All the norcotists were divided at random into the treatment group?35 cases）and the control group?8 cases? The single blind method was applied in this study(both drugs were filled into capsule in same color)．The narcotists in treatment group were given abstinence capsules，each containing 300mg of extracts from 8 traditional Chinese drugs such as Zhizi (Fructus Gardeniae), Muxiang (Radix Aucklandiae)，Dahuang（Radix et Rhizoma Rhei），Yuanhu (Rhizoma Corydalis)，etc．Patients in the control group were treated with lofexidine（each capsule contained 0.2mg of lofexidine）．
　　The narcotists in the treatment group were divided further into three subgroups (the
　　mild，moderate and severe) on the basis of the history, doses and ways of heroin taking, general conditions and addictive performances．The narcotists in different subgroups took different doses of abstinence capsules?　　The mild group? capsules as the first dose were given at admission and 6 capsules
　　12 hours after admission．Then the patients were treated once a day for 6 days? capsules on the second day and one capsule was decreased from the previous dosage for each of the following days．Persisting symptoms of narcotic withdrawal were observed from the 8th day to the 10th day during which no capsules were given?　　The moderate group：The first dose of 10 capsules，the second dose of 6 capsules 8
　　hours and the third dose of 4 capsules 20 hours after admission? capsules were given on the 3rd day，then the dosages from the 4th to the 8th days were 7? and 3 capsules respectively．Persisting symptoms of narcotic withdrawal were observed from the 9th day to 10th day during which no capsules were given?br /> 　　The severe group：The first dose was 10 capsules at admission，the second was 6 capsules 6 hours and the third was 8 capsules 18 hours after admission? capsules were given on the 3rd day after admission．From the 4th day to the 9th day，the patient was treated once a day，starting from a dose of 8 capsules with one capsule deducted from the previous dose for the rest of the days. Persisting symptoms of narcotic withdrawal were observed from the 10th day to the 11th day without administration of abstinence capsules.
　　 The narcotists in the control group were also divided into three subgroups (the mild, moderate and severe). The narcotists in different subgroups took different doses of
　　lofexidine orally.
　　The mild group: The dose of lofexidine was 2 capsules each time, bid, on the first day of admission; 2 capsules each time, tid, from the 2nd day to the 6th day; 2 capsules a time, bid, on the 7th day; one capsule each time, bid, on the 8th day; one capsule on the 9th day. Persisting symptoms of narcotic withdrawal were observed on the 10th day without lofexidine.
　　The moderate group: The dose of lofexidine was 2 capsules a time, bid, on the first day of admission; 2 capsules respectively in the morning and afternoon, 3 capsules in the evening, from the 2nd day to the 6th day; 2 capsules a time, tid, on the 7th day; 2 capsules a time, bid, on the 8th day; one capsule, bid, on the 9th day; one capsule on the 10th day. Persisting symptoms of narcotic withdrawal were observed on the 11th day without lofexidine.
　　The severe group: The dose of lofexidine was 2 capsules in the morning, 3 capsules in the evening, on the first day of admission; 3 capsules respectively in the morning and evening, 2 capsules at noon, from the 2nd day to the 6th day; 2 capsules a time, tid, on the 7th day; 2 capsules a time, bid, on the 8th day; one capsule, bid, on the 9th day; one capsule on the 10th day. The persisting symptoms of narcotic withdrawal were observed on the 11th day without lofexidine.

2. Method of observation:
　　All the participants in this research must be familiar with the protocol for the clinical trial and the criteria for taking marks. The recording was done by the same personnel. l). Case taking was briefly done for each subject; 2). A quantitative record for withdrawal symptoms: The symptoms were recorded before treatment and 9?0 o'clock every morning during the treatment. The clinical symptoms were divided into five classes and their severity into four degrees; 3). The Halmiton's anxiety scale: The narcotists were detected according to the scale before treatment and on the 8th day and the 10th day of the treatment; 4). Monitoring adverse actions: Adverse actions and their correlation with abstinence capsules or lofexidine were evaluated at 2 hours after each treatment.

General Data
　　All the narcotists in the study were voluntarily treated at the Center from March of 1995 to November of 1996. In the treatment group, 383 cases were male, and 52 cases female; their ages ranged from 16 to 38 years with an average of 23.4 years; the duration of narcotic taking varied from 5 months to 4.5 years, averaging 427.3 days. All the cases received an education of various degrees; 7 cases had a higher education, 86 cases senior middle school education, 193 cases junior middle school education, and 149 cases primary school education. The narcotic doses varied from 50 mg/day to 2.5 g/day, averaging 378 mg/day. 302 cases took heroin by intravenous injection, 127 cases by burning-inhalation, 6 cases by intramuscular injection; 93 cases had received three times and more of heroin abstinence treatment, 239 cases twice, 103 cases the first time. In the control group, 41 cases were male, and 7 cases female; their ages were from 17 to 33 years with an average of 22.7 years; the duration of narcotic taking varied from 7 months to 3.9 years, averaging 4435.7 days. 11 cases had senior middle school education, 18 cases junior middle school education, 19 cases primary school education. Narcotic doses were from 50 mg/day to 3g/day, averaging 423 mg/day. 43 cases took heroin by intravenous injection, 5 cases by burning-inhalation; 9 cases had received three times and more of heroin abstinence treatment, 23 cases twice, 16 cases the first time. Both groups of narcotists were diagnosed according to the criteria for DSM-III-R opiate dependence. The narcotists in both groups were similar in general condition with no psychonosema and other severe diseases. The narcotists with abnormal function of the liver were excluded.

Analysis for Therapeutic Effectiveness
　　1. Abstinence:
　　The total score for the three symptoms of eager desire, anxiety and sleeplessness was less than 10, or total mark less than 27; the urine test for opiate were negative; the test for inducing addiction with 0.4-0.8 mg of naloxone by intramuscular injection was negative.
　　2. Analysis of controlled symptoms of withdrawal:
　　The mark of withdrawal symptoms after treatment decreased remarkably as compared with that before treatment, and the decreased range was affected by the drug dose and the time of drug action. The abstinence capsule took effect 30-40 minutes after administration but had a wide safety range and less adverse actions, and may be repeatedly administered until a satisfied therapeutic dose was realized. Therefore, the curve of the mark of withdrawal in the treated group dropped rapidly and steadily. Lofexidine took effect rapidly in approximate 10 minutes after oral administration, but it could reach the therapeutic dose only in the second 24 hours after administration. Furthermore, it had severe adverse actions and less therapeutic effect on the symptoms caused by the excitation of parasympathetic nerves. Thus, the curve in the control group dropped slowly. In the treatment group of 468 cases, 11 cases (2'4%) were eliminated due to the positive reaction of uric opiate, 20 cases (4.3%) did not finish the treatment because of poor therapeutic effect, 2 cases withdrew early from the treatment due to mild dependence to heroin. In the control group of 61 cases, 4 cases (6.6%) were eliminated because of the positive reaction of uric opiate, 5 cases (8.2%) did not finish the treatment due to poor therapeutic effectiveness (Table).

Table. Daily Comparison in Total Score of
　　Withdrawal Symptoms between the Two Groups

Day Treated group Control group

Before treatment' 96.73±16.63 (468) 95.28± 15.78 (61)
　　After beginning treatment
　　1st day 36.23±1 I.67 (468)* 42.23±12.94 (61)
　　2nd day 23.53±11.26 (462)* 32.36±9.85 (59)
　　3rd day 14.97±8.70 (458)* 20.58 ±9.55 (52)
　　4th day 10.67±6.61 (451)* 16.20±8.78 (49)
　　5th day 8.43±5.88 (4M)* 12.25±8.01 (48)
　　6th day 7.30±4.94 (438)* 10.57±8.56 (48)
　　7th day 6.34±3.82 (438)* 9.23±7.21 (48)
　　8th day 6.89±4.37 (435)* 9.47±6.78 (48)
　　9th day 8.15±5.47 (435) 8.88±6.24 (48)
　　10th day 6.23±3.59(435) 7.51±5.78(48)

　　Notes: The data in the table: means SD (case number). * P<0.0l between the two groups
　　3. Effect on anxiety factor:
　　In the treatment group, the total scores of anxiety symptoms on the Hamilton's anxiety scale were respectively 23.2 ± 12.3, 14.3± 8.2 and 9.1±6.3 before treatment, on the 5th day of beginning treatment and after treatment. In the control group, the total scores were respectively 21.0±9.8, 12.2±9.8 and 10.21±6.9. The total scores in the two groups showed remarkable decrease booth p<0.ol) after treatment, and the decrease of the total scores in the treated group was similar to that in the control group (P<0.05).
　　According to analysis of anxiety factors, the abstinence capsule showed poor therapeutic effect on mental state of anxiety, nervousness, dysnmesia and sleeplessness, but marked therapeutic effect on other anxiety factors. Lofexidine showed poor therapeutic effect on mental state of anxiety, nervousness, fear, muscular system, cardiovascular systems, respiratory system and digestive system, but good therapeutic effect on other anxiety factors.
　　4. Effect on head rate and blood Pressure:
　　The abstinence capsule slowed down the heart rate markedly with heat rate of more than 50 beats per minute in all cases of the treatment group, but had no obvious effect on blood pressure. The decrease of heart rate in the control group was similar to that in the treatment group, but the heart rate in some cases in the control group was raised by 10-20 beats per minute after the treatment began; and the blood pressure was obviously affected in the control group.

Analysis of Adverse Effects
　　There was a low incidence rate of adverse effects in the treatment group. Such adverse effects as nausea, vomiting, appeared in a number of cases at the early stage of the treatment possibly because of the gastrointestinal reaction to the withdrawal symptoms. Some adverse effects like general weakness, somnolence and listlessness appeared after administration of larger doses of abstinence capsules, possibly because of corydalises in the abstinence capsule. There was a high incidence rate of adverse effects in the control group with dry mouth, dizziness and general lassitude frequently seen. 4 cases (6.6%) didn't finish the treatment due to adverse effects.
　　All cases received blood routine, urine routine, electrocardiography, ALT and urea nitrogen test. In the treatment group, ALT rose to 40~132 U/L (abnormal) in 25 cases (5.3%); While in the control group, it rose to 40-64 U/L in 4 cases (8.3%).
　　No Obvious' change was observed in other laboratory examinations in the both groups.

Discussion
　　Although a lot of non-opiate abstinence drugs are clinically used, only three drugs of
　　clonidine, lofexidine and Fukangpian (福康)? with a certain therapeutic effects on withdrawal symptoms have been officially approved by the State Drug Administration of in China at present. Lofexidine was selected as a control drug in this study because of its less adverse effects, reasonable price, good acceptability by patients. The abstinence capsule, developed according to “Jiu Mi Liang Fang (Wonderful Recipes for Confusion)?compiled by He Qiwei (Qing Dynasty) and the recipes of Liu Dongliang and Yu Yin gyi, has the effect of purging intense heat, detoxicating, promoting flow of Qi to remove blood stasis, and invigorating the spleen to benefit the lung as well as removing addiction. This study proves that the abstinence capsule has a better control of the withdrawal symptoms. 93.37% of the narcotists finished the abstinence treatment in the treatment group, and 78.68% of the narcotists finished the treatment in the control group; 4.3 % of the narcotists withdrawn from the treatment due to failure to control withdrawal symptoms in the treatment group, and 14.75% of narcotists withdrawn from the treatment due to the same reason in the control group. The two drugs used in the study belong to the expectant treatment without mental activity. The abstinence capsule has less therapeutic efficacy on eager desire and sleeplessness. 14.3% of the narcotists in the treatment group could not sleep until administration of tranquilizers, while 23.0% of the narcotists in the control group needed tranquilizers for sleep. The abstinence capsule has much better therapeutic effect on aching pain in skeletal muscles, anorexia and palpitation than lofexidine. The rate of some adverse effects such as xerostomia is low, and the rate of blurred vision, somnolence, and lassitude is high in the treatment group because there is no Yang Jin Hua (Flos Daturae) in the abstinence capsule. Nausea and vomiting in a few
　　narcotists are probably related to the gastrointestinal effect of withdrawal symptoms exacerbated by the abstinence capsule. In the treatment group, most adverse effects appeared at the early treatment stage with a large dose, but no obvious adverse effects, including the effect on blood pressure, appeared; and no case withdrawn from the treatment due to adverse effects at the middle and late stages of the treatment. In the control group, there were more adverse effects such as headache, unstable gait and palpitation, which affected the treatment; approximately 6.6% of the nacotists didn't finish the treatment because of these adverse effects. It is proved that the abstinence capsule has good therapeutic effects on withdrawal symptoms, better effect on controlling withdrawal symptoms, with less adverse effects than lofexidine. The drug has longer time of action so that mild and moderate narcotists need to take the drug only once a day. The abstinence capsule is a preparation of pure herbs, and therefore it has a bright prospect of development.