Effect of Electroacupuncture on Opioid-induced Constipation in Patients With Cancer: Study Protocol for a Multicenter Randomized Controlled Trial
Phase: NA
Conditions: Opioid-induced Constipation in Patients With Cancer
Sponsor: Guang'anmen Hospital of China Academy of Chinese Medical Sciences

Final protocol, the summary of changes from the published original protocol

Effects of electroacupuncture on opioid-induced constipation in patients with 
cancer: a multicenter randomized controlled trial 
Clinical Sites: 
1.
Guang’an men Hospital Affiliated to China Academy of Chinese Medical
Sciences
2.
Guizhou University of Traditional Chinese Medicine
3.
The Affiliated Hospital of Nanjing University of Chinese Medicine
4.
Hunan University of Chinese Medicine
5.
Wangjing Hospital Affiliated to China Academy of Chinese Medical Sciences
6.
Yantai Hospital of Traditional Chinese Medicine
7.
Zhejiang Hospital
Data Management and Statistical Centers: 
Linkermed Pharm Technology Co. Ltd, Beijing, China 
Data： 
Original protocol date: September 30, 2018 
Amendment date: November 29, 2019  
Confidentiality Statement 
This document is the intellectual property of the Investigators. The information 
provided in this document is strictly confidential and is available for review to the 
sponsor, investigators, potential investigators, appropriate Ethics Committees, 
Investigational Review Boards, and other government regulatory bodies. No 
disclosure should take place without written authorization from the protocol 
developing investigators, except to the extent necessary needed to obtain informed 
consent from potential subjects.

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Table of Contents 
 
  
1. Study Contact and Organization .................................................................................. 4 
1.1 Study Contacts ....................................................................................................... 4 
1.2 Recruiting Sites ...................................................................................................... 5 
1.3 Collaborating Sites ................................................................................................. 7 
2. Study Design ................................................................................................................... 7 
2.1 Study Overview ..................................................................................................... 7 
2.2 Background ............................................................................................................ 7 
2.3 Study Hypothesis ................................................................................................... 9 
2.4 Methodology .......................................................................................................... 9 
2.4.2 Subjects ............................................................................................................. 10 
2.4.3 Trial flow chart ................................................................................................. 14 
2.4.4 Outcomes Measurement.................................................................................... 17 
3. Safety Assessment ........................................................................................................ 20 
4. Interventions ................................................................................................................. 21 
4.1 EA ........................................................................................................................ 21 
4.2 SA ........................................................................................................................ 22 
4.3 Rescue medication ............................................................................................... 22 
5. Informed consent .......................................................................................................... 22 
6. Quality Control ............................................................................................................. 27 
7. Data Management ......................................................................................................... 28 
7.1 The Raw Data Management and Archiving ......................................................... 28 
7.2 Data Entry and Storage ........................................................................................ 28 
7.3 Data Verification and Problems Solving ............................................................. 29 
7.4 Medical Coding .................................................................................................... 29 
7.5 Data Report .......................................................................................................... 29 
7.6 Data Auditing ....................................................................................................... 30 
7.7 Database Locking................................................................................................. 30 
8. Statistical Consideration ............................................................................................... 30 
8.1 Statistical Analysis ............................................................................................... 31 
8.2 Statistical Analysis Plan (SAP) ............................................................................ 31 
9 Ethical principle ............................................................................................................. 31 
10 Funding ........................................................................................................................ 31 
11 References .................................................................................................................... 32 
12 Major update of the published protocol ....................................................................... 34 

 
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1 Study Contact and Organization 
1.1 Study Contacts 
Guang’anmen Hospital of China Academy of Chinese Medical Sciences: 
Zhishun Liu, MD PhD  (Principal Investigator for trial) 
Director of Acupuncture and moxibustion Department 
5 Beixian’ge Street, Xicheng District, Beijing, China, 100053 
Phone: +86 10 88002331 
Email: zhishunjournal@163.com 
 
Weiming Wang, MD PhD 
Acupuncture and moxibustion Department 
5 Beixian’ge Street, Xicheng District, Beijing, China, 100053 
Phone: +86 10 88002930 
Email: wangweiming1a1@163.com 
 
Yuanjie Sun, MD PhD 
Acupuncture and moxibustion Department 
5 Beixian’ge Street, Xicheng District, Beijing, China, 100053 
Phone: +86 10 88001123 
Email:  puzhisun@163.com 
 
Jinna Yu, MD PhD 
Acupuncture and moxibustion Department 
5 Beixian’ge Street, Xicheng District, Beijing, China, 100053 
Phone: 13520566715 
Email: 546872837@qq.com 
 
Lili Zhu, MD 
Acupuncture and moxibustion Department 

 
5
5 Beixian’ge Street, Xicheng District, Beijing, China, 100053 
Phone: 18851182160 
Email: julius.zhu@foxmail.com 
 
1.2 Recruiting Sites 
Guizhou University of Traditional Chinese Medicine 
Xiaofang Yang, MD PhD 
Acumox and Tuina College 
Dongqing South Road, Huaxi University Town, Guiyang, China, 550025 
Phone: +86 13984096366 
Email: yangxiaofang210@163.com 
 
Chao Liu MD 
Acumox and Tuina College 
Dongqing South Road, Huaxi University Town, Guiyang, China, 550025 
Phone: +86 18798089545 
Email: 549889429@qq.com 
 
The Affiliated Hospital of Nanjing University of Chinese Medicine 
Jianhua Sun, MD PhD 
Department of Acupuncture Rehabilitation 
155 Hanzhong Road, Qinhuai District, Nanjing, Zhejiang, China, 210029 
Phone: +86 13914722816 
Email: 377201634@qq.com 
 
Yuhang Wang, MD 
Department of Acupuncture Rehabilitation 
No.155, Hanzhong Road, Qinhuai District, Nanjing, Zhejiang, China, 210029 
Phone: +86 18752018817 
Email: wangyuhang@njucm.edu.cn 
 

 
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Hunan University of Chinese Medicine 
Zenghui Yue, MD 
College of Acupuncture and Tuina 
300 Xueshi Road, Yuelu District, Changsha, Hunan, China, 410208 
Phone: +86 13787293866 
Email: 624755064@qq.com 
 
Wangjing Hospital affiliated to China Academy of Chinese Medical Sciences 
Dianrong Lu, MD PhD 
Department of oncology 
6 Wangjing Zhonghuan South street, Chaoyang District, Beijing, China, 100102 
Phone: +86 13717998887 
Email: ludianrong@aliyun.com 
 
Yantai Hospital of Traditional Chinese Medicine 
Aihua Hou, MD 
Department of oncology  
39 Xingfu Road, Zhifu District, Yantai, Shandong, China 
Phone: +86 13001616877 
E-mail: zlk2127926@163.com 
 
Zhiwei Zang, MD 
Department of Acupuncture and Massage 
39 Xingfu Road, Zhifu District, Yantai, Shandong, China 
Phone: +86 15553553797 
E-mail: 860922902@qq.com 
 
Zhejiang Hospital 
Xiaoqing Jin, MD    
Department of Acupuncture 
No. 12 Lingyin Road, Hanzhou, Zhejiang, China, 310013 

 
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Phone: +86 13357102177 
Email: zjyyjxq@163.com 
 
1.3 Collaborating Sites 
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China 
Yan Liu, MD 
Key Laboratory of Chinese Internal Medicine of Ministry of Education 
5 Haiyuncang Dongcheng, Beijing, China, 100700 
Phone: +86 13811299493 
Email: sasliu@yeah.net 
 
Catholic Health System Internal Medicine Training Program, University at Buffalo, 
Buffalo, NY 
Kehua zhou, MD, DPT 
Phone: 716 986 4856 
Email: kehuazho@buffalo.edu 
 
2. Study Design 
2.1 Study Overview 
The objective of study is to assess the efficacy of electro-acupuncture (EA) for 
opioid-induced constipation(OIC) in adult patients with cancer pain. 
2.2 Background 
In advanced diseases, 70-80% of patients experience moderate to severe pain1. As the 
cornerstone of treatment for moderate to severe cancer pain, opiate analgesics, such as 
morphine and oxycodone, are recommended by WHO Cancer Pain Relief Guidelines 2-3. 
The use of systemic opioids is recommended by some studies for cancer patients 

 
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experiencing moderate to severe pain, regardless of the underlying causes4. Opioids 
stimulate receptors both in the central nervous system (CNS) and the peripheral nervous 
system, reducing pain and improving quality of life for patients 5. The drug can, however, 
be associated with serious adverse events (AEs) with a rate ranging from 1.8% to 
13.6%6-7, the most common of which is opioid-induced constipation (OIC). OIC 
represents a change in baseline bowel habits or defecation patterns that occurs following 
the administration or modification of opioid therapy 8-10. Approximately 41% of 
non-cancer patients and 94% of cancer patients who use opioids for pain have this 
condition 11-12. Symptoms of OIC are usually persistent and difficult to tolerate 9, which 
adversely affects patients' quality of life8，13-15 and results in reductions in dose or 
discontinuation of opioid analgesics 16. OIC is the result of multiple factors contributing 
to it 17: Opioids may activate μ-receptors throughout the gastrointestinal tract and cause 
changes to gut motility, decreases in gut secretion, and an increase in sphincter tone, 
which can lead to constipation 18. Various pharmacological and nonpharmacological 
interventions are used to manage OIC, such as laxatives and increased fluid intake 8-9，19. 
However, these interventions are limited in effectiveness, and they do not address the 
pathophysiological mechanisms of OIC 8-9. Several peripherally acting μ-opioid receptor 
antagonists (PAMORAs), such as naloxegol and methylnaltrexone, have recently been 
shown to be effective in treating OIC patients who do not respond to simple medications 
20. However, longer-term efficacy and safety of PAMORAs are unclear, and they haven't 
been approved in China yet. Clinical trials are still underway to test these drugs. 
Additionally, PAMORAs are often associated with AEs such as abdominal pain and 
flatulence21. As a result, it is still necessary to explore new treatment approaches for OIC. 
In traditional Chinese medicine, acupuncture has been used to treat gastrointestinal 
disease, including constipation, for thousands of years. According to two systematic 
reviews, acupuncture can improve spontaneous bowel movements (SBMs) in functional 
constipation 22-23. Additionally, the results of our study indicated that electroacupuncture 
(EA) could increase complete spontaneous bowel movements (CSBMs) and SBMs, with 
a long-term effect that continues for 24 weeks after treatment ceased among patients with 
chronic, severe functional constipation 24-25. Through stimulation of the somatic and 
peripheral nervous systems, acupuncture can facilitate the gut motility and improve 

 
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gastrointestinal function 26. The effectiveness of acupuncture for OIC is currently lacking 
evidence. The purpose of this study is to compare the efficacy and safety of EA with 
sham acupuncture (SA) in the treatment of OIC in cancer patients. 
2.3 Study Hypothesis  
We hypothesize that EA is better than SA in treating OIC in adult patients with cancer 
pain. 
2.4 Methodology 
2.4.1 Trial Design 
This is a multicenter, prospective, sham-controlled, parallel-group, subject- and 
assessor-blinded, randomized trial at 7 centers in China. Cancer patients must meet the 
Rome IV10 diagnostic criteria for OIC.  
2.4.1.1 Randomization 
Web-based central randomization will be performed by the Linkermed Pharm Technology 
Co. Ltd (Beijing, China). Participants will be randomly allocated, in a 1:1 ratio, to either 
the EA or the SA group using permuted block-randomization. Acupuncturists in each 
center will be responsible for getting random numbers. Via inputting the screening 
information of the participant in the central randomization system through the web, they 
will get the random number and group allocation. 
2.4.1.2 Blinding 
In this study, participants, outcome evaluators, and data analysts will be blinded to the 
group assignments. The acupuncturists who perform the treatment will not be blinded due 
to the nature of the acupuncture treatment. Participant blinding will be achieved via a 
minimal needling at non-acupoints. Bilateral sham points will be attached with the same 
EA apparatus using a continuous wave of 10Hz and a current intensity of 0.1–0.2mA for 
30 minutes after a brief activation period of 30 seconds. 
For blinding assessment, all participants will be requested to answer the following 
question:“Is EA the acupuncture modality that you have received?”within five minutes 
after any treatment at week 8. 

 
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2.4.1.3 Sample Size  
On the basis of unpublished data, a 14% response rate was assumed for the sham 
acupuncture group in this study. We estimated that a sample size of 100 participants 
would provide 90% power to detect a between-group difference of 31.4% at the 
two-sided significance level of 0.05 and 20% loss to follow-up. 
2.4.2 Subjects 
Participants with cancer will be publicly recruited from inpatient and outpatient 
departments through posters and networks from 6 centers in China.  
2.4.2.1 Inclusion Criteria 
(1) Cancer patients must meet the Rome IV10 diagnostic criteria for OIC. Participants 
have at least 2 of the following new or worsening symptoms of constipation following 
initiation, alteration, or increase in opioid treatment: fewer than three SBMs per week, 
straining (>25% of defecations), sensation of incomplete evacuation (>25% of 
defecations), lumpy or hard stools (>25% of defecations), and/or sensation of anorectal 
obstruction/blockage (>25% of defecations). For patients with a history of chronic 
functional constipation, he/she must have worsening symptoms of constipation when the 
opioid therapy is initiated, changed, or the dose is increased;(2)Patients recruited in this 
trial must have a history of OIC symptoms for at least 1 week;(3) Patients must be ≥18 
years of age and ≤85 years of age; (4) Patient’s cancer condition must be stable with a 
life expectancy that is more than six months; (5)Patients must have an Eastern 
Cooperative Oncology Group (ECOG)27performance status of 0-3; (6)Patients must have 
been receiving a stably maintained opioid regimen, consisting of a total daily dose of 30 
mg to 1000 mg oral morphine equivalents for at least 2 weeks prior to screening for 
cancer pain. Furthermore, it must be anticipated that the opioid will be maintained for at 
least 10 weeks;(7)The SBM frequency of the patients must be 2 times a week when 
laxatives are not being taken;(8)Patients must be capable of oral intake of drugs, food and 
beverages; (9)Provision of written informed consent before inclusion.  
2.4.2.2 Exclusive Criteria 
Participants will be excluded from this trial if they have any of the following conditions: 
(1) Patients diagnosed with clinically significant abnormal defecation due to functional 

 
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disorders or structural abnormalities of the gastrointestinal tract and other tissues related 
to gastrointestinal tract (not including OIC): inflammatory bowel disease, rectal prolapse, 
gastrointestinal obstruction, peritoneal metastasis, or peritoneal tumor at the time of 
enrollment; (2)Patients with a history of gastrointestinal tract operation, abdominal 
operation, or abdominal adhesion within one month prior to screening; history of 
intestinal obstruction within three months prior to screening; (3)Diagnosis of active 
diverticular disease; or severe hemorrhoid; or anal fissure; or artificial rectum or anus; 
(4) Patients with an intraperitoneal catheter or those that use a feeding tube to maintain 
vital signs; (5)Diagnosis of pelvic disorder, which are considered to have obvious effects 
on the intestinal transport of feces (such as uterine prolapse ≥degree 2, uterine fibroids 
[located in the posterior of the uterus with a diameter ≥ 5 cm] affecting bowel movement); 
(6)Patients that are being treated with a new cancer chemotherapy, which had never been 
administered in the past, within 14 days of the screening or are scheduled to receive such 
therapy during the study; (7)Patients that received radiotherapy within 28 days of the 
screening or are scheduled to receive such therapy during the study; (8)Patients that 
underwent a surgery or intervention that is considered to have an obvious effect on the 
gastrointestinal functions within 28 days of the screening or are scheduled to receive 
surgery or intervention which is considered to have obvious effects on the gastrointestinal 
functions during the study, or scheduled to receive surgery or intervention which will be 
anticipated to prevent the patients from completing the trial; (9)Patients with uncontrolled 
hyperthyroidism, severe hypertension, heart disease, systematic infection or blood 
coagulation disorders (hypercoagulation status or hemorrhagic tendency); (10)Patients 
that consumed >4 additional opioid doses per day, for breakthrough pain, for more than 3 
days during the baseline period, or if their maintenance opioid dosing regimen was 
modified during this period; (11)Patients with severe cancerous pain (e.g., typical average 
daily pain intensity rating of 7 to 10 on a numerical rating scales (NRS; 0 [no pain] to 10 
[the worst pain possible]) after the utility of routine dose and frequency of opioids) 
refractory to opioid therapy;(12) Patients with a history of opioid discontinuation due to 
severe adverse events or patients that are suspected to discontinue opioid use due to the 
potential risk of adverse events; (13)Patients that received an opioid receptor antagonist 
or agonist within one month of the screening, or those who are scheduled to receive such 

 
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therapy during the study; (14)  Patients with a history of nerve neurolysis;(15) Patients 
with severe cognitive impairment, aphasia, or psychiatric disorders; abdominal aortic 
aneurysm; hepatomegaly; or splenomegaly;(16) Patients that have received acupuncture 
within three months of the screening; (17)Other patients who are considered ineligible for 
the study by the investigator on the basis of concomitant therapy and medical findings. 
2.4.2.3 Subject Withdrawals 
There will be at least one oncologist or gastroenterologist in each center. They will assess 
the severe adverse events (SAEs) and then determine whether the participant to continue 
or terminate the trial. Subjects may leave the study at their own discretion, or the 
investigator may determine whether it is in the best interest of subjects to withdraw from 
the trial due to worsening of symptoms, or the occurrence of a serious adverse event.  
2.4.2.4 Subject Recruitment, Screen and Grouping Assignment 
Participants with cancer will be publicly recruited from inpatient and outpatient 
departments through posters and networks. Research assistants of each site will 
preliminarily screen the participants by recording their disease condition, history of the 
disease and treatment, and the demographic data. An oncologist or gastroenterologist of 
each site will take charge of the diagnosis and the differential diagnosis of the OIC. 
Potential participants will fill out a 1-week patient diary to record bowel movements, the 
stool consistency, degree of difficulty in defecation, the rescue medicine drugs and 
duration of usage, and the intensity of cancerous pain, etc. Eligible participants then will 
be randomized to EA or SA group. Acupuncturists are in charge of the participants’ group 
assignment, and the EA or SA treatments. They are also responsible for the assessment of 
safety during treatment. During the trial, the professional evaluators of each site will 
instruct the participants how to fill in patients' self- assessment related to the trial and 
their patient diaries and the evaluators will record the data on the case report form (CRF) 
through the whole trial period. The subject flow was shown in Figure 1.

1 
 
Initial contact at clinic visit. Patients screened for OIC by research assistants. Informed consent 
process 
Agree to participate 
Decline to participate 
Patients were diagnosed for OIC by oncologists or gastroenterologists: 1 
week as baseline (patient diary including the bowel movements, the stool 
consistency, degree of difficulty in defecation, the rescue medicine, and the 
intensity of cancerous pain were recorded), inclusion and exclusion criteria 
Eligible 
Ineligible 
Randomization to EA or SA by acupuncturists 
Data submission 
Outcome assessment: week 8 
Complete 
screening 
8-week treatment 
8-week follow-up 
Outcome assessment: week 16 
Data submission 
Data submission 
Figure 1. Subject flow 

1 
 
 
2.4.3 Trial flow chart 
The trial flow chart was shown in Figure 2.  
Enrollment 
Study Period 
Baseline 
Allocation 
Treatment 
Follow-up 
Weeks -1 
Week 0 
Weeks 1 to 8 
Weeks 13 to 16  
 
 
 
 
Eligibility criteria 
× 
 
 
 
Demography characteristics 
× 
 
 
 
Disease history of cancer 
× 
 
 
 
Disease history of OIC and constipation 
× 
 
 
 
Eligibility screen 
× 
 
 
 
Informed consent 
× 
 
 
 
Allocation 
 
× 
 
 
Interventions 
 
 
 
 
Electroacupuncture 
 
 
× 
 
Sham electroacupuncture 
 
 
× 
 
Assessments 
 
 
 
 
SBMs  
× 
 
× 
× 
CSBMs 
× 
 
× 
× 

 
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Abbreviations: OIC, Opioid-induced constipation; SBMs, spontaneous bowel movements; CSBMs, complete spontaneous bowel 
movements; PAC-SYM, Patient Assessment of Constipation-Symptom questionnaires; PAC-QOL, Patient Assessment of 
Constipation-Quality of Life questionnaires. 
Mean Bristol Stool Form Scale score for stool 
consistency of SBM 
× 
 
× 
× 
Mean score for straining of SBM 
× 
 
× 
× 
PAC-SYM total score and subscale scores 
× 
 
× 
× 
PAC-QOL total score and subscale scores 
× 
 
× 
× 
Patients’ global assessment of treatment efficacy 
 
 
× 
× 
Rescue medicine usage  
× 
 
× 
× (weeks 9 -16) 
Opioid usage  
× 
 
× 
× (weeks 9-16) 
Patients’ expectation of the acupuncture efficacy 
× 
 
 
 
Blinding assessment 
 
 
× 
 
Cancer pain  
 
 
× 
× 
Adverse events 
× 
 
× 
× (weeks 9-16) 
Safety assessment 
× 
 
× 
× (weeks 9-16) 

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Adults with cancer who experiencing constipation induced by opioid 
Screening for eligibility 
Baseline assessment(1-week run-out period)  
Demographics data, patient diary, PAC-SYM, 
PAC-QOL, rescue usage, opioid usage, 
patients’ expectation 
EA group (n=50) 
EA, 3 sessions per week for 8 weeks 
 (weeks 1-8) 
SA group (n=50) 
SA, 3 sessions per week for 8 weeks 
(weeks 1-8) 
 
Data collection and analysis 
Randomization 
8-week follow-up (weeks 9-16) 
 Primary outcome: the proportion of responders  
 Second outcomes: the mean weekly SBMs and complete 
spontaneous bowel movements, the mean Bristol Stool Form 
Scale score for stool consistency, the mean score for straining of 
SBM, the total and subscale scores of Patient Assessment of 
Constipation-Symptom questionnaires, and the total and subscale 
scores of Patient Assessment of Constipation-Quality of Life 
questionnaire, patients’ global assessment of treatment 
effectiveness, patients’ expectation towards the effectiveness of 
acupuncture and safety assessment 
Outcome measures 
At baseline 
At week 16 
100 participants 
At week 8 
Figure 3. The schedule of enrollment, interventions, and assessments 

17 
 
2.4.4 Outcomes Measurement 
2.4.4.1 Primary Outcome 
The primary outcome will be the the proportion of responders, defined as a patient that 
has ≥3 SBMs/wk and ≥ increase of 1 SBM from baseline simultaneously for at least 6 out 
of 8 weeks of the treatment period. SBM refers to a bowel movement that occurred 
without medication or assistance within the previous 24 hours. When a bowel movement 
occurs within 24 hours of the use of an optional assisted method (rescue medication or 
other bowel-treatment regimens) for defecation, it is not regarded as an SBM.  
Every participant will be required to keep a diary 13 weeks: baseline (run-out 
period before randomization), 8 weeks of treatment, and 4 weeks of follow-up. Diary 
entries include the frequency of bowel movements, the consistency of the stool, the 
difficulty in defecating, the rescue medicine drugs applied and their duration, and the 
intensity of the cancer pain. During the treatment period, the diary will be collected 
weekly, and during the follow-up period, it will be collected at the end of week 16. The 
outcome evaluators will examine the diary content and determine the SBM and frequency 
accordingly.   
2.4.4.2 Secondary Outcomes 
(1) Changes in the mean weekly SBMs from the baseline during weeks 1-8 and weeks 
13-16. The mean weekly SBMs equals the total frequency of SBMs divided by the 
numbers of week(s) recorded. Assessment time frame: at baseline, over weeks 1-8 and 
13-16.  
(2) The proportion of patients with ≥3 mean weekly SBMs during weeks 1-8 and weeks 
13-16. Assessment time frame: at baseline, over weeks 1-8 and 13-16. 
(3) The proportion of patients with an increase of ≥1 mean weekly SBM from the 
baseline during weeks 1-8 and weeks 13-16. Assessment time frame: at baseline, over 
weeks 1-8 and 13-16.  
(4) A change in the mean weekly CSBMs from the baseline during weeks 1-8 and weeks 
13-16. A CSBM is defined as an SBM with the feeling of complete evacuation. The mean 
weekly CSBMs equals the total frequency of CSBMs divided by number of week(s) 

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recorded. Assessment time frame: at baseline, over weeks 1-8 and 13-16. 
(5) The proportion of patients with ≥3 mean weekly CSBMs during weeks 1-8 and 
weeks 13-16. Assessment time frame: at baseline, over weeks 1-8 and 13-16. 
(6) The proportion of patients with an increase of ≥1 mean weekly CSBM from the 
baseline during weeks 1-8 and weeks 13-16. Assessment time frame: at baseline, over 
weeks 1-8 and 13-16.  
(7) A change in the mean Bristol Stool Form Scale score for stool consistency of SBMs 
from the baseline during weeks 1-8 and weeks 13-16. For stool consistency, each patient 
will be asked to record their stool consistency according to the Bristol Stool Form Scale28  
on the following seven points scale (scored from 1 to 7 for stool types 1 to 7, 
respectively). Assessment time frame: at baseline, over weeks 1-8 and 13-16. 
 
 Type 1: Separate hard lumps, like nuts (hard to pass) 
 Type 2: Sausage-shaped, but lumpy 
 Type 3: Like a sausage but with cracks on its surface 
 Type 4: Like a sausage or snake, smooth and soft 
 Type 5: Soft blobs with clear cut edges (passed easily) 
 Type 6: Fluffy pieces with ragged edges, a mushy stool 
 Type 7: Watery, no solid pieces. Entirely liquid 
 
 (8) A change in the mean score for the straining of SBMs from the baseline during 
weeks 1-8 and weeks 13-16. For assessment of the straining of SBMs, each patient will 
be asked to rate his/her score of straining, using the following five-point scale29: not at all 
difficult (0), a little bit difficult (1), moderately difficult (2), quite a bit difficult (3), 
extremely difficult (4). Assessment time frame: baseline, over weeks 1-8 and 13-16. 
(9)A change in the total and subscale score of the Patient Assessment of 

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Constipation-Symptom (PAC-SYM) questionnaire from the baseline at weeks 8 and 16. 
The PAC-SYM is a questionnaire used to evaluate the severity of chronic constipation in 
the past 2 weeks. It consists of 12 items, which are subdivided into abdominal (4 items), 
rectal (3 items), and stool (5 items) scales.34 36 The score of each item ranges from 0 to 
4, with 0 = symptom absent, 1 = mild, 2 = moderate, 3 = severe and 4 = very severe. 
Lower scores indicate a lower symptom burden. Each subscale score will be calculated as 
the mean of the completed items for that subscale. The total score will be calculated as 
the mean of all completed items. In this trial, the Chinese version of PAC-SYM, which 
has been validated to have a satisfactory psychometric property30, will be used. 
Assessment time frame: at baseline, at weeks 8 and 16. 
(10) A change in the total and subscale scores of the Patient Assessment of 
Constipation-Quality of Life (PAC-QOL) questionnaires from the baseline at weeks 8 and 
16. The PAC-QOL is a 28-item self-reported questionnaire to assess the burden of 
constipation on patients’ everyday functioning and well-being in the 2 weeks (14 days) 
prior to assessment31. This questionnaire is divided into four subscales: physical 
discomfort (items 1-4), psychosocial discomfort (items 5-12), worries/concerns (items 
13-23), and satisfaction (items 24 to 28). Each of the item scores ranges from 0 (not at all) 
to 4 (extreme), with lower scores indicating a better quality of life. For each visit, 
individual subscale scores will be calculated as the mean of the completed items for that 
subscale. The total score will be calculated as the mean of all of the completed items. We 
will use the Chinese version of this test32 in our trial, which has been demonstrated to be 
a reliable and valid tool. Assessment time frame: at baseline, at weeks 8 and 16. 
(11) Patients’ global assessment of treatment efficacy. Each patient will be asked to rate 
his/her efficacy of treatment using the following 7-point self-reporting scale: markedly 
worse (1), moderately worse (2), slightly worse (3), no change (4), slightly improved (5), 
moderately improved (6), markedly improved (7). Scales with seven response categories 
are easy to use and have shown a high reliability and validity33. This questionnaire will be 
completed at week 8 and week 16. Assessment time frame: baseline, at weeks 8 and 16. 
(12) The proportion of patients using rescue medicine and the mean frequency of rescue 
medicine use per week during weeks 1-8 and weeks 9-16. Assessment time frame: at 
baseline, over weeks 1-8 and 13-16. 

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Other Pre-specified Outcome Measures  
(13) The proportion of patients discontinuing the opioid, and those with a ≥30% weekly 
mean increase or decrease in the dose of opioid from baseline during weeks 1-8 and 
weeks 9-16. Assessment time frame: at baseline, at weeks 8 and 16. 
(14) The proportion of patients with a change from baseline in anti-tumor therapy that 
could impair the defecation during weeks 1-8 and weeks 9-16. Assessment time frame: at 
baseline, at weeks 8 and 16. 
(15) Patients’ belief in the efficacy of acupuncture. Participants will be asked to answer 
the following questions at baseline: “Do you think acupuncture will be effective in 
treating the disease in general?” and “Do you think acupuncture will be effective in 
improving the OIC?” For each question, patients will choose one of the following 
answers: “unclear/whatever”, “Yes”, or “No”. Assessment time frame: at baseline. 
(16) Blinding assessment. The blinding is regarded as successful when a patient guesses 
he/she has received a conventional EA. Before treatment, we told patients that they had a 
50% chance of receiving conventional electroacupuncture (EA) with a deeper insertion 
versus minimal electroacupuncture (SA) a superficial penetration. Conventional 
electroacupuncture and minimal electroacupuncture have a possible similar efficacy. Both 
treatments used a relatively small electric intensity, and they may or may not feel the 
stimulation during treatment. Patients were treated separately to avoid communication. 
To assess the success of blinding, within 5 minutes after treatment at week 8, patients 
were asked to guess whether they received conventional EA. Assessment time frame: at 
week 8.  
3. Safety Assessment 
All adverse events (AEs) will be recorded throughout the whole trial in Adverse Event 
Form (AEF) by patients themselves and outcome assessors. In our trial, the serious AEs 
will be defined as events that cause death, exacerbation of the preexisting condition, 
interruption of treatment, prolongation of existing hospitalization, permanent disability or 
damage, or required medical intervention to prevent one of the above outcomes. AEs will 

21 
 
be categorized as treatment related or non-treatment related based on its potential 
association with acupuncture needling procedure by acupuncturists and related specialists 
within 24 hours. The treatment related AEs defined as follows: dizziness, fainting, 
localized hematoma, localized minor infection, or some discomforts after acupuncture. 
Safety assessments also include an 11-point NRS (0 indicates no pain, and 10 indicates 
the severest pain) to evaluate the intensity of cancer pain. The mean and largest intensity 
of cancer pain during the preceding week will be evaluated at baseline, as well as weeks 
2, 4, 6, 8 and 16. 
4. Interventions 
The intervention scheme of this trial is based on our previous trials regarding acupuncture 
for functional constipation24, 25. Acupuncturists who had an acupuncture license and at 
least 2 years of clinical experience in acupuncture will perform the treatment. We will use 
disposable acupuncture needles (of the following sizes: 0.30 × 40, 0.30 × 50 and 0.30 × 
75 mm) and SDZ-V EA apparatus (all Hwato Brand, Suzhou Medical Appliance Factory, 
Suzhou, China) in this trial. The duration of the trial for each participant will be 17 weeks: 
1- week baseline assessment (run-out period), 8- week treatment and 8- week follow- up. 
4.1 EA 
Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. 
The location of the acupoints will be based on Nomenclature and location of acupuncture 
points34 drafted in 2006 by the National Standard of the People’s Republic of China 
(GB/T 12346–2006). The local skin will be routinely sterilized while the patient is in a 
supine position. For ST25 and SP14, 0.30×50 mm or 0.30×75 mm needles will be gently 
vertically inserted to the muscle layer of the abdominal wall, where patients will feel 
sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 
mm needles will be vertically inserted approximately 15 mm deep, followed by 
three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. 
Paired alligator clips of the EA apparatus will then be attached to the needle holders of 
the bilateral ST25, SP14, and ST37. The stimulation will be retained for 30 minutes, with 

22 
 
a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA. All needles will be 
removed after 30 minutes and pressure will be applied using a dry sterilized cotton ball to 
avoid bleeding. Patients will be followed up for another 8 weeks after the treatment 
stopped. 
4.2 SA 
The patients in the SA group will receive minimal needling at non-acupoints as bilateral 
sham ST25, SP14, and ST37. The sham ST25 and SP14 are located 2 cm horizontally 
outward of the points stimulaed in the EA group. The sham ST37 point is located outward 
of ST37 in the middle of the stomach and gallbladder channel. After sterilization of the 
skin, 0.30×40 mm needles will be directly inserted about 2 -3 mm until they can stand up 
when attached by the alligator clips. No manipulation will be used and no deqi sensation 
will be elicited at any of the sham points. The bilateral sham ST25, SP14, and ST37 
points will be attached by the same EA apparatus with a continuous wave of 10 Hz and 
current intensity of 0.1 to 0.2 mA for 30 minutes with only the initial 30 seconds on. 
 
Patients in both groups will receive 24 treatment sessions over an 8-week period (3 
sessions each week, ideally every other day). Each session will last for 30 minutes. 
Patients will be treated separately to prevent between-patient communication. Patients 
will be followed up for another 8 weeks after the treatment stopped. 
4.3 Rescue medication 
During the trial, other medication or intervention for OIC will be discouraged. However, 
if a patient has no bowel movement for 72 consecutive hours and cannot tolerate it, only 
bisacodyl (5 to 10 mg; up to 20 mg per day) or a 110ml glycerol enema will be permitted 
as a rescue medication. Details of drug use (time and frequency) will be recorded.  
5. Informed consent 
Informed Consent: Study Introduction 

23 
 
Dear participants： 
Opioid analgesics, such as morphine and oxycodone, are recommended as the 
cornerstone for the management of moderate to severe cancer pain by WHO Cancer Pain 
Relief Guidelines. Opioid-induced constipation (OIC) is the most prevalent serious 
adverse events (AEs). It is reported in 94% of cancer patients who take opioids for pain. 
OIC is defined as a change in baseline bowel habits or defecatory patterns following the 
initial administration or modification of opioid therapy. 
   Unlike many other opioid-related AEs, the symptoms of OIC tend to be persistent and 
difficult to tolerate, which can adversely reduce patients’ quality of life. The mechanism 
of OIC involves multiple contributing factors: exogenous opioids can activate μ-receptors 
throughout the gastrointestinal tract and lead to a change in gut motility, a decrease in gut 
secretion and an increase in sphincter tone, which will result in OIC. The management of 
OIC 
is 
multifaceted, 
involving 
a 
combination 
of 
pharmacological 
and 
non-pharmacological interventions, such as laxatives and increased fluid and fiber intake. 
However, the efficacy of these interventions is limited and these approaches do not 
address all of the underlying pathophysiological mechanisms of OIC. Recently, 
peripherally acting μ-opioid receptor antagonists (PAMORAs), such as naloxegol and 
methylnaltrexone, have been shown to be effective in treating OIC patients who response 
poorly to simple laxatives. However, these drugs are still under test in clinical trials with 
unclear long-term efficacy and safety; they have not been approved for use in China. In 
addition, the use of PAMORAs is often accompanied by AEs of abdominal pain and 
flatulence. At present, traditional Chinese medicine, glycerin enema and other methods 
are also can be used to treat OIC. 
   If you have been experiencing cancer-related pain and were haunted by the symptom 
of OIC. We invite you to participate in the study. This study was supported and funded by 
the 2019 National Administration of Traditional Chinese Medicine “Project of building 
evidence-based practice capacity for TCM--Project BEBPC-TCM” (NO. 2019XZZX-ZJ). 
The objective of this study is to assess the efficacy and safety of EA compared to sham 
acupuncture (SA) in the treatment of OIC in patients with cancer. Participating in this 
study can relieve symptoms of OIC while also contributing to the development of 
medicine, especially for acupuncture and moxibustion of Traditional Chinese medicine. 

24 
 
Patients with the following conditions should not participate in this study: If you cannot 
participate in the study, we will provide free scale testing and related consultation. 
 
(1) Patients diagnosed with clinically significant abnormal defecation due tostructural 
abnormalities of the gastrointestinal tract and other tissues related to gastrointestinal tract 
(not including OIC): inflammatory bowel disease, rectal prolapse, gastrointestinal 
obstruction, peritoneal metastasis, or peritoneal tumor at the time of enrollment;  
(2) Patients with a history of gastrointestinal tract operation, abdominal operation, or 
abdominal adhesion within one month prior to screening; history of intestinal obstruction 
within three months prior to screening;   
(3) Diagnosis of active diverticular disease; or severe hemorrhoid; or anal fissure; or 
artificial rectum or anus; 
(4) Patients with an intraperitoneal catheter or those that use a feeding tube to maintain 
vital signs;  
(5) Diagnosis of pelvic disorder, which are considered to have obvious effects on the 
intestinal transport of feces (such as uterine prolapse ≥degree 2, uterine fibroids 
[located in the posterior of the uterus with a diameter ≥ 5 cm] affecting bowel 
movement); 
(6) Patients that are being treated with a new cancer chemotherapy, which had never 
been administered in the past, within 14 days of the screening or are scheduled to receive 
such therapy during the study; 
(7) Patients that received radiotherapy within 28 days of the screening or are scheduled 
to receive such therapy during the study; 
(8) Patients that underwent a surgery or intervention that is considered to have an 
obvious effect on the gastrointestinal functions within 28 days of the screening or are 
scheduled to receive surgery or intervention which is considered to have obvious effects 
on the gastrointestinal functions during the study, or scheduled to receive surgery or 
intervention which will be anticipated to prevent the patients from completing the trial; 
(9) Patients with uncontrolled hyperthyroidism, severe hypertension, heart disease, 
systematic infection or blood coagulation disorders (hypercoagulation status or 
hemorrhagic tendency);  

25 
 
(10) Patients that consumed >4 additional opioid doses per day, for breakthrough pain, 
for more than 3 days during the baseline period, or if their maintenance opioid dosing 
regimen was modified during this period; 
(11)  Patients with severe cancerous pain (e.g., typical average daily pain intensity rating 
of 7 to 10 on a numerical rating scales (NRS; 0 [no pain] to 10 [the worst pain possible]) 
after the utility of routine dose and frequency of opioids) refractory to opioid therapy; 
(12) Patients with a history of opioid discontinuation due to severe adverse events or 
patients that are suspected to discontinue opioid use due to the potential risk of adverse 
events; 
(13) Patients that received an opioid receptor antagonist within one month of the 
screening, or those who are scheduled to receive such therapy during the study; 
(14) Patients with a history of nerve neurolysis; 
(15) Patients with severe cognitive impairment, aphasia, or psychiatric disorders; 
abdominal aortic aneurysm; hepatomegaly(liver span > 14cm at the mid-clavicular line 
by ultrasound examination); or splenomegaly(spleen length [cranial to caudal] > 13cm by 
ultrasound examination); 
(16) Patients that have received acupuncture within three months of the screening;  
(17) Other patients who are considered ineligible for the study by the investigator on the 
basis of concomitant therapy and medical findings. 
We plan to enroll a total of 100 participants with 50 in each group in this trial. If the 
patients can participate in this study, doctors will randomly assign them to conventional 
electroacupuncture(EA) group or minimal  electroacupuncture group. Each patient will 
have a 50% chance to be in the EA group or minimal  electroacupuncture group. 
Patients in both groups will receive 24 treatment sessions over an 8-week period (3 
sessions each week, ideally every other day). Patients will be followed up for another 8 
weeks after the treatment stopped. During the study period, subjects are required to 
cooperate with doctors to complete relevant scales and carry out necessary auxiliary 
examinations, as well as to adherence to the schedule for treatment, examination, and 
follow-up visit. Additionally, you are also responsible for reporting any changes in your 
physical and mental status to your doctor during the study process regardless of whether 
you think these changes are related to the study or not.  During the trial, other 

26 
 
medication or intervention for OIC will be discouraged. However, if a patient has no 
bowel movement for 72 consecutive hours, only bisacodyl (5 to 10 mg; up to 20 mg per 
day) or a 110ml glycerol enema will be permitted as a rescue medication. Details of drug 
use (time and frequency) will be recorded. The doctors will make every effort to prevent 
and treat any side effects brought on by this study. During acupuncture treatment, you 
may feel soreness, numbness, heavy, distension sensation, etc., which are normal 
reactions to acupuncture. Acupuncture treatment may have some adverse effects (e.g., 
dizziness, fainting, localized hematoma, localized minor infection), but it is rare and mild. 
We promise that in case of adverse events, we will do our best to provide treatment in 
accordance with the routine diagnosis and treatment according to professional judgment, 
and will follow the condition until it stabilizes or until the event is otherwise explained. 
The hospital will bear all the costs. Free treatment, consultation and scale measurement 
will be provided throughout the trial (including the follow-up period). You and your legal 
representative will be promptly notified of any information that may affect the subject's 
participation in the study. Whether to participate in this study will be entirely determined 
by the patients themselves, and the subjects' privacy will be kept strictly confidential 
within the scope of the law. Only the institutes responsible for the study, clinical research 
institutes, and ethics committees may have access to your medical records to verify 
clinical trial procedures and data. Your name will not appear in any publications or 
reports related to this study. Subjects have the right to withdraw from the study at any 
time during the study without any discrimination or retaliation, and without affecting any 
medical services. For your best interests(such as unbearable acupuncture pain or severe 
AEs), researchers may terminate your participation at any time during the study. Personal 
data of participants in the study are kept confidential. If you need more information, feel 
free to talk to your doctor. Subjects are entitled to ask our physicians at any time and to 
contact the ETHICS committee office if they have complaints. 
 
Patient statement  
I have been informed of the research purpose, content and method of this research, and I 
have fully understood the nature, significance, and possible risks and benefits of this 
research. I have the right to participate in this study voluntarily or not.My personal 

27 
 
information will be kept confidential.I grant access to the study data to the DRUG 
regulatory agency or the ethics committee. 
I have fully understood the above and made the decision on my own after full 
consideration: I volunteered to be a subject in the study "Effects of electroacupuncture on 
opioid-induced constipation in patients with cancer: a multicenter randomized controlled 
trial". I am willing to accept research requests and cooperate with researchers.I am 
willing to actively cooperate with relevant examinations and fulfill the rights and 
obligations of subjects to ensure the final completion of this study. 
Signature of patient                    Year month day 
Telephone:        
 
Researcher declaration: 
I have carefully explained to the subjects the situation of this study and the benefits 
and risks of participating in this study.His signature is valid.Medical problems, language 
or education do not preclude an understanding of the above. 
Signature of researcher                    Year month day 
Telephone:     
:      
6. Quality Control 
All staff members will undergo training prior to the trial. Monitors will check the case 
report forms and the acupuncture operation regularly. To improve adherence to 
intervention protocols, the majority of patients will come from the inpatient setting. The 
outcomes will be evaluated by independent assessors who are unaware of the group 
allocation. The data will be input by a clinical research coordinator according to the 
contents of CRF using the Electronic Data Capture System (EDC), which will be 
monitored by Clinical Research Associate. Detailed documentation of drop-outs and 
withdrawals, including the reasons, will be obtained throughout the trial. All of the 

28 
 
investigators will always maintain a strict privacy policy to protect confidentiality before, 
during and after the trial.  
 
7. Data Management 
7.1 The Raw Data Management and Archiving 
We use Electronic Data Capture System (EDC) system to perform data entry. The 
research assistants will fill out all the electrical CRF through RDC system. Researchers 
will inspect the eCRF, and signed electrically for the eCRF going into effect. The eCRF 
and the trace of eCRF revising will be left in the Oracle database. 
7.2 Data Entry and Storage 
7.2.1 Database Building and Testing, Data Entry Interface 
The eCRF will be noted through CDISC SDTM standard, and the data entry interface 
will be generated through the Oracle Clinical software. The data entry interface should be 
in accordance with the paper-version CRF as far as possible. The inputted data will be 
stored in the Oracle database. 
After preliminarily setting up the database, the entry clerks will input some analog data 
according to the CRF to test the database. The testing contains: (1) the agreement of the 
data entry interface and the paper-version CRF; (2) the agreement of the exported data 
from the database and the analog data; (3) the agreement of the structure of the exported 
database and the paper-version CRF. After the testing, data administrators should revise 
the database and make a testing report. Then they electrically signed on the approval page 
of the database to indicate that the testing is completed. The electrical files of the analog 
CRF, Noted CRF, screenshot of the data entry interface, database testing report, and the 
approval page of the database should be saved. If the database updates during the trial, 
the electrical files mentioned above are also need to be updated. 
7.2.2 Data Entry and Inspection 

29 
 
The research assistants take charge of the data entry for our trial. Before the entry, all the 
research assistants will accept the related training according to the data entry handbook. 
Researchers will inspect the database, and then sign electrically to let the data go in to 
effect. 
7.3 Data Verification and Problems Solving 
Researchers will verify the data through Data Verification Plan (DVP) approved by the 
data administrator and the statisticians. Data queries will be inputted to a data query 
database, and form the DCF. After being inspected, the DCF will then be handed back to 
the original site, and the researchers of the site should answer the queries. Any revision of 
the database will be recorded through the RDC software. 
7.4 Medical Coding 
A data administrator who has the medicine background will take charge of the medical 
coding. The contents of the coding are the clinical history, adverse events, and combined 
medication. The clinical history and adverse events will be coded through MedDRA 
dictionary (Version 13.0), and the combined medication will be coded via WHO DD 
dictionary (Version 2007.03). The lead researchers will verify the coded e-files. 
7.5 Data Report 
Data report contains the aspects as followed: (1) members of the project; (2) 
disagreement from the primary data management plan; (3) actual finish time of every 
project; (4) problems and the solution during the data management (if have any); (5) 
reconstruction of the database (if have any); (6) distribution of the participants; (7) 
participants who disobey the trial protocol; (7) classifying plan of the statistical analysis 
population.  
Data report will be performed monthly since the first entry of the eCRF. 

30 
 
7.6 Data Auditing 
When the data checking is finished, a data auditing and blinding review meeting will be 
hold. On the meeting, the data administrators, statisticians, researchers, clinical inspectors, 
and other related members would have a discussion on the following items according to 
the data management report and the data lists: 
 Distribution of the participants; 
 Protocol disobeying or not; 
 Possible outlier; 
 Baseline data; 
 Outcomes; 
 Statistical analysis plan. 
7.7 Database Locking 
The database will be locked if it fulfills all the aspects as followed: All the queries have 
been solved, and the database has been updated; No query has been found through the 
data inspection; The medical coding has been completed; The plan of the participants ’ 
classification has been approved; The final draft of the SAP has been made, and approved 
by the project leader. 
The statisticians and the data administrators will signed the data locking form, and then 
the database will be locked. The locked database will be sent to the statisticians for 
further statistical analysis through the data format of SAS. 
8. Statistical Consideration 
The following is an overview of the statistical considerations. Details of the pre-specified 
statistical analyses can be found in the Statistical Analysis Plan (SAP). 
 

31 
 
8.1 Statistical Analysis  
The primary study hypothesis is that EA is more effective than SA in the treatment of 
OIC in patients with cancer. The primary outcome is the proportion of responders, 
defined as a patient that has ≥ 3 SBMs/wk and ≥ increase of 1 SBM from baseline 
simultaneously for at least 6 out of 8 weeks of the treatment period. The primary analysis 
will be intention-to-treat, which is defined as all randomized participants. 
The following secondary outcomes will be analyzed using the t test, repeated measures 
analysis, Wilcoxon rank-sum test, Chi-square test or Fisher’s exact test, as appropriate: 
A two-side test with p<0.05 will be considered significant for all analyses. 
8.2 Statistical Analysis Plan (SAP) 
Prior to database lock and before code breaking, a final version of the SAP shall be issued 
and approved by the study statistician, and the principal investigator. The SAP will define 
all “pre-specified, planned analyses” and provide the general specifications for the 
analysis of the data to be collected and presented in the Clinical Study Report. 
9 Ethical principle  
For every study site, only when the trial protocol is approved by the IRB, the enrollment 
of participant will begin, but all should be after May 1, 2019. 
10 Funding 
This study was supported and funded by the 2019 National Administration of Traditional 
Chinese Medicine “Project of building evidence-based practice capacity for 
TCM--Project BEBPC-TCM” (NO. 2019XZZX-ZJ) by China Academy of Chinese 
Medical Sciences. 

32 
 
 
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12 Major update of the published protocol 
Important Changes Made to Study Design After Trial Commencement 
No. 
Item 
Original version 
Final version 
Reason(s) for 
making 
change(s) 
1 
Exclusion 
criteria 
(1)Patients 
diagnosed 
with 
clinically significant abnormal 
defecation due to functional 
disorders 
or 
structural 
abnormalities 
of 
the 
gastrointestinal tract and other 
tissues 
related 
to 
gastrointestinal 
tract 
(not 
including OIC) 
Patients 
diagnosed 
with 
clinically 
significant abnormal 
defecation 
due 
to 
structural 
abnormalities of the 
gastrointestinal 
tract 
and 
other 
tissues 
related 
to 
gastrointestinal 
tract 
(not including OIC) 
To reconsider 
the appropriate 
exclusion 
for 
more 
enrollment  
2 
Exclusion 
criteria 
(13)Patients that received an 
opioid receptor antagonist or 
agonist within one month of 
the screening, or those who 
are scheduled to receive such 
therapy during the study 
Patients that received 
an 
opioid 
receptor 
antagonist one month 
before the screening, 
or those who are 
scheduled to receive 
such therapy during 
the study 
To reconsider 
the appropriate 
exclusion 
for 
more 
enrollment