Belladonna and Opium Rectal Suppository Effect on Postoperative Pain and Nausea Following Total Laparoscopic and Robotic-Assisted Hysterectomy
Phase: PHASE4
Conditions: Hysterectomy, Pain, Postoperative
Sponsor: Anna Reinert

MMC 2015-63 Belladonna and Opium rectal suppository 
effect on postoperative pain and nausea following Total 
Laparoscopic and Robot-Assisted Hysterectomy. 
 
01/18/2017 
 
 

B&O for TLH Post-operative Pain and Nausea Study Protocol 
This study is a single-center, double-blind, randomized placebo-controlled trial to assess the 
impact of immediate postoperative Belladonna and Opium rectal suppository use on 
postoperative pain and nausea following total laparoscopic and robot-assisted 
hysterectomy.  Study activities to take place at Mercy Medical Center, involving both outpatient 
and inpatient surgical settings.  The duration of the trial will be 12 months, with a goal of 
enrolling 130 patients during this time period.  Patients eligible for trial participation are women 
between ages 18 and 75 undergoing level I total laparoscopic or robot-assisted hysterectomy 
with or without bilateral salpingo-oophorectomy, with or without cystoscopy performed post-
procedure, with or without lysis of adhesions, and with or without surgical treatment of 
endometriosis, with no additional surgical procedures being performed (i.e. no lymph node 
dissection or urogynecologic suspension or sling procedures).  Patients will be excluded from the 
study if they have contraindications to the use of B&O suppositories: these contraindications are 
glaucoma, severe hepatic or renal disease, bronchial asthma, history of narcotic idiosyncracies, 
respiratory depression, convulsive disorders, acute alcoholism or delirium tremens, or regular use 
of an anticholinergic medication (twice per week or more frequently).  Patients will be 
withdrawn from the study if the original planned surgery is not performed.  If the original 
planned study is not performed, a suppository will not be placed following surgery.  Patients may 
also opt to withdraw from the study, or may be withdrawn from the study if there is a failure of 
the research team to adhere to the study protocol.  There will be no financial incentives offered 
for trial participation.    
Only the patients of clinical investigators from this trial will be considered for participation in 
this study.  Clinical investigators posting patients for total laparoscopic or robotic hysterectomy 
at Mercy Medical Center will inform patients of the presence of the clinical trial at the time of 
surgical posting, using an IRB-approved script (appendix A).  The chart number of patients 
posted for total laparoscopic or robot-assisted hysterectomy will be forwarded to the co-
investigator by the clinic surgical coordinator at the time of surgical posting.  The co-investigator 
will review each chart and conduct a telephone interview with each patient prior to surgery to 
verify trial eligibility and to answer any questions about the trial.  Patients will be made aware 
that study participation is voluntary, and that if they chose to not participate, they will receive 
standard postoperative pain and nausea pharmacologic management.  On the day of surgery, a 
member of the research team will meet with the patient pre-operatively in a private pre-operative 
holding area to review and sign a written consent for participation in the trial (Appendix B).  
This member of the research team would be familiar with the study protocol and risks of the 
pharmacologic intervention under investigation.  These steps will allow patients to be fully 
informed, and will ensure patient safety and support during the short interval of the study.   
On the day of surgery, patients will be randomized to either B&O rectal suppository or to a 
placebo of glycerin rectal suppository.  This study employs a glycerin rectal suppository as a 
placebo because this over-the-counter medication has limited effects, similar to those of a 
Belladonna & Opium Supprette, and is similar in size, physical appearance and mechanical 
properties to a Belladonna & Opium Supprette.  A placebo-free comparison group will not be 
used, as this would change the study design from a double-blind clinical trial to a single-blind 
clinical trial, with greater potential for investigator bias to influence study results.  Additionally, 

it is not thought that results for a placebo-free comparison group would substantially differ from 
those of a glycerin suppository placebo group, and would require a larger study population and 
greater study resources to achieve findings of similar significance and power.  Randomization is 
to be performed by a biostatistician, with a sealed envelope to be created for each patient 
containing information regarding randomization to either placebo or intervention group.  In the 
operating room, this envelope will be opened, and the circulating nurse would draw the indicated 
medication from the Pyxis system.  Drug dictionary entries will be created within the Pyxis 
system by the Mercy Medical Center Department of Pharmacy, so that the Belladonna & Opium 
Supprette #16A (16.2mg / 60mg), and the glycerin suppository are represented as “Protocol Drug 
#1” and “Protocol Drug #2”.  The patient’s electronic medical record will reflect that “Protocol 
Drug #1” or “Protocol Drug #2” was received by the patient, so that the nurses caring for the 
patient postoperatively will be blinded as to which suppository the patient received.  
A suppository will be placed rectally by a member of the surgical team at the conclusion of 
surgery, prior to departure from the OR and awakening from anesthesia.  Post-operative 
placement was selected to minimize interaction with intraoperative anesthetic and analgesic 
medications, to maximize peak plasma concentrations and therapeutic efficacy of Belladonna 
alkaloids and Opium within the immediate postoperative period, and control for variation in 
procedure length between study participants.   The nurses caring for the patient postoperatively 
will be blinded to which suppository the patient did receive, but will be made aware that the 
patient had received a suppository containing either glycerin or one containing belladonna 
16.2mg and opium 60mg, equivalent to approximately 6mg of morphine.  These nurses will be 
educated about potential side effects of Belladonna & Opium suppositories, and of potential drug 
interactions; they will be asked to document and to inform the covering provider of the 
occurrence of any such adverse effects.  Patients remaining in the hospital overnight following 
their surgery will undergo a postoperative exam by a resident physician familiar with the study 
protocol and familiar with potential side effects of the B&O suppository; this physician will 
inquire about and document the presence of any such side effects. Standard of care at Mercy 
Medical Center is for nurses to assess patient’s postoperative pain by visual analog scale  at 
regular time intervals.  Data regarding patients’ visual analog pain scores for the first 12 hours 
following surgery will be extracted from the electronic medical record and analyzed by the 
research team.  PO and IV narcotic use in IV morphine equivalents, PO and IV NSAIDs, and PO 
and IV antiemetic use will also be assessed over the first 12 following surgery, this data is to be 
extracted from the electronic medical record and analyzed by the research team. Study 
surveillance will not extend beyond the duration of the participant's postoperative 
hospitalization, usually less than 24 hours. 
The costs of the Belladonna & Opium Supprettes and glycerin rectal suppositories used in this 
study will be covered by University of Maryland Medical Center, Department of Obstetrics, 
Gynecology and Reproductive Sciences as a supported resident research project.  The costs of 
glycerin suppositories will be covered by Mercy Medical Center Pharmacy.   
We do not anticipate that study participation will result in any uncovered medical costs, as 
serious side effects from Belladonna and Opium suppositories are estimated at less than 1% 
occurrence; however, if such adverse medical reactions were to occur, it would be within the 
postoperative setting and any associated medical costs would be billed to the patient's insurance 
company as part of the bundled cost of postoperative care. 

Due to their historical use, B&O rectal suppositories have not undergone the rigorous Phase I 
and II clinical trials required of modern pharmaceuticals seeking FDA approval [1], but are 
available while the FDA makes determinations of efficacy – a regulatory category shared by 
drugs hydrocodone and morphine [2,3,4].  Common side effects of B&O suppository are related 
to anticholinergic activity and include dry nose, mouth, throat, skin, and constipation. Serious 
side effect are estimated at less than 1% occurrence and include orthostatic hypotension, 
ventricular fibrillation, tachycardia, palpitation, confusion, drowsiness, headache, loss of 
memory, fatigue, ataxia, CNS depression, rash, antidiuretic hormone release, bloated feeling, 
nausea, vomiting, biliary tract spasm, dysuria, urinary retention, urinary tract spasm, increased 
intraocular pain, blurred vision, weakness, respiratory depression, histamine release, physical 
and psychological dependence, and diaphoresis [5].  Patients enrolled in this trial would be 
monitored for development of side effects with review to be performed by investigators on a 
rolling basis. 
Scopolamine is an alkaloid with antiemetic properties that is contained within extract of 
Belladonna.  A scopolamine transdermal patch contains 0.6mg of scopolamine alkaloid, and is 
sometimes used in the pre-operative setting to reduce nausea and emesis in patients reporting a 
history of motion sickness or of postoperative nausea and vomiting.  The recommended dose of 
scopolamine for use pre-operatively is 0.3 to 0.65mg [6].  Based on the USP Pharmacopeia and 
gas chromatography data on belladonna extract [7,8], the B&O rectal suppository contains less 
than 0.02mg of scopolamine, making the total dose of scopolamine received by a patient with a 
scopolamine patch and a B&O suppository 0.62mg, which is less than the recommended upper 
limit of dosing for the operative setting.  For this reason, patients receiving a pre-operative 
scopolamine patch will not be excluded from participation in this trial.   
The primary hypothesis of the study is that the use of a B&O rectal suppository is associated 
with decreased postoperative pain and nausea following total laparoscopic or robot-assisted 
hysterectomy.  The visual analog scale (VAS) to be used for assessment of postoperative pain 
has been demonstrated to be linear in the setting of mild-to-moderate pain [9], such that a 15% 
decrease in VAS score corresponds to a 15% decrease in subjectively experienced pain.  
Minimal clinically significant difference in score on the VAS has been shown to occur at 
approximately 11-14 mm regardless of pain severity [10]. Sample size calculation is based on 
VAS pain scores following laparoscopic hysterectomy as reported by Ghezzi, et al. [11].  Sample 
size is set at 65 patients per group (total trial enrollment of 130 patients) with a goal of detecting 
a 30% decrease in mean VAS score with 80% power, using p = 0.05 as a criteria for statistical 
significance, and accounting for a rate of up to 15% for trial withdrawal, incomplete data, and 
loss-to-follow-up [12].  
For statistical methodology, patient characteristics for the two study arms will be analyzed using 
a two-sided Student’s t-test for continuous variables, or a χ2 test for categorical variables and 
proportions.  To assess for clinical superiority of the B&O suppository intervention, one-sided 
Student’s t-test (for continuous outcomes) or a one-sided Fisher’s Exact test (for categorical 
outcomes) will be used. One-sided tests are to be used since the addition of B&O is not expected 
to increase pain, narcotic use, recovery time, or need for rescue anti-emetics a priori. Fisher’s 
Exact test was chosen as a more conservative measure for assessing outcomes, and due to the 
availability of a one-sided test. A linear regression will be performed on the outcome of PACU 
discharge readiness time using several different model specifications in order to check for 
robustness of results.  

 
 
Bibliography 
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http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2007/ucm076570.htm. 
[2] Alexander, Thomas J. Lauterio, and Matthew W. Davis Nasr, "Unapproved drugs in the United 
States and the Food and Drug Administration," Advances in therapy, vol. 28, no. 10, pp. 842-856, 
October 2011. 
[3] Culley CM, Carroll BA, and Skledar SJ, "Formulary decisions for pre-1938 medications," American 
Journal of Health-System Pharmacy, vol. 65, no. 14, pp. 1363-1367, July 2008. 
[4] Mary E Kremzner, and Brenda J Kiliany Renu Chhabra, "FDA Policy on Unapproved Drug Products: 
Past, Present, and Future ," Annals of Pharmacotherapy, vol. 39, no. 7-8, pp. 1260-1264, July 2005. 
[5] Truven Health Analytics Inc., "Belladonna/Opium," MicroMedex Solutions, July 2014. 
[6] Lexi-Comp Inc, "Scopolamine (systemic): Drug information," Lexi-Drugs, 2015, Accessed through 
UpToDate. 
[7] "Chapter 8 Tropane Alkaloids: Chromatography of Alkaloids - Part B: Gas-Liquid Chromatography 
and High Performance Liquid Chromatography," Journal of Chromatography Liprary, vol. 23, no. B, 
pp. 61-72, 1984. 
[8] (DSB05) Dietary Supplements - Botanicals. U.S. Pharmacopeia. [Online]. 
www.pharmacopeia.cn/v29240/usp29nf24s0_m7330.html 
[9] Troedel S, Boquest M, Reeves M Miles PS, "The Pain Visual Analog Scale: Is It Linear or Nonlinear?," 
Anesthesia & Analgesia, vol. 89, pp. 1517-1520, 1999. 
[10] Kelly AM, "The minimally clinically significant difference in visual analog scale pain score does not 
differ with severity of pain," Emergency Medicine Journal, vol. 18, pp. 205-207, 2001. 
[11] Uccella S, Cromi A, Siesto G, Serati M, Bogani P Ghezzi F, "Postoperative pain after laparoscopic and 
vaginal hysterectomy for benign disease: a randomized trial," Americal Journal of Obstetrics and 
Gynecology, vol. 203, no. 2, pp. 118e1-8, 2010. 
[12] Ball J Whitley E, "Statistics review 4: Sample size calculations," Critical Care, vol. 6, no. 4, pp. 335-
341, 2002. 

 
Belladonna and Opium Suppository Study Script 
“Because you are scheduled to undergo minimally invasive hysterectomy, you may be eligible to 
participate in a clinical trial that is underway at our institution.  The purpose of this trial is to 
improve our management of post-operative pain and nausea following minimally invasive 
hysterectomy.  The study looks at whether placement of a medicated rectal suppository at the end 
of surgery (before waking up from anesthesia) results in less post-operative pain and nausea.  A 
study coordinator for this clinical trial will contact you by phone to discuss your possible 
involvement in the study.” 
 
 
 

Mercy Medical Center - Research Consent Form 
Protocol Title:  Belladonna and Opium rectal suppository effect on postoperative pain and nausea 
following Total Laparoscopic and Robot-Assisted Hysterectomy. 
Principal Investigator: Dr. Kevin Audlin 
 
• 
This is a research study.  Participation in this study is entirely voluntary – you may choose to 
opt out of participation in this study at any point.  You may interrupt the consent process to 
ask questions at any time.   
 
PURPOSE OF STUDY 
• This is a clinical trial to assess whether a Belladonna and Opium rectal suppository placed at 
the conclusion of laparoscopic or robot-assisted hysterectomy can reduce pain and nausea 
following surgery. 
• Belladonna & Opium rectal suppositories are a medication that has been in use for over 75 
years.  Due to their historic use, the Belladonna & Opium rectal suppository is not an FDA-
approved medication, but the FDA allows their use (as is the case for morphine and 
hydrocodone).  Recently, the use of the Belladonna & Opium suppository in the 
postoperative setting has been studied in men undergoing prostate surgery. 
• An unmedicated glycerin suppository will be used as a placebo. 
• You are being asked to participate in this study because you are undergoing 
laparoscopic/robot-assisted hysterectomy at Mercy Medical Center 
• There will be 130 women participating in this study. 
PROCEDURES 
• 
Participants in the study will have a single rectal suppository placed at the end of surgery, 
prior to waking up from anesthesia.   
• 
Half of the study participants will receive a Belladonna & Opium rectal suppository.  Half of 
the study participants will receive an unmedicated glycerin suppository. 
• 
The treatment you get will be chosen by chance, like flipping a coin. You will have an equal 
chance of being given each treatment.  Neither you nor the study doctor will choose what 
treatment you get.  
• 
The data used in this study is information collected by nurses as part of routine postoperative 
healthcare.  Your participation in the study requires no additional surveys, questions, clinic 
visits, or telephone calls.  Study participation will not extend beyond the duration of your 
postoperative hospital stay.  
• 
There will be no blood draws or other collection of specimens for this study.  
 
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH? 
If you take part in this research, you will be responsible for honestly reporting your pain and nausea 
symptoms to your nurse following surgery up until the time of discharge home from the hospital. 

 
POTENTIAL RISKS/DISCOMFORTS: 
• 
Placement of a rectal suppository may cause mild local discomfort for some patients. 
• 
Common, mild side effects of Belladonna & Opium that you may experience include:  
• 
Dry nose, mouth, throat, skin, and constipation.  
• 
Rare (less than 1% occurrence), serious side effects of Belladonna & Opium that you may 
experience include:  
• 
Low blood pressure with changes in position from sitting to standing, heart 
arrhythmia or palpitations, fast heart rate, confusion, drowsiness, headache, loss of 
memory, fatigue, ataxia, CNS depression, rash, decreased urination/urinary retention, 
pain with urination, bloated feeling, nausea, vomiting, biliary tract spasm, urinary 
tract spasm, increased eye pain, blurred vision, weakness, difficulty breathing, 
histamine release, physical and psychological dependence, and sweating.  
• 
Loss of confidentiality of your personal health information is a risk of study participation; to 
prevent this from occurring, electronic data collected for this study will be secured by 
password protection, and paper data will be stored in a secure location.  If a breach in 
confidentiality were to occur, you would be notified of what information had been revealed 
and to whom it was revealed.   
POTENTIAL BENEFITS 
• 
You may or may not benefit by taking part in this study. There is no guarantee that you will 
receive direct benefit from your participation in this study. 
• 
You may experience less postoperative pain and less postoperative nausea as a result of study 
participation.  You may require less narcotic and NSAID medications for control of your 
postoperative pain, lessening your risk of side effects from these medications. 
ALTERNATIVES TO PARTICIPATION 
• 
Your alternative is to not take part in the study.  If you choose to not take part, your 
healthcare at Mercy Medical Center will not be affected.  If you do not participate, you will 
receive routine postoperative pain management including use of narcotics and NSAIDs (non-
steroidal anti-inflammatory drugs), and routine postoperative nausea management including 
use of appropriate antiemetic medications. 
 
COSTS TO PARTICIPANTS 
• 
It will not cost you anything to take part in this study.  Neither you, nor your insurance 
company will be responsible for the cost of medications used in this research protocol.  
• 
We do not anticipate that study participation will result in any uncovered medical costs, as 
serious side effects from Belladonna and Opium suppositories are estimated at less than 1% 
occurrence; however, if such adverse medical reactions were to occur, it would be within the 
postoperative setting and any associated medical costs would be billed to your insurance 
company as part of the bundled cost of postoperative care.   
 

PAYMENT TO PARTICIPANTS 
• 
Participants will not be paid for their involvement in this study.  
• 
Appropriate medical treatment will be provided if adverse side effects are encountered from 
the use of the medications under investigation.   
CONFIDENTIALITY AND ACCESS TO RECORDS 
• 
All information to be collected for this study will be extracted from the medical record, and 
then de-identified (a code will be used in lieu of your name or medical record number).   
• 
Efforts will be made to limit access to your personal information, including research study 
and medical records, to people who have a need to review this information. We cannot 
promise complete secrecy. Organizations that may inspect and copy your information include 
the IRB other representatives of this organization, the Food and Drug Administration, and the 
Department of Health and Human Services 
• 
The monitors, auditors, the IRB, the Food and Drug Administration will be granted direct 
access to your medical records for verification of the research procedures and date. By 
signing this document you are authorizing this access. 
• 
 The data from the study may be published. However, you will not be identified by name. 
People designated from the Mercy Medical Center and University of Maryland, Baltimore 
will be allowed to inspect sections of your medical and research records related to the study. 
Everyone using study information will work to keep your personal information confidential. 
Your personal information will not be given out unless required by law. 
• 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time. 
 
RIGHT TO WITHDRAW 
• 
Your participation in this study is voluntary.  You do not have to take part in this 
research.  You do not have to agree to participate in this research.  If you agree to 
participate, you are free to withdraw your consent at any time.   Refusal to take part or 
to stop taking part in the study will involve no penalty or loss of benefits to which you 
are entitled.  If you decide to stop taking part, or if you have questions, concerns, or 
complaints, or if you need to report a medical injury related to the research, please 
contact the investigator at XXX-XXX-XXXXX, and please contact the Mercy 
Investigational Review Board at 410-332-9692.   
• 
If you decide to withdraw from this study, already collected data may not be removed from 
the study database.  
CAN I BE REMOVED FROM THE RESEARCH? 
The person in charge of the research study can remove you from the research study without your 
approval.  Possible reasons for removal include change in eligibility for trial (including intraoperative 

conversion to open surgery).  If you were to be removed from the research study, you would be 
informed of this change and you would have a chance to ask questions  
Signing this consent form indicates that you have read this consent form (or have had it read to you), 
that your questions have been answered to your satisfaction, and that you voluntarily agree to 
participate in this research study. You will receive a copy of this signed consent form. 
 
If you agree to participate in this study, please sign your name below.   
 
Alternatively, you may choose to opt out of this study – in which case do not sign your name below.   
 
 
___________________________________ 
Participant’s Signature 
 
 
Date:______________________________ 
 
 
___________________________________ 
Investigator or Designee Obtaining Consent 
Signature 
 
Date:_______________________________ 
 
 
 
 

Study Participation Alert Form 
This patient is participating in study protocol MMC 2015-63 Belladonna and 
Opium Rectal Suppository Effect on Postoperative Pain and Nausea Following 
Total Laparoscopic and Robot-Assisted Hysterectomy.   
The Principal Investigator is Dr. Kevin Audlin, his contact number is XXX-XXX-
XXXX.  The resident study coordinator is Dr. Anna Reinert, her contact number is 
XXX-XXX-XXXX.  The Mercy IRB office contact number is 410-332-9692.   
This is a randomized, placebo-controlled, double-blinded clinical trial. 
This patient has received 1 of 2 drugs, placed rectally at the conclusion of surgery.  
Either: 
1. Belladonna & Opium rectal suppository containing 16.2mg of Belladonna 
plant extract and 60mg of Opium, equivalent to approximately 6mg of 
morphine.   
or 
2. Glycerin suppository (medically inactive placebo) 
Neither you, nor the patient will be informed which of the two drugs the patient 
received.  Please treat your patient with routine post-operative care, recognizing 
that they may have already received the equivalent of 6mg of morphine 
immediately prior to departure from the OR.  
Common side effects of B&O suppository are related to anticholinergic activity 
and include dry nose, mouth, throat, skin, and constipation. Serious side effect are 
estimated at less than 1% occurrence and include orthostatic hypotension, 
ventricular fibrillation, tachycardia, palpitation, confusion, drowsiness, headache, 
loss of memory, fatigue, ataxia, CNS depression, rash, antidiuretic hormone 
release, bloated feeling, nausea, vomiting, biliary tract spasm, dysuria, urinary 
retention, urinary tract spasm, increased intraocular pain, blurred vision, weakness, 
respiratory depression, histamine release, physical and psychological dependence, 
and diaphoresis.  Please notify the GYN resident/fellow if you suspect that your 
patient is experiencing any of these serious side effects.