Clinical trial NCT04941443
Conditions: Pain Medical Abortion
Keywords: Oral methadone Pain control
Sponsor: Boston Medical Center
Start date: 2021-10-04; Completion date: 2022-03-01
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Pain has been recognized to be the most common and predictable side effect of medication abortion, causing significant distress associated with the process. Yet there is little known about the appropriate management of pain during this process, with no current evidence based recommendations for optimal analgesic regimens during the first trimester.

The goal of this study is to evaluate the efficacy of oral methadone for pain control during medication abortion. The current medication regimen used to perform medication abortion is a dose of mifepristone (antiprogesterone) orally, followed by a dose of misoprostol (prostaglandin analogue) 24 to 72 hours later. Patients are prescribed a standard dose of ibuprofen 600-800mg tabs for pain control during the process. The investigators will conduct a non-randomized, pilot study with 25 patients evaluated at the Boston Medical Center family planning clinic at 10 weeks of gestation or less for medication abortion.

Detailed description:
The primary objective of this research study is to determine the feasibility of enrolling patients in a study that requires the consumption of methadone for acute pain management for medication abortion. Secondary objectives include the assessment of pain using: pain scores at 0, 4, 8, and 24 hours following misoprostol, use of supplementary analgesia, reported side effects, and patient satisfaction

All participants will be instructed to take methadone 5 mg orally (1 tablet) simultaneously with the consumption of misoprostol. The participants will be evaluated using an 11 point numeric rating pain scale with 0 (no pain) and 10 (most severe pain). Patients will be given a telephone number to which they will be asked to text study staff indicating that misoprostol and methadone have been consumed. Study staff will phone the participants at 0, 4, 8 and 24 hours post misoprostol consumption to conduct a survey posing questions about maximum pain scores, compliance with study medication and any adverse effects experienced. Participants will also be contacted at 48 hours for further evaluation of any reported adverse events and 1 week post misoprostol to assess ease of study design and instructions, pain experience, perisomal view on consumption of methadone and patient satisfaction.

Arms: arm 1: Participants will be given a preemptive analgesic in addition to a standard dose of ibuprofen while undergoing early medication abortion with mifepristone and misoprostol (not provided as part of the study). All participants will also be provided with supplementary non- opioid analgesics to be used at their own discretion during the process.
Interventions: intervention 1: Methadone Pill intervention 2: Ibuprofen
Intervention descriptions: intervention 1: All participants will be given a 5mg methadone tablet to be taken immediately following the misoprostol dose. intervention 2: All participants will be provided additional analgesics (ibuprofen 800mg x4 tabs) available for use as needed every eight hours.

Protocol documents:
Prot_SAP_000.pdf: 
Methadone for pain relief in first trimester medication abortion 
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Methadone for pain relief in first trimester medication abortion 
 
ClinicalTrials.gov number: NCT04941443 
Protocol Version Number: 1.5 
Protocol Version Date: 12/07/2021 
Principal Investigator: Rachel Achu 
 
Phone: 857-217-4995 
 
E-mail: rachel.achu@bmc.org 
 
 
 
 
 
 
 
 
Statistical analysis plan pages 15-16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization 
from the study sponsor. 
 
 


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TABLE OF CONTENTS 
1 List of Abbreviations ............................................................................................................................ 3 
2 Protocol Summary ............................................................................................................................... 3 
3 Background/Rationale & Purpose ..................................................................................................... 3 
3.1 
Background Information .............................................................................................................. 4 
3.2 
Rationale and Purpose ................................................................................................................. 5 
4 Objectives ............................................................................................................................................. 5 
4.1 
Study Objectives .......................................................................................................................... 5 
4.2 
Study Outcome Measures ............................................................................................................ 5 
4.2.1 
Primary Outcome Measures ........................................................................................ 5 
4.2.2 
Secondary Outcome Measures .................................................................................... 6 
5 Study Design ......................................................................................................................................... 6 
6 Potential Risks and Benefits ............................................................................................................... 7 
6.1 
Risks ............................................................................................................................................. 7 
6.2 
Potential Benefits ......................................................................................................................... 8 
6.3 
Analysis of Risks in Relation to Benefits ....................................................................................... 8 
7 Study Subject Selection ....................................................................................................................... 9 
7.1 
Subject Inclusion Criteria ............................................................................................................. 9 
7.2 
Subject Exclusion Criteria ............................................................................................................. 9 
8 Study Intervention ............................................................................................................................... 9 
9 Study Procedures ............................................................................................................................... 10 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ................................................ 12 
10.1 
Definitions .................................................................................................................................. 12 
10.2 
Safety Review ............................................................................................................................. 13 
10.3 
Reporting Plans .......................................................................................................................... 13 
10.4 
Stopping Rules............................................................................................................................ 14 
11 Data Handling and Record Keeping ................................................................................................. 14 
11.1 
Confidentiality ............................................................................................................................ 14 
11.2 
Source Documents ..................................................................................................................... 15 
11.3 
Case Report Forms ..................................................................................................................... 15 
11.4 
Study Records Retention............................................................................................................ 15 
12 Statistical Plan .................................................................................................................................... 15 
12.1 
Study Hypotheses ......................................................................... Error! Bookmark not defined. 
12.2 
Sample Size Determination and Statistical Methods ................................................................. 15 
13 Ethics/Protection of Human Subjects ............................................................................................. 16 
14 Literature References ........................................................................................................................ 16 
15 Appendix ............................................................................................................................................. 17 


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1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
WHO 
World Health Organization 
NMDAr 
N-methyl-D-aspartate receptor 
FDA 
Food and drug administration 
NRS 
numeric rating scale 
AE 
Adverse Event 
 
2 
Protocol Summary 
 
Title: 
Methadone for pain relief in first trimester medication abortion 
Population: 
Women who have consented to medical abortion at ≥10 weeks 
gestation, who report willingness to participate in this study. 
Inclusion criteria will be pregnant women, age 18 and older, 
gestational age 10 weeks or less, English speaking, able to receive 
and send text messages, opioid naïve, and healthy.  Exclusion 
criteria will be daily drug and alcohol use; opioid use in last 30 days; 
chronic use of pain medications; chronic use of benzodiazepines; 
any chronic disease including renal, liver, respiratory or cardiac 
disease; and any known allergies to nonsteroidal anti-inflammatory 
drugs (such as ibuprofen) and methadone.  
Intervention: 
Methadone 5mg tablet taken orally – to be taken with misoprostol 
in addition to standard ibuprofen dose 
 
Objectives: 
The primary objective is to determine the feasibility of enrolling 25 
participants in a study within 6 months of study approval that 
requires the consumption of methadone for acute pain control in 
early medication abortion.  
 Secondary objectives will be to evaluate pain scores at 0-, 4-, 8- and 
24-hours post-misoprostol and methadone, use of supplementary 
analgesia, reported adverse effects (up to 48 hours post 
methadone), and patient satisfaction evaluated 1 week post 
methadone consumption 
Design/Methodology: 
We propose a non-randomized pilot study where we expect to be 
able to feasibly study between 15 – 25 women (recruited within a 
time period of 6 months from study approval) who will be given a 
prophylactic analgesic (methadone) while undergoing medical 
abortion at <10 weeks gestation with mifepristone and misoprostol.   
Total Study Duration: 
August 2021-May 2022 
Subject Participation Duration: 1 week  
 
3 
Background/Rationale & Purpose 
 


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3.1 
Background Information 
Pain has been recognized as the most common and predictable side effect of medication abortion 
causing significant distress associated with the process.  Yet there is little known about the optimal 
management of pain during this process, with no current evidence-based recommendations for the 
optimal analgesic regimen during the first trimester.   The pain associated with medication abortion has 
been linked to the consumption of prostaglandin analogues, with women reporting high peak pain 
scores occurring 2.5 to 4 hours after the consumption of misoprostol (1).  The lack of standardization in 
pain management, conflicting study results on the efficacy of currently used analgesics (2, 3) and the 
described inadequate pain control during this process warrants the need to identify an effective 
analgesic regimen. 
 
Currently, non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen are routinely recommended for 
pain management for early medication abortion, including by the World Health Organization (5).  Study 
results on the efficacy of ibuprofen when given prophylactically versus therapeutically have been 
conflicting. A study reported no observed difference in mean maximum pain scores with the comparison 
of prophylactic versus therapeutic ibuprofen, while others reported that pre-emptive ibuprofen use 
showed statistically significant benefit for pain management (Raymond et al. 2, 4 Avraham et al.).    
 
In addition to NSAIDs, the WHO analgesic ladder for the management of acute and chronic non-cancer 
pain recommends the use of weak opioids with or without non-opioid analgesics for moderate pain and 
potent opioids (i.e. oxycodone, hydromorphone, or methadone) for severe and persistent pain with or 
without non-opioid analgesics (6).  Various studies conducted to evaluate different regimens for pain 
control with early medication abortions have demonstrated an average mean pain score range of 6.2 to 
8 out of 10 on a 11 point numerical rating scale (NRS) from 0 (no pain) to 10 (worst pain) (1,7).  
Consequently, the pain experienced in early medication abortion is significant and needs more research 
to investigate regimen options for pain reduction.  
 
The female reproductive organs are dually innervated by the hypogastric nerve branch of the lumbar 
splanchnic nerve and the pelvic nerves (9, 10), which are part of the visceral pain pathway. 
Pharmacological modulation of visceral afferents target receptors to control visceral pain is the subject 
of continued research.  Of the many target receptors available, modulation of the N-methyl-D-aspartate 
receptor (NMDAr) has moderating effects on the response of sensory afferents and spinal processing of 
visceral pain (10).  Tramadol is a synthetic opioid which binds to mu-opioid receptors and has some 
inhibitory effects on NMDAr. A multicontinental randomized controlled trial comparing the prophylactic 
administration of tramadol versus ibuprofen and metoclopramide versus placebo for pain control during 
early medication abortion did not elicit a statistically significant difference (Dragoman et al).  Although 
they hypothesized that women receiving prophylactic analgesia would report lower maximal pain scores 
in the first 8 hours following misoprostol, the results showed no difference in pain trajectories in either 
study arm (11). 
 
Methadone is a synthetic opioid with multiple actions qualitatively like morphine.  The primary 
therapeutic uses of methadone are for analgesia and maintenance therapy in opioid use disorder (12).  
Methadone is included on the third step of the WHO analgesic ladder as an opioid analgesic that can be 
used for persistent or severe pain (6).  Although methadone is a potent opioid agonist with similar mu-
receptor affinity to morphine, it also contributes to analgesia via non-opioid actions: inhibition of the 
reuptake of serotonin and norepinephrine and antagonism of the NMDAr.  Methadone is well absorbed 
following oral administration with levels detectable within 30 minutes and peak concentrations within 4 


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hours (13).  Consequently, analgesic duration of action typically ranges 4-8hours (12). Methadone has 
been studied extensively as a suitable therapy for cancer pain and chronic pain.  It is considered an 
acceptable alternate opioid when pain remains inadequately controlled with other opioids.  Multiple 
studies evaluating the reported improvement in pain control following the transition to methadone in 
patients with cancer pain reflected single dose or short-term use administration as opposed to longer 
term use, which is more relevant in clinical practice (15).   
 
We seek to investigate whether the administration of methadone, in addition to a standard dose of 
ibuprofen, will be effective in reducing pain associated with early medication abortion. The current 
standard of care is administration of ibuprofen. Our hypothesis is that this combination of analgesics 
would serve as a viable regimen for improved pain control during early medication abortion in an 
outpatient setting. This is the first study proposed to investigate the use of methadone as part of the 
analgesic regimen for early medication abortion. Although opioids are sometimes used for pain during 
early medication abortion, their efficacy has not been established.  Several small, randomized studies 
demonstrated no difference in pain scores in patients undergoing early medication abortion when 
opioids including codeine were added to ibuprofen or acetaminophen when compared to placebo (7), 
oxycodone versus placebo (1) or the use of hydrocodone-acetaminophen (8). 
 
This study will be conducted in compliance with the protocol, applicable regulatory requirements, and 
BMC/BU Medical Campus Human Research Protection policies and procedures. 
 
3.2 
Rationale and Purpose  
 
Pain is an expected consequence of medication abortion.  Reviews of multiple studies evaluating the 
experience of women undergoing medical abortion during the first trimester concluded that 
approximately 75% of women experience intense pain of a severity requiring narcotic analgesia (16).  In 
addition, neither an assessment of pain nor analgesic options are consistently reported in clinical trials 
of medical abortion (17).  This reflects oversight on the importance of pain as a significant side effect of 
medication abortion.  It is important that new analgesic strategies be evaluated to help reduce pain 
experienced during medical abortion to improve the quality of patients’ experiences and satisfaction 
with the process.  
 
 
4 
Objectives 
 
4.1 
Study Objectives 
 
 The primary objective is to determine the feasibility of enrolling 25 patients within a span of 6 months 
in a study that requires the consumption of methadone for acute analgesia experienced during early 
medication abortion.  The secondary objectives include evaluation of pain scores at 0, 4, 8 and 24 hours, 
use of supplementary analgesia, reported adverse effects, and participant satisfaction. 
 
4.2 
Study Outcome Measures 
 
 
4.2.1 
Primary Outcome Measures 
 


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The primary outcome will be the feasibility of the recruitment process in enrolling 25 study participants 
in 6 months into a study involving the administration of methadone for pain control during early 
medication abortion.  Feasibility would be determined by the ease of the recruitment process by 
evaluating the number of participants eligible for screening and recruitment, and actual number of 
participants recruited.  
 
 
4.2.2 
Secondary Outcome Measures 
 
The principal secondary outcome of this study is a participant reported pain score measured 4 hours 
after administration of misoprostol, on a clinically validated 11 point Numerical Rating Scale of pain 
(NRS). Several small randomized studies performed in the United States and Canada evaluating pain 
control with medication abortion while analyzing different pain regimens have reported an average 
maximum mean pain score of 7, ranging from 6.2 - 8 (2,11) measured with an 11-point NRS; (0-10) 
where 0 is equivalent to no pain and 10 is the worst pain. We hypothesisze that a change of at least 2 
points on the NRS within the first 4 hours after misoprosol administration would indicate a clinically 
significant reduction in average mean pain scores in our study patients in comparison to these studies.  
We also hypothesize a decrease in pain scores within 24 hours following misoprostol with the study 
intervention using the same NRS scale, a decrease in the use of supplementary analgesia and increase in 
patient satisfaction measured by developed surveys which would be administered at 0,4,8, 24, 48 hours 
and 1 week post the consumption of misoprostol and study intervention.  
 
We will also use descriptive statistics to report on use of supplementary analgesia (medications, 
dosages, and frequencies), reported adverse effects, and patient satisfaction utilizing a patient 
satisfaction survey. 
 
5 
Study Design 
 
We propose a non-randomized pilot study of women who will be given a preemptive analgesic 
(methadone) in addition to a standard dose of ibuprofen while undergoing early medication abortion 
with mifepristone and misoprostol at <10 weeks gestation. This is an open-label, single-arm study that 
will assess the feasibility of recruiting and enrolling 25 study participants into this study in a time period 
of 6 months from study approval.  All participants will also be provided with a prescription of 
supplementary ibuprofen to be used at their own discretion during the process. The current standard of 
care is administration of ibuprofen alone. 
 
Women presenting to the clinic with a request for early medication abortion will be screened for inclusion 
into the study (Appendix: Screening Form).  The eligible participants will be provided with an informed 
and voluntary consent for enrollment into the study only after the consent for the abortion procedure has 
been obtained separately. Copy of signed consent can be provided to patient if they choose to have one 
but study team will retain a signed copy for our records regardless of their choice to take the copy of 
signed consent. Participants will be given time to ask questions and talk to their family or friends, if 
desired, about the study. 
 
After study staff answers all questions and obtains written informed consent, participants will receive the 
standard medication abortion procedures #’s 1-3 and the research intervention (#4):  


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1) They will take mifepristone orally in the clinic 
2) They will be dispensed 800 mcg of misoprostol, with standard instructions to self-administer buccally 
approximately 24-48hours after taking mifepristone  
3) They will be prescribed ibuprofen 600 or 800 mg (per their preference) 
4) In addition to these standard abortion medications, a single dose of the study medication, methadone 
5mg, will be prescribed (both medications can be dispensed at the Yawkey outpatient pharmacy). 
Participants will be instructed to take methadone at the same time as their misoprostol. Participants will 
be provided with a telephone number to which they will be required to text study staff indicating that 
misoprostol and methadone have been consumed.   
 
Study staff will phone the participants at 0, 4, 8, and 24 hours post-misoprostol dosing.  These phone calls, 
lasting approximately 5 minutes, will include a survey asking the patients to indicate their maximum pain 
scores on a 0-10 NRS scale, their compliance with study medications, and any adverse effects experienced 
including dizziness, difficulty breathing, nausea or vomiting. Participants will also be contacted via phone 
at 48 hours after their methadone dose for further evaluation of any reported adverse events, and again 
at 1 week after misoprostol to assess ease of study design and instructions, pain experience, personal 
view on consumption of specific study medication (methadone) and patient satisfaction.  
 
 
6 
      Potential Risks and Benefits 
 
6.1 
Risks 
Package insert of methadone from FDA (Attached).  
 
While there are no known interactions between misoprostol, ibuprofen, or mifepristone and 
methadone, methadone has been associated with respiratory depression. Respiratory depression has 
been observed, particularly in the early dosing period and is associated with high initial dosing (12). 
Methadone has also been associated with cases of QT interval prolongation and serious arrhythmias 
(torsades de pointes), with most cases involving patients being treated with multiple, large daily doses 
of methadone (12). In our study, participants will receive only ONE dose of methadone (5mg), mitigating 
the risks of these occurrences.  
 
The common side effects associated with methadone, similar to other opioids, are sedation, dizziness, 
nausea, vomiting, lightheadedness, sweating, constipation, and dry mouth.  Methadone has been 
associated with respiratory depression, QT interval prolongation and serious arrhythmias (torsades de 
pointes) in patients receiving very high initial doses and doses commonly used for maintenance and 
treatment of opioid addiction, respectively (12).   
 
Participants will be informed about the low/ unlikely risk of opioid addiction.   
 
The Massachusetts prescription monitoring program will be used to confirm any prescriptions 
participants may have received using the online Massachusetts Prescription Awareness Tool, per 
standard prescribing policy. 
 
We will ensure that the study drug, methadone, is dispensed by the Yawkey pharmacy in a child-proof, 
tamper proof container.  
 


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Participants will be advised not to operate heavy machinery, operate a vehicle, or drink alcohol for 24 
hours following methadone dose.  
 
Participants may become tired of doing the surveys or they may be tired or in pain when we call.  We 
will do our best to conduct the surveys with these possibilities in mind and always be guided by the 
subject in regards to whether the survey can be completed at that time. 
The interviewers will be research assistants and physicians. Study principal investigators (PIs) will be 
available 24/7. If interviewers who are not physicians detect any adverse events, they will immediately 
contact the study PIs, who will be available 24/7. The study PIs will then contact the patient directly to 
obtain further information and make informed, shared decisions about triaging the adverse events. 
 
As per the family planning policy that is in place for routine medication abortions, the research team will 
be able to contact the family planning physician on call (there is 24/7 call coverage). If a participant 
expresses any emotional distress, study staff will assess for any suicidal ideation, which would prompt 
an urgent referral to the emergency department for evaluation. If the participant is not expressing any 
thoughts of harm to self or others, study staff will offer an urgent consult with social work, referral to 
behavior health, and give information about abortion hotlines. 
There is always a risk associated with breach of confidentiality; however, procedures are in place to 
make such breaches unlikely. All participant information will be deidentified using a master code 
unrelated to the PHI.  The review of subjects’ medical records is for limited information, and all data will 
be securely stored and deidentified behind BMC firewalls.  
 
 
6.2 
Potential Benefits 
 
Participants may or may not receive a direct benefit with study participation. They may experience less 
pain during their medication abortion. Their experiences will provide valuable information that may help 
identify a potential analgesic strategy that would aid in the prevention and reduction of pain associated 
with medication abortion, improving the quality of the experience and satisfaction with the process for 
future patients.  
 
6.3 
Analysis of Risks in Relation to Benefits 
 
 As described previously, literature in the field of pain management for medication abortions is scarce 
and its potential importance in reducing distress amongst women who undergo this procedure is 
significant. This study can provide evidence to guide clinicians, reduce the incidence of post-procedure 
pain, and improve patient satisfaction and outcomes. While there are adverse events associated with 
the use of high doses and repeated doses of methadone, we will only administer one single dose tablet 
of methadone: 5mg. The risk of addiction to opioids is minimal in these healthy, opioid naïve patients 
who are provided one dose. Our hypothesis is that therapeutic benefit of providing a single, small dose 
of methadone for pain relief would show preliminary signals of efficacy in providing pain relief for 
women undergoing medication abortion, outweighing the potential risks associated with its 
administration.     


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7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
 
To be eligible to participate in this study, an individual must meet all the following criteria: 
1. Women who have consented to undergoing medication abortion at or under 10 weeks gestation 
2. Age 18 years and older 
3. Fluent English speaking and reading 
4. Able and willing to receive and send text messages and receive phone calls 
(Appendix: Screening Form) 
 
 
7.2 
Subject Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Prior history of opioid abuse or opioid use disorder 
2. Reluctance or resistance to the use of opioids  
3. Participants who have any history of daily drug or alcohol use 
4. Participants with any significant medical illness, including renal, liver, neurologic, 
gastrointestinal, respiratory, or cardiac disease 
5. Opioid use in last 30 days 
6. Chronic use of pain medications, benzodiazepines, or on opioid-maintenance therapies (i.e. 
naloxone, naltrexone, buprenorphine, or combinations thereof) 
7. Chronic use of medications that may interact with methadone: 
antiretrovirals (i.e. abacavir, atazanavir, darunavir, indinavir, efavirenz, nevlfinavir, nevirapine, 
ritonavir, lopinavir, didanosine, stavudine, zidovudine), antibiotics (erythromycin, rifampicin), 
antifungals (fluconazole, ketoconazole), anticonvulsants (carbamazepine, phenobarbital), 
monoamine oxidase inhibitors (phenelzine), tricyclic antidepressants (desipramine), St. John’s 
Wort 
8.  Any known allergies to ibuprofen or methadone.   
9. Patients with known history of QT prolongation 
(Appendix: Screening Form) 
 
 
8 
Study Intervention 
 
The study intervention, a single dose of methadone 5mg, will be self-administered orally by the 
participant at the same time as buccal misoprostol and within the context of a medical abortion.   All 
participants will be provided with instructions about the study intervention, methadone, including 
timing of administration, administration route, and possible side effects.  
 
Although methadone is not a common first-line opioid, its use may be beneficial in opioid-naïve patients 
due to its slow onset and long duration of effect.  Guidelines published in 2000 by the College of 
Physicians and Surgeons of Ontario provided suggestions for starting doses in opioid naïve patients:  
2.5mg orally every 8 hours (14).  Per the Food and Drug Administration (FDA), initiation of therapy with 


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methadone in opioid non-tolerant patients may range from 2.5- 10 mg every 8-12 h (12).  These 
recommendations pertain to the use of methadone for the management of analgesia extending beyond 
one day. We propose the use of one 5mg dose of methadone to be administered ONCE to study 
participants for the management of acute pain associated with medication abortion.  
 
 
 
 
9 
Study Procedures 
 
 
See the Appendix 1 for the schedule of events.  
 
- 
As part of screening process, the electronic medical records of patients scheduled for 
medication abortion will be reviewed for eligibility. 
- 
After a patient who has been determined to be potentially eligible for the study per chart review 
has provided informed consent for a medication abortion, and has begun the medication 
abortion process by taking the first medication required for medication abortion (mifepristone) 
their clinician will ask if they want to hear about the study. If yes, the clinician will provide a 
warm hand-off to the study staff. 
- 
Researchers will review the study, including information about the study drug, clear instructions 
for use, and a review of the study contact points. No additional in-person visits are required for 
study participation. 
- 
The patients will have the opportunity to ask questions to the study staff, as well as talk to 
family and friends about the study. 
- 
If a patient is interested in participation, the study staff will review the eligibility criteria. If the 
patient is eligible, study staff will obtain written informed consent. 
- 
After informed consent has been obtained, study staff will review with participants their basic 
demographic information, medical and pregnancy history, history of prior medication abortions, 
and estimated gestational age. 
- 
Copy of signed consent can be provided to patient if they choose to have one but study team 
will retain a signed copy for our records regardless of their choice to take the copy of signed 
consent. 
- 
Study staff will also review other informational handouts that participants will be provided with 
including a detailed medication pamphlet explaining in detail the side effects of mifepristone, 
misoprostol, ibuprofen and the study drug methadone.  
- 
Participants will be counseled on the expectation of the presence of pain with cramping and 
bleeding that may be caused by misoprostol, and which may last up to several hours.  This pain 
has been described as mild, moderate and even severe but the intensity of pain is different for 
every individual.  
- 
Participants will also be counseled on the expectation of dizziness, diarrhea and mild fever.  Mild 
cramping for a few days after the abortion process may also be expected but is normally not 
enough to prevent them from going back to school or work.  The only restriction will be on the 
operation of heavy machinery, operating a vehicle or drinking alcohol for 24 hours following 
their methadone dose.  
- 
The participant will then receive a prescription of misoprostol to be taken 24-48hours later per 
standard of care.  


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- 
 The participant will also receive a prescription for the study drug and standard of care, 
ibuprofen, with written instructions about dosing of the medications and points of contact with 
study staff. 
- 
Participants will be instructed to send a text message to study staff indicating that they have 
self-administered misoprostol and the study medication, by texting the word “DONE” and their 
initials.  After the receipt of the text message by participants, study staff will then generate a 
telephone call to participants to conduct a survey at 0, 4, 8 and 24hours following 
misoprostol/methadone administration.   
- 
Study team will utilize a Google Voice number (857-217-4995) for contact with participants since 
this will enable PIs as well as other members of study team such as research assistant/ manager 
to have access to participants call or texts in case of adverse events or any emergencies in 
addition to regular follow-up texts. A reminder that no PHI will be transmitted over Google 
Voice. 
- 
Study team member will send the participant a text message after they sign the informed 
consent.  This text message will state "TEST".  This will ensure participants have the study team’s 
contact information (without needing to keep physical paperwork, if desired). 
- 
Study team will also suggest participant saves the team’s contact number as "BU Study Team". 
This will only be done IF the participant agrees.   
- 
Study staff will be provided a standardized script that will be constant for every phone 
interaction with a participant.  This script will not include the term “abortion” when calling 
participants to conduct the surveys.  
- 
These scripts will state:  “Hi.  We are calling from the BU team.  Can you please confirm your 
name?” 
- 
These telephone conducted surveys will include questions on maximum pain scores using the 
NRS (0-10) pain scale, when and whether methadone was consumed, when and whether 
ibuprofen was consumed, whether any side effects were experienced, and whether 
supplementary NSAIDs or acetaminophen were used. 
- 
Study staff will send a text message OR call study participants once every 24hrs after 
mifepristone administered in clinic to remind them about sending a text message when 
misoprostol and study medication are administered.  
- 
If we reach the participant by phone we confirm identity and then ask the participant if they've 
taken their misoprostol (second medication) yet. If they say no, we thank them and remind 
them of their next follow-up. If they say yes, that starts our "time 0".  If we're unable to reach 
them by phone, we send a text message stating "Reminder to call BU Study Team" at the 24 
AND 48 hour mark post-mifepristone (if the participant responds before 48 hour mark then call 
or message will not be sent). 
- 
No health information will ever be exchanged through text.  
- 
All participants will be contacted via telephone again at 48hours after consumption of 
misoprostol for evaluation of any side effects or reported adverse events, and again at 1 week 
following consumption of misoprostol to assess patient satisfaction. 
- 
If unable to reach study participants, three (3) attempted telephone contacts will be made and 
documented before considering the participant lost to follow-up.  
- 
Partial data will be stored for all participants who report pain scores up to 8 hours after 
consumption of methadone, but are unable to be reached for further assessment at the 24, 48 
hours and 1 week timeframe. 3 attempted telephone contacts will be made and documented 
before considering the patient lost to follow-up 


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- 
Standard of care after medication abortion is a follow-up appointment in 1-2 weeks to confirm 
abortion completion.   
- 
Participants will have been counseled by their family planning clinician that not taking the 
misoprostol will increase the risk of incomplete abortion, and that they are encouraged to 
follow-up with the clinician as scheduled whether or not they take the misoprostol. 
- 
During the study, we are asking participants to text us when they have taken the misoprostol; if 
they do not reach out to us or do not take the misoprostol, but do take the methadone, they are 
not at any higher risk from study involvement. We think it is highly unlikely that a participant will 
stay in contact with the study team but not take their misoprostol. 
 
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. In our study, the following routine study 
measurements are considered AEs but are not necessarily related to the subject’s participation in the 
research as they may be commonly associated with the medication abortion procedure, (though 
assessments on relatedness will be made for each occurrence): pain, vaginal bleeding, nausea, vomiting, 
fever, chills and diarrhea.  The following routine study measurement will not be considered an AE 
because it is defined as a study endpoint: abortion.  
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the event as it 
occurred.  
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 


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• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
The expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the 
adverse event. 
 
 
10.2 Safety Review 
 
Both the risks listed in Section 6.1 and unknown risks will be monitored as follows: subjects will be 
contacted via phone call at 0, 4, 8, 24, and 48 hours following administration of methadone and 
misoprostol. Subjects will be asked to report pain scores as well any side effects or adverse events. The 
PI and sub-investigator (physicians) will monitor and review the survey answers promptly. If the PI 
determines that any adverse events need further assessment, the subject will be contacted directly for 
further information and assessment.  Participants will be provided with information on when, how, and 
where to seek medical attention. 
 
Details about each AE will be recorded on an Adverse Event Form, and about SAE on a Serious Adverse 
Event Form.  These forms will require information to be collected on the AE, onset date/time, date/time 
study staff aware, resolution date, action taken and comments.  These forms will be completed by study 
staff and Principal Investigator informed as soon as possible.   
 
10.3 Reporting Plans 
The Principal Investigator at BMC will report Unanticipated Problems, and Adverse Events to the BMC 
IRB in accordance with IRB policies: 
• 
Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the IRB within 7 
days of the investigator learning of the event. 
• 
Any reports with recommended changes will be reported to the IRB within 7 days of the 
investigator receiving the report.  
• 
Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places subjects or others at a greater risk of harm than was previously 
known. 
• 
Any reports with no recommended changes will be reported to the IRB at the time of continuing 
review.  
 
 


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10.4 Stopping Rules 
 
The study will be stopped if two or more patients have a SAE.  A subject will be withdrawn from the 
study if they have adverse reactions associated with methadone use including: respiratory depression, 
signs and symptoms of arrhythmia and any other unaccounted event.  A subject can choose to no longer 
participate in the study at any time. 
  
 
11 Data Handling and Record Keeping 
 
11.1 Confidentiality 
 
Study staff will implement procedures to protect the confidentiality of patient and participant 
information. 
— When patients are screened for eligibility, we will record the responses in a way that does not 
identify the individual.  For those that choose to participate and sign the informed 
consent/HIPAA authorization, we will then write the study ID on the screening responses and 
keep these in the study files.  For those who are not eligible or who don’t want to participate, 
we will record the reasons for not taking part but we will not link this to the individual.   
— When a patient has enrolled in the study, we will collect participant contact information 
including phone numbers, medical record number, and email address. This information will be 
stored in a password-protected Excel file and kept on a secure hospital server. Only study staff 
will have access to this file. 
— We will create a single master key; all participants will be given a study number beginning with 
101. Study numbers will be recorded on the Excel file, which will be the only location where 
participant identifiers are connected to their study ID.  
— Study staff will record baseline information on demographics and medical history into a REDCap 
survey, using only the participant study ID.  
— All follow-up surveys obtained by telephone will be entered into REDCap, again using only the 
participant study ID. 
— Study staff will be provided a standardized script that will be constant for every phone 
interaction with a participant.  This script will not include the term “abortion” when calling 
participants to conduct the surveys.  
— This scripts will state:  “Hi.  We are calling from the BU team.  Can you please confirm your 
name?” 
— Once a participant has completed study activities, their information will be stored securely for 7 
years, then will be deleted from the master Excel file. All remaining information in the REDCap 
surveys will thus remain deidentified. 
 
All data containing patient identifiers, including patient phone numbers and text message data, will be 
stored on virtual drives behind the BMC firewall. The master code will contain the patient identifiers 
connected to a unique Study ID. Data will be coded and stored separately from the master code. All 
statistical analyses, as well as distribution, will only be performed on a final coded dataset in which 
subjects are identified only by a unique study-specific code assigned for the sole purpose of this 
research project. The master code, which connects study ID and identifiers, will be stored securely for 7 
years then will be destroyed.  This study is registered on ClinicalTrials.gov. 


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11.2 Source Documents 
 
Source data includes EPIC hospital records, clinical and office charts, anesthesia records, surgical report, 
participant text messages and laboratory notes.  
Data generated by the methods described in the protocol will be recorded in the subjects' medical 
records and/or study progress notes. Data will be transcribed directly into REDcap and will be 
deidentified. As described above, patients will be given a unique study identification code upon 
acceptance into the study.  This unique study ID code will be used in REDcap and will have no link to PHI. 
 
11.3 Case Report Forms 
 
A REDcap database will be the primary data collection instrument for the study. All data requested will 
be transcribed into REDcap. All missing data will be explained. If a data set on REDcap is left blank 
because the procedure was not done or the question was not asked, the code “9999” will be entered. If 
the item is not applicable to the individual case, “N/A” will be written. All entries will be entered directly 
into REDcap.  
 
See the Appendix for the following CRFs: REDcap 
 
11.4 Study Records Retention 
 
Study records, including participant consents, will be retained for at least seven years after completion 
of the study as is required by the BUSM/BMC IRB. These records will be retained in a locked file cabinet 
in the PI’s office within the Department of Anesthesiology.  
 
 
12 Statistical Plan 
 
12.1  
 
Study Hypotheses 
 
This is a feasibility study on the recruitment process of study participants in utilizing a study intervention 
drug, 5mg of oral methadone, along with a standard dose of ibuprofen, following medication abortion 
with misoprostol.  We hypothesize that it will be feasible to recruit and enroll 25 eligible women per 
mentioned screening criteria into this pilot study in the time period of 6 months post study approval.   
The feasibility of this study will aid in the planning of a larger sufficiently powered efficacy trial which 
would determine that there is a reduction in pain scores after the administration of misoprostol in 
medication abortion when the study intervention drug is consumed concomitantly  
 
 
12.2 Sample Size Determination and Statistical Methods 
 
In this planned pilot study of methadone as a one-time treatment for pain, we can expect to be able to 
feasibly study between 15-25 women within 6 months of study approval. From the literature we know 


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that previous studies have found a mean maximum pain score of 7 (range across studies 6.2-8) and most 
of these studies sued a standard deviation of 2 – 2.5.  We are hoping to power to see reduction in 
maximum pain scores by 2 points; meaning, we expect our intervention group will have a mean pain 
score of 5, compared to the historical mean of 7.  We thus can compute the upper bound of a two-sided 
95% confidence interval for an expected mean pain score of 5 and determine if this limit excludes the 
mean score from other studies (treated here as a target population mean). We assume a standard 
deviation of 2.25 for these computations.  With a sample of 15 participants, the upper bound of the 95% 
confidence interval is 6.25.  For 20 participants, the upper bound is 6.05 and for 25 participants it is 5.93.  
Thus, with even the smallest anticipated sample, we expect that the pain scores of women treated with 
methadone will statistically exclude in its upper confidence bound the population mean level of 7. We 
will analyze these data using a mixed linear model that will account for the correlated nature of the 
observations per patient. 
 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional policies 
(which are based in federal regulations, guidance, and ICH Good Clinical Practice guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator.  
 
All subjects for this study will be given a consent form, if they choose to have one, describing the study 
and providing sufficient information for subjects to make an informed decision about their participation 
in the study. The consent form will be submitted with the protocol for review and approval by the IRB. 
The consent of a subject, using the IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure. Consent will be documented as required by the IRB.   
 
14 Literature References 
 
1. Opioid Analgesia for Medical Abortion: A randomized controlled trial. Obstetrics and 
Gynecology, 2019; 134(6) 1163-70  
2. Prophylactic compared with therapeutic ibuprofen analgesia in first-trimester 
medical abortion: a randomized controlled trial. Obstetrics and Gynecology, 2013; 
122(3): 558-564  
3. Ibuprofen and paracetamol for pain relief during medical abortion: a double-blind 
randomized controlled study. Fertility and Sterility, 2009; 91(5): 1877-1880  
4. Pre-emptive effect of ibuprofen versus placebo on pain relief and success rates of 
medical abortion: a double-blind, randomized, controlled study. Fertility and Sterility, 
2012; 97(3): 612-5  
5. World Health Organization Clinical Practice handbook for Safe Abortion. World 
Health Organization, 2014.  


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6. WHO Analgesic Ladder. World Health Organization, 2020  
7. Pain Control in Medial Abortion. International Journal of Gynecology and Obstetrics, 
2001; 74(3): 275-80  
8. Hydrocodone-acetaminophen for pain control in first-trimester surgical abortion: a 
randomized controlled trial. Obstetrics and Gynecology, 2012; 120(5): 1060-9  
9. Female reproductive tract pain: targets, challenges, and outcomes. Frontiers in 
Pharmacology, 2014; 5: 17  
10. Visceral Pain: the Neurophysiological Mechanism. Handbook of Experimental 
Pharmacology, 2009; (194): 31-74  
11. Two prophylactic Medication approaches in addition to a pain control regimen for 
early medical abortion <63 days gestation with mifepristone and misoprostol: study 
protocol for a randomized, controlled trial. Reproductive Health, 2016; 13  
12. Methadone hydrochloride: FDA guidelines, updated 2015.  
13. The Assessment and Treatment of Addiction, 2019; 1-252.   
14. Evidence-based recommendations for medical management of chronic non-
malignant pain: reference guide for physicians. The College of Physicians and of 
Ontario, 2000.  
15. Methadone for cancer pain. Cochrane Database Syst Rev, 2017; (2)  
16. Pain control in first-trimester and second-trimester medical termination of 
pregnancy: a systematic review. Contraception, 2011; 83(2): 116-126  
17. Pain during medical abortion, the impact of the regimen: a neglected issue? A review. 
The European Journal of Contraception & Reproductive Health Care, 2014; 19(6), 
404-419  
18. Combination therapy with ibuprofen and methadone for chronic cancer pain. 
American Journal of Medicine, 2013; 77(1A): 78-83  
 
 
 
15 Appendix 
 
Schedule of Events, Screening Form, Surveys at 0, 4, 8, 24, 48 hours and 1 week.