Clinical trial NCT04981678
Conditions: Opioid-use Disorder
Sponsor: MaineHealth
Start date: 2022-01-01; Completion date: 2023-10-16
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There is limited guidance on the optimal management of buprenorphine perioperatively and both buprenorphine discontinuation and continuation are acceptable standards of care. Buprenorphine continuation at low analgesic dosing is also accepted, however is not provided as a potential treatment strategy by the Substance Abuse and Mental Health Services Administration (SAMHSA). There is the risk of inadequate pain control necessitating opioid escalation when buprenorphine is continued. Preliminary clinical observations support buprenorphine continuation at low analgesic doses (8mg) as it adequately facilitates postoperative pain management without interrupting opioid use disorder (OUD) treatment, however to date, no prospective trial has investigated this treatment strategy in comparison to full dose buprenorphine continuation. Since optimal perioperative dosing strategies remain unknown, the purpose of this study is to investigate if buprenorphine continuation at analgesic dosing is superior to full dose buprenorphine continuation in individuals presenting for elective surgery.

Detailed description:
The purpose of this study is to investigate whether buprenorphine continuation at analgesic dosing is superior to full dose buprenorphine continuation in individuals presenting for elective surgery. Adults scheduled for elective surgery who are taking ≥12mg buprenorphine for OUD treatment will be eligible for this study. Enrolled participants will be randomized to receive either a reduced analgesic dose of buprenorphine (8mg) or to continue buprenorphine on the day of surgery without dose reduction. The primary outcome of interest is postoperative pain scores. The secondary outcomes of interest are opioid consumption, opioid dispensing up to 30 days following the surgical procedure and OUD related symptoms, including opioid withdrawal, cravings and relapse. The investigators hypothesis is that there will be a clinically significant increase in pain scores when buprenorphine is continued in full compared to when it is continued at a lower analgesic dose. Clinical significance will be defined as a difference in composite pain scores of greater than 20% between groups. The investigators also hypothesize that opioid consumption and opioid dispensing will be greater with full dose buprenorphine continuation compared to low-dose continuation.

Arms: arm 1: Patients instructed to reduce buprenorphine to 8mg prior to surgery arm 2: Patients instructed to continue taking the full prescribed dose of buprenorphine.
Interventions: intervention 1: Buprenorphine intervention 2: Buprenorphine
Intervention descriptions: intervention 1: Patients randomized to this group will reduce their buprenorphine dose prior to surgery. intervention 2: Patients randomized to this group will continue their buprenorphine at the full prescribed dose.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 28 
A Prospective, Randomized Trial of the Effect of Buprenorphine Continuation 
versus Dose reduction on Pain Control and Post-Operative Opioid Use 
 
Version Date: 5/12/2022 
PI: Aurora Quaye, M.D. 
 
Introduction 
Buprenorphine is a high-affinity, partial mu opioid receptor agonist that is effective, life-
saving opioid maintenance treatment (OMT) for individuals with opioid use disorder 
(OUD). Due to the pharmacokinetics of buprenorphine, managing acute post-surgical 
pain can be challenging, especially when full mu opioid receptor agonists are used 
concomitantly. Currently, the Substance Abuse and Mental Health Services 
Administration (SAMHSA)- the national organization that provides guidance on the 
management of substance use disorder treatment- recommends discontinuation of 
buprenorphine prior to surgery, replacing it with full opioid agonists for withdrawal 
prevention, to facilitate postoperative analgesia.1 However, SAMHSA states as an 
advisory warning that this can introduce significant risks to an individual’s substance 
use recovery, including cravings and relapse. Conversely, SAMHSA also recommends 
full dose buprenorphine continuation perioperatively; however, they also warn that the 
risks associated with this management strategy include ineffective analgesia 
necessitating escalating opioid administration.  
Preliminary clinical observations support that buprenorphine continuation at low 
analgesic doses (8mg) can adequately facilitate postoperative pain management 
without interrupting OUD treatment.2,3 Over the past couple of years, there has been 
growing support for perioperative continuation of buprenorphine.4-6 At our institution, 
providers are currently more willing to recommend low dose buprenorphine 
continuation, a significant practice shift from a year prior when buprenorphine 
discontinuation was the accepted standard. Furthermore, there are recent reviews- 
based on professional opinion as opposed to prospective studies- that contend 
buprenorphine should be continued without dose adjustment perioperatively.4,7 This is 
paradoxical to the reports saturating the literature up until recently asserting that 
patients had poorly controlled postoperative pain when maintained on high doses of 


 
 
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buprenorphine, leading to increased opioid utilization and disruption of hospital 
courses.8,9  
 
To date, no prospective trial has investigated low dose buprenorphine continuation in 
comparison to buprenorphine discontinuation and SAMHSA has not endorsed low 
dose buprenorphine continuation as a management strategy. Similarly, no study has 
compared full dose buprenorphine continuation to buprenorphine dose reduction 
perioperatively. Because of this, there has been a call for prospective studies to 
investigate an optimal perioperative buprenorphine dosing strategy.3,5,7 Since there is 
growing acceptance that the risks of OUD relapse with buprenorphine discontinuation 
overshadow the risks of increased opioid utilization and potentially difficult pain control 
with buprenorphine continuation, our next course of action is to determine whether full 
dose buprenorphine continuation is superior to reducing buprenorphine to analgesic 
doses in individuals with OUD presenting for elective surgery. For this study, we 
propose to compare postoperative pain scores, opioid consumption, outpatient opioid 
dispensing, and OUD related symptoms between these two treatment strategies. The 
goal of our study is to inform the development of guidelines for the perioperative 
management of patients on buprenorphine that are based on science as opposed to 
expert opinion.  
 
Background 
Opioid use disorder (OUD) is a chronic neurobehavioral disease characterized by 
continued opioid use despite the desire to quit, often punctuated by cycles of 
remission and opioid use relapse. OUD is associated with high rates of medical co-
morbidity and life expectancy is two decades shorter when compared to those 
without OUD.10 In the past 20 years, opioid related deaths have risen 
exponentially.11,12 Maine has been especially devastated by this trend and, 
although OUD mortality rates declined in 2018, they are beginning to re-ascend. It 
is projected that the overdose death rates for 2020 will be the highest on record, as 
the first quarter of this year has seen a 23% increase in opioid related mortality.13 
Unfortunately, despite our national crisis, opioids remain prominent in perioperative 


 
 
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analgesic regimens for the millions of surgeries and procedures performed each 
year in the United States. 
Opioid maintenance therapy (OMT) with buprenorphine has reduced hospitalization 
rates and mortality for those with OUD.14 The optimal duration of OMT has not 
been established and relapse rates can be high when OMT is discontinued. A 
multi-site study sponsored by the National Institute on Drug Abuse (NIDA) reported 
relapse rates approaching 90% following the premature discontinuation of OMT.15  
Clinical opinion is mixed on whether buprenorphine should be held, continued at full 
dose, or reduced in the perioperative period as it is limited to case reports, case 
series and provider opinion. Acute post-surgical pain management can be 
challenging in these patients when standard pain regimens, including full mu opioid 
receptor agonists, are needed for post-operative pain management.16 
Buprenorphine has high receptor binding affinity, a long half-life, and displays 
partial mu opioid receptor agonism- all properties which can prevent effective 
analgesia from full mu opioid agonists used in conjunction for pain control. 
Therapeutic doses of buprenorphine for OUD treatment (16-32mg) are thought to 
saturate opioid receptors, rendering further opioid use for analgesia ineffective. 
There are published reports of patients with poorly controlled postoperative pain 
when buprenorphine was continued and some providers recommend 
buprenorphine discontinuation at about 72 hours prior to elective surgery and 
replacement with low dose opioid agonists to reduce the risk of opioid withdrawal. 
One report describes a 50 year-old man with acute limb compartment syndrome on 
buprenorphine for OUD requiring escalating doses of hydromorphone without pain 
control until buprenorphine had been discontinued for 48 hours. Similarly, a 47 
year-old female with OUD on buprenorphine had poor pain control with escalating 
doses of hydromorphone after thoracic surgery that did not resolve until her 
buprenorphine was discontinued.9  
However, case reports also describe difficult perioperative pain control regardless 
of buprenorphine discontinuation. In one report, a 37 year-old woman on 
buprenorphine underwent two separate uro-gynecologic procedures where 


 
 
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buprenorphine was continued for the first procedure and discontinued for the 
subsequent one.  Pain management was challenging for this patient in both 
instances.9  
Conversely, case series have reported effective pain management with full mu-
opioid agonists in patients maintained on buprenorphine perioperatively. In one 
report, five patients undergoing major surgery continued buprenorphine and their 
pain control was adequately treated with supplemental opioids given as needed. In 
a retrospective cohort study of 22 surgical patients taking buprenorphine, there was 
no difference in pain control on postoperative day one in the half for whom 
buprenorphine was continued vs the half for whom buprenorphine was 
discontinued.9  
There are preclinical data and evidence from patients taking buprenorphine for 
chronic pain at analgesic doses that the addition of opioid agonists is effective in 
treating breakthrough pain.9  Neuroimaging of opioid receptor availability in heroin 
dependent patients receiving buprenorphine suggest that 8mg of buprenorphine is 
the ideal dose where receptors are available for additional opioid agonists to bind 
and facilitate analgesia. We compiled this evidence to establish institutional 
guidelines to continue buprenorphine at an 8mg analgesic dose. We subsequently 
published a retrospective observational study about our experience with analgesic 
dosed buprenorphine continuation compared to discontinuation.3 We identified that 
outpatient opioid dispensing and PACU pain scores were significantly higher in the 
cohort where buprenorphine was discontinued compared to when it was continued. 
A recent retrospective study from Stanford University published similar findings, 
reporting that patients continued on buprenorphine perioperatively at varied tapered 
doses received significantly less opioid prescriptions without changes in pain 
scores when compared to patients where buprenorphine was discontinued.17 These 
clinical observations challenge previous assumptions that, due to its pharmacology, 
buprenorphine interferes with opioid based pain management. However, these 
studies are limited by their retrospective, non-randomized design, and their 
absence of controlled clinical conditions; also, they do not address relapse rates 
and postoperative OUD-related symptoms. Most importantly, current established 


 
 
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national guidelines are to continue buprenorphine without dose adjustment or to 
discontinue buprenorphine perioperatively, without evidence to support either 
strategy. The current national guidelines disclose that full dose buprenorphine 
continuation can lead to inability to treat pain with opioid agonists and 
discontinuation can lead to withdrawal, however, they do not include 
recommendation for adjusting buprenorphine to an analgesic dose to facilitate 
opioid based analgesia, while preventing withdrawal. 
Even though no prospective trial has been conducted to identify if buprenorphine 
continuation or discontinuation should be the preferred strategy for perioperative 
pain management, in the past couple of years there has been a paradigm shift 
where many contend that the risks of OUD relapse with buprenorphine 
discontinuation outweigh the risks of increased opioid utilization and potentially 
difficult pain control with buprenorphine continuation. This is evident from our initial 
study, designed as a head-to-head comparison of buprenorphine continuation to 
discontinuation. In our two months of active recruitment for this study, we found a 
significant number of patients that were reluctant to enroll in the study. When given 
the option to stop versus continue their buprenorphine at a lowered dose, patients 
were understandably inclined to continue their buprenorphine at the lowered dose 
due to their concerns and fears of relapse. Also, many of the patients stated that 
their doctor told them to continue their buprenorphine- in line with the current 
MaineHealth guidelines of low dose continuation that the authors of this study 
proposal helped establish in 2020.  
An outstanding question still remains regarding the optimal dosing of 
buprenorphine perioperatively. As stated previously, there is evidence to support 
that low dose buprenorphine continuation may be ideal, because when 
buprenorphine is at a lowered, analgesic dose, there would still be availability for 
full opioid agonists to work for pain control given increased opioid receptor 
availability. However, it is quite possible that even at elevated doses of 
buprenorphine and corresponding low opioid receptor availability, pain control is 
still possible and dose reduction is not required. Thus, we propose to compare full 
dose buprenorphine continuation to low dose buprenorphine continuation in 


 
 
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patients scheduled for elective surgery. It is worth noting that this revised proposal 
was intended to be our follow-up study upon completion of our prior study 
comparing buprenorphine continuation to discontinuation.  
Our proposed study will provide data to improve acute pain management delivery 
for the growing population of individuals receiving buprenorphine as OUD therapy. 
Not only will our study address a considerable gap in care delivery, but it will help 
establish consensus for a topic that currently has mixed opinion. If this clinical trial 
identifies that buprenorphine dose reduction is no different than full dose 
buprenorphine continuation, than we can change our MaineHealth guidelines to 
recommend continuation without having to make any adjustments to patient’s OUD 
treatment. If, however, we identify that patients with full buprenorphine continuation 
use more opioids and have prolonged hospital courses, it will confirm the need for 
our current guidelines, confirming our preliminary findings of adequate pain control 
with buprenorphine continuation at analgesic dosing. Additionally, it could help 
establish treatment plans where patients are provided with less opioids both as 
inpatients and outpatients decreasing opportunities for diversion and opioid related 
relapse. We will further explore the comprehensive effect of buprenorphine 
management strategies through engaging representatives from the substance use 
disorder community and the providers involved in the various phases of their care. 
Convening this group of stakeholders together as members of our Data Safety and 
Monitoring Review Board will help us identify the key concerns for patients with 
OUD. It will also allow us to tailor our study to address these issues, with the 
ultimate goal of reducing perioperative OUD severity and the risks associated with 
relapse. 
Hypothesis 
There is limited guidance on the optimal management of buprenorphine 
perioperatively and both buprenorphine discontinuation and continuation are 
acceptable standards of care.1 Buprenorphine continuation at low analgesic dosing 
is also accepted, however is not provided as a potential treatment strategy by 
SAMHSA.1 There is the risk of inadequate pain control necessitating opioid 


 
 
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escalation when buprenorphine is continued. Preliminary clinical observations 
support buprenorphine continuation at low analgesic doses (8mg) as it adequately 
facilitates postoperative pain management without interrupting OUD treatment, 
however to date, no prospective trial has investigated this treatment strategy in 
comparison to low dose buprenorphine continuation. Since optimal perioperative 
dosing strategies remain unknown, the purpose of this study is to investigate if 
buprenorphine continuation at analgesic dosing is superior to buprenorphine 
continuation in individuals presenting for elective surgery. 
Specific Aims 
Aim 1: To compare the efficacy of perioperative standard of care low dose 
buprenorphine continuation (STD-BUP) to full dose continuation (FULL-BUP) in 
adults maintained on buprenorphine for OUD. Hypothesis 1: Postoperative pain 
scores at postoperative day (POD) 1 will be higher in FULL–BUP patients 
compared to STD-BUP patients and this difference will be clinically significant 
(defined as a > 20% difference in pain scores between groups). We will measure 
pain using a numeric rating scale (NRS) of 0 to 10, a standard tool used in 
comparing analgesic efficacy between distinct treatment interventions. 
Aim 2: To compare postoperative opioid consumption (excluding buprenorphine 
formulations) in adults maintained on buprenorphine for OUD, measured as 
morphine milligram equivalents (MME) at 24, 48 and 72 hours postoperatively. 
Hypothesis 2: FULL-BUP patients will have higher opioid consumption at 24, 48 
and 72-hours postoperatively compared to STD-BUP patients. 
Aim 3: To compare OUD symptom severity and depressive symptoms; measured 
preoperatively and 30 days postoperatively using the Patient Health Questionnaire-
9 (PHQ-9), Current Opioid Misuse Measure (COMM), and Opioid Craving Scale 
(OCS) instruments. Hypothesis 3: There will be no difference in OUD symptom 
severity and depressive scores FULL-BUP patients compared to STD-BUP 
patients, both on day of surgery and at 30 days postoperatively.  
Aim 4: To compare the number of opioid prescriptions and quantity (in MME) of 
opioid medications dispensed, up to 30 days following surgery. Hypothesis 4: The 
number of opioid prescriptions and the quantity of MMEs dispensed will be higher 


 
 
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for FULL-BUP patients than for STD-BUP patients during the 30 day period 
following surgery. 
 
Significance 
Greater than two million Americans are estimated to currently suffer from opioid use 
disorder (OUD), and over the past two decades, opioid related mortality has 
exponentially increased. Buprenorphine is a Food and Drug Administration (FDA) 
approved treatment for OUD management. Reflective of its long-term, life-saving 
benefits, buprenorphine is currently the most frequently prescribed medication in 
the state of Maine, with the blood pressure medication, hydralazine, being the 
second most commonly prescribed.18 Buprenorphine works by binding strongly to 
opioid receptors- targets for drugs of abuse - for relatively extended periods of time, 
attenuating the cravings and withdrawal symptoms that fuel opioid addiction and 
relapse. When individuals on buprenorphine present for surgery, their acute post-
surgical pain can be challenging, as the opioid medications commonly given to 
provide analgesia are unable to easily displace buprenorphine. Currently, both 
buprenorphine discontinuation and continuation are recognized as acceptable 
standards of care. The Substance Abuse and Mental Health Services 
Administration (SAMHSA), the organization that manages the federal approval of 
buprenorphine prescribers, recommends either perioperative buprenorphine 
continuation or discontinuation, based upon patient and provider preference, with 
consideration of the inherent risks for each management strategy.1 However, there 
is limited specific guidance on the optimal perioperative management of 
buprenorphine in this patient population and low dose buprenorphine continuation 
is not currently described as a treatment option by SAMHSA .  
Preliminary clinical observations support that buprenorphine continuation at low 
analgesic doses can adequately facilitate postoperative pain management without 
interrupting OUD treatment.3,17 However, no prospective trial has investigated this 
treatment strategy. The purpose of this study is to investigate whether 
buprenorphine continuation at analgesic dosing is superior to buprenorphine 
continuation in individuals presenting for elective surgery. Adults scheduled for 


 
 
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elective surgery who are taking ≥12mg buprenorphine for OUD treatment will be 
eligible for this study. Enrolled participants will be randomized to receive either a 
reduced analgesic dose of buprenorphine (8mg) or to continue buprenorphine on 
the day of surgery without dose reduction. Our primary outcome of interest is 
postoperative pain scores. Our secondary outcomes of interest are opioid 
consumption, opioid dispensing up to 30 days following the surgical procedure and 
OUD related symptoms, including opioid withdrawal, cravings and relapse. We 
hypothesize there will be a clinically significant increase in pain scores when 
buprenorphine is continued in full compared to when it is continued at a lower 
analgesic dose. We will define clinical significance as a difference in composite 
pain scores of greater than 20% between groups. We also hypothesize that opioid 
consumption and opioid dispensing will be greater with full dose buprenorphine 
continuation compared to low-dose continuation. This will be the first randomized 
trial comparing competing perioperative buprenorphine treatment strategies and will 
yield critical preliminary data for larger, confirmatory studies.  Additionally, we 
envision that this study will lay groundwork for follow-up investigations in this 
patient population, focused on preventing opioid cravings and relapse 
perioperatively, along with other clinical scenarios where acute pain is anticipated, 
such as intensive care unit settings. 
Successful execution of this prospective trial will provide Dr. Quaye with the tools 
and critical experience necessary to pursue her aspirations of becoming a 
successful clinical investigator. Aurora Quaye has a mentorship team that is 
committed to her success and is led by her department chair, Dave Warters.  Her 
mentorship team also includes Wendy Craig, Cliff Rosen, Kathleen Fairfield, Irwin 
Brodsky, Kinna Thakarar and Liz Jacobs. Her mentorship team will help provide 
guidance as she mentors residents, including Yussr Ibrahim, that have expressed 
interest in engaging in clinical research. They will meet with her periodically and 
provide her with any feedback that is required, based upon the trial phase, to help 
promote successful trial completion.  
STUDY DESIGN AND RESEARCH PROCEDURES 


 
 
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This is a prospective, randomized, unblinded clinical trial comparing full dose 
buprenorphine continuation to buprenorphine continuation at analgesic dosing in 
adults with OUD maintained on 12mg or greater sublingual equivalent 
buprenorphine, who are scheduled for elective surgery.  
Randomization Plan 
Enrolled participants will be randomized 1:1 into one of two groups (defined below).  
The randomization scheme will be developed using NQuery Software (Statistical 
Solutions, Boston, MA).and will use permuted blocks of 4 and 6 patients to ensure 
balance between study arms. The analyst will provide the research coordinator with 
randomization assignments in sequentially-numbered opaque envelopes (one 
series of envelopes for each stratum of anticipated post-surgical pain) . The study 
coordinator will pass the next envelope in sequence to another member of the 
study team when it is time to assign a subject to a group.  Gerbershagen et. al. 
documented the distribution of pain scores for 179 different surgical procedures 
and we will use these data to establish randomization strata.19   For true practice 
generalizability on the association between buprenorphine management and 
postsurgical pain control, we will include surgical procedures based on average 
pain intensity on postoperative day (POD) 1, as opposed to limiting our criteria to a 
particular surgical type (see Appendix 1). 
Patients will be stratified according to their anticipated pain score on POD 1 (4-6/10 
range vs >6/10 range) and those within each stratum will be randomized to one of 
two groups as follows:   
• FULL-BUP group: buprenorphine formulation continued throughout the 
perioperative period 
• STD-BUP group: buprenorphine formulation reduced to 16mg the day prior 
to surgery and then 8mg on the day of surgery onwards. Participants in this 
group taking 12-16mg buprenorphine at baseline will have no change to their 
buprenorphine dose on the day prior to surgery. 
All participants will be transitioned back to their regular dose of buprenorphine 
when postoperative surgical pain has subsided as determined by their 


 
 
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buprenorphine provider following hospital discharge. This transition will be 
coordinated with their buprenorphine provider, which is our current standard 
practice when buprenorphine is reduced perioperatively.  
As the study is unblinded, both patients and providers will be aware of the 
randomization assignment. To help mitigate bias, the team members collecting and 
entering data will be masked regarding the patient’s assignment. The REDCap 
database has the randomization assignments in an instrument separate from the 
study data collection instruments, allowing for data entry without seeing which 
group the subject is in.  
Study Procedures 
On the day of surgery, prior to the procedure, participants will be asked to complete 
a series of questionnaires to obtain baseline self-assessments for opioid cravings, 
opioid misuse, and opioid withdrawal symptoms (see protocol schema and 
Measures for Aim 3 section for details). Patients will be asked to report early for 
their procedure to complete the study questionnaires in a private space.  
Both groups will receive identical preoperative, intraoperative and postoperative 
multimodal opioid sparing strategies, coordinated with the surgical, anesthetic, and 
psychiatric clinical care teams directly involved in the study participant’s care. 
Multimodal analgesia, or the administration of two or more drugs that act by 
different mechanisms, provides more effective analgesia compared to medications 
used individually. Multimodal analgesia has been well established at achieving 
early recovery after surgery and reducing pain scores. According to the American 
Society of Anesthesiologists (ASA) task force for acute pain management, 
multimodal pain management therapies should be used for the treatment of 
surgical pain whenever possible however it is not mandatory to use these methods 
routinely for all surgical procedures and they are utilized at the discretion of the 
anesthesiologist taking care of the patient. As such, we will adopt this standard of 
care practice for the treatment of post-surgical pain in both randomized 
groups.  Our multimodal analgesic strategy will consist of gabapentin, 
acetaminophen and Celebrex preoperatively and postoperative ketorolac, 
acetaminophen, opioids, nerve blocks infusions/epidural catheters, alpha agonists, 


 
 
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ketamine and lidocaine infusions as indicated. Postoperatively, opioid medications 
will be given IV or PO as second line analgesic agents. If a participant has an 
allergy or aversion to any of these medications, they will not receive the medication, 
but will be able to participate in the study with alternative medications. All analgesic 
medication administered will be documented by study staff. In the event of poorly 
controlled pain at any point during the study, we will provide the patient with 
appropriate analgesic rescue agents to ensure that post-surgical pain is adequately 
controlled. 
Intraoperative opioid consumption, type of anesthesia, total PACU opioid 
consumption, normalized for time spent in PACU, and 24, 48 up to 72-hour opioid 
consumption will be extracted from the patients’ charts. All opioid consumption will 
be converted into MME. One month postoperatively, participants will receive 
virtually- administered questionnaires, including: a substance use evaluation, where 
they will be asked to complete self-assessments identical to those administered on 
the day of surgery for comparison analysis. Patients will be encouraged to record 
postoperative pain and opioid consumption on the Timeline website regularly and 
reminded that compensation is tied to completion. Reminder phone calls will be 
made by study staff during this time period. 
We will contact each participant’s buprenorphine provider to collect data for 
buprenorphine treatment retention following surgery and will assess each patient’s 
Maine Prescription Awareness Tool (MainePAT) record to collect data for 
outpatient opioid utilization during the 30 days following surgery. Buprenorphine 
formulations will not be included in our MME total. 
Measures for Aim 1 (Pain scores) 
The primary outcome of this study will be composite pain scores 24 hours after 
surgery. Others have shown that composite pain scores quantify pain with greater 
accuracy than a single measurement. Jensen et. al. concluded in their study that 
composite pain intensity scores from two or more individual ratings of pain are valid 
for detecting treatment effects.20,21 Pain scores will be measured using a numeric 
rating scale (NRS) (0=no pain; 10= worst possible pain). “Worst,” “average,” and 


 
 
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“least” pain scores will be assessed for the preceding time interval at 24, 48, and 72 
hours following surgery. Inpatient pain scores will be collected as part of routine 
post-operative care and will be extracted from the medical record; there is no set 
protocol for routine pain score collection but typically it is done every 4-8 hours. To 
collect pain scores, nursing staff asks patients to rate their current pain on a scale 
from 0-10. If a participant is discharged prior to 72 hours after surgery, NRS scores 
will be assessed at the remaining time points via telephone. Prior to discharge, 
study staff will provide patients with a log to keep a record of their pain scores, at 
least once every 8 hours, in order to mitigate recall bias in anticipation of being 
contacted by research staff. Study staff will call discharged patients and ask them 
to report their pain scores for each 24 hour period between discharge and 72 hours 
postoperatively as recorded on the forms they were given at time of discharge. 
Measures for Aim 2 (Opioid consumption) 
For our opioid consumption assessments, data will be collected intraoperatively, in 
the PACU and at the 24hr, 48hr and 72hr timepoints following surgery. Information 
on opioid type and dose will be obtained through review of the participant’s 
electronic medical record or through phone assessment, depending on point of 
hospital discharge. Opioid amounts will be converted into MMEs. Patients who are 
discharged prior to 72 hours after surgery will be given a log to record the pain 
medications they consume during that period. Study staff will call patients to collect 
this data. 
Measures for Aim 3 (Depression and OUD severity) 
To evaluate depression severity, we will use the patient health questionnaire (PHQ-
9), a validated screening tool used to monitor depressive symptoms. For our OUD 
severity assessments, we will administer the Desires for Drug questionnaire (DDQ) 
and the opioid craving scale (OCS) to determine level of opioid cravings, the 
current opioid misuse measure (COMMS) to detect opioid misuse, and a 30-day 
Timeline Follow-Back questionnaire (https://www.smashlabs.org/timeline22) to 
obtain a quantitative estimate of substance use in the month prior to surgery.  
Timeline Follow-Back is a commonly used, validated tool in behavioral research; it 
is a calendar based method of collecting self-reported use of illicit substances.23 
We will compare the pre-operative and 30-day postoperative participant responses 


 
 
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to the above instruments to assess differences between the +BUP and –BUP 
groups. On the day of surgery, we will also administer the clinical opioid withdrawal 
scale (COWS) to detect opioid withdrawal. 
Measures for Aim 4 (Opioid Dispensing) 
For our assessments on outpatient opioid utilization during the 30 days following 
surgery, we will review each participant’s Maine Prescription Awareness Tool 
(MainePAT). MainePAT is part of the monitoring program that tracks all schedule II-
V medications prescribed in Maine, Massachusetts and Rhode Island. Using this 
resource, we will collect data on the number of opioid agonist prescriptions filled 
and the total amounts of opioids (in MME) dispensed. Buprenorphine formulations 
will not be included in our MME totals.  
Subject Selection 
Inclusion Criteria: Male or female; aged 18-75 years; American Society of 
Anesthesia (ASA) health class I-III; currently taking buprenorphine formulations 
equivalent to 12mg or greater for at least the prior 30 days for treatment of OUD (as 
defined by the Diagnostic and Statistical Manual of Mental Disorders- 5 (DSM-V) 
criteria); scheduled for surgery at MMC or SSC where a procedure with a greater 
than 4/10 intensity is expected on POD 1 (see Gerbershagen et.al. and appendix 1 
for list of surgeries).  
Exclusion Criteria: Unable to consent to the study; currently pregnant; current major 
medical illness that could limit the ability to utilize medications within our protocol 
driven multimodal analgesic plan (e.g. cancer, severe end-stage organ disease, or 
dementia).  
Inclusion of women and minorities. We will not exclude any adults on the basis of 
age, gender or ethnicity and our projected enrollment is based on most recent 
Maine census. See appendix 2 for projected enrollment table. 
Inclusion of individuals across the lifespan. We will exclude individuals under the 
age of 18 years from enrollment in this trial. These patients require personalized 
treatment strategies often coordinated by multiple providers therefore we will not 
alter these treatments decisions for study purposes.  


 
 
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Source of subjects, recruitment and retention methods: 
Participants will be recruited when they attend their pre-surgery appointment at the 
MMC Pre-Operative Readiness Education Program (PREP) clinic. Currently, the 
majority of patients scheduled for surgery receive consultation from the PREP 
Clinic, within two months prior to their procedure. Patients who are potentially 
eligible for the study will be identified by the PREP nurse practitioner or the 
physician provider who conducts the preoperative evaluation. As part of an IRB 
reviewed quality improvement project (IRBNet #15892224-1) there is a dashboard 
in Epic that identifies patients scheduled for surgery who are on buprenorphine. 
Study staff will review this dashboard to identify potential candidates for this study. 
The standard practice at MMC is when a patient is identified taking 
buprenorphine/naloxone through the preoperative chart review, the patient is 
referred to an anesthesiologist for instructions on the management of 
buprenorphine/naloxone prior to surgery. Our recruitment method for study 
participants, therefore, does not differ from this current established practice.  A 
member of study staff will then contact patients by calling the number obtained from 
the Epic Dashboard. We will introduce the study, and any patient who is interested 
in learning more about the study and potentially participating will have a consent 
form sent to them. The informed consent form will be provided electronically, or by 
mail, for the patient to review.  If patient requests the consent be mailed, a follow up 
phone call will be scheduled. During this phone call, further questions will be 
answered. Because consent needs to be given prior to day of surgery in order to 
randomize patients for this trial, we will use Docusign to obtain consent 
electronically for patients who would like to participate in the trial.   
Patients who choose to participate in the study will receive a phone call within one 
week prior to their surgery to confirm the buprenorphine management plan that 
they were assigned (see randomization plan, above). Participant confidentiality will 
be maintained throughout the consent process.   
Participants will be reminded that their involvement in the study is completely 
voluntary and that they can choose to withdraw from the study at any point. They 
will also be advised that withdrawing from the study would not affect the care they 


 
 
Page 16 of 28 
receive at MMC. All conversations about their history of OUD and the medications 
they are taking for treatment will be kept confidential and participating in this study 
would not cause any additional exposure to their health history outside of standard 
of care. 
To retain participants in this study, they will be reimbursed $10 for each combined 
postoperative pain and opioid consumption assessment at POD 0, 1, and 2, and 
$60 for completion of the one-month follow-up virtual session. The maximum 
compensation for participating in this study is $90 in the form of a reloadable 
reimbursement card. The appropriate amounts will be loaded at each milestone 
encounter. 
Safety 
We will ensure that appropriate plans are in place to guarantee the safety of 
enrolled subjects. All patients will be made aware of the possible risks associated 
with treatment group to which they are randomly assigned, as well as the risks 
inherent in experiencing postoperative pain.  For instance, both groups are at risk 
of experiencing OUD symptom exacerbation. The use of opioid agonists and 
perioperative pain itself may be risks for OUD symptom exacerbation and relapse. 
Reduction of buprenorphine to 8 mg before surgery as well as full dose 
buprenorphine continuation can potentially lead to OUD relapse since exposing 
patients to opioids with similar properties to the agents they abused in the past as 
management of their acute post-surgical pain can serve as a trigger for relapse. 
However, this risk is inherent in the current MMC standard of care. 
Another potential risk is difficult post-operative pain control due to buprenorphine 
continuation since the pharmacokinetics of buprenorphine may interfere with the 
effectiveness of full opioid agonists used for pain control. However, this risk is not 
greater than the current risk to patients, since full dose buprenorphine continuation 
is a practice endorsed by SAMHSA. If patients experience poorly controlled pain, 
they will receive opioid and non-opioid rescue analgesic agents such as nerve 
blocks or epidurals when indicated, ketamine infusions, and alpha agonist 
medications, as determined necessary by the treatment providers caring for the 


 
 
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patient. All participants will be transitioned back to their regular dose of 
buprenorphine when postoperative surgical pain has subsided as determined by 
their buprenorphine provider following hospital discharge. This transition will be 
coordinated with their buprenorphine provider, which is our current standard 
practice when buprenorphine is discontinued, or the dose is reduced, 
perioperatively.  
 
Data Integrity and Privacy Protection 
Our study will use a data safety monitoring board (DMSB) that will be scheduled to 
meet once the study reaches 50% enrollment and in response to any adverse 
event. The DSMB will review the progress of the study, monitor data, identify any 
inconsistencies or errors in data collection, and review patient safety.  Any errors in 
data collection that are identified will be reconciled immediately to ensure the 
validity of our findings. The DSMB will also ensure that this study will not continue 
to enroll patients if one treatment modality shows early and significant superiority. 
Below is a table of major and minor adverse outcomes (AEs) that will be reported to 
the DSMB during the study period and the actions that will be taken.  Any 
unanticipated adverse events will be reported within 7 days. For patients who 
experience AEs related to substance use in the outpatient setting, Dr. Silvia will 
provide patients with information regarding community resources available to 
patients- such as support groups and harm reduction resources. Study staff will 
contact the patient’s buprenorphine provider on record, as well.  
 
 


 
 
Page 18 of 28 
 
Table 1: Major and Minor Adverse Events 
 
Item 
Action  
Regulatory 
Reporting 
Major 
AE  
1. ED admission due to 
severe pain 
2. Intractable Pain 
Alert acute pain 
service (APMS) for 
management 
recommendations 
 
Immediate to 
DSMB; Within 
7 days to IRB 
3. Opioid 
misuse/relapse 
4. Opioid overdose 
5. Opioid Withdrawal 
Alert buprenorphine 
provider on record 
immediately; provide 
patients with 
community 
resources to seek 
help as needed  
Minor 
AE 
1. Hospital discharge 
delay due to poor pain 
control 
2. Pain worse than 
anticipated 
3. Cravings 
Alert integrated 
medication 
assistance treatment 
(iMAT) team and 
APMS as needed 
Within 30 days 
of event to 
DSMB; DSMB 
reports to IRB 
within 7 days 
 
The DSMB will determine study stop rules; however, we will recommend to them 
that when 10 patients have been enrolled in each group (25% enrollment), if >7 in 
either group have intractable pain interfering with hospital discharge or opioid 
overdose within 2 weeks of discharge, the study should be terminated. The DSMB 
members are Dr. Galina Korsunsky (Dept. of Anesthesiology); Dr. Issac 
Chemmanam (Dept. of Anesthesiology); Amy McAuliffe, NP (Psychiatric Nurse 


 
 
Page 19 of 28 
Practitioner); Maya Bulman, MD (Inpatient Psychiatry Consultation-Liaison Team) ; 
Christine Lary, PhD (Senior Biostatistician, MMCRI/CORE); and Dr. Marc Kimball 
(Family Medicine, Maine Medical Partners, graduate of MMC Addiction Medicine 
Fellowship). David Gagnon, PharmD (Faculty Scientist, Critical Care Pharmacy) will 
be the medical monitor for this study. 
All phases of this study will comply with Health Insurance Portability and 
Accountability Act (HIPAA) regulations. Data will be collected and stored in a 
REDCap database to preserve privacy and confidentiality. The 30-Day Timeline 
Followback will be completed on Timeline, a website 
(https://www.smashlabs.org/timeline) developed and supported by Brown 
University.22 Please also refer to the PDF copies of this data collection tool included 
in the IRBNet package. The responses on the Timeline website will be identified by 
study numbers only, no PHI will be collected or stored on this site. Information 
regarding substance abuse history, including illicit narcotic use, will remain 
confidential and personal identifiers will be removed during data storage. Only 
members of the research team will have access to the data that participants have 
consented to provide. Participants will be informed that they have the right to not 
answer any question that makes them feel uncomfortable. 
 
Biostatistical Analysis 
Sample Size:  
We estimated study size based on postoperative pain scores in a recent study of 
surgical patients at our institution (manuscript submitted); mean NRS was 50±28. 
Our estimate for effect size is based on published data showing that a difference in 
NRS of 20/100 points is clinically significant.24  A sample size of 32 per group will 
have 80% power to detect a difference in means of 20 (the difference between a 
Group 1 mean, m1, of 50 and a Group 2 mean, m 2, of 30) assuming the common 
standard deviation is 28 using a two group t-test with a 0.05 significance level.  To 
account for dropout, we will enroll an additional 8 patients for each group for a total 
sample size of 80 patients.  


 
 
Page 20 of 28 
Statistical Analysis:  
Data will be summarized using descriptive statistics and will be presented as 
means (SD), medians [IQR] or frequency counts (%), as appropriate. Data will be 
analyzed on an intention to treat basis.  We will first examine the success of 
randomization by comparing covariates demographic and clinical covariate 
measurements between the FULL-BUP and STD-BUP groups; to conserve study 
power, no formal statistical comparison will be performed and the data will be 
reviewed visually.  Next we will perform univariate analyses to compare outcome 
measures between the FULL-BUP and STD-BUP groups, using a two-sided t-test 
or Mann Whitney U test for continuous variables and chi square or Fisher exact 
tests for categorical data, as appropriate.  For paired analysis of pre/post surgery 
instruments, we will use McNemar’s test or the Wilcoxon test, as appropriate.  We 
will then explore the relationships between demographic and clinical variables and 
outcome measures in bivariate analyses, using the above methods or Pearson’s 
and/or Spearman’s correlation, ANOVA or Kruskal-Wallis test, as appropriate.  
Finally, we will explore further any observed differences in outcome measures 
between study arms by adjusting for covariates using analysis of covariance or (in 
the event of missing data), mixed models regression.  Covariates will be entered 
into the model if they demonstrate a significant (p≤0.1) association with outcome 
measures in bivariate analyses. 
We will perform an interim analysis at 50% enrollment and will terminate the study if 
a significant pain score difference is detected. Significance for the interim analysis 
will be accepted at p<0.003, based on 2 sequential tests and using an O’Brien-
Fleming spending function to determine test boundaries. Significance overall will be 
accepted at p<0.047 to account for interim analysis. All statistical analyses will be 
performed by the Navigation team at CORE using SPSS Statistical Software 
version 27 (IBM SPSS Inc., Armonk, NY). 
 
Study Team 
Our team consists of providers from the departments of Anesthesia, Perioperative 
Pain Medicine, and Addiction psychiatry. We also include researchers with a strong 


 
 
Page 21 of 28 
history of completing clinical trials successfully, utilizing the resources available at 
MMC. We are uniquely suited for executing this study because we are directly 
responsible for providing care for patients with Opioid Use Disorder as well as 
those experiencing complex acute pain conditions. Aurora Quaye, MD Principal 
Investigator, is a board-certified Anesthesiologist with expertise in Regional 
Anesthesia and Acute Pain Management. She currently leads the MaineHealth 
perioperative opioid task force, which manages the acute pain guidelines for 
patients with history of OUD. Her responsibilities also include directly educating 
providers on current best practice procedures for treating pain in opioid tolerant 
patients. Dr. Quaye will be responsible for IRB preparation, study design, 
implementation, and dissemination of the research plan, coordination of data 
collection, data management, data analysis and overseeing manuscript 
preparation. 
Kristen Silvia MD is co-Investigator and Director of the Division of Addiction 
Medicine at Maine Medical Center. Dr. Silvia chairs the MMC Substance Use 
Disorder steering committee and is a member of the Opioid Clinical Advisory 
Committee.  These committees, respectively, review the institutional and 
community resources available to individuals with OUD, while identifying barriers 
related to care delivery. Dr. Silvia’s strong connections to both the OUD patient and 
provider communities, as well as her extensive expertise in treating patients on 
buprenorphine, will help support patient recruitment and retention, while ensuring 
this study reflects the needs of this patient group.  
Dave Warters MD, FASA is chair of the Department of Anesthesia and 
Perioperative Pain Medicine at Maine Medical Center. Dr. Warters has an extensive 
career in academic medicine, engaging in and supporting clinical research trials. As 
co-investigator and department leader, Dr. Warters will ensure staff and space 
resource support, department and institutional adherence to protocol driven 
management plans, and administrative oversight. He will act as a mentor to Dr. 
Quaye and also assist with data interpretation and manuscript preparation. 


 
 
Page 22 of 28 
Wendy Craig, PhD is a Research Navigator for MaineHealth and Assistant 
Research Professor at Tufts University. As co-collaborator, Dr Craig will provide her 
extensive expertise in clinical research to ensure successful study completion, 
while providing mentoring to Dr. Quaye. She will assist with study design, data 
analysis- including conducting the statistical analyses- reviewing data integrity and 
manuscript preparation.  
Janelle Richard, BA and Yussr Ibrahim, MD will serve as study staff for this trial. 
They will create the data capture platform, will be involved in implementation of the 
research plan, including obtaining consent, administering study instruments both 
virtually and in-person, data collection, and manuscript preparation.  
Limitations 
A study limitation is that pain scores, craving scales, and drug use are all self-
reported measures, therefore complete accuracy cannot be assured. However, our 
randomization design should help prevent the introduction of bias, as inaccuracies 
based on self-report subjectivity would be randomly distributed between the two 
treatment arms. To encourage accurate drug-use reporting, we will remind 
participants that information they provide regarding drug use will not be included in 
their patient record, nor will their providers have access to the information.  Another 
limitation is that our study does not have a placebo arm, however, since 
randomization occurs prior to hospital admission and physical interaction with study 
staff, it is impractical to provide patients with placebo medication at the time of 
study commencement.  An additional limitation is that the study is not blinded to 
patients or treatment providers, however, we attempt to mitigate this limitation by 
masking the data collection and data entry, as described in the study design and 
research procedures section.  
 
Study Timeline and Future Plan 
We anticipate it will take 11 months to complete the subject recruitment for this trial. 
Data collection will begin at month 2 of the funding period and will be completed by 
month 12. Data analysis will begin at month 6 of the funding period and will be 
completed by month 12.  


 
 
Page 23 of 28 
The findings obtained from this study will provide the framework for investigating 
strategies to improve postoperative treatment retention and relapse. The 
perioperative period can be highly stressful and providing patients with analgesic 
medications abused in the past can be a strong trigger for relapse. We anticipate 
our research findings will help us identify the major points to focus on in future 
investigations identifying ways to reduce postoperative OUD symptom severity.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL SCHEMA  
 


 
 
Page 24 of 28 
 
 
 
 
 
 
 
 
 
 


 
 
Page 25 of 28 
APPENDIX 1 
 
Surgical inclusion criteria for elective procedures with greater than 4/10 average pain intensity on 
postoperative day (POD) 1 
 
 
MODERATE PAIN SCORE (4-6/10 POD1) 
Closed reduction internal fixation-upper and 
lower extremity procedures 
Arthroscopic upper and lower extremity joint 
procedures (i.e. shoulder arthroscopy) 
Clavicle repair/reconstruction  
Hip joint replacement 
Amputation above and below the knee 
Laminectomy 
Spinal canal decompression 
Laparoscopic abdominal surgical procedures 
including: 
   Appendectomy 
   Cholecystectomy 
   Bowel resection 
   Lysis of adhesions- bowel obstruction 
   Gastrectomy 
   Nissen Fundoplication 
Hernia repair (ventral, inguinal and femoral) 
Resections involving the rectum 
Thyroidectomy 
Nephrectomy (laparoscopic) 
Hysterectomy (vaginal) 
Laparoscopic gynecologic procedures 
including: 
   Myomectomy 
   Hysterectomy 
   Oophorectomy 
   Endometriosis excision  
Kidney transplantation (laparoscopic) 
Cystectomy 
Prostatectomy 
Orchidectomy 
Femoral and popliteal bypass graft 
procedures 
Sternotomy procedures 
Thorascopic procedures (i.e. lung wedge 
resection) 
Breast reconstruction 
Surgical reconstruction nasal septum 
 
 
SEVERE PAIN SCORE (>6/10 POD1) 
Open Reduction Internal Fixation- upper and 
lower extremity procedures 
Shoulder replacement  
Knee joint replacement 
Open and arthroscopic foot procedures 
Arthrodesis- foot and phalangeal joints 
Complex spinal reconstruction, (i.e. scoliosis 
repair) 
Spinal fusion  
Open gynecologic procedures including: 
   Myomectomy 
   Hysterectomy 
Open abdominal procedures including: 
   Pancreatectomy 
   Proctocolectomy 
   Splenectomy 
   Liver resection 
   Bowel resection 
Laparoscopic procedures converted to open 
Nephrectomy (open) 
Open thoracotomy procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Removal, reconstruction teeth 
 
 
Adapted from: 
Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day 
after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology. 2013 Apr;118(4):934-44  


 
 
Page 26 of 28 
Appendix 2 
Planned Enrollment Table 
 
Racial 
Categories 
Ethnic Categories 
# of Not Hispanic or 
Latino 
# of Hispanic or 
Latino 
Total # 
Female 
Male 
Female 
Male 
 
American 
Indian/Alaska 
Native 
1 
1 
0 
0 
2 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
35 
35 
1 
1 
72 
More than One 
Race 
1 
1 
 
 
2 
Total 
39 
39 
1 
1 
80 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 27 of 28 
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