A Prospective, Randomized Trial Evaluating Regional Anesthesia, Long-Acting Local Anesthesia, and Traditional Care for Pain Control of Operatively Treated Ankle Fractures
Phase: PHASE4
Conditions: Ankle Fractures
Sponsor: Lahey Clinic

H00014155 
2018-06-01 
 
Official Title: 
A Prospective, Randomized Trial Evaluating Regional Anesthesia, Long-Acting Local 
Anesthesia, and Traditional Care for Pain Control of Operatively Treated Ankle 
Fractures 
 
 
NCT Number: 
 
 
Date of the Document: 
June 01, 2018 
 
 

H00014155 
2018-06-01 
 
1. Title 
A Prospective, Randomized Trial Evaluating Regional Anesthesia, Long-Acting Local Anesthesia, and 
Traditional Care for Pain Control of Operatively Treated Ankle Fractures 
 
2. External IRB Review History 
N/A  
 
3. Prior Approvals  
N/A 
 
4. Objectives 
This study is a multicenter, three armed, prospective randomized control trial studying the effect of a 
long-acting local anesthetic “cocktail” in patients undergoing operative fixation of ankle fractures. 
 
Primary Hypothesis Driven Aims: 
1. Determine the effectiveness of a local anesthesia “cocktail” compared to regional block or 
standard of care in controlling pain in operatively treated ankle fractures. Nearly one out of ten 
fractures treated by both orthopaedic traumatologists and general orthopaedic surgeons taking call 
are ankle fractures.  As such, effective pain control in this group of patients represents an 
opportunity to make a large impact, especially in the context of the current opioid epidemic.  
Improved pain control can help improve patient satisfaction, outcomes, decrease length of stay, cost 
of care, and complications associated with traditional narcotic use. 
• 
Hypothesis 1A: Patients receiving the intraoperative cocktail will have improved post-
operative pain control compared to those receiving a peri-operative nerve block or 
standard of care. 
• 
Hypothesis 1B: Patients receiving the intraoperative cocktail or peri-operative nerve block 
will have improved post-operative pain control when compared to standard of care. 
• 
Null Hypothesis 1: There will be no difference in post-operative pain control between all 
treatment arms. 
2. Determine the economic impact of cocktail and regional blocks in ankle fractures. A common 
concern with the use of regional blocks is the cost of the additional procedure, along with logistic 
delays which are associated with coordinating a separate procedure. This study would provide 
valuable data about the additional costs associated with regional blocks and with cocktail 
administration which could help aid in making economically conscious treatment decisions. 
• 
Hypothesis 2: Local cocktail administration will have significantly lower costs than regional 
block, and not be significantly more expensive than standard of care. 
• 
Null Hypothesis 2:  There is no difference in cost between the modalities. 
 
 
Secondary Aim: 

H00014155 
2018-06-01 
 
Demonstrate the use of long-acting local anesthetic as a viable pain management strategy in 
fracture surgery. Although long-acting local anesthetics have an established track record in 
arthroplasty1-4, there is a paucity of evidence guiding their use in fractures. Small case series in 
trauma5 and foot/ankle patients6 have been encouraging, but a rigorously conducted, prospective 
trial in a relatively homogeneous group could generate pilot data to validate the use of long acting 
local anesthetics in fracture surgery. This knowledge may be translatable to other extremity injuries 
as well, having a greater impact than the scope of the proposed trial. 
 
5. Background 
Pain control after fixation of ankle fractures can improve patient satisfaction7. There has been growing 
interest in both multimodal pain control as well as in regional anesthesia8 for improving pain control 
above traditional methods, which typically rely on opiates.  High dose opiate use is associated with a 
multitude of complications, including respiratory depression, constipation, endocrine dysfunction, and 
complications associated with addiction/abuse9-11.  Given the current focus on opiate overuse and 
abuse12,13, it is imperative that we decrease the use of these medications whenever possible. 
 
For operatively treated ankle fractures, the choice of pain management is challenging. Regional 
anesthesia (usually in the form of a popliteal and saphenous nerve block) has been shown to be safe and 
have improved pain control compared to traditional treatment14, but has several drawbacks. Major 
concerns include the inability to monitor for nerve injury or compartment syndrome15,16, post-operative 
“rebound pain”17-19, the time and logistic issues involved in coordinating block placement, as well as the 
cost associated with an additional procedure. 
 
Intra-operative injection of local anesthetic avoids many of the problems associated with block, but has 
the potential drawback of limited duration of action, as well as the theoretical issue of increasing edema 
and swelling in the operative area where wound healing may be a concern. There also has recently been 
increased interest in the use of long acting local anesthetic agents, which has been successful in joint 
arthroplasty1-4, but has remained limited to small case reports in the fields of trauma5 and foot/ankle 
surgery6.  Although there was initially enthusiasm for commercially prepared liposomal bupivacaine and 
other long-acting formulations, recent data has questioned their cost effectiveness compared to 
relatively inexpensive “cocktails” of multimodal pain control medications20-23. 
 
Currently there exists little evidence to support the use of either peri-operative regional anesthestic or 
local anesthetic cocktail versus standard of care narcotic regimen.  The primary aim of this study is to 
conduct a prospective, randomized control trial comparing standard pain control methods to both 
perioperative block and local “cocktail” anesthesia in terms of post-operative pain control, narcotic 
requirements, patient satisfaction, and cost. We hypothesize that local cocktail will be superior with 
regards to pain control when compared to both regional block and standard of care, have significantly 
lower overall costs, and represent the most cost-effective means of pain control in this patient 
population.  Our null hypothesis is that there is no difference between any of the methods and the 
measured outcomes. 
 
Both primary investigators have experience in the conduction of prospective trials involving patient 
satisfaction, outcome, and substance use.  Eric Swart has prior research expertise in economic analysis 
and cost-effectiveness analysis, and experience in the development of multidisciplinary care pathways 
and protocols.   Both PIs have also been involved in the direct creation of pain control protocols for the 

H00014155 
2018-06-01 
 
purpose of improving patient care at their respective institutions via local, regional, and multi-modal 
therapies for pain control. 
 
Both PIs are also currently the recipients of an OTA Directed Topic Grant entitled: Does the use of 
Liposomal Bupivacaine Decrease Narcotic Requirements in Geriatric Hip Fractures? A Randomized, 
Double Blinded Control Trial. This study is evaluating the effect of intra-operatively locally administered 
liposomal bupivacaine in geriatric hip fracture patients.  Experience gained from this trial will help in 
successful completion of a pain control trial in ankle fractures. 
 
General anesthesia with opiate monotherapy, regional anesthesia, and local anesthesia are all practiced 
as standard of care at this institution. We do not have formal data on utilization, but approximately 40% 
of patients get general anesthesia only, 40% of patients get regional anesthesia, and 20% get local 
anesthetic for post-operative pain control. In the trauma group, the local anesthesia has historically been 
a single agent (bupivacaine or ropivacaine), although the “cocktail” is routinely used in arthroplasty 
services nationwide.3,22-25 
 
6. Inclusion and Exclusion Criteria 
Inclusion Criteria 
• 
Age 18 – 89 
• 
Sustained a bimalleolar ankle fracture (OTA/AO type 44 A2, B2, C1, and C2 fracture) with surgery 
indicated and an approach with medial and lateral incisions planned  
o Syndesmotic injuries will be included, due to the practical difficulty of reliably determining the 
presence of a syndesmotic injury preoperatively 
o Trimalleolar ankle fractures where fixation of the posterior malleolus is not planned will also 
be included 
• 
Isolated Injury 
 
Exclusion Criteria 
• 
Unifocal malleolar fractures 
• 
Bimalleolar fractures where fixation of only one malleolus is planned 
• 
Posterior malleolus fractures requiring fixation 
• 
Patients ineligible for a peripheral nerve block (e.g. concern for compartment syndrome) 
• 
Open injury 
• 
Patients treated with external fixation 
• 
Neurologic condition that would confound results (e.g. peripheral neuropathy) 
• 
Inability to consent 
• 
Chronic opioid use 
• 
History of opiate abuse 
• 
Polytrauma as defined as additional boney injury, visceral injury or moderate soft tissue injury 
(requiring suture repair or other invasive procedure)  
• 
Prisoners (unlikely to be accessible for follow-up) 
• 
Pregnant patients 
• 
Non-English-speaking subjects (post-operative data collection procedure involves conversations via 
phone calls. As we do not have access to translators for this research project, we will work exclusively 
with English-speaking subjects). 

H00014155 
2018-06-01 
 
• 
Subjects unable to take the standard post-operative pain regimen that consists of gabapentin, 
oxycodone, acetaminophen, and ibuprofen. 
 
7. Study-Wide Number of Subjects 
This is a multi-center study being conducted in conjunction with the University of Kentucky. The total 
recruitment goal is 70 patients, with a goal enrollment of 35 patients at University of Massachusetts, and 
35 patients at University of Kentucky.  
 
Recent studies looking at long acting local anesthesia arthroplasty patients or blocks in ankle fracture 
patients have showed a reduction in opiate use ranging from 50%-66%19,25. Within an individual patient 
group, variability in narcotic use has typically had standard deviations around 12.5% - 50% of the total 
dose18,19. Conservatively, to detect a 45% reduction in narcotics with a standard deviation of 50% of the 
total dose, with 80% power, 20 patients would be needed in each cohort. Allowing for a 10-20% drop-out 
rate gives a total of 70 patients. 
 
8. Study-Wide Recruitment Methods 
Recruitment methods will be the same at both University of Massachusetts and University of Kentucky. 
Refer to 24. Local Recruitment Methods for details of recruitment methods at University of 
Massachusetts. 
 
9. Study Timelines 
• Duration of an individual subject’s participation in the study 
An individual subject’s participation in the study begins at enrollment and ends after 12 weeks post-op 
follow-up period.  
• Duration anticipated to enroll all subjects 
From recent internal data review, we treat between 140 ankle fractures annually at UMMMC. We 
anticipate 30-50% of patients will be both eligible and willing to enroll in the study, so to enroll 35 
patients should take 6-12 months. 
• Estimated date for the investigators to complete this study (complete primary analyses) 
Primary analysis should be completed once the final cohort of patients complete their 12-week study 
window, so we expect 13-14 months after initiation of enrollment. 
 
10. Study Endpoints 
• 
Primary Outcome Variables: total morphine equivalents given within 72 hours of surgery 
• 
Secondary Outcome Variables:  pain VAS (2, 4, 8, 12, 18, 24, 48, and 72 hours after surgery), QOR-9 
score (24, 48, and 72 hours after surgery) and need for pain medication refill 
 
 

H00014155 
2018-06-01 
 
11. Procedures Involved 
• 
Patient identification: Patients will be identified on morning intake rounds by the trauma team and 
the research staff who are present daily to screen and enroll patients. 
• 
Screening/Enrollment: The research staff will review the charts to identify patients meeting the 
inclusion/exclusion criteria. Patients will be approached for study participation and enrolled in the 
study prior to surgery. For patients seen initially in the outpatient setting, this will be done at the time 
of their office visit where a surgical plan is made and discussed with the patient. For patients admitted 
to the hospital acutely for fixation, this will be done on the inpatient floor or in the preoperative area. 
o  For potential participants, the research staff will interview the patients, confirm willingness    
to participate and inclusion/criteria. 
□ At time of enrollment, preoperative demographics will be recorded which will include 
age, sex, comorbidities, current use of anti-epileptic/anti-depressive medications, 
fracture classification (using AO/OTA classification system). 
□ After this review and screening, the patient will be given the opportunity to ask 
researchers questions about the study. It will be reiterated to all patients during 
preoperative discussions that their enrollment status in no way will affect their ability 
to get adequate post-operative pain control. 
• 
Randomization: Once enrolled, participants will undergo block randomization (block size: 9) to one of 
three treatments through a computer-generated algorithm.  Participants will be randomized to 
receive patients will be randomized to receive 1) standard of care post-operative pain control with 
oral narcotics, 2) single injection perioperative peripheral nerve block, or 3) subcutaneous local 
cocktail injection at the conclusion of surgery. 
• 
Treatment: Surgical approach and fixation will be performed according to the attending surgeon and 
is independent of the study.  
o Anesthesia: Patients in all arms will receive general anesthesia 
□ Block: 
▪ 
0.5% ropivicaine -  30mL each sciatic and femoral/saphenous nerve 
▪ 
Ultrasound guided 
□ Although there is some data supporting the use of continuous nerve catheters over 
a single injection block18,19, we are using only a single injection nerve block as that 
is currently the more common procedure at our institutions and the more relevant 
comparison given our institutional infrastructure. Future projects could evaluate 
the cost and efficacy of long-acting local vs. indwelling perineural catheter based 
on the results of this study. 
o Cocktail mix / administration: For patients randomized to the cocktail group, the local 
anesthetic solution will be prepared by the pharmacy and delivered to the operating room 
at the conclusion of surgery and will be injected circumferentially around the incisions into 
the surrounding musculature, periosteum and subcutaneous layer in a standardized fashion. 
The cocktail mix/technique is based on published reports of solutions with demonstrated 
efficacy in the total joint arthroplasty literature3,23,25, although ketorolac has been removed 
due to theoretical concerns of the interaction between NSAIDs and fracture healing. It 
consists of: 
□ 0.5% Ropivicaine, 24.6 mL 
□ Clonidine 100 mcg/mL, 0.4mL 
□ Epinephrine 1mg/mL, 0.5mL 

H00014155 
2018-06-01 
 
□ Saline to total volume of 50 mL (24.5mL of saline) 
The total amount of solution prepared is 50mL, but typically 30mL is used based on the size 
of the incision. Additionally, total volume administered will be recorded. 
• 
Post-operative inpatient care: While admitted to the hospital, patients will receive medical 
care per routine, including a standardized post-operative pain control regimen. Post-
operatively, all patients will receive a uniform pain control protocol consistent with the 
current standard of care. We have worked with our anesthesia team to create a consensus-
driven protocol to ensure patients are evaluated for pain and having pain treated in an 
appropriate and uniform manner. Patients will be given 30mg of Toradol IV at the end of case. 
All patients will receive the same post-operative pain regimen and oral regimen consisting of 
gabapentin, oxycodone, acetaminophen, and ibuprofen that is consistent with the standard 
of care. Patients will be given a detailed instruction that outlines their pain regimen: “Ankle 
Fx Pain Control_H00014155_Pain Control Handout_06-01-18.” Protocol deviations will be 
recorded, and morphine equivalents will be recorded. We will collect the following data from 
inpatient hospitalization: 
o At the conclusion of the surgery, we will note tourniquet time, incision locations, fixation 
locations, and whether or not syndesmosis fixation was performed. 
▪ 
The medical record will be used to determine total morphine equivalents post-surgery, 
including recovery unit administration of narcotics in the immediate post-operative period. 
o It will also contain Pain Visual Analog Scale (VAS) scores administered by the nursing staff, 2 
hours after surgery. 
▪ 
Prior to discharge from the hospital, patients will be given a “Pain Journal” to document their 
narcotic use and VAS pain scores, and asked to fill it out any time they take pain medication. 
Once patients are discharged from the hospital, with the aim of gathering data about the 
timing of  “rebound pain” which has been reported after blocks and typically starts around 
8-24 hours after surgery17. 
o The patients will receive phone calls at 24, 48, and 72 hours after surgery. The phone calls 
will be administered by the research assistant. In the cases of emergency such that the 
patient requires further care on an urgent basis, corresponding medical representatives (e.g. 
resident on call) will be reached, and the patient will be treated based on standard of care, 
as a part separate from the study. Total narcotic use recorded in the pain journal as well as 
VAS pain scores will be reviewed. We will also administer the Quality of Recovery 9 (QOR-9) 
questionnaire. The QOR-9 is a 9- item questionnaire that assesses the general wellbeing of 
post-operative patients. It has been validated in large cohorts of surgical patients26, and 
specifically used in studies evaluating recovery from ankle fracture surgery as well14. 
• 
Post-Operative Rehabilitation: Post-operatively, patients will be immobilized in a short leg cast or 
splint for two weeks, until their first post-operative visit at 2-weeks where sutures will be removed. 
Weight bearing restrictions and DVT prophylaxis will be determined at the discretion of the treating 
surgeon. 
• 
Post-hospital follow-up: Post-operatively, patients will be seen in clinic 2, 6, and 12 weeks after 
surgery. At each of these time points, wound healing and/or complications will be noted.  
• 
Analysis:   The primary outcome will be assessed using a non-parametric Mann-Whitney test using a 
Bonferroni correction for multiple comparisons. Secondary outcomes will be compared using a 
Wilcoxon Signed-rank test, and Chi-Square for comparison of group characteristics.  
• 
Economic Analysis: In efforts to address aim 2, after the conclusion of the study, a cost analysis will 
be performed using the billing data.  Specific cost items measured will be procedural fees associated 

H00014155 
2018-06-01 
 
with blocks, cost of pain medication consumed (in all cohorts, including medications used in cocktail 
and in the block). We will also note length of stay (time from conclusion of surgery to discharge from 
hospital) as well as discharge disposition. Additional operative time due to application of local 
injection will not be quantified/analyzed for cost as it is a fixed-variable cost unlikely to change the 
global fees associated with operative fracture care.  Implant costs will not be measured. 
 
12. Data and Specimen Banking 
No specimens will be obtained or retained for future study. The stored deidentified data from the study 
will be kept for a minimum of 6 years for records in the event follow-up studies are pursued and will 
remain protected and encrypted. Data will be permanently deleted following this time period. The banked 
data will be stored on a password-protected research drive corresponding to “orthotrauma 
(\\ummhcnas03)”. Upon conclusion of the study, the data will be stored in a password encrypted file that 
only the PI has access to. 
 
13. Data Analysis and Management 
Following initial enrollment, each patient will be assigned a unique patient identifier. All electronic 
documentation containing total morphine equivalents, visual analogue scores and all other medical 
information will be associated with this unique patient identifier during analysis. All protected health 
information will be stored in a separate, password-protected research file that will not be accessed 
regularly. Following our secondary analysis, all personal health information will be removed from our 
electronic files and destroyed in accordance with patient privacy guidelines. 
 
Data obtained at UMMMC during the study will be recorded and stored using excel spreadsheet that will 
be maintained at the hospital by the research staff. The University of Kentucky will be responsible for their 
own data infrastructure. Upon conclusion of the study, the University of Kentucky will share de-identified 
data (with information relating to the study endpoints) with the University of Massachusetts for final 
analysis. Final analysis will be conducted using Excel spreadsheets. All documents will be stored on a 
password-protected research drive and only research personnel will have access to its content.  Paper 
documents, including consent forms, will be stored in a locked cabinet in a secure research room. 
 
Each researcher on the project has passed the CITI exam on ethical conduct of research and has received 
training and supervision regarding patient confidentiality.  Only approved research personnel will 
administer consents and perform phone surveys. All efforts will be made to maintain the confidentiality 
of the patient reported data. Only study personnel listed in eIRB will have access to identified study data.  
 
Consistent with other research projects through the UMass Orthopedic Trauma Center, all other research-
related files including but not limited to copies of consents and surveys will be stored on a password 
protected research drive or locked research cabinet. Research personnel also have allocated space with 
locked drawers for source document files and secure workspace apart from patient or public areas that is 
also locked. 
 
14. Provisions to Monitor the Data to Ensure the Safety of Subjects 
Subjects in this study will be exposed to minimal risk as all three treatment arms are considered standard 
postsurgical care.  The patients are monitored continuously as inpatients post-operatively and any issues 

H00014155 
2018-06-01 
 
with medication effects, wound healing, or other medical complications will be logged as adverse events. 
Blinding will only be broken for unexpected complications. The research team will meet monthly to 
monitor data collection and handling.  During this time, study staff will also review adverse events logs 
and pain scores. 
 
15. Withdrawal of Subjects Without Their Consent 
We do not anticipate any situation in which a subject would be withdrawn from the study by the 
researchers should they wish to remain.  We anticipate analyzing the data via an intention to treat analysis 
and thus would include data from all subjects initially enrolled, even if they developed an intolerance or 
medical contraindication to continuing the study. 
 
However, a subject may choose to withdraw from the study on their own accord, at any time, for any 
reason. Contact information and instructions detailing how to withdraw from the study will be provided 
in the consent form and will involve contacting the principal investigator directly. If a subject chooses to 
withdraw, any and all data that was previously collected will be included in the analysis; however, we will 
cease any further data collection. All personal health information collected prior to a patient’s withdrawal 
from the study will be destroyed in accordance with patient privacy laws. In addition, any paper 
documents obtained will be destroyed in accordance with standard HIPPA guidelines. Upon being notified 
of a patient’s decision to withdraw from the study, researchers will no longer contact the patient via 
phone, administer surveys, or access their medical information online.  
 
16. Risks to Subjects  
Surgical risks are described to the patient prior to surgery and are part of standard of care procedures for 
ankle fracture surgery.  There are no additional surgical risks to patients who participate in this study. 
 
The medications used post-operatively are commonly used for treatment of pain following surgery and 
carry the same risks when taking these medications for postoperative care. These represent the standard 
of care for post-operative pain control, and are already part of our existing post-operative pain control 
pathway. 
 
The treatment arms of this study involve randomization to general anesthesia (no additional pain 
control), regional anesthesia, or long acting local anesthesia cocktail. Regional blocks are routinely 
performed at this institution, and has the following risks: short-term pain at the site of block 
administration, bleeding, infection, or nerve injury. Local anesthesia administration is also routinely 
performed, and has the potential risk of additional wound complications. 
 
Although the medications given in both regional blocks and local anesthesia have cardiovascular and risk 
profiles, those risks are generally for systemic administration. When given locally, the systemic medical 
effects are effectively minimized. Our regional anesthesia team does not currently have any medical 
contraindications to performing nerve blocks (including renal or hepatic disease). Likewise, there are no 
standard medical contraindications to delivering local anesthetics to the surgical site. Nevertheless, the 
risks listed on the FDA insert of each of the individual components of the nerve block medication and 
long-acting local anesthesia cocktail are listed in the consent form. 
 

H00014155 
2018-06-01 
 
There is also a risk of a breach of confidentiality. All research team members are appropriately trained 
and understand the importance of confidentiality. 
 
17. Potential Benefits to Subjects  
The addition of local or regional anesthesia could potentially benefit patients by resulting in improved 
pain control, reduced opiate requirements, and a resultant decrease in medical complications.  
 
18. Vulnerable Populations  
Patients unable to consent for themselves will be excluded. Whenever possible, we will also discuss 
involvement in the study with the patient’s family (provided the patient gives permission for us to discuss 
with them) to ensure that the decision to participate in the study is made with appropriate consideration 
and that the entire family is comfortable with involvement. 
 
19. Multi-Site Research  
This study is being conducted in conjunction with the University of Kentucky. Both have equivalent 
recruitment goals. The two principal investigators, Eric Swart and Paul E. Matuszewski, are close 
colleagues who remain in constant communication and will maintain coordination to ensure that:  
• 
All sites have the most current version of the protocol, consent document, and HIPAA 
authorization.  
• 
All required approvals are obtained at each site (including approval by the site’s IRB of record).  
• 
All modifications are communicated to sites and approved (including approval by the site’s IRB of 
record) before the modification is implemented.  
• 
All engaged participating sites safeguard data as required by local information security policies.  
• 
All local site investigators conduct the study appropriately.  
• 
All non-compliance with the study protocol or applicable requirements is reported in accordance 
with local policy.  
• 
All sites are informed of problems, interim results, and the study closure.  
 
20. Community-Based Participatory Research  
N/A 
 
21. Sharing of Research Results with Subjects 
At the conclusion of the study, following de-identification and data analysis, results of this data collection 
may be shared with patients who have participated in this research as it becomes available, if they request 
it verbally or in writing.  This will only occur after final data analysis, if a subject inquires. 
 
22. Setting  
Research subjects will be identified, recruited and followed post-operatively as inpatients at the University 
Campus of UMass Memorial Medical Center (UMMMC). They will be followed post-discharge at the 

H00014155 
2018-06-01 
 
Ambulatory Care Center (ACC). Data analysis will primarily occur in locked, private offices at in one of two 
secure research offices located at the University Campus. 
 
23. Resources Available  
UMass Memorial is the largest health system in central Massachusetts. It consists of three separate 
campuses, Hahnemann, Memorial, and University campus. The Orthopedics Department has locations on 
all three campuses that each provide a dedicated research space, which contain computers with access 
to password-protected research drives. 
 
The Principle Investigator (PI) and the Co-Investigator will be responsible for overseeing the study and 
ensuring consistency throughout the project. The principal investigator will serve as the research 
coordinator and assist in data collection and analysis. The co-investigator of the project will serve as the 
representative of the anesthesiology team and be responsible for coordination between the 
anesthesiology team and the research team. Recruitment and consent will be performed by the PI or the 
research assistant. Each member of the research staff has passed the CITI exam on ethical conduct of 
research and have received training and supervision regarding patient confidentiality and study protocol. 
The PI will meet with all research staff periodically to review each role and ensure adequate training for 
the respective positions. Upon enrollment of each patient, the corresponding surgical team will be 
counseled concerning the details of the study and their role, prior to admitting the patient into the OR. 
 
The hospital research pharmacy has been approached about this study and a protocol is in place to ensure 
treatment occurs for the study-related portion. 
The PI and research assistant will be responsible for institutional /IRB communication as well as data 
review and assistance with follow-up patient coordination as needed. There are no anticipated adverse 
consequences associated with this study, however, the principal investigator and the research assistant 
will both be available should any unexpected medical or psychological problems arise. The research 
subjects will be provided with appropriate contact information in the consent form and will be provided 
with the PIs contact information at the time of enrollment as well.    
 
24. Local Recruitment Methods 
No formal external recruitment methods will be used for this study, as ankle fracture patients are 
universally admitted to the hospital after injury while awaiting surgery. Patients will be identified, 
screened, and approached for enrollment in the study as noted above (see 9. Study Timeline). After review 
and screening, the patient will be given the opportunity to ask researchers questions about the study. It 
will be reiterated to all patients during preoperative discussions that their enrollment status in no way 
will affect their ability to get adequate post-operative pain control. There will be no financial 
compensation in return for participation in this study. 
 
25. Local Number of Subjects  
The local recruitment goal at University of Massachusetts is 35 patients (see 7. Study-Wide 
Number of Subjects) 
 

H00014155 
2018-06-01 
 
26. Confidentiality  
As part of our design, all patient will be assigned a unique patient identifier. All patient personal 
information will be stored in a data collection excel file, only linked with that patient identifier. A master 
list that links the patient’s identifier to their medical record number and name will be maintained in a 
separate, locked file that only approved research personnel will have access to. During the data collection 
period, researchers will not directly use this master list and, instead, will draw upon information from a 
separate that contains only the patient’s unique patient identifier. 
 
All paper data collection documents are kept in locked file cabinets within locked offices that are 
accessible only to the project investigators and staff. All online databases are password protected to guard 
against unauthorized access and only approved research personnel will be granted access. 
 
27. Provisions to Protect the Privacy Interests of Subjects (HIPAA)  
All eligible subjects will identified by orthopedic trauma team and researchers during morning intake 
rounds.  After this point, only approved research personnel will have access to patients’ private health 
information. All research will be stored electronically on secure research drives or locked offices as 
described above. 
Only health information related to their orthopedic injury and surgery will be reviewed for the purposes 
of this study. Other unrelated personal health information will not be accessed or used in any way. All 
subjects will sign a HIPAA authorization form for use of any protected health information to be used for 
research purposes, as stated above. 
 
28. Compensation for Research-Related Injury  
There will be no additional compensation for research related injury as all treatments/medications are 
approved for postoperative pain management. Patients would be treated for any complications of surgery 
including non-union or fractures that may be slow to heal using approved methods by their treating 
surgeon consistent with standard of care.  The patient would be responsible for all costs associated with 
this treatment. 
 
29. Economic Burden to Subjects  
All treatment costs are within the standard of care and the expenses will be paid for by the patient and 
their health insurance. There is no additional post-operative follow-up required for this study beyond the 
surgeon’s standard follow-up routine. There will be no financial compensation in return for participation 
in this study. 
 
30. Consent Process 
We will obtain consent in accordance with the guidelines from the HRP-802 INVESTIGATOR GUIDANCE: 
Informed Consent (http://www.umassmed.edu/ccts/irb/investigator-guidance/). The consenting process 
will take place in the University Campus of UMass Memorial Medical Center (UMMMC) as previously 
described. All research personnel administering consents will be provided with copies of the above 
inclusion and exclusion criteria to apply to potential study participants. All subjects have the option to 

H00014155 
2018-06-01 
 
withdraw from the study at any time point by contacting the principal investigator. Consent will only be 
obtained by approved research personnel who have passed the CITI exam for ethical conduct of research.  
 
Patients will be given ample time to review the contents of the consent in private. The patient will be 
approached about the study as soon as they are identified to give them adequate time to review the study 
information prior to surgery. A researcher will then be available to answer all questions regarding the 
patient’s participation in the study, including but not limited to all risks and benefits. The patient may 
refuse to participate at any time during the consenting process or over the course of the study. 
 
31. Process to Document Consent in Writing  
The consent will be documented in accordance with the guidelines detailed previously in the HRP-803 
INVESTIGATOR GUIDANCE: Documentation of Informed Consent. The patient will receive a copy of this 
consent for their personal records during the enrollment process. This consent has been largely modeled 
after the Template Consent Document (HRP-502) and provides answers to many anticipated questions. 
Each signed consent will be stored in a locked cabinet in a secure research office that only approved study 
personnel are able to access. 
 
32. Drugs or Devices  
For information on drugs, please refer to the Treatment section in 11. Procedures Involved. 
Devices used for fixation of the ankle fracture are determined by the attending surgeon based on the 
injury characteristics, and are independent of involvement in this study. 
 
33. References 
1. 
Barrington, J. W.; Olugbode, O.; Lovald, S.; Ong, K.; Watson, H.; and Emerson, 
R. H., Jr.: Liposomal Bupivacaine: A Comparative Study of More Than 1000 Total 
Joint Arthroplasty Cases. Orthop Clin North Am, 46(4): 469-77, 2015. 
2. 
Bramlett, K.; Onel, E.; Viscusi, E. R.; and Jones, K.: A randomized, double-blind, 
dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an 
extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical 
analgesia in total knee arthroplasty. Knee, 19(5): 530-6, 2012. 
3. 
Ng, F. Y.; Ng, J. K.; Chiu, K. Y.; Yan, C. H.; and Chan, C. W.: Multimodal 
periarticular injection vs continuous femoral nerve block after total knee 
arthroplasty: a prospective, crossover, randomized clinical trial. J Arthroplasty, 
27(6): 1234-8, 2012. 
4. 
Lonner, J.: Role of liposomal bupivacaine in pain management after total joint 
arthroplasty. J Surg Orthop Adv, 23(1): 37-41, 2014. 
5. 
Hutchinson, H. L.: Local infiltration of liposome bupivacaine in orthopedic 
trauma patients: case-based reviews. Am J Orthop (Belle Mead NJ), 43(10 Suppl): 
S13-6, 2014. 
6. 
Herbst, S. A.: Local infiltration of liposome bupivacaine in foot and ankle surgery: 
case-based reviews. Am J Orthop (Belle Mead NJ), 43(10 Suppl): S10-2, 2014. 

H00014155 
2018-06-01 
 
7. 
Stein, B. E.; Srikumaran, U.; Tan, E. W.; Freehill, M. T.; and Wilckens, J. H.: 
Lower-extremity peripheral nerve blocks in the perioperative pain management 
of orthopaedic patients: AAOS exhibit selection. J Bone Joint Surg Am, 94(22): 
e167, 2012. 
8. 
Wang, J.; Liu, G. T.; Mayo, H. G.; and Joshi, G. P.: Pain Management for Elective 
Foot and Ankle Surgery: A Systematic Review of Randomized Controlled Trials. J 
Foot Ankle Surg, 54(4): 625-35, 2015. 
9. 
Compton, P., and Athanasos, P.: Chronic pain, substance abuse and addiction. 
Nurs Clin North Am, 38(3): 525-37, 2003. 
10. 
De Maeyer, J.; Vanderplasschen, W.; and Broekaert, E.: Quality of life among 
opiate-dependent individuals: A review of the literature. Int J Drug Policy, 21(5): 
364-80, 2010. 
11. 
Morrone, L. A.; Scuteri, D.; Rombola, L.; Mizoguchi, H.; and Bagetta, G.: Opioids 
Resistance in Chronic Pain Management. Curr Neuropharmacol, 15(3): 444-456, 
2017. 
12. 
Holman, J. E.; Stoddard, G. J.; and Higgins, T. F.: Rates of prescription opiate use 
before and after injury in patients with orthopaedic trauma and the risk factors 
for prolonged opiate use. J Bone Joint Surg Am, 95(12): 1075-80, 2013. 
13. 
Manchikanti, L.: National drug control policy and prescription drug abuse: facts 
and fallacies. Pain Physician, 10(3): 399-424, 2007. 
14. 
Elkassabany, N.; Cai, L. F.; Mehta, S.; Ahn, J.; Pieczynski, L.; Polomano, R. C.; 
Picon, S.; Hogg, R.; and Liu, J.: Does Regional Anesthesia Improve the Quality of 
Postoperative Pain Management and the Quality of Recovery in Patients 
Undergoing Operative Repair of Tibia and Ankle Fractures? J Orthop Trauma, 
29(9): 404-9, 2015. 
15. 
Cometa, M. A.; Esch, A. T.; and Boezaart, A. P.: Did continuous femoral and 
sciatic nerve block obscure the diagnosis or delay the treatment of acute lower 
leg compartment syndrome? A case report. Pain Med, 12(5): 823-8, 2011. 
16. 
Mar, G. J.; Barrington, M. J.; and McGuirk, B. R.: Acute compartment syndrome 
of the lower limb and the effect of postoperative analgesia on diagnosis. Br J 
Anaesth, 102(1): 3-11, 2009. 
17. 
Goldstein, R. Y.; Montero, N.; Jain, S. K.; Egol, K. A.; and Tejwani, N. C.: Efficacy 
of popliteal block in postoperative pain control after ankle fracture fixation: a 
prospective randomized study. J Orthop Trauma, 26(10): 557-61, 2012. 
18. 
Ding, D. Y.; Manoli, A., 3rd; Galos, D. K.; Jain, S.; and Tejwani, N. C.: Continuous 
Popliteal Sciatic Nerve Block Versus Single Injection Nerve Block for Ankle 
Fracture Surgery: A Prospective Randomized Comparative Trial. J Orthop 
Trauma, 29(9): 393-8, 2015. 
19. 
White, P. F.; Issioui, T.; Skrivanek, G. D.; Early, J. S.; and Wakefield, C.: The use 
of a continuous popliteal sciatic nerve block after surgery involving the foot and 
ankle: does it improve the quality of recovery? Anesth Analg, 97(5): 1303-9, 
2003. 

H00014155 
2018-06-01 
 
20. 
Schroer, W. C.; Diesfeld, P. G.; LeMarr, A. R.; Morton, D. J.; and Reedy, M. E.: 
Does Extended-Release Liposomal Bupivacaine Better Control Pain Than 
Bupivacaine After Total Knee Arthroplasty (TKA)? A Prospective, Randomized 
Clinical Trial. J Arthroplasty, 30(9 Suppl): 64-7, 2015. 
21. 
Bagsby, D. T.; Ireland, P. H.; and Meneghini, R. M.: Liposomal bupivacaine 
versus traditional periarticular injection for pain control after total knee 
arthroplasty. J Arthroplasty, 29(8): 1687-90, 2014. 
22. 
Joshi, G. P.; Cushner, F. D.; Barrington, J. W.; Lombardi, A. V., Jr.; Long, W. J.; 
Springer, B. D.; and Stulberg, B. N.: Techniques for periarticular infiltration with 
liposomal bupivacaine for the management of pain after hip and knee 
arthroplasty: a consensus recommendation. J Surg Orthop Adv, 24(1): 27-35, 
2015. 
23. 
Kelley, T. C.; Adams, M. J.; Mulliken, B. D.; and Dalury, D. F.: Efficacy of 
multimodal perioperative analgesia protocol with periarticular medication 
injection in total knee arthroplasty: a randomized, double-blinded study. J 
Arthroplasty, 28(8): 1274-7, 2013. 
24. 
Zhao, X.; Qin, J.; Tan, Y.; Mohanan, R.; Hu, D.; and Chen, L.: Efficacy of steroid 
addition to multimodal cocktail periarticular injection in total knee arthroplasty: 
a meta-analysis. J Orthop Surg Res, 10: 75, 2015. 
25. 
Busch, C. A.; Shore, B. J.; Bhandari, R.; Ganapathy, S.; MacDonald, S. J.; Bourne, 
R. B.; Rorabeck, C. H.; and McCalden, R. W.: Efficacy of periarticular multimodal 
drug injection in total knee arthroplasty. A randomized trial. J Bone Joint Surg 
Am, 88(5): 959-63, 2006. 
26. 
Myles, P. S.; Reeves, M. D.; Anderson, H.; and Weeks, A. M.: Measurement of 
quality of recovery in 5672 patients after anaesthesia and surgery. Anaesth 
Intensive Care, 28(3): 276-80, 2000.