Liposomal Bupivacaine in Implant Based Breast Reconstruction

• Sponsor: Loma Linda University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02659501
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Actual Duration (Months): 24
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Objectives:

1. To evaluate the effect of liposomal bupivacaine on postoperative pain levels.

2. To evaluate the effect of liposomal bupivacaine on postoperative opioid consumption and opioid related adverse events.

3. To evaluate the effect of liposomal bupivacaine on length of hospital stay.

4. To evaluate the effect of liposomal bupivacaine on patient satisfaction with postoperative pain control.

5. To evaluate the effect of liposomal bupivacaine on overall patient satisfaction.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Postoperative Pain	Drug: Liposomal bupivacaine; Drug: Bupivacaine with epinephrine; Drug: Morphine sulfate; Drug: Hydrocodone/acetaminophen; Drug: Diazepam	N/A

Detailed Description

Objectives:

1. To evaluate the effect of liposomal bupivacaine on postoperative pain levels.

2. To evaluate the effect of liposomal bupivacaine on postoperative opioid consumption and opioid related adverse events.

3. To evaluate the effect of liposomal bupivacaine on length of hospital stay.

4. To evaluate the effect of liposomal bupivacaine on patient satisfaction with postoperative pain control.

5. To evaluate the effect of liposomal bupivacaine on overall patient satisfaction.

The objective of this project is to evaluate the role of liposomal bupivacaine in postoperative pain control following tissue expander and implant based breast reconstruction. This unique formulation of bupivacaine lends this drug a longer duration of action and reduced plasma bupivacaine concentrations compared to plain bupivacaine. This agent has been demonstrated to be safe, well tolerated, and effective in a number of different clinical applications. However, its role has yet to be evaluated in the context of breast reconstruction.

Thus, the authors propose the first, randomized, controlled clinical trial of liposomal bupivacaine for postoperative pain management following tissue expander and implant based breast reconstruction. Patients will be stratified into two study groups. Patients in the Group 1 (Bupivacaine) will be treated intraoperatively with injections of 0.5% bupivacaine and epinephrine 1:200,000, with 50 mg delivered to perform a field block of each pocket. This is the current standard of care. Patients in the Group 2 (Liposomal Bupivacaine) will be treated intraoperatively with injections of 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. This is the experimental intervention. Postoperatively, the investigators will assess pain levels, opioid consumption, opioid related adverse events, length of stay, and satisfaction.

The findings from this study will allow the authors to better elucidate the role of liposomal bupivacaine in expander/implant based breast reconstruction. In doing so, they may allow the authors to identify the ideal pain regimen for these patients. This holds important implications, with the potential to reduce postoperative pain, opioid consumption, opioid related adverse events, length of stay, and patient satisfaction.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Liposomal Bupivacaine in Implant Based Breast Reconstruction
• Actual Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bupivacaine with epinephrine injections Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Drug: Bupivacaine with epinephrine; Bupivacaine, like other local anesthetics reduces the flow of sodium in and out of nerves. This decreases the initiation and transfer of nerve signals in the area in which the drug is injected. This leads first to a loss of sensation of pain, temperature, touch, and deep pressure. This drug is the current standard of care for local, postoperative local anesthesia following breast reconstruction. Epinephrine, a vasoconstrictor, is included in bupivacaine formulations to improve the duration of local anesthesia.; Other Names: Marcaine Sensorcaine ; Drug: Morphine sulfate; Morphine is an opiate pain medication administered intravenously for severe, breakthrough post-operative pain.; Other Names: Roxanol ; Drug: Hydrocodone/acetaminophen; Hydrocodone acetaminophen is a combination of an opiate pain medication (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain.; Other Names: Norco ; Drug: Diazepam; Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms in patient's following expander and implant-based breast reconstruction.; Other Names: Valium
Experimental: Liposomal bupivacaine Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Drug: Liposomal bupivacaine; Liposomal Bupivacaine is an aqueous suspension of multivesicular liposomes containing bupivacaine. After injection into soft tissue, bupivacaine is slowly released from the multivesicular liposomes, extending this drug's duration of action.; Other Names: Exparel ; Drug: Morphine sulfate; Morphine is an opiate pain medication administered intravenously for severe, breakthrough post-operative pain.; Other Names: Roxanol ; Drug: Hydrocodone/acetaminophen; Hydrocodone acetaminophen is a combination of an opiate pain medication (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain.; Other Names: Norco ; Drug: Diazepam; Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms in patient's following expander and implant-based breast reconstruction.; Other Names: Valium

Outcome Measures

Primary Outcome Measures

1. The Effect of Liposomal Bupivacaine on Average Postoperative Pain Levels on Postoperative Day 1. [Average Pain Scores 24 hours Post-Operatively]

   Postoperative pain levels were determined with a numeric rating scale (NRS), rating pain from 0 - 10, where 0 = no pain, 10 = worst possible pain. Higher scores indicate a worse outcome. Pain levels were determined during routine vital signs every 4 hours post-operatively.

2. The Effect of Liposomal Bupivacaine on Antiemetic Consumption [24 hours]

   The effect of liposomal bupivacaine on antiemetic consumption was assessed in mg of ondansetron consumed over first 24 hours post-operatively.

3. The Effect of Liposomal Bupivacaine on Postoperative Opioid Consumption [24 hours]

   Postoperative opioid consumption will be determined in each group. Opioid consumption post-operatively will be determined for patients in each group in standardized units of morphine milligram dosing equivalents per hour.

4. The Effect of Liposomal Bupivacaine on Postoperative Diazepam Consumption [24 hours]

   Benzodiazepine consumption, in mg of diazepam, was recorded for all patients and compared over the first 24 hours post-operatively.

5. The Effect of Liposomal Bupivacaine on Length of Hospital Stay [24-60 hours]

   Length of hospital stay will be determined for patients in each group, in total hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women undergoing immediate unilateral or bilateral tissue-expander breast reconstruction following skin-sparing or nipple-sparing mastectomy

Exclusion Criteria:

• Women who are unable to give informed consent to participate in this study

• Women with a documented history of hypersensitivity reactions to local-anesthetic agents

• Women with a diagnosis of chronic pain disorders such as fibromyalgia, chronic migraine headaches, or psychiatric disorders other than depression or anxiety

• Women who are currently pregnant

• Women undergoing tissue expander based breast reconstruction with a muscle flap in combination with a tissue expander

• Women with impaired hepatic function

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Health System	Loma Linda	California	United States	92354

Sponsors and Collaborators

• Loma Linda University

Investigators

• Principal Investigator: Subhas C. Gupta, MD, PhD, Loma Linda University
• Study Director: Wendy W. Wong, MD, Loma Linda University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr Med Res Opin. 2012 Oct;28(10):1609-15. doi: 10.1185/03007995.2012.721760. Epub 2012 Sep 3.
• Davidson EM, Barenholz Y, Cohen R, Haroutiunian S, Kagan L, Ginosar Y. High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans. Anesth Analg. 2010 Apr 1;110(4):1018-23. doi: 10.1213/ANE.0b013e3181d26d2a.
• Heller L, Kowalski AM, Wei C, Butler CE. Prospective, randomized, double-blind trial of local anesthetic infusion and intravenous narcotic patient-controlled anesthesia pump for pain management after free TRAM flap breast reconstruction. Plast Reconstr Surg. 2008 Oct;122(4):1010-1018. doi: 10.1097/PRS.0b013e3181858c09.
• Richard BM, Ott LR, Haan D, Brubaker AN, Cole PI, Nelson KG, Ross PE, Rebelatto MC, Newton PE. The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs. Expert Opin Investig Drugs. 2011 Oct;20(10):1327-41. doi: 10.1517/13543784.2011.611499. Epub 2011 Aug 26.
• Wheble GA, Tan EK, Turner M, Durrant CA, Heppell S. Surgeon-administered, intra-operative transversus abdominis plane block in autologous breast reconstruction: a UK hospital experience. J Plast Reconstr Aesthet Surg. 2013 Dec;66(12):1665-70. doi: 10.1016/j.bjps.2013.07.017. Epub 2013 Jul 31.

• Responsible Party: Subhas Gupta, MD, PhD, Principal Investigator, Loma Linda University
• ClinicalTrials.gov Identifier: NCT02659501
• Other Study ID Numbers: 5150012
• First Posted: Jan 20, 2016
• Last Update Posted: Jan 12, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Subhas Gupta, MD, PhD, Principal Investigator, Loma Linda University: Breast reconstruction; Bupivacaine; Liposomal bupivacaine; Postoperative analgesia
• Additional relevant MeSH terms: Pain, Postoperative; Acetaminophen; Acetaminophen, hydrocodone drug combination; Epinephrine; Diazepam; Morphine; Hydrocodone; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm will be treated intra-operatively with standard of care, 0.25% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered to each breast pocket. Postoperatively, pain will be treated with narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam. Bupivacaine with epinephrine: Bupivacaine is a local anesthetic. This drug is the current standard of care for local anesthesia following breast reconstruction. Morphine sulfate: Morphine is an opiate pain medication administered intravenously for severe post-operative pain. Hydrocodone/acetaminophen: Hydrocodone acetaminophen is a combination of an opiate (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain. Diazepam: Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to each breast pocket. Postoperatively, pain will be treated with narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam. Liposomal bupivacaine: Liposomal Bupivacaine is a suspension of multivesicular liposomes containing bupivacaine. After injection, bupivacaine is slowly released from the liposomes, extending this drug's duration of action. Morphine sulfate: Morphine is an opiate pain medication administered intravenously for severe post-operative pain. Hydrocodone/acetaminophen: Hydrocodone acetaminophen is a combination of an opiate (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain. Diazepam: Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms.
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine	Total
Arm/Group Description	Patients in the control arm will be treated intra-operatively with standard of care, 0.25% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered to each breast pocket. Postoperatively, pain will be treated with narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam. Bupivacaine with epinephrine: Bupivacaine is a local anesthetic. This drug is the current standard of care for local anesthesia following breast reconstruction. Morphine sulfate: Morphine is an opiate pain medication administered intravenously for severe post-operative pain. Hydrocodone/acetaminophen: Hydrocodone acetaminophen is a combination of an opiate (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain. Diazepam: Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to each breast pocket. Postoperatively, pain will be treated with narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam. Liposomal bupivacaine: Liposomal Bupivacaine is a suspension of multivesicular liposomes containing bupivacaine. After injection, bupivacaine is slowly released from the liposomes, extending this drug's duration of action. Morphine sulfate: Morphine is an opiate pain medication administered intravenously for severe post-operative pain. Hydrocodone/acetaminophen: Hydrocodone acetaminophen is a combination of an opiate (hydrocodone) and a non-steroidal anti-inflammatory drug (acetaminophen) given orally to patients for moderate post-operative pain. Diazepam: Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms.	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 75%	10 83.3%	19 79.2%
>=65 years	3 25%	2 16.7%	5 20.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.2 (12.6)	48.7 (11.1)	52.4 (12.9)
Sex: Female, Male (Count of Participants)
Female	12 100%	12 100%	24 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%	12 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	The Effect of Liposomal Bupivacaine on Average Postoperative Pain Levels on Postoperative Day 1.
Description	Postoperative pain levels were determined with a numeric rating scale (NRS), rating pain from 0 - 10, where 0 = no pain, 10 = worst possible pain. Higher scores indicate a worse outcome. Pain levels were determined during routine vital signs every 4 hours post-operatively.
Time Frame	Average Pain Scores 24 hours Post-Operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
Measure Participants	12	12
Mean (Standard Deviation) [score on a scale]	3.66 (0.33)	3.68 (1.35)

2. Primary Outcome

Title	The Effect of Liposomal Bupivacaine on Antiemetic Consumption
Description	The effect of liposomal bupivacaine on antiemetic consumption was assessed in mg of ondansetron consumed over first 24 hours post-operatively.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
Measure Participants	12	12
Mean (Standard Deviation) [mg of ondansetron]	7.33 (6.57)	5.75 (4.94)

3. Primary Outcome

Title	The Effect of Liposomal Bupivacaine on Postoperative Opioid Consumption
Description	Postoperative opioid consumption will be determined in each group. Opioid consumption post-operatively will be determined for patients in each group in standardized units of morphine milligram dosing equivalents per hour.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
Measure Participants	12	12
Mean (Standard Deviation) [Morphine equivalent dosage per hour]	1.31 (.72)	.76 (.55)

4. Primary Outcome

Title	The Effect of Liposomal Bupivacaine on Postoperative Diazepam Consumption
Description	Benzodiazepine consumption, in mg of diazepam, was recorded for all patients and compared over the first 24 hours post-operatively.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
Measure Participants	12	12
Mean (Standard Deviation) [mg of diazepam/hr]	0.35 (0.19)	0.18 (0.21)

5. Primary Outcome

Title	The Effect of Liposomal Bupivacaine on Length of Hospital Stay
Description	Length of hospital stay will be determined for patients in each group, in total hours.
Time Frame	24-60 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine With Epinephrine Injections	Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.	Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
Measure Participants	12	12
Mean (Standard Deviation) [hrs]	46.7 (21.1)	29.8 (15.3)

Adverse Events

Arm/Group Title	Bupivacaine With Epinephrine Injections		Liposomal Bupivacaine
Arm/Group Description	Patients in the control arm of the study will be treated intra-operatively with standard of care, 0.5% bupivacaine and epinephrine injection (1:200,000), with 50 mg delivered into each breast pocket to perform a field block of the breast pocket (see below). Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.		Patients in the experimental arm of the study will be treated intra-operatively with 1.33% liposomal bupivacaine, with 133 mg delivered to perform a field block of each breast pocket. Postoperatively, these patients will be treated with standard postoperative pain control, including narcotics as needed, such as morphine sulfate and hydrocodone/acetaminophen, and muscle relaxants, such as diazepam.
All Cause Mortality
	Bupivacaine With Epinephrine Injections		Liposomal Bupivacaine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bupivacaine With Epinephrine Injections		Liposomal Bupivacaine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Bupivacaine With Epinephrine Injections		Liposomal Bupivacaine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)

Limitations/Caveats

Our trial was terminated after 12 months at 24 patients. Early termination lead to smaller numbers of subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.