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Objectives:
Objectives:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bupivacaine with epinephrine injections | Active Comparator | 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. |
|
| Liposomal bupivacaine | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Liposomal bupivacaine | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| The Effect of Liposomal Bupivacaine on Average Postoperative Pain Levels on Postoperative Day 1. | 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. | Average Pain Scores 24 hours Post-Operatively |
| The Effect of Liposomal Bupivacaine on Antiemetic Consumption | The effect of liposomal bupivacaine on antiemetic consumption was assessed in mg of ondansetron consumed over first 24 hours post-operatively. | 24 hours |
| The Effect of Liposomal Bupivacaine on Postoperative Opioid Consumption | 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. | 24 hours |
| The Effect of Liposomal Bupivacaine on Postoperative Diazepam Consumption | Benzodiazepine consumption, in mg of diazepam, was recorded for all patients and compared over the first 24 hours post-operatively. | 24 hours |
| The Effect of Liposomal Bupivacaine on Length of Hospital Stay | Length of hospital stay will be determined for patients in each group, in total hours. | 24-60 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Subhas C. Gupta, MD, PhD | Loma Linda University | Principal Investigator |
| Wendy W. Wong, MD | Loma Linda University | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Loma Linda University Health System | Loma Linda | California | 92354 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18827631 | Background | 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. | |
| 23910912 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Bupivacaine With Epinephrine Injections | 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. |
| FG001 | 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 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Bupivacaine With Epinephrine Injections | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Effect of Liposomal Bupivacaine on Average Postoperative Pain Levels on Postoperative Day 1. | 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. | Posted | Mean | Standard Deviation | score on a scale | Average Pain Scores 24 hours Post-Operatively |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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Our trial was terminated after 12 months at 24 patients. Early termination lead to smaller numbers of subjects analyzed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Saba Motakef, Resident Physican | Loma Linda University, Department of Plastic Surgery | 714-925-8932 | smotakef@llu.edu |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| D010149 | Pain, Postoperative |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D002045 | Bupivacaine |
| D004837 | Epinephrine |
| D009020 | Morphine |
| C514822 | oxycodone-acetaminophen |
| D003975 | Diazepam |
| ID | Term |
|---|---|
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
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|
| Bupivacaine with epinephrine | Drug | 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. |
|
|
| Morphine sulfate | Drug | Morphine is an opiate pain medication administered intravenously for severe, breakthrough post-operative pain. |
|
|
| Hydrocodone/acetaminophen | Drug | 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. |
|
|
| Diazepam | Drug | Diazepam is a benzodiazepine medication that is administered orally to treat muscle spasms in patient's following expander and implant-based breast reconstruction. |
|
|
| 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. |
| 22900785 | Background | 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. |
| 21867476 | Background | 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. |
| 20357145 | Background | 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. |
| BG001 | 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 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | 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. |
|
|
| Primary | The Effect of Liposomal Bupivacaine on Antiemetic Consumption | The effect of liposomal bupivacaine on antiemetic consumption was assessed in mg of ondansetron consumed over first 24 hours post-operatively. | Posted | Mean | Standard Deviation | mg of ondansetron | 24 hours |
|
|
|
| Primary | The Effect of Liposomal Bupivacaine on Postoperative Opioid Consumption | 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. | Posted | Mean | Standard Deviation | Morphine equivalent dosage per hour | 24 hours |
|
|
|
| Primary | The Effect of Liposomal Bupivacaine on Postoperative Diazepam Consumption | Benzodiazepine consumption, in mg of diazepam, was recorded for all patients and compared over the first 24 hours post-operatively. | Posted | Mean | Standard Deviation | mg of diazepam/hr | 24 hours |
|
|
|
| Primary | The Effect of Liposomal Bupivacaine on Length of Hospital Stay | Length of hospital stay will be determined for patients in each group, in total hours. | Posted | Mean | Standard Deviation | hrs | 24-60 hours |
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | 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. | 0 | 12 | 0 | 12 |
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| D017437 |
| Skin and Connective Tissue Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D000588 |
| Amines |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D015306 | Biogenic Monoamines |
| D001679 | Biogenic Amines |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D001570 | Benzodiazepinones |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |