Bupivacaine Injection for Post-Traumatic Headache

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Yale University

Must not be taking: Amide anesthetics

Disqualifiers: Skull defect, Pregnancy, others

No Placebo Group

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

The acute and subacute sensations that occur on the scalp with injection of different concentrations of bupivacaine for grater occipital nerve blockade will be compared. Each Veteran participant will be randomized to receive three different concentrations, which will be injected one week apart each.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Bupivacaine Injection for treating post-traumatic headache?

Research shows that liposomal bupivacaine, a form of bupivacaine, is effective in reducing postoperative pain and opioid use in surgeries, suggesting it may help manage pain in other conditions too. Additionally, bupivacaine is widely used in obstetrics for pain relief with minimal side effects, indicating its potential for safe and effective pain management. ^{1 2 3 4 5}

Is Bupivacaine safe for use in humans?

Bupivacaine, used under various names like Marcaine and Exparel, has been shown to be generally safe in humans when used as directed, with minimal side effects. Studies have shown it to be safe in obstetrical analgesia and for postsurgical pain relief, with limited side effects when proper dosing guidelines are followed. ^{1 4 5 6 7}

How is the drug Bupivacaine Injection unique for treating post-traumatic headache?

Bupivacaine Injection, particularly in its liposome formulation (Exparel), is unique because it is designed to provide long-lasting pain relief by slowly releasing the medication over time, which is different from standard pain treatments that may require more frequent dosing. ^{1 3 8 9 10}

Research Team

Eligibility Criteria

This trial is for U.S. Military Veterans within the VA Connecticut Healthcare System who suffer from chronic post-traumatic headaches, occurring at least twice a week. Participants must have had an MRI brain scan recently and their medical records should not indicate another source for their headaches. Pregnant individuals or those with certain allergies, heart conditions related to amide anesthetics, or skull defects cannot participate.

Inclusion Criteria

Veterans receiving care at the VA Connecticut Healthcare System.

My MRI shows my headache isn't caused by another health issue.

I have had headaches for over three months after a head injury.

Exclusion Criteria

You have a hole or defect in your skull.

You have had a bad reaction to certain numbing medicines like lidocaine.

Pregnant or lack of adequate birth control

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive different concentrations of bupivacaine for greater occipital nerve blockade, injected one week apart

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• Bupivacaine Injection (Local Anesthetic)

Trial Overview The study tests how different concentrations of Bupivacaine affect scalp sensations when used in greater occipital nerve blockade in veterans with post-concussion headache. Each participant will receive three varying concentrations of Bupivacaine injections over three separate weeks through random assignment.

Participant Groups

Group I: Group 4 Experimental Treatment 1 Intervention

bupivacaine \[0.01% or 0.05%\], \[0.05% or 0.1%\], and 0.05% in random order, one week apart each

Group II: Group 3 Experimental Treatment 1 Intervention

bupivacaine 0.0%, 0.1%, and 0.5% in random order, one week apart each

Group III: Group 2 Experimental Treatment 1 Intervention

bupivacaine 0.1%, 0.05%, and 0.1% in random order, one week apart each

Group IV: Group 1 Experimental Treatment 1 Intervention

bupivacaine 0.0%, 0.01%, and 0.05% in random order, one week apart each

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

National Headache Foundation

Collaborator

Trials

3

Recruited

40+

VA Connecticut Healthcare System

Collaborator

Trials

86

Recruited

8,800+

Alfred A. Montoya Jr.

VA Connecticut Healthcare System

Chief Executive Officer since 2019

Master’s degree in Healthcare Administration from Walden University, Bachelor’s degree from Wayland Baptist University

Dr. Anthony J. Lisi

VA Connecticut Healthcare System

Chief Medical Officer since 2016

MD from Yale University School of Medicine

Findings from Research

In a retrospective analysis of 575 subjects across 6 clinical trials, liposome bupivacaine showed a similar safety profile to both bupivacaine HCl and normal saline, with 76% of liposome bupivacaine recipients experiencing adverse events (AEs).

The most common AEs for liposome bupivacaine included nausea and hypesthesia, and serious AEs occurred in 8% of subjects, indicating that the side effects are likely related to the surgical procedure rather than the medication itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral Nerve Blocks. Ilfeld, BM., Viscusi, ER., Hadzic, A., et al.[2022]

In a study of 20 patients undergoing lingual nerve microsurgery, those who received liposomal bupivacaine (LB) reported significantly less postoperative pain and consumed fewer opioid pills compared to those who received bupivacaine hydrochloride (BH).

The findings suggest that LB, with its prolonged duration of action, is more effective in reducing postoperative pain and opioid consumption, supporting its use in surgical procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine use in exploratory lingual nerve microsurgery: does liposomal bupivacaine use decrease postoperative pain and opioid consumption compared to bupivacaine hydrochloride? A pilot study. Jacobus, D., Mehr, S., Ziccardi, V.[2021]

In a pilot study involving 25 pigs, subarachnoid administration of liposomal bupivacaine resulted in a longer duration of pain relief compared to standard bupivacaine hydrochloride, with effects lasting up to 32 hours for higher doses.

No signs of neurotoxicity were observed in any treatment group, suggesting that liposomal bupivacaine may be a safe option for extended analgesia in the neuraxial space, warranting further studies for potential human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological and histological outcomes after subarachnoid injection of a liposomal bupivacaine suspension in pigs: a pilot study. Zel, J., Hadzic, A., Cvetko, E., et al.[2019]

Bupivacaine (Marcaine) is effective for epidural analgesia in obstetrics, providing excellent sensory block with minimal impact on motor function and few side effects for both mothers and newborns.

When used at concentrations below 0.5%, and with careful dosing during labor, the risk of side effects and toxicity is low, and significant effects on newborns are rare due to the drug's high protein binding limiting its transfer across the placenta.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The use of Marcaine in obstetrical analgesia]. Seebacher, J., Chareire, F., Galli-Douant, P., et al.[2013]

Bupivacaine liposome injectable suspension provided significantly longer sensory (11.2 hours) and motor (10.0 hours) blockade compared to standard bupivacaine HCl (3.2 hours sensory and 4.0 hours motor), indicating enhanced efficacy in pain management.

Both formulations of bupivacaine, when injected intraneurally in pigs, showed no signs of neurotoxicity, as there were no changes in axonal density or myelin structure, suggesting they are safe for use in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity of intraneural injection of bupivacaine liposome injectable suspension versus bupivacaine hydrochloride in a porcine model. Damjanovska, M., Cvetko, E., Kuroda, MM., et al.[2019]

In a study involving 823 patients across various surgical settings, liposome bupivacaine demonstrated a lower incidence of adverse events (62%) compared to bupivacaine HCl (75%) and placebo (43%), indicating better tolerability.

Serious adverse events were less common in the liposome bupivacaine group (2.7%) compared to bupivacaine HCl (5.4%), suggesting that liposome bupivacaine may be a safer option for local analgesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of liposome bupivacaine, a novel local analgesic formulation. Viscusi, ER., Sinatra, R., Onel, E., et al.[2022]

In a study of 34 patients undergoing breast augmentation, liposomal bupivacaine provided statistically significant lower pain scores compared to standard bupivacaine at multiple time points post-surgery, indicating it may offer better pain control.

Despite the statistical significance, the differences in pain relief were small, and 70% of patients felt the additional cost of liposomal bupivacaine was not justified by the benefits, suggesting limited clinical relevance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine Versus Liposomal Bupivacaine for Postoperative Pain Control after Augmentation Mammaplasty: A Prospective, Randomized, Double-Blind Trial. Nadeau, MH., Saraswat, A., Vasko, A., et al.[2022]

In a phase 2 study involving 138 patients undergoing total knee arthroplasty, bupivacaine extended-release liposome injection showed no significant changes in ECG parameters, such as QRS and QTcF durations, indicating a favorable cardiac safety profile.

Across multiple studies with a total of 1459 patients, no clinically relevant cardiac adverse events were associated with bupivacaine extended-release, suggesting it is safe for use in postsurgical pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile. Bergese, SD., Onel, E., Morren, M., et al.[2019]

In a phase 3 study involving 189 patients undergoing hemorrhoidectomy, bupivacaine extended-release significantly reduced pain intensity scores compared to placebo, indicating its efficacy in providing long-lasting postoperative analgesia.

Patients receiving bupivacaine extended-release were more likely to remain opioid-free for longer periods and reported higher satisfaction with pain management, highlighting its potential to reduce opioid consumption after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Gorfine, SR., Onel, E., Patou, G., et al.[2022]

In a pooled analysis of 823 patients from 10 clinical studies, liposome bupivacaine demonstrated significantly lower pain scores compared to standard bupivacaine HCl in several treatment arms, indicating its efficacy in providing prolonged postsurgical analgesia.

Liposome bupivacaine was well tolerated and resulted in significant systemic levels of bupivacaine that could last up to 96 hours, although these levels did not correlate with local pain relief, suggesting a unique mechanism of action for sustained pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. Bergese, SD., Ramamoorthy, S., Patou, G., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral Nerve Blocks. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Liposomal bupivacaine use in exploratory lingual nerve microsurgery: does liposomal bupivacaine use decrease postoperative pain and opioid consumption compared to bupivacaine hydrochloride? A pilot study. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Neurological and histological outcomes after subarachnoid injection of a liposomal bupivacaine suspension in pigs: a pilot study. [2019]

4. France pubmed.ncbi.nlm.nih.gov

[The use of Marcaine in obstetrical analgesia]. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Neurotoxicity of intraneural injection of bupivacaine liposome injectable suspension versus bupivacaine hydrochloride in a porcine model. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

The safety of liposome bupivacaine, a novel local analgesic formulation. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Bupivacaine Versus Liposomal Bupivacaine for Postoperative Pain Control after Augmentation Mammaplasty: A Prospective, Randomized, Double-Blind Trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. [2022]