Bupivacaine Injection for Post-Traumatic Headache

Overseen By Emmanuelle Schindler, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Amide anesthetics

Disqualifiers: Skull defect, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different concentrations of bupivacaine, a numbing medication, to determine its effect on headaches persisting after a head injury. Participants will receive scalp injections targeting a nerve associated with headache pain. The goal is to identify which concentration best relieves headache symptoms. This trial suits U.S. military veterans who have experienced post-traumatic headaches for at least three months and have headaches at least twice a week. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive it.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that bupivacaine is generally safe for people. Studies have found its safety comparable to normal saline, meaning it usually doesn't cause serious side effects. Reported side effects are typically mild, such as temporary numbness or tingling. As this is a phase 1 trial, the main focus is on safety. Bupivacaine's use in other medical applications suggests a history of safety when used correctly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about bupivacaine injections for post-traumatic headaches because they offer a new approach by targeting pain directly at the source. Unlike standard oral medications that can take time to work throughout the body, bupivacaine is injected, potentially providing faster and more localized relief. This treatment also explores varying concentrations, which could optimize pain management and minimize side effects. By delivering the anesthetic directly, it might offer a more immediate and effective solution for individuals suffering from debilitating post-traumatic headaches.

What evidence suggests that this trial's treatments could be effective for post-traumatic headache?

Research has shown that bupivacaine injections can effectively block nerve pain, including headaches. Studies indicate that bupivacaine provides better pain relief than some other treatments. For post-traumatic headaches, it numbs the greater occipital nerve, reducing pain. While most research has focused on long-lasting bupivacaine, regular bupivacaine also appears promising for easing pain in various conditions. This trial will evaluate different concentrations of bupivacaine to determine its effectiveness in managing post-traumatic headaches. These findings suggest that bupivacaine could be a useful treatment for this condition. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Bupivacaine Injection

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.

How Is the Trial Designed?

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

Bupivacaine Injection is already approved in United States, European Union for the following indications:

Approved in United States as Marcaine for:

• Local Anesthesia
• Postoperative Pain
• Cesarean Section
• Epidural Anesthesia
• Caudal Blocks
• Sympathetic Nerve Block
• Peripheral Nerve Block

Approved in European Union as Sensorcaine for:

• Local Anesthesia
• Regional Anesthesia
• Pain Management

Approved in United States as Posimir for:

• Post-surgical Analgesia for up to 72 hours following arthroscopic subacromial decompression

Approved in United States as Xaracoll for:

• Acute postsurgical analgesia for up to 24 hours in adults following open inguinal hernia repair

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Headache Foundation

Collaborator

Trials

3

Recruited

40+

VA Connecticut Healthcare System

Collaborator

Trials

86

Recruited

8,800+

Published Research Related to This Trial

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]

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 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 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 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]

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 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 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]

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]

Citations

1. withpower.com withpower.com/trial/phase-1-post-traumatic-headache-9-2023-39a2a

Bupivacaine Injection for Post-Traumatic Headache What data supports the effectiveness of the drug Bupivacaine Injection for treating post-traumatic headache? Research shows that liposomal bupivacaine, a form ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33372949/

Clinical Effectiveness of Liposomal Bupivacaine ... Ninety-two percent of trials (11 of 12) suggested a peripheral nerve block with unencapsulated bupivacaine provides superior analgesia to infiltrated liposomal ...

3. withpower.com withpower.com/clinical-trials/using-exparel?page=2

Top Treatment for Exparel Clinical Trials | Power This study will be a single center, prospective triple blinded randomized controlled study, comparing the use of liposomal bupivacaine (Exparel) to regular ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12496121/

Effect of liposomal bupivacaine combined with ... Liposomal bupivacaine (LB) is bupivacaine encapsulated in liposomes, and it is reported that its duration of action can extend up to 72 hours.

5. link.springer.com link.springer.com/article/10.1007/s44254-025-00095-5

Efficacy and safety of liposomal bupivacaine administration ... The existing literature suggests that LB may reduce pain scores, hospital costs, length of hospital stay, and opioid use.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26204387/

Safety and Side Effect Profile of Liposome Bupivacaine ... Liposome bupivacaine has a similar safety and side effect profile to bupivacaine HCl and normal saline, suggesting that most of the more common AEs are ...

7. fda.gov fda.gov/media/111001/download

EXPAREL with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: results of a randomized controlled trial.