Ketamine vs Fentanyl for Traumatic Injury Pain Management

(PAIN Trial)

Recruiting at7 trial locations

Overseen by Jason Sperry, MD, MPH

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Jason Sperry

Disqualifiers: No IV access, Age <18, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The Prehospital Analgesia INtervention trial (PAIN) is a proposed 4 year (3-year enrollment) multicenter, prehospital, randomized, double-blind, clinical trial that will enroll approximately 994 patients at select LITES Network sites. The objective is to perform a prospective, interventional, randomized trial among prehospital trauma patients with compensated shock (SI≥0.9) and an indication for pain management, comparing patient centered outcomes following prehospital administration of ketamine hydrochloride versus fentanyl citrate.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the drug ketamine compared to fentanyl for traumatic injury pain management?

Research shows that low-dose ketamine provides greater pain control compared to fentanyl in prehospital settings, with a significant reduction in pain and a higher proportion of patients experiencing at least a 50% reduction in pain. Additionally, ketamine has been associated with fewer adverse events, supporting its effectiveness as a pain management option. ^{1 2 3 4 5}

Is it safe to use ketamine and fentanyl for pain management in humans?

Research shows that both ketamine and fentanyl are generally safe for pain management in humans, with studies reporting no significant adverse events when used in controlled settings. Ketamine, in particular, has been noted for its effective pain relief without significant side effects in prehospital and emergency department settings. ^{2 3 6 7 8}

How does the drug Ketamine differ from Fentanyl for traumatic injury pain management?

Ketamine, when used with Fentanyl, may provide better pain relief and reduce the need for additional opioids compared to using Fentanyl alone. Ketamine can be administered intranasally, which is a non-invasive method, and it may also help decrease the risk of developing PTSD and chronic pain after a traumatic injury. ^{1 2 3 5 9}

Research Team

Jason Sperry, MD, MPH

Principal Investigator

University of Pittsburgh

Eligibility Criteria

The PAIN trial is for trauma patients with compensated shock (SI>0.9) who need IV pain medication and are being transported to a LITES Trauma center. It's not for those under 18, women under 50, anyone with high blood pressure (SBP>180 mmHg), prior pain meds or advanced airway management, prisoners, allergy to the drugs tested, or if they or family object.

Inclusion Criteria

I was taken to a PAIN Trauma center immediately after my injury.

I needed strong pain medication through an IV because of severe pain before getting to the trauma center.

Patient with compensated shock as defined by Shock Index (SI) >0.9

Exclusion Criteria

I am a woman under 50 years old.

Wearing a 'NO PAIN STUDY' bracelet

I or a family member have expressed concerns about participating in the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Prehospital Treatment

Participants receive prehospital administration of ketamine hydrochloride or fentanyl citrate for pain management

Immediate

1 visit (prehospital)

Hospitalization

Participants are monitored and treated in the hospital following prehospital intervention

Up to 30 days

Follow-up

Participants are monitored for long-term outcomes including opioid use and pain assessment

6 months

Treatment Details

Interventions

• Fentanyl Citrate (Opioid Analgesic)
• Ketamine Hydrochloride (NMDA Receptor Antagonist)

Trial Overview This study tests how effective ketamine hydrochloride is compared to fentanyl citrate in managing pain for prehospital trauma patients with shock. Patients will be randomly assigned one of these medications without knowing which one they're getting during their transport to the hospital.

Participant Groups

Group I: Ketamine Hydrochloride Experimental Treatment 1 Intervention

2 blinded doses 2.5mg/ml ketamine hydrochloride in separately sealed pre-filled syringes Subjects will be administered the first dose over approximately 2 minutes via slow IV push. Pain assessment following administration will be obtained and recorded every 15 minutes. Redosing may occur after approximately 15 minutes if the subject has a qualifying pain score, there are no contraindications to pain medication per local protocol, and no exclusion criteria have been met.

Group II: Fentanyl Citrate Active Control 1 Intervention

2 blinded doses 10mcg/ml in separately sealed pre-filled syringes Subjects will be administered the first dose over approximately 2 minutes via slow IV push. Pain assessment following administration will be obtained and recorded every 15 minutes. Redosing may occur after approximately 15 minutes if the subject has a qualifying pain score, there are no contraindications to pain medication per local protocol, and no exclusion criteria have been met.

Fentanyl Citrate is already approved in Canada for the following indications:

Approved in Canada as Fentanyl Citrate for:

• Severe pain
• Chronic pain
• Breakthrough pain
• Preoperative anesthesia
• Postoperative pain

Who Is Running the Clinical Trial?

Jason Sperry

Lead Sponsor

Trials

9

Recruited

6,900+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

Findings from Research

In a study of 213 U.S. service members with serious combat injuries, those treated with prehospital ketamine had significantly lower odds of developing PTSD in the first year post-injury, particularly among patients without traumatic brain injury (TBI).

Despite fewer patients receiving ketamine compared to opioids, those who did had more severe injuries, yet the use of ketamine was associated with better PTSD outcomes, suggesting it may be a beneficial alternative to opioids in combat casualty care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is Prehospital Ketamine Associated With a Change in the Prognosis of PTSD? Melcer, T., Walker, GJ., Dye, JL., et al.[2022]

This study aims to evaluate whether adding intranasal ketamine to fentanyl improves pain management in adults with severe acute trauma, potentially reducing the need for additional opioids and the risk of developing PTSD.

The trial will assess pain reduction within 30 minutes of treatment and follow participants for 90 days to monitor for PTSD and chronic pain, providing valuable data on the efficacy and safety of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain: Design and Rationale of a Randomized Controlled Trial. McMullan, J., Droege, C., Strilka, R., et al.[2021]

This study is the first randomized controlled trial comparing the effectiveness of intranasal (IN) ketamine and IN fentanyl for treating moderate to severe pain in children with isolated musculoskeletal limb injuries, involving participants aged 3 to 13 years.

If IN ketamine is found to be equally effective as IN fentanyl, it could offer an additional safe and effective option for acute pain relief in pediatric emergency settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PICHFORK (Pain InCHildren Fentanyl OR Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial. Graudins, A., Meek, R., Egerton-Warburton, D., et al.[2021]

In a systematic review of five randomized controlled trials, ketamine was found to provide similar pain relief compared to fentanyl for pediatric orthopedic emergencies, with no significant differences in pain scores at 15 to 30 minutes after administration.

However, ketamine was associated with a higher risk of side effects, including increased nausea and dizziness, suggesting that while it may be effective, its safety profile needs careful consideration in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of ketamine versus fentanyl on pain relief for pediatric orthopedic emergencies: A meta-analysis of randomized controlled studies. Qiu, J., Xie, M.[2023]

In a study of 63 patients requiring procedural sedation in the emergency department, subdissociative-dose ketamine was found to be significantly safer than fentanyl, with fewer cardiorespiratory events occurring during sedation.

Both ketamine and fentanyl provided similar efficacy in sedation, but patients receiving fentanyl experienced more serious intrasedation events, with 83.9% of fentanyl patients having events compared to only 46.9% of those receiving ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial. Messenger, DW., Murray, HE., Dungey, PE., et al.[2022]

This pilot trial will assess the safety and efficacy of intranasal subdissociative (INSD) ketamine compared to intranasal fentanyl in 80 children aged 4-17 with acute pain from suspected extremity fractures, focusing on side effects and pain reduction.

The study aims to explore whether INSD ketamine can reduce overall opioid use during emergency department stays, potentially offering a safer alternative to traditional opioid analgesics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol of a randomised controlled trial of intranasal ketamine compared with intranasal fentanyl for analgesia in children with suspected, isolated extremity fractures in the paediatric emergency department. Reynolds, SL., Studnek, JR., Bryant, K., et al.[2018]

A case report demonstrated that nebulized ketamine delivered via a breath-actuated nebulizer significantly reduced a patient's pain from 8/10 to 3/10 after a traumatic ankle injury, indicating its efficacy as an analgesic in the prehospital setting.

Nebulized ketamine may be a valuable alternative to opioids for pain management in acute traumatic limb injuries, especially for patients with challenging IV access or when opioid-sparing options are desired.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nebulized Ketamine Used for Managing Ankle Fracture in the Prehospital Emergency Setting: A Case Report. Quinn, E., Dhanraj, S., Liu, J., et al.[2023]

References

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

Is Prehospital Ketamine Associated With a Change in the Prognosis of PTSD? [2022]

2. England pubmed.ncbi.nlm.nih.gov

Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain: Design and Rationale of a Randomized Controlled Trial. [2021]

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

Intravenous Low-Dose Ketamine Provides Greater Pain Control Compared to Fentanyl in a Civilian Prehospital Trauma System: A Propensity Matched Analysis. [2020]

4. England pubmed.ncbi.nlm.nih.gov

The PICHFORK (Pain InCHildren Fentanyl OR Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial. [2021]

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

Influence of ketamine versus fentanyl on pain relief for pediatric orthopedic emergencies: A meta-analysis of randomized controlled studies. [2023]

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

Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial. [2022]

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

Study protocol of a randomised controlled trial of intranasal ketamine compared with intranasal fentanyl for analgesia in children with suspected, isolated extremity fractures in the paediatric emergency department. [2018]

8. India pubmed.ncbi.nlm.nih.gov

Comparison of Ketamine with Midazolam versus Ketamine with Fentanyl for Pediatric Extracorporeal Shock Wave Lithotripsy Procedure: A Randomized Controlled Study. [2022]

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

Nebulized Ketamine Used for Managing Ankle Fracture in the Prehospital Emergency Setting: A Case Report. [2023]