Nebulized Ketamine vs Fentanyl for Acute Pain

(KETAFEN Trial)

Overseen By Sergey Motov, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Antonios Likourezos

Must not be taking: Opioids, NSAIDs

Disqualifiers: Pregnancy, Head injury, Unstable vitals, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Up to 120 minutes

150 Participants Needed

Trial Summary

What is the purpose of this trial?

In situations where intravenous access is not readily available or is unobtainable and the intranasal route is not feasible, another non-invasive route of ketamine administration, such as inhalation via breath-actuated Nebulizer (BAN), is becoming a viable alternative. The BAN allows the controlled, patient-initiated delivery of analgesics in a measured and titratable fashion. (18) Ketamine has been studied as a nebulized drug in a lot of different settings and for a lot of different reasons, such as to treat acute pain after surgery (like a sore throat after being intubated), as a pre-medication for general anesthesia, to treat cancer pain, and as a therapy for asthmaticus. Our research team has published two case series of 10 adult patients who were given nebulized ketamine (via BAN) for a variety of acute traumatic and non-traumatic painful conditions. The patients showed a 60% decrease in pain and a small number of side effects. Furthermore, our group published a randomized, double-blind trial of 120 adult patients evaluating the analgesic efficacy and safety of nebulized ketamine at three different dosing regimens for acute pain in the ED (0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg), showing similar analgesic efficacy between the three different dosing regimens for short-term (up to 120 minutes) pain relief. Lastly, we recently completed a randomized, double-blind, double-dummy clinical trial comparing the analgesic efficacy and safety of nebulized ketamine and intravenous ketamine in managing acute pain in adult ED patients, with data currently being analyzed. Nebulized fentanyl given in the ED to adults with acute traumatic and non-traumatic pain syndromes at a dose range of 1.5-4 mcg/kg showed the same or even better pain-relieving effects than IV fentanyl and IV morphine alone. Our objective is to compare the analgesic efficacy and rates of side effects of a 0.75 mg/kg dose of ketamine administered via breath-actuated nebulizer (BAN) to a dose of 3 mcg/kg of fentanyl administered via breath-actuated nebulizer (BAN) in adult patients presenting to the ED with acute painful conditions.

Will I have to stop taking my current medications?

The trial requires that you have not taken opioids or opioid-related medications within 4-6 hours before arriving and NSAIDs within 6 hours before arriving. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Nebulized Ketamine for acute pain?

Research shows that nebulized ketamine can effectively reduce pain in emergency department patients with acute traumatic pain, as seen in a case series where all patients experienced pain relief after receiving the drug. ^{1 2 3 4 5}

Is nebulized ketamine safe for managing acute pain?

Research shows that low-dose ketamine, whether given intravenously or through a nebulizer, is generally safe for managing acute pain, with no significant adverse events reported in studies comparing it to fentanyl. ^{1 2 5 6 7}

How does nebulized ketamine differ from other drugs for acute pain?

Nebulized ketamine is unique because it is administered through inhalation, which can be more convenient and less invasive than intravenous methods. It provides effective pain relief in sub-dissociative doses, making it a novel option for managing acute pain in emergency settings. ^{1 5 6 7 8}

Research Team

Sergey Motov, MD

Principal Investigator

Maimonides Medical Center

Eligibility Criteria

Adults aged 18-64 in the ED with acute pain who can rate their pain as 5 or higher on a scale, are awake and aware, understand the study's consent process, and can communicate any side effects they experience.

Inclusion Criteria

I am fully aware of who I am, where I am, and the current time.

Demonstrated understanding of the informed consent process and content

I can describe any side effects I experience.

Exclusion Criteria

I have taken opioids or NSAIDs within 6 hours before coming.

Unstable vital signs (systolic blood pressure <90 mmHg or >180 mmHg, pulse rate <50 beats/min or >150 beats/min, and respiration rate <10 breaths/min or >30 breaths/min)

I am unable to give consent by myself.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive nebulized ketamine or fentanyl via breath-actuated nebulizer for acute pain management in the ED

Up to 120 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including pain scores and adverse effects

2 hours

1 visit (in-person)

Treatment Details

Interventions

• Nebulized Fentanyl
• Nebulized Ketamine

Trial Overview The trial is testing nebulized ketamine against nebulized fentanyl for emergency department patients. It aims to see which one is better at managing pain when IV access isn't available or practical.

Participant Groups

Group I: Nebulized KetaBAN Active Control 1 Intervention

Nebulized ketamine administered at 0.75 mg/kg via BAN to adult patients presenting to the ED of Maimonides Medical Center with acute painful conditions of moderate to severe intensity.

Group II: Nebulized FentaBAN Active Control 1 Intervention

Nebulized fentanyl administered at 3 mcg/kg via BAN to adult patients presenting to the ED of Maimonides Medical Center with acute painful conditions of moderate to severe intensity.

Nebulized Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Induction of anesthesia
• Maintenance of anesthesia
• Pain management
• Sedation

Approved in European Union as Ketalar for:

• Induction of anesthesia
• Maintenance of anesthesia
• Pain management
• Sedation

Approved in Canada as Ketalar for:

• Induction of anesthesia
• Maintenance of anesthesia
• Pain management
• Sedation

Who Is Running the Clinical Trial?

Antonios Likourezos

Lead Sponsor

Trials

41

Recruited

8,600+

Findings from Research

Intranasal ketamine is effective for managing acute pain in children, showing similar pain reduction compared to intranasal fentanyl, based on a meta-analysis of 4 trials involving 276 patients.

While ketamine had a higher risk of non-serious adverse events compared to fentanyl, it did not lead to any serious adverse events, making it a potential alternative to opioids for pediatric pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal ketamine for acute pain management in children: A systematic review and meta-analysis. Oliveira J E Silva, L., Lee, JY., Bellolio, F., et al.[2021]

In a study involving 22 children with moderate to severe pain, intranasal (IN) ketamine did not provide better pain relief compared to IN fentanyl after 20 minutes, indicating that ketamine may be less effective for acute pain management in this setting.

The ketamine group experienced significantly more adverse effects, including sedation and dizziness, with 64% of patients showing sedation compared to none in the fentanyl group, raising concerns about its safety profile in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic Efficacy of Intranasal Ketamine Versus Intranasal Fentanyl for Moderate to Severe Pain in Children: A Prospective, Randomized, Double-Blind Study. Quinn, K., Kriss, S., Drapkin, J., et al.[2023]

Intranasal ketamine resulted in a higher frequency of minor side effects compared to intranasal fentanyl, but no serious adverse events were reported, indicating it is generally safe for use in children with acute pain.

Both ketamine and fentanyl provided similar levels of pain relief at 20 minutes, suggesting that ketamine could be a viable alternative to opioids for managing acute pain in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures. Reynolds, SL., Bryant, KK., Studnek, JR., et al.[2019]

In a study of 80 children aged 3 to 13 with moderate to severe limb pain, both intranasal fentanyl and ketamine provided similar pain relief, with median reductions of 40 mm and 45 mm respectively at 30 minutes after administration.

Ketamine was associated with a higher incidence of mild adverse events (78%) compared to fentanyl (40%), indicating that while both medications are effective, ketamine may have a higher risk of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Graudins, A., Meek, R., Egerton-Warburton, D., et al.[2022]

In a case series of five adult patients in the emergency department, nebulized ketamine provided effective pain relief for acute traumatic pain, with all patients reporting decreased pain levels within 120 minutes after administration.

The study utilized varying doses of nebulized ketamine (1.5 mg/kg, 0.75 mg/kg, and 1 mg/kg), suggesting that inhalation may be a promising method for pain management in emergency settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of Nebulized Ketamine for Managing Acute Pain in the Emergency Department: A Case Series. Drapkin, J., Masoudi, A., Butt, M., et al.[2020]

In a study of 79 matched pairs of adult patients with severe pain, low-dose intravenous ketamine resulted in a significantly greater reduction in pain compared to intravenous fentanyl, with a mean decrease of -5.5 versus -2.5 on the pain scale.

Patients receiving ketamine also had a higher response rate, with 67% achieving at least a 50% reduction in pain, and no clinically significant adverse events were reported, suggesting that ketamine is a safe and effective option for prehospital pain management.

NCBI (Pubmed)

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. Bronsky, ES., Koola, C., Orlando, A., et al.[2020]

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]

In a study involving 41 children with acute pain, nebulized fentanyl citrate (3.0 microg/kg) provided significant pain relief, with a mean decrease of 77.8 mm on the pain scale, compared to 55.1 mm for intravenous fentanyl (1.5 microg/kg).

Nebulized fentanyl was found to be a feasible alternative to intravenous fentanyl for pain management in children older than 3 years, with no adverse events reported, although younger patients had difficulties using the nebulizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to the emergency department with acute pain. Miner, JR., Kletti, C., Herold, M., et al.[2022]

References

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

Intranasal ketamine for acute pain management in children: A systematic review and meta-analysis. [2021]

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

Analgesic Efficacy of Intranasal Ketamine Versus Intranasal Fentanyl for Moderate to Severe Pain in Children: A Prospective, Randomized, Double-Blind Study. [2023]

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

Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures. [2019]

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

The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. [2022]

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

Administration of Nebulized Ketamine for Managing Acute Pain in the Emergency Department: A Case Series. [2020]

6. 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]

7. 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]

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

Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to the emergency department with acute pain. [2022]