Naloxone + Remifentanil for Hyperalgesia

Overseen By Ariana Nelson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Disqualifiers: Allergy to opiates, Chronic pain, Psychiatric illness, Substance abuse, BMI > 35, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Intraoperative

8 Participants Needed

Trial Summary

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's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination of Naloxone and Remifentanil for reducing hyperalgesia?

Research shows that using low-dose naloxone with high-dose remifentanil during surgery can reduce increased sensitivity to pain (hyperalgesia) after surgery, compared to using remifentanil alone. ^{1 2 3 4 5}

Is the combination of Naloxone and Remifentanil safe for humans?

Remifentanil, often used in anesthesia, can increase pain after surgery and is not approved for certain types of administration due to safety concerns. It may cause hyperalgesia (increased sensitivity to pain) and interacts with specific receptors in the body, which complicates its effects. ^{2 3 4 5 6}

How is the drug Ultiva (remifentanil) unique for treating hyperalgesia?

Ultiva (remifentanil) is unique because it is a potent, short-acting opioid that can increase pain sensitivity (hyperalgesia) by directly activating NMDA receptors, which are involved in pain transmission. This makes its use in treating hyperalgesia complex, as it may both relieve and exacerbate pain. ^{2 3 4 5 6}

What is the purpose of this trial?

The purpose of this study is to evaluate whether using ultra-low dose naloxone, an opioid antagonist, has the potential to block remifentanil-induced hyperalgesia and tolerance following surgery. There are 3 study groups: (1) low dose remifentanil (LO, 0.1 micrograms/kg/mL), (2) high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL), or (3) high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone). The hypothesis of the study is that occurrence of remifentanil-induced hyperalgesia (low score in mechanical pain threshold) in the HN group will be lower than in the HI group.

Research Team

Ariana Nelson, MD

Principal Investigator

Associate Clinical Professor

Eligibility Criteria

This trial is for adults of any gender, aged 18 or older, who are undergoing posterior spinal fusion surgery and can give written consent. It's not for those with opiate allergies, chronic pain unrelated to their surgery, psychiatric illnesses, substance abuse issues including alcohol or cannabis, a BMI over 35, or pregnant women.

Inclusion Criteria

Subjects who provide written informed consent

I have had a spinal fusion surgery on my back.

I am either male or female.

Exclusion Criteria

You have a mental illness.

You have had problems with alcohol or cannabis abuse in the past.

I have chronic pain not related to the reason I need surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either low dose remifentanil, high dose remifentanil with placebo, or high dose remifentanil with ultra-low dose naloxone during surgery

Intraoperative

1 visit (in-person)

Immediate Postoperative Monitoring

Participants are monitored for pain and opioid-induced hyperalgesia using various pain scales and questionnaires

48 hours

Continuous monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Remifentanil
• Ultra-low dose naloxone

Trial Overview The study tests if ultra-low dose naloxone can prevent increased sensitivity to pain caused by remifentanil after surgery. Participants will be divided into three groups: one receiving low-dose remifentanil; another high-dose with placebo; and the last group high-dose with ultra-low dose naloxone.

Participant Groups

Group I: LO-low dose remifentanil Active Control 1 Intervention

low dose remifentanil (LO, 0.1 micrograms/kg/mL),

Group II: HI-high dose remifentanil with placebo Active Control 1 Intervention

high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)

Group III: HN-high dose remifentanil with ultra-low dose naloxone Active Control 1 Intervention

high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone).

Remifentanil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ultiva for:

• Anesthesia adjunct
• Pain management

Approved in European Union as Ultiva for:

• General anesthesia
• Pain relief

Approved in Canada as Ultiva for:

• Anesthesia adjunct
• Pain management

Approved in Japan as Ultiva for:

• General anesthesia
• Pain relief

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Findings from Research

Intraoperative use of low-dose naloxone alongside high-dose remifentanil significantly reduced the incidence of postoperative hyperalgesia compared to high-dose remifentanil alone, indicating a potential strategy to mitigate pain sensitivity after surgery.

Despite the reduction in hyperalgesia, the combination treatment did not affect overall pain intensity or analgesic consumption post-surgery, suggesting that while naloxone can help with hyperalgesia, it does not compromise the analgesic effects of remifentanil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial. Koo, CH., Yoon, S., Kim, BR., et al.[2022]

In a case involving a nurse's death, remifentanil was not detected in her system, despite the presence of its metabolite GR90291 in various organs, indicating that remifentanil may have been metabolized quickly or not used shortly before death.

Midazolam was found in both blood samples and hair analysis, suggesting its use, while benzodiazepines were the only substances detected in standard toxicology screenings, highlighting the need for specialized testing for certain drugs like remifentanil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suicide with remifentanil and midazolam: a case report. Asselborn, G., Yegles, M., Wennig, R.[2018]

Ultiva® (remifentanil) hyperpolarizes spinal dorsal horn neurons and suppresses excitatory synaptic responses, indicating it can effectively reduce nociceptive transmission in the spinal cord.

The analgesic effects of Ultiva® when administered intrathecally differ from its intravenous use, primarily acting through glycine receptors rather than μ-opioid receptors, which may explain its potential to provoke opioid-induced hyperalgesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct Effect of Remifentanil and Glycine Contained in Ultiva® on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses. Sumie, M., Shiokawa, H., Yamaura, K., et al.[2022]

The study found that the remifentanil formulation Ultiva stimulates human NMDA receptors, which may explain its association with increased postoperative pain and analgesic requirements, based on experiments conducted on Xenopus laevis oocytes.

Ultiva activates NMDA receptors through an allosteric mechanism, with a much lower effective concentration (EC50) compared to traditional agonists like glutamate, indicating a unique interaction that could influence pain management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes. Hahnenkamp, K., Nollet, J., Van Aken, HK., et al.[2019]

Accidental epidural administration of Ultiva™, which contains remifentanil and glycine, led to significant respiratory depression and loss of consciousness in a patient, highlighting the risks associated with its use outside approved methods.

The case suggests that both remifentanil and glycine may diffuse into the cerebrospinal fluid, causing severe side effects, and emphasizes the importance of adhering to approved administration routes for safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accidental administration of the remifentanil formulation Ultiva™ into the epidural space and the complete time course of its consequences: a case report. Nishimoto, K., Sakamoto, S., Mikami, M., et al.[2022]

Remifentanil hydrochloride does not directly activate NMDA receptors, but it can enhance the NMDA-induced current in neurons, indicating a complex interaction rather than a direct effect.

The NMDA current observed with Ultiva (which includes remifentanil and glycine) is primarily due to glycine, and the potentiation of this current by remifentanil involves mu-opioid receptors, suggesting a mechanism that could contribute to postoperative pain management challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord. Guntz, E., Dumont, H., Roussel, C., et al.[2022]

References

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

Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial. [2022]

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

Suicide with remifentanil and midazolam: a case report. [2018]

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

Direct Effect of Remifentanil and Glycine Contained in Ultiva® on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses. [2022]

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

Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Accidental administration of the remifentanil formulation Ultiva™ into the epidural space and the complete time course of its consequences: a case report. [2022]

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

Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord. [2022]