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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding a tiny amount of naloxone, a drug that blocks opioid effects, can prevent increased pain sensitivity and drug tolerance after surgery when using the painkiller remifentanil (also known as Ultiva). The trial includes three groups: one receiving a low dose of remifentanil, another receiving a high dose plus a placebo, and a third receiving a high dose plus a very low dose of naloxone. The researchers aim to determine if the group with naloxone experiences less pain sensitivity than the placebo group. This trial seeks participants scheduled for posterior spinal fusion surgery. As a Phase 2 trial, it focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, low-dose remifentanil proved safe for patients during surgeries, without causing major issues like hyperalgesia, which is increased sensitivity to pain. Another study showed that higher doses of remifentanil could lead to this increased pain sensitivity, especially when the medication is stopped.

Research suggests that using high-dose remifentanil with a very small amount of naloxone might lower this risk. Studies indicate that naloxone may help prevent the extra pain sensitivity caused by remifentanil, potentially making it safer for patients.

Overall, the treatments in this trial have shown promise in being well-tolerated, especially with the addition of naloxone. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for hyperalgesia focus on managing symptoms with opioids or non-steroidal anti-inflammatory drugs (NSAIDs). But the investigational combinations of remifentanil and naloxone offer a novel approach. Researchers are excited about these treatments because they explore how remifentanil, an opioid, can be effectively combined with naloxone, which is typically used to counteract opioid effects. The use of ultra-low dose naloxone alongside high-dose remifentanil is particularly promising, as it might help alleviate hyperalgesia without the usual risk of increased sensitivity to pain that opioids can cause. These combinations could potentially enhance pain management while minimizing some of the downsides associated with traditional opioid treatments.

What evidence suggests that this trial's treatments could be effective for hyperalgesia?

This trial will compare different combinations of remifentanil and naloxone. Research has shown that a very small amount of naloxone can prevent the increased sensitivity to pain caused by remifentanil, a pain medication. One study found that adding naloxone to remifentanil reduced this sensitivity after surgery, though it did not change overall pain levels. Another study found that a tiny dose of naloxone with remifentanil improved pain control post-surgery. In contrast, using a high dose of remifentanil alone has been linked to higher pain levels after surgery, lasting up to two days. This trial aims to determine if combining a very small dose of naloxone with remifentanil can better manage pain by reducing this increased sensitivity. ^{1 4 6 7 8}

Who Is on the Research Team?

Ariana Nelson, MD

Principal Investigator

Associate Clinical Professor

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11017745/

Remifentanil-induced hyperalgesia in healthy volunteers The primary outcome was pain intensity assessment at 30 ± 15 minutes after RF or placebo discontinuation, assessed by any pain scale and using any quantitative ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40283953/

Pharmacological Efficacy of Intravenous Magnesium in ... Intravenous magnesium appears beneficial in remifentanil-based anesthesia, but further large-scale, methodologically robust trials are needed to confirm optimal

3. bmcanesthesiol.biomedcentral.com bmcanesthesiol.biomedcentral.com/articles/10.1186/s12871-023-02388-3

Postoperative pain after different doses of remifentanil infusion ... In the present study, the higher pain scores in the high-dose remifentanil regimen lasted for 2 days after surgery. Owing to the absence of ...

4. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0313749

A systematic review and network meta-analysis of preclinical ... Interestingly, reviews of randomised controlled trials suggest that remifentanil does not induce hyperalgesia to a clinically significant degree in healthy ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0952818016000465

Remifentanil and worse patient-reported outcomes ... Our study suggests that remifentanil-based anesthesia is associated with worse pain-related PROs in patients undergoing thyroidectomy despite more frequent ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5898588/

Remifentanil-induced postoperative hyperalgesia Remifentanil administration by target-controlled infusion is effective and safe in the reduction of pain intensity during ambulatory procedure ( ...

7. associationofanaesthetists-publications.onlinelibrary.wiley.com associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/abs/10.1111/anae.13602

Remifentanil tolerance and hyperalgesia: short‐term gain ... Infusion rates greater than 0.2 μg.kg−1.min−1 are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia.

8. clinicalpainadvisor.com clinicalpainadvisor.com/news/low-dose-remifentanil-opioid-induced-hyperalgesia/

Low-Dose Remifentanil Unlikely to Elicit Significant Opioid ... Low-dose remifentanil infusion may be safe for patients undergoing same-day surgical procedures, as outcomes such as clinically significant ...