Effect of Ultra-low Dose Naloxone on Remifentanil-Induced Hyperalgesia

July 3, 2023 updated by: Ariana M. Nelson, University of California, Irvine

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Purpose:

Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or limit opioid tolerance. Remifentanil, a rapid onset/offset opioid that is often used as an anesthesia adjunct intraoperatively, has been associated with the development of hyperalgesia and opioid tolerance postoperatively. Opioid-induced hyperalgesia (OIH) induced by remifentanil intraoperatively may be a factor contributing to an increase in postoperative pain as well as difficulty in controlling such pain. The purpose of this study will be to evaluate whether an ultra-low dose of naloxone, an opioid antagonist, could block remifentanil-induced hyperalgesia and tolerance following surgery.

This research will help elucidate the degree of OIH after surgeries involving remifentanil and determine if a new technique can be employed to decrease remifentanil-induced OIH. By mitigating OIH, patients should have a decrease in postoperative pain and an increase in patient satisfaction at UCI and other hospitals where such a technique is employed.

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).

Background:

Opioid-induced hyperalgesia is a paradoxical increase in pain sensitivity following opioid exposure. The mechanism for this is likely due to an alteration in opioid receptor signaling with disruption of G-protein coupling and opioid-induced activation and hypertrophy of spinal glial cells (gliosis). Opioid-induced hyperalgesia has been noted with many different opioids, and the most well documented hyperalgesic effect is with remifentanil.

Various agents have been used in an attempt to reduce the development hyperalgesia following remifentanil. While there are few reports on the effect of ultra-low dose naloxone on opioid-induced hyperalgesia, recent evidence is emerging regarding its use in pain management. Ultra-low dose naloxone has been shown to prevent remifentanil-induced pain hypersensitivities (allodynia and hyperalgesia) in rats. However, there are little to no studies on reducing the adverse effects of remifentanil with naloxone in human subjects.

Existing knowledge and previous research:

Attempts have been made with various agents to reduce the development of tolerance and hyperalgesia following remifentanil. Postoperative hyperalgesia and its prevention has been studied with ketamine , Magnesium , Gabapentin, Clonidine, Lornoxicam , Dextromethorphan , Paracetamol , Morphine , Dexmedetomidine , Adenosine, COX inhibitors , Amantadine , Nitrous oxide, Fentanyl, Pregabalin , Buprenorphine, Midazolam, Dexamethasone. Relevant to our current hypothesis is the report that concomitant administration of ultra-low dose naloxone and naltrexone with remifentanil prevented OIH. However, there are no studies on reducing the adverse effects of remifentanil with ultra-low dose naloxone in human subjects.

While the traditional role of opiate antagonists have been in cases of opioid overmedication, recent evidence is emerging regarding their use in pain management. Gan et al. 1997 used an ultra-low dose naloxone infusion (0.00025 mg/kg/h or 0.001 mg/kg/h) in postoperative patients receiving IV morphine via a patient-controlled analgesia (PCA) device. Good pain relief was experienced in all groups, however consumption of PCA morphine was significantly reduced in patients that received the lowest infusion of naloxone and opioid-induced side effects (nausea, vomiting, pruritus) were reduced by naloxone at both dose.

Naloxone and/or naltrexone at ultra-low doses may enhance the analgesic effects of opioids, enhance the antinociceptive effects of methadone, and decrease or block the development of opioid tolerance in rodents. The combination of oxycodone with an ultra-low dose of the antagonist naltrexone as a singular oral medication, Oxytrex, has been developed to prevent the development of tolerance in the treatment of moderate to severe chronic pain.

Aguado et. al. 2013 recently evaluated the effects of the opioid antagonist, naloxone, on remifentanil-induced tolerance or hyperalgesia in rats. Hyperalgesia was considered to be a decrease in mechanical nociceptive thresholds (von Frey), while opioid tolerance was considered to be a decrease in sevoflurane MAC reduction by remifentanil. An ultra-low dose of naloxone was able to block remifentanil-induced hyperalgesia and the MAC increase associated with hyperalgesia, but did not change opioid tolerance under inhaled anesthesia.

Study Type

Interventional

Enrollment (Estimated)

105

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • Orange, California, United States, 92868
        • Recruiting
        • UC Irvine Medical Center
        • Contact:
        • Principal Investigator:
          • Aaron Przybysz, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subjects who provide written informed consent.
  • Age 18 years old or older (no upper age limit for inclusion)
  • Gender: male or female.
  • Surgery: Posterior spinal fusions

Exclusion Criteria:

  • Allergy to opiates
  • Chronic pain other than the primary indication for surgery
  • Psychiatric illness
  • History of substance abuse problem including alcohol &/or cannabis
  • BMI > 35
  • Subjects under 18 years of age.
  • Subject without the capacity to give written informed consent. 8. Female subjects who are pregnant

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: LO-low dose remifentanil
low dose remifentanil (LO, 0.1 micrograms/kg/mL),
Drug: Remifentanil
0.1 micrograms/kg/mL
Other Names:
  • LO
Active Comparator: HI-high dose remifentanil with placebo
high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)
Drug: Remifentanil+ Placebo
high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)
Other Names:
  • HI
Active Comparator: HN-high dose remifentanil with ultra-low dose naloxone
high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone).
Drug: Remifentanil +ultra-low dose naloxone
high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone
Other Names:
  • HN

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of Opioid-induced hyperalgesia (OIH)
Time Frame: 24 hr Post-surgery
Mechanical Pain Threshold-determined by von Frey filaments around the incision site
24 hr Post-surgery
Occurrence of Opioid-induced hyperalgesia (OIH)
Time Frame: 48 hr Post-surgery
Mechanical Pain Threshold-determined by von Frey filaments around the incision site
48 hr Post-surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Opioid consumption
Time Frame: 24 hr post surgery
Opioid consumption required to control pain by Oral morphine equivalents
24 hr post surgery
Opioid consumption
Time Frame: 48 hrs post surgery
Opioid consumption required to control pain by Oral morphine equivalents
48 hrs post surgery
Cold Pressure Test
Time Frame: 24 hr post surgery
Pain Threshold and Pain tolerance
24 hr post surgery
Cold Pressure Test
Time Frame: 48 hrs post surgery
Pain Threshold and Pain tolerance
48 hrs post surgery
Visual Analog Scale (VAS) Pain scores
Time Frame: Baseline
VAS pain scores measured prior to surgery and at 4, 8 and 12h after extubation and again at 24h and 48h post-operatively
Baseline
McGill short form questionnaire
Time Frame: Baseline
The McGill questionnaire provides an assessment of pain quality and descriptors
Baseline
Brief Pain Inventory
Time Frame: Baseline
Brief Pain Inventory assesses both pain intensity and pain unpleasantness (the emotional component of pain is considered to be a better metric of subject satisfaction and quality of life).
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Irvine

Investigators

  • Principal Investigator: Ariana Nelson, MD, Associate Clinical Professor

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 25, 2023

Primary Completion (Estimated)

December 31, 2023

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

February 21, 2017

First Submitted That Met QC Criteria

February 23, 2017

First Posted (Actual)

February 28, 2017

Study Record Updates

Last Update Posted (Actual)

July 6, 2023

Last Update Submitted That Met QC Criteria

July 3, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB # 20141345

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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