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

Sponsor
University of California, Irvine (Other)
Overall Status
Recruiting
CT.gov ID
NCT03066739
Collaborator
(none)
105
Enrollment
1
Location
3
Arms
7.3
Anticipated Duration (Months)
14.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Remifentanil
  • Drug: Remifentanil+ Placebo
  • Drug: Remifentanil +ultra-low dose naloxone
 Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
105 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Effect of Ultra-low Dose Naloxone on Remifentanil-Induced Hyperalgesia
Actual Study Start Date :
Aug 23, 2021
Anticipated Primary Completion Date :
Apr 1, 2022
Anticipated Study Completion Date :
Apr 1, 2022

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Occurrence of Opioid-induced hyperalgesia (OIH) [24 hr Post-surgery]

      Mechanical Pain Threshold-determined by von Frey filaments around the incision site

    2. Occurrence of Opioid-induced hyperalgesia (OIH) [48 hr Post-surgery]

      Mechanical Pain Threshold-determined by von Frey filaments around the incision site

    Secondary Outcome Measures

    1. Opioid consumption [24 hr post surgery]

      Opioid consumption required to control pain by Oral morphine equivalents

    2. Opioid consumption [48 hrs post surgery]

      Opioid consumption required to control pain by Oral morphine equivalents

    3. Cold Pressure Test [24 hr post surgery]

      Pain Threshold and Pain tolerance

    4. Cold Pressure Test [48 hrs post surgery]

      Pain Threshold and Pain tolerance

    5. Visual Analog Scale (VAS) Pain scores [Baseline]

      VAS pain scores measured prior to surgery and at 4, 8 and 12h after extubation and again at 24h and 48h post-operatively

    6. McGill short form questionnaire [Baseline]

      The McGill questionnaire provides an assessment of pain quality and descriptors

    7. Brief Pain Inventory [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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UC Irvine Medical Center Orange California United States 92868

    Sponsors and Collaborators

    • University of California, Irvine

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    University of California, Irvine
    ClinicalTrials.gov Identifier:
    NCT03066739
    Other Study ID Numbers:
    • UCIANES10 [HS# 2014-1345]
    First Posted:
    Feb 28, 2017
    Last Update Posted:
    Nov 16, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Additional relevant MeSH terms:
    Hyperalgesia
    Remifentanil
    Naloxone

    Study Results

    No Results Posted as of Nov 16, 2021