A Phase 2 interventional study of Remifentanil and Remifentanil+ Placebo in Hyperalgesia, sponsored by University of California, Irvine. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-06-04.
Sponsored by University of California, Irvine · Phase 2, Interventional, and Treatment
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.
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.
166 studies on the registry are indexed under Hyperalgesia; 14 are open to participants now.
This study's enrollment of 8 is below the median of 50 across 142 interventional studies indexed under Hyperalgesia.
Browse Hyperalgesia studies →University of California, Irvine is the lead sponsor of 476 studies on the registry; 98 are open to participants now.
Of its 41 completed or terminated interventional studies of FDA-regulated products, 30 (73%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
low dose remifentanil (LO, 0.1 micrograms/kg/mL),
Drug: Remifentanil
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 ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone).
Drug: Remifentanil +ultra-low dose naloxone
0.1 micrograms/kg/mL
Also known as: LO
high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)
Also known as: HI
high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone
Also known as: HN
Occurrence of Opioid-induced Hyperalgesia (OIH)
Mechanical Pain Threshold-determined by von Frey filaments around the incision site. The force required to elicit a pain response was recorded in grams. Higher values indicate higher pain thresholds (i.e., less hyperalgesia), while lower values indicate greater pain sensitivity.
Time frame: 24 hr Post-surgery
Occurrence of Opioid-induced Hyperalgesia (OIH)
Mechanical Pain Threshold-determined by von Frey filaments around the incision site.The force required to elicit a pain response was recorded in grams. Higher values indicate higher pain thresholds (i.e., less hyperalgesia), while lower values indicate greater pain sensitivity.
Time frame: 48 hr Post-surgery
Opioid Consumption
Opioid consumption required to control pain by Oral morphine equivalents
Time frame: 24 hr post surgery
Opioid Consumption
Opioid consumption required to control pain by Oral morphine equivalents
Time frame: 48 hrs post surgery
Cold Pressure Test
Pain threshold and pain tolerance were assessed using the Cold Pressor Test. Pain threshold was defined as the time to first pain sensation, and pain tolerance as the total duration the participant kept the hand immersed in cold water. Time was recorded in seconds. Higher values indicate greater pain tolerance and lower pain sensitivity.
Time frame: 24 hr post surgery
Cold Pressure Test
Pain Threshold and Pain tolerance
Time frame: 48 hrs post surgery
Visual Analog Scale (VAS) Pain Scores
Visual Analog Scale (VAS) pain scores are measured tp represent the severity of symptoms from 0 "no symptoms" to 10 "very severe symptoms." Its use is standard-of-care and is measured prior to surgery and at 4, 8 and 12h after extubation and again at 24h and 48h post-operatively.
Time frame: Baseline, 4, 8 and 12h after extubation and again at 24h and 48h post-operatively
McGill Short Form Questionnaire
The Short-Form McGill Pain Questionnaire Total Score (SF-MPQ PRI-T) is a validated patient-reported outcome measure assessing pain quality and intensity. The total score (PRI-T) is calculated by summing the 11 sensory descriptor scores (range 0-33) and the 4 affective descriptor scores (range 0-12), resulting in a total score range of 0-45. Each descriptor is rated on a 4-point intensity scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. Higher scores indicate worse pain outcomes, and lower scores indicate less pain.
Time frame: Baseline
Brief Pain Inventory - Average Pain Severity
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).Average pain severity was assessed using the Brief Pain Inventory (BPI). Participants rated their average pain during the past 24 hours on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine).
Time frame: Baseline
| Milestone | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Started | 1 | 1 | 6 |
| Completed | 1 | 1 | 4 |
| Not completed | 0 | 0 | 2 |
| Withdrew: Protocol violation | 0 | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 0 | 1 |
Mechanical Pain Threshold-determined by von Frey filaments around the incision site. The force required to elicit a pain response was recorded in grams. Higher values indicate higher pain thresholds (i.e., less hyperalgesia), while lower values indicate greater pain sensitivity.
| force in grams | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Occurrence of Opioid-induced Hyperalgesia (OIH) | 300 ± 0 | 300 ± 0 | 89.5 ± 137.6 |
Mechanical Pain Threshold-determined by von Frey filaments around the incision site.The force required to elicit a pain response was recorded in grams. Higher values indicate higher pain thresholds (i.e., less hyperalgesia), while lower values indicate greater pain sensitivity.
| force in grams | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Occurrence of Opioid-induced Hyperalgesia (OIH) | 300 ± 0 | 6 ± 0 | 117.3 ± 158.2 |
Opioid consumption required to control pain by Oral morphine equivalents
| milligram morphine equivalents (MME) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Opioid Consumption | 47.6 | 78.9 | 36.4 ± 9.2 |
Opioid consumption required to control pain by Oral morphine equivalents
| milligram morphine equivalents (MME) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Opioid Consumption | 74.8 | 109.6 | 63.4 ± 5.8 |
Pain threshold and pain tolerance were assessed using the Cold Pressor Test. Pain threshold was defined as the time to first pain sensation, and pain tolerance as the total duration the participant kept the hand immersed in cold water. Time was recorded in seconds. Higher values indicate greater pain tolerance and lower pain sensitivity.
| seconds | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| first pain sensation | 50 ± 0 | 60 ± 0 | 23.5 ± 27.7 |
| Pain tolerance | 54 ± 0 | 76 ± 0 | 32.3 ± 27 |
Pain Threshold and Pain tolerance
| seconds | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| first pain sensation | 60 ± 0 | 25 ± 0 | 45.5 ± 36.9 |
| Pain Tolerance | 180 ± 0 | 38 ± 0 | 55 ± 45 |
Visual Analog Scale (VAS) pain scores are measured tp represent the severity of symptoms from 0 "no symptoms" to 10 "very severe symptoms." Its use is standard-of-care and is measured prior to surgery and at 4, 8 and 12h after extubation and again at 24h and 48h post-operatively.
| Scores on a Scale | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| baseline | 8 ± 0 | 5.5 ± 0 | 6.9 ± 1.6 |
| 4 hours | 6 ± 0 | 5 ± 0 | 6.8 ± 2.4 |
| 8 hours | 7 ± 0 | 5 ± 0 | 5 ± 1 |
| 12 hours | 7 ± 0 | 6 ± 0 | 6.3 ± 1.5 |
| 24 hours | 7 ± 0 | 6 ± 0 | 7.3 ± 1.5 |
| 48 hours | 6 ± 0 | 0 ± 0 | 7.8 ± 2.2 |
The Short-Form McGill Pain Questionnaire Total Score (SF-MPQ PRI-T) is a validated patient-reported outcome measure assessing pain quality and intensity. The total score (PRI-T) is calculated by summing the 11 sensory descriptor scores (range 0-33) and the 4 affective descriptor scores (range 0-12), resulting in a total score range of 0-45. Each descriptor is rated on a 4-point intensity scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. Higher scores indicate worse pain outcomes, and lower scores indicate less pain.
| points | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| McGill Short Form Questionnaire | 21 ± 0 | 6 ± 0 | 17.2 ± 14.4 |
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).Average pain severity was assessed using the Brief Pain Inventory (BPI). Participants rated their average pain during the past 24 hours on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine).
| score on a scale | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Brief Pain Inventory - Average Pain Severity | 7 ± 0 | 2 ± 0 | 5.4 ± 2.7 |
Collected over From study enrollment (day of surgery) through 48 hours post-surgery.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| LO-low Dose Remifentanil | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| HI-high Dose Remifentanil With Placebo | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| HN-high Dose Remifentanil With Ultra-low Dose Naloxone | 0/4 (0%) | 0/4 (0%) | 1/4 (25%) |
| Event | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone |
|---|---|---|---|
| Participant found ineligible after enrollmentSocial circumstances | 0/1 | 0/1 | 1/4 |
Eight participants were enrolled. One participant withdrew before completing baseline assessments, and one participant was later determined to meet an exclusion criterion (undisclosed history of substance use disorder) and was removed from all analyses. Therefore, baseline analysis includes the six participants who completed baseline assessments and met eligibility criteria.
| Age, Categorical(Participants) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 0 | 0 | 2 | 2 |
| >=65 years | 1 | 1 | 2 | 4 |
| Age, Continuous(Years) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| Mean | 73 ± 0 | 68 ± 0 | 65 ± 12.75 | 66.83 ± 10.41 |
| Sex: Female, Male(Participants) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| Female | 1 | 1 | 2 | 4 |
| Male | 0 | 0 | 2 | 2 |
| Ethnicity (NIH/OMB)(Participants) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 1 | 4 | 6 |
| Region of Enrollment(participants) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| United States | 1 | 1 | 4 | 6 |
| Cold Pressor Pain Threshold(seconds) | LO-low Dose Remifentanil | HI-high Dose Remifentanil With Placebo | HN-high Dose Remifentanil With Ultra-low Dose Naloxone | Total |
|---|---|---|---|---|
| Mean | 80 ± 0 | 100 ± 0 | 10.25 ± 8.54 | 36.83 ± 36.83 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Feb 2023 to primary completion in Dec 2024, 21 months.
Results were first posted in Jun 2026, 1 year 5 months after primary completion.
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Studies of the drug tested here: Remifentanil
University of California, Irvine →