HyperalgesiaPhase 2NCT03066739
Effect of Ultra-low Dose Naloxone on Remifentanil-Induced Hyperalgesia
A Phase 2 study testing Remifentanil and Remifentanil +ultra-low dose naloxone in people with Hyperalgesia, run by University of California, Irvine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hyperalgesia
- What is being tested?
- Remifentanil and Remifentanil +ultra-low dose naloxone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Feb 2023to 1 Dec 2025
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Hyperalgesia
- Being tested
- Remifentanil, Remifentanil+ Placebo, Remifentanil +ultra-low dose naloxone
- Medical subject headings
- Hyperalgesia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RemifentanilDrug
Also called LO
0.1 micrograms/kg/mL
Remifentanil+ PlaceboDrug
Also called HI
high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)
Remifentanil +ultra-low dose naloxoneDrug
Also called HN
high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone
| Study group | Role | What they receive |
|---|---|---|
| LO-low dose remifentanil | Active comparator | low dose remifentanil (LO, 0.1 micrograms/kg/mL), Receives: Drug: Remifentanil |
| HI-high dose remifentanil with placebo | Active comparator | high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL) Receives: Drug: Remifentanil+ Placebo |
| HN-high dose remifentanil with ultra-low dose naloxone | Active comparator | high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone). Receives: Drug: Remifentanil +ultra-low dose naloxone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 48 hr Post-surgery
Secondary outcomes (7)
Opioid Consumption
Opioid consumption required to control pain by Oral morphine equivalents
Measured: 24 hr post surgery
Opioid Consumption
Opioid consumption required to control pain by Oral morphine equivalents
Measured: 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.
Measured: 24 hr post surgery
Cold Pressure Test
Pain Threshold and Pain tolerance
Measured: 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.
Measured: 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.
Measured: 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).
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2017
- Study start25 Feb 2023
- Primary completion10 Dec 2024
- Study completion1 Dec 2025
Why it stopped: Study terminated early due to low enrollment. Only 8 participants enrolled out of the target 105.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for HyperalgesiaStudies of the same condition, open and under way.
- More trials run by University of California, IrvineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Irvine
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ariana M. Nelson, University of California, Irvine
- Investigators
- Ariana Nelson, MD, Principal investigator, Associate Clinical Professor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03066739
- Sponsor's protocol ID
- 20141345
- Status last verified
- May 2026
- First submitted
- 21 Feb 2017
- Last updated
- 4 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bekhit MH. Opioid-induced hyperalgesia and tolerance. Am J Ther. 2010 Sep-Oct;17(5):498-510. doi: 10.1097/MJT.0b013e3181ed83a0.
PubMed 20844348Lin SL, Tsai RY, Shen CH, Lin FH, Wang JJ, Hsin ST, Wong CS. Co-administration of ultra-low dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords. Pharmacol Biochem Behav. 2010 Aug;96(2):236-45. doi: 10.1016/j.pbb.2010.05.012. Epub 2010 May 15.
PubMed 20478329King T, Ossipov MH, Vanderah TW, Porreca F, Lai J. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals. 2005;14(4):194-205. doi: 10.1159/000087658.
PubMed 16215302Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998 Jun;86(6):1307-11. doi: 10.1097/00000539-199806000-00033.
PubMed 9620525Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.
PubMed 10910490Hansen EG, Duedahl TH, Romsing J, Hilsted KL, Dahl JB. Intra-operative remifentanil might influence pain levels in the immediate post-operative period after major abdominal surgery. Acta Anaesthesiol Scand. 2005 Nov;49(10):1464-70. doi: 10.1111/j.1399-6576.2005.00861.x.
PubMed 16223391Ma JF, Huang ZL, Li J, Hu SJ, Lian QQ. [Cohort study of remifentanil-induced hyperalgesia in postoperative patients]. Zhonghua Yi Xue Za Zhi. 2011 Apr 12;91(14):977-9. Chinese.
PubMed 21609550Cahill CM, Holdridge SV, Morinville A. Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci. 2007 Jan;28(1):23-31. doi: 10.1016/j.tips.2006.11.003. Epub 2006 Dec 5.
PubMed 17150262Holdridge SV, Armstrong SA, Taylor AM, Cahill CM. Behavioural and morphological evidence for the involvement of glial cell activation in delta opioid receptor function: implications for the development of opioid tolerance. Mol Pain. 2007 Mar 12;3:7. doi: 10.1186/1744-8069-3-7.
PubMed 17352824Yalcin N, Uzun ST, Reisli R, Borazan H, Otelcioglu S. A comparison of ketamine and paracetamol for preventing remifentanil induced hyperalgesia in patients undergoing total abdominal hysterectomy. Int J Med Sci. 2012;9(5):327-33. doi: 10.7150/ijms.4222. Epub 2012 Jun 20.
PubMed 22745573Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.
PubMed 15983467Song JW, Lee YW, Yoon KB, Park SJ, Shim YH. Magnesium sulfate prevents remifentanil-induced postoperative hyperalgesia in patients undergoing thyroidectomy. Anesth Analg. 2011 Aug;113(2):390-7. doi: 10.1213/ANE.0b013e31821d72bc. Epub 2011 May 19.
PubMed 21596876Aguado D, Abreu M, Benito J, Garcia-Fernandez J, Gomez de Segura IA. Effects of naloxone on opioid-induced hyperalgesia and tolerance to remifentanil under sevoflurane anesthesia in rats. Anesthesiology. 2013 May;118(5):1160-9. doi: 10.1097/ALN.0b013e3182887526.
PubMed 23407105Kraemer WJ, Joseph MF, Volek JS, Hoffman JR, Ratamess NA, Newton RU, Fragala MS, French DN, Rubin MA, Scheett TP, McGuigan MR, Thomas GA, Gomez AL, Hakkinen K, Maresh CM. Endogenous opioid peptide responses to opioid and anti-inflammatory medications following eccentric exercise-induced muscle damage. Peptides. 2010 Jan;31(1):88-93. doi: 10.1016/j.peptides.2009.09.031. Epub 2009 Oct 2.
PubMed 19800931Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg. 2003 Mar;96(3):726-732. doi: 10.1213/01.ANE.0000048086.58161.18.
PubMed 12598253
Study at a glance
From the registry record, last updated by the sponsor on 4 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Ultra-low Dose Naloxone on Remifentanil-Induced Hyperalgesia
- ClinicalTrials.gov ID
- NCT03066739
- Acronym / sponsor ID
- 20141345
- Conditions
- Hyperalgesia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study terminated early due to low enrollment. Only 8 participants enrolled out of the target 105.
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University of California, IrvineUniversity, hospital or other
- Study start
- 25 Feb 2023 (actual)
- Primary completion
- 10 Dec 2024 (actual)
- Study completion
- 1 Dec 2025 (actual)
- First posted
- 28 Feb 2017 (actual)
- Results
- Posted 4 Jun 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| LO-low dose remifentanil | Active comparator | Drug: Remifentanillow dose remifentanil (LO, 0.1 micrograms/kg/mL), |
| HI-high dose remifentanil with placebo | Active comparator | Drug: Remifentanil+ Placebohigh dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL) |
| HN-high dose remifentanil with ultra-low dose naloxone | Active comparator | Drug: Remifentanil +ultra-low dose naloxonehigh dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RemifentanilAlso: LO0.1 micrograms/kg/mL | Drug | LO-low dose remifentanil |
| Remifentanil+ PlaceboAlso: HIhigh dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL) | Drug | HI-high dose remifentanil with placebo |
| Remifentanil +ultra-low dose naloxoneAlso: HNhigh dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone | Drug | HN-high dose remifentanil with ultra-low dose naloxone |
Primary outcome
Occurrence of Opioid-induced Hyperalgesia (OIH)
Time frame: 24 hr Post-surgery
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.
Occurrence of Opioid-induced Hyperalgesia (OIH)
Time frame: 48 hr Post-surgery
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.
7 secondary outcomes
Opioid Consumption
Time frame: 24 hr post surgery
Opioid Consumption
Time frame: 48 hrs post surgery
Cold Pressure Test
Time frame: 24 hr post surgery
Cold Pressure Test
Time frame: 48 hrs post surgery
Visual Analog Scale (VAS) Pain Scores
Time frame: Baseline, 4, 8 and 12h after extubation and again at 24h and 48h post-operatively
McGill Short Form Questionnaire
Time frame: Baseline
Brief Pain Inventory - Average Pain Severity
Time frame: Baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 20844348Bekhit MH. Opioid-induced hyperalgesia and tolerance. Am J Ther. 2010 Sep-Oct;17(5):498-510. doi: 10.1097/MJT.0b013e3181ed83a0.
- Background: PubMed 20478329Lin SL, Tsai RY, Shen CH, Lin FH, Wang JJ, Hsin ST, Wong CS. Co-administration of ultra-low dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords. Pharmacol Biochem Behav. 2010 Aug;96(2):236-45. doi: 10.1016/j.pbb.2010.05.012. Epub 2010 May 15.
- Background: PubMed 16215302King T, Ossipov MH, Vanderah TW, Porreca F, Lai J. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals. 2005;14(4):194-205. doi: 10.1159/000087658.
- Background: PubMed 9620525Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998 Jun;86(6):1307-11. doi: 10.1097/00000539-199806000-00033.
- Background: PubMed 10910490Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.
- Background: PubMed 16223391Hansen EG, Duedahl TH, Romsing J, Hilsted KL, Dahl JB. Intra-operative remifentanil might influence pain levels in the immediate post-operative period after major abdominal surgery. Acta Anaesthesiol Scand. 2005 Nov;49(10):1464-70. doi: 10.1111/j.1399-6576.2005.00861.x.
- Background: PubMed 21609550Ma JF, Huang ZL, Li J, Hu SJ, Lian QQ. [Cohort study of remifentanil-induced hyperalgesia in postoperative patients]. Zhonghua Yi Xue Za Zhi. 2011 Apr 12;91(14):977-9. Chinese.
- Background: PubMed 17150262Cahill CM, Holdridge SV, Morinville A. Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci. 2007 Jan;28(1):23-31. doi: 10.1016/j.tips.2006.11.003. Epub 2006 Dec 5.
- Background: PubMed 17352824Holdridge SV, Armstrong SA, Taylor AM, Cahill CM. Behavioural and morphological evidence for the involvement of glial cell activation in delta opioid receptor function: implications for the development of opioid tolerance. Mol Pain. 2007 Mar 12;3:7. doi: 10.1186/1744-8069-3-7.
- Background: PubMed 22745573Yalcin N, Uzun ST, Reisli R, Borazan H, Otelcioglu S. A comparison of ketamine and paracetamol for preventing remifentanil induced hyperalgesia in patients undergoing total abdominal hysterectomy. Int J Med Sci. 2012;9(5):327-33. doi: 10.7150/ijms.4222. Epub 2012 Jun 20.
- Background: PubMed 15983467Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.
- Background: PubMed 21596876Song JW, Lee YW, Yoon KB, Park SJ, Shim YH. Magnesium sulfate prevents remifentanil-induced postoperative hyperalgesia in patients undergoing thyroidectomy. Anesth Analg. 2011 Aug;113(2):390-7. doi: 10.1213/ANE.0b013e31821d72bc. Epub 2011 May 19.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ariana Nelson, MD principal investigator
Associate Clinical Professor
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Remifentanil and Remifentanil +ultra-low dose naloxone in people with Hyperalgesia, run by University of California, Irvine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Jun 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Occurrence of Opioid-induced Hyperalgesia (OIH) (time frame: 24 hr Post-surgery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03066739, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2026.