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

NCT03066739 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: 20141345
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperalgesia

Outcome Measures

Primary Outcomes (2)

• Occurrence of Opioid-induced hyperalgesia (OIH)

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

  24 hr Post-surgery

• Occurrence of Opioid-induced hyperalgesia (OIH)

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

  48 hr Post-surgery

Secondary Outcomes (7)

• Opioid consumption

  24 hr post surgery

• Opioid consumption

  48 hrs post surgery

• Cold Pressure Test

  24 hr post surgery

• Cold Pressure Test

  48 hrs post surgery

• Visual Analog Scale (VAS) Pain scores

  Baseline

Study Arms (3)

LO-low dose remifentanil

ACTIVE COMPARATOR

low dose remifentanil (LO, 0.1 micrograms/kg/mL),

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)

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).

Drug: Remifentanil +ultra-low dose naloxone

Interventions

Remifentanil DRUG

0.1 micrograms/kg/mL

Also known as: LO

LO-low dose remifentanil

Remifentanil+ Placebo DRUG

high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL)

Also known as: HI

HI-high dose remifentanil with placebo

Remifentanil +ultra-low dose naloxone DRUG

high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone

Also known as: HN

HN-high dose remifentanil with ultra-low dose naloxone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects who provide written informed consent.
• Gender: male or female.
• Surgery: Posterior spinal fusions

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Irvine: lead

Study Sites (1)

UC Irvine Medical Center

Orange, California, 92868, United States

Location

Related Publications (20)

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  PMID: 20844348 BACKGROUND

• Lin 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.

  PMID: 20478329 BACKGROUND

• King 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.

  PMID: 16215302 BACKGROUND

• Vinik 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.

  PMID: 9620525 BACKGROUND

• Guignard 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.

  PMID: 10910490 BACKGROUND

• Hansen 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.

  PMID: 16223391 BACKGROUND

• Ma 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.

  PMID: 21609550 BACKGROUND

• Cahill 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.

  PMID: 17150262 BACKGROUND

• Holdridge 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.

  PMID: 17352824 BACKGROUND

• Yalcin 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.

  PMID: 22745573 BACKGROUND

• Joly 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.

  PMID: 15983467 BACKGROUND

• Song 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.

  PMID: 21596876 BACKGROUND

• Aguado 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.

  PMID: 23407105 BACKGROUND

• Kraemer 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.

  PMID: 19800931 BACKGROUND

• Luginbuhl 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.

  PMID: 12598253 BACKGROUND

• Sen H, Sizlan A, Yanarates O, Emirkadi H, Ozkan S, Dagli G, Turan A. A comparison of gabapentin and ketamine in acute and chronic pain after hysterectomy. Anesth Analg. 2009 Nov;109(5):1645-50. doi: 10.1213/ANE.0b013e3181b65ea0.

  PMID: 19843803 BACKGROUND

• Xuerong Y, Yuguang H, Xia J, Hailan W. Ketamine and lornoxicam for preventing a fentanyl-induced increase in postoperative morphine requirement. Anesth Analg. 2008 Dec;107(6):2032-7. doi: 10.1213/ane.0b013e3181888061.

  PMID: 19020155 BACKGROUND

• Lopez-Alvarez S, Mayo-Moldes M, Zaballos M, Iglesias BG, Blanco-Davila R. Esmolol versus ketamine-remifentanil combination for early postoperative analgesia after laparoscopic cholecystectomy: a randomized controlled trial. Can J Anaesth. 2012 May;59(5):442-8. doi: 10.1007/s12630-012-9684-x. Epub 2012 Mar 2.

  PMID: 22383085 BACKGROUND

• Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.

  PMID: 12826855 BACKGROUND

• Engelhardt T, Zaarour C, Naser B, Pehora C, de Ruiter J, Howard A, Crawford MW. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg. 2008 Oct;107(4):1170-5. doi: 10.1213/ane.0b013e318183919e.

  PMID: 18806023 BACKGROUND

MeSH Terms

Conditions

Hyperalgesia

Interventions

Remifentanil

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Ariana Nelson, MD

  Associate Clinical Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Clinical Professor

Study Record Dates

• First Submitted: February 21, 2017
• First Posted: February 28, 2017
• Study Start: February 25, 2023
• Primary Completion: December 10, 2024
• Study Completion: December 10, 2024
• Last Updated: May 25, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)