Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia During a Burn Injury

NCT02684669 | Completed Phase 2 DMC

• 1 other identifier: H-15018869-BI
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

In several rodent studies, it has been demonstrated that very high doses of opioid antagonists (i.e., naloxone 3-10 mg/kg) administered after weeks after recovery from an inflammatory injury may lead to a reinstatement of hyperalgesia and pain behavior. This latent sensitization has recently been demonstrated also to take place in humans. The present study examines if it is possible to foresee individuals who will demonstrate a larger degree of latent sensitization upon challenge with an injury, than others. Using an enriched design high sensitizers (e.g., the upper quartile of individuals developing large areas of secondary hyperalgesia following a mild burn injury) are compared with low sensitizers (lower quartile), regarding the propensity for developing latent sensitization

Conditions

Healthy Subjects

Keywords

burn injury; controlled trial; latent sensitization; naloxone; secondary hyperalgesia; volunteers

Outcome Measures

Primary Outcomes (1)

• Changes in areas of secondary hyperalgesia will be assessed before and after naloxone/placebo administration by a weighted-pin instrument

  The secondary hyperalgesia area is determined using a "weighted-pin" stimulator (PinPrick stimulators, MRC Systems GmbH, Heidelberg, Germany; 128 mN \[2,606 kPa\]). The borders of the areas are assessed by stimulating along eight symmetrical lines, converging towards the center of the burn injury. The stimulation path starts at least 12 cm outside the borders of the burn injury area. The participants are instructed to report, with their eyes closed, when the perception of the stimulus changes from an innocuous pin-prick to a stinging, smarting and unpleasant sensation, and the position is indicated by a marker.

  Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury

Secondary Outcomes (6)

• Pain during burn injury

  Baseline, ½min, 1min, 2min, 3min, 4min, 5min, 6min and 7min during the burn injury

• Pin-prick pain thresholds (PPT) assessed by weighted-pin instruments at primary and secondary hyperalgesia areas

  Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 168h 25min after the burn injury

• Online Reaction Time

  Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min

• Clinical Opiate Withdrawal Scale (COWS)

  Baseline and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury

• Hospital Anxiety and Depression Scale (HADS)

  Baseline

Study Arms (2)

High-dose naloxone

EXPERIMENTAL

naloxone 4 mg/ml i.v. infusion, total 3.25 mg/kg, target controlled infusion with three infusion rates (0.25 mg/kg; 0.75 mg/kg; 2.25 mg/kg) each of 25 min duration.

Drug: Naloxone

Normal saline

PLACEBO COMPARATOR

0.9% physiological saline, i.v. infusion, total 0.81 ml/kg, target controlled infusion with three infusion rates (0.06 ml/kg; 0.19 ml/kg; 0.56 ml/kg) each of 25 min duration.

Drug: Normal saline

Interventions

Naloxone DRUG

active drug infusion

Also known as: Naloxon "B. Braun"

High-dose naloxone

Normal saline DRUG

placebo comparator

Also known as: Physiologic Saline

Normal saline

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male
• Signed informed consent
• Urin-sample without traces of opioids (morphine, methadone, buprenorphine, codeine, tramadol, ketobemidone, oxycodone, hydromorphone, dextro-methorphan)
• ASA I
• Body mass index (BMI): 18 \< BMI \< 30 kg/sq.m
• In addition Days 2-4:
• Secondary hyperalgesia areas 1 hr after a burn injury belonging to the upper quartile (Q3: high-sensitizers \[n = 20\]) or the lower quartile (Q1: low-sensitizers \[n = 20\]) The selection is made during a separate test day (Day 0 \[n = 80\]).

You may not qualify if:

• Participants, who do not speak or understand Danish
• Participants, who cannot cooperate with the investigation
• Allergic reaction against morphine or other opioids (including naloxone)
• Abuse of alcohol or drugs - according to investigator's evaluation
• Use of psychotropic drugs
• Neurologic or psychiatric disease
• Signs of neuropathy in the examination region
• Previous severe trauma to the lower legs with sequelae
• Scarring or tattoos in the examination areas
• Chronic pain condition
• Regular use of analgesic drugs
• Use of prescription drugs one week before the trial
• Use of over-the-counter (OTC) drugs 48 hours before the trial
• Does not develop measurable secondary hyperalgesia areas after BI

Sponsors & Collaborators

• mads u werner: lead
• University of Kentucky: collaborator

Study Sites (1)

Neuroscience Center, Copenhagen University Hospital

Copenhagen, 2100, Denmark

Location

Related Publications (11)

• Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills. 2004 Oct;99(2):679-87. doi: 10.2466/pms.99.2.679-687.

  PMID: 15560360 BACKGROUND

• Taylor BK, Corder G. Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci. 2014;20:283-325. doi: 10.1007/7854_2014_351.

  PMID: 25227929 BACKGROUND

• Werner MU, Pereira MP, Andersen LP, Dahl JB. Endogenous opioid antagonism in physiological experimental pain models: a systematic review. PLoS One. 2015 Jun 1;10(6):e0125887. doi: 10.1371/journal.pone.0125887. eCollection 2015.

  PMID: 26029906 BACKGROUND

• Brennum J, Kaiser F, Dahl JB. Effect of naloxone on primary and secondary hyperalgesia induced by the human burn injury model. Acta Anaesthesiol Scand. 2001 Sep;45(8):954-60. doi: 10.1034/j.1399-6576.2001.450806.x.

  PMID: 11576045 RESULT

• Pielsticker A, Haag G, Zaudig M, Lautenbacher S. Impairment of pain inhibition in chronic tension-type headache. Pain. 2005 Nov;118(1-2):215-23. doi: 10.1016/j.pain.2005.08.019. Epub 2005 Oct 3.

  PMID: 16202520 RESULT

• Koppert W, Filitz J, Troster A, Ihmsen H, Angst M, Flor H, Schuttler J, Schmelz M. Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. J Pain. 2005 Nov;6(11):757-64. doi: 10.1016/j.jpain.2005.07.002.

  PMID: 16275600 RESULT

• Campillo A, Cabanero D, Romero A, Garcia-Nogales P, Puig MM. Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol. 2011 Apr 25;657(1-3):89-96. doi: 10.1016/j.ejphar.2011.01.059. Epub 2011 Feb 4.

  PMID: 21300053 RESULT

• Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403.

  PMID: 24052307 RESULT

• Pereira MP, Werner MU, Ringsted TK, Rowbotham MC, Taylor BK, Dahl JB. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study. PLoS One. 2013 May 31;8(5):e64608. doi: 10.1371/journal.pone.0064608. Print 2013.

  PMID: 23741350 RESULT

• Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU. Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human. PLoS One. 2015 Aug 25;10(8):e0134441. doi: 10.1371/journal.pone.0134441. eCollection 2015.

  PMID: 26305798 RESULT

• Werner MU, Petersen KL, Rowbotham MC, Dahl JB. Healthy volunteers can be phenotyped using cutaneous sensitization pain models. PLoS One. 2013 May 9;8(5):e62733. doi: 10.1371/journal.pone.0062733. Print 2013.

  PMID: 23671631 RESULT

MeSH Terms

Conditions

Burns; Hyperalgesia

Interventions

Naloxone; Saline Solution

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Mads U Werner, MD, DMSc

  Neuroscience Center, Copenhagen University Hospital, Denmark

  PRINCIPAL INVESTIGATOR

• Bradley K Taylor, M.Sc., Ph.D.

  Department of Physiology, University of Kentucky Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, DMSci

Study Record Dates

• First Submitted: February 10, 2016
• First Posted: February 18, 2016
• Study Start: February 1, 2016
• Primary Completion: September 1, 2016
• Study Completion: January 1, 2017
• Last Updated: February 23, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)