Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia During a Burn Injury (TCI-NX-BI)

February 21, 2024 updated by: mads u werner

Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia During a Burn Injury. A Randomized, Placebo-controlled, Double-blind Crossover Study

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Naloxone is a mu-opioid-receptor (MOR) antagonist drug, which dose-dependently exhibits hypo-algesic and hyper-algesic properties. Naloxone (and other MOR-antagonists) have been used in research to study the role of endogenous opioids in central processing of pain. It has been hypothesized that the endogenous opioid modulation of pain is impaired or altered in chronic pain conditions.

In a previous study using an electrical pain model in human patients, naloxone (21 microg/kg) increased the established area of secondary hyperalgesia. Further, administration of naloxone and naltrexone to animals following resolution of an inflammatory condition, have demonstrated a reinstatement of hypersensitivity to a noxious stimulus, indicating latent sensitization. It has thus been speculated that endogenous opioids may play an important role in the transition from acute to chronic pain in humans.

Recently, however, the investigators were unable to show reinstatement of secondary hyperalgesia after resolution of a burn injury by administrating naloxone in a low dose (21 microg/kg). Based on these finding the investigators hypothesized, that the negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

The systemic doses of opioid antagonists used in animal studies to demonstrate latent sensitization have been 0.3 to 3.0 mg/kg of naltrexone or 3-10 mg/kg of naloxone. Further, high doses of 1-2 mg/kg of naloxone have been used in clinical and experimental psychiatric, endocrinological, neurological and nutritional studies in patients and healthy individuals. In one pain related study, 6 mg/kg of naloxone was given to healthy patients intramuscularly. Only mild to moderate, transitory side-effects were recorded in these studies.

The investigators, therefore, initiated a second translational study in which it was hypothesized that a higher dose of naloxone (2 mg/kg) would reinstate secondary hyperalgesia in human patients following resolution of a mild burn injury and thus show latent sensitization in humans. The investigators demonstrated in 4 out of 12 patients that naloxone administered 7 days after a mild burn injury was associated with the reinstatement of secondary hyperalgesia.

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.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Neuroscience Center, Copenhagen University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • 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]).

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Normal saline
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
placebo comparator
Other Names:
  • Physiologic Saline
Experimental: High-dose naloxone
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
active drug infusion
Other Names:
  • Naloxon "B. Braun"

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in areas of secondary hyperalgesia will be assessed before and after naloxone/placebo administration by a weighted-pin instrument
Time Frame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pain during burn injury
Time Frame: Baseline, ½min, 1min, 2min, 3min, 4min, 5min, 6min and 7min during the burn injury
Assessments are obtained by a visual analog rating scale (VAS)
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
Time Frame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 168h 25min after the burn injury
Pin-prick pain thresholds (PPTs) in the primary BI-area and in the secondary hyperalgesia area are assessed by "weighted-pin" stimulators (8 to 512 mN [81 to 10,424 kPa]), starting with the lightest pin-prick stimulator (8 mN), and applying a modified Dixon's up-and-down technique. Participants are instructed to report the number of stimuli perceived as unpleasant after a total of five pin-prick stimuli. The lowest pinprick force associated with ≥ 3 unpleasant stimuli is defined as the PPT. The median value of the five PPTs is used in further data analysis. The PPT-data (8, 16, 32, 64, 128, 256, 512 mN) are converted to corresponding ordinal values 1 to 8, where the "cut-off" value of 8 is registered if no pain is elicited during assessment with the heaviest pin-prick stimulator (512 mN).
Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 168h 25min after the burn injury
Online Reaction Time
Time Frame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min
Online Reaction Time is measured using http://getyourwebsiteherecom/jswb/rttest01.htm. This computer-application shows a red-green traffic light. Participants are instructed to press the button when the light changes from red to green. Three measurements are used and the median value is used as a representative estimate of reaction time.
Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min
Clinical Opiate Withdrawal Scale (COWS)
Time Frame: Baseline and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury
The Clinical Opiate Withdrawal Scale (COWS) is an examiner-based scale evaluating signs of opioid-withdrawal. Grading of symptoms, i.e. heart rate changes, sweating, restlessness, pupil size, bone or joint aches, running nose or tearing, nausea, vomiting, diarrhea, tremor, yawning, anxiety or irritability and "goose-flesh", are made in 11 categories. COWS-scores are divided into: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe ;> 36 = severe withdrawal reactions.
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)
Time Frame: Baseline
The Hospital Anxiety and Depression Scale (HADS) is used to assess anxiety and signs of depression. Based on 14 questions about the subject's status in the previous week, HADS measures agitation/anxiety and depression via two subscales (each containing seven questions). Participants have to answer each question on a scale of 0 to 3. The two subscales are summed separately. The maximum score of each subscale is 21 points and a score of 11 or more points suggests that the participant might be suffering from anxiety or depression. In case of score > 11 points in the depression subscale of the HADS, a physician will decide if there are clinical signs of depression. If there are signs of depression, this diagnosis will be told to the participant. The participant will be informed that the diagnosis of depression is based on clinical assessments - the HADS scale can be included in the diagnostic procedure. If it is the participants wish, he should visit his general practitioner for diagnosis
Baseline
Pain Catastrophizing Scale (PCS)
Time Frame: Baseline
The Pain Catastrophizing Scale (PCS) consists of 13 questions divided into three sections: rumination, exaggeration and helplessness. The questions are answered in accordance to a scale of 0 to 4. There is evidence of catastrophizing thoughts at a total score > 30 points.
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

mads u werner

Collaborators

University of Kentucky

Investigators

  • Principal Investigator: Mads U Werner, MD, DMSc, Neuroscience Center, Copenhagen University Hospital, Denmark
  • Study Chair: Bradley K Taylor, M.Sc., Ph.D., Department of Physiology, University of Kentucky Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2016

Primary Completion (Actual)

September 1, 2016

Study Completion (Actual)

January 1, 2017

Study Registration Dates

First Submitted

February 10, 2016

First Submitted That Met QC Criteria

February 17, 2016

First Posted (Estimated)

February 18, 2016

Study Record Updates

Last Update Posted (Actual)

February 23, 2024

Last Update Submitted That Met QC Criteria

February 21, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-15018869-BI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No plan to make individual participant data (IPD) available

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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