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

Sponsor

mads u werner (Other)

Overall Status

Completed

CT.gov ID

NCT02684669

Collaborator

University of Kentucky (Other)

Enrollment

Location

Arms

Duration (Months)

7.3

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects	Drug: Naloxone Drug: Normal saline	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

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

Study Start Date :

Feb 1, 2016

Actual Primary Completion Date :

Sep 1, 2016

Study Completion Date :

Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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"
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

Arm

Intervention/Treatment

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"

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Pain during burn injury [Baseline, ½min, 1min, 2min, 3min, 4min, 5min, 6min and 7min during the burn injury]
Assessments are obtained by a visual analog rating scale (VAS)
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]
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).
Online Reaction Time [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.
Clinical Opiate Withdrawal Scale (COWS) [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.
Hospital Anxiety and Depression Scale (HADS) [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
Pain Catastrophizing Scale (PCS) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neuroscience Center, Copenhagen University Hospital	Copenhagen		Denmark	2100

Sponsors and Collaborators

mads u werner
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