Clinical trial NCT02684669: Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia During a Burn Injury
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Healthy Subjects
Keywords: burn injury
controlled trial
latent sensitization
naloxone
secondary hyperalgesia
volunteers
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
Collaborators: name: University of Kentucky
First posted: 2016-02-18
Enrollment: 80
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in areas of secondary hyperalgesia will be assessed before and after naloxone/placebo administration by a weighted-pin instrument
timeFrame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury
Secondary outcomes:
measure: Pain during burn injury
timeFrame: Baseline, ½min, 1min, 2min, 3min, 4min, 5min, 6min and 7min during the burn injury
measure: Pin-prick pain thresholds (PPT) assessed by weighted-pin instruments at primary and secondary hyperalgesia areas
timeFrame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 168h 25min after the burn injury
measure: Online Reaction Time
timeFrame: Baseline, 1h, 2h and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min
measure: Clinical Opiate Withdrawal Scale (COWS)
timeFrame: Baseline and 165h, and, (during target-controlled-infusion) 167h 35min, 167h 59min and 168h 25min after the burn injury
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: Baseline
measure: Pain Catastrophizing Scale (PCS)
timeFrame: Baseline
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Neuroscience Center, Copenhagen University Hospital
Study officials:
affiliation: Neuroscience Center, Copenhagen University Hospital, Denmark
name: Mads U Werner, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Physiology, University of Kentucky Medical Center
name: Bradley K Taylor, M.Sc., Ph.D.
role: STUDY_CHAIR
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citation: 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.
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