Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia During a Burn Injury
Condition: Healthy Subjects
MeSH terms: Hyperalgesia; Burns
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Naloxone; Normal saline
Intervention type(s): Drug; Drug
Intervention description(s): active drug infusion; placebo comparator
Other intervention name(s): Naloxon "B. Braun"; Physiologic Saline
Intervention MeSH terms: Naloxone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: burn injury; controlled trial; latent sensitization; naloxone; secondary hyperalgesia; volunteers