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

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

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