Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe
burn-associated
pain is typically treated with
opioids such as
fentanyl,
morphine, and
methadone. Side effects of
opioids include
respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of
hyperalgesia, tolerance and dependence. These effects have led us to search for novel
analgesics for the treatment of
burn-associated
pain in wounded combat service members.
Tetrodotoxin (TTX) is a selective
voltage-gated sodium channel blocker currently in clinical trials as an
analgesic. A phase 3 clinical trial for
cancer-related pain has been completed and phase 3 clinical trials on
chemotherapy-induced
neuropathic pain are planned. It has also been shown in mice to inhibit the development of
chemotherapy-induced
neuropathic pain. TTX was originally identified as a
neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive
sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after
burn injuries. To date, the
analgesic effect of TTX has not been tested in
burn-associated
pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 μg/kg) was administered once a day systemically by
subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury.
Thermal hyperalgesia and
mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced
thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on
mechanical allodynia. These results suggest that systemic TTX may be an effective, rapidly acting
analgesic for battlefield
burn injuries and has the potential for replacing or reducing the need for
opioid analgesics.