Disclosed are compositions for treatment of pain comprising a first compound and a second compound, where the first compound is an opioid antagonist that treats pain by blocking Toll-like receptor 4 (TLR4) and the second compound is a direct-acting alpha-2 adrenergic agonist that enhances the pain treatment effect and abates adverse effects of the first compound, synergistic pharmaceutical compositions thereof, and their use in the treatment, prevention, and reversal of pain, particularly neuropathic pain.
