Currently, the picture is a little less straight forward with FAAHIs, especially the most well-studied of them so far, URB597. In 2006, Jayamanne, et al., observed that although systemically administered URB597 was effective in a rat model against inflammation-induced allodynia and hyperalgesia, it was not effective when the two types of pain where neuralgia-induced (17). Interpretation of these results is limited, however, by the fact only one dosage was tested. Later that year, a bit more light was shed on the situation by Jhaveri and colleagues. They found that whether or not local administration URB597 was able to inhibit activation of spinal pain neurons in rats with nerve damage was dependent on if the drug was administered to the site of pain or to the spinal neurons themselves. Only administration to the spine inhibited spinal pain neuron activation in a test of hind leg allodynia. Administration of URB597 to the hind leg also did not increase anandamide levels in the hind leg. In rats without nerve damage, URB597 administered to the hind leg increased anandamide levels in the hind leg while decreasing spinal pain nerve activation. Only when a dose large enough to be potentially systemically active was administered to the hind leg of rats with nerve damage was the activation of the spinal nerves by allodynia in these rats inhibited. In further support that this was not a localized action, anandamide levels in the hind leg were not elevated by the larger dose of URB597 (18). The next year in 2007, Russo, et al., tested how URB597 performed in a mouse model of neuropathic allodynia and hyperalgesia bearing greater resemblance to TN than the rat model in the earlier two studies. Using a wide range of oral doses, they found that systemic URB597 dose-dependently inhibited both allodynia and hyperalgesia induced by chronic nerve constriction. The antinociception produced by this FAAHI was blocked by a cannabinoid receptor antagonist with a moderate affinity for the CB1 receptor suggesting the antineuralgia potential of URB597 is primarily CB1 mediated (19). Recently an endogenous chemical related to anandamide but lacking activity at the CB receptors (palmitoylethanolamide a.k.a., PEA) has been identified as being an endogenous FAAHI. A chemical derivative of PEA know as palmitoylallylamide (PAA) was tested in three rat models of neuropathic pain including the one common to many of the other studies covered in this article. It was found to be effective at reducing expression of allodynia and/or hyperalgesia in all three models without effecting motor skills. In the most commonly used rat model of neuralgia discussed so far, antineuralgia effect of PAA was found to be partially inhibited by either CB1 or CB2 antagonism (20).
It appears that anandamide transporter inhibitors like AM404 may prove to be particularly useful in the management of TN. In high enough doses or when applied more directly to the damaged nerve, URB597 may also prove useful. On the plus side, URB597 appears to have a very wide therapeutic margin when administrated orally so larger doses would not likely be an issue. New endogenously derived FAAHI’s may prove more effect against TN and especially well tolerated. One question that has yet to be addressed is how well the two types of endocannabinoid manipulation might perform when administered together as a single combined treatment. This combination may just prove to be the most effective yet.