What is the current status of the cannabinoids to treat pain?
There are two cannabinoid receptors, CB1 and CB2. Both receptors are G protein coupled positively to potassium channels and negatively to N-type and P/Q-type calcium channels, resulting in postsynaptic membrane hyperpolarization and a presynaptic reduction in neurotransmitter release. CB1 receptors are located peripherally and centrally in the nervous system. CB2 receptors are found mainly on inflammatory cells, and activation has potent antiinflammatory effects. There are two families of naturally occurring endocannabinoids, anandamide and 2-arachidonyl glycerol. Both have degrading enzymes, and there have been attempts at developing inhibitors of these enzymes that would theoretically result in higher levels of circulating endocannabinoids and analgesia. An inhibitor of anandamide, fatty acid amino hydrolase, was being developed by Pfizer but failed in clinical trials. However, other companies continue to develop these inhibitors. Cannabidiol (CBD) is a cannabinoid that is promising in that it is a cannabinoid receptor agonist that is void of psychoactive effects seen with tetrahydrocannabinol (THC). Due to the high lipid solubility of the cannabinoids, both transdermal and transmucosal delivery is feasible. Both synthetic and cannabis-based medicinal extracts are being developed for transdermal and transmucosal delivery. Nabixomols is a sublingual spray of a THC: CBD combination approved to treat multiple sclerosis pain in Canada. It was being developed in the United States to treat cancer pain. A phase II study met the primary efficacy endpoint for the low and medium dose, but not the high dose. A phase III trial failed to meet the primary endpoint, and further development is in question.
There is a rapid movement across the United States for the legalization of marijuana for medicinal purposes. Currently 23 states and the District of Columbia have legalized medicinal marijuana, with at least 16 states having ballots for the next elections. Although synthetic and cannabis based extracts are important, they may not completely meet the effects that the whole plant provides, in that there are many active compounds in the plant with medicinal properties. This is a strong argument of many medicinal marijuana advocates. This recently led the American Pain Society to commission the first white paper on medical marijuana, which will hopefully provide physicians with needed guidelines for patients using medical marijuana.
