Cannabis and pain
''Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms.''
Almost 120 of the chemical compounds in the cannabis plant, named phytocannabinoids, have the structure of a cannabinoid. Of these, D9-tetrahydrocannabinol (THC) is the best characterized and the primary psychoactive component of the plant. THC has an impact on many pathophysiological processes, including anti-nociception, through the activation of CB1 and CB2 receptors. However, its clinical utility is limited due to its unwanted central nervous system side effects. Cannabidiol is another important phytocannabinoid gaining attention recently. Unlike THC, it does not cause any psychoactivity, but exerts many positive pharmacological effects, including anti-anxiety, anti-epileptic, anti-bacterial, anti-inflammatory, anti-cancer and anti-diabetic properties. In addition to its wide therapeutic spectrum, cannabidiol is proposed to reverse some of the central side effects of THC. Nabiximols (Sativex®), a herbal cannabis extract containing THC and cannabidiol at a 1:1 ratio in an oromucosal spray, has been approved for the treatment of neuropathic pain and spasticity associated with multiple sclerosis and intractable cancer pain. Dronabinol (Marinol®), a synthetic THC, and its analogue nabilone (Cesamet®) are the currently used synthetic cannabinoids. They have been approved for indications, such as chemotherapy-associated emesis and anorexia associated with AIDS-related weight loss.
To explain how cannabinoids modulate nociception, it is important to understand the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid CB1 and CB2 receptors, endogenous agonists of these receptors, “endocannabinoids”, and the processes playing a role in biosynthesis, release, transport and metabolism of these endogenous lipid-signalling molecules.
Arachidonyl ethanolamide (AEA, anandamide), 2-arachidonylglycerol (2-AG), O-arachidonyl ethanolamine (virodhamine), N-arachidonyl dopamine (NADA), and 2-arachidonyl glyceryl ether (noladin ether) are the putative endocannabinoids. Of these endogenous metabolites of eicosanoid fatty acids, AEA and 2-AG are the best characterized. Endocannabinoids activate CB1 and/or CB2 receptors to modulate physiological and pathological conditions, including memory, appetite, immune function, sleep, stress response, thermoregulation, addiction, and no wonder analgesia.
The discovery of CB1 and CB2 receptors, their endogenous ligands (endocannabinoids), and the processes responsible for the biosynthesis, release, transport and metabolism of these compounds were a huge help in understanding the role of endocannabinoids in various physiological and pathological conditions, including pain modulation. Elevating endocannabinoid levels locally by the inhibition of endocannabinoid degrading enzymes, FAAH and MAGL, using pharmacological agents, and thereby reducing the unwanted central effects of exogenous cannabinoids, will also make an additional contribution to this knowledge.