CANNABINOIDS FOR NEUROPATHIC PAIN
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Treatment options for neuropathic pain have limited efficacy and use is fraught with dose-limiting adverse effects. The endocannabinoid system has been elucidated over the last several years, demonstrating a significant interface with pain homeostasis. Exogenous cannabinoids have been demonstrated to be effective in a range of experimental neuropathic pain models, and there is mounting evidence for therapeutic use in human neuropathic pain conditions. This article reviews the history, pharmacologic development, clinical trials results, and the future potential of nonsmoked, orally bioavailable, nonpsychoactive cannabinoids in the management of neuropathic pain.
ENDOCANNABINOID SYSTEM, CANNABINOIDS AND PAIN
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The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB1 receptors) and in the periphery (primarily but not exclusively CB2 receptors) are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids) and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking), as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.
Pain is an unpleasant, commonly occurring, and universal human experience; it is also a very complex phenomenon. The experience of pain and the resultant emotional state depends as much or perhaps more on the contextual circumstances (how, when, where, and why) of the pain-inciting event as the intensity of the noxious stimulus. And a seemingly similar pain-producing event may be experienced (and communicated) quite differently from person to person, situation to situation, and among various cultures. The neurophysiology of acute pain due to a brief single noxious event is best understood. The nociceptive components of the peripheral and central nervous systems are highly refined to signal warnings of potential or actual tissue damage; reflex and conscious responses are usually adaptive for self-protection. Fortunately, most occurrences of pain are self-limited, resolving quickly with discontinuation of the noxious stimulus or in tandem with tissue healing or resolution of the insult to somatic or visceral structures.
But pain that continues relentlessly due to on-going nociceptive stimulation from unresolved disease (nociceptive pain) or pathophysiological changes within the nervous system (neuropathic pain) serves little purpose. In contrast to acute pain, unresolved pain leads to subliminal and conscious reflex responses that are often maladaptive. It imparts a tremendous burden on the pain sufferer’s health, social interactions, occupational performance, emotional state, and finances. In turn, chronic pain incurs a significant direct and indirect financial toll on society. In evaluating the prevalence and impact of pain, a recent report by the National Academy of Sciences’ Institute of Medicine concluded that pain-related medical services and loss of productivity cost the United States economy close to one trillion US dollars annually when pain-related costs associated with patients in long-term care and within the military are included.