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14 cannabis patient care | vol. 3 no. 1 cannapatientcare.com research focus Cannabinoid receptors are "strategically located" along the pathways of both the central and peripheral nervous system "where pain signaling is intricately controlled" (14). The ECS mediates pain signals as they ascend and descend pain path- ways by acting on cannabinoid receptors located on peripher- al nerves, within the spine, and within the brain (13–16). Can- nabis can thus be used to mitigate overactive pain activity along the body's pain signaling pathways. Modify Pain Perception Cannabis can reduce chronic pain by changing how we perceive and experience pain in several respects. First, independently of the strength of the stimulus, nega- tive emotional states, including anxiety and depression, can exacerbate pain experiences. Cannabis's ability to reduce both anxiety and depression have been well-documented (17). Cannabis thus reduces pain by mitigating negative emotional states that exacerbate sensations of pain. Second, cannabis can reduce chronic pain experiences by helping to distract us from focusing our attention on pain (18,19). And third, while cannabis may not decrease the intensity of pain, it has been found to decrease the perceived unpleasant- ness of pain (20–22). Other In addition to its direct mechanisms for addressing pain, cannabis also indirectly aids in reducing pain through indirect mechanisms, including improving sleep, and reducing the need for other pain medications. Enhance Sleep Lack of sleep exacerbates perceptions of pain directly as well as indirectly, by exacerbating mood disorders (anxiety and de- pression) and attention problems, which themselves exacerbate pain. Many researchers have thus noted the benefits of using cannabis to "normalize" patients' sleep, which, in turn, helps decrease pain (24–26). Decreased Use of Opioids One of the increasingly celebrated benefits of cannabis is the associated reduction in use of other pain medications, notably opioids. A substantial body of research describes how opiates and cannabinoids complement each other. The two substances "use overlapping signaling systems in the body having to do with drug tolerance, pain, and dependence" (27). As a result, supplementation of opioid use with cannabis can decrease, if not eliminate, the need for opioids (27–30). In fact, studies have shown that Medicare reimbursements for opioids significantly decrease after states legalize medical cannabis (31). Clinical Trials There have been many clinical studies performed to assess to efficacy of cannabis for treating pain. One way to summarize the f indings is by study type. A good number of sur veys—several of them are sur veys of hundreds or thousands of patient s—consistently repor t that most medical cannabis patient s use cannabis to treat pain, depression or anxiety, and sleep. Fur thermore, sur vey par ticipant s generally repor t cannabis as being ef fec tive for these uses. Additionally, there have been a fair number of placebo-controlled studies of cannabis for pain. Some three and a half dozen randomized controlled trials and an additional three dozen (non-randomized) placebo-con- trolled trials have been per formed to assess cannabis Figure 3