How do you treat Chronic Pain?
Cannabis and its components are being widely used for chronic pain, especially given the multifaceted and persistent nature of chronic pain in many conditions . Cannabidiol (CBD), one of the major phytocannabinoids, has gained significant attraction because it is devoid of the psychoactive effects associated with tetrahydrocannabinol (THC), another major constituent of cannabis (Leweke et al., 2012). With the recent rescheduling (Schedule V) of CBD as Epidiolex for the treatment of Dravet and Lennox-Gastaut syndromes there has been a major shift in the view of these ancient molecules for their medicinal potential (Laux et al., 2019). Preclinical and clinical studies have indicated a potential benefit of CBD use in chronic pain associated with multiple conditions (Wade et al., 2003). However, increasing access to cannabis derived products especially CBD partly because of their approval for recreational and medicinal use in the United States poses risks with inadvertent side-effects from overuse, contamination with adulterants in preparation or harsh chemicals in the plant cultivation, and its teratogenicity in the offspring of users (Bonn-Miller et al., 2017; Young-Wolff et al., 2017; Rubin, 2019).
1 Pros and cons of cannabidiol use in chronic pain.
Chronic Pain In The United States
Chronic pain affects between 50 and 116 million American adults, a staggering number that surpasses those affected by heart disease, cancer, and diabetes combined (Committee on Advancing Pain Research Care and Education, 2011; Nahin, 2015; NIH, 2020). In addition, these reports conclude that chronic pain costs between $560 and $635 billion annually in both medical expenses and lost productivity. Although there have been some recent therapeutic advances, many patients with chronic pain develop tolerance to conventional medical treatments or suffer adverse effects from widely used prescription medications, such as non-steroidal anti-inflammatory agents or opiates, that have high addictive potential (Labianca et al., 2012). As early as 2003, formulations containing CBD have been used in the clinic to study its efficacy in reducing pain when traditional treatment options have failed.
Reliability and Safety of Cannabidiol Labeled Products
Human use of Cannabis sativa L. for rituals and medicine dates back millennia, and it has made recent advances in treatment of varied conditions (Kalant, 2001; Whiting et al., 2015; Aviram and Samuelly-Leichtag, 2017; Ren et al., 2019). CBD is the major non-psychoactive constituent of cannabis and is also found in hemp, a subspecies of Cannabis sativa that does not produce psychoactive compounds in significant amounts. With the exception of Epidiolex, a Schedule V preparation, which is a pharmaceutical CBD extract from the plant, cannabis-derived CBD still remains a Schedule I substance according to the United States (US) Drug Enforcement Administration (Drug Enforcement Administration, 2018). However, the US Hemp Farming Act of 2018 legalized the cultivation and refinement of hemp and its constituents, thus beginning a trend of mass marketing for CBD products both legal and illegal (Hemp Production and the 2018 Farm Bill, 2019; Mead, 2019). In states where cannabis has been approved for recreational and/or medical use, there are efforts to equip dispensary staff with scientific knowledge to make evidence-based recommendations, but these efforts are limited and often overshadowed by anecdotal understanding of CBD and other cannabinoids (Haug et al., 2016; Piermarini and Viswanath, 2019). Of major concern, CBD-labeled products have flooded the markets, including, but not limited to, inhalants, bath salts, cookies, ointments, and liquids, for human use. Many forms tout medicinal value for claims that have not been scientifically evaluated. Reports indicate that the cannabinoid content in products purchased online were only accurate in 26 of the 84 products tested (Bonn-Miller et al., 2017). In a more recent report, safety of using unregulated CBD products has been questioned because, of 20 popular CBD products tested by CannaSafe, a cannabis-testing company in California, only 3 contained the contents claimed on the labels (Rubin, 2019). Of these, 2 products had no CBD, and about half of the CBD products had less than 20% of the CBD content claimed. Additionally, toxic gases and solvents were reported in some of these CBD products. Thus, these unregulated products labeled CBD may be a serious health hazard. An urgent need is to regulate CBD products after reliable testing to prevent the inadvertent harmful effects of unidentified constituents of products labeled CBD.
Clinical Outcomes for Cannabidiol in Intractable Chronic Pain
Since the early 2000s, clinical trials involving CBD for the treatment of chronic pain have shown effects ranging from placebo-equivalent to highly effective; many of these studies have been well-designed randomized, double-blinded, and placebo-controlled. In a mixed cohort of patients suffering from intractable pain due to multiple sclerosis, spinal cord injury, brachial plexus injury, and limb amputation, CBD treatment significantly reduced pain on a visual analog scale (Wade et al., 2003). However, these studies were often limited by small cohorts, and the varied disease states indicated that the beneficial effects of CBD are context dependent, which was illustrated in a study where treatment did not improve outcomes in patients suffering from Crohn’s disease (Naftali et al., 2014). CBD was also seemingly effective in treatment of chronic pain associated with kidney transplantation and when given topically to patients suffering from peripheral neuropathy of their lower extremities (Cuñetti et al., 2018; Xu et al., 2019). As well, in patients with fibromyalgia, CBD treatment decreased pain by more than 30% in significantly more patients than placebo (Van De Donk et al., 2019). In studies of generalized chronic pain, CBD treatment did not significantly reduce measures of pain, however there was consistent improvement in patient-reported quality of life and quality of sleep (Notcutt et al., 2004; Capano et al., 2020). A New Zealand study on the safety of CBD treatment in 400 non-cancer chronic pain patients indicated its safety for prolonged use, which was accompanied by self-reported improvements in pain and quality of life.
The majority of clinical studies for the treatment of intractable chronic pain with CBD typically utilized a combination of 1:1 CBD : THC, which was often in the form of the well-tolerated oromucosal spray Sativex (Nabiximols in the US) (Johnson et al., 2013; Sellers et al., 2013). Combination of the two often improved upon the deleterious and psychoactive effects of THC-only administration (Ueberall et al., 2019). The CBD : THC formulations were effective at reducing mean pain scores in chronic pain patients with multiple sclerosis, improved neurophysical measurements in response to noxious stimuli, reduced intractable chronic pain in advanced cancer, and improved refractory/neuropathic pain following failed spinal cord surgery (Rog et al., 2005; Conte et al., 2009; Johnson et al., 2010; Portenoy et al., 2012; Mondello et al., 2018). There is contradictory evidence that CBD : THC treatment does not always relieve chronic pain in patients with brachial plexus avulsion or advanced-cancer, as evidenced by studies in two-independent cohorts, thus indicating the heterogeneity in disease contexts for which cannabinoids may be effective; of note, although pain was not significantly improved, patients in these studies indicated an improved quality of life . There is a demonstrated need to further understand the mode of action of CBD, and these results are promising, but efficacy of treatment must also be evaluated in other disease states that produce chronic pain such as diabetic neuropathy, rheumatic diseases, and sickle cell disease (Fitzcharles et al., 2016).
Mechanistic Insights For Cannabidiol Treatment Of Chronic Pain
Few preclinical studies have been performed to evaluate the mechanism of analgesia for CBD treatment of chronic pain. Currently available studies rely on rodent and in vitro models but suggest molecular pathways that may be used to enhance CBD use in the clinic, or offer alternative approaches for higher efficacy. Evidence strongly supports that prolonged treatment (i.e. > 7 days) with CBD alleviates chronic pain caused by chronic constriction injury of the sciatic nerve in rats and mice in a cannabinoid receptor-independent manner, and treatment is coincident with decreased hepatic cytochrome p450 and intestinal P-glycoprotein that may increase bioavailable circulating CBD (Costa et al., 2007; Comelli et al., 2008; Casey et al., 2017; Abraham et al., 2019). In vitro studies using human embryonic kidney cells reveal that at high doses CBD interacts with and selectively activates α1– and α1ß-glycine receptors, but these results have yet to be confirmed in vivo (Ahrens et al., 2009; Foadi et al., 2010). Alternatively, there is preliminary evidence that CBD may interact with α3-glycine receptors to reduce inflammation and hyperalgesia following simulated neuropathic pain by ligation of the L5 spinal nerve in adult Sprague-Dawley rats. CBD also attenuates hyperalgesia in a mouse model of diabetic neuropathy with data suggesting that treatment reduced inflammatory milieu (Toth et al., 2010). Mouse models of pain associated with chemotherapy were simulated by Paclitaxel treatment, in which CBD produced an analgesic and anti-inflammatory effect via interactions with spinal cord 5-HT(1A) receptors (Ward et al., 2014; King et al., 2017). CBD also exerts analgesia in a 5-HT(1A)-dependent manner in streptozotocin-induced diabetic neuropathy in rats (Jesus et al., 2019). Similar to human studies, CBD did not produce complete analgesia in all models of chronic pain; in a cisplatin-induced mouse model of neuropathy, CBD attenuated but did not prevent hyperalgesia (Harris et al., 2016). Mechanical hyperalgesia was improved by CBD treatment following traumatic brain injury in mice, myofascial pain in rats, and 6-hydroxydopamine-induced mouse model of Parkinson’s disease, however these studies require follow-up to inspect potential mechanisms of action (Belardo et al., 2019; Wong and Cairns, 2019; Crivelaro Do Nascimento et al., 2020). The preclinical work being done to disentangle the mechanisms of CBD in providing analgesic support in chronic pain is flourishing, but much remains in the wake of chronic disease and enhancing our understanding of the mechanisms at play.
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