ArticleLiterature Review

Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids

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Abstract

Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain. Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms. While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain. OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics. The body's innate endocannabinoid system (ECS) has been shown to ameliorate all of these pain subtypes. This review summarizes the components of the ECS and details the latest research pertaining to plant-based and man-made cannabinoids for the treatment of OA pain. Recent pre-clinical evidence supporting a role for the ECS to control OA pain is described as well as current clinical evidence of the efficacy of cannabinoids for treating OA pain in mixed patient populations.

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... 9 Opioids are another line of treatment utilized to control OA pain, but their low efficacy and abuse potential represent serious concerns. 8,9 Nearly 60% of OA patients are not satisfied with their current pain management, 10 thus, there is a need to discover nonaddictive therapies that can control OA pain with fewer side effects. ...
... Cannabis use to control pain in OA patients is continuously increasing, with numerous preclinical studies supporting its efficacy. [10][11][12] Cannabinoids exert their effects by targeting the endocannabinoid system (ECS), a homeostatic regulator of neurotransmitter activity that functions in the brain, skin, digestive tract, liver, cardiovascular system, genitourinary function, bone, 13 and most relevantly cartilage. [14][15][16] The ECS consists predominantly of anandamide (AEA) and 2arachidonoylglycerol (2-AG), which regulate pain through cannabinoid receptors. ...
... The ECS is activated in several different diseases where it is involved in inflammation and cell differentiation. It is expressed in all joint compartments where evidence demonstrates its involvement in (1) modulating chronic pain and (2) ameliorating joint inflammation and degeneration in OA. 7,10,14,17,18 Anecdotal evidence suggests the efficacy of cannabinoids in regulating chronic pain with the ECS being the key target. 10,19 Studies in animal models have identified possible ECS pathways in arthritis, 20 with growing evidence for the analgesic and anti-inflammatory effects of cannabinoids in OA. 7,21 This suggests that targeting the ECS with cannabinoids is a promising therapeutic strategy in OA. 7,10,17 CBD is the main nonpsychoactive cannabinoid derived from cannabis that has been used in OA. 10,22,23 While cannabigerol (CBG) is another recently emerging nonpsychoactive cannabinoid, and is the precursor molecule to both CBD and D 9 -THC in the plant, 24,25 its effects in OA have not been investigated. ...
Article
Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.
... Naturally, cannabinoids are produced from cannabis plants, with more than 100 cannabinoids identified (10). The main cannabinoids produced are tetrahydrocannabinol (THC) and cannabidiol (CBD), but in contrast to the highly psychoactive THC, CBD has virtually no psychoactive properties (10,11). In people, there is evidence that CBD may be a useful treatment for various chronic pain conditions (11)(12)(13). ...
... The main cannabinoids produced are tetrahydrocannabinol (THC) and cannabidiol (CBD), but in contrast to the highly psychoactive THC, CBD has virtually no psychoactive properties (10,11). In people, there is evidence that CBD may be a useful treatment for various chronic pain conditions (11)(12)(13). The effectiveness of CBD via oral or oraltransmucosal administration for the treatment of osteoarthritis in dogs has also been recently reported (14)(15)(16)(17). ...
... TRPV1 channels are predominantly expressed in sensory neurons and have an important role in nociception (13,30). Regarding joint pain, an anti-nociceptive effect of locally administered CBD has been reported, attributed to decreased joint nociceptors firing and decreased local inflammation, which resulted in decreased pain behavior in an end-stage osteoarthritis model in rats (11,31). ...
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A 14-year-old intact mixed breed dog (26 kg) was submitted for a novel cannabidiol (CBD) analgesic treatment. The dog was cachectic and had a testicular neoplasia, hip and elbow osteoarthritis and severe cervical pain. Analgesic treatment included canine osteoarthritic supplement, robencoxib and gabapentin. An additional liposomal CBD injectable formulation at 5 mg/kg was administered subcutaneously between the shoulder blades. The dog was monitored using an activity monitoring collar (PetPace), owner wellbeing questionnaire (Canine Brief Pain Inventory; CBPI), pain interactive visual analog scale (iVAS), blood work and CBD plasma concentrations. A week from the injection and up to 3 weeks afterwards the dog had improved CBPI and iVAS pain scores, and increased collar activity scores. CBD was quantified in plasma for 28 days. Due to disease progression, further difficulty to rise and walk, and relapse to pain after 3 weeks, the owners requested a second liposomal CBD injection, which was performed 4 weeks following the first injection using 3 mg/kg dose. Two days later, the dog was found dead in the yard under direct sun, while environmental temperature was 37°C. Major findings on necropsy revealed evidence of heat stroke and severe cervical disc protrusion with spinal hematoma, none related to liposomal CBD. In conclusion, subcutaneous liposomal CBD produced quantifiable CBD plasma concentrations for 28 days and may be an effective additional treatment as part of multimodal pain management in dogs.
... There is some scientific evidence of the beneficial effects of specific nutritional interventions in providing symptom relief to OA patients; however, nutritional research on OA is only in its infancy and only a few ingredients have been tested to date [13]. An endocannabinoid system has been identified in OA joints, and animal studies have shown that cannabinoids reduce OA pain, inflammation, and nerve damage [14,15]. However, only a few clinical trials have tested the efficacy and safety of medical cannabis [15]. ...
... An endocannabinoid system has been identified in OA joints, and animal studies have shown that cannabinoids reduce OA pain, inflammation, and nerve damage [14,15]. However, only a few clinical trials have tested the efficacy and safety of medical cannabis [15]. ...
... The effects on the perception of pain and on the reduction of BALP may be partly attributable to the action of cannabinoids present in HS [29,30]. In fact, the endocannabinoid system (ECS) in bone metabolism appears to play a key role [31] in modulating the pathophysiology of OA and in reducing painful symptoms related to OA [15]. The ECS is, therefore, considered as a possible therapeutic target for pain management. ...
Article
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Osteoarthritis is a type of degenerative joint disease that results from the breakdown of joint cartilage and underlying bone. Due to their antioxidants and anti-inflammatory action, the phytochemical constituents of many vegetable varieties could represent a new frontier for the treatment of patients with Osteoarthritis and are still being explored. The aim of this pilot human study was to investigate the effects of pasta enriched with hemp seed flour on osteoarticular pain and bone formation markers in patients in post-arthroplasty rehabilitation. Another purpose was to evaluate the effect of hemp seed extract on bone metabolism, in vitro. A pilot, controlled, clinical study was conducted to verify the feasibility of pain symptom reduction in patients with Osteoarthritis undergoing arthroplasty surgery. We also investigated the effect of hemp seed extract on the Wnt/β-catenin and ERK1/2 pathways, alkaline phosphatase, RANKL, RUNX-2, osteocalcin, and COL1A on Saos-2. After 6 weeks, the consumption of hemp seed pasta led to greater pain relief compared to the regular pasta control group (−2.9 ± 1.3 cm vs. −1.3 ± 1.3 cm; p = 0.02). A significant reduction in serum BALP was observed in the participants consuming the hemp seed pasta compared to control group (−2.8 ± 3.2 µg/L vs. 1.1 ± 4.3 µg/L; p = 0.04). In the Saos-2 cell line, hemp seed extract also upregulated Wnt/β-catenin and Erk1/2 pathways (p = 0.02 and p = 0.03) and osteoblast differentiation markers (e.g., ALP, OC, RUNX2, and COL1A) and downregulated RANKL (p = 0.02), compared to the control. Our study demonstrated that hemp seed can improve pain symptoms in patients with osteoarthritis undergoing arthroplasty surgery and also improves bone metabolism both in humans and in vitro. However, more clinical studies are needed to confirm our preliminary findings.
... Studies conducted in animal models have paid particular attention to verifying the role of the ECS in neuropathic, cancer and osteoarthritic (OA) pain: in all cases, the "endocannabinoid machine" is present and able to modulate the excitability of nociceptors and spinal neurons (51)(52)(53). ...
... Several preclinical studies have investigated phytocannabinoids' efficacy in animal OA pain models. Overall, data indicate that the activation of the ECS by exogenous cannabinoids proves effective in limiting joint pain both centrally and peripherally (53). ...
Article
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In the last 5 years, interest has grown in using phytocannabinoids, particularly cannabidiol (CBD), in veterinary medicine to treat several pathologies, including pain, epilepsy, anxiety, nausea, anorexia, skin lesions, and even some types of cancer, among others. Indeed, due to a positive perception of CBD use, many pet owners are increasingly requesting this option to relieve their pets, and many veterinarians are exploring this possibility for their patients. Besides the widespread empiric use of CBD in pets, the research is trying to obtain proof of its efficacy and lack of adverse effects and to know its pharmacokinetics to define an appropriate posology. This review summarizes all data published so far about the canine pharmacokinetics, efficacy, and tolerability of CBD and cannabidiolic acid (CBDA). Despite a certain number of available pharmacokinetic studies, the kinetic profile of CBD has yet to be fully known, probably because of the very different experimental conditions. In terms of efficacy, most studies have tested CBD’ ability to relieve osteoarthritic pain. In contrast, few studies have evaluated its role in epilepsy, behavioral disorders, and skin lesions. From obtained results, some evidence exists supporting the beneficial role of CBD. Nevertheless, the limited number of published studies and the occurrence of bias in almost all require caution in interpreting findings. From tolerability studies, CBD’ side effects can be classified as mild or unremarkable. However, studies were prevalently focused on short- to medium-term treatment, while CBD is usually employed for long-term treatment. Further studies are warranted to define better whether CBD could be a valid adjunct in canine treatment.
... Emerging research suggests that the endocannabinoid system (ECS) is a promising target for this purpose. 16 Cannabis (Cannabis spp.) has been used in human medicine for thousands of years. 17 However, it is only during the last century that studies of its molecular composition have revealed that it is composed of over 400 molecules. ...
... 18 The discovery of specific cell membrane receptors for cannabinoid molecules and endocannabinoids in the 1990s, suggests that the ECS is a promising therapeutic target for OA pain. 16,19,20 The ECS is a signalling system composed of cannabinoid cell membrane receptors and their agonists, endogenous cannabinoids (endocannabinoids), whose concentrations are determined by enzymes that either synthesise or degrade them. 21 Cannabinoid type 1 (CB1) and type 2 (CB2) cell receptors are distinct G protein-coupled membrane receptors. ...
Article
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Background Osteoarthritis (OA) is a major cause of equine lameness. Cannabinoid (CB) receptors are now considered to be promising therapeutic targets in human rheumatology for pain and inflammation, however, little is known about the equine endocannabinoid system. Objectives The primary goal was to assess the presence and expression pattern of CB1 and CB2 in the synovium of healthy joints. A secondary goal was to explore the relationship between the CB expression, degree of synovitis and OA pathology. Study design Ex vivo experimental study. Methods Metacarpophalangeal joints (n = 25) from a tissue bank were studied. The joints were dissected, and the articular cartilage lesions were scored. Synovial membrane specimens (n = 45) were harvested, fixed and the degree of synovitis was graded on histological sections. Colocalised synovial sections were also immunostained with antibodies to CB1 and CB2. Five regions of interest were randomly selected from digital images of manually segmented synovial intima and scored blindly for positive cellular immunoreactive staining by two independent observers. Interobserver agreement was calculated with an intraclass correlation coefficient (ICC). Relationships between CB1 and CB2 immunoreactive scores and synovitis or joint OA grade were explored with mixed linear models. Results CB1 was expressed in synovial intimal cells in all specimens studied whereas CB2 expression was identified in 94%. Both receptors were also expressed in the subintimal blood vessel walls. ICCs were 84.6% (CB1) and 92.9% (CB2) for the immunoreactivity scores. Both CB1 and CB2 expression were significantly upregulated (p = 0.04 and p = 0.03, respectively) with increasing degree of synovitis. Conversely, CB1 expression significantly decreased (p = 0.03) with increasing severity of OA. Main limitations The type of synovial cell expressing CB1 or CB2 was not investigated. Conclusion Equine synovial intimal cells constitutively express both CB1 and CB2 receptors that are upregulated with synovitis and may have a role in joint pain. They are potential targets for therapy with cannabinoid molecules or their derivatives.
... MC has also been shown to be effective in treating orthopaedic pain when compared to a placebo; however, studies have yet to show efficacy when compared to an active comparator [10]. There are limited studies into the use of MC for the management of chronic pain caused by musculoskeletal etiologies such as OA, in part due to hesitancy from physicians to prescribe it [11]. Preliminary studies in patients with OA and rheumatoid arthritis have shown that the cannabinoid receptor system is present in the synovium of affected joints, providing evidence that MC has potential for therapeutic pain management in these patients [12]. ...
... Most studies utilize patient surveys, which are inherently subjective, to measure opioid use [18][19][20][21][22]26]. Additionally, very few studies investigate how the use of MC affects opioid usage specifically for chronic pain due to OA [11,26,27]. Our study provides an objective quantification metric of opioid utilization and adds to current literature regarding MC use for chronic pain due to OA. ...
Article
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Background Osteoarthritis (OA) can result in significant pain, requiring pain management with opioids. Medical cannabis (MC) has the potential to be an alternative to opioids for chronic pain conditions. This study investigates whether MC used in the management of OA-related chronic pain can reduce opioid utilization. Methods Forty patients with chronic OA pain were certified for MC. Average morphine milligram equivalents (MME) per day of opioid prescriptions filled within the six months prior to MC certification was compared to that of the six months after. Visual analog scale (VAS) for pain and Global Health scores were measured at baseline, three, and six months post MC certification. Results Average MME/day decreased from 18.2 to 9.8 (n=40, p<0.05). The percentage of patients who dropped to 0 MME/day was 37.5%. VAS scores decreased significantly at three and six months, and Global Physical Health score increased significantly by three months. Conclusions MC reduces opioid prescription for patients with chronic OA pain and improves pain and quality of life.
... Emerging research suggests that the endocannabinoid system (ECS) is a promising target for this purpose. 16 Cannabis (Cannabis spp.) has been used in human medicine for thousands of years. 17 However, it is only during the last century that studies of its molecular composition have revealed that it is composed of over 400 molecules. ...
... 18 The discovery of specific cell membrane receptors for cannabinoid molecules and endocannabinoids in the 1990s, suggests that the ECS is a promising therapeutic target for OA pain. 16,19,20 The ECS is a signalling system composed of cannabinoid cell membrane receptors and their agonists, endogenous cannabinoids (endocannabinoids), whose concentrations are determined by enzymes that either synthesise or degrade them. 21 Cannabinoid type 1 (CB1) and type 2 (CB2) cell receptors are distinct G protein-coupled membrane receptors. ...
... 13 However, the full effects of CBD are still not fully understood. Although animal models have shown CBD to decrease OA-related pain, [14][15][16][17][18][19] its efficacy in humans has not been fully supported. 18,20,21 As the stigma surrounding THC and CBD use decreases and these products become more readily available, the prevalence of their use will likely increase. ...
... Although animal models have shown CBD to decrease OA-related pain, [14][15][16][17][18][19] its efficacy in humans has not been fully supported. 18,20,21 As the stigma surrounding THC and CBD use decreases and these products become more readily available, the prevalence of their use will likely increase. Previously, research has been hampered by lack of funding and the Schedule I classification of cannabis. ...
Article
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Introduction: State legalization and widespread marketing efforts have increased the accessibility and consumption of off-label, non-FDA approved, cannabinoid (CBD) products. Although clinical evidence is largely absent for the treatment of musculoskeletal pain, patients are experimenting with these products in efforts to relieve joint pain. Assessment of the prevalence, perceived efficacy compared to other non-surgical modalities, and usage patterns is warranted. The purpose of this study was to report the prevalence and perceived self-efficacy of CBD products in patients with symptomatic hip and/or knee osteoarthritis (OA). Methods: Two-hundred consecutive patients presenting with painful hip or knee osteoarthritis were surveyed at their initial evaluation at a large academic center. Utilizing single-assessment numeric evaluation (SANE) scores, survey questions assessed perceived pain and effectiveness of CBD products, in addition to other non-surgical treatment modalities. Chart review provided demographic factors. Descriptive statistics were used to characterize the data. Results: Of the 200 patients (80 hip OA, 108 knee OA, 12 both), 66% were female, average age was 67 years (range 36-89). Twenty-four percent (48/200) of patients endorsed use of CBD products prior to their presentation. The average presenting SANE score (range 0-100) for non-CBD users was 50.8 compared to 41.3 among CBD utilizers (p=0.012). Sixty percent of patients learned about CBD through friends and 67% purchased CBD directly from a dispensary. Oral tinctures (43%) and topical applications (36%) were the most commonly used forms. Additionally, 8% of participants in this study had tried marijuana for their pain. Conclusion: There was a 24% incidence of CBD usage among patients presenting with hip or knee OA. There appears to be no significant perceived benefit of CBD use compared to non-use, as patients who used CBD reported significantly worse SANE and VAS scores than non-users at baseline. Follow-up studies are warranted to assess these findings. Keywords: cannabinoid, CBD, marijuana, total hip arthroplasty, total knee arthroplasty, non-operative treatment
... Additionally, there are many different strains of cannabis used across the literature [18]. Currently, there are no guidelines or consistency in the literature and further study is needed on these newer cannabis-based therapies [19,20,24,25,29,37]. ...
... Additionally, there are many different strains of cannabis used across the literature [18], and funded randomized controlled level 1 studies on cannabis and CBD products are extremely difficult to execute. Currently, there are no guidelines or consistency in the literature and further study is needed on the newer cannabis-based therapies [19,20,24,25,29,37]. ...
Article
Background Given the opioid crisis in America, patients are trying alternative medications including tetrahydrocannabinol (THC) and other cannabidiol (CBD) containing products in the perioperative period, especially in states where these products are legal. This study sought to analyze usage rates of CBD/THC products in the perioperative period for primary unilateral total hip and knee arthroplasty (THA/TKA) patients and identify a possible association with post-operative opioid use. Methods A prospective cohort of primary unilateral THA/TKA patients were enrolled at a single institution. Patients who completed detailed pain journals were retrospectively surveyed for CBD/THC product usage. Pain medications were converted to morphine milligram equivalents (MME). Results Data from 195 of the 210 patients (92.9% response rate) following primary arthroplasty were analyzed. Overall, 16.4% of arthroplasty—22.6% (n = 19) of TKA and 11.7% (n = 13) of THA—patients used CBD/THC products in the perioperative period. There was a wide variety of usage patterns among those using CBD/THC products. In comparing CBD/THC users and non-users, there was no significant difference in the length of narcotic use, total morphine milligram equivalents taken, narcotic pills taken, average post-op pain scores, the percentage of patients requiring a refill of narcotics, or length of stay. Conclusion Understanding that CBD/THC usage was not consistent for patients who used these products, 22.6% of TKA and 11.7% of THA patients tried CBD/THC products in the perioperative period. In this small sample, CBD/THC use was not associated with a major effect on narcotic requirements. Further studies on the effects of CBD/THC are needed as these therapies become more widely available.
... Despite the growing interest in cannabis as a therapeutic agent, there has been limited human research due to its illegal status in many countries, as well as the challenges posed by the complexity of the cannabis plant compared to single agent, pharmaceutical forms of cannabis (e.g., nabilone) [11,12]. Notwithstanding these challenges, there is emergent research on the potential role of cannabis-based medicines in the management of health conditions common among older adults, including osteoarthritis [13], sleep disorders [14], dementia [15], and Parkinson's [16,17], which are also prevalent among individuals residing at long-term care (LTC) facilities. For example, several studies have found cannabisbased medicines to significantly reduce neuropsychiatric symptoms and improve quality of life among people living with Alzheimer's Disease [18][19][20]. ...
Article
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Background Following the legalization of cannabis in Canada in 2018, people aged 65 + years reported a significant increase in cannabis consumption. Despite limited research with older adults regarding the therapeutic benefits of cannabis, there is increasing interest and use among this population, particularly for those who have chronic illnesses or are at end of life. Long-term Care (LTC) facilities are required to reflect on their care and policies related to the use of cannabis, and how to address residents’ cannabis use within what they consider to be their home. Methods Using an exploratory case study design, this study aimed to understand how one LTC facility in western Canada addressed the major policy shift related to medical and non-medical cannabis. The case study, conducted November 2021 to August 2022, included an environmental scan of existing policies and procedures related to cannabis use at the LTC facility, a quantitative survey of Healthcare Providers’ (HCP) knowledge, attitudes, and practices related to cannabis, and qualitative interviews with HCPs and administrators. Quantitative survey data were analyzed using descriptive statistics and content analysis was used to analyze the qualitative data. Results A total of 71 HCPs completed the survey and 12 HCPs, including those who functioned as administrators, participated in the interview. The largest knowledge gaps were related to dosing and creating effective treatment plans for residents using cannabis. About half of HCPs reported providing care in the past month to a resident who was taking medical cannabis (54.9%) and a quarter (25.4%) to a resident that was taking non-medical cannabis. The majority of respondents (81.7%) reported that lack of knowledge, education or information about medical cannabis were barriers to medical cannabis use in LTC. From the qualitative data, we identified four key findings regarding HCPs’ attitudes, cannabis access and use, barriers to cannabis use, and non-medical cannabis use. Conclusions With the legalization of medical and non-medical cannabis in jurisdictions around the world, LTC facilities will be obligated to develop policies, procedures and healthcare services that are able to accommodate residents’ use of cannabis in a respectful and evidence-informed manner.
... The ECS plays a major role in the pain trafficking pathway, at both central and peripheral levels, and modification of this system may open novel therapeutic targets [15,16]. To date, it is known that cannabis-based drugs have important therapeutic potential in people, not only in treating inflammatory diseases (such as osteoarthritis and inflammatory bowel disease), in dermatological diseases such as atopic dermatitis and psoriasis, but also in neurodegenerative diseases such as Alzheimer's, multiple sclerosis and Parkinson's, and neurological pathologies that induce seizures and eating disorders [17][18][19]. Cannabinoid-based drugs may also be useful in human trigeminal neuralgia [7,20,21]. Recently, Longworth et al. [21] reported that cannabis-based medicines offered therapeutic benefits in 6 out of 8 treatments for people with chronic facial pain, and in all cases, they did not cause undesirable effects. ...
Article
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Cannabinoid receptors are expressed in human and animal trigeminal sensory neurons; however, the expression in the equine trigeminal ganglion is unknown. Ten trigeminal ganglia from five horses were collected post-mortem from an abattoir. The expression of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and the cannabinoid-related receptors like transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARɣ), and G protein-related receptor 55 (GPR55) in the trigeminal ganglia (TG) of the horse were studied, using immunofluorescence on cryosections and formalin-fixed paraffin-embedded (FFPE) sections. Neurons and glial cells were identified using fluorescent Nissl staining NeuroTrace® and an antibody directed against the glial marker glial fibrillary acidic protein (GFAP), respectively. Macrophages were identified by means of an antibody directed against the macrophages/microglia marker ionized calcium-binding adapter molecule 1 (IBA1). The protein expression of CB1R, CB2R, TRPV1, and PPARɣ was found in the majority of TG neurons in both cryosections and FFPE sections. The expression of GPR55 immunoreactivity was mainly detectable in FFPE sections, with expression in the majority of sensory neurons. Some receptors were also observed in glial cells (CB2R, TRPV1, PPARγ, and GPR55) and inflammatory cells (PPARγ and GPR55). These results support further investigation of such receptors in disorders of equine trigeminal neuronal excitability.
... Among them, research interests are focused on chronic pain control and the potential use of marijuana derivatives as alternatives to reduce opioid usage, which are the most commonly cited methods for pain management [3]. There are many ongoing trials for which the medical effects of cannabinoids are being explored, including orthopedic research [4]. For example, the Cannabinoid Profile Investigation of Vaporized Cannabis in Patients with Osteoarthritis of the Knee study was initiated in 2014 (NCT02324777), and another clinical trial is evaluating combinations of cannabinoids, opioids, and benzodiazepines for their pain-relieving effects in a small number of patients with osteoarthritis (NCT03098563). ...
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Medical marijuana (versus Marijuana derivatives) has been reported to possess analgesic, immunomodulatory, and anti-inflammatory properties. Recent studies in animal models of arthritis showed that cannabinoids, a group of compounds produced from marijuana, may attenuate joint damage. However, whether marijuana byproducts can suppress osteoarthritis (OA)-associated cartilage degradation has not been previously reported. In this study, human chondrocytes were isolated from healthy articular cartilage, expanded in vitro, and subjected to pellet culture in a chondrogenic medium to form cartilage tissues. We first examined the influence of marijuana byproducts on normal cartilage by treating chondrocyte-derived tissues with a synthetic cannabinoid agonist, Win-55,212-2 (Win), at different concentrations ranging from 0.01 to 10 µM. After treatment, the tissue phenotype was assessed using glycosaminoglycan (GAG) assay and real-time PCR. Next, cartilage tissues were pre-treated with interleukin-1β (IL-1β) to generate an inflamed phenotype and then cultured with Win to assess its therapeutic potential. The results showed that at concentrations lower than 1 µM, Win treatment did not significantly impair chondrocyte growth or cartilage formation capacity, but at a high level (>10 µM), it remarkably suppressed cell proliferation. Interestingly, under the condition of IL-1β pre-treatment, Win was able to partially preserve the cartilage matrix and decrease the production of interleukin-6, although the protective effect was mild. Taken together, our results indicated that the variable effects of Win on chondrocytes occur in a concentration-dependent manner. Whether cannabinoid derivatives can be used to treat cartilage degradation or can alter other structural changes in OA deserve further investigation.
... While there are currently some studies supporting a potential positive effect of CBD on fracture healing, 21 osteoarthritis progression, 22,32,39 and bone density, 20,33,36 there are few high-quality prospective clinical studies that have investigated the effect of CBD on musculoskeletal pain, which are limited to hand osteoarthritis 16,41 and total knee arthroplasty. 13 To our knowledge, there is a single published level 1 evidence study within the field of sports medicine: Alaia et al 2 recently found in a double-blinded, placebo-controlled randomized trial that patients who received buccally absorbed CBD after arthroscopic rotator cuff repair experienced a reduction in acute pain (postoperative days 1 and 2), providing evidence of its potential therapeutic benefit for postoperative pain. ...
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Background Cannabidiol (CBD) is a known pain modulator that is garnering increased attention in the orthopaedic world. There may be a considerable knowledge gap among orthopaedic sports medicine providers and their perception of its therapeutic value. Purpose To (1) examine the knowledge and beliefs of sports medicine orthopaedic providers with respect to CBD, (2) deliver an educational component, and (3) elucidate potential barriers to its widespread application. Study Design Cross-sectional study. Methods A 3-component, 25-question online survey was distributed to members of the American Orthopaedic Society for Sports Medicine and the Arthroscopy Association of North America between July and October 2022. The first 20 questions assessed baseline knowledge and opinions regarding CBD, followed by an educational component, and then 5 questions assessing whether the respondents’ opinions had changed after learning more about CBD. Responses were compared according to age, practice setting, and state’s cannabinoid legalization status using the chi-square test, and changes in opinions from before to after the educational component were compared using the paired t test. Results There were 101 survey responses, for a response rate of approximately 1%. Most respondents believed that there is a role for CBD in postoperative pain management (76%), acute pain and inflammation after an injury (62%), and chronic pain (94%). Most respondents admitted that they were not knowledgeable about the mechanism of action (89%) or their state’s laws (66%) concerning CBD. A minority (25%) believed that CBD has psychoactive properties. While most respondents (76%) did not believe that they would be stigmatized if they were to suggest CBD to a patient, only 48% had ever suggested CBD. Notably, 94% of respondents had encountered patients who reported trying CBD to treat pain. After reading the fact sheet, 51% of respondents stated that their opinion on CBD had changed, and 63% felt inclined to investigate the topic further. Conclusion Most survey respondents believed that CBD has a role in postoperative and chronic pain management. Although there was a relative familiarity with CBD, there was a knowledge gap, suggesting that increased attention, education, and research are necessary.
... While THC is highly psychoactive and may result in neurological signs in dogs (10,11), CBD has no psychoactive activity and can be administered safely at high doses or for long periods (10,12,13). CBD was reported to alleviate chronic pain in people (14)(15)(16), and recently its effectiveness was reported in dogs with osteoarthritis (17)(18)(19)(20). The recommended route of administration is orally with a frequency of twice daily (17,19). ...
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Introduction Osteoarthritis is a common disease in dogs resulting in chronic pain and decreased wellbeing. Common analgesics such as non-steroidal anti-inflammatories may fail to control pain and can produce major adverse effects. Study objectives were to evaluate pharmacokinetics, therapeutic efficacy, and safety of subcutaneous liposomal-cannabidiol (CBD) as an additional analgesic therapy in dogs suffering from naturally-occurring osteoarthritis. Methods Six such dogs were recruited following ethics approval and owner consent. Dogs were administered a single subcutaneous injection of 5 mg/kg liposomal-CBD. Plasma concentrations of CBD, blood work, activity monitoring collar data, wellbeing questionnaire (owners) and pain scoring (veterinarian) were performed at baseline and monitored up to six weeks following intervention. Data overtime were compared with baseline using linear-regression mixed-effects. P-value was set at 0.05. Results CBD plasma concentrations were observed for 6 weeks; median (range) peak plasma concentration (Cmax) was 45.2 (17.8–72.5) ng/mL, time to Cmax was 4 (2–14) days and half-life was 12.4 (7.7–42.6) days. Median (range) collar activity score was significantly increased on weeks 5–6; from 29 (17–34) to 34 (21–38). Scores of wellbeing and pain evaluations were significantly improved at 2–3 weeks; from 69 (52–78) to 53.5 (41–68), and from 7.5 (6–8) to 5.5 (5–7), respectively. The main adverse effect was minor local swelling for several days in 5/6 dogs. Conclusion Liposomal-CBD administered subcutaneously produced detectable CBD plasma concentrations for 6 weeks with minimal side effects and demonstrated reduced pain and increased wellbeing as part of multimodal pain management in dogs suffering from osteoarthritis. Further placebo-controlled studies are of interest.
... A systematic review with meta-analysis 144 showed a significant reduction of up to 30% in pain intensity with the use of CBMs, but noted that these data should be evaluated with caution as the evidence is of moderate to low quality. Analgesia of up to 30% is considered compatible with placebo effect 145 . ...
Article
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BACKGROUND AND OBJECTIVES Several studies have shown the growing interest and consumption of cannabinoids and medical cannabis (MC), with management of chronic pain being one of its main therapeutic recommendations. The objective of this study was to review and analyze the results of the most recent preclinical and clinical research on the application of MC and cannabinoids to understand their analgesic efficacy. CONTENTS A literature review was performed in Pubmed. Preclinical research has shown the role of the endocannabinoid system in pain pathways through the identification of its action sites and pain modulation mechanisms. Numerous clinical studies have endeavored to demonstrate the efficacy of CM and cannabinoids in the management of various pain syndromes. Some international guidelines have already incorporated the use of MC and cannabinoids, but as third or fourth-line treatment and, in most cases, with weak recommendation. CONCLUSION Despite the growing production of scientific knowledge, the data currently available still lack high-quality evidence to define the efficacy and analgesic potency of cannabinoids. Larger preclinical and clinical research are needed to understand the status of cannabinoids in pain management, as well as to generate high-quality evidence to include or not the use of MC and cannabinoids in guidelines for the management of the various pain syndromes. Keywords: Cannabis; Cannabinoids; Medical marijuana; Pain; Pain management
... A systematic review with meta-analysis 144 showed a significant reduction of up to 30% in pain intensity with the use of CBMs, but noted that these data should be evaluated with caution as the evidence is of moderate to low quality. Analgesia of up to 30% is considered compatible with placebo effect 145 . ...
... 32 CBD exhibits these effects by acting on the endocannabinoid system, and this biochemical signaling system is thought to play a role in osteoarthritis pathogenesis and analgesia. 33 A pharmacokinetic study by Spittler and colleagues 32 in 2021 evaluating 2 doses (25 and 50 mg/kg) of CBD in an almond oil suspension revealed that parameters increased in a dose-dependent manner in guinea pigs. Based on the pharmacokinetic data, guinea pigs had poor absorption rates of CBD. ...
Article
Limited information on the analgesic efficacy and safety of even clinically commonly used analgesic drugs in guinea pigs and chinchillas is available. Buprenorphine and meloxicam are currently the most common analgesics routinely used to treat painful conditions in guinea pigs and chinchillas. Hydromorphone has also shown to be an effective analgesic drug in these species, with limited adverse effects. Tramadol in chinchillas does not provide analgesia even at high doses, and no information is available on the efficacy of this drug in guinea pigs. Multimodal analgesic protocols should be considered whenever possible.
... Finding non-opioid alternatives to treat chronic pain is a principle of philosophy for many clinicians [15]. Interestingly, the endocannabinoid system (ECS) appears to repair dysfunction in osteoarthritis, as synovial tissues express CB1 and CB2 receptors; patients with OA also have detectable levels of endogenous endocannabinoids, anandamide (AEA), and 2arachidonoylglycerol (2-AG), in synovial fluid in comparison to samples from healthy individuals that do not [16]. Patients may find efficacy in utilizing cannabinoid therapy for the treatment of complex pain syndromes. ...
Article
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Chronic pain is a common diagnosis that patients may face, resulting in increased morbidity and mortality and affecting the overall quality of life. In addition to established multidisciplinary pain management, medical cannabis may offer an approach to improving pain outcomes and functionality. This case involves a 72-year-old female patient, with chronic neck, lower back, and diffuse arthritic pain due to comorbid osteoarthritis (OA), scleroderma, and scoliosis. Medical cannabis therapy was certified based on the goals of improving pain control and simultaneously reducing the patient's chronic opioid medication dose. Using potential opioid alternatives, such as medical cannabis, may prove beneficial to clinicians looking to improve pain management and reduce opioid therapy in patients.
... 51 Pre-clinical studies have revealed that the endocannabinoid system plays a crucial role in the pathogenesis of OA, joint neuropathy, and pain control, as it is present in rat joints, where it has been found to regulate joint pain and inflammation. 52,53 Authors assessed mechanosensitivity for 15 min after CBD infusion (at doses of 100, 200, or 300 mg in 100 mL, intra-articular) and observed increased threshold in the von Frey test in rats with MIA. Moreover, in end-stage OA, intra-articular injection of 300 lg of CBD improved unrestrained hindlimb weight-bearing and hind paw withdrawal threshold. ...
Article
The incidence of chronic pain is around 8% in the general population, and its impact on quality of life, mood, and sleep exceeds the burden of its causal pathology. Chronic pain is a complex and multifaceted problem with few effective and safe treatment options. It can be associated with neurological diseases, peripheral injuries or central trauma, or some maladaptation to traumatic or emotional events. In this perspective, animal models are used to assess the manifestations of neuropathy, such as allodynia and hyperalgesia, through nociceptive tests, such as von Frey, Hargreaves, hot plate, tail-flick, Randall & Selitto, and others. Cannabidiol (CBD) has been considered a promising strategy for treating chronic pain and diseases that have pain as a consequence of neuropathy. However, despite the growing body of evidence linking the efficacy of CBD on pain management in clinical and basic research, there is a lack of reviews focusing on chronic pain assessments, especially when considering pre-clinical studies, which assess chronic pain as a disease by itself or as a consequence of trauma or peripheral or central disease. Therefore, this review focused only on studies that fit our inclusion criteria: (1) used treatment with CBD extract; (2) used tests to assess mechanical or thermal nociception in at least one of the following most commonly used tests (von Frey, hot plate, acetone, Hargreaves, tail-flick, Randall & Selitto, and others); and (3) studies that assessed pain sensitivity in chronic pain induction models. The current literature points out that CBD is a well-tolerated and safe natural compound that exerts analgesic effects, decreasing hyperalgesia, and mechanical/thermal allodynia in several animal models of pain and patients. In addition, CBD presents several molecular and cellular mechanisms of action involved in its positive effects on chronic pain. In conclusion, using CBD seems to be a promising strategy to overcome the lack of efficacy of conventional treatment for chronic pain.
... FAAH is an integral membrane enzyme responsible for the hydrolysis of anandamide and 2-arachidonoylglcerol in the endocannabinoid system, which has been involved in chronic pain treatment for decades (48,49). Genetic or pharmacological inactivation of FAAH has shown analgesic, anti-inflammatory, anxiolytic and antidepressant response while apparently causing no undesirable side effects (50). ...
Article
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We describe a purified biochemical system to produce monoclonal antibodies (Abs) in vitro using activation-induced deoxycytidine deaminase (AID) and DNA polymerase η (Polη) to diversify immunoglobulin variable gene (IgV) libraries within a phage display format. AID and Polη function during B-cell affinity maturation by catalyzing somatic hypermutation (SHM) of immunoglobulin variable genes (IgV) to generate high-affinity Abs. The IgV mutational motif specificities observed in vivo are conserved in vitro. IgV mutations occurred in antibody complementary determining regions (CDRs) and less frequently in framework (FW) regions. A unique feature of our system is the use of AID and Polη to perform repetitive affinity maturation on libraries reconstructed from a preceding selection step. We have obtained scFv Abs against human glucagon-like peptide-1 receptor (GLP-1R), a target in the treatment of type 2 diabetes, and VHH nanobodies targeting Fatty Acid Amide Hydrolase (FAAH), involved in chronic pain, and artemin, a neurotropic factor that regulates cold pain. A round of in vitro affinity maturation typically resulted in a 2- to 4-fold enhancement in Ab-Ag binding, demonstrating the utility of the system. We tested one of the affinity matured nanobodies and found that it reduced injury-induced cold pain in a mouse model.
... Chondrocyte cultures from people with OA also have cannabinoid receptors, [82], and in cell culture, CB2 agonist WIN protected chondrocytes from inflammatory damage [81]. As is well reviewed by O'Brien and McDougall [83], inflammation and painrelated behaviors are inhibited by cannabinoids in rat and mouse models of OA [84][85][86]. ...
Article
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Purpose of Review Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain. Recent Findings The number of publications related to rheumatic disease and cannabis has increased, but recent literature skews heavily toward reviews vs primary research. Data supporting a role for cannabinoids in rheumatic disease continue to grow. Observational and survey studies show increased use of medicinal cannabis, both by people with rheumatic disease and the general population, and suggest that patients find these treatments beneficial. Prospective studies, however, including randomized controlled clinical trials, are rare and sorely needed. Summary As medicinal cannabis use for rheumatic diseases rises, despite lack of evidence, we review the sparse data available and provide tips for conversations about medicinal cannabis for rheumatologists.
... Caution must be used when prescribing selective serotonin reuptake inhibitors (SSRI) because of their activity on platelet serotonin reuptake and related inhibition of platelet aggregation with an increased risk of bleeding [91]. The endocannabinoid system is a promising target for osteoarthritis pain [92]. The role of cannabinoids in hemophilic arthropathy has not been studied yet, so in the future these molecules may be used to tackle chronic pain management. ...
Article
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Introduction: Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint. Methods: We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management. Results: In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients. Conclusions: The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.
... 25 Otros estudios clínicos están evaluando el uso de cannabis y cannabinoides para OA, pero todavía no están publicados. 26 Varios estudios han mostrados que los cannabinoides y sus receptores podrían jugar un rol en la ES, dado que los modelos animales muestran la sobreexpresión de los mismos en losbroblastos de estos pacientes. 18,27 Un estudio en animales también muestra que el tratamiento con cannabinoides previno el desarrollo de brosis cutánea y pulmonar, así como redujo la proliferación de broblastos y el desarrollo de anticuerpos. ...
Article
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Medical marijuana has been proposed in recent years as a solution to some medical problems refractory to other treatments. Chronic pain is a common symptom among patients who consult a rheumatologist. Different diseases can be involved in this pan-syndrome that ranges from autoimmune diseases, locoregional pain syndromes, degenerative diseases to disorders with psychological components. In many of these cases, especially the last two, pharmacological interventions are not always effective or safe in the short, medium or long term. In this review, the most current literature on the subject regarding cannabinoids and the treatment of rheumatic diseases will be analyzed. Despite the focus of the issue in recent years and the recent regulation of the Medical Cannabis Law for its self-cultivation and sale in pharmacies in Argentina, there is still insufficient data for the use of cannabinoids in the short, medium and long-term in rheumatic diseases. In recent years, some physiological studies have appeared about the potential immunomodulatory effect of cannabinoids in rheumatoid arthritis and systemic sclerosis (SS), and some clinical studies in SS, but there is still a long way to go to travel in this direction. In this review, the current literature on cannabinoids in the treatment of rheumatic diseases will be analyzed and this evidence will be discussed in relation to the local regulatory context.
... 25 Otros estudios clínicos están evaluando el uso de cannabis y cannabinoides para OA, pero todavía no están publicados. 26 Varios estudios han mostrados que los cannabinoides y sus receptores podrían jugar un rol en la ES, dado que los modelos animales muestran la sobreexpresión de los mismos en losbroblastos de estos pacientes. 18,27 Un estudio en animales también muestra que el tratamiento con cannabinoides previno el desarrollo de brosis cutánea y pulmonar, así como redujo la proliferación de broblastos y el desarrollo de anticuerpos. ...
... 10 Recent investigations have found wide expression of cannabinoid receptors in osseous tissue and evidence of positive cannabinoid impact on osteoarthritis disease progression, cartilage formation, and bone density. [11][12][13][14][15][16][17] Despite increasing public enthusiasm, political support, and research in the medical applications of cannabinoids, a stigma regarding their use persists in both patients and practitioners. The sources of this stigma are myriad, but minimal research has been conducted regarding the current knowledge and sentiments that medical professionals have regarding cannabinoids. ...
Article
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Introduction: Cannabinoids are an increasingly popular therapy among orthopaedic patients for musculoskeletal conditions. A paucity of evidence to support their use in orthopaedics exists, likely because of the incongruence of federal and state legalization and the stigma surrounding cannabis. The purpose of this study is to elucidate sentiments and knowledge base of the orthopaedic trauma community with regard to cannabinoid-containing compounds. Methods: A 21-question online survey was distributed to the members of the Orthopaedic Trauma Association with a response window of 3 months. Results: We evaluated 251 responses. Most (88%) of the respondents did not believe that they were knowledgeable about the mechanism of action of cannabis/cannabidiol (CBD) but did feel that cannabis or CBD products play a role in managing postoperative pain (73%). Most respondents did not believe that they would be stigmatized if they suggested CBD (83%) or cannabis (67%) to patients. Despite this, fewer respondents have suggested CBD (38%) or cannabis (29%) to their patients. Conclusions: Sentiment toward cannabinoids among orthopaedic traumatologists is remarkably favorable; however, in-depth understanding is admittedly poor and routine use is uncommon. More clinical research for cannabinoids is needed to help orthopaedic traumatologists provide guidance for patients seeking advice for this recently popular therapeutic.
... In addition to its role in the mature nervous system, the ECS also influences the development of the immature nervous system, which may have far-reaching consequences in adults (Diaz-Alonso et al. 2012;Galve-Roperh et al. 2009;Sun and Dey 2008;Younts and Castillo 2014;Zhou et al. 2014). Since ECS-related drugs are widely studied for their therapeutic potential and are being introduced into clinical applications (Basavarajappa et al. 2017;Cristino et al. 2020;Hernández-Cervantes et al. 2017;O'Brien and McDougall 2018), it is necessary to elaborate on the roles of ECS in development to avoid unwanted side effects or to exert certain therapeutic effects. Fortunately, over the last 15 years, the roles of the ECS on neurodevelopment and subsequent pathological implications have been gradually elucidated. ...
Article
In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.
... Studies using animal models have demonstrated promising results. Studies in humans are lacking but clinical trials have begun (O'Brien and McDougall, 2018). Future studies also need to identify which population (source of pain, inflammation, mechanical load, neuropathic) will benefit the most from the various cannabis products available. ...
... and a second clinical trial is evaluating a combination of cannabinoids, opioids, and benzodiazepines for their pain-relieving effects in a small number of OA patients (NCT03098563-NIH Clinical trials database; URL: Clinicaltrials.gov) [26]. ...
Article
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Cannabis use has increased dramatically in America with recent regulatory policy changes. Despite growing access and prevalence of use of cannabinoids both medically and recreationally, scientific evidence describing its safety and efficacy are limited, especially in the context of treating musculoskeletal pathology. The purpose of this review is to present data evaluating the role of cannabinoids as an adjunct in multimodal pain management, as a modulator in bone metabolism, and as a potential agent in combating the opioid epidemic.
... It acts on the vanilloid receptors but proves that the endocannabinoid system has physiological and/or pathophysiological roles in the modulation of pain [22]. The CB2 receptor studied in comparison with the CB1 receptor showed that the CB2 receptor plays a predominant role affecting joint pain and is likely to be involved in the adaptive changes in the opioids system, which was induced in the chronic pain state [23]. This beneficial aspect of controlling pain in the opioid system can lessen the burden of opioid side effects and complications. ...
Article
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The burden of chronic pain has affected many individuals leading to distress and discomfort, alongside numerous side effects with conventional therapeutic approaches. Cannabinoid receptors are naturally found in the human body and have long been an interest in antinociception. These include CB1 and CB2 receptors, which are promising candidates for the treatment of chronic inflammatory pain. The mechanism of action of the receptors and how they approach pain control in inflammatory conditions show that it can be an adjunctive approach towards controlling these symptoms. Numerous studies have shown how the targeted approach towards these receptors has activated them promoting a release in cytokines, all leading to anti-inflammatory effects and immune system regulation. Cannabinoid activation of glycine and gamma-aminobutyric acid (GABA) models also showed efficacy in pain management. Chronic conditions such as osteoarthritis were shown to also benefit from this considerable treatment. However, it is unclear how the cannabinoid system works in relation with the pain pathway. Therefore, in this review we aim to analyse the role of the cannabinoid system in chronic inflammatory pain.
... Further, a body of evidence indicates that tDCS modulates a variety of CNS antinociceptive pathways, including the endogenous opioidergic system as well as the serotonergic, noradrenergic, cannabinoid, GABAergic, and glutamatergic systems [50]. Specifically, regarding the endogenous opioidergic system and the cannabinoid pathway, tDCS may provide a noninvasive adjunct/alternative intervention to several other analgesic treatments for OA pain (e.g., opioids [51]; cannabinoids [52]). Finally, tDCS has been shown to reduce levels of peripheral circulating cytokines [35] and alleviate symptoms of depression [53]. ...
Article
Objective: The present study examined the effects of home-based remotely supervised transcranial direct current stimulation on quantitative sensory testing measurements in older adults with knee osteoarthritis. Participants were hypothesized to experience improved pain measurements over time. Design: Open-label, single-arm trial. Setting: Southeast Texas between March and November 2018 at a nursing school and participant homes. Subjects: Older adults (aged 50-85 years) with self-reported unilateral or bilateral knee osteoarthritis pain who met eligibility criteria set by the American College of Rheumatology. Methods: The intervention was applied with a constant current intensity for 20 minutes every weekday for two weeks (10 total sessions). Quantitative measures of pain were collected three times over 10 days (days 1, 5, and 10) and included heat threshold and tolerance, pressure pain threshold, punctate mechanical pain, pain, and conditioned pain modulation. Analyses used nonparametric tests to evaluate differences between day 1 and day 10. Generalized linear mixed models were then used to evaluate change across all three time points for each measure. Bayesian inference was used to provide the posterior probability of longitudinal effects. Results: Nonparametric tests found improvements in seven measures, and longitudinal models supported improvements in 10 measures, with some nonlinear effects. Conclusions: The home-based, remotely supervised intervention improved quantitative measurements of pain in older adults with knee osteoarthritis. This study contributes to the growing body of literature supporting home-based noninvasive stimulation interventions.
... 36 Other clinical trials assessing the use of cannabis and cannabinoids for OA are currently ongoing or are yet to be published. 37 Several studies have also shown that cannabinoids and cannabinoid receptors might play a role in SSc, as cannabinoid receptors have been shown to modulate SSc in murine models, 9 and were also found to be over-expressed in SSc fibroblasts. 38 A study on a murine model also found that treatment with cannabinoids prevented the development of cutaneous and pulmonary fibrosis and decreased the proliferation of fibroblasts and antibody development. ...
Article
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Chronic pain is a common complaint among patients, and rheumatic diseases are a common cause for chronic pain. Current pharmacological interventions for chronic pain are not always useful or safe enough for long-term use. Cannabis and cannabinoids are currently being studied due to their potential as analgesics. In this review we will discuss current literature regarding cannabinoids and cannabis as treatment for rheumatic diseases. Fibromyalgia is a prevalent rheumatic disease that causes diffuse pain, fatigue, and sleep disturbances. Treatment of this syndrome is symptomatic, and it has been suggested that cannabis and cannabinoids could potentially alleviate some of the symptoms associated with fibromyalgia. In this review we cite some of the evidence that supports this claim. However, data on long-term efficacy and safety of cannabinoid and cannabis use are still lacking. Cannabinoids and cannabis are commonly investigated as analgesic agents, but in recent years more evidence has accumulated on their potential immune-modulatory effect, supported by results in animal models of certain rheumatic diseases. While results that demonstrate the same effect in humans are still lacking, cannabinoids and cannabis remain potential drugs to alleviate the pain associated with rheumatic diseases, as they were shown to be safe and to cause limited adverse effects.
Article
Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.
Article
The purpose of this study was to conduct a scoping review to describe the evidence on the efficacy and safety of using cannabis-based medicines for osteoarthritis. The review was conducted following the framework proposed by Arksey and O’Malley and reported following PRISMA extension for scoping reviews guidelines. We conducted a comprehensive search across various databases including MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, and Proquest, spanning from inception of each database to March 2023. We retrieved 2533 citations, and after deduplication, title and abstract screening, and full-text screening, 10 articles were included for analysis. These studies were composed of randomized-controlled trials (n = 4/10), cross-sectional surveys (n = 3/10), case studies (n = 2/10), and a cohort study (n = 1/10). Evidence for using cannabis-based medicines was mixed, with just 60% (n = 6/10) of included studies reporting statistically significant improvements in pain. Studies with larger samples sizes and longer durations of exposure did not find significant benefits for pain. The few adverse effects reported were generally mild and affected a minority of participants. Several studies also discovered that cannabis-based medicines were associated with a reduction in opioid use. Currently available data on the use of cannabis-based medicines in osteoarthritis is insufficient to make recommendations. Future research should address concerns regarding small sample sizes and short treatment durations to provide a more robust evidence base. Key Points • Current evidence remains mixed; studies that found a positive benefit with using cannabis-based medicines had limitations with small sample sizes and short durations of exposure • The use of cannabis-based medicines in osteoarthritis appears to be generally well tolerated, adverse effects are mild and experienced by a minority of participants • Cannabis-based medicines may decrease the use of opioids in patients with osteoarthritis • Future research should address the gaps in long-term efficacy and safety data
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Background: Cannabis is increasingly used for management of chronic pain; however, the benefits and harms of this therapy remain uncertain. We conducted a systematic review to inform harms associated with inhaled cannabis for chronic pain. Methods: We searched MEDLINE, EMBASE, PsychInfo, and Web of Science for non-randomized studies reporting on harms associated with inhaled cannabis use, from inception to October 6, 2021. We used random-effects models for meta-analyses and assessed the certainty of evidence using the GRADE approach. Results: We identified 29 eligible studies enrolling 174,562 participants that reported 145 adverse events. Moderate certainty evidence suggests inhaled cannabis use is probably associated with dry mouth (prevalence: 56%; 95%CI 49 to 64), thirst (prevalence: 44%; 95% CI 33 to 55), fatigue (prevalence: 38%; 95%CI 31 to 45), nausea (prevalence: 17%; 95%CI 8 to 27), increased appetite (prevalence: 13%; 95%CI 9 to 18), dizziness (prevalence: 10%; 95%CI 6 to 14), diarrhea (prevalence: 9%; 95%CI 3 to 18), confusion (prevalence: 9%; 95%CI 5 to 13), mood changes (prevalence: 8%; 95%CI 4 to 15), hallucinations (prevalence: 7%; 95%CI 4 to 10), amnesia (prevalence: 6%; 95%CI 3 to 11), impaired coordination (prevalence: 5%; 95%CI 4 to 6), and disorientation (prevalence: 3%; 95%CI 1 to 7). Moderate certainty evidence shows that, compared to non-users, inhaling cannabis is probably associated with increased risk of shortness of breath (risk difference [RD]: 7%; 95%CI 4 to 10). Conclusions: Our review found moderate certainty evidence that dry mouth, thirst, and fatigue are probably frequently experienced with inhaled cannabis use. Several other adverse events are also probable associated with inhaled cannabis use but were less common. Rigorously conducted cohort studies are needed to inform harms associated with inhaled medical cannabis for chronic pain.
Article
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Background The metacarpophalangeal joint undergoes enormous loading during locomotion and can therefore often become inflamed, potentially resulting in osteoarthritis (OA). There are studies indicating that the endocannabinoid system (ECS) modulates synovium homeostasis, and could be a promising target for OA therapy. Some cannabinoid receptors, which modulate proliferative and secretory responses in joint inflammation, have been functionally identified in human and animal synovial cells. Objective To characterize the cellular distribution of the cannabinoid receptors 1 (CB1R) and 2 (CB2R), and the cannabinoid-related receptors transient receptor potential vanilloid type 1 (TRPV1), G protein-related receptor 55 (GPR55) and peroxisome proliferator-activated receptor alpha (PPARα) in the synovial membrane of the metacarpophalangeal joint of the horse. Animals The dorsal synovial membranes of 14 equine metacarpophalangeal joints were collected post-mortem from an abattoir. Materials and methods The dorsal synovial membranes of 14 equine metacarpophalangeal joints were collected post-mortem from an abattoir. The expression of the CB1R, CB2R, TRPV1, GPR55, and PPARα in synovial tissues was studied using qualitative and quantitative immunofluorescence, and quantitative real-time reverse transcriptase PCR (qRT-PCR). Macrophage-like (MLS) and fibroblast-like (FLS) synoviocytes were identified by means of antibodies directed against IBA1 and vimentin, respectively. Results Both the mRNA and protein expression of the CB2R, TRPV1, GPR55, and PPARα were found in the synoviocytes and blood vessels of the metacarpophalangeal joints. The synoviocytes expressed the mRNA and protein of the CB1R in some of the horses investigated, but not in all. Conclusions and clinical importance Given the expression of the CB1R, CB2R, TRPV1, GPR55, and PPARα in the synovial elements of the metacarpophalangeal joint, these findings encouraged the development of new studies supporting the use of molecules acting on these receptors to reduce the inflammation during joint inflammation in the horse.
Article
Acute and chronic pain management remains an ongoing challenge for hand surgeons. This has been compounded by the ongoing opioid epidemic in the United States. With the increasing legalization of medical and recreational cannabis throughout the United States and other countries, previous societal stigmas about this substance keep evolving, and recognition of medical cannabis as an opioid-sparing pain management alternative is growing. A review of the current literature demonstrates a strong interest from patients regarding the use of medical cannabis for pain control. Current evidence demonstrates its efficacy and safety for chronic musculoskeletal and neuropathic pain. However, definitive conclusions regarding the efficacy of cannabis for pain control in hand and upper extremity conditions require continued investigation. The purpose of this article is to provide a general review of the mechanism of medical cannabis and a scoping review of the current evidence for its efficacy, safety, and potential applicability in hand and upper extremity conditions.
Article
Chronic pain is a persistent, complex condition that contributes to impaired mood, anxiety and emotional problems. Osteoarthritis (OA) is one of the major causes of chronic pain in adults and elderly people. A substantial body of evidence demonstrate that hippocampal neural circuits, especially monoamine dopamine and serotonin levels, contributes to negative affect and avoidance motivation experienced during pain. Current pharmacological strategies for OA patients are unsatisfying and the endocannabinoid system modulation might represent an alternative for the treatment of OA-related pain. In the present study, we used a rat model of osteoarthritis induced by intra-articular injection of sodium monoiodoacetate to assess, 28 days post-induction, the contribution of endocannabinoid system on the possible alteration in pain perception and affective behavior, in LTP and monoamine levels in the lateral entorhinal cortex-dentate gyrus pathway. The results show that OA-related chronic pain induces working memory impairment and depressive-like behavior appearance, diminishes LTP, decreases dopamine levels and increases serotonin levels in the rat dentate gyrus. URB597 administration (i.p., 1 mg/kg) reduces hyperalgesia and mechanical allodynia, improves recognition memory and depressive-live behavior, restores LTP and normalizes monoamine levels in the hippocampus. The effect was observed 60–120 min post-treatment and was blocked by AM251, which proves the action of URB597 via the CB1 receptor. Therefore, our study confirms the role of anandamide in OA-related chronic pain management at the behavioral and hippocampal levels. This article is part of the Special Issue on ‘Advances in mechanisms and therapeutic targets relevant to pain’.
Article
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Since ancient times cannabis has been used for recreational and medicinal purposes. It is a significant source of chemical compounds, most of them called phytocannabinoids. These compounds have several physiological effects and produce their effects primarily by binding to endogenous cannabinoid receptors such as CB1 and CB2, among others. Cannabis has potential therapeutic properties and its preparations have been used as traditional remedies to treat pain and emesis. Synthetic cannabinoids are used clinically as analgesics, antispastics, antiemetics, and appetite stimulants. Significant cannabis toxicity is rare in adults; however, it can produce countless acute and chronic side effects. The quality of the evidence in this field is limited by the short duration of the trials, poor sample sizes, lack of a control group, and the existence of bias in most of the reviewed studies. Therefore, a larger number of studies with better methodological quality is required to support the safe use of this therapy. The decision to include cannabinoids as a treatment for any of the conditions described will depend on the evidence, the use of previous therapies, and the type of patient.
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Introduction: In this study, the effects of the cannabinoid CBD were assessed on cyclooxygenase (COX)-1 and COX-2 expression and activity in resting and activated human neutrophils (polymorphonuclear [PMN] leukocytes). Methods: COX expression was measured at the mRNA levels, whereas COX activity was assessed by enzyme-linked immunosorbent assay measurement of prostaglandin (PG)E2. In vitro experiments in a standard commercial acellular assay of COX-1/COX-2 activity completed the study. Results: Results show that CBD profoundly inhibits expression of COX-1 and COX-2 mRNA in activated PMN, however, without any significant consequences for PGE2 production. CBD, however, was able to induce a slight but significant direct inhibition of COX-2 in the acellular model. Conclusion: The effects of CBD occur in the μM concentration range, which is attained in humans with therapeutic doses of the drug, suggesting the clinical relevance of these findings.
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Background Multimodal analgesia has become the standard of care for pain management following total knee arthroplasty (TKA). Cannabidiol (CBD) is increasingly utilized in the postoperative period. The purpose of this study was to analyze the analgesic benefits of topical CBD following primary TKA. Methods In this randomized double-blinded placebo-controlled trial, 80 patients undergoing primary unilateral TKA applied topical CBD (CBD; n=19), essential oil (EO; n=21), CBD and essential oil (CBD+EO; n=21), or placebo (PLA; n=19) thrice daily around the knee for two weeks postoperatively. This supplemented a standardized multimodal analgesic protocol. Outcomes included visual analog scale (VAS) pain and numeric rating scale (NRS) sleep scores (collected on postoperative day [POD] 0, 1, 2, 7, 14, 42), and cumulative postoperative opioid use (42 days). Results Demographic characteristics were similar among the four cohorts. Preoperative VAS and NRS scores were similar among groups. The CBD cohort had a higher mean VAS pain score on POD 2 compared to the EO cohort (CBD: 69.9 ± 19.3 vs. EO: 51.0 ± 18.2; p=0.013). No significant differences existed for VAS scores at other times, and no significant differences were observed for postoperative NRS sleep scores or postoperative opioid use at any time point. Conclusions Utilization of topical CBD in supplement to multimodal analgesia did not reduce pain or opioid consumption, or improve sleep scores following TKA. These results suggest the local effects of topical CBD are not beneficial for providing additional pain relief after TKA.
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A medical marijuana plant contains more than 100 different chemical constituents, which are collectively referred to as “cannabinoids”. The cannabinoids you’ve likely heard about in recent years, which are often used for medicinal purposes, are cannabidiol (CBD) and tetrahydrocannabinol (THC). Both are scientifically proven for their therapeutic properties. CBD does not give marijuana the psychoactive effect while THC does. Patients who have gotten a medical marijuana recommendation from a qualified doctor can purchase marijuana products like tinctures, edibles, and topicals from regulated dispensaries. Medical marijuana products must contain no more than the legally permissible level of THC, as determined by the regulations of the state in which they are purchased.The art of Medical Marijuana and plant-based medicine involves determining what ratio and strain are optimal for a certain patient, how to deliver the plant as medication, and how to use patient input to get the greatest results.
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Background With the increasingly widespread availability of cannabidiol-derived products, more patients with hand and wrist pain are seeking evidence for use of these products. We explored current utilization practices of medical cannabis for treatment of pain in patients with a diagnosis of thumb basal joint arthritis. Secondary aims were to determine patient and thumb arthritis disease characteristics of cannabis users and nonusers and to investigate patient perceptions of the efficacy of medical cannabis in various formulations for the treatment of thumb arthritis pain. Methods Patients with thumb basal joint arthritis were identified using International Classification of Diseases, Tenth Revision codes between May and June 2020. All patients received an invitation to complete a survey regarding perceptions of cannabis and related products. Medical records were retrospectively reviewed to gather demographic information and thumb basal joint arthritis factors, including laterality, date of initial diagnosis, and prior treatment. Results The survey was completed by 103 patients. Twenty-five percent reported a history of oral medical cannabis use, and 21% reported topical medical cannabis use. Twelve of 25 oral users and 7 of 21 topical users believed that the product was effective in relieving pain and consequently worth the financial cost. Of the patients surveyed, 69% would be interested in trialing an oral formulation and 80% would be interested in trialing a topical formulation for treatment of their thumb pain. Conclusions Patients with thumb basal joint arthritis use cannabis-related products, with mixed reports on efficacy. Large numbers of these patients would be interested in trialing either oral or topical formulations of medical cannabis for treatment of their thumb basal joint pain. Clinical relevance It is important for medical providers to understand the current data available regarding analgesic properties of cannabidiol-related products to respond to patient inquiries about the use of cannabinoids in treating medical conditions.
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Cannabidiol (CBD) has gained widespread popularity as a treatment for osteoarthritis (OA) in pets; however, there is minimal scientific evidence regarding safe and effective dosing. This study determined plasma and tissue pharmacokinetics after oral CBD oil suspension administration in Hartley guinea pigs (Cavia porcellus), which spontaneously develop OA at 3 months of age. Ten, 5-month-old, male guinea pigs were randomly assigned to receive 25 (n = 5) or 50 mg/kg (n = 5) CBD oil once orally. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h timepoints. Open-field enclosure monitoring revealed no adverse effects. After euthanasia, stifle cartilage and infrapatellar fat pads were collected to quantitate CBD. CBD concentrations were determined using a validated liquid chromatography-mass spectrometry method, and pharmacokinetic parameters were calculated using noncompartmental analysis. The area under the plasma concentration-versus-time curve was 379.5 and 873.7 h*ng/mL, maximum plasma concentration was 42 and 96.8 ng/mL, time to maximum plasma concentration was 1.6 and 4.8 h, and terminal phase half-life was 8.1 and 10.8 h for the 25 and 50 mg/kg doses, respectively. CBD was detected in joint tissues of all animals. Further studies, including work in female guinea pigs, are needed to determine the efficacy of CBD for OA.
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Purpose This article aims to review the treatment options for osteoarthritis and discuss the potential efficacy of cannabidiol (CBD) as an alternative treatment. Method A PubMed literature search was conducted with search terms osteoarthritis (OA), cannabidiol, and CBD. Sixteen pertinent articles were retrieved and served as the basis for this clinical review. Three additional citations were used to provide supplementary information. Results The ability of CBD to reduce acute OA synovitis, reduce neuropathic joint pain, and prevent the progression of OA pain has resulted in increased interest in CBD as an alternative treatment for arthritis. Clinical studies with systemic CBD administration showed no evidence of adverse side effects in animals. Preliminary studies show promising results on pain relief and functional activity in rats. Conclusion The use of alternative treatments of OA may provide symptomatic relief with limited associated risk. CBD is a non–euphoria-producing compound retrieved from the hemp plant that has shown less severe adverse effects than other analgesic medications. We must continue developing and using new treatment options to alleviate the pain related to OA and increase the patient's quality of life where surgical treatment is not indicated. The Food and Drug Administration has not approved CBD products for treatment of OA, and no human trials are available at this time. Futures studies are needed to compare the efficacy of CBD to nonsteroidal anti-inflammatory drugs or corticosteroid injections, to determine the efficacy and safety profile on human subjects, and to determine the mode of CBD administration that is most effective.
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Aim: To evaluate the prevalence of self-directed cannabidiol (CBD) use in patients with end-stage degenerative hip and knee arthritis who underwent total hip arthroplasty and total knee arthroplasty. Materials & methods: Anonymous surveys for 109 patients were completed at 6 weeks follow-up after either total hip arthroplasty or total knee arthroplasty at a single tertiary care US orthopedic hospital. Results: Within the perioperative window encompassing both preoperative and postoperative periods, 22% (95% CI: 14–30%) of patients used CBD. Conclusion: There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-directed perioperative CBD use and the mixed body of evidence, further research is needed to better understand whether CBD is safe and effective.
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The objective of this study was to provide preliminary data describing the safety and effect of cannabidiol (CBD) for symptom relief of canine osteoarthritis-associated pain in a clinical setting using objective outcome measures. Twenty-three client-owned dogs with naturally occurring osteoarthritis of appendicular joints completed this prospective, double-blinded, crossover, placebo-controlled study. Baseline data were acquired for 4 wk, followed by random allocation to either placebo or CBD treatment for 6 wk, followed by 6 wk with the opposite treatment. Outcome measures included objective gait analysis, activity counts (via accelerometry) and clinical metrology instruments. There were no differences noted between groups at any time point for any of the recorded outcome measures. Adverse events associated with CBD administration included elevation in liver enzymes (n =14) and vomiting (n =2).
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In many countries, liberalisation of the legislation regulating the use of cannabis has outpaced rigorous scientific studies, and a growing number of patients presenting for surgery consume cannabis regularly. Research to date suggests that cannabis can impact perioperative outcomes. We present recommendations obtained using a modified Delphi method for the perioperative care of cannabis-using patients. A steering committee was formed and a review of medical literature with respect to perioperative cannabis use was conducted. This was followed by the recruitment of a panel of 17 experts on the care of cannabis-consuming patients. Panellists were blinded to each other's participation and were provided with rater forms exploring the appropriateness of specific perioperative care elements. The completed rater forms were analysed for consensus. The expert panel was then unblinded and met to discuss the rater form analyses. Draft recommendations were then created and returned to the expert panel for further comment. The draft recommendations were also sent to four independent reviewers (a surgeon, a nurse practitioner, and two patients). The collected feedback was used to finalise the recommendations. The major recommendations obtained included emphasising the importance of eliciting a history of cannabis use, quantifying it, and ensuring contact with a cannabis authoriser (if one exists). Recommendations also included the consideration of perioperative cannabis weaning, additional postoperative nausea and vomiting prophylaxis, and additional attention to monitoring and maintaining anaesthetic depth. Postoperative recommendations included anticipating increased postoperative analgesic requirements and maintaining vigilance for cannabis withdrawal syndrome.
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At present, the growth of public and political support for the use of marijuana as a medical treatment is outpacing the growth of scientific evidence. ➤ Despite limited evidence, marijuana-based compounds (including cannabidiol) are promoted as alternatives to opioid pain medication in the treatment of ongoing bodily pain for which people seek care. ➤ Clinical research on the medical applications of marijuana-based compounds is limited by federal regulations, and most commercially available products are not available to researchers for study.
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A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (ie, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that ‘medicinal’ cannabis or cannabinoid-based medications relieve pain in human diseases, such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here, we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.
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Abstract Background The endocannabinoid system has been shown to reduce inflammatory flares and pain in rodent models of arthritis. A limitation of endocannabinoids is that they are rapidly denatured by hydrolysing enzymes such as fatty acid amide hydrolase (FAAH) which renders them physiologically inert. Osteoarthritis (OA) is primarily a degenerative joint disease; however, it can incorporate mild inflammation and peripheral neuropathy. The aim of this study was to determine whether early blockade of FAAH bioactivity could reduce OA-associated inflammation and joint neuropathy. The ability of this treatment to prevent end-stage OA pain development was also tested. Methods Physiological saline or sodium monoiodoacetate (MIA; 0.3 mg) was injected into the right knee of male C57Bl/6 mice (20–42 g) and joint inflammation (oedema, blood flow and leukocyte trafficking) was measured over 14 days. Joint inflammation was also measured in a separate cohort of animals treated on day 1 with either saline or the FAAH inhibitor URB597 (0.03–0.3 mg/kg topical onto the knee joint). In other experiments, von Frey hair tactile sensitivity was determined on days 1 and 14 in MIA-injected mice treated prophylactically with URB597 (0.3 mg/kg s.c. over the knee joint on days 0–3). Saphenous nerve myelination was also assessed in these animals on day 14 by G-ratio analysis. Results Intra-articular injection of MIA caused an increase in joint oedema (P
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Background Arthritis pain is reported as one of the most common reasons for persons using medical herbal cannabis in North America. “Severe arthritis” is the condition justifying legal use of cannabis in over half of all authorizations in Canada, where cannabis remains a controlled substance. As champions for the care of persons with arthritis, rheumatologists must be knowledgeable of treatment modalities both traditional and non-traditional, used by their patients. As study of cannabinoid molecules in medicine is recent, we have examined the confidence in the knowledge of cannabinoids expressed by Canadian rheumatologists. Methods The confidence of rheumatologists in their knowledge of cannabinoid molecules and mechanisms relevant to rheumatology, and their ability to advise patients about cannabinoid treatments was recorded by an online questionnaire circulated via email to the entire Canadian Rheumatology Association membership. Results Over three quarters of the 128 respondents lacked confidence in their knowledge of cannabinoid molecules. While 45% of respondents believed there was no current role for cannabinoids in rheumatology patient care, only 25% supported any use of herbal cannabis. With 70% never having previously prescribed or recommended any cannabinoid treatment, uncertainty regarding good prescribing practices was prevalent. Concerns about risks of cannabis use were in line with the current literature. Conclusions Rheumatologists lacked confidence in their knowledge of cannabinoid molecules in general and in their competence to prescribe any cannabinoid for rheumatic complaints. In line with this uncertainty, there is reticence to prescribe cannabinoid preparations for rheumatology patients. Guidance is required to inform rheumatologists on the evidence regarding cannabinoids.
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Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.
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OA is a painful joint disease that predominantly affects the elderly. Pain is the primary symptom of OA, and it can present as either intermittent or constant. OA pain mechanisms are complex and have only recently been determined. Both peripheral and central processes are involved in creating the OA pain experience, making targeted therapy problematic. Nociceptive, inflammatory and neuropathic pains are all known to occur in OA, but to varying degrees in a patient- and time-specific manner. A better understanding of these multifactorial components of OA pain will lead to the development of more effective and safer pain treatments.
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There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain.
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Two nationwide surveys were carried out using an electronic poll of 2,000 GPs and postal questionnaires were sent to 30,000 patients with osteoarthritis (OA). Both surveys found a high level of gastro-intestinal (GI) side-effects in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). Almost every GP (97%) reported experience of patients suffering GI symptoms while on an NSAID, 38% reported patients who had been hospitalised and 4% reported patients who had died owing to NSAID-induced side-effects. Most GPs (92%) said they were concerned about GI safety when prescribing an NSAID and almost a third (32%) said they were concerned about litigation from patients who had experienced a bleed. Use of NSAIDs in OA remained high, with 44% of GPs prescribing conventional NSAIDs to at least three quarters of their patients, 57% of GPs using simple analgesia and just 12% using a cyclo-oxygenase-2 (COX-2) selective inhibitor in over 74% of patients. Some 45% of patients reported receiving NSAIDs compared with 43% on simple analgesia and 4% on COX-2 selective inhibitors. Most GPs (69%) stated that their main therapeutic objective in using an NSAID to treat OA was to control pain without GI side-effects. Almost a quarter (24%) said they used low-dose NSAIDs in the hope that this would control pain without GI side-effects. Dissatisfaction with treatment was the most common reason reported by GPs for patients on an NSAID to re-present, with 73% citing either breakthrough pain or incomplete pain relief as the most common reason for patient dissatisfaction. This mirrored the patients' perception, with 63% citing inadequate pain relief as their main reason for dissatisfaction with current painkillers compared to 17% who cited stomach upsets or irritation. Patient and GP appear to be united in their concern at the GI risks of NSAID treatment. In the light of this and recent data on the efficacy, safety profile and cost-effectiveness of COX-2 selective inhibitors, GPs should re-examine their medical management of OA.