Manage Pain with CBD and Promote Better Healing of Broken Bones
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CBD shown to be as or more effective than NSAIDs & Opioids in Managing Pain and Promoting better healing of Broken Bones
CBD continues to amaze people in its range to impact our health. Further, it continues to show very strong positive results in studies performed by major universities, the NIH (National Institute of Health) and other prominent organizations around the world. The study below says that the ability to manage pain with CBD is generally deemed to be very safe, highy effective and is extremely affordable. In fact, managing pain with CBD is more favorable, i.e. better, faster, cheaper, than NSAIDs and Opioids.
Clipped from: https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.4902
ABSTRACT - Manage Pain with CBD and Promote Better Healing
Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodeling. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential.
Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate postfracture pain without impeding the healing. Here, we investigated the analgesic efficacy of two nonpsychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Pain management with CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs.
Interestingly, the ability to manage pain with CBD and CBG was further enhanced by its ability to promote bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors. During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone-marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest the ability to manage pain with CBD and CBG as therapeutic agents that can replace NSAIDs in managing postfracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Introduction - Manage Pain with CBD and Promote Better Healing of Broken Bones
Bone healing proceeds through a sequence of overlapping processes that can be divided into three main phases: inflammation, repair, and remodeling.(1, 2) The inflammatory phase initiates bone repair via the formation of a hematoma that is rich in immune cells. The microenvironment in the healing hematoma induces immune cells to secrete high levels of cytokines, growth factors, and angiogenic factors.(1, 2) These factors are vital for neovascularization as well as recruitment of mesenchymal stem cells (MSCs) and bone progenitors that are required for bone regeneration.(1, 2) The repair of most cortical bone fractures proceeds via the initial formation of a fibrocartilaginous (soft) callus that is filled with proliferating chondrocytes.(1, 2) These chondrocytes undergo hypertrophy and mineralization at later stages of the repair phase, which hardens the cartilaginous area that bridges the fracture gap and allows new blood vessels to invade the mineralized soft callus.(1, 2) The mineralized soft callus is then replaced by newly formed woven bone (WB) to form the bony callus, which undergoes remodeling to reestablish the characteristic laminar structure of the cortical bone.(1, 2)
Bone fracture results in the distortion and damage of the mechanosensitive nerve fibers that innervate the bone, leading to the development of the initial sharp pain sensation experienced by fracture patients.(3) (The stromal and immune cells that populate the fracture site to initiate the repair process secrete neurotransmitters, growth factors, and cytokines. These factors cause ectopic nerve sprouting, which exacerbates pain sensation, resulting in restricted patient movement. (Managing pain with CBD is very effective) dAs effective healing of a load-bearing bone (such as the femur or the tibia) requires proper movement-induced loading of the injured bone within the tolerable limits, inappropriate pain management results in suboptimal bone loading and, hence, delayed healing.(3) Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are currently used to manage fracture pain.(4, 5) Preclinical and clinical studies indicate that NSAIDs, including indomethacin and celecoxib, inhibit bone repair, mainly by inhibiting the inflammatory phase of the repair process.(6-12) Several factors remain unclear with regard to the use of NSAIDs in fracture patients, including the dose and treatment duration of the NSAID that can be safely used. Generally, many orthopedic surgeons believe that NSAIDs are contraindicated in bone fracture patients.(4, 6, 13-16) Opioids do not offer a better alternative as they interfere with the functional status of the patients and their ability to go back to work.(17) Importantly, recent studies have also shown that opioids increase the risk of bone fracture and delay bone healing.(18, 19) These drawbacks of the available analgesics are among the reasons that bone fracture patients fail to participate in an effective rehabilitation program.(4, 6, 13-16) Accordingly, the ability to manage pain with CBD in fracture patients remains an unmet clinical problem that awaits the discovery of potent analgesics with minimal negative impact on the healing process.(20) In this regard, there is increasing interest in the potential therapeutic uses of phytocannabinoids, and alleviating pain is one area where cannabinoids hold great therapeutic promise.(21) However, the potential of cannabinoids in managing fracture pain has not been investigated so far, and in general, the lack of scientific evidence for the efficacy of cannabinoids in different applications hinders their clinical prescription.
Cannabidiol (CBD) is a nonpsychotropic cannabinoid and one of the major constituents of cannabis.(21) In 2018, pure CBD was approved by the FDA for treatment of seizures in pediatric patients with Lennox–Gastaut or Dravet syndrome.(21) Thus, the safety profile and the pharmacokinetics of pure CBD when used in human patients are well characterized, which facilitates CBD repurposing to other medical indications. Only a few studies investigated the impact of CBD on fracture healing and bone homeostasis. One study reported that CBD enhanced the biomechanical properties of the newly formed bone in a rat fracture model,(22) and another study demonstrated that CBD attenuated bone loss in a rat model of spinal cord injury-induced bone loss.(23) Hence, there is a dearth of information with regard to whether CBD affects bone healing in species other than rat as well as the pathways whereby CBD impacts bone homeostasis and regeneration. Cannabigerol (CBG) is another nonpsychotropic cannabinoid that has been attracting growing attention recently(24); yet, its impact on bone health and repair has never been investigated.
Here, we use a mouse model of endochondral fracture healing to assess the analgesic efficacy of CBD and CBG in postfracture pain and compare their analgesic effects to those of NSAIDs. Importantly, we investigate the impact of managing pain with CBD and CBG on the different phases of healing and assess their impact on the proliferation, viability, and homeostasis of bone progenitors, bone cells, and soft-callus chondrocytes. In parallel, we assess the influence of CBD and CBG on the structure and quality of the newly formed bone.
Materials and Methods (See Study)
CBD and CBG alleviate hypersensitivity to mechanical, cold, and hot stimuli in mice with tibial fracture
To determine the impact of CBD or CBG on fracture-associated pain, we performed a set of pain behavior tests. We first tested changes in the mechanical nociception in response to CBD or CBG treatment by performing the von Frey test, during which we pressed a microfilament against the paw of the fractured leg and measured the threshold that was needed to evoke a withdrawal response.(33) The vehicle-treated fractured mice exhibited mechanical allodynia as indicated by an approximately threefold reduction in the response threshold relative to its level in the sham-operated mice (Fig. 2A). Treatment with CBD or CBG alleviated the observed mechanical allodynia and increased the response threshold in the fractured mice to a level comparable to that measured in the sham-operated mice (Fig. 2A). Importantly, the effects of CBD and CBG on mechanical allodynia were comparable to those of indomethacin and celecoxib, which are widely used NSAIDs that we employed as positive controls (Fig. 2A).
Fig. 2
Managing Pain with CBD and CBG shows it ameliorates postfracture pain as effectively as NSAIDs.
See study for full details.
We also tested for increased sensitivity to cold and hot stimuli by performing acetone evaporation and hot plate tests, respectively. Compared to the sham groups, the vehicle-treated fractured mice exhibited hypersensitivity to both stimuli as evidenced by an approximately threefold reduction in the time required to elicit a nociceptive response (Fig. 2B,C). Treatment with CBD, CBG, indomethacin, or celecoxib ameliorated this hypersensitivity and increased response times in both tests to their values in the sham groups (Fig. 2B,C). These results indicate that CBD and CBG ameliorate postfracture pain as effectively as NSAIDs.
As expected, the tibial fracture impaired the gait of mice, resulting in shortened stride length (Fig. 2D), stance length (Fig. 2E), and sway distance (Fig. 2F), and reduced the paw print intensity (Fig. 2G). Treatment with CBD, CBG, indomethacin, or celecoxib significantly recovered all gait parameters (Fig. 2D–G). The only exception was the failure of celecoxib to enhance the sway distance (Fig. 2F).
CBD and CBG accelerate the mineralization of the soft callus
To assess the impact of CBD or CBG on the repair phase of fracture healing, we first analyzed day 14 after the fracture (d14). ... However, the fibrocartilaginous callus in the mice that were treated with CBD or CBG exhibited approximately two- to threefold increases in the expression of Col I (Fig. 3A), OC (Fig. 3D), and SP7 (Fig. 3E). Taken together, these data suggest that treatment with either CBD or CBG induces the expression of the factors that mediate soft-callus mineralization and endochondral ossification. See study for further details.
Fig. 3
CBD and CBG promote the mineralization of the fibrocartilaginous callus.
See study for further details.
CBD and CBG augment WB formation
We next analyzed the WB area in the callus of d14 using μCT. We found that the calli of the CBD- or CBG-treated mice exhibited more BV/TV, BMD, Tb.Th, and Tb.N than the calli of the vehicle-treated mice (Fig. 4A,B). These results indicate that CBD and CBG promoted bone formation. Consistently, treatment with CBD or CBG enhanced the expression of Col I in the WB region (Fig. 5A), increased the number of osteoblasts per WB surface area (Fig. 5B), and reduced the level of apoptosis in the region of WB (i.e., bone cells and BM cells) (Fig. 5C).
Fig. 4
CBD and CBG enhance bone formation
on d14 after fracture. (A) μCT images of fractured right hindlimb captured on d14. (B) Results of μCT analysis of d14 callus in specified treatment groups (N = 6 mice). All box-and-whisker plots are presented as min to max and line at median; *p < 0.05, **p < 0.01, ***p < 0.001, using one-way ANOVA followed by Tukey's post hoc test.
Fig. 5
CBD and CBG enhance cell viability and promote Col I expression in woven bone area of d14 callus.
See Study.
CBD and CBG accelerate bony bridging of fracture gap
We next analyzed the calli isolated from the different treatment groups on d21 after the fracture. At this time point, the fracture callus of the vehicle-treated mice was filled by newly formed WB, and the soft callus was nearly completely resorbed (Fig. S2A). μCT analysis indicated that the BV/TV, BMD, Tb.Th, and Tb.N remained higher in the calli of the mice that were treated with CBD or CBG compared to the calli of the vehicle-treated mice (Fig. 6A,B). Consistent with the results on d14, treatment with CBD or CBG increased the number of osteoblasts per bone surface area (Fig. 6C). Furthermore, treatment with CBD or CBG induced the proliferation of osteoblasts/bone lining cells and BM cells (Fig. 6D). The number of apoptotic cells was comparable in all groups (Fig. S2B). Notably, the WB area of the vehicle-treated mice contained fewer apoptotic cells on d21 than on d14 (Figs. 5C and S2B).
Fig. 6
CBD and CBG accelerate bony bridging of fracture gap.
See Study.
CBD and CBG substantially increased the biomechanical Strength of the healed bone
See Study.
Taken together with the results from d14 and d21, these data indicate that CBD and CBG promote bone formation and fracture repair throughout the healing process.
Fig. 7
CBD or CBG treatment enhances biomechanical properties of newly formed bone.
As our results indicated that CBD and CBG enhanced bone formation (Figs. 3-7), we next investigated whether they impact bone progenitors. Growing evidence indicates the involvement of periosteal precursors in fracture healing. See Study for further notes.
Fig. 8
See Study for further notes:
Treatment with either CBD or CBG increases the abundance of PDGFRα+ progenitors during early phases of healing
....The results indicated that treatment with CBD or CBG increased the abundance of the PDGFRα+ progenitors approximately three- to fourfold (Fig. 9A). Furthermore, when we differentiated the PDGFRα+ progenitors in vitro in the presence of vehicle, CBD, or CBG, both CBD and CBG promoted the osteogenic commitment of the progenitors and enhanced the formation of mineralizing bone cells (Fig. 9B). Taken together, CBD and CBG increased the number of bone progenitors during the early phases of healing and promoted the osteogenic differentiation of these progenitors. These data unravel a mechanism whereby CBD and CBG promote bone formation during fracture healing.
Fig. 9
Treatment with CBD or CBG increases the abundance of PDGFRα+ progenitors in the healing callus.
See Study for further notes.
Discussion
We propose the FDA-approved cannabinoid CBD and the investigational cannabinoid CBG as therapeutic agents that not only attenuate postfracture pain efficiently but also promote bone healing. Our results demonstrate that mice with fractured tibiae exhibited impaired gait (Fig. 2D–G) and hypersensitivity to mechanical, cold, and hot stimuli (Fig. 2A–C). Treatment with the NSAID indomethacin or celecoxib normalized the gait and alleviated pain sensitivity in fractured mice (Fig. 2A–G). CBD and its derivative dihydroxy CBD have been reported to suppress chronic neuropathic and persistent inflammatory pain.(45) Derivatives of CBG have also been reported to possess anti-inflammatory and analgesic properties.(29) However, the analgesic potential of CBD or CBG in the context of postfracture pain has never been investigated. The results we are reporting here demonstrate that CBD and CBG are as effective as NSAIDs in normalizing pain sensitivity in fractured limbs (Fig. 2A–G). It is noteworthy that mice with fractured tibiae that were treated with either CBD or CBG displayed normalized gait parameters, reflecting better loading of the fractured hindlimb relative to the vehicle-treated mice (Fig. 2G). This might have contributed to the improved healing observed in the cannabinoid-treated groups (Figs. 3-7).
Both the innate and adaptive immune systems play crucial roles in bone healing.(46) Modulation of the immune response by CBD is well studied. A considerable body of in vitro and in vivo studies indicates anti-inflammatory and immunosuppressive effects of CBD that involve both the innate and adaptive responses.(47) In contrast, several other studies have shown immunostimulatory and pro-inflammatory effects of CBD.(47) In general, the impact of CBD on the immune response/inflammation depends on several factors, which include the tissue/system in which CBD is studied, whether CBD is studied in healthy or disease conditions,(48) and, importantly, the administered dose/concentration of CBD. Although the immunomodulatory effects of CBG are far less studied than those of CBD, CBG derivatives have also been shown to modulate inflammation and immune response.(29, 49) Our study did not directly address the impact of CBD or CBG on the inflammatory/immune response during the healing process; however, our data clearly demonstrate that neither CBD nor CBG modulated the inflammatory response in a way that negatively impacted the healing (Figs. 3-7). In fact, as early as d3 after fracture, the modulatory effects of either CBD or CBG on the microenvironment of the fracture hematoma favored the proliferation and/or recruitment of periosteal PDGFRα+ progenitors (Fig. 9A). This positive impact of CBD or CBG on the healing process was sustained throughout the later phases of healing (Figs. 3-7).
Generally, CBD exhibits low affinity to CNR1 and CNR2(55, 56); further, some of the physiological effects of CBD have been reported to be independent of CNR1 and/or CNR2.(57-59) However, CBD can also signal through CNR1 and/or CNR2 via indirect mechanisms that involve inhibiting the fatty acid amide hydrolase (FAAH), which results in accumulation of anandamide that possesses high affinity to CNR1 and CNR2.(60-62) CBD might also act as an allosteric modulator of CNR1 and CNR2.(63-66) Similarly, CBG can effectively regulate endocannabinoid signaling by acting as a partial agonist of CNR2 or modulating CNR1 signaling, although the underlying mechanisms of the latter are unclear.(24) The mechanisms whereby CBD or CBG might modulate the homeostasis of bone cells or chondrocytes in vivo are uninvestigated. Our data revealed striking similarities between CBD and CBG in promoting both early and late phases of bone healing. During the inflammatory phase, both CBD and CBG increased the abundance of the PDGFRα+ progenitors in the healing hematoma (Fig. 9A), which might be the outcome of increasing the proliferation and/or the infiltration of these progenitors in the fracture callus. CBD and CBG also directly promoted the osteogenic differentiation of primary PDGFRα+ progenitors in vitro (Fig. 9B). As healing proceeded to the repair phase, CBD and CBG enhanced the expression of the osteogenic proteins Col I, OC, and SP7 in the chondrocytes (Fig. 3A,D,E). These proteins are essential for the mineralization of the soft callus and for endochondral bone formation. Both CBD and CBG inhibited the apoptosis and enhanced the proliferation of bone and BM cells (Figs. 5C and 6D). Accordingly, CBD and CBG exhibited protective and proliferative effects on several types of cells that play central roles during different phases of healing. The plasma concentrations that we detected after injecting 5 mg/kg/day (i.p.) of either CBD or CBG for 3 or 4 weeks were ~100–150 ng/mL (Fig. 1E). The reported plasma concentration of CBD in patients, following administration of 20 mg/kg/day for 22 days, is 400 ng/mL (i.e, ~1.2 μM).(67) Therefore, the therapeutic effects of CBD that we observed in this study can be achieved without exceeding the clinically approved dose.(67) A previous study investigated the effect of CBD alone or in combination with the psychoactive cannabis constituent Δ9-tetrahydrocannabinol (THC) on fracture healing using a rat model of femur fracture.(22) The study reported that CBD, but not THC, enhanced the biomechanical properties of healed bone, as indicated by an increase in the maximal load and work to failure, but not stiffness,(22) which is consistent with our data. However, the study did not detect any significant increase in the callus material density as a result of CBD and/or THC treatment.(22) More preclinical studies are required to investigate the therapeutic effects of CBD and CBG in other fracture models, and future clinical studies will also be required to assess the effects of CBD and CBG in fracture patients. Notably, previous studies reported that CNR2 agonists could reduce breast cancer-induced bone loss and pain,(68) providing further evidence for the wide therapeutic potential of cannabinoids as well as modulators of cannabinoid receptors in bone diseases.
We performed in vitro osteogenic differentiation of PDGFRα+ progenitors in the presence of 1 μM of CBD Fig. 9B), a concentration that was chosen to be comparable to the clinically reported plasma level of CBD.(67) In fact, when we used >10 μM of either CBD or CBG in these in vitro differentiation experiments, we observed significant apoptosis, and when the concentration of either drug exceeded 50 μM, most of the cells died within 24 to 48 h (data not shown). These data show how the outcome of in vitro experiments might change drastically based on the concentration for each cannabinoid. Accordingly, upon designing in vitro studies, it is advisable to use cannabinoid concentrations that are relevant to the endogenous conditions.
Overall, the protective, proliferative, and pro-osteogenic effects that we identified for CBD and CBG during the different healing phases culminated in accelerated repair, promoted bone formation, and enhanced biomechanical strength of the healed bone. These data extend our understanding of the impact of CBD on fracture healing and demonstrate for the first time the therapeutic potential of CBG in the context of bone regeneration and repair. Taken together, the data we present here propose CBD and CBG as effective alternatives to NSAIDs in managing pain in fracture patients.
Acknowledgments
Analysis of the plasma concentrations of CBD and CBG was performed at the Mass Spectrometry Core Facility (small molecules) (RRID no. is SCR_017831), and the FC analysis was performed at the Flow Cytometry and Cell Sorting core (RRID no. SCR_021134) at the Penn State University College of Medicine. Kent E. Vrana (and the Penn State College of Medicine) is the recipient of research support from PA Options for Wellness (a state-approved medical marijuana clinical registrant). The funding sources were not involved in study design, providing any experimental materials, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication. The authors would like to acknowledge members of the state-approved medical marijuana academic clinical research center at Penn State for insights and comments on the data and study design. This work was supported by National Institutes of Health (NIH) grants R01 DK121327 to Reyad A. Elbarbary and R01 AR071968 to Fadia Kamal.
Author Contributions
Deepak Kumar Khajuria: Methodology; validation; data curation; formal analysis; software. Vengadeshprabhu Karuppagounder: Methodology; data curation. Irena Nowak: Methodology; data curation. Diana E. Sepulveda: Data curation; methodology. Gregory S. Lewis: Formal analysis; validation; supervision; software. Christopher C. Norbury: Formal analysis; supervision. Wesley M. Raup-Konsavage: Formal analysis; writing – review and editing. Kent E. Vrana: Supervision; writing – review and editing; conceptualization. Fadia Kamal: Conceptualization; funding acquisition; writing – original draft; writing – review and editing; formal analysis; project administration; supervision; resources. Reyad A. Elbarbary: Conceptualization; investigation; funding acquisition; writing – original draft; writing – review and editing; formal analysis; project administration; supervision; resources.
Disclosures
The authors declare no conflicts of interest.
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