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Cbd oil for osteoarthritus

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis

* Corresponding author. Address: Departments of Pharmacology and Anaesthesia, Pain Management and Perioperative Medicine, Dalhousie University, 5850 College St, Halifax, NS B3H 4R2, Canada. Tel.: (902) 494-4066; fax: (902) 494-1388. E-mail address: [email protected] (J. J. McDougall).

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Abstract

Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.

1. Introduction

The most prominent form of synovial joint disease, osteoarthritis (OA), is characterised by joint degeneration, pain, and in some patients, articular neuropathy. 21 Chronic pain associated with OA is a major concern for which there are few viable treatments. The first-line therapy used to treat OA pain is nonsteroidal anti-inflammatory drugs; however, with long-term use their efficacy declines and they can lead to major adverse gastrointestinal and cardiovascular events. Historically, OA has been classified as noninflammatory arthritis; however, there is now overwhelming evidence that synovitis can occur in response to pro-inflammatory mediators being released into the joint. 10,11,13,29,32 It is believed that this low-level inflammation contributes to degenerative changes that affect the entire joint leading to the development of peripheral sensitisation and nociceptive pain. 18,22,37 In addition to structural defects, there is growing evidence to suggest that approximately 30% of patients with OA have neuropathic pain. 1,34 Thus, a therapeutic which can block inflammation, neuropathy, and pain is sorely needed.

The endocannabinoid system (ECS) plays an important physiological role in the regulation of tissue inflammation and pain. 23,38 A functional ECS has been demonstrated in the joints of animals 36 and humans, 31 which acts tonically to maintain joint homeostasis. Immunohistological and pharmacological evidence confirm that cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors are expressed on the neurones and microvasculature that supply rat knee joints. 23,24,36 In addition, CB2 receptors are colocalized with pronociceptive transient receptor potential vanilloid-1 (TRPV1) channels where, through common intra-cellular pathways, they act together to modulate joint pain. 23,24,36 This suggests that drugs which target the ECS have the potential to regulate painful arthritis and inflammatory joint disease.

Cannabidiol is the main noneuphoria producing component of the cannabis plant. 26 Pharmacologically, CBD has a complex signalling mechanism whereby it can both activate and silence classical cannabinoid receptors as well as modulate noncanonical cannabinoid receptor pathways. In in vitro studies, CBD has been shown to be an inverse agonist at CB2 receptors, 40 and a full antagonist at CB1 receptors 40 and G protein-coupled receptor-55 (GPR55). 33 In vitro, CBD was found to be an agonist at TRPV1 3 and transient receptor potential ankyrin 1 (TRPA1), 9 which play a central role in the development of OA. 27 In musculoskeletal disease models, systemic administration of CBD suppressed the progression of collagen-induced arthritis by reducing inflammatory cytokine production. 20 Although these preliminary findings indicate a possible role for CBD in relieving joint inflammation, the local effect of articularly applied CBD on OA and joint pain has not been investigated.

The initial aim of this study was to assess the effect of locally administered CBD on joint pain in animals with end-stage OA. Since acute inflammation can contribute to the long-term development of OA joint pain, 32 the ability of CBD to reduce acute OA synovitis and prevent the subsequent progression of persistent OA pain was also investigated. Finally, the effect of prophylactic CBD treatment on OA joint neuropathy was assessed.

2. Methods

2.1. Animals

Male Wistar rats (150-175 g; Charles River Laboratories, Senneville, QC, Canada) were housed in ventilated racks at 22°C ± 2°C on a 12:12 hours light:dark cycle (light-on from 7:00 to 19:00). After arrival at the animal care facility, all rats were permitted at least 1 week to acclimate to their environment. Animals were housed in pairs, cages were lined with woodchip bedding, and animals were provided with environmental enrichment. Standard laboratory chow and water were provided ad libitum. All experimental protocols were approved by the Dalhousie University Committee on the Use of Laboratory Animals, which acts in accordance with Animal Research: Reporting of In Vivo Experiments (ARRIVE) and the standards put forth by the Canadian Council for Animal Care.

2.2. Sodium monoiodoacetate model of osteoarthritis

Animals were deeply anaesthetised (2%-4% isoflurane; 100% oxygen at 1 L/min) until cessation of all sensory reflexes. The right knee joint was shaved, swabbed with 100% ethanol and 50 μL of sodium monoiodoacetate (MIA) (3 mg in saline) was injected into the joint space (intra-articular; i.artic.). The knee was then manually extended and flexed for 30 seconds to disperse the solution throughout the joint.

2.3. Electrophysiological recording of joint afferents

After OA development (14-19 days after MIA), animals were deeply anaesthetised using urethane (25% solution; 2 g/kg i.p.). Core body temperature was measured by a rectally inserted thermometer and maintained at 37°C ± 1°C by a thermostatically controlled heating blanket (CWE Inc, Ardmore, PA). After loss of the pedal withdrawal reflex, the trachea was cannulated to allow for artificial ventilation with a Harvard rodent respiratory pump (Harvard Apparatus, Holliston, MA) with 100% O2 (stroke volume: 2.5 mL; breath frequency: 52 breaths/min). The left carotid artery was cannulated to allow for continuous measurement of the mean arterial blood pressure. The cannula was attached to an in-line pressure transducer (Kent Scientific Corp, Torrington, CT) attached to a differentially amplified blood pressure monitor (World Precision Instruments, Sarasota, FL). The jugular vein was cannulated for administration of the muscle relaxant gallamine triethiodide (50 mg/kg), which eliminated neural interference from hind limb musculature, and the distal saphenous artery was cannulated for close intra-arterial (i.a.) administration of CBD or vehicle to the knee joint (100 μL injection volume). A specialised clamp was fixed to the mid-shaft of the isolated right femur and attached to a stereotaxic frame to prevent movement of the proximal aspect of the rat hind limb. The right hind paw was then placed in a shoe-like holder that was connected to a force transducer and torque meter (Data Track 244-1-R; Intertechnology, ON, Canada) to standardise the amount of rotational force being applied to the knee joint. A longitudinal skin incision was made along the medial aspect of the hind limb and the reflected skin was sutured to a metal “O” ring to create a pool which was filled with warm mineral oil to prevent tissue desiccation. The medial articular branch of the saphenous nerve was isolated and transected in the inguinal region to prevent spinal reflexes. The epineurium was removed and the nerve teased to isolate fine neurofilaments which were then placed on a platinum recording electrode to measure single-unit activity. To identify a joint afferent fibre and its receptive field, the knee joint was gently probed with a blunt glass rod. The mechanical threshold of each recorded joint afferent was determined by gradually increasing the torque applied to the joint until the fiber elicited an action potential. The conduction velocity of the fibres were determined by electrically stimulating the receptive field with a pair of silver bipolar stimulating electrodes (0.6 Hz, 2 ms pulse width, 1-15 V). The mechanosensitivity of the joint fibre was assessed by applying noxious outward rotations to the knee and counting the number of action potentials elicited during the rotation. Noxious rotation refers to torque occurring outside the normal range but not severe enough to cause soft tissue injury.

2.3.1. Experimental timeline

On day 14 post-MIA induction, 3 sets of noxious rotations, each lasting 5 seconds, were applied 5 minutes apart as a baseline measurement of afferent activity. After close i.a. infusion of CBD (100, 200, or 300 μg in 100 μL) or vehicle (100 μL), joint mechanosensitivity was assessed for an additional 15 minutes. To minimise the use of animals, multiple doses of CBD or vehicle were assessed in each fibre. A washout period of at least 50 minutes was observed between the administration of varying doses of CBD or vehicle to allow afferent firing to return to baseline levels. The percentage change in afferent activity before and after administration of CBD or vehicle was calculated offline using Spike2 software (Cambridge Electronic Design, Cambridge, United Kingdom). All recorded fibres fired in response to close i.a. administration of potassium chloride (KCl; 1 mM, 0.1 mL) at the conclusion of the experiment, confirming that administered drugs had reached the mechanosensory nerve endings and that the recorded fibre was still viable.

2.4. Behavioural pain measurements

2.4.1. Von Frey hair mechanosensitivity

Von Frey hair mechanosensitivity was used as a measure of secondary allodynia. Alert, unanaesthetised animals were placed in a Plexiglas chamber with a metal mesh flooring which allowed access to the plantar surface of each hind paw. After allowing the animal to acclimate until exploratory behaviour ceased (approximately 10 minutes), ipsilateral hind paw mechanosensitivity was assessed using a modification of the Dixon up–down method. 5 A von Frey hair was applied perpendicular to the plantar surface of the ipsilateral hind paw (avoiding the toe pads) until the hair flexed; the filament was then held in place for 3 seconds. If there was a positive response (ie, withdrawal, shaking, or licking of the hind paw), the next lower strength hair was applied; if there was a lack of response, the next higher strength hair was applied up to a cut-off of 15 g bending force. The 50% withdrawal threshold was determined using the following formula: 10 (Xf + kδ) /10,000; where Xf = value (in log units) of the final von Frey hair used, k = tabular value for the pattern of the last 6 positive and/or negative responses, and δ = mean difference (in log units) between stimuli.

2.4.2. Hind limb incapacitance

To perform dynamic weight bearing (DWB) measurements, animals were placed in a Perspex chamber (model BIO-DWB-AUTO-R; Bioseb, Boulogne, France) with a pressure-sensitive floor and allowed to move freely. Hind limb weight bearing was tracked and recorded over a 3-minute period. Weight borne on the ipsilateral hind paw was calculated as a percentage of the total weight borne on the hind limbs.

2.4.3. Experimental timeline

Animals underwent baseline von Frey hair mechanosensitivity and DWB testing. Separate cohorts were treated on day 14 post-MIA with an i.artic. injection of either vehicle (50 μL) or CBD (100-300 μg/50 μL). In other experimental cohorts, day 14 OA rats were treated with the highest dose of CBD (300 μg/50 μL) and either the CB1 receptor antagonist, AM281 (75 μg/50 μL), the CB2 receptor antagonist, AM630 (75 μg/50 μL), or the TRPV1 receptor antagonist, SB-366791 (30 μg/50 μL) administered locally (subcutaneously; s.c.) over the joint 10 minutes before i.artic. CBD administration. Behavioural pain measurements for these experiments were conducted at 30, 60, 120, 180, and 240 minutes after drug administration. To investigate the prophylactic effects of CBD on OA pain and peripheral neuropathy, a separate cohort of rats was treated with CBD (300 μg/50 μL) or vehicle (50 μL) s.c. over the knee joint 30 minutes before i.artic. injection of MIA (3 mg/50 μL) and once daily on each of the subsequent 3 days; behavioural pain measurements were conducted on days 0, 1, 2, 3, 7, 10, and 14.

2.5. Inflammation measures

Animals were deeply anaesthetised by an intraperitoneal injection of urethane (25% solution; 2g/kg i.p.). A longitudinal incision was made along the ventral skin of the neck to expose the trachea which was cannulated with PE-200 tubing to permit unrestricted breathing. The right carotid artery was also cannulated with PE-30 tubing filled with heparinised saline (1 U/mL) to allow for continuous monitoring of the mean arterial pressure (MAP).

2.5.1. Intravital microscopy

Both hind limbs were immobilised and the capsule of the ipsilateral knee was exposed by surgically removing a small ellipse of the overlying skin and superficial fascia. Physiological buffer (37°C ± 1°C) was immediately and continuously perfused over the exposed joint.

Intravital microscopy was used to assess leukocyte-endothelial interactions within the microcirculation of the knee joint, as described previously. 2 The synovial microcirculation was visualised under incident fluorescent light using a Leica DM2500 microscope with a HCX APO L 20X objective and an HC Plan 10X eyepiece giving a final magnification of ×200. In vivo leukocyte staining was achieved by intravenous administration of 0.05% rhodamine 6G (in saline). Straight, unbranched postcapillary venules (15-50 μm in diameter) were chosen for visualisation and 3 fluorescent videos (per time point) were captured for 1 minute each by a Leica DFC 3000 camera (Leica Microsystems Canada Inc, Richmond Hill, ON, Canada). Two measures of leukocyte-endothelial interactions were used to assess articular inflammation: (1) the number of rolling leukocytes to pass an arbitrary line perpendicular to the venule in 1 minute were counted and (2) the number of adherent leukocytes within a 100-μm portion of the venule. Rolling leukocytes were defined as positively stained blood cells travelling slower than the surrounding blood flow, and adherent leukocytes were defined as positively stained cells that remained stationary for a minimum of 30 seconds.

2.5.2. Laser speckle contrast analysis

In the same animals, knee joint blood flow was measured by laser speckle contrast analysis (LASCA) using a PeriCam PSI System (Perimed Inc, Ardmore, PA). At each time point, 1-minute recordings of the exposed knee joint were taken at a working distance of 10 cm with a frame capture rate of 25 images per second. Using dedicated software (PIMSoft, Version 1.5.4.8078), images were averaged to generate 1 perfusion image per second. At the end of the experiment, rats were euthanised and a dead scan of the knee was taken. This “biological zero” value was subtracted from all measurements to account for any Brownian motion in the tissue. Images were analysed offline where mean blood perfusion (perfusion units) in a defined region of interest approximating the knee joint was calculated.

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2.5.3. Experimental timeline

Inflammation measures were conducted on day 1 post-MIA induction, which corresponds to the peak of inflammation in this OA model. After baseline intravital microscopy and LASCA recordings (1 minute) a 50-μL bolus of CBD (300 μg) or vehicle (separate cohort) was applied topically over the exposed knee joint. Subsequent recordings were taken at 5, 15, 30, 60, 120, and 180 minutes after drug administration. In separate cohorts, day 1 MIA rats were treated with the highest dose of CBD (300 μg/50 μL) and either the CB1 receptor antagonist, AM281 (75 μg/50 μL), the CB2 receptor antagonist, AM630 (75 μg/50 μL), or the TRPV1 receptor antagonist, SB-366791 (30 μg/50 μL) administered topically over the joint 10 minutes before CBD administration.

2.6. G-ratio analysis of the saphenous nerve

A segment of the saphenous nerve was isolated proximal to the ipsilateral knee joint and placed in 2.5% glutaraldehyde (diluted with 0.1 M sodium cacodylate buffer), and stored at 4°C for at least 1 week. The nerve samples were then removed from the fixative and rinsed 3 times with 0.1 M sodium cacodylate buffer. The samples were fixed in 1% osmium tetroxide for 2 hours, rinsed with distilled water, and then placed in 0.25% uranyl acetate (4°C) overnight. The samples were then dehydrated in a graduated series of acetone (50%, 70%, 95%, and finally 100%). The samples were then dried in 100% acetone for 10 minutes. Epon–araldite resin was used to mount the samples. The samples were placed in a 3:1 ratio of dried 100% acetone to resin for 3 hours, followed by a 1:3 ratio of dried 100% acetone to resin overnight. Next the samples were placed in 100% Epon–araldite resin for 3 hours and cured in an oven at 60°C for 48 hours. Finally, using an LKB Huxley ultramicrotome with a diamond knife, the samples were sectioned into 100 nm thick slices. Cross-sectional slices of nerves were placed onto a copper wire grid consisting of 300 individual squares per inch (each square measuring 83 × 58 μm) and then stained with 2% aqueous uranyl acetate for 10 minutes and finally lead citrate for 4 minutes.

The copper wire grids containing the saphenous nerve sections were inserted into a JEOL JEM 1230 transmission electron microscope (JEOL Corp Ltd, Tokyo, Japan). The microscope was set at a voltage of 80.0 kV, and images were captured at ×2500 using a Hamamatsu ORCA-HR digital camera (Hamamatsu Photonics, Hamamatsu City, Japan). One nerve cross-section image was visually partitioned into 9 quadrants and 3 images were captured (from quadrants 1, 5, and 9). All fibres were assessed using the G-ratio plugin in ImageJ processing software. The G-ratio was calculated using the equation where, a is the internal axonal area and A is the total axonal area of the fibre. The higher the G-ratio the higher the degree of demyelination.

2.7. Drugs and reagents

Cannabidiol (2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) was obtained from Tocris Bioscience (Bio-Techne, Abingdon, United Kingdom). AM281 (CB1 receptor antagonist; 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and AM630 (CB2 receptor antagonist; 6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone) were obtained from Cayman Chemicals (Ann Arbor, MI). SB-366791 (N-(3-methoxyphenyl)-4-chlorocinnamide), rhodamine 6G, cremophor, dimethyl sulphoxide (DMSO), urethane, and MIA were obtained from Sigma-Aldrich (St. Louis, MO). Solutions of CBD, AM281, AM630, and SB-366791 were prepared in vehicle (1:1:18; DMSO:cremophor:saline) on the day of use. Rhodamine 6G (0.05%) and MIA were dissolved in saline. Physiological buffer (135 mM NaCl, 20 mM NaHCO3, 5 mM KCl, 1 mM MgSO4*7H2O, pH = 7.4) was prepared in the laboratory.

2.8. Statistical analysis

All data were expressed as mean ± SEM. Data were tested for Gaussian distribution by the Kolmogorov–Smirnov test. All data were normally distributed and were therefore analysed using parametric statistics (2-way analysis of variance (ANOVA), 1-way ANOVA, unpaired 2-tailed Student t test, and paired 2-tailed Student t test). A P value less than 0.05 was considered statistically significant.

3. Results

3.1. Effect of acute administration of cannabidiol on joint afferent mechanosensitivity

A total of 17 afferent fibres were recorded in this study. Fibres were characterised based on mechanical and electrical threshold, and conduction velocity (summarised in Table ​ Table1 1 ).

Table 1

Characterisation of the recorded fibres in the electrophysiology experiments.

3.2. Effect of acute administration of cannabidiol on sodium monoiodoacetate–induced pain

Intra-articular injection of MIA produced secondary allodynia and weight-bearing deficits in the ipsilateral hind paw and hind limb, respectively, 14 days after injection (P < 0.0001; n = 24; Fig. ​ Fig.2A 2 A and P < 0.0001; n = 24; Fig. ​ Fig.2 2 B).

When compared with vehicle control, low dose CBD (100, 200 μg) had no effect on withdrawal threshold or hind limb weight bearing (P > 0.05; n = 8; Figs. ​ Figs.2A 2 A and B). The 300 μg dose of CBD, however, significantly increased hind paw withdrawal threshold and hind limb weight bearing over the time course tested (P < 0.0001; n = 8; Figs. ​ Figs.2A 2 A and B). All subsequent experiments used the 300 μg dose of CBD.

To determine whether CBD was acting locally, 300 μg of the drug was injected into the contralateral knee and the withdrawal threshold was assessed in the ipsilateral joint 1 hour later and hind limb weight bearing was assessed in the ipsilateral joint 3 hour later. It was found that the high dose of CBD administered to the contralateral knee had no effect on ipsilateral hind paw withdrawal thresholds indicating that CBD was not acting centrally in this pain test (P < 0.01; n = 8-10; Fig. ​ Fig.3A). 3 A). However, in the hind limb weight-bearing test, contralateral CBD was not statistically different from the ipsilateral CBD group (P > 0.05; n = 8-22; Fig. ​ Fig.3 3 B).

Effect of contralaterally administered CBD on ipsilateral pain behaviour. The improvement in hind paw withdrawal threshold seen with ipsilateral CBD was not observed when CBD (300 μg i.artic.) was administered to the contralateral knee (A). Contralateral CBD did not significantly decrease hind paw weight bearing (B) when compared with ipsilateral CBD. (*P < 0.05, **P < 0.01 1-way ANOVA with Fisher post hoc test; n = 8-9). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; VEH, vehicle.

The cannabinoid receptor antagonists AM281 and AM630 had no effect on CBD-induced analgesia (P > 0.05; n = 6-8; Figs. ​ Figs.4A 4 A and B). Conversely, the TRPV1 antagonist, SB-366791, significantly inhibited the analgesic effect of CBD (P < 0.05; n = 6-8; Fig. ​ Fig.4A) 4 A) with respect to the hind paw withdrawal threshold, but did not have a significant effect on hind limb weight bearing at 3 hours after injection (P > 0.05; n = 6-22; Fig. ​ Fig.4 4 B).

Contribution of cannabinoid and noncannabinoid receptors to the analgesic effects of CBD. Both hind paw withdrawal threshold (A) and hind limb weight bearing (B) were unaltered compared with control after local administration of the CB1 receptor antagonist AM281 (75 μg) or CB2 receptor antagonist AM630 (75 μg). Hind paw withdrawal threshold (A) was reduced compared with control after local administration of the TRPV1 antagonist SB-366791 (30 μg), but hind limb weight bearing (B) was unaffected. (*P < 0.05, **P < 0.01 1-way ANOVA with Fisher post hoc test; n = 6-8). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; VEH, vehicle.

3.3. Effect of acute administration of cannabidiol on sodium monoiodoacetate–induced inflammation

Anti-inflammatory action of CBD on day 1 MIA-induced inflammation. When compared with naïve controls, intra-articular MIA significantly increased rolling (A) and adherent (B) leukocytes, and caused synovial hyperaemia (C) (****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05, P > 0.05, unpaired t test; n = 6-12). Over a 3-hour time course, CBD (300 μg) significantly decreased leukocyte rolling (A) leukocyte adherence (B) and knee joint blood flow (C) when compared to vehicle. (****P < 0.0001, **P < 0.01, *P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 6). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; PU, perfusion unit; VEH, vehicle.

Contribution of cannabinoid and noncannabinoid receptors to the anti-inflammatory effects of CBD. The anti-rolling effect of CBD at 30 minutes was blocked (A) by CB2 receptor antagonist AM630 (75 μg) and TRPV1 antagonist SB-366791 (30 μg), but not CB1 receptor antagonist AM281 (75 μg). The anti-adherence effect of CBD in day 1 MIA joints was blocked by SB-366791 (B). (****P < 0.0001, ***P < 0.001 1-way ANOVA with Fisher LSD post hoc test; n = 60). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; VEH, vehicle.

3.4. Prophylactic effect of cannabidiol on sodium monoiodoacetate–induced osteoarthritis pain

Prophylactic treatment of MIA-injected knee joints with CBD (on days 0–3 of MIA) significantly attenuated the development of MIA-induced tactile allodynia during both the acute and late phase of OA development (P < 0.0001; n = 8; Fig. ​ Fig.7A). 7 A). Conversely, early treatment with CBD had no effect on hind limb weight bearing, when compared with vehicle-treated animals (P > 0.05; n = 8; Fig. ​ Fig.7 7 A).

Effect of prophylactic CBD administration on the development of pain over 14 days post-MIA injection. Treating MIA knee joints with CBD (300 μg; s.c.; days 0–3) significantly improved von Frey hair withdrawal threshold over the 14-day development of OA when compared with vehicle (A). Pretreatment of MIA knee joints with CBD had no significant effect on hind limb weight bearing (B) (****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 8). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; OA, osteoarthritis; s.c., subcutaneous; VEH, vehicle.

3.5. Cannabidiol prophylaxis and sodium monoiodoacetate–induced peripheral nerve damage

Treatment of OA knees with CBD during the acute inflammatory phase of the MIA model (days 0–3 of MIA) inhibited saphenous nerve demyelination on day 14 compared with vehicle-treated knees (P < 0.05; n = 6-8; Fig. ​ Fig.8 8 B).

Prophylactic CBD reduces joint nerve demyelination in MIA-induced OA. Representative sections of electron micrographs of axons found in saphenous nerves taken at day 14 from MIA treated with vehicle (A) (days 0–3), or CBD (300 μg; days 0–3). (B) G-ratio calculations showing that MIA-induced axonal demyelination is prevented by CBD treatment. Scale bar is 6 μm. (*P < 0.05 unpaired t test; n = 6 = 8). Data are presented as mean values ± SEM. CBD, cannabidiol; MIA, sodium monoiodoacetate; OA, osteoarthritis; VEH, vehicle.

4. Discussion

Pain and disease progression are poorly managed in many patients with OA because of the multifactorial nature of the disease. Intra-articular injection of MIA produces monoarthritis with several features that resemble human OA, including joint pain, intermittent inflammation, and joint nerve damage. This study aimed to address, for the first time, whether the inflammatory and neuropathic pain associated with MIA could be blocked by local administration of the noneuphoria producing phytocannabinoid CBD.

It has previously been shown that the pain associated with the MIA model of OA is mediated in part by the sensitisation of joint afferent fibres. 35,37 Peripheral administration of CBD dose-dependently decreased joint afferent firing on day 14 after MIA injection. These electrophysiology data confirm that CBD has a peripheral site of action in knee joints. Because all recordings were made from Aδ or C fibres during noxious movement of the knee, this suggests that CBD can inhibit the mechanosensitivity of joint nociceptors.

In end-stage OA, intra-articular injection of 300 μg of CBD improved unrestrained hind limb weight bearing and hind paw withdrawal threshold (Fig. ​ (Fig.2). 2 ). These observations, along with our electrophysiology data, assert that CBD acts locally in the joint to reduce joint mechanical pain as revealed by improved weight bearing as well as a reduction in centrally mediated secondary allodynia as determined by hind paw withdrawal threshold. Contralateral injection of CBD had no discernible effect on ipsilateral secondary allodynia confirming that the analgesic effect of intra-articular CBD was localised to the site of administration for this pain test. The anti-nociceptive effect of low dose CBD (100 and 200 μg) observed with electrophysiology was not seen in the behavioural pain assessments. This may be because electrophysiology is a highly sensitive technique that detects subtle response to test agents in the periphery, whereas pain behaviours are more complex and encompass the entire pain pathway. The rationale for using two pain behavioural tests in this study was to interrogate different aspects of the pain pathway. Dynamic incapacitance is a measure of spontaneous pain that is associated with joint degeneration or inflammation arising from peripheral sensitisation. 4,28 In contrast, von Frey hairs were used to investigate evoked, reflexive responses (ie, paw withdrawal, shake, and lick) at a site distal to the injured joint. 28 This secondary allodynia is a consequence of central sensitisation in late stages of the MIA model, 16 and can be indicative of nerve injury. Thus, it seems that local injection of CBD is effective at reducing direct nociceptive and inflammatory pain in the joint as well as ameliorating neuropathic features of OA pain.

Both CB1 and CB2 receptor antagonists failed to block the CBD-mediated improvements in hind paw withdrawal threshold and weight bearing. Although CBD has been shown to act as an inverse agonist at CB2 receptors and a full antagonist at CB1 receptors, 40 it has also been shown to act through GPR55, serotonin receptors (eg, 5-HT1A), and various transient receptor potential ion channels. Transient receptor potential vanilloid-1 is known to be involved in MIA-induced peripheral sensitisation, 17 therefore, antagonist experiments were performed to test the involvement of this ion channel in CBD-mediated analgesia. Here, the TRPV1 antagonist SB-366791 attenuated the secondary allodynia imparted by CBD in established OA. This mechanism of action has been previously reported in in vitro studies using human embryonic kidney (HEK 293) cells and using cell membranes from mouse and rat brains. 3 In vivo, TRPV1 antagonism has also been shown to block the pain-relieving effect of CBD in a model of carrageenan-induced paw oedema 7 and in the chronic constriction injury model of neuropathic pain. 6 Although these data show that the action of CBD is mediated in part by TRPV1, it remains unclear if CBD is acting directly on TRPV1 or if there is an indirect mechanism occurring in the joint. Cannabidiol has been shown to inhibit fatty acid amide hydrolase (FAAH) and the uptake of anandamide. 3 Inhibition of FAAH and anandamide reuptake would elevate anandamide levels in the joint which if high enough could ultimately lead to the activation of TRPV1. 3

Intra-articular injection of MIA produced an acute inflammatory response on day 1 after injection. This acute phase of inflammation was evinced by an increase in leukocyte trafficking and a moderate increase in joint blood flow. Local application of CBD significantly reduced these acute, inflammatory changes corroborating what has previously been reported in other inflammatory models. 8,12,20 Oral administration of CBD, for example, has been shown to be anti-inflammatory and anti-hyperalgesic in the carrageenan model of plantar oedema. 8 Malfait et al., showed that systemic administration of CBD, both intraperitoneally and orally, suppressed disease severity and decreased serum inflammatory cytokine levels in the collagen model of rheumatoid arthritis. 20 Moreover, CBD administered by a transdermal gel reduced joint swelling, immune cell infiltration, synovial membrane thickening, and the synthesis of pro-inflammatory biomarkers in the Freund complete adjuvant model of inflammatory arthritis. 12 The data presented here demonstrate for the first time that CBD has the capacity to reduce the inflammatory flares associated with OA.

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The inhibitory effect of CBD on leukocyte trafficking was blocked by the TRPV1 antagonist SB-366791. Opening of TRPV1 ion channels causes the peripheral release of inflammatory neuropeptides which promote neurogenic inflammation and enhanced leukocyte trafficking in joints. 19,41 Thus, the anti-inflammatory effects of CBD observed here could be due to desensitisation of TRPV1 ion channels as has been shown elsewhere. 14 The anti-rolling effect of CBD on joint leukocytes was also blocked by AM630 suggesting that CB2 receptors may be involved in opposing leukocyte capture in day 1 MIA joints. Zhao et al. showed that activation of CB2 receptors can inhibit the expression of P-selectin which is the adhesion molecule responsible for leukocyte rolling. 43 Whether CBD inhibits joint P-selectin activity by a CB2 receptor mechanism requires further investigation.

A central hypothesis of this study was that early inhibition of OA-related inflammation with CBD would reduce the development of persistent joint pain. Prophylactic treatment of OA joints with CBD on days 1 to 3 after MIA induction prevented secondary allodynia at day 14, but had no effect on hind limb weight bearing. Inflammation associated with MIA diminishes by day 7, 4 therefore the pain associated with end-stage OA in this model is largely due to joint degeneration and peripheral neuropathy. Thus, by abolishing early inflammation with prophylactic treatment, CBD attenuates central sensitisation and neuropathic pain development in OA.

Previous studies have shown that MIA-induced OA causes peripheral nerve damage. 25,39 Demyelination of the ipsilateral saphenous nerve was confirmed by an increase in G-ratio, purporting MIA-induced peripheral neuropathy compared with saline control animals. 25 This study showed that prophylactic treatment with CBD during the early inflammatory phase of MIA prevented this loss of nerve myelin 14 days later, suggesting that blockade of inflammatory flares during OA could protect against joint nerve damage. The G-ratio data would benefit from future studies examining the expression of a biomarker for peripheral nerve damage to further support this finding.

The findings presented here and elsewhere support the concept that MIA recapitulates the neuropathic aspect of OA pain, which is found in approximately 30% of patients. 1,34 CBD treatment may be a beneficial therapeutic for the population of patients who experience neuropathic arthritis, and are refractory to currently used first- and second-line analgesics. Several cannabis compounds, including CBD, have been shown to be neuroprotective in other musculoskeletal disorders. In a preclinical model of multiple sclerosis, CBD was shown to improve clinical recovery and rotarod scores in animals, correlating with and indicative of a neuroprotective effect. 30 In addition, CBD and ∆ 9 -tetrahydrocannabinol have both been implicated in slowing the progression and promoting the survival of neurones in a preclinical model of amyotrophic lateral sclerosis. 15,42 These studies, in addition to the results presented here, highlight the potential utility of CBD as an analgesic and neuroprotective agent in OA.

Cannabidiol is a noneuphoria producing compound and has a more desirable side effect profile compared with other cannabinoid compounds and commonly prescribed analgesics. Animal studies where CBD was administered systemically showed that the animals had no signs of adverse side effects. 12,20 For example, exploratory behaviour in rats was not altered by systemic CBD, indicating limited central effects of treatment. 12 Our study shows for the first time that CBD is an effective anti-nociceptive and anti-inflammatory agent when administered locally around the joint. Successful relief of OA symptoms by peripherally administered CBD suggests a therapeutic option that has a low chance of adverse effects which is more desirable for patients.

5. Conclusions

This study showed for the first time that local CBD administration inhibited pain and peripheral sensitisation in established OA. Topical treatment with CBD reduced leukocyte trafficking and joint hyperaemia during the early stages of MIA. By attenuating this initial inflammatory response with CBD, end-stage OA pain and peripheral neuropathy were abrogated. Thus, CBD may be a safe therapeutic to treat OA pain locally as well as block the acute inflammatory flares that drive disease progression and joint neuropathy.

Conflict of interest statement

The authors have no conflicts of interest to declare.

This work was supported by an operating grant provided by The Arthritis Society.

Ethics: All experimental protocols were approved by the Dalhousie University Committee on Laboratory Animals, which acts in accordance with the standards put forth by the Canadian Council for Animal Care.

Availability of data and materials: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Acknowledgements

The technical assistance of Allison Reid is gratefully acknowledged.

Author contributions: H. T. Philpott conducted the pain behaviour experiments, the inflammation measurements (IVM and LASCA), performed the G-ratio measurements, analysed data, and helped draft the manuscript. M. O’Brien conducted all electrophysiology experiments, analysed the data, and helped draft the manuscript. J. J. McDougall conceived the study, participated in its design and coordination, helped analyse data, and helped draft the manuscript. All authors read and approved the final manuscript.

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

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Using CBD for Arthritis: Tips for How to Get Started

Enthusiasts of cannabidiol (better known as CBD) rave about the substance’s health benefits. Some small studies have shown that CBD could be a remedy for anxiety and help children with post-traumatic stress disorder get to sleep. The substance was even FDA-approved last year as a prescription drug to manage rare, severe forms of epilepsy.

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So naturally, you might be wondering: Can CBD help people with arthritis and related diseases cope with pain? Anecdotal reports from patients and some preliminary research suggests yes, but the science is still emerging and more research is needed.

Here’s what you need to know right now about how to use CBD to ease arthritis symptoms, how to find a high-quality CBD product, and how to work with your doctor to incorporate CBD into your arthritis treatment plan.

What Is CBD, and Can It Help with Arthritis?

CBD is a chemical found derived from hemp. Hemp and marijuana are both types of cannabis plants, but they are very different from each other. They each have different quantities of various phytocannabinoids, which are substances naturally found in the cannabis plant. (It’s sort of like how different kinds of berries contain different combinations of antioxidants.)

  • Marijuana contains an abundance of THC (tetrahydrocannabinol), which is the cannabinoid that gets you high.
  • Hemp contains less than 0.3 percent THC. It contains CBD, which is a cannabinoid that doesn’t have any psychoactive effects. CBD cannot make you feel high. Instead, CBD works in other ways with your endocannabinoid system, which is a group of receptors in the body that are affected by the dozens of other documented cannabinoids.

“Cannabinoids can inhibit or excite the release of neurotransmitters [brain chemicals] and play a role in modulating the body’s natural inflammatory response, which are the two things we’re concerned about when talking about CBD for arthritis,” says Hervé Damas,MD, a Miami-based physician and founder of Grassroots Herbals, a CBD product company.

CBD is thought to work on pain in two parts of the body: the site of soreness (such as your finger joints) and the central nervous system, which sends pain signals to the brain when it detects certain stimulation or damage to nerves and cells.

The ability for CBD to calm that response is one reason the compound might be a viable pain remedy for people with arthritis. Another is CBD’s anti-inflammatory properties. Inflammation occurs when your body is fighting a perceived infection. In autoimmune diseases such as rheumatoid arthritis, the immune system is attacking healthy parts of your body like your joints.

It’s important to note that while early research on animals has shown promise for CBD, more research is needed before we can draw anything conclusive for humans. However, anecdotal reports from people who have started incorporating CBD into their arthritis treatment are positive. One CreakyJoints member shared on Facebook that topical CBD “helps better than any other ointment I’ve ever used.” CBD could be worth exploring as a potential solution to pain as part of an overall arthritis treatment plan.

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With more and more people using marijuana and CBD to treat chronic pain, it is now more important than ever to have research-backed information and advice. Subscribe to CreakyJoints (it’s free) and we’ll notify you when opportunities to participate in CBD and medical marijuana research become available in your area, for your condition.

How to Find the Right CBD Product for You

From supermarkets and pharmacies to health food stores and online retailers, CBD can be found just about everywhere. But how do you choose the right CBD product for your health needs?

1. Pick the CBD Formulation You Want to Use

CBD comes in a few different forms. Commonly used ones include:

  • Edibles: You eat CBD infused into gummies, chocolates, sodas, baked goods, and other edible items
  • Vaporizer: You inhale CBD through a vape pen that heats up the oil
  • Sublingual drops: You take a few drops under your tongue of a high-concentrate solution of CBD
  • Topicals: You apply creams, lotions, balms and other products with CBD directly to your skin

The different types of CBD take effect in your body at different rates. Here’s how long you can expect different types of CBD products to kick in, according to Dr. Damas:

  • Edibles: 30 minutes to two hours
  • Vaporizer: Two minutes
  • Sublingual drops: 15-30 minutes
  • Topicals: 10 minutes

2. Look for Signs of High-Quality CBD

Don’t just buy the least expensive one on the shelf. There are lots of poor-quality CBD products on the market (some of which don’t contain the amount of CBD they claim, per these FDA warning letters).

Dr. Damas recommends looking for CBD products that are made in the United States, use a carbon dioxide-based extraction method (“It’s the cleanest,” he says), come from organically grown hemp, and don’t contain a lot of extra ingredients. Consumer Reports also has a thorough guide to shopping for CBD that can help you find a high-quality product.

3. Pick the Right Dose

As for dosing of CBD oil, the jury’s still out on just how much you should take. Start with a low dose (such as 5 to 10 mg), and gradually work your way up over a few weeks until you notice the effects.

“Usually people find pain relief when they take 20 to 35 milligrams of CBD daily,” says Dr. Damas.

You can take the full dose at once or break it up throughout the day. Experiment with what makes you feel best. You should start seeing improvements shortly after you start supplementing with CBD, with more noticeable effects kicking in after two weeks.

How to Discuss CBD with Your Doctor

You should talk to the doctor who treats your arthritis before you start taking CBD or any other supplement. They can let you know if CBD might interact with any medications you currently take or potentially worsen a chronic condition. For example, “CBD may make it easier to bleed,” says Dr. Damas. “So if you’re going to have surgery, you might want to stop taking it before the procedure.”

Check out this list of potential drug interactions with CBD from the U.S. National Library of Medicine, but you should always check with your doctor about your individual case.

Keep in mind that your doctor’s knowledge of CBD might be limited. There isn’t a lot of research about the benefits of CBD or about ideal dosages or formulations, so your doctor might not be able to be overly specific in terms of their recommendations. However, they still need to know that you’re taking CBD. Chances are, they’ll be interested in hearing about your experience using CBD products and your self-reports on how CBD may be helping to manage your pain or other symptoms.

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About CreakyJoints

CreakyJoints is a digital community for millions of arthritis patients and caregivers worldwide who seek education, support, advocacy, and patient-centered research. We represent patients through our popular social media channels, our website CreakyJoints.org, and the 50-State Network, which includes nearly 1,500 trained volunteer patient, caregiver and healthcare activists.

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The contents of this website are for informational purposes only and do not constitute medical advice.CreakyJoints.org is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition.
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Complementary treatments and arthritis – from turmeric to cannabis oil

People use complementary medicine for many different reasons, including:

  • wanting to use more natural treatments
  • their symptoms aren’t fully controlled by conventional medicine.

Read more about complementary therapies which can help to ease the symptoms of arthritis, from yoga to meditation.

Are they right for me?

As with all complementary treatments, different things work for different people and it isn’t possible to predict which might be the most useful or effective.

There are some key points to consider if you’re thinking about using any complementary treatments.

  • What are you hoping to achieve? Pain relief? More energy? Better sleep? Reduction in medication?
  • What are the financial costs?
  • Is there any evidence for their effectiveness?

Are complementary medicines safe?

Complementary medicines are relatively safe, although you should always talk to your doctor before you start any new treatment.

In specific cases they may not be recommended, for example, if you are pregnant or breastfeeding, or they may interact with certain medication.

A starter for five

Here we share a spotlight on the most popular complementary medicines that people call our helpline about.

Turmeric

It’s thought that turmeric can possibly reduce inflammation, which could help people with arthritis.

People with knee osteoarthritis who took part in a research trial reported improvements to their pain levels after taking turmeric. The evidence is limited however, as it is from just one trial. What evidence there is suggested that people only had minor side-effects after taking turmeric.

Turmeric can be bought from health food shops, pharmacies and supermarkets in the form of powder.

Glucosamine

Glucosamine sulphate and glucosamine hydrochloride are nutritional supplements. Animal studies have found that glucosamine can both delay the breakdown of and repair damaged cartilage.

The results for the use of glucosamine for osteoarthritis are mixed and the size of the effect is modest. There’s some evidence that more recent trials and those using higher-quality methods are less likely to show a benefit.

Capsaicin

Capsaicin is taken from chilli peppers. It works mainly by reducing Substance P, a pain transmitter in your nerves. Results from randomised controlled trials assessing its role in treating osteoarthritis suggest that it can be effective in reducing pain and tenderness in affected joints, and it has no major safety problems. Evidence for its effectiveness for fibromyalgia is related to a single trial.

Other names: Axsain®, Zacin®, chilli, pepper gel, cayenne

Capsaicin is licensed in the UK for osteoarthritis and you can get it on prescription in the form of gels, creams and plasters.

There are no major safety concerns in applying capsaicin gel/cream. A review of capsaicin applied to the skin to treat chronic pain (not specifically related to osteoarthritis, rheumatoid arthritis or fibromyalgia) concluded that around one third of people experience a reaction around the area where the treatment is applied. It’s important to keep capsaicin away from your eyes, mouth and open wounds because it will cause irritation. There have been no reported drug interactions.

Fish oils

Fish oils are rich in omega-3 essential fatty acids, which have strong anti-inflammatory properties. Fish liver oil is also a rich source of vitamin A (a strong antioxidant) and vitamin D (which is important for maintaining healthy joints).

Evidence suggests that fish body oil can improve the symptoms of rheumatoid arthritis. Unconfirmed evidence also suggests a combination of fish body and liver oils might also be useful in the long term, particularly in reducing the use of non-steroidal anti-inflammatory drugs (NSAIDs). There isn’t enough evidence for the use of fish liver oil for osteoarthritis.

Omega-3 fatty acids also play a role in lowering cholesterol and triglyceride levels in your blood, so they can reduce the risk of heart disease and stroke in people with inflammatory arthritis.

In the UK, dietary guidelines recommend eating two portions of fish a week, including one oily. Fish oil is considered to be well tolerated at this dose.

At the correct doses, side-effects are usually minor and uncommon.

Cannabis oil (CBD)

CBD is type of cannabinoid – a natural substance extracted from the cannabis plant and often mixed with an oil (such as coconut or hemp) to create CBD oil. It does not contain the psychoactive compound called tetrahydrocannabidiol (THC) which is associated with the feeling of being ‘high’.

Research in cannabinoids over the years suggests that they can be effective in treating certain types of chronic pain such as pain from nerve injury, but there is currently not enough evidence to support using cannabinoids in reducing musculoskeletal pain. We welcome further research to better understand its impact and are intently following developments internationally.

CBD oil can be legally bought as a food supplement in the UK from heath food shops and some pharmacies. However, CBD products are not licensed as a medicine for use in arthritis by MHRA (Medicines and Healthcare products Regulatory Authority) or approved by NICE (National Institute for Health and Care Excellence) or the SMC (Scottish Medicines consortium).

We know anecdotally from some people with arthritis, that CBD has reduced their symptoms. If you’re considering using CBD to manage the pain of your arthritis, it’s important to remember it cannot replace your current medicines, and it may interact with them, so please do not stop/start taking anything without speaking to a healthcare professional.

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