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Unraveling the use of CBD in veterinary medicine - Jill Lopez

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It was about the 3rd week into Bastion’s recovery from his TPLO surgery and he was already having a rough time. Bastion was a gregarious yellow Labrador who had his injured stifle about 25 days ago. Fortunately, his family elected for him to have his stifle surgically reconstructed. Initially, he had recovered well from surgery. But one day in particular, he presented to the hospital because he had a brief setback. He was limping far more severely than what would be normally expected at this stage of recovery.

The osteotomy from his surgery had not yet completely healed and he was still in the middle of his prescribed 5 weeks of exercise strict restriction. His family was trying their best but Bastion wasn’t having it. He was too active at home and his humans were growing frustrated. Anti-anxiety medications had been dispensed but they were not given. Instead, his family had decided to give him CBD oil at home. When I asked why the prescribed medications had not been given, the client responded, “I found CBD oil at the local farmer’s market and I figured it would work just as well.” 

Like Bastion, an increasing number of pets are receiving cannabidiol (CBD) supplements. The popularity of CBD continues to rise and many clients are incorporating CBD as part of the medication protocol for their pets, either as an adjunct or, as alternative treatment option.

Perhaps the initial interest in the benefits of CBD can be traced back to 1998, or possibly earlier, when scientists at the National Institutes of Health discovered that CBD could protect cells from oxidative stress. These findings fueled interest in the human medical field and, in large part, that appeal has been  transmuted into veterinary medicine.  The regard for this molecule has risen to such levels that in many homes, CBD is being used as the sole treatment option for a variety of medical conditions.

Veterinarians are becoming more fluent in the fascinating pharmacology regarding the use of this phytocannabinoid. A recent survey indicated that most veterinarians (61.5%) felt comfortable discussing the use of CBD with their colleagues, but only 45.5% felt comfortable discussing this topic with clients.1 Furthermore, veterinarians and clients in states with legalized recreational marijuana were more likely to talk about the use of CBD products to treat canine ailments than those in other states.2 Lastly, CBD was most frequently discussed as a potential treatment for pain management, anxiety and seizures.1 At first glance, the use of CBD has tangential or limited relevance in the world of veterinary surgery. However, as one takes a closer look at the putative, and proven benefits,  it is clear that we are just scratching the surface of its therapeutic benefits.  This article takes a brief dive into the world of CBD and its promise in the field of veterinary surgery. 

Pain

Whether you perform surgery within a specialty discipline (oncology, orthopedics, neurology, soft tissue surgery, mixed animal, oral/dental, etc), or surgery is only a small part of your general practice, every veterinarian endeavors to aggressively manage pain. The first choice for pain relief among many clinicians are the medications that have been more extensively studied including, but not limited to,  anti-inflammatories, gabapentinoids, opioids, local anesthetics, and other analgesics (acetaminophen, amantadine, cerenia etc). These medications or a combination thereof, have been prescribed to treat pain from orthopedic surgery, soft tissue surgery, surgical neuropathic conditions, pain from intestinal surgery, to name just a few.  In the most basic schema, pain is divided into four categories: nociceptive pain (a response to damaged tissue), neuropathic pain (a response to directly-damaged sensory or spinal nerves), centralized pain (the result of pain signals being improperly amplified), and inflammatory pain.1 Cannabinoids may have a role to play in mediating all four of these types of pain states. When tissue is damaged, histamine, serotonin, TNF-alpha, IL-1-beta, IL-6, and Il -17 6, and interleukin 17 are released.2  Cannabinoids bind to the CB1 receptors and attenuate the pain signal by slowing down the release of those neurotransmitters.3 This process can take place locally or in the central nervous system.3  Cannabinoids have also been shown to inhibit the release of GABA, a well known neurotransmitter associated with pain.3 Although there is a paucity of clinical research on the use of CBD to treat postoperative pain in the veterinary medical setting, there has been heartening research conducted in humans. Indeed, National Academies of Sciences, Engineering, and Medicine concluded that there is, “substantial evidence that cannabis is an effective treatment for chronic pain in adults.”  

Opioids have long been the go to option, or cornerstone of pain management, however, the potential for the adverse events associated with the use of opioids in veterinary patients is universally accepted.38 I have seen how distressing it can be for a family to see their pet experiencing any of the unpleasurable side effects of opioids including urine retention, delayed bowel movements, whining, panting, disorientation, or other manifestations of dysphoria. Those are just some of the challenges that clinicians face when using opioids for chronic pain management. Considering the ongoing consequences of the opioid epidemic, there is a search for pain management solutions that are innovative, prone to less adverse events, and are more effective.  As the scientific community begins to evaluate the evidence for use of CBD , it is clear that more research is needed. 

Anecdotal reports of CBD’s efficacy as a pain reliever are ubiquitous but more are turning to scientific data for evidence of CBD’s efficacy. A study in 2020 evaluating effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients found that over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens.5 Almost all CBD users (94%) reported quality of life improvements.5  And in a recent study evaluating orally consumed cannabinoids for long-lasting relief of allodynia in a mouse model, found that cannabinoids reduced hyperalgesia and a similar effect was not found with morphine.4  Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine.4 The study demonstrated that cannabinoids provide long-term relief of chronic pain states.4 If research shows that use of cannabinoids in animals, specifically, CBD, can help to decrease the use of opioids for pain management, that would help make more animals comfortable and potentially help to fight the tragic epidemic of human prescription opioid abuse. Further research is needed in a variety of species, specifically, both the canine and feline species. 

Bone Healing

Both general veterinary practitioners and veterinary surgeons commonly diagnose and treat fractures. A large retrospective study of fracture incidence in dogs in North America has not been published since 1994; however, the findings from that study are still informative regarding the frequency of bone injuries. That study demonstrated that approximately 24% of all patients in the population studied over a 10 year period were affected by a disorder of the musculoskeletal system, with fractures contributing the largest proportion (over 29%) of all of the diagnosis of the appendicular skeletal system.7 Although that research is dated, the conclusions from this study - at the very least, indicate that fractures are commonplace in the clinical veterinary setting.7 Fracture repair has gradually become more straightforward due to improvements in technology. Because of these innovations, speciality surgeons and general practitioners who repair fractures have begun to see better surgical outcomes. So whether you primarily stabilize fractures with implants, or if external coaptation of fractures with the intention to refer (or perhaps as the primary means of fixation) is your treatment of choice, all veterinary practitioners aim to help fractured bones heal quickly. Despite these technological improvements, bone healing can be protracted or non existent with some fractures. There are a variety of options at a veterinarian’s disposal to kick-start the healing process but perhaps in the near future, CBD may be added to that armamentarium. The effect of CBD in fracture healing has been investigated evaluating bone callus formation in femur fractures in a rat model.8 The findings demonstrated enhanced biomechanical properties of healing fractures in those given CBD compared with a control group.8 This effect was not found in those only given Δ9-THC. Moreover, the bone forming effects (osteogenic) of CBD were weakened when test subjects were given equal amounts of CBD and Δ9-THC.6  Another in vivo research study indicated that when CBD is incorporated into a surface that promotes bone growth (osteoconductive scaffold) it can stimulate stem cell migration and osteogenic differentiation.9  Further studies are needed to better evaluate the role of CBD in healing and bone metabolism of companion animals so that these findings can be applied in the clinical setting.  

Additionally, cannabis has been shown to be a useful addition in treatment plans optimized to improve bone health in laboratory studies. A study endeavored to more closely understand the role of CB2 receptors in maintaining bone health. CB2 receptors in bone cells have been linked to maintaining bone density and stimulating growth, and may therefore have a part in reversing the effects of osteoporosis.10   One study evaluating role of CB2 receptors, found that in mice whose genes had been altered to remove the CB1 or CB2 receptors, those that developed signs of bone weakness that were far more pronounced than those in the control group.12 Another study in 2009, investigated the relationship between CB2 expression and bone disease in humans.  The study found that people with dysfunctional CB2 receptors to have significantly weaker hand bones.11

Arthritis

Osteoarthritis (OA) affects many dogs, large and small. Most often, OA is the consequence of a developmental orthopedic disease that often affects a single joint or a pair of joints, and, less often, affects multiple joints. It is axiomatic that ‘Mother Nature likes symmetry’ thus developmental orthopedic diseases frequently affect both left and right joints. For example, hip dysplasia is reportedly bilateral in >60% of affected dog,s13 and elbow dysplasia is bilateral in approximately 50% of affected dogs.14 Osteoarthritis occurs secondary to a myriad of primary orthopedic conditions that affect a variety of joints including: the hip (most common causes of OA in the hip: hip dysplasia, Perthes disease);  stifle (patellar luxation, cranial cruciate ligament disease, osteochondritis dissecans [OCD]);  elbow (elbow dysplasia, elbow OCD, fragmentation of the medial coronoid process, incomplete ossification of the humeral condyle); shoulder (shoulder OCD, developmental shoulder subluxation); tarsus (OCD of the talus), and carpus (carpal laxity, carpal subluxation secondary to chondrodystrophy); and metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joint degenerative osteoarthritis (digital osteoarthritis) .  


Cannabinoids were found to treat pain secondary to inflammation in a variety of studies on humans. Some of the most compelling research has shown that cannabis can reduce the inflammation in the joint caused in human patients diagnosed with immune mediated arthritis.15   One study found that cannabinoids could simultaneously reduce the secretion of cytokines involved in inflammation from one type of TH immune cells, which were being under-produced, while also increasing their numbers to correct their scarcity.15  Furthermore in a study in 2003, researchers found that plant-based cannabinoids could suppress the expression of interleukin-1beta—one of the most prominent markers for inflammation in patients with rheumatoid arthritis—by as much as 50%.16  And finally, in 2006, transdermal applications of CBD were shown to  decrease biomarkers that can contribute to neurogenic inflammation in a sample of arthritic rats. 17

 A report published in the journal of PAIN, lead by researchers at Baylor College of Medicine revealed the results of a large, double blinded, placebo controlled study on the positive effects CBD had in the fight against osteoarthritis.18 The study was designed with two main goals: The first portion of the research studied the effect CBD had on the inflammatory molecules and cells in mice.18 The second portion of the study, investigated whether CBD improved the quality of life in dogs diagnosed with osteoarthritis.  In lab tests and in mouse models, CBD significantly decreased the production of natural chemicals that promote inflammation and it increased the natural chemicals that fight inflammation.18 Essentially, what they saw was a drop in proinflammatory cytokines and an increase in anti-inflammatory cytokines. 18  For dogs with osteoarthritis, CBD significantly decreased pain and increased mobility in a dose-dependent fashion. Importantly, A lower dose of  liposomal CBD was as effective as the highest dose of nonliposomal CBD, indicating that the effect of CBD was quicker and more effective when CBD was delivered encapsulated in liposomes than without.18  Blood samples indicated no significant harmful side effects, or adverse events, over the 4-week analysis period.18 Although this study is very promising and it supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain in dogs, it is important to consult with your pet’s veterinarian before giving any supplement or medication. 

In the veterinary population, use of cannabidiol and other alternative treatments may have the potential to obviate the need for other medications, and thus spare patients from adverse effects associated with their use.  More likely, the use of cannabinoids could be additive or synergistic in a multimodal treatment strategy and could increase quality-of-life issues associated with painful arthritic conditions.


Intervertebral Disk Disease

 As our patients age, discs in the spine also undergo degenerative changes. Thus, degeneration of intervertebral discs is evitable.  This process of degeneration is multifactorial process and it involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content.39 The magnitude and severity of disc degeneration can vary widely between patients. The most common locations of clinically relevant disc disease are located in the cervical spine, thoracolumbar spine, and the lumbosacral spine.40 Although there are various manifestations of disc disease, broad classifications of Hansen Type I and Type II are typically used to describe the condition.  In short, disc material may either extrude (acute herniations) or protrude (chronic herniations), both of which compress the spinal cord which ultimately can cause pain, paresis, paralysis and other neurological deficits.40 The prevalence of thoracolumbar disc disease dogs has been estimated at 3.5%.40  Depending on the neurologic examination, diagnosis, severity, prognosis, and other factors, surgery may be recommended to decompress the spinal cord.

After surgical decompression, there are a host of challenges that the the patient, the family, and the surgeon, may have to work through including a potentially protracted recovery, recurrence of neurological signs, post surgical pain, spinal instability, urinary disorders, (cystitis, urinary tract infection, urinary retention, micturition disorders), ascending myelomalacia, and others.41 Could CBD play a part in helping to improve those affected by disc disease pre-, intra-, or post-operatively and what types of spinal disorders could benefit from CBD?  A study conducted on the use of CBD in mice with degenerative disc disease showed promise in mitigating the effect of disc damage and wear.19 Instead of being ingested orally, CBD was injected at the site of the disc.  Researchers investigated the effects of cannabidiol intradiscal injection using a combination of MRI and histological analyses.19 A puncture was created in the disc and then CBD was injected into the disc (30, 60 or 120 nmol) shortly after.19 The effects of intradiscal injection of cannabidiol were analyzed within 2 days by MRI.17 Fifteen days later, the group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses after the cannabidiol injection.19 What they found was that cannabidiol significantly decreased the effects of disc injury induced by the needle puncture.19 These results suggest that this compound could be useful in the treatment of intervertebral disc degeneration perhaps using a novel route of administration. 

Unfortunately, the exact mechanism for how CBD oil helped protect disc damage is still being investigated. The hope is that the neuroprotective properties of cannabidiol can also be found in the study of canine and feline disc disease to ultimately improve functional recovery. 

References:

  1. Kogan L, Schoenfeld-Tacher R, et al. US Veterinarians' Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions.   Front Vet Sci. 2018;5:338.

  2. Abd-Elsayed A., Deer T.R. (2019) Different Types of Pain. In: Abd-Elsayed A. (eds) Pain. Springer, Cham. https://doi.org/10.1007/978-3-319-99124-5_3

  3. Manzanares J, Julian MD, Carrascosa A. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes Curr Neuropharmacol. 2006 Jul; 4(3): 239–257.

  4. Abraham AD, Leung EJ, Brenden A, Wong BA, Rivera ZM, Kruse LC, et al. Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain. 2020 Jun;45(7):1105-1114. doi: 10.1038/s41386-019-0585-3. Epub 2019 Dec 7.

  5. Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020 Jan;132(1):56-61. doi:10.1080/00325481.2019.1685298. Epub 2019 Nov 12.

  6. Abraham AD, Leung EJ, Wong BA, Rivera  ZM, Kruse LC,  Clark JJ,  Land BB. Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain. Neuropsychopharmacology. 2020: 45:1105–1114.

  7. Johnson, J., Austin, C., & Breur, G. Incidence of Canine Appendicular Musculoskeletal Disorders in 16 Veterinary Teaching Hospitals from 1980 through 1989. Veterinary and Comparative Orthopaedics and Traumatology, 07(02), 56–69. (1994). doi:10.1055/s-0038-1633097 

  8. Kogan NM, Melamed E, Wasserman E. Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts J Bone Miner Re. 2015 Oct;30(10):1905-13. doi: 10.1002/jbmr.2513. Epub 2015 May 10.

  9. Kamali, A., Oryan, A., Hosseini, S., Ghanian, M. H., Alizadeh, M., Baghaban Eslaminejad, M., & Baharvand, H. Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects. Materials Science and Engineering: (2019). C, 101, 64–75. doi:10.1016/j.msec.2019.03.070 

  10. Bab I, Zimmer  A. Cannabinoid Receptors and the Regulation of Bone Mass. British Journal of Pharmacology. 2007 153:182-188 doi:10.1038/sj.bjp.0707593

  11. I. Idris, A. Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies. Current Neuropharmacology. 2010. 8(3), 243–253. doi:10.2174/157015910792246173

  12. Meliha Karsak et al. The Cannabinoid Receptor Type 2 (CNR2) Gene Is Associated with Hand Bone Strength Phenotypes in an Ethnically Homogeneous Family Sample. Human Genetics. 2009. 5:629-36 doi:10.1007/s00439-009-0708-8.

  13.  Loder, R. T., & Todhunter, R. J. The Demographics of Canine Hip Dysplasia in the United States and Canada. Journal of Veterinary Medicine. 2017 1–15. doi:10.1155/2017/5723476 

  14. O’Neill DG, Brodbelt DC, Hodge R,. Church DB, Meeson RL.  Epidemiology and clinical management of elbow joint disease in dogs under primary veterinary care in the UK.  Canine Medicine and Genetics. 2020 volume 7:1 

  15. Susan H. Pross et al. Differential Suppression of T-cell Subpopulations by THC (delta-9- tetrahydrocannabinol). International Journal of Immunopharmacology 12, no. 5 (1990): 539-44. doi:10.1016/0192-0561(90)90118-7

  16.  Robert B. Zurier et al. Suppression of Human Monocyte Interleukin-1β Production by Ajulemic Acid, a Nonpsychoactive Cannabinoid.  Biochemical Pharmacology. 2003 4:649-55. doi:10.1016/s0006-2952(02)01604-0.

  17.  D.c. Hammell et al. Transdermal Cannabidiol Reduces Inflammation and Pain-related Behaviours in a Rat Model of Arthritis.  European Journal of Pain. 2015  6:936-48. doi:10.1002/ejp.818

  18. Verrico, C. D., Wesson, S., Konduri, V., Hofferek, C. J., Vazquez-Perez, J., Blair, E., … Halpert, M. M. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. 2020. Pain. doi:10.1097/j.pain.0000000000001896 

  19. Silveira, J. W., Issy, A. C., Castania, V. A., Salmon, C. E. G., Nogueira-Barbosa, M. H., Guimarães, et al. Protective Effects of Cannabidiol on Lesion-Induced Intervertebral Disc Degeneration. 2014. PLoS ONE 9:12 doi:10.1371/journal.pone.0113161 

  20. Yam, M., Loh, Y., Tan, C., Khadijah Adam, S., Abdul Manan, N., & Basir, R. . General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. International Journal of Molecular Sciences. 2018 19(8), 2164. doi:10.3390/ijms19082164 

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  38. White, D. M., Mair, A. R., & Martinez-Taboada, F. Opioid-free anaesthesia in three dogs. Open Veterinary Journal. 2017 7(2), 104. doi:10.4314/ovj.v7i2.5 

  39. Hansen T, Smolders LA, Tryfonidou MA, et al: The Myth of Fibroid Degeneration in the Canine Intervertebral Disc: A Histopathological Comparison of Intervertebral Disc Degeneration in Chondrodystrophic and Nonchondrodystrophic Dogs. Vet Pathol 2017 Vol 54 (6) pp. 945-952.

 

40.       Jeffery ND, Levine JM, Olby NJ, et al: Intervertebral disk degeneration in dogs: consequences, diagnosis, treatment, and future directions. J Vet Intern Med 2013 Vol 27 (6) pp. 1318-33.

41.       Balducci F, Canal S, Contiero B, et al: Prevalence and Risk Factors for Presumptive Ascending/Descending Myelomalacia in Dogs after Thoracolumbar Intervertebral Disk Herniation. J Vet Intern Med 2017 Vol 31 (2) pp. 498-504.

 

 

 

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