Medical cannabis to treat pain in companion animals

Cannabis has been used as a medicine for 5,000 years. Thanks to research in different disciplines, it is known that the plant was used in ancient cultures such as Chinese, Indian and Egyptian. The use was not only in humans. It was also used on animals. At the beginning of the 20th century it was used on horses and cattle. 

Among the medicinal uses of cannabis, one of the most frequent is pain relief.

Pain is a complex process involving the body and the mind. The body's sensory organs perceive pain and report it to the Central Nervous System (CNS). In turn, emotional, motivational, affective and cognitive evaluation components are involved. In other words, pain is an individual experience influenced by many factors.

Endocannabinoid system and pain

The endocannabinoid system (ECS) is an intercellular communication system composed of cannabinoid receptors (CBRs), endocannabinoids and their respective synthesis and degradation enzymes. CB1 receptors are mainly located in the CNS, while CB2 receptors are found in immune tissues. By interacting with CB1 receptors, endocannabinoids help modulate the conduction of pain signals. They also regulate the release of neurotransmitters in the CNS (12).

Similarly, CB2 receptors regulate neuroimmune interactions and interfere with excessive pain due to inflammation (inflammatory hyperalgesia). Thus, tissues or organs that have suffered damage are able to synthesize a greater amount of endocannabinoids. In addition, it has been observed that the number of CB2 receptors increases when there is inflammation in the tissues. These responses provide relief from inflammation (4).

Many other receptors besides CB1 and CB2 have been related to pain perception. Among them we can mention: voltage-gated ion channels (6,11) glycine receptors (GlyR) (5), G protein-coupled receptors such as GPR55 (2) and transient receptor potentials (TRPs) (7). Indirect interactions of SEC with other pain-related systems such as the opioid system (10) and serotonergic neurons have also been reported (1).

Medical cannabis should not be smoked

Several studies have been conducted on pain and cannabinoids in human medicine, some of which used cannabis smoked in cigarettes. It is important to remember that medical cannabis should not be administered through smoke inhalation as there are the same risks as smoking tobacco cigarettes. This restriction also applies to use in animals. 

Laboratory animal research

Philpott et al. (2017) conducted research to determine whether CBD has antinociceptive properties in osteoarthritis. Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases in humans and animals. For both it is a major cause of pain and disability. In this study, end-stage osteoarthritis was induced in rats and then pain responses were measured when CBD was administered.

Results observed with CBD: (8)

• Intra-articular administration provided analgesic effects.

• Increased tolerance to painful stimuli.

• Increased the degree of support of the limb with induced OA.

• Reduced acute joint inflammation.

• Local administration of CBD blocked the pain caused by OA.

• There are neuroprotective effects of CBD, as it prevents neuropathic pain and nerve damage in joints with induced OA.

A Canadian study by De Gregorio et al. (2019) used rats to determine the effects of CBD in models of induced neuropathic pain with intact orspared nerve injury ( SNI).

They found the following: (1)

• An administration of CBD decreased or inhibited the activity of serotonergic neurons by interacting with pain mediators such as 5-HT1A and TRPV1 receptors, depending on the dose.

• Repeated administration of CBD increased the activity of these same neurons by desensitizing 5-HT1A receptors.

• Tolerance to painful stimuli in the injured limb increased after seven days of treatment.

• Stimulation of TRPV1 channels is required to obtain antinociceptive effects with CBD.

• CBD stimulates 5-HT1A receptors for anxiolytic effects.

This research confirms that CBD has analgesic (pain relieving) and anxiolytic (anxiety reducing) activity. These effects are not the result of CB1 cannabinoid receptors, but of the interaction of CBD with serotonergic receptors (5-HT1A) and transient receptor potential (TRPV1). This demonstrates a wide range of benefits due to its action on different receptors. 

Thus, the analgesic and anxiolytic activity of CBD on serotonergic neurons through 5-HT1A and TRPV1 receptors is confirmed without interacting directly on CB1 receptors; being able to prevent the abnormal perception of pain, generated by a mechanical or thermal stimulus that usually would not cause pain (mechanical allodynia) and aberrations in serotonergic neurotransmission, in addition to alleviating anxious behaviors related to pain.

Research in dogs

Studies in domestic animals are still very scarce. There are a few conducted in dogs for certain conditions (epilepsy, cancer and osteoarthritis pain) where the usefulness of phytocannabinoids has already been demonstrated. 

In the case of osteoarthritis, the presence of CBRs in chondrocytes and bone suggests a role of endocannabinoids in its pathophysiology. Human studies have shown elevation of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in synovial fluid of patients with arthritis, whereas they were not found in patients with healthy joints.(9)

A 2017 pilot study by Valastro et al. assessed the presence of endocannabinoids in the synovial fluid of dogs with OA. The degree of inflammation and level of two proinflammatory cytokines: tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were also analyzed. We worked with 10 dogs with OA undergoing knee surgery. Samples of synovial fluid from the affected limb and healthy knee were obtained from the patients. The results showed elevated levels of inflammatory cells in the affected knees and elevated levels of AEA and 2-AG compared to the healthy joints.(12)

These two studies show that endocannabinoids (AEA and 2-AG) are increased in human and animal patients with OA. Thus, it is shown that SEC modulates these reactions and is activated to try to decrease inflammation, pain and impairment in affected joints.

In 2018, Gamble et al. performed a study where CBD was used for pain management in 22 dogs with osteoarthritis that were diagnosed by X-ray and presented with severe pain. The dogs were administered CBD or placebo every 12 hours for 4 weeks. Simultaneously, pharmacokinetic analysis was performed at two doses of CBD (2mg/kg and 8 mg/kg), where the elimination half-life of cannabidiol was found to be 4.2 hours for both doses. Pain was measured using theBrief Canine Pain Inventory surveys and HudsonActivity Scores, which assess signs of pain and limitation in the dogs' normal activities as a result of pain. Only 16 of the 22 individuals completed treatment and were included in the statistical analysis. The results showed a statistically significant decrease in pain during the CBD treatment, as opposed to the acclimatization time without treatment and in comparison to the placebo-treated group. (3)

Conclusions

These studies show that CBD has beneficial effects on the regulation of pain and inflammation, signs that are very prevalent in diseases regardless of their cause. Cannabis and its phytocannabinoids have already been shown in anecdotal use and preclinical research to be a powerful tool to reduce pain, inflammation and even anxiety due to pain, thus improving the quality of life of the patient and his family. However, in order to use it, it is imperative to go to a veterinarian trained in the use of medical cannabis and to use products that guarantee its quality, legality and contents. Otherwise, there is a risk of overdose, intoxication, or problems due to contaminated products or products that do not even contain CBD.

References

1.     De Gregorio, D., et al. (2019). Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain, 160 (2019) 136–150. DOI: https://dx.doi.org/10.1097%2Fj.pain.0000000000001386 Disponible en: <Página web> 

2. Di Marzo, V. (2018). New approaches and challenges to targeting the endocannabinoid system. In Nature Reviews Drug Discovery (Vol. 17, Issue 9, pp. 623-639). Nature Publishing Group. DOI: https://doi.org/10.1038/nrd.2018.115

3.     Gamble, L.J., Boesch, J. M., Frye, C. W., Schwark, W. S., Mann, S., Wolfe, L., Brown, H., Berthelsen, E. S., & Wakshlag, J. J. (2018). Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Frontiers in Veterinary Science, 5(July), 1–9. https://doi.org/10.3389/fvets.2018.00165 Disponible en: <Página web> 

4.     Hill, K. P., Palastro, M. D., Johnson, B., & Ditre, J. W. (2017). Cannabis and Pain: A Clinical Review. Cannabis and Cannabinoid Research, 2(1), 96–104. https://doi.org/10.1089/can.2017.0017 Disponible en: <Página web> 

5. Lynch, J. W., Zhang, Y., Talwar, S., & Estrada-Mondragon, A. (2017). Glycine Receptor Drug Discovery. In Advances in Pharmacology (1st ed., Vol. 79, Issue September). Elsevier Inc. DOI: https://doi.org/10.1016/bs.apha.2017.01.003

6. Moldovan, M., Alvarez, S., Romer Rosberg, M., & Krarup, C. (2013). Axonal voltage-gated ion channels as pharmacological targets for pain. European Journal of Pharmacology, 708(1-3), 105-112. DOI: https://doi.org/10.1016/j.ejphar.2013.03.001

7. Muller, C., Morales, P., & Reggio, P. H. (2019). Cannabinoid ligands targeting TRP channels. Frontiers in Molecular Neuroscience, 11(January), 1-15. DOI: https://doi.org/10.3389/fnmol.2018.00487

8.     Philpott H.T., O’Brien M., McDougall, J. (2017). Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017 Dec; 158(12): 2442–2451. DOI: https://dx.doi.org/10.1097%2Fj.pain.0000000000001052 Disponible en: <Página web> 

9. Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA, Kendall DA, Scammell BE, Reeve AJ, Chapman V. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2008;10:43.

10. Russo, E. B., & Hohmann, A. G. (2013). Role of Cannabinoids in Pain Management. In T. R. Deer, M. S. Leong, A. Buvanendran, V. Gordin, P. S. Kim, S. J. Panchal, & A. L. Ray (Eds.), Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches (Issue December, pp. 181-197). Springer New York. DOI: https://doi.org/10.1007/978-1-4614-1560-2_18

11. Tibbs, G. R., Posson, D. J., & Goldstein, P. A. (2016). Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain? Trends in Pharmacological Sciences, 37(7), 522-542. DOI: https://doi.org/10.1016/j.tips.2016.05.002

12.  Valastro et al. (2017). Characterization of endocannabinoids and related acylethanolamides in synovial fluid of osteoarthritic dogs: a pilot study. BMC Veterinary Research (2017) 13:309. DOI: https://dx.doi.org/10.1186%2Fs12917-017-1245-7 Disponible en: <Página web>