The role of cannabinoids in pain

Updated: Nov 18

Can I use CBD for analgesia?


This pain update explores the evolution of the targeting of the endocannabinoid system and reviews the literature on the use of CBD in pain.


Currently there is strong interest in the use of cannabinoids for pain. The biological effects of cannabinoids are mediated by CB1 and CB2 receptors. These are G protein coupled receptors located both peripherally and centrally. To date, the psychoactive effect of cannabinoids has limited their therapeutic benefit. We now have products at our disposal which are certified to contain no tetrahydrocannabinol (THC) – the component responsible for psychoactive effects. It is the cannabidiol (CBD) component which we are interested in for the analgesic benefit.


The CB receptors (CBR) have endogenous agonists, known as the endocannabinoids, which are derivatives of arachidonic acid. These are AEA and 2-AG. AEA is a high affinity partial agonist of CB1R with little CB2R activity, whereas 2-AG is a full agonist at both CB receptors with moderate to low affinity. TRPV1 receptors are also activated by AEA. These endocannabinoids are produced in response to increased intracellular calcium. The CB1R amino acid sequence is very close across three species – human, rat and mouse. The CB2R has greater species differences. Both receptors have different distributions throughout the body.


How do endocannabinoids work?

The signalling pathway is retrograde, meaning that endocannabinoids (EC) are produced on the post-synaptic terminal as a result of neuronal activation. Production of 2-AG is in response to increased intracellular calcium. The ECs (AEA and 2-AG) are lipid soluble and readily cross the synaptic cleft to activate CB1Rs located presynaptically. When activated, the CB1R is able to inhibit neurotransmitter release by suppressing calcium influx and by inhibiting adenylyl cyclase and cAMP – a process known as long-term depression (LTD) of signalling. AEA is also synthesized in the post-synaptic terminal which activates intracellular CB1Rs and TRPV1 Rs. AEA also has a presynaptic effect.


There is also a subpopulation of CB1Rs located not on the cell membrane, but in a subcellular location. Those located on liposomes are able to increase intracellular calcium levels and mitochondrial CB1Rs play a role in regulation of cellular energy production. Whether there is a role in pain is unclear.


CB1 receptors are distributed throughout the brain. Receptors are highly concentrated on pre-synaptic terminals and also found on astrocytes and microglia. In the peripheral nervous system CB1Rs are widely expressed in sympathetic nerve terminals, the trigeminal and dorsal root ganglia and nerve endings of sensory neurons. CB1R play a role in cardiac, gastrointestinal, respiratory, hepatic and muscle function in addition to roles in nociception. modulation of GI motility as well as a number of other GI functions.

CB2 receptors play a role in the CNS and PNS in nociception, drug addiction and neuroinflammation.


Several studies document the extensive actions of CB receptors beyond the G protein signalling role role in reducing cAMP and hence cellular calcium levels. The widespread location and roles of CBRs makes manipulation of the EC system difficult – the aim is to produce a therapeutic effect without generating adverse effects.


The EC system is a key regulator of nociception which is of interest to us. Effects in different types of pain are well documented including heat, chemical and mechanical – neuropathic, inflammatory and cancer pain.


Paracetamol has a wide variety of mechanisms – and one of those is as an antihyperalgesic through actions on CB1 receptors. One of the metabolites of paracetamol, AM404, increases concentrations of AEA. It has been shown in mice with inflammatory pain that paracetamol exerts this anti-hyperalgesic effect and that this effect is lost in mice with no CB1 receptors. This effect is said to be downstream from prostaglandin-induced inflammation; meaning the it occurs after the PGs are produced, subsequently shown to be a supraspinal effect. Translated, this means paracetamol blocks the effect of those inflammatory mediators at the level of the brain – so it makes sense to use paracetamol alongside other drugs such as NSAIDs which themselves directly target inflammation. Read more about paracetamol here.


Prescribing CBD on the cascade

There is no licensed CBD preparation for veterinary use. Canidol V is a THC-free extemporaneous product with certified batch analysis. It is a sublingual product for dogs and cats. The recent availability of the human product Epidyolex brings some questions. In theory Epidyolex is higher on the cascade than Canidol V, however Epidyolex is only available to specialist doctors. This means we can use Canidol V, which sits on the next rung of the cascade.


A second CBD product is available for veterinary use. This is a CBD-rich hemp nutraceutical marketed as Ellevance and does have some clinical research in dogs with OA. This product contains CBDA as well as CBD. The CBDA is reported to improved absorption when taken orally.

In a 4 week cross over study dogs with radiographically confirmed OA were given the test product or placebo. The main outcome measure was the Canine Brief Pain Inventory (CBPI), a validated pain scale for dogs with OA. Reductions in total CBPI score at weeks 2 and 4 were significantly different compared baseline in the CBD group and in the placebo group there were no significant changes in scores. Limitations here were size of the study with 16 of the 22 enrolled dogs completing the study and one note of caution being that some dogs were treated with NSAIDs but not all.

This product shows promise on the analgesia front and further clinical studies are anticipated.


UPDATE May 2020

A study by Verrico et al examined whether CBD can modulate the production of inflammatory cytokines in vitro and in mouse models of inflammation. They also examined whether CBD in a liposome encapsulated form could increase bioavailability of the drug in mice and humans. The next stage of the work was to examine whether the non-liposome CBD or the liposome CBD (L-CBD) could reduce pain in a dog model of OA.


In vitro and in mouse models CBD significantly attenuated the production of pro-inflammatory cytokines IL-1 and TNF-alpha. It also increased levels of anti-inflammatory IL-10. In the canine study CBD significantly decreased pain in the dogs and increased their mobility – a change that was dose-dependent. Efficacy was confirmed for both the liposomal and non-liposomal formulations.


The drive for this study is down to the fact that previous studies in rodents have documented a benefit, yet these studies in humans have resulted in late-stage failures to prove a benefit. The challenge here is that pre-clinical models do not reflect the entity of the clinical picture of osteoarthritis in humans. Therefore a study documenting a benefit in dogs give hope that such a compound may prove effective in people, given that the OA picture in dogs is closer to that in people.


The CBD in this study was certified to be THC free. Dogs in the placebo controlled, blinded study were client-owned pets with a diagnosis of OA, lameness and joint pain. Any other medications were discontinued 2 weeks prior. Outcomes were evaluation by the vet and an owner-completed Helsinki Chronic Pain Index (HCPI) on days 0, 30 and 45. Two daily doses of non-liposome encapsulated CBD were trialled (20 mg & 50 mg) as well as 20 mg L-CBD.


Veterinary assessments mirrored the HCPI results. The lower dose of NL-CBD was ineffective but the higher NL-CBD and L-CBD were effective. This shows a dose-dependent change and also demonstrates that use of the liposome to encapsulate the CBD allows use of a lower dose, due to improved bioavailability. No adverse events or alterations in blood work were noted.

To date we haven’t really had a dose to work from with CBD but this study gives some insight. The preparations we are using currently are not liposome encapsulated. To extrapolate from this study we probably need to be using 50 mg/kg - which is higher than I've ever used.


Currently it appears we are at the forefront of knowledge of the endocannabinoid system. We have paracetamol, an under-used and effective drug in dogs. The market is heating up with CBD products. We need to know the exact content of such products – and the more evidence these companies can present to us as pain clinicians, the more likely we are to use them successfully to reduce pain as much as possible for our patients.


Guidance for prescribing CBD

A 12 week safety study concluded that 2mg/kg BID is a safe and well tolerated dose. One cat experienced a transient increase in ALT which could not be linked to product use. Monitoring hepatic parameters is recommended for long term (>3 month) use.


Potential drug interactions

Avoid concurrent benzodiazepine use.

Transient lethargy, inappetence and abnormal behaviours has been noted in dogs receiving gabapentin, acepromazine and phenobarbital concurrently.

No adverse effects with trazodone have been described to date.

Any adverse events should be reported to the supplier/manufacturer.


References

Klinger-Gratz PP et al (2018) Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla. 10;38(2):322-334. doi: 10.1523/JNEUROSCI.1945-17.2017

Verrico, C. D., Wesson, S., Konduri, V., Hofferek, C. J., Vazquez-Perez, J., Blair, E., Dunner, K., Salimpour, P., Decker, W. K., & Halpert, M. M. (2020). A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. In Pain. https://doi.org/10.1097/j.pain.0000000000001896

Zou S & Kumar U (2018) Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System Int J Mol Sci.19(3): 833. doi: 10.3390/ijms19030833


This post was written by Matt Gurney.


Matt & Carl established Zero Pain Philosophy to provide educational resources to veterinary professionals enabling optimal management of pain.


Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is President of the European College of Veterinary Anaesthesia & Analgesia.


Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists.

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