The role of cannabinoids in pain

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.

A recent research publication in JSAP aimed to understand the motivations and perceptions about cannabidiol use in companion animals in the USA. This work was an owner survey which reported wide differences around the use of CBD as a supplement - which is not surprising when owners make these choices without veterinary guidance. The paper can be found here.

The section in the discussion which starts with 'Studies evaluating dogs with chronic osteoarthritis' summarises the evidence that we have detailed below - and draws the same conclusions we have, notably 'more studies are needed on the efficacy, dosing, formulation, and medication combination.' This research is useful to us in understanding the drive by owners to seek out such options.

What does the evidence so far suggest?

Gamble et al (2018) conducted one of the first studies we have.

The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).

1. Single-dose pharmacokinetics was performed using two different doses of CBD enriched (2 and 8 mg/kg) oil.

2. A randomized placebo-controlled, vete, and owner blinded, cross-over study was conducted.

Dogs received each of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 h. Each treatment lasted for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment and at weeks 2 and 4. Haematology, serum chemistry and physical examinations were performed at each visit. Outcome measures were the Canine Brief Pain Inventory and Hudson activity scores.

Twenty-two client-owned dogs with clinically and radiographically confirmed evidence of osteoarthritis were recruited. Sixteen of these dogs completed the trial and were included in the analyses.

Initial power analysis was performed to assess number of dogs needed for this study and when calculated it was assumed that 14 dogs would be necessary to find differences in outcomes of interest.

Results on pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects, hence the selection of the 2mg/kg for the efficacy study.

Clinically, CBPI and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. The differences in CBPI scores were certainly significant when you eyeball the data - with decreases of 5 points for pain and 10 points for interference. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). Unsurprisingly me for there was no decrease seen in lameness - which highlights the importance of outcome measures which evaluate the impact of the pain. No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01).

Nine of the 16 dogs in the study were treated concurrently with NSAIDs - 6 with carprofen and 3 with meloxicam. Although this could be considered a confounding factor we also recognise that each dog was assessed at baseline and then at 2 and 4 weeks - and then crossed-over into the other group. It would also be challenging from an ethical perspective to remove NSAIDs from dogs in pain where the NSAIDs are effective.

This is where the 2mg/kg BID dose is derived from.

The authors conclude that this pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.

A 2020 study published in the journal Animals by Brioschi et al assessed the effects on pain relief and quality of life in dogs with OA. The CBD preparation was an orotransmucosal formulation.

All 21 dogs in the study received gabapentin, amitriptyline and anti-inflammatories. In 9 of those dogs the OTM CBD product was incorporated. The dose used was 2mg/kg. The outcome measure used was the CBPI, at baseline then weeks one, two, four and twelve. Pain severity scores were significantly lower in the CBD group compared to the other dogs until week four. Pain interference scores were lower in the CBD group at these same time points. Quality of life was scored higher only at week one. But let's look at some detail before we walk away with these conclusions!

In their introduction these authors summarise OA as one of the main causes of chronic pain in dogs, due to active inflammation and a maladaptive component due to central sensitisation. They state management of OA includes treatment with NSAIDs and corticosteroids - they don't clarify route of admin of steroids - I would not include oral here as an option and would say the only route we use steroids of OA is intra-articularly. Correctly they state that anti-inflammatories do not provide complete pain relief, leading to a discussion of gabapentin and amitriptyline as adjunct options. For me, there was no mention of NMDA antagonists - and we have evidence for NMDA antagonists whereas there is no evidence for gabapentin or amitriptyline. The authors do state that there is no evidence for gabapentin or amitriptyline but do not mention amantadine or memantine.

They state that the OTM route offers the advantage that bioavailability is increased due to avoidance of hepatic first pass effect.

In the study 24 client-owned dogs were included. Inclusion criteria included radiographic evidence of OA, pain on joint examination and OA-associated signs of joint dysfunction. Dogs receiving analgesics within four weeks of the study were excluded.

One of my major issues with this study is that the anti-inflammatory used was either firocoxib or prednisolone - and personally I do not consider these drugs equivalent in their effect. You can already see that the authors have introduced a confounding factor into this study of 24 dogs. They state that firocoxib was the first line treatment, but if adverse effects to firocoxib were seen then dogs were switched to prednisolone. Not sure how that passed ethics. I would have asked for these dogs to be excluded from the study.

Now the study gets more confusing in that they reduced the doses of medications during the study - dropping the firocoxib and prednisolone by 50% in the second week and 50% for the remainder of the study. Why would you do that when this is not a clinically relevant strategy for OA management? Gabapentin started at 10mg/kg then reduced to 5mg/kg BID.

There was no placebo product used in the dogs in the non-CBD group which certainly could influence owner opinion. To me this is a major shortfall of this work.

A sample size calculation was performed , which is a positive to this work suggesting 7 dogs per group were required. There were 9 dogs in the CBD group and 12 in the control group that completed the study.

So this is a perfect example of where you get a different message from reading the abstract compared to delving into the whole paper. In our podcast Matt digs deeper into the paper - you can listen 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.

(June 2023 - Canidol V supply unreliable at present)

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. The product that I have used are the Big Bites.

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 gives 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 have a 2mg/kg dose to work from with CBD but this does depend on the preparation. The preparations we are using currently are not liposome encapsulated. To extrapolate from this study we probably need to be using higher doses - but further work is required.

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. Those studies need a greater number of subjects to draw definitive conclusions.

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

Brioschi FA, Di Cesare F, Gioeni D, Rabbogliatti V, Ferrari F, D'Urso ES, Amari M, Ravasio G. Oral Transmucosal Cannabidiol Oil Formulation as Part of a Multimodal Analgesic Regimen: Effects on Pain Relief and Quality of Life Improvement in Dogs Affected by Spontaneous Osteoarthritis. Animals (Basel). 2020 Aug 26;10(9):1505. doi: 10.3390/ani10091505. PMID: 32858828; PMCID: PMC7552307.

Gamble LJ, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES, Wakshlag JJ. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Front Vet Sci. 2018 Jul 23;5:165. doi: 10.3389/fvets.2018.00165. PMID: 30083539; PMCID: PMC6065210.

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 Past President of the European College of Veterinary Anaesthesia & Analgesia. Matt works at Anderson Moores Veterinary Specialists.

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