Cannabinoids and pain in small animal medicine

Photo: Volha/Adobe Stock

The use of medical marijuana and other approved D-9-tetrahydrocannabinol (THC) or mixed THC and cannabidiol (CBD) products, such as nabiximols and dronabinol, is becoming commonplace to treat pain in humans.¹ Findings from a recent meta-analysis in human medicine that examined randomized clinical trials indicated no benefits from CBD in studies of up to 12 weeks, with dosing being highly variable (20 to 1600 mg per day).² Adding to the heterogeneity was the number of different pathologies being treated, from topical joint pain to oral dosing for ailments such as cancer-related pain, psoriatic arthritis, rheumatoid arthritis, opioid-induced hyperalgesia, irritable bowel disease, and peripheral neuropathic pain.^2,3

Overview

These findings are not particularly encouraging for the use of CBD isolate for the treatment of pain in dogs or cats. There does, however, appear to be differences in absorption of CBD across species. It has been shown that a dose as low as 1 to 4 mg/kg allows for serum concentrations to reach maximal levels of 100 to 250 ng/mL or greater within 1 to 2 hours in both dogs and cats, with half-lives suggesting twice-daily dosing at minimum.^4-10 When dosing humans for seizure disorders, the recommended dose of CBD is 10 to 20 mg/kg per day, which allows for serum concentrations in the 100 to 300 ng/mL range.^11-12 This, however, has led to some of the confusion regarding cannabinoids and their potential efficacy.^13-14 It has also been deduced that using a food matrix or oil is likely the best way to deliver cannabinoids because of slightly better pharmacokinetics when administered alongside food.^11-12

Many products on the market are either CBD isolates, broad-spectrum CBD-rich hemp, or full-spectrum CBD-rich hemp. Broad-spectrum products may also contain minor cannabinoids, such as cannabidiolic acid (CBDA), THC, tetrahydrocannabinolic (THCA), cannabichromene, cannabichromenic acid, cannabigerol (CBG), and cannabigerolic acid—to name a few of the more prominent minor cannabinoids. Full-spectrum blends will also include terpenes and flavonoids from the plant. This lends to the idea of the “entourage effect,” with some researchers postulating that these additional molecules may act synergistically and improve absorption of cannabinoids to help mitigate pain.¹⁵ A study of Holstein steers provides an example of this concept. Whole hemp—containing little to no CBD or THC but rich in CBDA and THCA—along with other acidic molecules was provided to cattle, resulting in lower overall cortisol and prostaglandin E2 concentrations and improved comfort levels.¹⁶ Interestingly, the few studies examining CBDA absorption and retention in dogs and cats have found a 3- to 5-fold better absorption of CBDA than CBD.^6,9

Current literature

If we examine the current clinical literature on pain mitigation in dogs and primarily focus on randomized, blinded, placebo-controlled studies, there are 5 studies in dogs that evaluated osteoarthritis pain and 1 study of acute pain mitigation after tibial plateau osteotomy.^4,17-21 A study on osteoarthritis pain in dogs published in Frontiers in Veterinary Science in 2018 used a full-spectrum CBD/CBDA-rich hemp product, which contained an equal mix of CBD and CBDA and was dosed at 2 mg/kg every 12 hours. The product was delivered in an olive oil base and provided to dogs in a crossover, placebo-blinded study over 4 weeks; each arm of the study had a 2-week washout period between treatments. Results showed benefits based on validated subjective measurements using the Canine Brief Pain Inventory (CBPI), with an approximately 25-point drop in pain scores at weeks 2 and 4 that were not observed in the placebo group.⁴ Hudson activity scores were also evaluated, demonstrating a 20-point increase in the activity index during treatment vs a mild worsening of scores with the placebo.⁴ During the veterinary evaluations at the 2- and 4-week time points, there were no observations of improved lameness or weight-bearing capacity but pain scores did improve in the dogs treated with the full-spectrum CBD/CBDA mixture.⁴

A second study on canine osteoarthritis pain utilized a smaller cohort of dogs using a CBD-rich hemp product. Four groups with 5 dogs each received either a medium chain triglyceride (MCT) oil placebo (20 mg/dog/ day), a CBD-rich isolate (50 mg/dog/day) in an MCT base, or a microsomal-encapsulated CBD-rich hemp product (20 mg/kg/ day). The trial lasted 1 month and utilized the Helsinki Chronic Pain Index (HCPI) at the end of the treatment period. All dogs treated with one of the CBD products showed a significant drop in pain index scores. The HCPI scores for the CBD-rich isolate (50 mg/kg/day) group dropped from a mean of 21 to a mean of 14, and the HCPI scores for the CBD-rich hemp product (20 mg/kg/day) group decreased from a mean of 23 to a mean of 13. As part of the assessment, a veterinarian evaluated ease of rising, ease of walking, and lameness on ambulation and noted that Helsinki pain indices improved for ease of rising and ease of walking in both CBD groups.¹⁷

A third study—a randomized, placebo-controlled trial—examined dogs with clinical arthritis that were concurrently managed on firocoxib or low-dose prednisone in addition to amitriptyline and gabapentin. This drug choice could not be changed during the 12-week trial. The CBD isolate in MCT oil was dosed at 2 mg/kg orally every 12 hours, although the authors could not deduce based on the description whether this was truly a CBD isolate or a more complex product. Evaluation via CBPI at 0, 1, 2, 4, and 12 weeks of treatment showed significant decreases in pain compared with placebo; significant differences in the pain score from baseline were observed over time in the treatment group only, with differences in the pain score noted between the groups throughout the study. More importantly, this was the longest study utilizing a CBD-rich hemp product to date, and it appeared to demonstrate safety with concomitant use of other commonly utilized medications; there were, however, no reported serum chemistry parameters to confirm this during the study.¹⁸

The fourth study was a randomized, placebo-controlled, crossover trial of 23 dogs with osteoarthritis-associated pain that were administered placebo (hempseed oil) or treatment (2.5 mg/kg of a CBD isolate in hempseed oil) for 6 weeks before crossover.1⁹ The outcome measures at 3, 6, 9, and 12 weeks were compared with initial screening and included the CBPI, the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire, assessments of total weight bearing, and percentage of weight bearing. For nearly all subjective and objective observations, there were greater improvements during the CBD-rich isolate treatment vs placebo on the pain sensitivity scale and pain interference portion of the CBPI survey as well as on the LOAD questionnaire.¹⁹ Significant effects from placebo at each time point were not observed.¹⁹ What was confounding about this study was that dogs were provided approximately 0.1 mL/kg of hempseed oil twice daily, unlike the previous studies that utilized higher-saturated-fat oil sources; hempseed is very rich in both α-linolenic acid and γ-linolenic acid, which may both have mild anti-inflammatory properties.^22,23 Further confusing was that the placebo group and the CBD group showed measurable levels of THC in the bloodstream,¹⁹ indicating contamination of the hempseed oil used. The THC levels were high enough in the treatment group,¹⁹ to suggest that a broad- or full -spectrum CBD product was used rather than a CBD isolate.¹⁹

The same research group recently published results from another placebo-controlled, crossover study 42 dogs with mobility impairments, in which the subjects received either a 5 mg/kg dose of CBD isolate in an MCT oil base twice daily or placebo for 6 weeks. A secondary assessment was to better understand the therapy’s use in conjunction with carprofen as a standard nonsteroidal anti-inflammatory drug (NSAID) treatment for osteoarthritis. The measures included standard subjective owner and veterinary assessments at 6 weeks and objective kinetics around ground reaction forces. What was evident is that both subjective owner and veterinary assessments regarding pain were improved during treatment with this CBD product vs placebo treatment; however, ground reaction forces were not statistically different between the placebo and CBD treatment.²¹ The researchers also noted sporadic increases in alkaline phosphatase (ALP) in some of the dogs in the treatment group as well as a statistically significant increase in alanine aminotransferase (ALT) in dogs with concomitant use of carprofen, although there were no differences in dogs above the reference range interval in either group.²¹ The investigators also found that for the dogs that underwent procedures for hepatic cytology (with owner consent), there was no degenerative pathology associated with the treatments, but they cautioned that further studies are needed.²¹ These results are different from a 2018 investigation that used another CBD product at a lower dose, where ALT increases were not associated with NSAID use.⁴ These conflicting results may be caused by the product or because dosing was higher in the most recent study.

Acute pain management

Osteoarthritis is a generalized chronic pain syndrome, often with a neuropathic component, with a different presentation than acute pain. The utility of cannabinoids for acute pain in dogs is now emerging, with only 1 study demonstrating that a full-spectrum CBD/CBDA product at 2 mg/ kg in a sesame oil base showed no differences compared with placebo.²⁰ The study of acute pain mitigation after tibial plateau osteotomy evaluated more than 20 dogs in each group, utilized owner CBPI scores, and examined bone healing and the need for postoperative trazodone use. Although there were no improvements in pain or bone healing between the treatment groups over the 4-week time period, there appeared to be decreased trazadone use in the dogs in the treatment group at the 2-week recheck²⁰; this suggests that cannabinoids may help maintain lower activity during the healing process.

In several studies, serum chemistry showed no significant alterations in parameters other than a rise in ALP.^4,17,21 This increase in serum ALP is thought to be innocuous because ALT, γ-glutamyl transferase, and other hepatic parameters are not altered with stand-alone CBD treatment. Two recent studies examining the tolerability of CBD (10 mg/day) or mixtures of CBD isolate along with other minor cannabinoids such as CBG and CBDA (~5 mg/day) in dogs demonstrated safety, with only mild rises in ALP and no significant elevations in ALT.^24,25 Another study looked at long-term safety in cats dosed with CBD at 4 mg/kg once daily and show no significant rises in hepatic enzymes.⁸

When it comes to cats and cannabinoids, far less data are available on pharmacokinetics or efficacy. It is evident in cats that serum concentrations resulting from use of different products are highly variable6; delivery matrix may also play a larger part in absorption and/or retention of CBD and other cannabinoids.^5,6,8,25 Further complicating treatment is that there are no studies examining osteoarthritis pain in cats, other than a study that used a mixed cannabinoid product.²⁶ Another study suggests that in cats with chronic gingivostomatitis, use of approximately 1 mg/kg of a CBD-based powder diluted in water and administered orally once daily provided mild benefit.²⁷ Although the healing and oral lesions were no different between the placebo and treatment groups, weight loss was more abrupt in the placebo group compared to the CBD group.²⁸ It is undetermined whether this was because of pain mitigation or appetite stimulation, but it does suggest some utility in cats. Further investigation of this in cats is needed before solid recommendations can be made for treating conditions in domestic cats.

Potential drug interactions

Although several potential drug interactions are associated with the concurrent use of cannabinoids, in clinical practice, there are few situations where cannabinoid use is contraindicated. A 2023 study showed that different enzymes from the cytochrome P450 family were responsible for metabolism of cannabidiol via various metabolic pathways,²⁹ so clinicians should be mindful of concurrent drug administration. However, commonly utilized veterinary analgesic drugs such as nonsteroidals, steroids, gabapentin, amantadine, acetaminophen, ketamine, and amitriptyline present few concerns. Benzodiazepines will cause profound sedation if concurrently administered,³⁰ and although not yet seen in veterinary or human medicine, there is a risk of serotonin syndrome following the concurrent administration with some antidepressant medications.

Takeaway

The use of CBD-rich hemp products is in its infancy and has potential benefits; however, additional studies are needed to fully appreciate the long-term utility of cannabinoids for arthritis pain. Cannabinoids appear appropriate for a pain regimen and can be used as a stand-alone product when adverse reactions occur with other pharmaceuticals. The paucity of studies on cannabinoids for acute pain and in felines provides a ripe platform for investigation. Furthermore, it is becoming evident that because of the heterogeneity in the products sold, efficacy studies on each product are necessary due to differences in absorption and retention.

References

1. Karst M. Overview: chronic pain and cannabis-based medicines. Pharmacopsychiatry. 2024;57(3):152-159. doi:10.1055/a-2231-6630
2. Moore A, Straube S, Fisher E, Eccleston C. Cannabidiol (CBD) products for pain: ineffective, expensive, and with potential harms. J Pain. 2024;25(4):833-842. doi:10.1016/j.jpain.2023.10.009
3. Villanueva MRB, Joshaghani N, Villa N, et al. Efficacy, safety, and regulation of cannabidiol on chronic pain: a systematic review. Cureus. 2022;14(7):e26913. doi:10.7759/cureus.26913
4. Gamble LJ, Boesch JM, Frye CW, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci. 2018;5:165. doi:10.3389/fvets.2018.00165
5. Deabold KA, Schwark WS, Wolf L, Wakshlag JJ. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals (Basel). 2019;9(10):832. doi:10.3390/ani9100832
6. Wang T, Zakharov A, Gomez B, et al. Serum cannabinoid 24 h and 1 week steady state pharmacokinetic assessment in cats using a CBD/CBDA rich hemp paste.Front Vet Sci. 2022; 9:895368. doi:10.3389/fvets.2022.895368
7. Jukier T, Cruz-Espindola C, Martin D, Boothe DM. Disposition of a single oral dose of a cannabidiol medication in healthy cats.Front Vet Sci. 2023;10:1181517. doi:10.3389/fvets.2023.1181517
8. Coltherd JC, Bednall R, Bakke AM, et al.Healthy cats tolerate long-term daily feeding of cannabidiol.Front Vet Sci. 2024;10:1324622. doi:10.3389/fvets.2023.1324622
9. Wakshlag JJ, Schwark WS, Deabold KA, et al. Pharmacokinetics of cannabidiol, cannabidiolic acid, D9-tetrahydrocannabinol, tetrahydrocannabinolic acid and related metabolites in canine serum after dosing with three oral forms of hemp extract.Front Vet Sci. 2020;7:505. doi:10.2289/fvets.2020.00505
10. Bradley S, Young S, Bakke AM, et al. Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs.Front Vet Sci. 2022;9:977457. doi:10.3389/fvets.2022.977457
11. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects.CNS Drugs. 2018; 32(11):1053-1067. doi:10.1007/s40263-018-0578-5
12. Abbotts KSS, Ewell TR, Butterklee HM, et al. Cannabidiol and cannabidiol metabolites: pharmacokinetics, interaction with food, and influence on liver function.Nutrients. 2022;14(10):2152. doi:10.3390/nu14102152
13. Della Rocca G, Paoletti F, Conti MB, et al. Pharmacokinetics of cannabidiol following single oral and oral transmucosal administration in dogs.Front Vet Sci. 2023;9:1104152. doi:10.3389/fvets.2022.1104152
14. Polidoro D, Temmerman R, Devreese M, et al. Pharmacokinetics of cannabidiol following intranasal, intrarectal, and oral administration in healthy dogs.Front Vet Sci. 2022;9:899940. doi:10.3389/fvets.2022.899940
15. Anderson LL, Etchart MG, Bahceci D, Golembiewski TA, Arnold JC. Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations.Sci Rep. 2021;11(1):14948. doi:10/1038/s41598-021-94212-6
16. Kleinhenz MD, Weeder M, Montgomery S, et al. Short term feeding of industrial hemp with a high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress and inflammation in Holstein steers.Sci Rep. 2022;12(1):3683. doi:10.1038/s41598-022-07795-z
17. Verrico CD, Wesson S, Konduri V, et al. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain. 2020;161(9):2191-2202. doi:10.1097/j.pain.0000000000001896
18. Brioschi FA, Di Cesare F, Gioeni D, et al. 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;10(9):E1505. doi:3390/ani10091505
19. Mejia S, Duerr FM, Griffenhagen G, McGrath S. Evaluation of the effect of cannabidiol on naturally occurring osteoarthritis-associated pain: a pilot study in dogs. J Am Anim Hosp Assoc. 2021;57(2):81-90. doi:10.5326/JAAHA-MS-7119
20. Klatzkow S, Davis G, Shmalberg J, et al. Evaluation of the efficacy of a cannabidiol and cannabidiolic acid rich hemp extract for pain in dogs following a tibial plateau leveling osteotomy. Front Vet Sci. 2023;9:1036056. doi:10.3389/fvets.2022.1036056
21. Talsma B, Elam LH, McGrath S, Zhou T, Webb CB, Duerr FM. Evaluation of the effect of cannabidiol administration with and without nonsteroidal anti-inflammatory drugs in dogs with mobility disorders: a prospective double-blind, crossover, placebo-controlled study. Front Vet Sci. 2024;11:1449343. doi:10.3389/fvets.2024.1449343
22. Zurier RB, Rossetti RG, Jacobson EW, et al. Gamma-linolenic acid treatment of rheumatoid arthritis. a randomized, placebo-controlled trial.Arthritis Rheum. 1996;39(11):1808-1817. doi:10.1002/art.1780391106
23. Veselinovic M, Vasiljevic D, Vucic V, et al. Clinical benefits of n-3 PUFA and γ-linolenic acid in patients with rheumatoid arthritis.Nutrients. 2017;9(4):325. doi:10.3390/nu9040325
24. Corsato Alvarenga I, Wilson KM, McGrath S. Tolerability of long-term cannabidiol supplementation to healthy adult dogs.J Vet Intern Med. 2024;38(1):326-335. doi:10.1111/jvim.16949
25. Bookout W, Dziwenka M, Valm K, Kovacs-Nolan J. Safety study of cannabidiol products in healthy dogs.Front Vet Sci. 2024;11:1349590. doi:10.3389/fvets.2024.1349590
26. Rozental AJ, Gustafson DL, Kusick BR, Bartner LR, Castro SC, McGrath S. Pharmacokinetics of escalating single-dose administration of cannabidiol to cats.J Vet Pharmacol Ther. 2023;46(1):25-33. doi:10.1111/jvp.13100
27. Gutierre E, Crosignani N, García-Carnelli C, di Mateo A, Recchi L. A case report of CBD and THC as analgesic therapy in a cat with chronic osteoarthritic pain.Vet Med Sci. 2023;9(3):1021-1025. doi:10.1002/vms3.1057
28. Coelho JC, Duarte N, Bento da Silva A, Bronze MDR, Mestrinho LA.Placebo-controlled trial of daily oral cannabidiol as adjunctive treatment for cats with chronic gingivostomatitis.Animals (Basel). 2023;13(17):2716. doi:10.3390/ani13172716
29. Court MH, Mealey KL, Burke NS, Jimenez TP, Zhu Z, Wakshlag JJ. Cannabidiol and cannabidiolic acid: preliminary in vitro evaluation of metabolism and drug–drug interactions involving canine cytochrome P-450, UDP-glucuronosyltransferase, and P-glycoprotein. J Vet Pharmacol Ther. 2024;47(1):1-13. doi:10.1111/jvp.13403
30. Turner M. CBD and Our Pets . Ethos Veterinary Health. Published August 10, 2023. Accessed October 31, 2024. https://www.ethosvet.com/blog-post/cbd-and-our-pets/