CBD for Dog Glaucoma?

Hello, Summarians!

Here are a couple of studies that examine some new mechanisms of action that we do not consistently use in veterinary medicine. Let me know what you think!

If it is valuable to you please consider sending it on to a friend 😄 

Dosing Levetiracetum in Dogs

Levetiracetam, a second-generation antiepileptic drug, is used for various seizures in humans and shows linear pharmacokinetics over a dose range of 250-5000 mg/day. Combination therapy may require higher doses to achieve similar serum concentrations. Though therapeutic and toxic concentrations are not well-defined, a proposed reference range is 12-46 μg/mL, with some studies suggesting 20-40 μg/mL for higher efficacy. In dogs, levetiracetam is used for idiopathic and structural epilepsy, but results on its efficacy are mixed. Factors such as observational vs. randomized trial methodologies, patient numbers, epilepsy types, and short-term vs. long-term efficacy can explain discrepancies. No established therapeutic serum concentration range exists for dogs. Studies suggest a dosage of 20 mg/kg q8h in monotherapy, which may result in trough concentrations below 20 μg/mL. Concurrent phenobarbital administration lowers levetiracetam concentrations, recommending a higher dose of 30 mg/kg q8h. 

In this study, a moderate correlation was found between the PO dose and serum concentration in dogs, explaining 59% of the variation. Other influencing factors, such as time of day and individual pharmacokinetics, need consideration. To achieve a minimum serum concentration of 20 μg/mL, a higher starting dose of 99 mg/kg/day (33 mg/kg q8h) is suggested, increasing to 216 mg/kg/day (72 mg/kg q8h) when combined with phenobarbital. The study confirmed phenobarbital's negative effect on levetiracetam concentration, with increasing phenobarbital doses diminishing the correlation between levetiracetam PO dose and serum concentration. 

A median reduction in seizure frequency of 78% was observed, with 71% showing ≥50% reduction and 24% achieving complete response. These results align with other studies reporting a 54%-77% reduction. However, a placebo-controlled study found no significant difference in seizure frequency. No significant association was found between serum levetiracetam concentration and clinical efficacy, likely due to the small sample size and variability in concentrations. The retrospective nature of the study and subjective seizure assessments also limited precise evaluation. 

The study concludes that a higher starting dose of levetiracetam (33 mg/kg q8h for monotherapy) is needed for clinically effective serum concentrations, increasing further when combined with phenobarbital. Despite these recommendations, a minimum therapeutic serum concentration could not be determined. 

Saint-Maxent M, Juette T, Parent J, Castel A, Parmentier T. Factors influencing serum concentrations of levetiracetam in dogs with epilepsy. J Vet Intern Med. 2024; 38(4): 2249-2256. doi:10.1111/jvim.17128 

Bottom line — May need to adjust the dose depending on the patient.

CBD Ocular Effects

The endocannabinoid system plays a crucial role in regulating various biological functions in humans and animals, including mood, memory, sleep, pain, immunity, and metabolism. Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are well-known exogenous cannabinoids derived from Cannabis sativa. THC has been used in human medicine to treat conditions like HIV neuropathy, chemotherapy-induced vomiting, autism, and epilepsy. However, THC is not well-tolerated by dogs. In contrast, CBD shares structural similarities with THC but lacks psychotropic effects, making it safer for canine use. Recent studies have shown that orally administered CBD is effective and safe for treating idiopathic epilepsy, aggression, and osteoarthritis in dogs, with the main side effect being an increase in serum alkaline phosphatase (ALP). 

Despite the potential benefits, cannabinoid use in veterinary medicine remains illegal in many countries due to limited evidence. There is a lack of research on the long-term ocular effects of CBD in dogs. This study aimed to assess the chronic effects (36 weeks) of oral CBD on tear production, intraocular pressure (IOP), and CBD levels in tears in healthy beagles. The study found that oral CBD (5 or 10 mg/kg/day) did not significantly affect tear production or IOP. The mean values for Schirmer tear test-1 (STT-1) and IOP were consistent with previously reported values for healthy dogs, showing no significant difference between morning and evening measurements. 

The study noted a diurnal variation in IOP, with higher values in the morning, aligning with existing literature. Unlike previous studies in mice and humans where CBD increased IOP, this study found no effect on IOP in non-glaucomatous dogs. The difference may be due to the prolonged study duration compared to the shorter time frames in other studies. Additionally, CBD levels were measured in tears after 36 weeks, showing fluctuation without significant differences between treatment groups. 

This study is the first to report CBD concentrations in canine tears following long-term oral administration. Although the study did not find significant differences in ocular parameters between CBD and placebo groups, it observed a significant week effect on PM STT-1, AM IOP, and PM IOP, suggesting potential seasonal influences. However, the controlled environment for the dogs makes this finding intriguing. Seasonal variations in IOP have been reported in other studies, but there is limited data on seasonal effects on tear production in dogs. 

Limitations of the study include a small sample size (six dogs) and a homogenous population of healthy beagles, making it unclear if results would differ in dogs with systemic or ocular conditions. In conclusion, chronic oral CBD administration did not significantly impact IOP or STT-1 in healthy dogs, providing new information to guide future pharmacokinetic studies on long-term CBD use in tear fluid. 

Jost HE, Spitznagel K, Alvarenga IC, et al. Long-term effect of oral cannabidiol administration to healthy adult dogs on tear production, intraocular pressure, and tear concentrations. Vet Ophthalmol. 2024; 27: 357-366. doi:10.1111/vop.13164 

Bottom line — Did not appear to be beneficial in this study

Insulin Pump to Deliver Ketamine in Dogs

The Omnipod® system, a human SC insulin delivery device, offers a promising alternative for hands-free SC drug infusion in veterinary patients. This study investigated the pharmacokinetics of SC ketamine infusion using the Omnipod® system in dogs post-spinal surgery. The Omnipod® system was well-tolerated and effectively delivered ketamine, with peak plasma concentrations showing high variability due to differences in breed, age, size, and BMI. Previous human studies suggest ketamine reduces opioid consumption and central sensitization, while veterinary studies indicate it decreases pain scores and hospitalization times. 

The study found that SC ketamine achieved plasma concentrations over 100 ng/mL, though for less than an hour, likely due to high drug clearance. Limitations included a small sample size, restricted to dogs under 40 kg, and limited blood sampling, which affected the accuracy of the elimination half-life estimation. No adverse reactions were observed, though potential risks like Omnipod® dislodgement and possible hallucinogenic effects in dogs were noted. 

The Omnipod® system proved adaptable for low-dose ketamine use post-surgery in dogs, delivering therapeutic plasma concentrations briefly. Further research is needed to determine effective ketamine concentrations for acute pain in dogs, assess its full elimination phase and bioavailability, and explore its impact on pain scores and the need for rescue analgesia in perioperative settings. 

Colón, C., Early, P., Muñana, K., Olby, N., Mariani, C., Mancini, S., Fefer, G., Li, Z., Briley, J., Bailey, K., Lascelles, D., & Messenger, K. (2024). Pharmacokinetics of subcutaneous ketamine administration via the Omnipod® system in dogs. Journal of Veterinary Pharmacology and Therapeutics, 47, 353–358. https://doi.org/10.1111/jvp.13440 

Bottom line — Potentially useful protocol for dogs in the future when the price for the technology is more affordable.

Just putting things in perspective …