“Pain management is central to veterinary practice, not adjunctive.”

~ AAHA/AAFP Pain Management Guidelines for Dogs and Cats (2015)¹

Pain management, an everyday concern for most veterinarians, can be a challenging therapeutic area to treat considering the different origins and areas of pain. Several commercially manufactured products are labelled for the treatment of pain among veterinary patients. In some patients, these products will be an appropriate therapeutic choice. In others, particularly species the products are not originally labelled for, these products may not be the best choice. Perhaps the dosage required is not obtainable from the concentration of the product. Excipients in commercially available veterinary drug products are not required to be disclosed, therefore making it difficult to determine if the product is appropriate for use in species that are not included in the labelling. The dosage form also may not be acceptable for the target species. In these cases, the veterinarian will have to think outside of the box to administer individualized medical therapy. Such scenarios are where a compounding pharmacist, who combines compounding processes and appropriate veterinary compounding education, can be an asset to
the veterinarian.

Why compound?

Canadian compounding pharmacists can provide many innovations that help in the administration of medications to challenging veterinary patients. For instance, non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat arthritis in animals. There are several commercial product choices labelled for use in canines, some for felines and equine patients, but none for other species.

An example of this is meloxicam, which is the NSAID of choice for most bird species.² The commercially available veterinary meloxicam drug product is an oral suspension marketed and approved for use in canine patients. In the case of birds, or other species, veterinarians must determine if the commercial product is appropriate for their patient or find another option.

Compounders have access to pure quality active pharmaceutical ingredients (APIs) in powder form that make alternate dosage forms an option. Some dosage forms include solutions or suspensions of alternate strength or flavouring, chewable treats of various sizes and permeation-enhanced gel preparations…the options are endless! In the case of birds, higher concentrations of solutions or suspensions may be desirable to decrease administration volumes.

Gabapentin

In chronic degenerative diseases, such as arthritis or cancer, patients that present preexisting or unmanaged pain may require additional therapy. Many patients stop responding to common analgesic drugs due to spinal cord wind-up. The central nervous system adapts negatively to constant pain impulses after prolonged stimulation of nociceptors. This can cause a profound effect on the nervous system’s construction, thereby changing the way pain is processed. When spinal neurons are subjected to repeat or high-intensity nociceptive impulses, they progressively become more sensitive even after the stimulus is removed. For example, when a patient with degenerative disk disease cries out in pain when touched on other parts of their body, not just the original site of pain.³ This condition is known as wind-up phenomenon or central sensitization and leads to non-responsive or chronic intractable pain.

Wind-up is the combination of two phases of change in the nervous system. In the first phase, pain-transmitting nerve fibre threshold is reset. This resetting results in hyperalgesia. Secondly, nerve fibres that normally do not carry pain information are recruited and become part of the pain-transmission process. This is known as allodynia. Allodynia results in normally non-painful sensations being interpreted as painful sensations.

Gabapentin can be helpful as an adjunctive agent that prevents or manages pain in such patients. Gabapentin is an analog of gamma-aminobutyric acid (GABA) that has GABA agonist activity. It has anticonvulsant action as well as analgesic effects in dogs and cats, and can help prevent hyperalgesia and allodynia.⁴ Gabapentin has shown benefit in neuropathic pain in horses as well.⁵

Commercially available gabapentin liquid products may contain xylitol as a sweetening agent. As xylitol is a known toxin to dogs, the compounding veterinary pharmacist can formulate a xylitol-free product. In patient cases where the oral route of administration is not an option due to handling considerations, gabapentin may be formulated in a permeation-enhanced base.

Permeation-enhanced  products are normally applied to the pinna, so there are constraints with the amount of volume that can be administered. The normal volume for pinna application for most canine and feline patients is 0.1 mL to 0.25 mL. Gabapentin also has concentration limits due to the drug’s solubility limits.

The highest concentration that gabapentin can be formulated at is 100 mg/mL or 10 mg/0.1mL. Going above this concentration may cause the drug to crystallize. This crystallization will adversely affect the action of the product. Chewable treats are another option that can be considered as well. This is chemistry that the compounding pharmacist will be aware of.

Amantadine

Thought to be helpful with allodynia, amantadine is also beneficial for neuropathic pain and the prevention of pain wind-up. Amantadine is used as a N-methyl-D-aspartate (NMDA) antagonist in the adjunctive treatment of neuropathic and chronic pain for small animal species, often in patients who no longer get relief from NSAIDs or opioids that are intolerant to higher dosages.⁴ It is normally not effective when used alone and more commonly used in conjunction with NSAIDs, opioids and gabapentin or pregabalin.⁴

For patients that require amantadine in a liquid dosage form, there is the option of a commercial drug product formulated for human patients. As overdoses of this drug are potentially very serious for smaller species,⁴ it is prudent to compound it to a more appropriate strength for improved dosing accuracy. Most species do not like the bitter taste of the commercial amantadine product.⁴ The compounder can mask bitterness with a natural sweetener, flavours can also be customized to the palette of the patient on the recommendation of the owner.

As with gabapentin, other dosage forms may be formulated to fit the needs of the species being treated. Given it is a narrow therapeutic index drug and toxicities are a possibility,⁴ caution should be used when considering the permeation-enhancing route of administration. This author did not find any published studies looking at the pharmacokinetics of amantadine when administered by the transdermal route in animals as of the writing of this article.

Tramadol

Tramadol is widely used in veterinary medicine as an analgesic for postoperative or chronic pain. It is a centrally acting opioid agonist with primarily mu-receptor activity that can also inhibit reuptake of serotonin and norepinephrine.⁴ All these actions contribute to tramadol’s analgesic properties. Tramadol is most useful when combined with NSAIDs or other analgesic drugs such as amantadine or gabapentin.⁴ Tramadol’s analgesic efficacy is most robust in cats.⁶ It has shown limited efficacy in chronic pain for horses and has poor
oral bioavailability.^7,4

Currently, there are no commercially available veterinary tramadol products. However, there are several products for humans. These include immediate and extended-release tablets which may or may not be appropriate for the patient. It is not advised to administer the extended-release products to dogs because they are not absorbed well. There is a potential for overdosage if the tablets are chewed or crushed.

Tramadol is also very bitter, which affects compliance for dogs as well as cats. A compound that masks bitterness, such as an oral suspension, or a compound that offers an alternate route of administration such as a permeation-enhanced gel may be a better option. Tramadol HCL 50 mg/mL Oil Oral Suspension (Vet) is an example of a formula that can have bitter masking agents and flavouring appropriate for dogs as well as cats.

Tramadol can also be combined with other agents, such as gabapentin, into a single formula to decrease the number of administered medications and increase efficacy.⁴ Gabapentin 5 mg/0.1/Tramadol HCL 10 mg/0.1mL Topical (Permeation-Enhanced Vehicle) is an example of a combination API formula. There have been several reports of better outcomes when tramadol is administered in a formula that uses a permeation-enhanced transdermal base. These reports are anecdotal.

Choosing a compounding pharmacy

It is important to “vet” a local compounding pharmacy by:

• Determining whether they use quality chemicals, bases, follow current NAPRA regulatory guidelines, perform regular testing, and continually educate staff.
• Ask where they purchase their chemicals and bases, then check the supplier to make sure they are following Canadian regulatory requirements and are regularly inspected.
• The pharmacy staff should include a pharmacist that is educated in veterinary compounding
  as well.
• The pharmacy should also have reliable formulation resources to ensure that appropriate processes and chemistry are applied in the compounding process and meet quality standards.

Compounding provides valuable options to the veterinarian in the management of pain for multiple species. From individualized dosage form options to unique API combinations that improve compliance and help improve therapeutic outcomes, a quality compounding pharmacy optimizes every veterinarian’s treatment arsenal.

Deborah Clark, RPh, FACVP, is a clinical compounding pharmacist and a member of the PCCA’s clinical services team. Clark’s passion and area of expertise is veterinary compounding; however, she also helps pharmacists in other areas of specialty, such as bioidentical hormone replacement, pain and wound care, pediatrics, and dermatology. Clark regularly speaks on these topics at PCCA symposiums and other outside conferences. She is a graduate of the University of North Carolina (UNC) Eshelman School of Pharmacy and licensed to practice in North Carolina. She is a Fellow of the American College of Veterinary Pharmacists (ACVP). She lives outside of Charlotte, N.C. with her family and Westie, Cody. In her spare time, Clark enjoys riding the equestrian discipline of dressage, hiking and golfing.

References

¹ Epstein, Mark E et al. “2015 AAHA/AAFP pain management guidelines for dogs and cats.” Journal of feline medicine and surgery vol. 17,3 (2015): 251-72. doi:10.1177/1098612X15572062.

² Guzman, D.S.-M. and Beaufrère, H. (2021). Avian Pain Management and Anesthesia. In Exotic Animal Emergency and Critical Care Medicine (eds J.E. Graham, G.A. Doss and H. Beaufrère). https://doi.org/10.1002/9781119149262.ch28

³ Shaffran, N. “Managing Difficult Pain Cases: Neuropathic Pain & Wind-Up Phenomenon” World Small Animal Veterinary Association World Congress Proceedings, 2013 https://www.vin.com/apputil/content/defaultadv1.aspx?pId=11372&catId=35310&id=5709881 (accessed 10-9-23)

⁴ Plumb’s Veterinary Drugs. www.plumbs.com

⁵ Landis-Hanna, A. “WVC 2017: Pain Control for the Aging Horse.” August 28, 2017. https://www.americanveterinarian.com/journals/amvet/2017/august2017/pain-control-for-the-aging-horse#:~:text=This%20type%20of%20pain%20may,day%20withholding%20period%20for%20gabapentin. (10-9-23 access)

⁶ Guedes AGP, Meadows JM, Pypendop BH, Johnson EG. Evaluation of tramadol for treatment of osteoarthritis in geriatric cats. J Am Vet Med Assoc. 2018;252(5):565-571.

⁷ Mama, Khursheed and Hector, Rachel. “Therapeutic developments in equine pain management.” The Veterinary Journal 247 (2019) 50–56.