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Pharmacogenetics for pain

20 May 2019, at 9:30am

Does pharmacogenetics play a role in the management of pain in companion animal species?

Pharmacogenetics is the study of genetics as it relates to individual variation in the response to drugs. Alterations in the genes coding for drug receptors, drug transporters and drug metabolising enzymes may cause clinical manifestations such as: altered drug efficacy; duration of action; or drug-drug interactions.

Although pharmacogenetics and personalised medicine are well established in clinical human medicine, they remain an area of emerging interest and ongoing research in veterinary science. Currently there are few studies describing how genetic polymorphisms may affect the efficacy of analgesic drugs used in companion animal species; or conversely, the occurrence of adverse drug reactions. This article aims to review some of the recent literature describing pharmacogenetic differences in dogs and cats.

Drug metabolising enzymes

Cytochrome P450 isoenzymes (CYPs) are a superfamily of hepatic enzymes. They are involved in the metabolism of a wide range of endogenous (eg steroids and fatty acids) and xenobiotic compounds. CYP enzymes are divided into families identified by numbers: CYP1, 2 and 3 and subfamilies designated by capital letters (eg CYP2B). Individual members of a subfamily (ie represented by a single gene) are identified by a further number (CYP2B11). CYP enzymes are responsible for the metabolism of many anaesthetic and analgesic drugs.

CYP2B11 (human equivalent CYP2B6)

In dogs, the CYP2B11 enzyme metabolises several sedative and anaesthetic drugs in vitro, ie: medetomidine, midazolam, ketamine, propofol and atipamezole. Whilst midazolam and ketamine are substrates for this enzyme, medetomidine and atipamezole are inhibitors. Although breed-related differences in CYP enzyme expression have been described, detailed information about the activity of the enzymes is lacking. Previously, CYP2B11 was identified as the enzyme responsible for the metabolism of propofol in Greyhounds; genetic polymorphisms have not been reported in this breed but pharmacokinetic differences exist.

A preliminary study describing polymorphisms in the canine CYP2B11 gene identified breed-specific abnormalities in: Collies, Labrador Retrievers and German Shepherd Dogs. In an unrelated study, the Border Collie, Labrador Re-triever and German Shepherd were found to exhibit genetic polymorphisms within the CYP1A2 and CYP2B11 genes. The authors assert that alterations in drug sensitivity may result from these genetic changes.

In dogs, methadone is reported to be a CYP substrate and may be metabolised primarily by CYP2B11, which contrasts with humans. It remains unclear whether genetic polymorphisms in this enzyme affect the efficacy of methadone in dogs.

FIGURE (1) Individual plasma concentrations of cimicoxib (ng/mL) vs time (h) after a single intravenous administration of cimicoxib (2mg/kg) in 12 Beagle dogs (Jeunesse et al., 2013). Two subgroups of dogs are shown: “poor metabolisers” (red dotted line) and “extensive metabolisers” (blue continuous line)
FIGURE (1) Individual plasma concentrations of cimicoxib (ng/mL) vs time (h) after a single intravenous administration of cimicoxib (2mg/kg) in 12 Beagle dogs (Jeunesse et al., 2013). Two subgroups of dogs are shown: “poor metabolisers” (red dotted line) and “extensive metabolisers” (blue continuous line)

CYP2D15 (human equivalent CYP2D6)

In dogs, tramadol has little reported analgesic efficacy. This is thought to result from its metabolism and rapid conjugation and elimination in the urine. In humans, CYP2D6 is responsible for the metabolism of tramadol to the active metabolite M1, which is attributed with the major analgesic effect of the drug. Thus far no studies have determined whether genetic polymorphisms could affect the efficacy of tramadol in the dog.

A study performed in Beagle dogs identified differences in the duration of action of the non-steroidal anti-inflammatory drug cimicoxib (Figure 1). Dogs were designated arbitrarily as: extensive metabolisers (EM) and poor metabolisers (PM) on the basis that differences in pharmacodynamic effects were attributable to alterations in CYP2D15 enzyme activity.

This terminology was based on an in vitro study in which CYP2D15 was purported to metabolise celecoxib. Dogs with the PM phenotype showed a significantly longer duration of effect compared with the EM group.

Opioid receptor studies

Opioid analgesics form the mainstay of acute pain management in dogs and cats. Genetic polymorphisms within the mu-opioid receptor coding have been described in the dog and cat. Alterations in the canine receptor suggest a greater likelihood of opioid-related dysphoria in the Labrador Retriever, Alaskan Malamute and Siberian Husky.

In a feline study, two groups of cats (groups A and B) were genetically distinct from one another. When pharmacodynamic data were assessed, differences existed in the efficacy of fentanyl and butorphanol, with group A cats showing a greater responsiveness to fentanyl while group B had a longer time to maximal effect. Conversely, group A cats showed a lower peak analgesic effect and more variability in response to butorphanol when compared with group B. This work suggests that genetic polymorphisms may alter analgesic drug efficacy in individual cats, although more work is required to determine the significance of these findings in the feline population of the UK.

Drug transporter proteins

P-glycoprotein (P-gp) is an efflux transporter, which functions to exclude xenobiotic substances from the brain among other tissues. A deletion mutation in the gene coding for P-gp exists in several dog breeds, most commonly the Rough Collie, but also in several other herding dog breeds (see Neff et al., 2004).

A study comparing the magnitude and duration of sedation following acepromazine administration described a greater area-under-the-curve in homozygous negative animals when compared with heterozygotes and homozygous positive dogs. Although acepromazine has no analgesic properties, it is often used in combination with opioid analgesic drugs. Caution may be warranted in dogs with this mutation when known P-gp substrates are used clinically.

Feline P-glycoprotein genetic polymorphisms have been reported. Affected cats may behave in a similar manner to dogs which carry the P-glycoprotein mutation.

There is limited evidence available for the role of pharmacogenetics in the pain management of dogs and cats. Further studies would allow a more informed approach to the management of acute and chronic pain in these species. Notwithstanding the need for further work in this field, clinicians should consider genetic polymorphisms if lack of efficacy is suspected when analgesic drugs are used.

References
Author Year Title
Jeunesse, E. C., Schneider, M., Woehrle, F., Faucher, M., Lefebvre, H. P. and Toutain, P. L 2013 Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog. BMC Veterinary Research, 9, 250.
Neff, M. W., Robertson, K. R., Wong, A. K., Safra, N., Broman, K. W., Slatkin, M., Mealey, K. L. and Pedersen, N. C. 2004 Breed distribution and history of canine mdr-1 Delta, a pharmacogenetics mutation that marks the emergence of breeds from the collie lineage. Proceedings of the National Academy of Science of the United States of America,

Rachel Bennett, MA VetMB, CertVA, DACVAA, PhD, is a Diplomate of the American College of Veterinary Anaesthesia and Analgesia and completed a PhD in the clinical pharmacology of the peripheral α2-adrenoceptor antagonist vatinoxan in 2017. She works as a freelance anaesthetist and is co-editor-in-chief of Veterinary Anaesthesia and Analgesia

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