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BMC veterinary research2022; 18(1); 196; doi: 10.1186/s12917-022-03299-0

Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses.

Abstract: In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency. Results: Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied. Conclusions: The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.
© 2022. The Author(s).
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Publication Date: 2022-05-25 PubMed ID: 35614473PubMed Central: PMC9131543DOI: 10.1186/s12917-022-03299-0Google Scholar: Lookup
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  • Journal Article
  • Randomized Controlled Trial
  • Veterinary

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates the effects of various doses of codeine, a commonly used painkiller, on horses. The study aimed to prove that administering codeine could provide effective pain relief with fewer side effects compared to morphine.

Methodology

  • Seven horses were given different treatments: saline, three doses of codeine (0.3, 0.6, and 1.2 mg/kg), and morphine (0.2 mg/kg) for comparison. This process was carried out in a randomized and balanced design, which ensured each horse was subjected to different conditions in a certain order.
  • After the drug administration, blood samples were taken until 72 hours post administration. The samples were used to determine the amounts of codeine, its derivatives, and morphine metabolites in the blood, using a technique called liquid chromatography-mass spectrometry.
  • Several indicators of the horses’ conditions were recorded, such as their behavior, movement activity, heart rate, and gastrointestinal sounds. The researchers also tested for the horses’ sensitivity to pain by measuring thermal threshold latency.

Results

  • The morphine concentrations in the blood were highest in the group that received the morphine dose. Nevertheless, the concentrations of a morphine-like metabolite (M6G) were significantly higher in all codeine groups than in the morphine group, starting one hour after drug administration and up to 72 hours in the group that received the highest dose of codeine (1.2 mg/kg).
  • The administration of codeine was well-tolerated, with only one horse showing signs of colic after receiving the lower doses of codeine (0.3 and 0.6 mg/kg). On the other hand, administration of morphine led to agitation, tremors, and excitement in horses.
  • It was also found that there was no significant effect on thermal nociception (the horses’ response to potentially harmful heat stimuli) in any of the dose groups studied.

Conclusions

  • The results provide useful insights into the metabolic profile and pharmacokinetics of codeine in horses. The findings could be instrumental in designing future studies on the pain-relieving effects of opioids in horses, with the ultimate goal of promoting the judicious and safe use of this essential drug class.
  • Despite the promising findings, the lack of significant effect on thermal nociception across all dose groups suggests that more extensive studies are necessary to fully understand the analgesic capabilities of codeine in the equine species.

Cite This Article

APA
Knych HK, Stucker K, Gretler SR, Kass PH, McKemie DS. (2022). Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses. BMC Vet Res, 18(1), 196. https://doi.org/10.1186/s12917-022-03299-0

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 18
Issue: 1
Pages: 196

Researcher Affiliations

Knych, Heather K
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA. hkknych@ucdavis.edu.
  • Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA. hkknych@ucdavis.edu.
Stucker, Kristen
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA.
Gretler, Sophie R
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA.
Kass, Philip H
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.
McKemie, Daniel S
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA.

MeSH Terms

  • Analgesics, Opioid
  • Animals
  • Codeine / adverse effects
  • Codeine / pharmacokinetics
  • Glucuronides / adverse effects
  • Glucuronides / pharmacokinetics
  • Horses
  • Morphine
  • Morphine Derivatives / adverse effects
  • Morphine Derivatives / pharmacokinetics
  • Nociception

Conflict of Interest Statement

Philip Kass is a member of the BMC Veterinary Research Editorial Board (Associate Editor). No other authors have any competing interests or declarations.

References

This article includes 41 references
  1. S N, Van Hout M. Over-the-Counter-from Therapeutic Use to Dependence, and the Grey Areas in between. Current Topics in Behavrioal Neurosciences Cham: Springer; 2015.
    pubmed: 26768736
  2. Oguri K, Hanioka N, Yoshimura H. Species differences in metabolism of codeine: urinary excretion of codeine glucuronide, morphine-3-glucuronide and morphine-6-glucuronide in mice, rats, guinea pigs and rabbits. Xenobiotica 1990;20(7):683–688.
    doi: 10.3109/00498259009046884pubmed: 2238703google scholar: lookup
  3. Dean L. Codeine Therapy and CYP2D6 Genotype. Medical Genetics Summaries Bethesda (MD): National Center for Biotechnology Information (US); 2012.
    pubmed: 28520350
  4. Barnett M. Alternative opioids to morphine in palliative care: a review of current practice and evidence. Postgrad Med J 2001;77(908):371–378.
    doi: 10.1136/pmj.77.908.371pmc: PMC1742058pubmed: 11375449google scholar: lookup
  5. Osborne R, Joel S, Trew D, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990;47(1):12–19.
    doi: 10.1038/clpt.1990.2pubmed: 2295214google scholar: lookup
  6. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992;34(2):130–138.
    doi: 10.1111/j.1365-2125.1992.tb04121.xpmc: PMC1381529pubmed: 1419474google scholar: lookup
  7. Hanna MH, Peat SJ, Knibb AA, Fung C. Disposition of morphine-6-glucuronide and morphine in healthy volunteers. Br J Anaesth 1991;66(1):103–107.
    doi: 10.1093/bja/66.1.103pubmed: 1997044google scholar: lookup
  8. Stain F, Barjavel MJ, Sandouk P, Plotkine M, Scherrmann JM, Bhargava HN. Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat. J Pharmacol Exp Ther 1995;274(2):852–857.
    pubmed: 7636748
  9. Vree TB, van Dongen RT, Koopman-Kimenai PM. Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Pract 2000;54(6):395–398.
    pubmed: 11092114
  10. Lötsch J, Skarke C, Schmidt H. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin Pharmacol Ther 2006;79(1):35–48.
    doi: 10.1016/j.clpt.2005.09.005pubmed: 16413240google scholar: lookup
  11. Srinivasan V, Wielbo D, Tebbett IR. Analgesic effects of codeine-6-glucuronide after intravenous administration. Eur J Pain Lond Engl 1997;1(3):185–190.
    doi: 10.1016/s1090-3801(97)90103-8pubmed: 15102399google scholar: lookup
  12. Stevenson AJ, Weber MP, Todi F. The influence of furosemide on plasma elimination and urinary excretion of drugs in standardbred horses. J Vet Pharmacol Ther 1990;13(1):93–104.
    doi: 10.1111/j.1365-2885.1990.tb00753.xpubmed: 2319641google scholar: lookup
  13. Westermann CM, Laan TT, van Nieuwstadt RA, Bull S, Fink-Gremmels J. Effects of antitussive agents administered before bronchoalveolar lavage in horses. Am J Vet Res 2005;66(8):1420–1424.
    doi: 10.2460/ajvr.2005.66.1420pubmed: 16173487google scholar: lookup
  14. Gretler SR, Finno CJ, McKemie DS, Kass PH, Knych HK. Metabolism, pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses. Vet Anaesth Analg 2020;47(5):694–704.
    doi: 10.1016/j.vaa.2020.04.004pmc: PMC7872472pubmed: 32654915google scholar: lookup
  15. Dönselmann P, Hopster K, Kästner S. Einfluss von Morphin, Butorphanol und Levomethadon in unterschiedlicher Dosierung auf den thermischen nozizeptiven Schwellenwert bei Pferden. Tierärztl Prax Ausg G Großtiere Nutztiere 2017;45(02):98–106.
    doi: 10.15653/TPG-160655pubmed: 28075433google scholar: lookup
  16. Knych HK, Steffey EP, McKemie DS. Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses. J Vet Pharmacol Ther 2014;37(4):374–381.
    doi: 10.1111/jvp.12098pubmed: 24479785google scholar: lookup
  17. Hamamoto-Hardman BD, Steffey EP, Weiner D, McKemie DS, Kass P, Knych HK. Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses. J Vet Pharmacol Ther 2019;42(4):401–410.
    doi: 10.1111/jvp.12759pubmed: 30919469google scholar: lookup
  18. Devine EP, KuKanich B, Beard WL. Pharmacokinetics of intramuscularly administered morphine in horses. J Am Vet Med Assoc 2013;243(1):105–112.
    doi: 10.2460/javma.243.1.105pubmed: 23786198google scholar: lookup
  19. Hamamoto-Hardman BD, Steffey EP, Weiner D, McKemie DS, Kass P, Knych HK. Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses. J Vet Pharmacol Ther 2019;42(4):401–410.
    doi: 10.1111/jvp.12759pubmed: 30919469google scholar: lookup
  20. Figueiredo JP, Muir WW, Sams R. Cardiorespiratory, gastrointestinal, and analgesic effects of morphine sulfate in conscious healthy horses. Am J Vet Res 2012;73(6):799–808.
    doi: 10.2460/ajvr.73.6.799pubmed: 22620693google scholar: lookup
  21. Lin JH. Dose-dependent pharmacokinetics: experimental observations and theoretical considerations. Biopharm Drug Dispos 1994;15(1):1–31.
    doi: 10.1002/bdd.2510150102pubmed: 8161713google scholar: lookup
  22. Brunk SF, Delle M. Morphine metabolism in man. Clin Pharmacol Ther 1974;16(1):51–57.
    doi: 10.1002/cpt1974161part151pubmed: 4843237google scholar: lookup
  23. KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy greyhound dogs. J Vet Pharmacol Ther 2010;33(1):15–21.
    doi: 10.1111/j.1365-2885.2009.01098.xpmc: PMC2867071pubmed: 20444020google scholar: lookup
  24. Shah J, Mason WD. Pharmacokinetics of codeine after parenteral and oral dosing in the rat. Drug Metab Dispos 1990;18(5):670–673.
    pubmed: 1981718
  25. Knych HK, Baden RW, Gretler SR, McKemie DS. Characterization of the in vitro CYP450 mediated metabolism of the polymorphic CYP2D6 probe drug codeine in horses. Biochem Pharmacol 2019;168:184–192.
    doi: 10.1016/j.bcp.2019.07.005pubmed: 31295464google scholar: lookup
  26. Gretler SR, Finno CJ, Kass PH, Knych HK. Functional phenotyping of the CYP2D6 probe drug codeine in the horse. BMC Vet Res 2021;17(1):77.
    doi: 10.1186/s12917-021-02788-ypmc: PMC7881596pubmed: 33581736google scholar: lookup
  27. Poulsen L, Brøsen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996;51(3–4):289–295.
    doi: 10.1007/s002280050200pubmed: 9010701google scholar: lookup
  28. De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, Regazzi M. Morphine metabolism, transport and brain disposition. Metab Brain Dis 2012;27(1):1–5.
    doi: 10.1007/s11011-011-9274-6pmc: PMC3276770pubmed: 22193538google scholar: lookup
  29. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27(7):524–528.
    doi: 10.1046/j.1440-1681.2000.03290.xpubmed: 10874511google scholar: lookup
  30. Im Sande PD, Hopster K, Kästner S. Einfluss von Morphin, Butorphanol und Levomethadon in unterschiedlicher Dosierung auf den thermischen nozizeptiven Schwellenwert bei Pferden. Tierärztl Prax Ausg G Großtiere Nutztiere 2017;45(02):98–106.
    doi: 10.15653/TPG-160655pubmed: 28075433google scholar: lookup
  31. Sanchez LC, Robertson SA. Pain control in horses: what do we really know?. Equine Vet J 2014;46(4):517–523.
    doi: 10.1111/evj.12265pubmed: 24645799google scholar: lookup
  32. Wu D, Kang Y, Bickel U, Pardridge W. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab Dispos 1997;25(6):768–771.
    pubmed: 9193881
  33. Bickel U, Schumacher O, Kang Y, Voigt K. Poor permeability of morphine 3-glucuronide and morphine 6-glucuronide through the blood-brain barrier in the rat. J Exp Ther 1996;278(1):107–113.
    pubmed: 8764341
  34. Hanks GW, Hoskin PJ, Aherne GW, Turner P, Poulain P. Explanation for potency of repeated oral doses of morphine?. Lancet Lond Engl 1987;2(8561):723–725.
    doi: 10.1016/s0140-6736(87)91083-xpubmed: 2888950google scholar: lookup
  35. Lötsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology 1999;90(4):1026–1038.
    doi: 10.1097/00000542-199904000-00016pubmed: 10201674google scholar: lookup
  36. Söbbeler FJ, Kästner SB. Effects of transdermal lidocaine or lidocaine with prilocaine or tetracaine on mechanical superficial sensation and nociceptive thermal thresholds in horses. Vet Anaesth Analg 2018;45(2):227–233.
    doi: 10.1016/j.vaa.2017.10.003pubmed: 29415859google scholar: lookup
  37. Hamamoto-Hardman BD, Steffey EP, McKemie DS, Kass PH, Knych HK. Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses. BMC Vet Res 2020;16(1):368.
    doi: 10.1186/s12917-020-02564-4pmc: PMC7528573pubmed: 32998730google scholar: lookup
  38. McGowan KT, Elfenbein JR, Robertson SA, Sanchez LC. Effect of butorphanol on thermal nociceptive threshold in healthy pony foals. Equine Vet J 2013;45(4):503–506.
    doi: 10.1111/j.2042-3306.2012.00673.xpubmed: 23126609google scholar: lookup
  39. Elfenbein JR, Robertson SA, MacKay RJ, KuKanich B, Sanchez L. Systemic and anti-nociceptive effects of prolonged lidocaine, ketamine, and butorphanol infusions alone and in combination in healthy horses. BMC Vet Res 2014;10(Suppl 1):S6.
    doi: 10.1186/1746-6148-10-S1-S6pmc: PMC4123056pubmed: 25238633google scholar: lookup
  40. Poller C, Hopster K, Rohn K, Kästner SB. Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses - comparison of different locations and environmental conditions. BMC Vet Res 2013;9(1):4.
    doi: 10.1186/1746-6148-9-4pmc: PMC3551666pubmed: 23298405google scholar: lookup
  41. Poller C, Hopster K, Rohn K, Kästner SBR. Nociceptive thermal threshold testing in horses - effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites. BMC Vet Res 2013;9:135.
    doi: 10.1186/1746-6148-9-135pmc: PMC3708779pubmed: 23837730google scholar: lookup

Citations

This article has been cited 2 times.
  1. Blum S, Gisler J, Dalla Costa E, Montavon S, Spadavecchia C. Investigating conditioned pain modulation in horses: can the lip-twitch be used as a conditioning stimulus?. Front Pain Res (Lausanne) 2024;5:1463688.
    doi: 10.3389/fpain.2024.1463688pubmed: 39512387google scholar: lookup
  2. Scantamburlo G, Nofziger C, Paulmichl M, Vanoni S. Genetic analysis of the equine orthologues for human CYP2D6: unraveling the complexity of the CYP2D family in horses. Front Vet Sci 2023;10:1188633.
    doi: 10.3389/fvets.2023.1188633pubmed: 37929279google scholar: lookup
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