Top image by Anne Reynolds, Port Macquarie

The aim of this study was to describe the pharmacokinetic profile of tramadol (and that of its active metabolite) in the koala when injected by a single subcutaneous injection, and to predict its likely efficacy to result in analgesia.

Summary of findings

  • It is probable that a 4 mg/kg subcutaneous injection is likely to provide analgesic relief for up to 24 hours in the koala
  • There is a sex difference in koalas in how quickly they eliminate tramadol. Male koalas eliminate tramadol and its metabolites, faster than females.

Important information about tramadol

Tramadol is an analgesic used in veterinary medicine to control moderate to moderately severe, pain (Pypendop & Ilkiw, 2008). Its mechanism of action is by interacting with the body’s opioid, adrenergic and serotonin receptors (Raffa, Friderichs et al., 1992; Desmeules, Piguet et al., 1996). A significant portion of tramadol’s analgesic effect is reported to be due to its main metabolite O-desmethyltramadol (O-DSMT, also referred to as ‘metabolite 1’ [M1]) which has a 300-fold greater affinity for mu (m) opioid receptors than its parent compound (Hennies, Friderichs et al., 1988; Gillen, Haurand et al., 2000). However the number of metabolites varies depending on species.

Koalas

Six, mature, clinically normal koalas (3 male, 3 female) with body weights from 5.4 to 9.0 (median: 7.8) kg, were recruited from the Taronga Zoo population (Mosman, NSW). Data from two additional male koalas come from those cared for, by the ‘Friends of the Koala’, (Lismore, NSW). The Taronga koalas were considered clinically normal based on regular physical examinations, haematology and biochemical analyte values. Koalas were housed in enclosures, either singly or in a group, and supplied with food (various Eucalyptus spp. foliage) and water ad-libitum. The study was approved by The University of Sydney Animal Ethics committee protocol 2015/877 and Taronga Conservation Society of Australia, Animal Ethics Committee protocol 3a/10/18.

Koalas Baxter (Male) and Sydney (Female) (Taronga zoo) were administered 2 mg/kg sc; Triumph (M) from Friends of the Koala was also administered 2 mg/kg.  Dules (M) treated by Dr Ray Austin was also administered tramadol at 4 mg/kg sc.

Koalas: Banks (Male), Pirra (M), Sydney (F) and Willow (F) from Taronga zoo were administered 4 mg/kg as a subcutaneous injection.  We could not detect any tramadol or its metabolites in Pirra’s blood. It is our intention to request Taronga Conservation Animal Ethics committee if we can redose Pirra and collect his blood samples in the 2020 new year.

Results

The chromatograms between male and female koalas are slightly different and the sex can be identified by looking at the chromatogram. The peak for O-desmethyltramadol (O-DSMT) seen at 3.00 mins, has a different appearance to that seen in the male vs female in the chromatograms in Figure 1.  In males, O-DSMT is associated with a double peak and females have a single peak (see left arrow and in the circle).

Figure 1: Chromatogram detecting tramadol and O-desmethyltramadol (O-DSMT) in the plasma of one female and one male koala dosed with tramadol at 2 mg/ kg sc.

Tramadol graph fpr blog17012020

Outcomes of the study

On the basis of the relatively long in-vivo half-life of O-DSMT in the koala (16.01 ± 13.073 h) and the fact that in people the minimally effective analgesic plasma concentrations of M1 has a median range of 36.2 hg/mL (Lehmann, Kratzenberg et al., 1990), it is estimated that  an injection of 2 mg/kg dose does not meet the effective human analgesic plasma concentration but does, when administered at 4 mg/kg s.c. (0-DSMT Cmax = 135.82 ± 12.73 ng/mL). Furthermore, although tramadol has a reasonably short half-life of 2.87 ± 1.00 h, the active M1 metabolite has a relatively long in-vivo half-life of 11.62 ± 5.43 h, and theoretically, a dosing frequency of dosing of > 24 h may be adequate to provide analgesia. The M1 : tramadol AUC ratio is another marker of likely analgesic efficacy  e.g. this ratio is 1 – 1.2 in the cat (Pypendop & Ilkiw, 2008), 0.35 in humans (Grond & Sablotzki, 2004) and 0.003 in the dog (KuKanich & Papich, 2004). This ratio at 2 mg/kg sc injection in the koala is 0.32 which is similar to that of humans however at 4 mg/kg the ratio is 0.79. However there is a caveat; that is, the effective analgesia plasma concentration has been taken from that for people to compare with the plasma concentrations in the koala. This study did not investigate whether the 2 mg/kg or 4 mg/kg had an analgesic effect in the koala. Studies supporting that tramadol has some analgesic activity in non-human species are limited, and are generally equivocal (Vettorato, Zonca et al., 2010; KuKanich & Papich, 2011; Buhari, Hashim et al., 2012) and it is possible that the tramadol / M1 effective plasma concentrations may differ across species.

Research into the best medicines for koalas and other Australian wildlife species

I am a veterinary researcher at The University of Sydney, NSW, Australia. I am the only researcher that investigates the best medicines for koalas. Koalas are not like dogs and cats….. due to koalas having a unique eucalyptus diet, so they have a different physiology to most other species. So the medicines used for koalas are sometimes not the same for cats and dogs. All funds will go to supporting research to ensure the best medicines for koalas. This research will be reported on this blog for all wildlife zoos and hospitals to use. A sincere thank you for your donation. Dr Merran Govendir Associate Professor in Veterinary Pharmacology, The University of Sydney, Sydney. New South Wales, Australia

A$10.00

Acknowledgements

Thank you to Dr Larry Vogelnest and the koala keepers at Taronga Zoo who provided many samples as well as Dr Ray Austin, Keen St Veterinary Clinic, Lismore.

Thank you to the Koala Hospital, Port Macquarie and the Winifred Violet Scott Charitable Foundation. Specifically, the financial support was for Dr Kimble to develop and validate the assay and to analyse the koala plasma samples.

References

Buhari, S., Hashim, K., Yong Meng, G., Mustapha, N.M. & Gan, S.H. (2012) Subcutaneous administration of tramadol after elective surgery is as effective as intravenous administration in relieving acute pain and inflammation in dogs. The Scientific World Journal, 2012

Desmeules, J.A., Piguet, V., Collart, L. & Dayer, P. (1996) Contribution of monoaminergic modulation to the analgesic effect of tramadol. Journal of Veterinary Pharmacology and Therapeutics, 41, 7-12

Gillen, C., Haurand, M., Kobelt, D.J. & Wnendt, S. (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor. Naunyn-Schmiedeberg’s Archives of Pharmacology, 362, 116-121

Gordon, G. (1991) Estimation of the age of the koala, Phascolarctos cinereus (Marsupialia: Phascolarctidae) from tooth wear and growth. Australian Mammalogy, 14, 5-12

Gourlay, G.K., Kowalski, S.R., Plummer, J.L., Cousins, M.J. & Armstrong, P.J. (1988) Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesthesia and analgesia, 67, 329-337

Grond, S. & Sablotzki, A. (2004) Clinical pharmacology of tramadol. Clinical pharmacokinetics, 43, 879-923

Hennies, H., Friderichs, E. & Schneider, J. (1988) Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung, 38, 877-880

KuKanich, B. & Papich, M. (2004) Pharmacokinetics of tramadol and the metabolite O‐desmethyltramadol in dogs. Journal of Veterinary Pharmacology and Therapeutics, 27, 239-246

KuKanich, B. & Papich, M.G. (2011) Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. American journal of veterinary research, 72, 256-262

Lehmann, K.A., Kratzenberg, U., Schroeder-Bark, B. & Horrichs-Haermeyer, G. (1990) Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. The Clinical journal of pain, 6, 212-220

Pypendop, B.H., Brosnan, R.J., Majewski‐Tiedeken, C., Stanley, S.D. & Ilkiw, J. (2014) Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane‐anesthetized cats. Journal of veterinary pharmacology and therapeutics, 37, 13-17

Pypendop, B.H. & Ilkiw, J. (2008) Pharmacokinetics of tramadol, and its metabolite O‐desmethyl‐tramadol, in cats. Journal of Veterinary Pharmacology and Therapeutics, 31, 52-59

Raffa, R.B., Friderichs, E., Reimann, W., Shank, R.P., Codd, E.E. & Vaught, J.L. (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an’atypical’opioid analgesic. Journal of Pharmacology and Experimental Therapeutics, 260, 275-285

Vettorato, E., Zonca, A., Isola, M., Villa, R., Gallo, M., Ravasio, G., Beccaglia, M., Montesissa, C. & Cagnardi, P. (2010) Pharmacokinetics and efficacy of intravenous and extradural tramadol in dogs. The Veterinary Journal, 183, 310-315