Michael Laurence

This thesis addresses the mitigation of opioid-induced respiratory depression in wild African antelope species.

Potent opioids such as etorphine or thiafentanil are often used for the immobilisation of wild herbivores. One disadvantage of using these potent opioids is that they can cause clinically significant respiratory depression which is due to their potent effect on mu-opioid receptors. Activation of mu-opioid receptors in the respiratory centres of animals depresses neurons that generate the normal respiratory rhythm. At the same time activation of mu-opioid receptors on chemo receptors in the brain stem, on the aortic arch and carotid bodies depresses the normal respiratory drive as these chemo receptors become less sensitive to activation by hypercapnia, hypoxaemia and acidaemia. This effect in turn leads to a reduction of the respiratory frequency and tidal volume. Furthermore, pulmonary vasoconstriction, caused by the sympathomimetic actions of etorphine, decreases pulmonary perfusion. This effect leads to impaired diffusion of oxygen through the alveolar membrane. Studies have found that serotonergic ligands, specifically 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), improved blood oxygenation by reducing opioid-induced respiratory depression and improving pulmonary perfusion through their serotonergic effects on the lungs and brain. More specifically, 8-OH-DPAT binds to 5-HT1A and 5-HT7 serotonin receptors in the lungs and brain. This binding results in smooth muscle relaxation and improved pulmonary perfusion without affecting catatonia and sedation caused by opioids. It was thought that the use of the R-enantiomer of 8-OH-DPAT (R-8-OH-DPAT) in comparison to the racemic form (RS-8-OH-DPAT), might produce even better results because of its high specificity at the 5- HT1A receptors.

Although some literature on the pharmacokinetic data of 8-OH-DPAT in rats and marmosets existed, there was no published literature available on the pharmacokinetics of 8-OH-DPAT in ungulates.

Therefore, the investigation into the pharmacokinetics and bioavailability of R-8-OH-DPAT in goats served as the first step in a series of experiments to understand the viability of adding R-8-OH-DPAT to an opioid-based immobilisation protocol for wild antelope species in order to alleviate respiratory depression. It was hypothesised that the pharmacokinetics and bioavailability of R-8-OH-DPAT in goats would be similar but different to that reported in other species. It was established that the bioavailability of R-8-OH-DPAT when injected intramuscularly (IM) into goats was 66%. At the dosage used in this experiment (0.1 mg kg- 1), signs of serotonin toxicity were observed in some of the goats. The bioavailability results, as well as the encountered side effects in goats, guided the choice of three experimental R-8- OH-DPAT dosages for the next experiment.

The second experiment aimed to determine the ability of R-8-OH-DPAT, when administered in combination with etorphine in a dart, to prevent opioid-induced respiratory depression in blesbok (Damaliscus pygargus phillipsi) and impala (Aepyceros melampus). The experiment also aimed to establish the most clinically effective dosage of R-8-OH-DPAT, in these species.

Blesbok and impala were chosen for the second experiment as they were abundant and readily available in the study area. Both are antelope species commonly immobilised with potent opioids. Impala are regularly used in immobilisation experiments. It was hypothesised that R-8-OH-DPAT would mitigate opioid-induced respiratory depression in wild ungulates without affecting the quality of immobilisation. R-8-OH-DPAT did not influence induction, immobilisation or recovery scores in either of the species. However, this experiment revealed that there were substantial differences between the two antelope species and their physiological changes after the administration of etorphine alone as well as etorphine in combination with 0.005, 0.02 and 0.07 mg kg-1 R-8-OH-DPAT respectively. Surprisingly, opioid-induced hypoxia was substantially more severe in impala compared to blesbok. Respiratory rate in blesbok, but not impala, increased with an increasing dosage of R-8-OHDPAT but this did not translate into clinically relevant improvements in partial arterial oxygen pressure (PaO2) values in blesbok.

In impala, the medium and higher dosages of R-8-OH-DPAT combined with etorphine led to an improved PaO2 and decreased opioid-induced tachycardia during the first ten minutes of immobilisation.

It was concluded that species-specific effects and the possibility of serotonin toxicity at higher dosages, which seemed most effective, might not allow the routine use of R-8-OHDPAT at appropriate dosages for wildlife immobilisation.

These results lead to the third experiment which aimed at comparing physiological effects of two commonly used potent opioids, namely etorphine and thiafentanil, in both antelope species. It was hypothesised that the time to recumbence, immobilisation quality and physiological variables during immobilisation of blesbok and impala respectively would differ between the two potent opioids.

The results of this experiment demonstrate that both opioids used in high dosages are suitable for immobilisation of blesbok and impala without the addition of any sedative or tranquillisers. Both, blesbok and impala developed hypertension with either of the opioids. The thiafentanil treated animals of both species developed higher systemic blood pressure compared to the etorphine treated animals. The healthy animals used for these experiments recovered from hypertension without apparent adverse consequences.

Thiafentanil in impala achieved a faster time to recumbence compared to etorphine but thiafentanil also was responsible for more incidences of prolonged apnoea during the beginning of the monitoring period in impala. Overall, there were large differences in the reaction of individual impalas to the opioid immobilisation, which seemed to result in unpredictable immobilisation.

In blesbok, opioid-induced respiratory depression, hypoxia and hypercapnia were much less pronounced than in impala. Thiafentanil treated blesbok had higher respiratory rates, higher PaO2 and lower partial arterial carbon dioxide pressure (PaCO2) compared to etorphine treated blesbok. There was no difference in time to recumbence between the two opioids in blesbok.

In conclusion, for short term management procedures of impala and blesbok, both opioids are suitable. No matter which opioid is used, both cause hypoxaemia to a greater or lesser degree and oxygen supplementation should be considered for both species.

Veterinarians should also be aware that in some species, such as impala, thiafentanil can achieve a faster time to recumbence than etorphine. However, this statement cannot be applied across all species as in blesbok there was no significant difference between both drugs with regards to time to recumbence. In addition, time to recumbence has to be weighed against potential negative respiratory, pulmonary and cardiovascular side-effects of the drug.

While these experiments did not give the desired positive results with regards to the use of R-8-OH-DPAT to alleviate opioid-induced respiratory depression, they led to insights into differences between the two opioids which will enable veterinarians to make a more educated decision as to which opioid should be used preferentially.

New insights into the differences between blesbok and impala with respect to reaction and physiological changes caused by opioids will also enable researchers to make decisions with regards to species selection for wildlife trials. It may also explain some of the difficulties encountered when immobilising impala.