Although the usefulness of epidural analgesia in horses is well documented in the literature, only scarce information about plasma concentrations of morphine following epidural administration is available.
So far, no pharmacokinetic studies about morphine and its metabolites after repeated epidural administration have been reported in horses. Natalini (2006)  investigated the plasmatic concentration of morphine after a single epidural injection of 0.1 mg/kg in horses and found maximum plasmatic concentration of 90 ng/ml at 120 min post-injection; no clinical variables were reported.
In another study, following intravenous (IV) and intramuscular (IM) administration of 0.05 or 0.1 mg/kg morphine in horses, values higher than 8 ng/ml were found and they were not correlated with any respiratory or behavioural modifications, except mild reduction of gut sounds (with no reduction in faeces production) . However, in the same study, an increase in heart rate and blood pressure developed for approximately two minutes after IV injection, associated with morphine plasmatic level > 150 ng/ml.
In another study in horses, behavioural responses, such as fasciculations, sweating and increase in locomotor activity were noticed for about 45 min after morphine IV injection at dosages of 0.2 to 0.5 mg/kg .
To the authors’ knowledge, no available data on minimum effective plasmatic concentrations of morphine and its metabolites in equine species are known. In the present study, values between 6.4 and 21.9 ng/ml for morphine, 8.3 and 14.2 ng/ml for M6G and 235.6 and 339.2 ng/ml for M3G were found during the SBS. As successful analgesia was achieved in absence of clinically relevant side effects, plasmatic concentrations in the reported ranges could be considered as effective. Moreover, they did not exceed the level previously reported to induce tachycardia and increase in blood pressure in horses .
In the present case, when the SBC was performed, peak plasmatic concentration of morphine and its metabolites were found 1-h post injection and trough 5.5 h post injection (30 min before the next injection).
A strong agonism of M6G to mu-receptors have been reported [14,15,16,17]. Around 85% of the analgesic effect of morphine is supposed to derive from the M6G . In contrast, M3G has up to 200 times lower mu-receptor binding compared with morphine  and it seems to lack analgesic activity, with some studies suggesting an antagonist [10, 16, 20] or just a weak agonist activity .
It is interesting to notice that when the blood sample was taken during the excitatory period, morphine concentration was 69.6 ng/ml, around three times higher than the peak plasmatic concentration found during the SBS, while M6G and M3G were consistent with the previously measured concentrations (10.4 ng/ml for M6G and 164.4 ng/ml for M3G). From these results it could be hypothesized that the high concentration of morphine, rather than its metabolites, could be the cause of the excitatory side effects, but the reason why there was an increase in morphine and not of its metabolites is not clear. Full blood work was performed the same day, but no pathological findings, especially in the liver function tests, were found.
Up to date, there were no reports describing plasmatic concentrations of morphine in neonatal foals born from mares receiving long-term epidural morphine. Moreover it is not known whether there might be a correlation between maternal morphine plasmatic concentration and the occurrence of undesired side effects in the new born foal. At the concentrations found in the present case, no side effects (respiratory depression, reduced appetite, dysphoria, among others) were seen, and no problems were encountered until discharge from the hospital. It is interesting to notice that plasmatic concentrations of morphine before the first meal were slightly higher in the foal compared to the mare, whereas plasmatic concentration of its metabolites were substantially higher in the mare compared to the foal. The immature liver function could have led to accumulation of the parent drug and reduction of its metabolization.
If the presence of morphine in the blood during the last phase of gestation can lead to pain pathway abnormalities/addiction in the future is not known for horses. In humans, neonates born from opioid dependent women are more likely to have low weight at birth, to be admitted to the neonatal intensive care unit and to require prolonged treatment for neonatal abstinence syndrome [22, 23]. The neonatal abstinence syndrome is a drug withdrawal syndrome after birth that affects 45–94% of infants born from opioid dependent mothers, resulting in significant neonatal morbidity [24,25,26]. Sometimes it can also appear after few days from birth . Even though morphine has a low lipid solubility compared to other opioids, its poor protein binding favour its passage through the placenta. In the present case, no abnormalities were noticed during the hospitalization period and no abnormalities were reported from the owner up to 3 months after birth. The difference in placental structure between humans and horses, as well as the different maturity at birth could play an important role in drug transfer and effects on the foetus.
The possible passage from the mare to the foal during lactation should also be considered. In a case series of women undergoing surgery during the lactation period (at least 1 month after giving birth) receiving IV or IM morphine, only mild and occasionally observed respiratory depression or drowsiness in the child occurred . In another clinical study in women receiving epidural morphine for delivery, measurable quantities in the milk were found only in three samples within the following 36 h . In the present case no analysis of the milk was performed. However, plasmatic concentration of morphine and its metabolites in the foal decreased from day 0 (before first meal) to day 2, reflecting a possible null or minimal passage of the drug from the milk to the neonate.
A last point to consider is that differences in plasmatic volume during pregnancy could have led to different plasma concentrations compared to non-pregnant horses. Recently, a review about pharmacokinetic and pharmacodynamics of morphine in pregnant women has been published. Compared to non-pregnant women, morphine in pregnant women has an unchanged volume of distribution, a clearance > 70% and a decreased half-life . In another study, the area under the curve for unconjugated morphine within two days after morphine epidural injection in pregnant women was similar to those reported for epidural administration in the non-pregnant ones . To the authors knowledge, the influence of gestation on the morphine pharmacokinetics and pharmacodynamics in pregnant horses is not known.
This case report presents plasmatic concentrations of morphine and its metabolite after a long-term epidural treatment in a pregnant mare. Results show that plasmatic level reached over prolonged epidural administration do not exceed those previously reported to be effective and at the same time safe for the animal. Sudden increase in morphine plasmatic concentration in the mare can occur and side effect appear; careful treatment to the lowest effective dose and continuous monitoring of the clinical condition of the treated horse should be performed. No clinically relevant effects on the foetus were noticed during the whole gestation period; moreover, the plasmatic concentrations found after birth did not affect the essential steps during the first phases of life.