A 550 Kg, 20 years old pregnant mare was presented at the equine teaching hospital due to severe hindlimbs lameness. A heart rate of 56 beats per minute, a respiratory rate of 16 breaths per minute and clear signs of pain were present at the clinical examination. A radiological study revealed a high-grade, chronic tendinopathy of the suspensory branches on the right and left side. Since foal delivery was expected within 2 months, the horse was hospitalised for pain and supportive therapy. During the hospitalization, pain could not be easily controlled, despite the adoption of a multimodal systemic analgesic plan. A pain score [] was used in order to monitor the analgesic efficacy of the attempted treatments. Due to the inefficacy of a combination of methadone, non-steroidal anti-inflammatory agents and gabapentin in controlling pain over the first week, an epidural catheter placement was planned, in order to provide repeated morphine administrations into the epidural space. The sacro-coccigeal area was clipped and aseptically prepared, and a Tuohy needle was inserted targeting the sacro-coccigeal space, with the needle opening pointing cranially. The hanging drop technique with sterile saline was used to confirm the needle tip location into the epidural space. An epidural catheter was advanced through the Tuohy needle, for a length previously calculated in order to reach the L4-L5 vertebra. A bacterial filter was applied to the injection port and the catheter was secured to the skin with adhesive material and covered with adhesive dressing. The systemic analgesic treatment was stopped. An initial epidural dose of 0.1 mg/kg of morphine (Morphin HCl Sintetica, Sintetica S.A., Switzerland) every 8 h was started, with immediate improvement of the clinical condition. After each drug injection, the epidural catheter was always flushed with a volume of 6 ml of sterile saline. An abdominal ultrasound examination was repeatedly performed in order to check the clinical condition of the foal, with no abnormalities detected until delivery. On day 16 (from now on, days are reported as “days after starting the epidural analgesic treatment”), a strong excitatory phase with increased locomotor activity, dysphoria and photophobia occurred and lasted for few hours. Even if it could not be correlated to any particular injection or time interval after injection, a morphine overdose was suspected. Its administration was stopped and epidural methadone (0.1 mg/kg) (Methadone Sintetica, Sintetica S.A., Switzerland) was given instead. Two days later, due to stable clinical conditions, methadone was stopped and morphine restarted. During the excitatory period, the horse was moved to an isolated and quiet stable and the windows were covered with black light-reflecting material. On day 21, due to a weaning of the analgesic effect of morphine within one hour before administration, shorter intervals (6 h) were adopted and ketamine (Ketasol, Graeub AG, Switzerland) was added (0.1 mg/kg every 6 h). On day 42, a second but milder excitatory episode occurred; also in this case, it could not be correlated to any particular injection or time interval after injection. Morphine was interrupted for 24 h and it was substituted by epidural methadone (0.1 mg/kg). The day after, due to stable clinical conditions, methadone was stopped and morphine restarted at half of the dosage. On day 49, the foal was delivered and morphine dose was further reduced to 0.025 mg/kg. On day 53, epidural administration was stopped and morphine (0.025 mg/kg) and ketamine (0.5 mg/kg) were injected intramuscularly, every 8 h. On day 56 the epidural catheter was removed. A bacterial examination of the catheter tip was performed and no contamination was found. Finally, on day 57, the mare and the foal were discharged from the hospital in stable clinical conditions and the analgesic therapy of the mare was continued at home by the private veterinarian. During the whole hospitalization period, reduction in faeces production occurred but no signs of colic were noticed. After obtaining owner consent, the plasmatic levels of morphine ant its metabolites (M3G and M6G) were evaluated to titrate the analgesic treatment over time. Moreover, blood samples were taken from the foal (in concomitance with already needed blood withdrawal for routine tests) in order to rule out morphine overdosing. On day 36, a sequential blood sampling (SBS) from the mare was performed, at 30 min before and 1, 3 and 5 h after morphine administration. Another sample was taken on day 42, one hour and a half after morphine injection, during the episode of excitation and increased locomotor activity. Further blood samples were taken on day 49, 50 and 51 (day of delivery and 1 and 2 days post-delivery). For each blood collection, 10 ml of blood were withdrawn and put aside, 10 ml were then collected in an EDTA syringe and the previous blood administered back to the horse. The blood was immediately centrifuged (3000 rotation per minute for 10 min at 20 °C) and the plasma successively stored at − 80° in special cryotube (CryoPure Tube, Sarstedt, Germany). Withdrawal of blood from the foal was performed on day 0 (after delivery, before first meal), on day 1 and on day 2. In this case, 1.5 ml of blood was taken and transferred in an EDTA tube; then, the same centrifugation and storages process as for the mare was applied. Measurement of morphine, M3G and M6G plasmatic concentration were performed using liquid chromatography-tandem mass spectrometry. Results are presented in Tables and.