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Comparison of cervical epidural morphine with intravenous morphine administration on antinociception in adult horses using thermal threshold testing

Published:March 15, 2022DOI:https://doi.org/10.1016/j.vaa.2022.03.003

      Abstract

      Objective

      To compare the antinociceptive effects of morphine administered via cervical epidural catheter to intravenously administered morphine using a thermal threshold (TT) testing model in healthy adult horses.

      Study design

      Prospective, randomized, blinded experimental study.

      Animals

      A total of six university-owned adult horses.

      Methods

      Horses were instrumented with a cervical (C1–C2) epidural catheter and TT testing device with probes at withers and thoracic limb coronary bands. All horses underwent three TT testing cycles including cervical epidural morphine administration (treatment EpiM; 0.1 mg kg–1), systemic morphine administration (treatment SystM; 0.1 mg kg–1) and no morphine administration (treatment Control). Baseline TT was established prior to treatments, and TT was tested at 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 600 and 720 minutes following treatment. Horses underwent a 5 day washout period between treatments and the order of treatment was randomized. Differences between treatments were analyzed with repeated measures anova.

      Results

      Systemic and epidural morphine administration resulted in significantly higher TT values compared with baseline and control treatment. The duration of effect was significantly longer in treatment EpiM (10–12 hours) than in treatment SystM (1.5–2.0 hours). Horses in treatment EpiM had significantly higher TT values at time points 180–600 minutes (withers) and 300–600 minutes (coronary band) than horses in treatment SystM.

      Conclusions and clinical relevance

      Cervical epidural administration of morphine provided antinociceptive effects as measured by increased TT for 10–12 hours compared with 1.5–2.0 hours for intravenously administered morphine. No complications or adverse effects were noticed following epidural placement of a C1–C2 catheter and administration of morphine. The use of a cervical epidural catheter can be considered for analgesia administration in treatment of thoracic limb and cervical pain in the horse.

      Keywords

      Introduction

      Provision of analgesia to horses in pain is an essential tenet of humane and ethical treatment of animals. Methods to deliver analgesia can vary depending on the source and severity of the pain. Pharmacological treatments to relieve pain are frequently provided systemically, which may be associated with undesirable side effects (
      • Sanchez L.C.
      • Robertson S.A.
      Pain control in horses: what do we really know?.
      ).
      Spinal analgesia is the provision of analgesics directly at the level of the spinal cord. Caudal epidural analgesia and caudal epidural catheters to deliver these analgesic drugs such as morphine and others are well described in the literature (
      • Natalini C.C.
      Spinal anesthetics and analgesics in the horse.
      ;
      • van Loon J.P.A.M.
      • Menke E.S.
      • L’Ami J.J.
      • et al.
      Analgesic and anti-hyperalgesic effects of epidural morphine in an equine LPS-induced acute synovitis model.
      ). These techniques are often sufficient for treating painful conditions with less side effects than with systemic administration, particularly for severe pelvic limb and caudal abdominal pain (
      • Sysel A.M.
      • Pleasant R.S.
      • Jacobson J.D.
      • et al.
      Efficacy of an epidural combination of morphine and detomidine in alleviating experimentally induced hindlimb lameness in horses.
      ;
      • Goodrich L.R.
      • Nixon A.J.
      • Fubini S.L.
      • et al.
      Epidural morphine and detomidine decreases postoperative hindlimb lameness in horses after bilateral stifle arthroscopy.
      ;
      • Natalini C.C.
      Spinal anesthetics and analgesics in the horse.
      ). However, the delivery of highly effective analgesia to horses with painful conditions of the thoracic limbs, chest and neck poses a challenge to equine practitioners.
      In humans with painful conditions of the arms and chest, tunneled cervical epidural catheters have shown value in providing analgesia and a reduction in postoperative opioid use and dependence. Continuous cervical epidural analgesia (CCEA) has been described in humans and employed in a variety of clinical scenarios, including painful conditions of the neck, pectoral girdle and upper limb appendicular skeleton. CCEA used for postoperative pain management for shoulder (
      • Narouze S.N.
      • Govil H.
      • Guirguis M.
      • Mekhail N.A.
      Continuous cervical epidural analgesia for rehabilitation after shoulder surgery: a retrospective evaluation.
      ) and hand (
      • Noyan A.
      • Cepel S.
      • Ural S.
      • Ozel A.
      Continuous cervical epidural anesthesia in hand surgery.
      ) surgery and rehabilitation with opioid and/or local anesthetic has improved pain scores (visual analog scale), range of motion and greater rate of rehabilitation metric (
      • Narouze S.N.
      • Govil H.
      • Guirguis M.
      • Mekhail N.A.
      Continuous cervical epidural analgesia for rehabilitation after shoulder surgery: a retrospective evaluation.
      ). In most human patients, the catheter is placed under imaging guidance and tunneled under the skin. Therapies evaluated in humans include fentanyl, bupivacaine (
      • Narouze S.N.
      • Govil H.
      • Guirguis M.
      • Mekhail N.A.
      Continuous cervical epidural analgesia for rehabilitation after shoulder surgery: a retrospective evaluation.
      ) and articaine (
      • Noyan A.
      • Cepel S.
      • Ural S.
      • Ozel A.
      Continuous cervical epidural anesthesia in hand surgery.
      ). CCEA has reduced the number of patients needing systemic opioids for postoperative analgesia in a study evaluating glenohumeral joint capsulitis (
      • Narouze S.N.
      • Govil H.
      • Guirguis M.
      • Mekhail N.A.
      Continuous cervical epidural analgesia for rehabilitation after shoulder surgery: a retrospective evaluation.
      ). This benefit of providing surgical capsular relief also reduces pain wind-up and the need for prescription drug usage (
      • Narouze S.N.
      • Govil H.
      • Guirguis M.
      • Mekhail N.A.
      Continuous cervical epidural analgesia for rehabilitation after shoulder surgery: a retrospective evaluation.
      ).
      Cervical epidural catheters are placed for long-term use in humans rehabilitating from cancer or patients with prolonged pain following thoracic surgery (
      • Bomberg H.
      • Kubulus C.
      • Herberger S.
      • et al.
      Tunnelling of thoracic epidural catheters is associated with fewer catheter-related infections: a retrospective registry analysis.
      ). Interestingly, catheters have been placed from 7 to 18 days in a study evaluating the treatment of intractable hiccups (
      • Kim J.E.
      • Lee M.K.
      • Lee D.K.
      • et al.
      Continuous cervical epidural block: treatment for intractable hiccups.
      ). In that study, low-dose ropivacaine and several epidural treatments were administered without patient complications and had a favorable cure rate (
      • Kim J.E.
      • Lee M.K.
      • Lee D.K.
      • et al.
      Continuous cervical epidural block: treatment for intractable hiccups.
      ).
      Recently, the placement of a cervical epidural catheter using imaging guidance in standing adult horses was described (
      • Hurcombe S.D.
      • Morris T.B.
      • VanderBroek A.R.
      • et al.
      Cervical epidural and subarachnoid catheter placement in standing adult horses.
      ). The horses with a cervical epidural catheter showed no signs of pain or discomfort at the catheter site and no clinically significant local tissue reaction over the 72 hour study period. Placement of cervical epidural catheters in horses for administering analgesic drugs may offer an alternative route for effective analgesia for painful conditions of the thoracic limb and pectoral girdle.
      Testing the efficacy of antinociceptive therapies can be challenging in horses. Techniques that are objective and measurable are preferred over subjective or scoring system-based methods. Thermal thresholds (TTs) have been used to assess the antinociception effects of a variety of drugs in standing horses (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ,
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ). The technique is based on a thermal probe sensor applied to the skin that progressively heats up, creating a noxious stimulus. Once perceived by the horse as discomfort, the subject will respond with a hoof withdrawal response, panniculus reflex or turn to look at the site of stimulation. It is this temperature that is indexed against the skin temperature of the animal and maximum cut-off temperature to determine a temperature excursion.
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      showed that TT located at the withers and nostril produce repeatable results. Further, they demonstrated that to minimize errors in measurement, during testing, the horses should be housed in a familiar environment with warm ambient temperatures (>20 °C) (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ). The TT testing appears to be safe in horses and does not lead to long-term adverse reactions at the site of stimulation. Owing to the cut-off mechanism and set maximum temperatures, minimal skin trauma was observed when thermal probes were applied to the skin of the withers or nostril (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ).
      The present study was designed to investigate the effects of cervical epidural administration of morphine in horses. We hypothesized that horses treated with cervical epidural morphine would have higher antinociceptive thresholds than horses administered intravenous (IV) morphine or a saline control.

      Material and methods

      This study was performed as a prospective, blinded, experimental study. The protocol was approved by the University of Pennsylvania Institutional Animal Care and Use Committee (no. 806698). An a priori power analysis (alpha 0.05, beta 0.8, effect size f = 3) revealed that a minimum of six horses would be necessary to detect significant differences in TTs (6.5 °C).
      University-owned research/teaching horses (two mares and four geldings) aged 6–19 years and weighing 420–560 kg were used. They were healthy based on physical examination including basic lameness evaluation (palpation, flexion tests and jogging in hand on a firm surface), packed cell volume and total solids values. Horses were housed in a temperature-controlled 3.5 × 3.5 m box stall at the Department of Clinical Studies, New Bolton Center, PA, USA, and fed ad libitum hay and water for the duration of the experiment. The horses were returned to the teaching herd of the department at the end of the experiment.

      Instrumentation

      The day prior to testing and following physical and lameness screening examinations, a 14 gauge, 13.3 cm catheter was placed in a jugular vein under aseptic conditions (MILA International Inc., KY, USA). The horse was then sedated using detomidine (0.01 mg kg–1; Dormosedan; Orion Corporation, Finland) IV and a cervical (C) epidural catheter was placed at the C1–C2 location as previously described (
      • Hurcombe S.D.
      • Morris T.B.
      • VanderBroek A.R.
      • et al.
      Cervical epidural and subarachnoid catheter placement in standing adult horses.
      ).
      The skin over the proposed catheterization site was clipped (12 × 12 cm) and aseptically prepared with povidone-iodine solution and alcohol. Mepivicaine (Carbocaine, 2%; Zoetis Inc., MI, USA) was infiltrated at the area and a second surgical scrub performed. Ultrasonic guidance was used to confirm the correct site of needle and catheter placement using a sterile dressed ultrasound probe (Philips Lumify, C5-2 broadband curved array 2-5MHz; Philips Healthcare North America, MA, USA). A 17 gauge, 15.24 cm Tuohy needle (FlexBlock; Arrow International Inc., PA, USA) was inserted through the skin into the C1–C2 epidural space. The loss of resistance and hanging drop technique was used to confirm correct positioning. A 19 gauge, 60 cm epidural catheter (FlexBlock; Arrow International Inc.) was inserted through the Tuohy needle in a caudal direction approximately 5 cm into the epidural space and then secured to the skin using a suture. Confirmation of epidural placement was performed using contrast radiography. Both venous and epidural catheters were then flushed with 0.9% saline and wrapped with sterile gauze and adhesive dressing.
      Finally, a 3 × 3 cm site over the left and right withers and left and right thoracic limb dorsal pastern regions were clipped and shaved in preparation for placement of the TT sensors (thermal probes). The horse was then returned to the stall for the day and night prior to the first day of the experiment.

      Thermal threshold testing

      Each horse was fitted with a wireless TT testing device [Wireless Thermal Threshold Testing System (WTT 1); Topcat Metrology Ltd, UK], which was attached to the back of the horse with a belt and Velcro strips. The thermal probes were placed over the pre-prepared sites of the withers and pastern. Contact with the skin over the withers was maintained using air bladders pressurized to approximately 80 mmHg. After equilibrating to skin temperature, the heating rate was set at 0.6 °C second–1 for stimulation and the cut-out temperature was set at 55 °C as previously reported (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ,
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ).
      Detection of thermal sensation was recorded as the horse lifting the thoracic limb or looking at the limb or by skin twitch (cutaneous trunci muscle reflexive movement) or movement of the head and neck toward the stimulated side (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ,
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ). The temperature was recorded at the time when these responses were noted. If no response was noted, the cut-out temperature of 55 °C was recorded (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ,
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ).

      Experimental design

      All horses underwent three TT testing cycles during cervical epidural morphine administration (treatment EpiM), IV morphine administration (treatment SystM) and no morphine administration (treatment Control). Horses were randomly assigned to the order of treatment using a random number generator (www.randomization.com) with 5 days between treatments.
      In treatment EpiM, morphine (0.1 mg kg–1 diluted to 5 mL in saline; Morphine Sulfate Injection, Preservative and Antioxidant Free; Pfizer Inc., TX, USA) was injected through the epidural catheter and simultaneously a 5 mL bolus of saline was injected through the IV catheter. In treatment SystM, morphine (0.1 mg kg–1 diluted to 5 mL) was injected through the venous catheter and simultaneously a 5 mL bolus of saline through the epidural catheter. In treatment Control, 5 mL of saline was injected through both catheters. All catheters were flushed after treatment administration with 1 mL heparinized saline. Syringes were prepared by an investigator (ARW) who was not involved in TT or data acquisition. Treatments were administered and TT evaluated by a second investigator blinded to the treatment protocol (KH).
      The baseline TT in each horse was tested three times with 15 minutes between testing and the mean value was used as baseline TT. After treatment administration, the TT testing was repeated at 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 600 and 720 minutes. The TT device was then removed from the horses, but all catheters were maintained in place and flushed every 12 hours with 1 mL heparinized saline for the duration of the experiment.
      On days 5 and 10, respectively, the TT device was reapplied as described above, and the next assigned treatment performed such that all horses were studied with all treatments. The same observer, who was unaware of the assigned treatment, always performed the TT and recorded the data.
      Each horse was observed in the stalls throughout the study period following medication administration and then every 6 hours for signs of adverse reactions such as recumbency, excitability, increased locomotion, changes in behavior, appetite and fecal production. At the completion of the study, all catheters were removed and iodine ointment placed over the insertion sites.

      Statistical analysis

      Statistical analysis was performed using GraphPad Prism Version 9.1.0 (GraphPad Software Inc., CA, USA). Data were assessed for normality using visual analysis of the QQ plots and Shapiro–Wilk test. All data are reported as mean ± standard deviation. The influence of drug administration site on the horse was analyzed using a two-way analysis of variance with repeated measurements within subjects and post hoc Tukey–Kramer test for multiple pairwise comparisons. The alpha was set at 5% (p < 0.05).

      Results

      There was no significant change in skin temperature over the course of the experiment in any treatment. There was no negative impact (burn, redness) from the thermal probe on the skin at the placement sites at any point in the study. No adverse effects or behavior changes were seen following morphine administration in any subject. The fecal output of the horses counted and recorded in the medical record over 2 days did not change after any treatment.
      In treatment EpiM, TT values significantly increased from baseline at the withers for 600 minutes and at the coronary band for 720 minutes (p < 0.05; Figure 1, Figure 2). In treatment SystM, TT was significantly increased from baseline at the coronary band at 30–90 minutes and at the withers at 30–120 minutes (Figure 1, Figure 2). The injection of saline did not change the TT at any time point. TT was significantly higher in treatment EpiM than in treatment SystM at 180–600 minutes at the withers and at 300–600 minutes at the coronary band.
      Figure 1
      Figure 1Mean ± standard deviation of the thermal threshold temperature (°C) at the withers in six horses treated with cervical epidural morphine (circles), systemic (intravenous) morphine (squares) or saline (control; triangles). Time 0, baseline measurement. ∗Significantly different from time 0 (p < 0.05).
      Figure 2
      Figure 2Mean ± standard deviation of thermal threshold temperature (°C) at the coronary band in six horses treated with cervical epidural morphine (circles), systemic (intravenous) morphine (squares) or saline (control; triangles). Time 0, baseline measurement.∗Significantly different from time 0 (p < 0.05).

      Discussion

      The results of this study showed that both IV and cervical epidural administration of morphine (0.1 mg kg–1) resulted in increased TT compared with baseline at the withers and the coronary band in healthy horses. The duration of effect was markedly longer following cervical epidural administration (10–12 hours) than after IV administration (1.5–2.0 hours). Furthermore, TT in treatment EpiM was significantly higher than TT in treatment SystM at multiple time points at the withers and the coronary band, indicating that cervical epidural morphine resulted in stronger antinociceptive effects than systemic morphine for a longer period. No complications were observed during placement of the epidural catheter or behavioral changes in the horses during morphine administration and for the duration of the study, suggesting that this procedure was well tolerated by the horses. No publication describing the use of morphine administration via a cervical epidural catheter to provide antinociception for thoracic limbs in horses was identified on literature search.
      Effective analgesia in horses is an important part of effective treatment as it can prevent pain and lameness associated complications of conditions such as laminitis in adults and angular limb deformities in foals (
      • Peloso J.G.
      • Cohen N.D.
      • Walker M.A.
      • et al.
      Case-control study of risk factors for the development of laminitis in the contralateral limb in Equidae with unilateral lameness.
      ;
      • Young D.R.
      • Richardson D.W.
      • Nunamaker D.M.
      • et al.
      Use of dynamic compression plates for treatment of tibial diaphyseal fractures in foals: nine cases (1980–1987).
      ;
      • Caldwell F.J.
      Flexural deformity of the distal interphalangeal joint.
      ). Non-steroidal anti-inflammatory drug use is standard for short-term therapy but can lead to nephrotoxicity and right dorsal colitis following prolonged administration. There is little convincing evidence that systemically administered morphine is effective at controlling superficial, somatic or visceral pain in horses for a clinically relevant length of time (
      • Kalpravidh M.
      • Lumb W.V.
      • Wright M.
      • Heath R.B.
      Effects of butorphanol, flunixin, levorphanol, morphine, and xylazine in ponies.
      ;
      • Kohn C.W.
      • Muir W.W.
      Selected aspects of the clinical pharmacology of visceral analgesics and gut motility modifying drugs in the horse.
      ;
      • Bennett R.C.
      • Steffey E.P.
      Use of opioids for pain and anesthetic management in horses.
      ). This may be due, in part, to the short duration of action and the narrow therapeutic index of systemically administered morphine, above which undesirable systemic side effects of increased central excitation, muscle fasciculations and increased locomotor activity (
      • Knych H.K.
      • Steffey E.P.
      • McKemie D.S.
      Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses.
      ;
      • Hamamoto-Hardman B.D.
      • Steffey E.P.
      • Weiner D.
      • et al.
      Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses.
      ) are seen. Decreased gastrointestinal motility has also been reported from 8 to 24 hours following treatment with systemic morphine in addition to decreased fecal production (
      • Knych H.K.
      • Steffey E.P.
      • McKemie D.S.
      Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses.
      ;
      • Hamamoto-Hardman B.D.
      • Steffey E.P.
      • Weiner D.
      • et al.
      Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses.
      ). Morphine also induces hyperphagia in horses and causes gastric distension in a dose-dependent manner following systemic administration (
      • Tessier C.
      • Pitaud J.P.
      • Thorin C.
      • Touzot-Jourde G.
      Systemic morphine administration causes gastric distention and hyperphagia in healthy horses.
      ). By contrast, the epidural administration of opioids not only provides effective and long-lasting analgesia (
      • Goodrich L.R.
      • Nixon A.J.
      • Fubini S.L.
      • et al.
      Epidural morphine and detomidine decreases postoperative hindlimb lameness in horses after bilateral stifle arthroscopy.
      ;
      • Natalini C.C.
      Spinal anesthetics and analgesics in the horse.
      ) but also has fewer complications (
      • Martin C.A.
      • Kerr C.L.
      • Pearce S.G.
      • et al.
      Outcome of epidural catheterization for delivery of analgesics in horses: 43 cases (1998–2001).
      ). Morphine administered into the epidural space is absorbed into the cerebrospinal fluid. It acts on receptors in the substantia gelatinosa of the dorsal horn of the spinal cord by inhibiting the release of substance P from the A delta and C fibers of the spinal cord (
      • Pernow B.
      Substance P.
      ). Because substance P is important in pain perception, inhibition of spinal transmission of painful stimuli is possible using spinal or epidural opiates (
      • Pernow B.
      Substance P.
      ). Therefore, dosage, volume and time until onset can be shortened when opioids are administered epidurally and action is at the spinal level (
      • Skarda R.T.
      • Muir W.W.
      Caudal analgesia induced by epidural or subarachnoid administration of detomidine hydrochloride solution in mares.
      ). In addition, the duration of action of epidurally administered morphine is longer than that of systemically administered morphine because morphine is released slowly from the epidural space into the plasma (
      • Andersen H.B.
      • Christensen B.
      • Findlay J.W.
      • Jansen J.A.
      Pharmacokinetics of intravenous, intrathecal and epidural morphine and fentanyl in the goat.
      ).
      Placement of an epidural catheter initially requires operator training. Once inserted, the epidural catheter facilitates effective and long-term analgesia while avoiding potential trauma from multiple epidural injections and minimizes the need for systemic opioid treatment. Studies report minimal complications in horses with caudal or cervical catheters (
      • Martin C.A.
      • Kerr C.L.
      • Pearce S.G.
      • et al.
      Outcome of epidural catheterization for delivery of analgesics in horses: 43 cases (1998–2001).
      ;
      • Hurcombe S.D.
      • Morris T.B.
      • VanderBroek A.R.
      • et al.
      Cervical epidural and subarachnoid catheter placement in standing adult horses.
      ). Complications that do occur are generally related to technical aspects of the catheter such as dislodgement and leaking, or self-limiting local inflammation at the insertion site (
      • Martin C.A.
      • Kerr C.L.
      • Pearce S.G.
      • et al.
      Outcome of epidural catheterization for delivery of analgesics in horses: 43 cases (1998–2001).
      ). In the human literature, complications such as bradycardia and hypotension have been reportedly associated with cervical epidural catheter placement, while nausea and vomiting are associated with opioid administration via the cervical epidural catheter (
      • Wenk M.
      • Massoth C.
      • Pöpping D.M.
      • Möllmann M.
      Feasibility of cervical epidural anesthesia for breast cancer surgery.
      ). These complications have not been noted in standing horses; however, it is possible that they occur and are undetected.
      Whereas caudal epidural catheters have been used successfully for morphine treatment of pelvic limb pain, treatment of thoracic limb pain is less reliable and usually requires a higher injectate volume (
      • Natalini C.C.
      Spinal anesthetics and analgesics in the horse.
      ). A previous study described ultrasound-guided placement of catheters in the cervical (C1–C2) epidural space in both standing and recumbent horses (
      • Hurcombe S.D.
      • Morris T.B.
      • VanderBroek A.R.
      • et al.
      Cervical epidural and subarachnoid catheter placement in standing adult horses.
      ). This technique allows treatment of cervical or thoracic limb pain using smaller opioid volumes at longer dosing intervals compared with systemic therapy. A recently published case report showed that cervical epidural administered morphine resulted in a substantial improvement in severe thoracic limb lameness without resulting in clinically detectable adverse effects (
      • Watkins A.R.
      • Hopster K.
      • Levine D.
      • Hurcombe S.D.
      Cervical epidural spinal analgesia for acute management of severe unilateral forelimb lameness: case report.
      ).
      The TT testing model was used in the current study to detect changes in nociception among the treatments. TT has been used in multiple equine studies to assess the efficacy of many analgesics including acepromazine and buprenorphine (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ) and meperidine (
      • Hamamoto-Hardman B.D.
      • Steffey E.P.
      • McKemie D.S.
      • et al.
      Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses.
      ) in adult horses, and butorphanol in foals (
      • McGowan K.T.
      • Elfenbein J.R.
      • Robertson S.A.
      • Sanchez L.C.
      Effect of butorphanol on thermal nociceptive threshold in healthy pony foals.
      ). The protocol used in the present study closely follows the standardized methodologies established within the equine community as described by a recent review article (
      • Gozalo-Marcilla M.
      • Luna S.P.L.
      • Gasthuys F.
      • Schauvliege S.
      Thermal, mechanical and electrical stimuli in antinociceptive studies in standing horses: an update.
      ). The TT measured at the withers and at the coronary band fluctuated by approximately 3–4 °C, which is also seen in other studies describing the use of the WTT system (
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites.
      ,
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ). Interestingly, the repeated stimulation resulted in a nonsignificant peak after 240 and 480 minutes at the withers and coronary band, respectively, which could indicate mild hypersensitization of these areas. However, this trend was neither continuous nor resulted in a significant difference from baseline thresholds.
      There are limitations inherent to TT testing in horses that must be addressed. First and most importantly, the thermal stimulus does not provide an identical stimulus to clinical pain and, therefore, may not fully depict the range of antinociceptive qualities of the analgesic being tested. In the current study, a relatively slow rate of heating (0.6 °C second–1) of the thermal probe was selected so the pain response is likely mediated by type C unmyelinated fibers. This would create a more poorly localized insidious pain stimulus than induced by surgical or traumatic injury. Second, there are confounding factors to the use of TT testing such as temperature, sex differences and environmental stimuli (
      • Love E.J.
      • Murrell J.
      • Whay H.R.
      Thermal and mechanical nociceptive threshold testing in horses: a review.
      ). To avoid these factors the testing was performed in a warm ambient temperature to prevent the vasoconstriction and ischemia of nerves that is hypothesized to increased thermal threshold (
      • Chambers J.P.
      • Waterman A.E.
      • Livingston A.
      Further development of equipment to measure nociceptive thresholds in large animals.
      ;
      • Poller C.
      • Hopster K.
      • Rohn K.
      • Kästner S.B.
      Evaluation of contact heat thermal threshold testing for standardized assessment of cutaneous nociception in horses – comparison of different locations and environmental conditions.
      ). Both mares and geldings are represented in the study population. The testing was performed in a quiet barn; however, the presence of a researcher may affect the subject’s behavior. Remote-controlled TT devices could be used in the future to avoid this potential confounding factor (
      • Taylor P.
      Remote controlled nociceptive threshold testing systems in large animals.
      ). Therefore, we conclude that the results of the present study are valid and suggest that epidurally administered morphine is superior to systemically administered morphine to modify nociception in horses.
      The current study is limited by the small sample size; however, each horse was tested three times to maximize study robustness while reducing the number of horses required. Another limitation is that plasma morphine concentration was not measured during the study. Therefore, it cannot be stated that the washout period was sufficient to prevent interaction between testing periods. TT baseline values were assessed before every treatment to ensure that no residual morphine effects would interfere with the results. Finally, TTs had not returned to baseline in treatment EpiM at the end of the testing period; therefore, it was impossible to determine duration of action of this treatment.

      Conclusions

      Morphine (0.1 mg kg–1 diluted to 5 mL with saline) was administered to standing horses through a cervical epidural catheter at C1–C2, or IV. Epidurally administered morphine provided antinociceptive effects as measured by increased TT for 10–12 hours compared with 1.5–2.0 hours for systemically administered morphine. No adverse behavior or complications were observed in the horses during or after the epidural administration of morphine. The use of cervical epidural catheters can be considered for analgesic treatment of thoracic limb and cervical pain in the horse.

      Authors’ contributions

      KH and SDH: conception and design of study, data acquisition, analysis and interpretation of data, manuscript preparation. ARW: contributed to study design and data acquisition, preparation of manuscript. All authors read and approved the final version of the manuscript.

      Conflict of interest statement

      Authors declare no conflict of interest.

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