A 24-year-old 732-kg (1,610-lb) Belgian mare was admitted to the veterinary teaching hospital for evaluation of intermittent colic of 3 days' duration. The mare was reported to be 320 days' pregnant, with prior gestations lasting between 340 and 360 days. The mare had undergone surgery at 3 years of age to relieve sand impaction of the large colon. Prior to admission, the mare reportedly had an increase in gastrointestinal tract sounds, and distention of the large colon was detected during palpation per rectum. Treatment by the referring veterinarian included administration of flunixin meglumine (1.1 mg/kg [0.5 mg/lb], IV) and nasogastric intubation (no reflux was obtained), with administration of water containing 12 oz of disodium succinate. Over the next 24 hours, the mare appeared comfortable and was passing manure. The following morning, however, the mare again appeared uncomfortable and was therefore referred to the veterinary teaching hospital for further diagnostic testing.
On initial examination at the veterinary teaching hospital, heart rate (60 beats/min) and respiratory rate (36 breaths/min) were high, and capillary refill time (3 seconds) was prolonged. Reduced borborygmi were ausculted in the right dorsal and ventral quadrants. Palpation per rectum revealed distention of the large intestine in the upper right quadrant of the abdomen and a gravid uterus. Abdominal ultrasonography revealed normal motility in visualized bowel segments as well as a viable fetus with a heart rate of 93 beats/min and normal-appearing uterine and placental walls. Results of a CBC, serum biochemical profile, and venous blood gas analyses were all within reference limits. The mare was sedated with xylazine hydrochloride (0.2 mg/kg [0.09 mg/lb], IV) during physical examination.
A tentative diagnosis of right dorsal displacement of the large colon was made. The mare was treated with lactated Ringer's solution (2 L/h, IV) and taken for frequent walks. Colic signs were mild at this time. Approximately 7 hours after admission, the mare became acutely painful with noticeable abdominal distention. A nasogastric tube was passed at this time, and 14 L of enterogastric reflux was obtained. In addition, palpation per rectum now revealed gas distention of the small and large intestines. Therefore, a decision was made to take the mare immediately to surgery. Potassium penicillin (22,000 U/kg [10,000 U/lb], IV), gentamicin (6.6 mg/kg [3 mg/lb], IV), and flunixin meglumine (1.1 mg/kg, IV) were administered prior to surgery.
The mare was sedated with xylazine (0.2 mg/kg, IV) and butorphanol (0.014 mg/kg [0.006 mg/lb], IV) and anesthetized with guaifenesin (48 mg/kg [22 mg/lb], IV) and ketamine (2.2 mg/kg [1 mg/lb], IV). The mare was hoisted via hobbles attached to all 4 limbs and placed in dorsal recumbency on 6-inch–thick padding. Anesthesia was maintained with isoflurane in oxygen administered with a large animal circle rebreathing circuit, and a balanced electrolyte solution was administered (27 mL/kg [12.3 mL/lb], IV) over a period of 3 hours. Mean arterial blood pressure was maintained at ≥ 70 mm Hg by adjustment of anesthetic depth and intermittent administration of dobutamine (5 μg/kg/min [2.3 μg/lb/min], IV). Blood gas analysis 20 minutes after anesthetic induction revealed hypoxemia with a PaO2 of 41 mm Hg. Adjustment of ventilatory parameters and administration of aerosolized albuterol (990 Mg divided into 3 doses over 60 minutes) increased the PaO2 to 77 mm Hg.
At surgery, extreme distention of the small intestine, cecum, and large colon was found. The cause of the gas distention was believed to be external compression of the ileum by the fetus. No displacements or torsions were found. The intestines were decompressed multiple times and placed back in the abdomen, and the incision was routinely closed. Total anesthesia time, including the time necessary for positioning on the surgery table, sterile preparation, and draping of the abdomen, was 3.25 hours. Surgery time was approximately 2.5 hours. Following discontinuation of anesthesia, the mare was hoisted again and placed in lateral recumbency in a padded recovery stall. Head and tail ropes were placed on the mare to assist recovery. The mare stood approximately 45 minutes after placement in the recovery stall. The recovery was complicated by an inability to bear weight on the left hind limb and flexion of the proximal interphalangeal, tarsal, and stifle joints in that limb. These signs were attributed to femoral nerve paresis. Palpation of the muscles of the hindquarters did not reveal any signs of pain, and the muscles were soft during palpation, suggesting that there was no concurrent myositis. Following surgery, potassium penicillin (22,000 U/kg, IV, q 6 h), gentamicin (6.6 mg/kg, IV, q 24 h), and flunixin meglumine (1.1 mg/kg, IV, q 12 h) were administered, along with lactated Ringer's solution (2 L/h, IV) to which calcium gluconate had been added. Butorphanol was also added to the lactated Ringer's solution at a quantity sufficient to provide a dosage of 0.015 mg/kg/h (0.007 mg/lb/h). A 5% solution of dimethyl sulfoxide (1 g/kg [0.45 g/lb], IV) was administered once after surgery.
The mare's condition was stable overnight, and signs of femoral neuropathy remained unchanged. The following morning, a CBC revealed a decrease in WBC count (3.82 × 103 cells/μL; reference range, 5.5 to 10.49 cells/μL), and serum biochemical analyses revealed mild increases in serum creatine kinase (2,865 U/L; reference range, 147 to 635 U/L) and aspartate transaminase (639 U/L; reference range, 216 to 365 U/L) activities. Results were otherwise unremarkable. A milk calcium test was performed, and results (calcium, 14.9 mg/dL; reference range, < 20 mg/dL) were inconsistent with impending parturition.
Beginning approximately 33 hours after recovery from surgery, the mare began to show signs of worsening pain in the hind limbs, including muscle tremors, stomping of the hind feet, and agitated circling in the stall. The muscle tremors and foot stomping were worse in the left hind limb than in the right hind limb. The mare also had generalized hind limb weakness and was having difficulty standing. Administration of butorphanol was discontinued in case the agitation was a reaction to the opioid. Xylazine (0.25 to 0.3 mg/kg [0.11 to 0.14 mg/lb], IV) was administered on 3 occasions within an hour to help control pain, but the mare became progressively more anxious over the next hour. Detomidine hydrochloride (0.01 mg/kg [0.0045 mg/lb], IV) was then administered to allow for more extensive examination. Abdominal ultrasonography was performed and did not reveal any abnormalities of the fetus or placenta. Subjectively, motility of the small and large intestines was also normal. Palpation per rectum did not reveal any abnormalities, although the examination was incomplete because the mare showed signs of extreme agitation when forced to stand still. The mare began to sweat profusely, have diffuse muscle tremors, and circle compulsively to the left in its stall. If forced to stand still, the mare would obsessively stomp its left hind limb and, occasionally, its right hind limb and then begin circling again. When forced to turn around, the mare would begin circling to the right, but when taken out of the stall, would walk in a straight line. There had been no signs of CNS disease prior to the onset of circling.
Given the clinical signs, the history of femoral nerve damage, and the lack of response to conventional pain medications, a diagnosis of neuropathic pain was made. A constant rate infusion of lidocaine was initiated at a dosage of 0.05 mg/kg/min (0.023 mg/lb/min), IV, for additional analgesia. However, the mare remained extremely agitated and uncomfortable. Therefore, the constant rate infusion of lidocaine was discontinued, and a constant rate infusion of detomidine (4 μg/kg/h [1.8 μg/lb/h], IV) was begun. At this dosage, the mare became quite sedate and lay down in the stall. When the dosage was decreased to 3 μg/kg/h (1.4 μg/lb/h), the mare would again become agitated, despite being heavily sedated. Acepromazine maleate was administered at a dosage of 0.03 mg/kg (0.014 mg/lb), IV, with no apparent improvement in clinical signs. At this time, epidural administration of morphine was attempted; however, the procedure could not be performed because of excessive motion on the part of the mare.
Given the tentative diagnosis of neuropathic pain, a decision was made to begin treatment with gabapentin (2.5 mg/kg [1.1 mg/lb], PO, q 8 h), with the dosage extrapolated from the dosage used in small animals. The constant rate infusion of detomidine was continued at a dosage of 3 μg/kg/h, and 2 additional doses of acepromazine were administered 6 hours apart. Within 2 hours after administration of the first dose of gabapentin, the mare appeared less agitated. The compulsive circling in the stall decreased in frequency and eventually stopped within 36 hours after initiation of gabapentin administration, and although the mare continued to stomp its left hind limb, the frequency of stomping was greatly decreased.
The morning after administration of gabapentin was begun, treatment with detomidine and acepromazine was discontinued. After 24 hours of treatment with gabapentin, the dosage was decreased to 2.5 mg/kg, PO, every 12 hours, for an additional 3 days. During this time, the mare's condition continued to improve, with only mild muscle tremors and weakness in the left hind limb after walking and grazing. Intravenous administration of antimicrobials was discontinued 5 days after surgery, and the mare was weaned from the fluid therapy and flunixin treatment. Abdominal ultrasonography performed at that time did not reveal any abnormalities of the fetus or placenta; fetal heart rate was 85 beats/min. The mare had been started back on feed 2 days after surgery and was gradually reintroduced to a normal ration over 5 days.
After 3 days of administration at a dosage of 2.5 mg/kg every 12 hours, the gabapentin dosage was again decreased to 2.5 mg/kg every 24 hours for an additional 2 days, and administration was then discontinued. The mare was discharged 7 days after surgery. Results of serum biochemical analyses performed at the time of discharge were unremarkable, with the exception of slightly high serum aspartate transaminase activity (776 U/L). The mare was taken to a local veterinary practice to foal. Foaling was observed, but unassisted, and proceeded without complications. No abnormalities were detected in the foal. Shortly after parturition, the mare developed a uterine infection that was treated with uterine lavage and intrauterine administration of antimicrobials. The uterine infection resolved without complications, and the mare was reportedly doing well 6 weeks after surgery, with only mild signs of femoral nerve damage persisting in the left hind limb.
Discussion
Postoperative neuropathy with or without concomitant myopathy is a relatively common occurrence following general anesthesia in draft horses, with reported incidence rates ranging from 5% to 12%.1-3 The higher incidence of this complication in draft horses, compared with lighter horses, has been associated with the greater size and weight of draft horses in combination with prolonged duration of recumbency, improper positioning, and inadequate padding. It is also possible that in the mare described in the present report, the weight of the hind limb when placed in a frog-leg position may have caused some stretch damage to the femoral nerve. The presence of a large, near-term fetus may have contributed to the femoral nerve damage seen following surgery as a result of the additional weight.
Development of neuropathic pain following surgery in the mare described in the present report was unusual, in that to the authors' knowledge, neuropathic pain has not been reported previously in draft horses with postanesthetic neuropathies. The diagnosis of neuropathic pain can be difficult, and there are no specific tests to identify neuropathic pain in veterinary species. In general, the clinical picture in patients with neuropathic pain can be described as a delayed onset of pain in an area of sensory loss after development of a nervous system lesion.4 Experimental models involving surgically induced peripheral neuropathies have shown that hyperalgesic responses occur within 1 day after surgery,5 which was similar to the onset of signs of pain in the mare described in the present report.
The diagnosis of neuropathic pain was made in the mare described in the present report on the basis of clinical signs of peripheral nerve dysfunction following surgery and the response to treatment, after other possible causes of pain and neurologic disease were ruled out. Differential diagnoses considered for the signs of pain in this mare included neuropathic pain, traumatic musculoskeletal injury to the left hind limb, abdominal pain, and impending parturition. The lack of response to conventional analgesic treatment combined with normal findings during palpation per rectum and the lack of ultrasonographic abnormalities excluded parturition and recurrence of colic as potential causes of the signs of pain. Musculoskeletal injury was ruled out on the basis of results of limb palpation, including palpation of the muscles of the hind limb, and the fact that serum muscle enzyme activities were only mildly increased. Neurologic diseases that cause circling in horses generally include peripheral and central vestibular diseases and brainstem disease, although hepatic encephalopathy may also cause circling. These diseases were considered unlikely given the clinical signs, the ability of the mare to circle in both directions and to walk in a straight line if led, and the results of serum biochemical testing.
Treatment of neuropathic pain can be difficult because of the lack of understanding of the underlying pathophysiologic mechanisms involved, and a poor response to commonly used analgesic medications is typically seen. In general, following nerve injury, sensitization of the brain and dorsal horn of the spinal cord can occur, leading to an upregulation of the nociceptive system.4,6 The mechanism by which this happens may vary from patient to patient, and multiple mechanisms may be active in any individual patient. This makes choosing a therapeutic modality difficult in most cases. Classes of drugs that are frequently used to treat neuropathic pain in people include antidepressants (eg, amitriptyline),7 anticonvulsants (eg, gabapentin),6 sodium channel blockers (eg, lidocaine),8 and opioids (eg, butorphanol). Although opioids are effective in treating acute pain, they are generally considered to be poorly effective for treating neuropathic pain, and in fact, neither butorphanol nor lidocaine was effective in controlling signs of pain in the mare described in the present report. Consequently, gabapentin was chosen to treat the neuropathic pain in this mare. Alternatively, antidepressants could have been tried, but they were more expensive and not readily available.
Gabapentin was first discovered over 40 years ago. It is labeled for use in human medicine as an antiepileptic and for treatment of postherpetic neuralgia. Use as an adjunct for treatment of seizures in veterinary species has also been reported.9 In those species in which it has been studied, it has a favorable pharmacokinetic profile, has been associated with few acute or chronic toxicoses, and has no effect on the hepatic P450 enzyme system.10 To the authors' knowledge, use of gabapentin in a horse has not been reported previously.
Gabapentin was originally thought to act by increasing the concentration or receptor affinity of GABA in the CNS, which would explain its anticonvulsant and antianxiety effects as well as its effectiveness as a treatment for neuropathic pain. This theory has subsequently been questioned, however, as various studies6,11 have shown that gabapentin does not have any significant effects on GABAA or GABAB receptors or on GABA uptake in the CNS. Additionally, the antihyperalgesic effects of gabapentin are not reversed by the use of GABAB receptor antagonists.12 More recent work has shown that gabapentin binds to the α2δ subunits of voltage-dependent calcium-channel complexes.11,13 These α2δ subunits have been found in numerous tissues in humans and rats, including the brain, and affinity for this binding site has been correlated with the antihyperalgesic potency of gabapentin.14 Once bound to the subunit, gabapentin acts in an inhibitory manner, resulting in a decrease in calcium influx in presynaptic nerve terminals and inhibition of the release of excitatory amino acids.15 Interestingly, this effect was seen in only hyperalgesic subjects, and no effect was seen in control subjects, suggesting that the effects are stimulus dependent.11
In the mare described in the present report, the dosage of gabapentin was gradually decreased prior to discontinuing administration. Abrupt discontinuation of gabapentin administration has been associated with withdrawal-like symptoms in people (ie, agitation, anxiety, and irritability),16 seizures,17 and rebound pain. The mare was treated for a total of only 6 days, and no problems were seen following discontinuation of gabapentin administration.
The use of gabapentin in this mare appeared to be safe and effective and was also affordable. The cost of the generic gabapentin tablets that were used was $6/dose. During treatment, the mare appeared mildly sedated; however, she continued to eat and drink normally. Fecal production and gastrointestinal tract motility were normal throughout the treatment period. Gabapentin crosses the blood-placental barrier in other species,10,18 and in humans, umbilical cord blood concentrations of gabapentin are almost double the concentrations found in the mother's plasma, suggesting an active transport mechanism.18 However, differences in placentation between mares and humans make it difficult to extrapolate findings regarding drug transfer to the fetus in horses. Gabapentin has been shown to extensively distribute into the milk in humans18 and may also be present in mare's milk. There were no apparent ill effects on the fetus during the short term of treatment in the last month of gestation in the mare described in the present report. A preliminary study19 in humans did not show any increase in the risk of adverse maternal or fetal effects in women administered gabapentin during pregnancy.
Findings for the mare described in the present report suggest that gabapentin may have additional uses in equine medicine. Other neuropathic pain syndromes reported in horses include trigeminal neuralgia20 and complex regional pain syndrome.21 Gabapentin may also be useful for long-term sedation of horses in stall confinement, given the mild sedative effects observed in this mare. A dose of 2.5 mg/kg, PO, every 12 hours was effective in this mare. However, further work needs to be done to study the pharmacokinetics of this drug in horses and establish safety, efficacy, and optimal dosage regimens.
ABBREVIATIONS
| GABA | J-Aminobutyric acid |
References
- 1
Rothenbuhler R, Hawkins JF & Adams SB, et al. Evaluation of surgical treatment for signs of acute abdominal pain in draft horses: 72 cases (1983–2002). J Am Vet Med Assoc 2006;228:1546–1550.
- 2
Kraus BM, Parente EJ, Tulleners EP. Laryngoplasty with ventriculectomy or ventriculocordectomy in 104 draft horses (1992–2000). Vet Surg 2003;32:530–538.
- 3↑
Gleed R, Short CE. A retrospective study of the anesthetic management of adult draft horses. Vet Med Small Anim Clin 1980;75:1409–1416.
- 4↑
Jensen TS, Gottrup H & Sindrup SH, et al. The clinical picture of neuropathic pain. Eur J Pharmacol 2001;429:1–11.
- 5↑
Gustafsson H, Flood K & Berge OG, et al. Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Exp Neurol 2003;182:427–434.
- 6↑
Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain 2002;6 (suppl A):61–68.
- 7↑
Sindrup SH, Otto M & Finnerup NB, et al. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005;96:399–409.
- 8↑
Smith LJ, Shih A & Miletic G, et al. Continual systemic infusion of lidocaine provides analgesia in an animal model of neuropathic pain. Pain 2002;97:267–273.
- 9↑
Govendir M, Perkins M, Malik R. Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent. Aust Vet J 2005;83:602–608.
- 10↑
Radulovic LL, Turck D & vonHodenberg A, et al. Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab Dispos 1995;23:441–448.
- 11↑
Maneuf YP, Luo ZD, Lee K. alpha2delta and the mechanism of action of gabapentin in the treatment of pain. Semin Cell Dev Biol 2006;17:565–570.
- 12↑
Shimizu S, Honda M & Tanabe M, et al. GABAB receptors do not mediate the inhibitory actions of gabapentin on the spinal reflex in rats. J Pharmacol Sci 2004;96:444–449.
- 13
Gee NS, Brown JP & Dissanayake VU, et al. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 1996;271:5768–5776.
- 14↑
Field MJ, Hughes J, Singh L. Further evidence for the role of the alpha(2)delta subunit of voltage dependent calcium channels in models of neuropathic pain. Br J Pharmacol 2000;131:282–286.
- 15↑
Patel MK, Gonzalez MI & Bramwell S, et al. Gabapentin inhibits excitatory synaptic transmission in the hyperalgesic spinal cord. Br J Pharmacol 2000;130:1731–1734.
- 18↑
Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy? Epilepsia 2005;46:1621–1624.
- 19↑
Montouris G. Gabapentin exposure in human pregnancy: results from the Gabapentin Pregnancy Registry. Epilepsy Behav 2003;4:310–317.
- 20↑
Newton SA, Knottenbelt DC, Eldridge PR. Headshaking in horses: possible aetiopathogenesis suggested by the results of diagnostic tests and several treatment regimes used in 20 cases. Equine Vet J 2000;32:208–216.
- 21↑
Collins NM, Keen JA & Barakzai SZ, et al. Suspected complex regional pain syndrome in 2 horses. J Vet Intern Med 2006;20:1014–1017.
