• View in gallery

    Mean ± SD heart rate in 6 horses before and after administration of physiologic saline (0.9% NaCl) solution (black circles), butorphanol (white circles), acepromazine (inverted black triangles), or NBB (inverted white triangles). Butorphanol was administered IV as a bolus (18 μg/kg) followed by CRI at 13 μg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline solution (2 mL) were administered IV as a bolus followed by CRI of saline solution (10 mL/h) for 2 hours. Time of bolus administration was designated as time 0. *Within a treatment, value differs significantly (P < 0.05) from the value at time 0. Within a time point, value differs significantly (P < 0.05) from values for all other treatments.

  • View in gallery

    Mean ± SD respiratory rate in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

  • View in gallery

    Mean ± SD nose-to-ground height in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

  • View in gallery

    Mean ± SD colorectal distention threshold pressure in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

  • View in gallery

    Mean ± SD duodenal distention threshold pressure in 5 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. ‡Significant (P < 0.05) difference from time 0 because no time × group interaction was detected. See Figure 1 for remainder of key.

  • View in gallery

    Representative tracing of duodenal motility in a horse obtained by use of an automated barostat. Baseline pressure was set at 4 mm Hg. A bolus dose of NBB was administered IV at time 0. Stepwise inflation of a 20-cm diameter balloon inserted into the proximal portion of the duodenum (bar) was performed to ascertain duodenal distention threshold pressure.

  • 1.

    Traub-Dargatz JL, Kopral CA, Seitzinger AH, et al. Estimate of the national incidence of and operation-level risk factors for colic among horses in the United States, spring 1998 to spring 1999. J Am Vet Med Assoc 2001;219:6771.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Kaneene JB, Ross WA, Miller R. The Michigan equine monitoring system. II. Frequencies and impact of selected health problems. Prev Vet Med 1997;29:277292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Cole FL, Hodgson DR, Reid SW, et al. Owner-reported equine health disorders: results of an Australia-wide postal survey. Aust Vet J 2005;83:490495.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Cohen ND, Carter GK, Mealey RH, et al. Medical management of right dorsal colitis in 5 horses: a retrospective study (1987–1993). J Vet Intern Med 1995;9:272276.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Karcher LF, Dill SG, Anderson WI, et al. Right dorsal colitis. J Vet Intern Med 1990;4:247253.

  • 6.

    MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993;202:7177.

    • Search Google Scholar
    • Export Citation
  • 7.

    Glerum LE, Egger CM, Allen SW, et al. Analgesic effect of the transdermal fentanyl patch during and after feline ovariohysterectomy. Vet Surg 2001;30:351358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Robinson TM, Kruse-Elliott KT. Markel MD, et al. A comparison of transdermal fentanyl versus epidural morphine for analgesia in dogs undergoing major orthopedic surgery. J Am Anim Hosp Assoc 1999;35:95100.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Sloan PA, Moulin DE, Hays H. A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain. J Pain Symptom Manage 1998;16:102111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kamerling SG, Dequick DJ, Weckman TJ, et al. Dose-related effects of fentanyl on autonomic and behavioral responses in performance horses. Gen Pharmacol 1985;16:253258.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Roger T, Bardon T, Ruckebusch Y. Comparative effects of mu and kappa opiate agonists on the cecocolic motility in the pony. Can J Vet Res 1994;58:163166.

    • Search Google Scholar
    • Export Citation
  • 12.

    Bennett RC, Steffey EP. Use of opioids for pain and anesthetic management in horses. Vet Clin North Am Equine Pract 2002;18:4760.

  • 13.

    Johnston GM. The risks of the game: the confidential enquiry into perioperative equine fatalities. Br Vet J 1995;151:347350.

  • 14.

    Johnston GM, Eastment JK, Taylor PM, et al. Is isoflurane safer than halothane in equine anaesthesia? Results from a prospective multicentre randomised controlled trial. Equine Vet J 2004;36:6471.

    • Search Google Scholar
    • Export Citation
  • 15.

    Johnston GM, Taylor PM, Holmes MA, et al. Confidential enquiry of perioperative equine fatalities (CEPEF-1): preliminary results. Equine Vet J 1995;27:193200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Al Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 2000;119:12761285.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Steffey EP, Kelly AB, Farver TB, et al. Cardiovascular and respiratory effects of acetylpromazine and xylazine on halothane-anesthetized horses. J Vet Pharmacol Ther 1985;8:290302.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Marntell S, Nyman G, Funkquist P, et al. Effects of acepromazine on pulmonary gas exchange and circulation during sedation and dissociative anaesthesia in horses. Vet Anaesth Analg 2005;32:8393.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Muir WW. Standing chemical restraint in horses: tranquilizers, sedatives and analgesics. In: Muir WW, Hubbell JA, eds. Equine anesthesia: monitoring and emergency therapy. St Louis: Mosby Year Book, 1991;247260.

    • Search Google Scholar
    • Export Citation
  • 20.

    Doherty TJ, Andrews FM, Provenza MK, et al. The effect of sedation on gastric emptying of a liquid marker in ponies. Vet Surg 1999;28:375379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Wooldridge AA, Eades SC, Hosgood GL, et al. Effects of treatment with oxytocin, xylazine butorphanol, guaifenesin, acepromazine, and detomidine on esophageal manometric pressure in conscious horses. Am J Vet Res 2002;63:17381744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Wooldridge AA, Eades SC, Hosgood GL, et al. In vitro effects of oxytocin, acepromazine, detomidine, xylazine, butorphanol, terbutaline, isoproterenol, and dantrolene on smooth and skeletal muscles of the equine esophagus. Am J Vet Res 2002;63:17321737.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Davies JV, Gerring EL. Effect of spasmolytic analgesic drugs on the motility patterns of the equine small intestine. Res Vet Sci 1983;34:334339.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Briggs SL, Sneed K, Sawyer DC. Antinociceptive effects of oxymorphone-butorphanol-acepromazine combination in cats. Vet Surg 1998;27:466472.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Kalpravidh M, Lumb WV, Wright M, et al. Effects of butorphanol, flunixin, levorphanol, morphine, and xylazine in ponies. Am J Vet Res 1984;45:217223.

    • Search Google Scholar
    • Export Citation
  • 26.

    Kalpravidh M, Lumb WV, Wright M, et al. Analgesic effects of butorphanol in horses: dose-response studies. Am J Vet Res 1984;45:211216.

  • 27.

    Merritt AM, Burrow JA, Hartless CS. Effect of xylazine, detomidine, and a combination of xylazine and butorphanol on equine duodenal motility. Am J Vet Res 1998;59:619623.

    • Search Google Scholar
    • Export Citation
  • 28.

    Sellon DC, Monroe VL, Roberts MC, et al. Pharmacokinetics and adverse effects of butorphanol administered by single intravenous injection or continuous intravenous infusion in horses. Am J Vet Res 2001;62:183189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Sellon DC, Roberts MC, Blikslager AT, et al. Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J Vet Intern Med 2004;18:555563.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Boatwright CE, Fubini SL, Grohn YT, et al. A comparison of N-butylscopolammonium bromide and butorphanol tartrate for analgesia using a balloon model of abdominal pain in ponies. Can J Vet Res 1996;60:6568.

    • Search Google Scholar
    • Export Citation
  • 31.

    Roelvink ME, Goossens L, Kalsbeek HC, et al. Analgesic and spasmolytic effects of dipyrone, hyoscine-N-butylbromide and a combination of the two in ponies. Vet Rec 1991;129:378380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Campbell-Thompson ML, Merritt AM. Basal and pentagastrin-stimulated gastric secretion in young horses. Am J Physiol 1990;259:R1259R1266.

    • Search Google Scholar
    • Export Citation
  • 33.

    Robertson SA, Sanchez LC, Merritt AM, et al. Effect of systemic lidocaine on visceral and somatic nociception in conscious horses. Equine Vet J 2005;37:122127.

    • Search Google Scholar
    • Export Citation
  • 34.

    Dixon MJ, Robertson SA, Taylor PM. A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 2002;72:205210.

  • 35.

    Lascelles BD, Robertson SA. Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats. Am J Vet Res 2004;65:10851089.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Johnson JA, Robertson SA, Pypendop BH. Antinociceptive effects of butorphanol, buprenorphine, or both, administered intramuscularly in cats. Am J Vet Res 2007;68:699703.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Skarda RT, Muir WW III. Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular effects and rectal pain threshold after controlled rectal distention in mares. Am J Vet Res 2003;64:137144.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Muir WW, Robertson JT. Visceral analgesia: effects of xylazine, butorphanol, meperidine, and pentazocine in horses. Am J Vet Res 1985;46:20812084.

    • Search Google Scholar
    • Export Citation
  • 39.

    Brunson DB, Majors LJ. Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse, using dental dolorimetry. Am J Vet Res 1987;48:10871091.

    • Search Google Scholar
    • Export Citation
  • 40.

    Doherty TJ, Geiser DR, Rohrbach BW. Effect of acepromazine and butorphanol on halothane minimum alveolar concentration in ponies. Equine Vet J 1997;29:374376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 1994;107:271293.

  • 42.

    Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 2001;93:714.

Advertisement

Effect of acepromazine, butorphanol, or N-butylscopolammonium bromide on visceral and somatic nociception and duodenal motility in conscious horses

View More View Less
  • 1 Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.
  • | 2 Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.
  • | 3 Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.

Abstract

Objective—To evaluate effects of butorphanol, acepromazine, and N-butylscopolammonium bromide (NBB) on visceral and somatic nociception and duodenal motility in conscious, healthy horses.

Animals—6 adult horses.

Procedures—Visceral nociception was evaluated by use of colorectal distention (CRD) and duodenal distention (DD) threshold. Somatic nociception was evaluated via thermal threshold (TT). Nose-to-ground height, heart rate, and respiratory rate were also measured. Each horse received each treatment in randomized order; investigators were not aware of treatments. Butorphanol was administered IV as a bolus (18 μg/kg) followed by constant rate infusion at 13 μg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline (0.9% NaCl) solution (2 mL) were administered IV as a bolus followed by constant rate infusion with saline solution (10 mL/h) for 2 hours. Variables were measured before and for 3 hours after treatment. Data were analyzed by use of a 3-factor ANOVA followed by a Bonferroni t test for multiple comparisons.

Results—Nose-to-ground height decreased after acepromazine. Respiratory rate decreased after acepromazine and increased after butorphanol. Heart rate increased briefly after NBB. Some horses had an increase in TT after butorphanol and acepromazine, but there was not a significant treatment effect over time. Drug effect on DD or motility was not evident. The CRD threshold increased significantly at 5, 65, 155, and 185 minutes after acepromazine and from 5 to 65 minutes after NBB.

Conclusions and Clinical Relevance—Each drug caused predictable changes in sedation and vital signs, but consistent anti-nociceptive effects were not evident.

Abstract

Objective—To evaluate effects of butorphanol, acepromazine, and N-butylscopolammonium bromide (NBB) on visceral and somatic nociception and duodenal motility in conscious, healthy horses.

Animals—6 adult horses.

Procedures—Visceral nociception was evaluated by use of colorectal distention (CRD) and duodenal distention (DD) threshold. Somatic nociception was evaluated via thermal threshold (TT). Nose-to-ground height, heart rate, and respiratory rate were also measured. Each horse received each treatment in randomized order; investigators were not aware of treatments. Butorphanol was administered IV as a bolus (18 μg/kg) followed by constant rate infusion at 13 μg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline (0.9% NaCl) solution (2 mL) were administered IV as a bolus followed by constant rate infusion with saline solution (10 mL/h) for 2 hours. Variables were measured before and for 3 hours after treatment. Data were analyzed by use of a 3-factor ANOVA followed by a Bonferroni t test for multiple comparisons.

Results—Nose-to-ground height decreased after acepromazine. Respiratory rate decreased after acepromazine and increased after butorphanol. Heart rate increased briefly after NBB. Some horses had an increase in TT after butorphanol and acepromazine, but there was not a significant treatment effect over time. Drug effect on DD or motility was not evident. The CRD threshold increased significantly at 5, 65, 155, and 185 minutes after acepromazine and from 5 to 65 minutes after NBB.

Conclusions and Clinical Relevance—Each drug caused predictable changes in sedation and vital signs, but consistent anti-nociceptive effects were not evident.

Colic and lameness represent 2 of the biggest causes of morbidity and fatalities in horses throughout the world.1–3 The most commonly used analgesics in horses are the nonsteroidal antiinflammatory drugs flunixin meglumine and phenylbutazone, both of which can be associated with effects on the gastrointestinal tract, such as gastric ulcers and right dorsal colitis.4–6 In other species, opioids, including fentanyl, buprenorphine, and morphine, are commonly used as analgesics for animals with moderate to severe pain.7–9 In horses, however, the use of opioids has been limited because of the perception that these agents commonly cause unacceptable adverse effects, such as CNS excitation, increased locomotor activity, and decreased gastrointestinal tract motility.10–12

Acepromazine is a phenothiazine tranquilizer that is widely used by equine practitioners. Acepromazine clearly reduces the risk of perioperative death in horses,13–16 and this effect may be a result of its antiarrhythmic, hemodynamic, calming, or anesthetic-sparing actions. In normovolemic anesthetized horses, acepromazine (0.03 and 0.06 mg/kg, IV) caused a significant decrease in total peripheral resistance and arterial blood pressure but a significant and sustained increase in cardiac output.17 Acepromazine added to a sedation protocol of romifidine (an α2-adrenergic receptor agonist) and butorphanol improved hemodynamic variables and arterial oxygenation during the sedation period as well as the subsequent anesthetic episode.18

Phenothiazine tranquilizers decrease smooth muscle tone and peristalsis, probably through a central depressant effect or peripheral anticholinergic action19; however, despite the widespread use of acepromazine, little is known about its actions on the gastrointestinal tract in horses. Use of a liquid marker revealed that acepromazine delays gastric emptying in ponies.20 Acepromazine can alter activity of esophageal smooth muscle, which induces a relaxant effect and a change in the peristaltic pattern.21,22 In a study23 in which investigators used 3 ponies prepared with Thiry-Vella loops (ie, isolated segments of jejunum), bipolar electrodes, and strain gauge transducers, acepromazine reduced electrical activity, compared with baseline values, but volume transport through the gastrointestinal tract was increased. In a study24 to evaluate experimentally induced visceral pain in cats (inflation of a rectal balloon), the addition of acepromazine to butorphanol and oxymorphone significantly increased the degree of antinociception.

Hemodynamic advantages of acepromazine may be lost in volume-depleted animals; however, many horses with signs of abdominal pain attributable to so-called spasmodic colic are not dehydrated, and assuming intestinal effects of acepromazine are beneficial, it could be a useful drug in the management of these affected horses. The α2-adrenergic receptor agonists are commonly used in horses with signs of abdominal pain to provide analgesia and sedation, yet these agonists have important negative effects on cardiopulmonary function.

The synthetic opioid butorphanol is an agonist at κ (ie, OP2) receptors but an antagonist at μ (ie, OP3) receptors. When administered by bolus injection, butorphanol provides a moderate degree of somatic analgesia and a slightly greater degree of visceral analgesia in horses; however, it also causes decreases in gastrointestinal tract motility25–28 It has been suggested that administration of this agent via CRI reduces the adverse effects on gastrointestinal tract motility, but objective data about the analgesic efficacy for this protocol are limited.28,29 In 1 study,29 investigators reported that the clinical efficacy of butorphanol administered via CRI in postoperative colic patients had definite promise for analgesia without substantial risk of postoperative ileus. Thus, objective analysis of this protocol for somatic and visceral analgesia as well as gastrointestinal tract motility would provide much needed direct evidence for expanding the clinical use of CRI of butorphanol in horses with lameness as well as in nonstrangulating or postoperative colic patients.

N-butylscopolammonium bromide has anticholinergic and antispasmodic properties and has been commercially available in Europe (in combination with hyoscine) for the treatment of horses with spasmodic colic for many years. It has recently been approved (without hyoscine) for similar use in the United States. In experiments in which distention of a cecal balloon was used, NBB had an analgesic effect in 6 of 8 ponies in 1 study,30 In a similar study,31 NBB had a brief analgesic effect as well as a transient negative effect on cecal contractions in ponies.

Thus, the objective of the study reported here was to use each of 3 drugs (butorphanol, acepromazine, and NBB) at commonly used clinical dosages to evaluate visceral and somatic nociception and duodenal motility in conscious, clinically normal horses. Our hypotheses were that each drug would provide significant visceral antinociception in conscious horses, that only butorphanol would provide significant somatic antinociception, and that NBB and butorphanol (but not acepromazine) would decrease duodenal motility.

Materials and Methods

Animals—Six adult Thoroughbred or Thoroughbred-crossbred horses (3 mares and 3 geldings; mean age, 13.2 years [range, 7 to 23 years]; mean body weight, 538 kg [range, 485 to 608 kg]) were used in the study. Each had a permanently implanted gastric cannula,32 which had been inserted at least 2 years prior to the start of our study. Between trials, horses were housed on pasture, where they had unlimited access to water, a mineral block, paddock grass, and coastal hay and received sweet feed twice daily to maintain body condition. All horses were clinically normal with no evidence of gastrointestinal tract disease. Horses were moved to a stall 12 to 18 hours prior to each trial, where they had unlimited access to water but not to feed. Mares were used during behavioral diestrus. All procedures were approved by the University of Florida Institutional Animal Care and Use Committee (protocol No. E164).

Treatments—For the experimental procedures, each horse was restrained in stocks by lead ropes loosely attached to the halter; all horses were familiar with the testing procedures. A minimum of 1 week was allowed between treatments. Each horse received each of 4 treatments (physiologic saline [0.9% NaCl] solution, butorphanol tartrate,a acepromazine maleate,b and NBBC) in accordance with a randomized block design. Saline solution was administered IV as a bolus injection of 2 mL followed by CRI of saline solution at 10 mL/h for 2 hours. Butorphanol was administered IV as a bolus (18 μg/kg) followed by CRI (13 μg/kg/h diluted in saline solution to achieve a final rate of 10 mL/h) for 2 hours. Acepromazine was administered IV as a bolus (0.04 mg/kg) followed by CRI of saline solution at 10 mL/h for 2 hours. The NBB was administered IV as a bolus (0.3 mg/kg) followed by CRI of saline solution at 10 mL/h for 2 hours. Bolus doses were administered in ≤ 5 seconds. All CRIs were accomplished by use of a syringe pump.d.

Thermal threshold—Thermal threshold was determined as described elsewhere.33 Briefly, a probe with heater and temperature sensor elements was placed flat on a shaved area over the most-dorsal aspect of the shoulders (ie, withers) of each horse and connected to a threshold testing device by use of a long cable that enabled the horses to move during and between tests.34 A cutoff point of 45°C was used to prevent thermal burns. Probes were calibrated prior to attachment to each horse and allowed to equilibrate to skin temperature for at least 10 minutes prior to testing. A positive response was recorded when a horse twitched its withers or turned its head to look at its side.

Colorectal distention—Colorectal distention was performed as described elsewhere.33 Briefly, a 45-cm diameter balloone (total capacity of 12 L) attached to pressure and transducer tubing was placed within the rectum at a point 45 to 50 cm proximal to the external anal sphincter. Balloon distention was computer controlled by use of an electronic barostat,f and a ramp distention protocol (2 mm Hg at the start, which was followed by increases of 2 mm Hg every 20 seconds) was initiated. Maximum pressure was 45 mm Hg. Expulsion of the balloon was considered a positive response.

Duodenal distention and motility—The gastric cannula was opened. Residual stomach contents were flushed from the cannula, and the cannula was drained. Balloon placement and the duodenal distention protocol were similar to those described elsewhere.33 Briefly, endoscopic guidance was used to insert a 20-cm diameter balloong approximately 100 cm aborad to the gastroduodenal sphincter. Inflation was controlled by use of an electronic barostatf (15 mm Hg at the start, which was followed by increases of 5 mm Hg every 60 seconds). Maximum pressure was 45 mm Hg. A positive response required at least 2 signs of abdominal discomfort (pawing the ground, looking at the flank, rapid shifting of weight bearing in the hind limbs, kicking at the abdomen, or a flehmen reaction).

Between distention periods, the balloon was maintained at a baseline pressure of 2 mm Hg. Continuous volume or pressure recordings were used for the assessment of duodenal motility. Two variables were used to assess motility. A contraction was defined as a deflection of pressure > 5 mm Hg from the baseline pressure. Frequency was defined as the number of contractions per unit time. Amplitude of a given contraction was defined as the deflection of pressure from the baseline pressure. Frequency and amplitude were each compiled in 15-minute blocks for the duration of each experiment, and periods during duodenal distentions were excluded.

Measurement of variables—Investigators who recorded all data were unaware of the treatment administered to each horse. Prior to each treatment, thermal threshold was measured 3 times with at least a 15-minute interval between measurements. Colorectal distention, heart rate (by manual palpation of the facial artery), respiratory rate (by visual observation), general attitude, and nose-to-ground distance were measured once prior to initiation of treatment, whereas duodenal distention was measured twice prior to initiation of treatment. Tape measures permanently attached to the stocks were used for determination of the nose-to-ground distance.

Initial injection of the treatments was designated as time 0. All measurements were conducted again 5 minutes after initial administration. Thereafter, attitude, thermal threshold, heart rate, respiratory rate, and nose-to-ground distance were determined every 15 minutes for 3 hours, whereas colorectal distention and duodenal distention thresholds were determined every 30 minutes for 3 hours. Testing order for colorectal distention and duodenal distention was randomly assigned by a coin toss. When thermal, duodenal, and colorectal threshold measurements were conducted at the same time point, thermal threshold was always determined first.

Statistical analysis—When a horse reached the maximum allowable value for a given response variable, the maximum value was used as the threshold response for that variable. Data were analyzed by use of a splitplot ANOVA in accordance with the model Y = treatment + period + horse + erro1 + time + (treatment × time) + error2, where Y is the response variable, error1 is error2 for treatment and period, and error is error for time and treatment × time. Response variables were skin temperature, thermal threshold, colorectal distention pressure, duodenal distention pressure, nose-to-ground distance, heart rate, and respiratory rate. Because period was not a significant factor for any of the response variables, period was eliminated from each model and data were then analyzed by use of a 3-factor ANOVA with the fixed factors of time and treatment and the random factor of horse. When significant main effects or interactions were detected, post hoc comparisons were made by use of the Bonferroni t test. A commercial software programh was used for all analyses, and values of P < 0.05 were considered significant. For post hoc comparisons, the critical value of P = 0.05 was divided by the number of comparisons.

Results

Animals—Overall, all treatments were tolerated well by most horses. One horse became agitated and had evidence of visceral discomfort consistent with clinical signs of colic immediately after NBB administration. This behavior resolved after treatment with xylazine hydrochloride and flunixin meglumine, but experimental evaluation was discontinued immediately and NBB was not readministered to that horse. No other adverse events or alterations in general attitude were detected.

Heart rate—After NBB administration, heart rate was increased from 5 to 35 minutes, compared with the value at time 0 (Figure 1). Heart rate was also increased after NBB administration, compared with the rate after butorphanol administration from 5 to 50 minutes and after administration of saline solution and acepromazine from 5 to 80 minutes.

Figure 1—
Figure 1—

Mean ± SD heart rate in 6 horses before and after administration of physiologic saline (0.9% NaCl) solution (black circles), butorphanol (white circles), acepromazine (inverted black triangles), or NBB (inverted white triangles). Butorphanol was administered IV as a bolus (18 μg/kg) followed by CRI at 13 μg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline solution (2 mL) were administered IV as a bolus followed by CRI of saline solution (10 mL/h) for 2 hours. Time of bolus administration was designated as time 0. *Within a treatment, value differs significantly (P < 0.05) from the value at time 0. Within a time point, value differs significantly (P < 0.05) from values for all other treatments.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Respiratory rate—After butorphanol administration, respiratory rate was increased from 125 to 185 minutes, compared with the rate at time 0 (Figure 2). Butorphanol administration also resulted in a significant increase in respiratory rate, compared with the rate after administration of acepromazine, from 50 to 185 minutes. Acepromazine administration resulted in a decreased respiratory rate, compared with the rate after administration of saline solution at 110, 155, 170, and 185 minutes and after administration of NBB from 95 to 125 minutes and again at 170 minutes.

Figure 2—
Figure 2—

Mean ± SD respiratory rate in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Nose-to-ground height—After acepromazine administration, the nose-to-ground height was significantly less, compared with the height at time 0, (Figure 3). Nose-to-ground height after administration of acepromazine was also significantly less, compared with height after administration of butorphanol and NBB at 20 to 185 minutes and after administration of saline solution from 20 to 170 minutes.

Figure 3—
Figure 3—

Mean ± SD nose-to-ground height in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Thermal threshold—One horse did not respond to the thermal threshold device; thus, data were available for only 5 horses. Twenty minutes after butorphanol administration, mean ± SD thermal threshold (44.7 ± 0.6°C) was significantly higher, compared with the value at time 0 (41.2 ± 1.1°C). Thermal threshold at 20 minutes after butorphanol administration also was significantly higher, compared with values at the same time point after administration of saline solution (40.2 ± 2.3°C), acepromazine (40.9 ± 2.0°C), and NBB (41.1 ± 2.4°C). A few other sporadic significant differences were detected, including a higher thermal threshold at 50 minutes after acepromazine administration, compared with the value after administration of saline solution (43.9 ± 2.7°C and 40.7 ± 2.0°C, respectively), and a higher threshold at 125 minutes after administration of acepromazine, compared with the value after administration of NBB (43.9 ± 1.9°C and 40.4 ± 1.6°C, respectively). Thermal threshold was significantly lower 185 minutes after administration of saline solution, compared with the value at time 0 (38.9 ± 1.1°C and 42.9 ± 0.7°C, respectively). At 185 minutes after administration of saline solution, thermal threshold was also significantly lower, compared with values after administration of acepromazine (43.2 ± 1.5°C) and NBB (43.1 ± 1.4°C).

Colorectal distention threshold—The colorectal distention threshold was increased at 5, 65, 155, and 185 minutes after acepromazine administration, compared with the value at time 0 (Figure 4). Acepromazine also caused an increase in colorectal distention threshold, compared with values after administration of saline solution and butorphanol at 65, 125, 155, and 185 minutes and after administration of NBB at 155 and 185 minutes. The threshold was increased at 5, 35, and 65 minutes after NBB administration, compared with the value at time 0. The colorectal threshold was also increased after administration of NBB, compared with the value after administration of saline solution at 5 minutes and after administration of butorphanol at 35 minutes.

Figure 4—
Figure 4—

Mean ± SD colorectal distention threshold pressure in 6 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. See Figure 1 for key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Duodenal distention threshold—Because of the anatomic location of the gastric cannula, insertion of the duodenal balloon was not possible in 1 horse. Therefore, data on duodenal distention and motility were available for only 5 horses. There were no significant differences among treatments. There was an overall decrease in duodenal distention threshold from 65 to 185 minutes, compared with the value at baseline (Figure 5).

Figure 5—
Figure 5—

Mean ± SD duodenal distention threshold pressure in 5 horses before and after administration of physiologic saline solution, butorphanol, acepromazine, or NBB. ‡Significant (P < 0.05) difference from time 0 because no time × group interaction was detected. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Duodenal motility—We did not detect significant differences among treatments for frequency or amplitude of duodenal contractions. For all treatments, amplitude was decreased from 15 to 195 minutes and frequency was decreased from 105 to 195 minutes, compared with the amplitude and frequency, respectively, at time 0. When evaluating individual motility tracings, an immediate profound effect of NBB administration was apparent, but this effect was extremely brief (15 to 20 minutes; Figure 6).

Figure 6—
Figure 6—

Representative tracing of duodenal motility in a horse obtained by use of an automated barostat. Baseline pressure was set at 4 mm Hg. A bolus dose of NBB was administered IV at time 0. Stepwise inflation of a 20-cm diameter balloon inserted into the proximal portion of the duodenum (bar) was performed to ascertain duodenal distention threshold pressure.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.579

Discussion

Butorphanol administration provided a brief period of somatic antinociception but a nonsignificant alteration in indices of visceral antinociception. Because the SD was greater than expected in some measurements, the sample size used in the study reported here may have precluded detection of a small difference between treatments (type II error). This may be especially true for the thermal threshold measurements after butorphanol administration because many horses received the maximum temperature; thus, they were recorded as 45°C even though their actual threshold may have been higher. In addition, large individual variations in thermal antinociception have been reported for butorphanol in other species, with some animals being considered nonresponders.35,36.

Regardless of the constraints attributable to sample size, all visceral threshold measurements decreased after bolus administration and any pattern toward an effect was not continued throughout the CRI of butorphanol. This differs from a clinical report29 whereby there was a reduction in pain scores after colic surgery during a 24-hour infusion of butorphanol. This could have been because butorphanol administration decreased the initial painful stimuli immediately after surgery, which thus prevented a wind-up phenomenon. Butorphanol administered IV as a bolus has provided somatic and visceral antinociception in other horses with experimentally induced pain,37–39 and in cats it provided somatic antinociception.35.

Administration of NBB resulted in tachycardia and visceral antinociception, which was indicated by a significant increase in colorectal distention threshold and a slight but nonsignificant increase in duodenal distention threshold. These changes were of short duration (15 to 20 minutes), which is similar to results in other reports.30,31 The effect of NBB on duodenal motility was obvious and consistent when evaluation of the individual traces for each horse was conducted. But because the group × time interaction was not significant (P = 0.228), any subsequent comparisons could not be made with statistical confidence. Thus, this could have been a type II error and would need a larger sample size or, potentially, to be broken down into smaller time periods immediately following the bolus injection to make this conclusion. Administration of a combination of NBB and hyoscine can decrease cecal contractions for 20 minutes.31 In that study, the NBB-hyoscine combination did not provide an antinociceptive effect. Butorphanol and NBB have similar periods of visceral antinociception after bolus injection at dosages of 0.1 and 0.3 mg/kg, respectively, in horses with experimentally induced cecal distention.30.

Acepromazine administration resulted in prolonged sedation, which was indicated by a decrease in nose-to-ground height. Acepromazine administration also resulted in a decrease in respiratory rate, as well as an increase in colorectal distention threshold, at various time points later in the study. A reason for these effects was not clear because these changes did not coincide with the peak period of sedation (35 minutes) or with each other. Although typically classified as a sedative without analgesic effects, acepromazine has minimum alveolar concentration–sparing effects for halothane when administered alone or in conjunction with butorphanol, whereas butorphanol has an inconsistent effect.40 The difference between alterations in duodenal and colorectal distention thresholds was likely related to the criteria used for a positive response. Because expulsion of the balloon was used for determination of the colorectal distention threshold, this may have been related to an urge-to-defecate endpoint, rather than an endpoint for a noxious stimulus. This is consistent with the lower threshold pressures detected with this testing modality. In other species, pressures > 40 to 60 mm Hg are considered noxious.41,42 Thus, the acepromazine-related alteration in colorectal distention threshold may have been related to sedation and alteration of the urge-to-defecate response, rather than to true visceral analgesia.

Each treatment in the study reported here caused a predictable change in sedation or vital signs. Butorphanol administration resulted in a brief somatic antinociceptive effect, and butorphanol, acepromazine, or NBB administration resulted in a visceral colorectal distention antinociceptive effect of varying duration. Also, none of the treatments caused a significant decrease in duodenal motility although administration of NBB consistently resulted in a visual change in motility pattern of extremely short duration. From a clinical perspective, the negative effects of butorphanol administration on duodenal motility may be limited to bolus injection. However, additional investigations into the effects of prolonged administration of butorphanol via CRI are warranted.

ABBREVIATIONS

CRI

Constant rate infusion

NBB

N-butylscopolammonium bromide

a.

Torbugesic, Wyeth, Madison, NJ.

b.

Acepromazine maleate injection, Boehringer Ingelhiem Vetmedica Inc, St Joseph, Mo.

c.

Buscopan, Boehringer Ingelhiem Vetmedica Inc, St Joseph, Mo.

d.

Medfusion Protégé 3010, Medex Inc, Carlsbad, Calif.

e.

18-inch Mylar balloon, Factory Card Outlet, Gainesville, Fla.

f.

Isobar 3, G&J Electronics, Willowdale, ON, Canada.

g.

12-inch Mylar balloon, Factory Card Outlet, Gainesville, Fla.

h.

PROC MIXED, SAS, version 9.1, SAS Institute Inc, Cary NC.

References

  • 1.

    Traub-Dargatz JL, Kopral CA, Seitzinger AH, et al. Estimate of the national incidence of and operation-level risk factors for colic among horses in the United States, spring 1998 to spring 1999. J Am Vet Med Assoc 2001;219:6771.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Kaneene JB, Ross WA, Miller R. The Michigan equine monitoring system. II. Frequencies and impact of selected health problems. Prev Vet Med 1997;29:277292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Cole FL, Hodgson DR, Reid SW, et al. Owner-reported equine health disorders: results of an Australia-wide postal survey. Aust Vet J 2005;83:490495.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Cohen ND, Carter GK, Mealey RH, et al. Medical management of right dorsal colitis in 5 horses: a retrospective study (1987–1993). J Vet Intern Med 1995;9:272276.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Karcher LF, Dill SG, Anderson WI, et al. Right dorsal colitis. J Vet Intern Med 1990;4:247253.

  • 6.

    MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993;202:7177.

    • Search Google Scholar
    • Export Citation
  • 7.

    Glerum LE, Egger CM, Allen SW, et al. Analgesic effect of the transdermal fentanyl patch during and after feline ovariohysterectomy. Vet Surg 2001;30:351358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Robinson TM, Kruse-Elliott KT. Markel MD, et al. A comparison of transdermal fentanyl versus epidural morphine for analgesia in dogs undergoing major orthopedic surgery. J Am Anim Hosp Assoc 1999;35:95100.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Sloan PA, Moulin DE, Hays H. A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain. J Pain Symptom Manage 1998;16:102111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kamerling SG, Dequick DJ, Weckman TJ, et al. Dose-related effects of fentanyl on autonomic and behavioral responses in performance horses. Gen Pharmacol 1985;16:253258.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Roger T, Bardon T, Ruckebusch Y. Comparative effects of mu and kappa opiate agonists on the cecocolic motility in the pony. Can J Vet Res 1994;58:163166.

    • Search Google Scholar
    • Export Citation
  • 12.

    Bennett RC, Steffey EP. Use of opioids for pain and anesthetic management in horses. Vet Clin North Am Equine Pract 2002;18:4760.

  • 13.

    Johnston GM. The risks of the game: the confidential enquiry into perioperative equine fatalities. Br Vet J 1995;151:347350.

  • 14.

    Johnston GM, Eastment JK, Taylor PM, et al. Is isoflurane safer than halothane in equine anaesthesia? Results from a prospective multicentre randomised controlled trial. Equine Vet J 2004;36:6471.

    • Search Google Scholar
    • Export Citation
  • 15.

    Johnston GM, Taylor PM, Holmes MA, et al. Confidential enquiry of perioperative equine fatalities (CEPEF-1): preliminary results. Equine Vet J 1995;27:193200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Al Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 2000;119:12761285.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Steffey EP, Kelly AB, Farver TB, et al. Cardiovascular and respiratory effects of acetylpromazine and xylazine on halothane-anesthetized horses. J Vet Pharmacol Ther 1985;8:290302.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Marntell S, Nyman G, Funkquist P, et al. Effects of acepromazine on pulmonary gas exchange and circulation during sedation and dissociative anaesthesia in horses. Vet Anaesth Analg 2005;32:8393.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Muir WW. Standing chemical restraint in horses: tranquilizers, sedatives and analgesics. In: Muir WW, Hubbell JA, eds. Equine anesthesia: monitoring and emergency therapy. St Louis: Mosby Year Book, 1991;247260.

    • Search Google Scholar
    • Export Citation
  • 20.

    Doherty TJ, Andrews FM, Provenza MK, et al. The effect of sedation on gastric emptying of a liquid marker in ponies. Vet Surg 1999;28:375379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Wooldridge AA, Eades SC, Hosgood GL, et al. Effects of treatment with oxytocin, xylazine butorphanol, guaifenesin, acepromazine, and detomidine on esophageal manometric pressure in conscious horses. Am J Vet Res 2002;63:17381744.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Wooldridge AA, Eades SC, Hosgood GL, et al. In vitro effects of oxytocin, acepromazine, detomidine, xylazine, butorphanol, terbutaline, isoproterenol, and dantrolene on smooth and skeletal muscles of the equine esophagus. Am J Vet Res 2002;63:17321737.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Davies JV, Gerring EL. Effect of spasmolytic analgesic drugs on the motility patterns of the equine small intestine. Res Vet Sci 1983;34:334339.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Briggs SL, Sneed K, Sawyer DC. Antinociceptive effects of oxymorphone-butorphanol-acepromazine combination in cats. Vet Surg 1998;27:466472.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Kalpravidh M, Lumb WV, Wright M, et al. Effects of butorphanol, flunixin, levorphanol, morphine, and xylazine in ponies. Am J Vet Res 1984;45:217223.

    • Search Google Scholar
    • Export Citation
  • 26.

    Kalpravidh M, Lumb WV, Wright M, et al. Analgesic effects of butorphanol in horses: dose-response studies. Am J Vet Res 1984;45:211216.

  • 27.

    Merritt AM, Burrow JA, Hartless CS. Effect of xylazine, detomidine, and a combination of xylazine and butorphanol on equine duodenal motility. Am J Vet Res 1998;59:619623.

    • Search Google Scholar
    • Export Citation
  • 28.

    Sellon DC, Monroe VL, Roberts MC, et al. Pharmacokinetics and adverse effects of butorphanol administered by single intravenous injection or continuous intravenous infusion in horses. Am J Vet Res 2001;62:183189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Sellon DC, Roberts MC, Blikslager AT, et al. Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J Vet Intern Med 2004;18:555563.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Boatwright CE, Fubini SL, Grohn YT, et al. A comparison of N-butylscopolammonium bromide and butorphanol tartrate for analgesia using a balloon model of abdominal pain in ponies. Can J Vet Res 1996;60:6568.

    • Search Google Scholar
    • Export Citation
  • 31.

    Roelvink ME, Goossens L, Kalsbeek HC, et al. Analgesic and spasmolytic effects of dipyrone, hyoscine-N-butylbromide and a combination of the two in ponies. Vet Rec 1991;129:378380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Campbell-Thompson ML, Merritt AM. Basal and pentagastrin-stimulated gastric secretion in young horses. Am J Physiol 1990;259:R1259R1266.

    • Search Google Scholar
    • Export Citation
  • 33.

    Robertson SA, Sanchez LC, Merritt AM, et al. Effect of systemic lidocaine on visceral and somatic nociception in conscious horses. Equine Vet J 2005;37:122127.

    • Search Google Scholar
    • Export Citation
  • 34.

    Dixon MJ, Robertson SA, Taylor PM. A thermal threshold testing device for evaluation of analgesics in cats. Res Vet Sci 2002;72:205210.

  • 35.

    Lascelles BD, Robertson SA. Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats. Am J Vet Res 2004;65:10851089.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Johnson JA, Robertson SA, Pypendop BH. Antinociceptive effects of butorphanol, buprenorphine, or both, administered intramuscularly in cats. Am J Vet Res 2007;68:699703.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Skarda RT, Muir WW III. Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular effects and rectal pain threshold after controlled rectal distention in mares. Am J Vet Res 2003;64:137144.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Muir WW, Robertson JT. Visceral analgesia: effects of xylazine, butorphanol, meperidine, and pentazocine in horses. Am J Vet Res 1985;46:20812084.

    • Search Google Scholar
    • Export Citation
  • 39.

    Brunson DB, Majors LJ. Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse, using dental dolorimetry. Am J Vet Res 1987;48:10871091.

    • Search Google Scholar
    • Export Citation
  • 40.

    Doherty TJ, Geiser DR, Rohrbach BW. Effect of acepromazine and butorphanol on halothane minimum alveolar concentration in ponies. Equine Vet J 1997;29:374376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 1994;107:271293.

  • 42.

    Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 2001;93:714.

Contributor Notes

Dr. Elfenbein's present address is Large Animal Teaching Hospital, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Supported by a grant from the State of Florida Pari-Mutuel Wagering Trust.

Presented in part at the World Congress of Veterinary Anesthesia, Santos, Brazil, September 2006, and at the American College of Veterinary Internal Medicine Forum, Seattle, June 2007.

The authors thank Hilken Kuck for technical assistance and Dr. Joe Hauptman for assistance with the statistical analysis.

Address correspondence to Dr. Sanchez.