Pharmacokinetics of the opioid antagonist N-methylnaltrexone and evaluation of its effects on gastrointestinal tract function in horses treated or not treated with morphine

Pedro Boscan Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Linda M. Van Hoogmoed Comparative Gastroenterology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616.
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Bruno H. Pypendop Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Thomas B. Farver Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Jack R. Snyder Comparative Gastroenterology Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616.
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Abstract

Objective—To determine the pharmacokinetics and effects of the morphine antagonist N-methylnaltrexone (MNTX) on gastrointestinal tract function in horses when administered alone and in combination with morphine.

Animals—5 healthy adult horses.

Procedures—Horses were treated with MNTX (1 mg/kg, IV), and serial blood samples were collected for determination of drug pharmacokinetics. For evaluation of effects on the gastrointestinal tract when administered alone, MNTX was administered at a dosage of 0.75 mg/kg, IV, twice daily for 4 days. For evaluation of effects when administered concurrently with morphine, MNTX (0.75 mg/kg, IV, q 12 hours) and morphine (0.5 mg/kg, IV, q 12 hours) were administered for 6 days. Gastrointestinal variables evaluated were defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, and borborygmus scores.

Results—The time-concentration data for MNTX disposition best fit a 2-compartment model with a steady-state volume of distribution of 244.6 ± 21.8 mL/kg, t1/2 of 47.04 ± 11.65 minutes, and clearance of 11.43 ± 1.06 mL/min/kg. Adverse effects were not observed at doses ≤ 1 mg/kg. Administration of MNTX increased daily fecal weight. When administered concurrently with morphine, MNTX partially prevented the effects of morphine on the gastrointestinal tract by increasing defecation frequency, fecal weight, fecal moisture content, and borborygmus score, and by preventing increases in intestinal transit time.

Conclusions and Clinical Relevance—Because MNTX does not cross the blood-brain barrier, administration of the drug should not alter the analgesic effects of opioids and may attenuate the adverse gastrointestinal effects associated with use of opioids in horses.

Abstract

Objective—To determine the pharmacokinetics and effects of the morphine antagonist N-methylnaltrexone (MNTX) on gastrointestinal tract function in horses when administered alone and in combination with morphine.

Animals—5 healthy adult horses.

Procedures—Horses were treated with MNTX (1 mg/kg, IV), and serial blood samples were collected for determination of drug pharmacokinetics. For evaluation of effects on the gastrointestinal tract when administered alone, MNTX was administered at a dosage of 0.75 mg/kg, IV, twice daily for 4 days. For evaluation of effects when administered concurrently with morphine, MNTX (0.75 mg/kg, IV, q 12 hours) and morphine (0.5 mg/kg, IV, q 12 hours) were administered for 6 days. Gastrointestinal variables evaluated were defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, and borborygmus scores.

Results—The time-concentration data for MNTX disposition best fit a 2-compartment model with a steady-state volume of distribution of 244.6 ± 21.8 mL/kg, t1/2 of 47.04 ± 11.65 minutes, and clearance of 11.43 ± 1.06 mL/min/kg. Adverse effects were not observed at doses ≤ 1 mg/kg. Administration of MNTX increased daily fecal weight. When administered concurrently with morphine, MNTX partially prevented the effects of morphine on the gastrointestinal tract by increasing defecation frequency, fecal weight, fecal moisture content, and borborygmus score, and by preventing increases in intestinal transit time.

Conclusions and Clinical Relevance—Because MNTX does not cross the blood-brain barrier, administration of the drug should not alter the analgesic effects of opioids and may attenuate the adverse gastrointestinal effects associated with use of opioids in horses.

The effects of opioid drugs on the gastrointestinal tract are mediated indirectly through the CNS and directly via local actions in the intestinal tract itself.1,2 In humans, administration of opioids, especially morphine, induces potent analgesia as well as debilitating constipation.3 Results of the companion study4 indicate that parenteral administration of morphine to healthy horses for 6 days increased intestinal transit time, delayed gastic emptying, and decreased fecal moisture content, compared with untreated controls. Those effects could predispose horses treated with opioid drugs to developing intestinal ileus, a complication that has been reported.5

Use of peripherally acting opioid antagonists in humans circumvents the gastrointestinal tract dysfunction associated with opioid administration.6–9 In clinical and experimental trials, administration of peripherally acting opioid antagonists, which do not cross the blood-brain barrier and therefore do not interfere with the centrally mediated analgesic effects, substantially improved gastrointestinal tract function.10–13

Methylnaltrexone is a quaternary derivative of the pure opioid antagonist naltrexone.8 Methylation of the amine group yields a charged substance with greater polarity and less lipid solubility and prevents the drug from crossing the blood-brain barrier.8,13,14 The clinical result is that the drug does not reverse the analgesic effects of morphine in the CNS but effectively antagonizes the effects of morphine at the level of the intestinal tract. In a double-blinded controlled study9 in humans, MNTX rapidly reversed opioid-induced constipation while sparing analgesia, with no observed adverse effects.

Methylnaltrexone directly stimulates isolated smooth-muscle strips from equine jejunum and colon15; the drug's dual actions of inhibiting intestinal dysfunction secondary to morphine administration while also directly stimulating intestinal contraction make MNTX potentially useful clinically. The objective of this study was to determine the pharmacokinetic profile of MNTX and evaluate the drug's efficacy at preventing morphine-induced intestinal dysfunction.

Materials and Methods

Five healthy geldings (2 Thoroughbreds, 2 Quarter Horses, and 1 Irish Sport Horse) with a mean age of 9 ± 4 years were used in a crossover study so that horses served as their own controls. In the companion study4, the effects of high-dose morphine administered for 6 days on intestinal tract function were evaluated. In the present study, MNTX pharmacokinetics and efficacy in preventing the effects of morphine on the intestine were evaluated. Horses were acclimatized to the environment by being stabled in stalls with rubber flooring 48 hours before the study began. Water was available ad libitum, and horses were fed alfalfa and grass hay twice a day. The study was approved by the University of California-Davis Institutional Animal Care and Use Committee.

MNTX test—The first trial was conducted to determine whether any adverse effects were associated with MNTX administration. Two horses received a dose of 0.5 mg/kg, IV, on the first day; 1 mg/kg on the second day; and 10 mg/kg on the third day. This protocol was used so that adverse effects associated with any single injection could be detected. Venous blood samples were obtained 1, 5, 10, 30, 60, 90, 120, 240, 300, and 360 minutes after injections to establish the preliminary pharmacokinetic profile of the drug for the 0.5 and 1 mg/kg doses. After a 2-week washout period, all 5 horses received MNTX (1 mg/kg, IV) for the pharmacokinetic study.

Pharmacokinetic study—A dose of 1 mg/kg was selected for the pharmacokinetic study because none of the horses had an adverse reaction to that dose and because the dose is in the range of doses used in humans. The MNTX dose was administered IV as a bolus into a jugular vein, and blood samples (5 mL) were collected 1, 2, 3, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 50, 60, 90, 120, 150, 180, 210, and 240 minutes after administration in all 5 horses. Blood samples were transferred to empty sterile tubes and centrifuged for 10 minutes, after which serum was extracted and stored at −20°C until analysis.

Concentrations of MNTX in the sera were determined by use of liquid chromatography–mass spectrometrya (LC-MS) after a solid-phase extraction clean-up procedure. Calibrators were prepared by adding appropriate volumes of the working standard solutions to drug-free control serum. The range of concentrations used for serum calibrators was 0.01 to 14.0 μg/mL for MNTX. The analytic reference standard of MNTXa was diluted to standard concentrations with methanol.

Serum samples (500 μL aliquots) were diluted with 2 mL of 0.3M ammonium formate buffer (pH, 7.0) and internal standard solution (benzyldimethylphenylammonium; concentration, 500 ng/mL). Solid-phase extraction was performed after centrifugation (14,000 rpm). Columns were conditioned sequentially with 2 mL of methanol and 3 mL of a 0.1M ammonium formate buffer solution (pH, 7.0). Serum samples were loaded onto the column at a flow rate of 1 to 2 mL/min with low-pressure nitrogen gas. Columns were rinsed with 3 mL of water and 3 mL of methanol. Each column cartridge was dried with nitrogen gas (at a pressure of 20 psi for 5 minutes. To collect the MNTX from the samples, 1.7 mL of a 99:1 (vol:vol) methanol:formic acid solution was applied to the column and the fraction collected. The eluent was dried in a nitrogen evaporator at 50 ± 5°C.

For quantitative measurements, highperformance liquid chromatographya and a quadrupole ion-trap mass spectrometer with electrospray interfaceb were used. The chromatography system included a C18, 10-cm × 2.1-mm, 3-μm column and a linear gradient of acetonitrile in water with 0.2% formic acid at a flow rate of 0.4 mL/min. The acetonitrile concentration was held at 3% for 0.2 minutes, increased from 3% to 32% over 4.0 minutes, increased from 32% to 75% over 3.0 minutes, and increased from 75% to 90% over 1.5 minutes. Prior to analysis, extracts of all samples, controls, and calibrators were redissolved in 200 μL of the initial mobile phase. Injection volumes were 5.0 μL.

Detection and quantification involved use of full-scan LC-MS-MS-MS transitions of initial product ions for MNTX (mass-to-charge ratio, 356.2). Total response for the major product ions of MNTX (mass-to-change ratio, 338.2 and 284.2) was plotted and peaks at the proper retention time were integrated by use of statistical software.c Software programs were used to generate calibration curves and quantitate analytes in all samples.

Serum MNTX concentrations were analyzed via nonlinear least-squares regression by use of a computer program.c Data were weighted by the reciprocal of the serum MNTX concentration squared. Data from each horse were fitted to 1-, 2-, and 3-compartment models. The appropriate model was selected according to the Akaike information criterion.16,17 Standard compartmental equations were used to estimate pharmacokinetic variables for each horse. Values from 4 of the 5 horses were averaged, and results were reported as mean ± SD; data from the fifth horse were excluded because of erroneous sampling.

Effects of MNTX on gastrointestinal tract function—After at least 2 weeks had elapsed from administration of MNTX for the pharmacokinetic portion of the study, horses received MNTX at a dosage of 0.75 mg/kg, IV, every 12 hours for 4 consecutive days to assess gastrointestinal effects of the drug. Morning injections were administered at 8:00 AM and evening injections at 8:00 PM. Prior to administration of the first injection, 200 BISsd (sphere diameter, 3.2 mm; weight, 20 mg) were deposited in the stomach of each horse via nasogastric intubation. Feces were collected every 2 hours for the next 4 days.

Variables recorded to detect effects of MNTX on intestinal function were defecation frequency, weight of feces produced, and intestinal transit time. Those variables were recorded every 2 hours for the next 3 days (4 days for calculation of intestinal transit time). For determination of fecal weight, manure was weighed on a calibrated scale shortly after retrieval, so that measurements pertained to the wet weight of feces produced during the 3 days. Intestinal transit time was assessed by measuring the time required for passage of BISs in feces18 collected for 4 days after administration. All feces collected during those 4 days was imaged radiographically, and the number of BISs detected was recorded. Times for the first appearance of BISs in feces (T1) and for 10%, 25%, 50%, 75%, and 90% of BISs to appear in feces were reported (T10, T25, T50, T75, and T90, respectively). Heart rate, respiratory rate, behavior in the stall, and signs of abdominal discomfort (colic) were assessed 2 and 8 hours after the 8:00 AM drug administration on each day by use of the same protocols described.4

Effects of MNTX administered concurrently with morphine sulfate—For this portion of the study, MNTX (0.75 mg/kg, IV) was administered first and morphine sulfate (0.5 mg/kg, IV) was administered 1 to 2 minutes later, every 12 hours for 6 consecutive days. The dose of morphine was the same as that used in part I of the study, in which the gastrointestinal effects of morphine administered alone were assessed. Because the same group of horses was used, the effects in control horses and in horses treated with morphine alone, MNTX alone, and MNTX and morphine concurrently could be evaluated. The injection protocol was the same as that used in the first part of the study. Horses were randomly allocated to treatment groups to prevent confounding of results by time.

On the morning of the third day of treatment, 200 BISs were administered via nasogastric tube to each horse. Feces were collected every 2 hours for the remaining 3 days of the study. Defecation frequency, wet weight of feces produced, and fecal moisture content were determined from feces collected on those 3 days, whereas intestinal transit time was calculated by determining the time required for passage of the BISs in feces collected and radiographed every 2 hours for the ensuing 4 days. Values for T1,T10, T25, T50, T75, and T90 were reported and compared. Also recorded was a borborygmus score; 2 and 8 hours after the morning injections, intestinal sounds were assessed by auscultation of 4 abdominal quadrants over a 1-minute period for each quadrant during the 3 days after initiation of the treatments (quadrants were designated as the dorsal and ventral regions of the portion of the abdomen caudal to the ribs, on each side). Borborygmi were scored by use of a scheme used previously in horses19–21 and modified for use in the present study as described in part I. In addition to borborygmus, the heart rate, respiratory rate, behavior in the stall, and signs of abdominal discomfort were also recorded.

Statistical analysis—Statistical analysis was performed by means of a Student t test or repeated-measures ANOVA with a post-hoc Bonferroni test for comparison of data between groups. Unless indicated, the test applied was a repeated-measures ANOVA with a post-hoc Bonferroni test. Values of P < 0.05 were considered significant, and results were reported as mean ± SD.

Results

MNTX test—Administration of single doses of MNTX, administered IV at 0.5 and 0.75 mg/kg to 2 horses, did not result in differences in heart rate, respiratory rate, or behavior and borborygmus scores when compared with baseline values observed in the horses before treatment. In the 5 horses that received a dose of 1 mg/kg, no changes in heart rate, respiratory rate, or behavior score were observed. However, in those horses, mean borborygmus scores decreased from 11.3 ± 3.6 to 5.5 ± 2.5 for the first 30 minutes after treatment and then returned to approximate (9.8 ± 4.8) baseline values 40 minutes after drug injection. In the 2 horses that received a dose of 10 mg/kg, heart rate increased from 32 and 45 beats/min to 55 and 60 beats/min, and respiratory rate increased from 25 and 18 breaths/min to 30 and 32 breaths/min. The behavior score in both horses was 4, with pacing in the stall and hyperresponsiveness to external stimuli observed. One horse had a colic score of 1, and the other had a score of 2. Both horses paced and repeatedly lifted the tail as if preparing to defecate. The horse with the higher colic score repeatedly assumed the urination posture and sweated for at least 90 minutes. The borborygmus score changed from 9 and 15 to 0 in those 2 horses, and no gastrointestinal sounds were detected in any abdominal quadrant for ≥ 90 minutes. Two hours after MNTX administration, borborygmus scores had increased to 5 in both horses but remained below baseline for 3 hours after treatment.

MNTX pharmacokinetics—A 2-compartment model best fit the time-concentration data in all 4 horses. No differences were found among horses in any pharmacokinetic variable (Figure 1). The volume of distribution was 106.6 ± 14.6 mL/kg, and distribution and elimination half-lives were Tα = 5.09 ± 0.94 minutes and Tβ = 47.04 ± 11.65 minutes, respectively, whereas the value for clearance was 11.43 ± 1.06 mL/min/kg (Table 1).

Table 1—

Pharmacokinetic variables for disposition of MNTX after IV administration of a 1 mg/kg dose in 4 healthy horses. Values best fit a 2-compartment model in which plasma concentration (C) at time (t) was described by the following equation: Ct = Aeαt+ Beβt.

VariableValue
A (μg/mL)9.16 ± 1.15
B (μg/mL)0.34 ± 0.13
α(1/min)0.139 ± 0.02
β (1/min)0.015 ± 0.003
V1 (mL/kg)106.6 ± 14.6
Vss (mL/kg)244.6 ± 21.8
AUC (min•μg/mL)88.03 ± 8.8
Tα(min)5.09 ± 0.94
Tβ(min)47.04 ± 11.65
Cmax (μg/mL)9.51 ± 1.25
CL (mL/min/kg)11.43 ± 1.06

V1 = Volume of distribution of the central compartment. VSS = Volume of distribution at steady state. AUC = Area under the time-concentration curve. Tα = Distribution half-life. Tβ= Elimination half-life. Cmax = Maximum plasma concentration. CL = Clearance. A, B = Coefficients for plasma concentration. α, β = Exponents.

Figure 1—
Figure 1—

Serum concentrations of MNTX over time in 4 healthy horses treated with a 1 mg/kg dose administered IV. Data for each horse are represented by a different symbol.

Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.998

MNTX administered alone

Frequency of defecation and wet fecal weights—During the period of MNTX administration, all horses defecated throughout the day with no observed temporal association between defecation and time of injection. Mean number of defecations was 11.1 ± 2.8 (range, 8 to 18) bowel movements/24-hour period. Mean wet weight of feces produced per bowel movement was 1.3 ± 0.1 kg, with total fecal production of 16.2 ± 0.4 kg in a 24-hour period (Figure 2). Mean cumulative fecal production over the 3day data collection period increased linearly (r = 0.99) to a total of 48.5 ± 1.4 kg of feces produced by the end of the study. Compared with the control group4, there was no significant (P = 0.27) difference in the number of defecations per day in treated horses (11.1 ± 2.8 defecations/d in the MNTX group vs 13.1 ± 0.2 defecations/d in the control group). However, treated horses produced a greater quantity of feces, compared with controls (16.2 ± 0.4 kg in treated horses vs 12.4 ± 0.3 kg in controls; P = 0.01).

Figure 2—
Figure 2—

Data regarding fecal output from 5 horses during a 3 day period of MNTX administration (0.75 mg/kg, IV, q 12 h).A—Daily weights of feces as determined by weighing all feces collected during a period of 3 days. Horizontal bars indicate mean weights/24h; values for each group were significantly (P = 0.01) different. B—Mean ± SD cumulative weight of feces collected during the 3 days.

Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.998

Transit time—Intestinal transit time was determined by counting the number of BISs appearing in feces collected from stalls every 2 hours. The value for T1 was 12 hours after MNTX administration, and the number of spheres recovered increased in a sigmoid pattern, reaching a plateau at 55 to 65 hours. Values for T10, T25, T50, T75, and T90 were 16, 22, 32, 46, and 68 hours, respectively. None of the transit times recorded were significantly (P > 0.05) different from those in controls (Figure 3). At the end of the study (ie, at 4 days after administration), 188.2 ± 2.2 BISs had been passed in feces.

Figure 3—
Figure 3—

A—Mean ± SD intestinal transit times as calculated by radiographic detection of BISs in feces during 4 days of administration of saline (0.9% NaCl) solution (10 mL IV, q 12 h; control treatment) or MNTX (0.75 mg/kg, IV, q 12 h; A) and during treatment with morphine (0.5 mg/kg, IV, q 12 h) alone4 or with MNTX and morphine administered concurrently (same doses; B) in the same horses as in Figure 2. T1, T10, T25, T50, T75, and T90 = First time of appearance of BISs and subsequent passage of 10%, 25%, 50%, 75%, and 90% of administered BISs, respectively.

Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.998

Heart rate, respiratory rate, and scores for behavior and colic—Administration of MNTX at 0.75 mg/kg every 12 hours for 4 consecutive days caused no significant (P > 0.1) change in heart rate or respiratory rates, or in behavior or colic scores, compared with baseline values. Mean ± SD heart rate after MNTX administration was 40.2 ± 12 beats/min, mean respiratory rate was 19.3 ± 7.1 breaths/min, mean behavior score was 3 ± 0, and mean colic score was 0.

MNTX administered concurrently with morphine sulfate

Frequency of defecation and wet fecal weights—The decrease in weight of feces produced in association with morphine administration was evident only during the first 6 hours after administration.4 For that reason, we only evaluated the effects of treatment with the combination of MNTX and morphine on output during the first 6 hours after treatment. The mean number of defecations during the 6-hour period after administration of the combination of drugs was 1.6 ± 1, compared with 3.1 ± 0.9 (P < 0.01) defecations in the control group and 0.9 ± 0.5 (P < 0.01) defecations in the morphine group. Mean wet weight of feces produced during the 6 hours after treatment with the combination (2.6 ± 1.1 kg) was significantly (P = 0.02) greater than that produced after morphine alone (1.1 ± 0.7 kg; Figure 4).

Figure 4—
Figure 4—

Mean ± SD weight (A) and percentage of moisture content (B) of feces collected from the same horses as in the preceding Figures during the 6 hours after administration of morphine (0.5 mg/kg, IV, q 12 h) and MNTX (0.75 mg/kg, IV, q 12 h). Value significantly (P = 0.02 for fecal weight; P = 0.01 for fecal moisture content) different from that in horses treated with both drugs.

Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.998

Fecal moisture content—During the 6 hours after morphine administration, mean fecal moisture content decreased from 76.1 ± 2.9% (in control horses) to 73.5 ± 2.9% after treatment.4 Fecal moisture content in horses treated with morphine and MNTX was 75.9 ± 2.5% (P = 0.01; Figure 4), indicating that MNTX had an antagonizing effect on the reduction in fecal moisture content induced by morphine. The difference of 2.4% in water moisture content between the 2 groups represents a net retention of 0.5 to 1 L of water/d from gastrointestinal tract contents.

Transit time—Administration of the morphine-MNTX combination appeared to antagonize the delay in transit time observed after administration of morphine alone. Morphine administration was associated with displacement of the intestinal transittime curve to the right. When MNTX and morphine were administered, transit time was significantly (P < 0.05) decreased, resulting in movement of the first half of the curve back to the left (Figure 3). When MNTX and morphine were administered, values for T1, T10, T25, T50, T75, and T90 were 12, 24, 42, 52, 72, and 94 hours, respectively (compared with values of 32, 44, 48, 58, 68, and > 96 hours for T1, T10, T25, T50, T75, and T90, respectively, after morphine administration). Values for T1, T10, and T25 were significantly (P < 0.05) lower during the period of MNTX administration than values associated with administration of morphine alone. Feces from horses treated with MNTX and morphine were not covered with mucus, as was observed in horses receiving morphine alone.

Borborygmus score—Mean borborygmus score was greater (ie, more intestinal activity) after administration of MNTX and morphine than were scores derived after treatment with morphine alone (12.4 ± 3.2 and 6.3 ± 3.9, respectively).

Heart rate, respiratory rate, and scores for behavior and colic—When MNTX was administered concurrently with morphine, mean respiratory rate was not different from rates in control horses or from treatment of horses with MNTX alone or morphine alone (P > 0.05). Mean heart rate increased (P < 0.01), compared with that in control horses, but not compared with treatment with MNTX or morphine alone (P > 0.05). Mean respiratory and heart rates during treatment with MNTX and morphine together were 21.3 ± 7.8 breaths/min and 38.6 ± 6.4 beats/min, respectively.

Two horses paced in the stall and pawed during the first 3 days of treatment with the combination; effects lasted from 2 to 4 hours after drug administration. No abnormal behavior was observed in the remaining 3 horses. Mean behavior score during the first 6 hours after drug administration was 3.2 ± 0.4. None of the horses treated with the combination of MNTX and morphine had clinical signs of colic, resulting in a colic score of 0.

Discussion

In the present study, administration of MNTX prevented the gastrointestinal tract stasis and reduction in fecal moisture content observed after administration of high doses of morphine in the same horses. Those results were in accordance with findings from studies8,9,22,23 involving other species. In the present study, administration of MNTX alone did not elicit a prokinetic effect on the gastrointestinal tract, as intestinal transit time was not significantly decreased and the number or frequency of defecations was not significantly increased, compared with the control group. Horses treated with MNTX appeared to produce more feces during the day, and more spheres were passed during the first 70 hours than in the control group, although the differences were not significant. This finding could represent a potential advantage for the clinical use of this drug. Administration of MNTX may have dual effects in the gastrointestinal tract: mild, direct stimulation of intestinal smooth muscle and concurrent prevention of opioid-induced stasis. Additional investigations are necessary before the effects of MNTX on horses with clinical conditions that affect gastrointestinal function can be determined.

Although only 5 horses were evaluated, administration of MNTX at a dose of 0.75 mg/kg appeared to be safe because adverse effects were not observed. Furthermore, no severe adverse effects were associated with a dose (10 mg/kg) 12 times as high as than the dose studied. Nevertheless, additional studies in which more horses and additional drug doses are evaluated are necessary for complete assessment of adverse effects and establishment of safety guidelines.

We chose the dose of 0.75 mg/kg of MNTX for assessment of whether the drug would antagonize the effects of morphine because doses of 1 mg/kg decreased borborygmus in all horses for 30 minutes, and in the pilot study, 0.75 mg/kg was the highest dose evaluated that did not induce any undesirable effects. Use of the highest appropriate dose possible was deemed important so that the high doses of morphine used could successfully be antagonized and to increase the likelihood that adverse drug effects, if any developed, would be detected. Nevertheless, generation of a dose-response curve would be the ideal method for identifying the optimal dose of MNTX to use in horses.

A literature search yielded 1 study24 in which the use of naltrexone (the parent compound of MNTX) in horses was evaluated. Naltrexone doses of 0.04 to 0.4 mg/kg were administered IV to reduce cribbing behavior for as long as 7 hours. No important adverse effects were reported, although semifluid feces were often observed. Adverse effects observed in humans that received doses of MNTX between 0.45 and 1.25 mg/kg, or in whom plasma concentrations > 1.4 μg/mL were reached, included transient orthostatic hypotension and abdominal cramping.23,25

The dose of morphine used in this study (0.5 mg/kg) was higher than doses commonly used in clinical practice. We selected this dose so that detectable alterations in gastrointestinal tract function could be observed, as was described.4 This was important for evaluation of the efficacy of MNTX administration in antagonizing the opioid influence on the intestinal tract.

Addition of an opioid antagonist to an analgesic treatment plan that includes morphine is not a new strategy. In humans with cancer, constipation is a severe and debilitating consequence of opioid administration for pain relief and, in some instances, necessitates reduction of the doses of analgesics used. Use of MNTX at low doses has resulted in relief from constipation and stimulation of laxation without withdrawl symptoms.23,26 The use of peripherally acting opioid antagonists has been associated with a reduction in time to first flatus; first bowel movement; and discharge after major abdominal surgery, including intestinal resection, in humans.27–29

Plasma concentrations of neither morphine nor MNTX were correlated with drug activity in the intestinal tract. The half-life of morphine in horses after IV administration of 1 or 2 mg/kg is approximately 60 minutes.30,31 However, in the present study, signs of gastrointestinal tract dysfunction were observed with a lower morphine dose (0.5 mg/kg) and lasted for approximately 6 hours. Similarly, the pharmacokinetic profile of MNTX revealed a terminal half-life of 47 minutes after IV administration, yet the anti-opioid effects on the intestinal tract were apparent for much longer. In humans, the effect of MNTX on the gastrointestinal tract is not correlated with plasma concentrations, but is correlated with drug concentrations in the intestinal lumen.13 Morphine can be detected in the intestinal lumen of rats 10 to 20 minutes after IV administration and may persist for a prolonged time.32 Similar mechanisms may exist for MNTX.

One possible reason for the failure of MNTX to fully antagonize the effects of morphine is that the MNTX dose used and subsequent plasma concentrations attained were insufficient to completely reverse the occupation of intestinal opioid receptors by morphine. Because MNTX is a competitive opioid antagonist, high concentrations of morphine compete with MNTX at receptor binding sites. A second possibility is that the effects of MNTX on the intestine are more transient than the effects of morphine. To our knowledge, morphine and MNTX gastrointestinal receptor kinetics have not been described in horses. A third possible explanation is that the effects of morphine on the gastrointestinal tract may be partially mediated at the level of the CNS. In the present study, the excitatory pacing behavior induced by morphine was not inhibited by MNTX, a finding consistent with the supposition that MNTX does not cross the bloodbrain barrier. It is also possible that unlike in humans, MNTX is a poor opioid antagonist in the equine gastrointestinal tract. Further studies are necessary to delineate more precisely the mechanism for effects observed in this investigation.

ABBREVIATIONS

MNTX

N-methylnaltrexone

BIS

Barium-impregnated spheres

a.

Jones Chromatography Inc, Bellefonte, Pa.

b.

Thermo Electron Corp, San Jose, Calif.

c.

WinNolin Pro, version 4.1, Pharsight, Cary, NC.

d.

Barium impregnated spheres, Precision Plastic Balls Co, Franklin Park, Ill.

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